Fetal and Perinatal Skeletal Dysplasias: An Atlas of Multimodality Imaging [2 ed.] 0367764431, 9780367764432

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Fetal and Perinatal Skeletal Dysplasias This atlas is intended to give obstetricians, paediatricians, neonatologists, radiologists, molecular and clinical geneticists and anatomo-pathologists a thorough insight into the conditions (and variants) of skeletal dysplasias. Clinical and imaging findings are properly illustrated, enriched by updated genetic information. This acclaimed text returns in a revised form, with updated material, particularly on the new knowledge surrounding the genetic basis and mechanism of the various skeletal dysplasias. No clinician dealing with fetal or neonatal skeletal diagnosis or treatment will want to be without access to the wealth of illustrations and detail condensed here. • Presents a clear and consistent rubric for approaching approximately 150 types of skeletal dysplasias • Meets the needs of clinical gynaecologists, obstetricians, paediatricians, radiologists and geneticists • Offers an essential, concise resource for the diagnosis of skeletal dysplasias which present prenatally and perinatally

Fetal and Perinatal Skeletal Dysplasias An Atlas of Multimodality Imaging Second Edition

Edited by

Christine M Hall, MBBS, DMRD, FRCR, MD Consultant Paediatric Radiologist (Retired) Emeritus Professor of Paediatric Radiology London, UK

Amaka C Offiah, BSc, MBBS, MRCP, FRCR, PhD, FRCPCH HEFCE Clinical Senior Lecturer Honorary Consultant Radiologist Chair in Paediatric Musculoskeletal Imaging University of Sheffield, UK

Francesca Forzano, MD, FRCP Consultant and Clinical Geneticist King’s College London, UK

Mario Lituania, MD Director, Fetal and Perinatal Medicine Unit Genova, Italy

Gen Nishimura, MD Visiting Professor, Center for Intractable Diseases Saitama Medical University Hospital Japan

Valérie Cormier-Daire, MD, PhD Professor, Genetics Université Paris Centre France

Cover Image: Christine M Hall Second edition published 2024 by CRC Press 2385 NW Executive Center Drive, Suite 320, Boca Raton, FL 33431 and by CRC Press 4 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN CRC Press is an imprint of Taylor & Francis Group, LLC © 2024 Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Gen Nishimura and Valerie Cormier-Daire First edition published by CRC Press 2012 This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have been made to publish reliable data and information, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. The publishers wish to make clear that any views or opinions expressed in this book by individual editors, authors or contributors are personal to them and do not necessarily reflect the views/opinions of the publishers. The information or guidance contained in this book is intended for use by medical, scientific or health-care professionals and is provided strictly as a supplement to the medical or other professional’s own judgement, their knowledge of the patient’s medical history, relevant manufacturer’s instructions and the appropriate best practice guidelines. Because of the rapid advances in medical science, any information or advice on dosages, procedures or diagnoses should be independently verified. The reader is strongly urged to consult the relevant national drug formulary and the drug companies’ and device or material manufacturers’ printed instructions, and their websites, before administering or utilizing any of the drugs, devices or materials mentioned in this book. This book does not indicate whether a particular treatment is appropriate or suitable for a particular individual. Ultimately it is the sole responsibility of the medical professional to make his or her own professional judgements, so as to advise and treat patients appropriately. The authors and publishers have also attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged, please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, access www.copyright.com or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. For works that are not available on CCC please contact mpkbookspermissions@ tandf.co.uk Trademark Notice: Product or corporate names may be trademarks or registered trademarks and are used only for identification and explanation without intent to infringe. ISBN: 9780367764432 (hbk) ISBN: 9780367764470 (pbk) ISBN: 9781003166948 (ebk) DOI: 10.1201/9781003166948 Typeset in Times by KnowledgeWorks Global Ltd.

Contents Preface & Acknowledgements���������������������������������������������������������������������������������������������������������������������������������������������������������������������������� x Contributors�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������� xi Authors������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������� xiii PART 1.  Normal Fetal Skeletal Growth and Development����������������������������������������������������������������������������������������������������������������������� 1 PART 2.  Diagnosis of Fetal Skeletal Dysplasias�����������������������������������������������������������������������������������������������������������������������������������������13 PART 3.  Individual Conditions Grouped According to the International Nosology and Classification of Genetic Skeletal Disorders�������������������������������������������������������������������������������������������������������������������������������35

FGFR3 Chondrodysplasias 1. Thanatophoric Dysplasia, Types 1 and 2, FGFR3-Related������������������������������������������������������������������������������������������������������������� 36 2. Achondroplasia, FGFR3-Related������������������������������������������������������������������������������������������������������������������������������������������������������� 46 3. Hypochondroplasia, FGFR3-Related������������������������������������������������������������������������������������������������������������������������������������������������ 54

Type 2 Collagen Disorders 4. Achondrogenesis Type 2/Hypochondrogenesis, COL2A1-Related��������������������������������������������������������������������������������������������������58 5. Platyspondylic Dysplasia, Torrance Type, COL2A1-Related�����������������������������������������������������������������������������������������������������������67 6. Spondyloepiphyseal Dysplasia Congenita and Spondyloepimetaphyseal Dysplasia (SEMD) Strudwick Type, COL2A1-Related������������������������������������������������������������������������������������������������������������������������������������������������������73 7. Kniest Dysplasia, COL2A1-Related��������������������������������������������������������������������������������������������������������������������������������������������������� 82 8. Stickler Syndrome, COL2A1-Related������������������������������������������������������������������������������������������������������������������������������������������������ 89

Type 11 Collagen Disorders 9. Fibrochondrogenesis, COL11A1- and COL11A2-Related���������������������������������������������������������������������������������������������������������������� 95 10. Otospondylomegaepiphyseal Dysplasia, Recessive and Dominant Types, COL11A2-Related���������������������������������������������������� 98

Sulphation Disorders 11. Achondrogenesis (Type 1B), SLC26A2-Related�������������������������������������������������������������������������������������������������������������������������������105 12. Atelosteogenesis (Type 2), SLC26A2-Related����������������������������������������������������������������������������������������������������������������������������������108 13. Diastrophic Dysplasia, SLC26A2-Related����������������������������������������������������������������������������������������������������������������������������������������111 14. Chondrodysplasia with Congenital Joint Dislocations (Recessive Larsen Syndrome), CHST3-Related����������������������������������117

Dysplasias with Multiple Joint Dislocations 15. Desbuquois Dysplasia, CANT1-Related��������������������������������������������������������������������������������������������������������������������������������������������121 16. SEMD with Joint Laxity (SEMD-JL, Hall Type), KIF22-Related������������������������������������������������������������������������������������������������127 17. SEMD with Joint Laxity (SEMD-JL, Beighton Type), B3GALT6-Related����������������������������������������������������������������������������������129 18. Multiple Joint Dislocations, Short Stature, Craniofacial Dysmorphisms and Skeletal Dysplasia, with or without Heart Defects (Pseudodiastrophic Dysplasia), B3GAT3-Related����������������������������������������������������������������������133

Filamins and Related Disorders 19. Frontometaphyseal Dysplasia, FLNA-, MAP3K7- and TAB2-Related������������������������������������������������������������������������������������������137 20. Melnick-Needles Syndrome (Osteodysplasty), FLNA-Related������������������������������������������������������������������������������������������������������141 21. Otopalatodigital Syndrome Type 1, FLNA-Related������������������������������������������������������������������������������������������������������������������������145 22. Otopalatodigital Syndrome Type 2, FLNA-Related������������������������������������������������������������������������������������������������������������������������148

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Contents 23. Larsen Syndrome, FLNB-Related����������������������������������������������������������������������������������������������������������������������������������������������������151 24. Atelosteogenesis Type 1 (Includes Boomerang Dysplasia), FLNB-Related����������������������������������������������������������������������������������156 25. Atelosteogenesis Type 3, FLNB-Related�������������������������������������������������������������������������������������������������������������������������������������������162

Proteoglycan Core Protein Disorders 26. Dyssegmental Dysplasia, HSPG2-Related���������������������������������������������������������������������������������������������������������������������������������������166 27. Myotonic Chondrodystrophy (Schwartz-Jampel Syndrome), HSPG2-Related���������������������������������������������������������������������������172

TRPV4 Disorders 28. Metatropic Dysplasia, TRVP4-Related (Various Forms)����������������������������������������������������������������������������������������������������������������176

Skeletal Disorders Caused by Abnormalities of Cilia or Ciliary Signalling 29. Short Rib-Polydactyly Syndrome Type 1 and 3, IFT80-, DYNC2H1-, WDR34-, WDR60- and DYNC2L11-Related���������������182 30. Short Rib-Polydactyly Syndrome Type 2 (Majewski), NEK1-, DYNC2H1-, IFT81- and IFT154-Related��������������������������������186 31. Short Rib-Polydactyly Syndrome Type 4 (Beemer), IFT80-Related���������������������������������������������������������������������������������������������191 32. Short Rib-Thoracic Dysplasia (Jeune)����������������������������������������������������������������������������������������������������������������������������������������������196 33. Chondroectodermal Dysplasia (Ellis-van Creveld), EVC1-, EVC2-, WDR35-, DYNC2LIL-, GLIL- and SMO-Related������������������������������������������������������������������������������������������������������������������������������������������������������������������� 203 34. Orofaciodigital Syndrome Type 4, TCTN3-Related����������������������������������������������������������������������������������������������������������������������� 209 35. Cranioectodermal Dysplasia (Levin-Sensenbrenner), IFTI22-, WDR35-, WDR19-, IFT40- and IFT43-Related�������������������212 36. Meckel Syndrome, TMRM67-, CEP290-, RPGRIP1L-, CC2D2A MKS1-, TMEM216-, NPHP3-, TCTN2-, B9D1-, B9D2-, TMEM231-, KIF14-, TMEM107- and TXNDC15-Related���������������������������������������������������������������������217 37. Thoracolaryngopelvic Dysplasia (Barnes)�������������������������������������������������������������������������������������������������������������������������������������� 222

Metaphyseal Dysplasias 38. Cartilage-Hair Hypoplasia/Anauxetic Dysplasia Spectrum, RMRP-Related����������������������������������������������������������������������������� 224 39. Metaphyseal Dysplasia with Pancreatic Insufficiency and Cyclical Neutropenia (ShwachmanBodian-Diamond Syndrome, SBDS), SBDS-, EFL1-, DNAJC21- and SRP54-Related�������������������������������������������������������������� 229 40. Metaphyseal Anadysplasia, MMP13- and MMP9-Related�������������������������������������������������������������������������������������������������������������232

Spondylometaphyseal Dysplasias (SMDs) 41. Odontochondrodysplasia, TRIP11-Related��������������������������������������������������������������������������������������������������������������������������������������235

Spondyloepi(Meta)Physeal Dysplasias (SE[M]Ds) 42. SEMD Short Limb-Abnormal Calcification Type, DDR2-Related�����������������������������������������������������������������������������������������������241 43. SEMD with Immune Deficiency and Intellectual Disability, EXTL3-Related���������������������������������������������������������������������������� 246 44. SEMD, NANS-Related����������������������������������������������������������������������������������������������������������������������������������������������������������������������� 249 45. Rhizomelic Spondylo-Metaphyseal Dysplasia with Remission, LBR-Related�����������������������������������������������������������������������������253

Severe Spondylodysplastic Dysplasias 46. Achondrogenesis Type 1A, TRIP11-Related����������������������������������������������������������������������������������������������������������������������������������� 256 47. Schneckenbecken Dysplasia, SLC35D1-Related����������������������������������������������������������������������������������������������������������������������������� 260 48. Spondylometaphyseal Dysplasia, Sedaghatian Type, GPX4-Related������������������������������������������������������������������������������������������� 262 49. Opsismodysplasia, INPPL1-Related������������������������������������������������������������������������������������������������������������������������������������������������ 266

Mesomelic AD Rhizo-Melic Dysplasias 50. Mesomelic Dysplasia, Langer Type (Homozygous Dyschondrosteosis), SHOX-Related������������������������������������������������������������270 51. Omodysplasia, Recessive and Dominant Types, GPC6- and FZD2-Related��������������������������������������������������������������������������������273

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52. Robinow Syndrome, Recessive and Dominant Types, ROR2-, NXN-, WNT5A-, DVL1-, DVL3and FZD2-Related������������������������������������������������������������������������������������������������������������������������������������������������������������������������������276 53. Mesomelic Dysplasia, Kozlowski-Reardon Type�����������������������������������������������������������������������������������������������������������������������������281 54. Grebe Dysplasia, GDF5- and BMPR1B-Related���������������������������������������������������������������������������������������������������������������������������� 283

Brachydactylies (Isolated) 55. Brachydactyly Type B, ROR2- and NOG-Related�������������������������������������������������������������������������������������������������������������������������� 286 56. Brachydactyly Type C, GDF5-Related�������������������������������������������������������������������������������������������������������������������������������������������� 288

Brachydactylies as Part of Syndromes 57. Catel-Manzke Syndrome, TGDS-Related��������������������������������������������������������������������������������������������������������������������������������������� 293 58. Rubinstein-Taybi Syndrome, CREBBP- and EP300-Related������������������������������������������������������������������������������������������������������� 295 59. Brachydactyly Temtamy Type, CHSY1-Related����������������������������������������������������������������������������������������������������������������������������� 298 60. Hyperphalangism, Characteristic Facies, Hallux Valgus and Bronchomalacia (Chitayat Syndrome), ERF-Related��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������� 300

Bent Bones Dysplasia Group 61. Campomelic Dysplasia, SOX9-Related�������������������������������������������������������������������������������������������������������������������������������������������� 302 62. Stüve-Wiedemann Dysplasia, LFR-Related�������������������������������������������������������������������������������������������������������������������������������������311 63. Kyphomelic Dysplasia with Facial Dysmorphism, KIF5B-Related and Other Forms����������������������������������������������������������������313 64. Bent Bone Dysplasia, FGFR2-Related����������������������������������������������������������������������������������������������������������������������������������������������319

Primordial Dwarfism and Slender Bones Group 65. 3M Syndrome, CUL7-, OBSL1- and CCDC9-Related�������������������������������������������������������������������������������������������������������������������� 325 66. Osteocraniostenosis, FM111A-Related�������������������������������������������������������������������������������������������������������������������������������������������� 328 67. Hallermann-Streiff Syndrome, GJA1-Related��������������������������������������������������������������������������������������������������������������������������������333 68. Microcephalic Osteodysplastic Primordial Dwarfism Types 1 and 3, RNU4ATAC-Related������������������������������������������������������338 69. Saul-Wilson Syndrome, COG4-Related������������������������������������������������������������������������������������������������������������������������������������������ 342

Lysosomal Storage Diseases with Skeletal Involvement 70. Mucolipidosis II (I-Cell Disease), GNPTAB-Related��������������������������������������������������������������������������������������������������������������������� 348

Chondrodysplasia Punctata (CDP) Group 71a. Chondrodysplasia Punctata X-Linked Recessive, Brachytelephalangic Type, ARSE-Related�������������������������������������������������352 71b. Chondrodysplasia Punctata X-Linked Dominant Type, Conradi-Hünermann Type, EBP-Related����������������������������������������357 71c. Rhizomelic Type Chondrodysplasia Punctata, PEX7-, DHPAT-, AGP5-, FAR1- and PEX5-Related���������������������������������������362 71d. Chondrodysplasia Punctata Tibia-Metacarpal Type���������������������������������������������������������������������������������������������������������������������367 72. Greenberg Dysplasia, LBR-Related��������������������������������������������������������������������������������������������������������������������������������������������������371 73. Warfarin Embryopathy���������������������������������������������������������������������������������������������������������������������������������������������������������������������375 74. Maternal Systemic Lupus Erythematosus���������������������������������������������������������������������������������������������������������������������������������������378 75. Cerebro-Hepato-Renal (Zellweger) Syndrome������������������������������������������������������������������������������������������������������������������������������� 382 76. Astley-Kendall Dysplasia������������������������������������������������������������������������������������������������������������������������������������������������������������������ 386

Osteopetrosis and Related Osteoclast Disorders 77. Osteopetrosis, Neonatal or Infantile Forms, TCRG1-, CLCN7- and SNX10-Related: Osteopetrosis, Infantile Form with Nervous System Involvement, OSTM1-Related��������������������������������������������������������������������������������������������������������������������� 388 78. Pycnodysostosis, CTSK-Related������������������������������������������������������������������������������������������������������������������������������������������������������� 394 79. Dysosteosclerosis, SLC29A3-, TNFRSF11A- and CSF1R-Related�������������������������������������������������������������������������������������������������398

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Contents

Osteosclerotic Disorders 80. Raine Dysplasia, FAM20C-Related������������������������������������������������������������������������������������������������������������������������������������������������� 403 81. Caffey Disease (Including Infantile and Attenuated Forms), COL1A1-Related������������������������������������������������������������������������� 408 82. Caffey Dysplasia (Severe Lethal Variant)����������������������������������������������������������������������������������������������������������������������������������������411 83. Dysplastic Cortical Hyperostosis, Kozlowski-Tsuruta Type����������������������������������������������������������������������������������������������������������416 84. Dysplastic Cortical Hyperostosis, Al-Gazali Type, ADAMTSL2-Related������������������������������������������������������������������������������������418 85. Osteopathia Striata with Cranial Sclerosis, AMER1-Related�������������������������������������������������������������������������������������������������������421 86. Lenz-Majewski Hyperostotic Dysplasia, PTDSS1-Related����������������������������������������������������������������������������������������������������������� 426

Osteogenesis Imperfecta and Bone Fragility Group 87. Osteogenesis Imperfecta��������������������������������������������������������������������������������������������������������������������������������������������������������������������429 88. Bruck Syndrome, FKBP10- and PLOD2-Related�������������������������������������������������������������������������������������������������������������������������� 447 89. Osteogenesis Imperfecta with Craniosynostosis (Cole-Carpenter Syndrome), P4HB- and SEC24D-Related�������������������������������������������������������������������������������������������������������������������������������������������������������������450

Disorders of Bone Mineralisation 90. Hypophosphatasia, Perinatal Lethal and Infantile Forms, ALPL-Related���������������������������������������������������������������������������������452 91. Neonatal Hyperparathyroidism, Severe Form, CASR-Related�����������������������������������������������������������������������������������������������������457

Skeletal Disorders of Parathyroid Hormone Signalling Cascade 92. Metaphyseal Dysplasia, Jansen Type, PTHR1-Related������������������������������������������������������������������������������������������������������������������461 93. Blomstrand Dysplasia, PTHR1-Related������������������������������������������������������������������������������������������������������������������������������������������ 464

Osteolysis Group 94. Hajdu-Cheyney Syndrome Including Serpentine Fibula Syndrome, NOTCH2-Related����������������������������������������������������������� 467

Overgrowth (Tall Stature) Syndromes and Segmental Overgrowth 95. Marfan Syndrome, FBN1-Related����������������������������������������������������������������������������������������������������������������������������������������������������471 96. Marshall-Smith Syndrome, NFIX-Related��������������������������������������������������������������������������������������������������������������������������������������475 97. Proteus Syndrome, AKT1-Related����������������������������������������������������������������������������������������������������������������������������������������������������478

Cleidocranial Dysplasia and Related Disorders 98. Cleidocranial Dysplasia, RUNX2-Related�������������������������������������������������������������������������������������������������������������������������������������� 482 99. Yunis-Varon Dysplasia, FIG4- and VAC14-Related����������������������������������������������������������������������������������������������������������������������� 488

Syndromes Featuring Craniosynostosis 100. Pfeiffer Syndrome, FGFR1- and FGFR2-Related���������������������������������������������������������������������������������������������������������������������������491 101. Apert Syndrome, FGFR2-Related��������������������������������������������������������������������������������������������������������������������������������������������������� 496 102. Antley-Bixler Syndrome, FGFR2- and POR-Related�������������������������������������������������������������������������������������������������������������������� 500 103. Shprintzen-Goldberg Syndrome, SKI-Related������������������������������������������������������������������������������������������������������������������������������� 504 104. Carpenter Syndrome, RAB23- and MEGF8-Related�������������������������������������������������������������������������������������������������������������������� 507

Craniofacial Dysostoses 105. Acrofacial Dysostosis, Nager Type, SF384-Related������������������������������������������������������������������������������������������������������������������������510 106. Acromelic Frontonasal Dysostosis, ZSW1M6-Related��������������������������������������������������������������������������������������������������������������������514

Vertebral and Costal Dysostoses 107. Spondylocostal Dysostosis, DLL3-, MESP2-, LFNG-, HES7-, TBX6- and RIPPLY2-Related���������������������������������������������������517

Contents

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108. Cerebro-Costo-Mandibular Syndrome (Rib Gap Syndrome), SNRPB-Related�������������������������������������������������������������������������521 109. Diaphanospondylodysostosis, BMPER-Related����������������������������������������������������������������������������������������������������������������������������� 524 110. Uniparental Disomy, Paternal, for Chromosome 14 (UPD14; Kagami-Ogata Syndrome)���������������������������������������������������������528 111. VATER/VACTERL Association�������������������������������������������������������������������������������������������������������������������������������������������������������531

Limb Hypoplasia – Reduction Defects Group 112. Holt-Oram Syndrome, TBX5- and SALL4-Related������������������������������������������������������������������������������������������������������������������������536 113. Cornelia De Lange Syndrome, NIPBL-, SMC1A-, SMC3-, RAD21- and HDAC8-Related�������������������������������������������������������� 540 114. Limb Reduction Syndrome (Al-Awadi Raas-Rothschild Limb-Pelvis Hypoplasia-Aplasia), WNT7A-Related���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������� 546 115. Cousin Syndrome, TBX15-Related�������������������������������������������������������������������������������������������������������������������������������������������������� 548 116. Roberts Syndrome, ESCO2-Related�������������������������������������������������������������������������������������������������������������������������������������������������550 117. Tibial Hemimelia-Polysyndactyly-Triphalangeal Thumb (Werner Syndrome), ZRS-Related��������������������������������������������������553 118. Gollop-Wolfgang Complex�����������������������������������������������������������������������������������������������������������������������������������������������������������������556 119. Femoral Facial Syndrome����������������������������������������������������������������������������������������������������������������������������������������������������������������� 560 120. Femur-Fibula-Ulna Syndrome��������������������������������������������������������������������������������������������������������������������������������������������������������� 566 121. Sirenomelia����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������� 568 122. Fanconi Anaemia��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������573

Split Hand/Foot with and without Other Manifestations 123. Split Hand-Foot Malformation (Isolated Form, Types 1–6)����������������������������������������������������������������������������������������������������������576

Polydactyly-Syndactyly-Triphalangism Group 124. Mirror-Image Polydactyly of Hands and Feet (Laurin-Sandrow), SHH-Related���������������������������������������������������������������������� 580 125. Greig Cephalopolysyndactyly Syndrome, GLI3-Related���������������������������������������������������������������������������������������������������������������583 126. Pallister-Hall Syndrome, GLI3-Related�������������������������������������������������������������������������������������������������������������������������������������������587

Conditions Not Included in the International Nomenclature (2023) 127. Cerebroarthrodigital Syndrome�������������������������������������������������������������������������������������������������������������������������������������������������������591 128. Cerebro-Osseous-Digital Syndrome�������������������������������������������������������������������������������������������������������������������������������������������������593 129. DK Phocomelia����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������� 596 130. Kaufman-McKusick Syndrome, MKKS-Related��������������������������������������������������������������������������������������������������������������������������� 599 131. Menkes Disease, ATP7A-Related������������������������������������������������������������������������������������������������������������������������������������������������������ 602 132. Multiple Pterygium Syndrome, CHRNG-, CHRNAL- and CHRND-Related����������������������������������������������������������������������������� 605 133. OEIS Complex������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������ 608 134. Schinzel-Giedion Syndrome, SETBP1-Related�������������������������������������������������������������������������������������������������������������������������������611 Appendix 1:  Fetal Growth Charts and Biometric Measurements for Different Countries�������������������������������������������������������������������615 Appendix 2:  Gamuts���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������616 Index������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������659

Preface Skeletal dysplasias are rare, largely genetically determined conditions affecting bone and cartilage growth and development. The genetic pathogenic variants continue to exert their influence throughout the life of the individual. Malformation syndromes may be genetic, sporadic or environmentally determined. They occur during embryogenesis, and apart from growth, the malformations remain static during further development. They may affect the skeletal system in addition to other systems; therefore, this atlas aims to incorporate some of the more commonly encountered syndromes with skeletal malformations. This atlas presents perinatal images of rare skeletal disorders to include skeletal dysplasias and malformation syndromes on a case-by-case basis. There are 134 conditions described and more than 2000 images of over 500 patients listed in an order based on the 2023 International Nosology and Classification of Genetic Skeletal Disorders. In the nosology, altogether 771 different skeletal dysplasias are recognised and 552 different genes. In this updated classification, disorders are grouped according to families of common gene mutations when this is known (for example, the families of FGFR3, COL2, sulphation disorders and FLMN disorders); otherwise, the conditions are grouped by common clinical/radiographic features (gracile bone disorders, dense bone disorders). In the new classification, a dyadic approach has been introduced so that each condition’s name consists of an anatomic description (for example, metaphyseal dysplasia), followed by the common name in brackets (type McKusick), and then the specific gene pathogenic variants (SLC25A-related). While the complete name for each condition has been used in the table of contents and as the chapter heading, it is not used in the main text, where a common synonym is used. The table of contents includes the most up-to-date information on the individual conditions to include the mutated gene. The first two chapters deal with normal development

of the fetal skeleton to include radiographic images of normal fetuses at different gestational ages and with imaging and diagnostic strategies from the combined perspective of the international authors; the third chapter deals with 134 individual conditions. Each condition has a brief summary to include synonyms; confirmation of diagnosis, genetics, age at presentation; clinical, prenatal ultrasound, fetal and postnatal radiological features including CT and MRI findings when available; prognosis; and differential diagnosis. An up-todate list of references is included, and following this, images are presented with each case illustrating different imaging modalities. Brief clinical findings are given if known. The appendices include a chart of normal fetal development, as well as growth charts. A gamuts section is also included; this comprises lists of specific abnormal features with the listed conditions in which they occur, as referred to in the book text. By identifying two or more of these abnormal findings in a fetus or neonate, a process of triangulation may be used to establish diagnostic possibilities. While information is readily available on individual rare conditions, this is only useful in the context of prior accurate evaluation and interpretation of images (among other diagnostic tools). It is anticipated that this book will be of value to all clinicians and technicians working in fetal medicine and neonatal care. This includes obstetricians, neonatologists, radiologists, sonographers, clinical and molecular geneticists and fetal and perinatal pathologists. We recognise the multidisciplinary input required to make these diagnoses and have drawn together the different clinical disciplines involved in prenatal and postnatal care and diagnosis. We hope that a greater awareness of clinical and imaging findings, together with genetic correlation, will improve diagnostic accuracy and thus provide affected families and their clinicians with the information needed to make informed management decisions.

Acknowledgements Without the generosity of the patients’ families and of our clinical colleagues for sharing images and data about their patients, this atlas would not have been possible. We would like to acknowledge the great contributions to the first edition

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made by coauthors Dr Michelle Fink and Professor Deborah Krakow. We include a list of contributing clinicians here; please accept our sincere apologies if we have failed to recognise your valuable contribution.

Contributors Clinical Geneticists Hatice Mutlu Albayrak Samsun, Turkey Umut Altunoglu Istanbul, Turkey Meena Balasubramanian Sheffield Children’s NHS Foundation Trust Sheffield, UK Gary A. Bellus Pennsylvania, USA Meenaksi Bhat Bangalore, India Lorenzo Botto Utah, USA

Saumya Shekhar Jamuar Singapore Girisha Katta Manipal, India Thong Meow Keong Kuala Lumpur, Malaysia Masashi Koyama Shizioka, Japan Alison Male Great Ormond Street Hospital London, UK Sahar Mansour St George’s Hospital London, UK

Michael Parker Sheffield Children’s NHS Foundation Trust Sheffield, UK Stephen Robertson Dunedin, New Zealand Hideaki Sawai Nishinimiya, Japan Sarah Smithson Bristol Royal Infirmary UK Mohnish Suri Nottingham, UK Yves Sznzjer Brussels, Belgium

George McGillivray Royal Children’s Hospital Melbourne, Australia

PA Terhal Utrecht, Netherlands

Peter Meinecke Hamburg, Germany

Peter Turnpenny Exeter, UK

Oivind Braaten Oslo, Norway

Kaye Metcalfe Manchester, UK

Anthony Vandersteen Northwick Park Hospital London, UK

Marco Castori Fondazione IRCCS–Casa Sollievo della Sofferenza San Giovanni Rotondo, Italy

Shahida Moosa Cape Town, South Africa

Sarah Bowdin Birmingham Women’s NHS Foundation Trust Birmingham, UK

Denise P Cavalcanti Campinas, Brazil David Chitayat Toronto, Canada Carlos Fereirra National Institutes of Health Washington, DC, USA Giedre Grigelioniene Karolinska Hospital Stockholm, Sweden Melita Irving Guy’s and St Thomas’ London, UK

Naoya Morisada Hyogo, Japan Jun Murotsuki Sendai, Japan Sheela Nampoothiri Kerala, India Sarah Nikkel Ottawa, Canada Tsutomu Ogata Hamamatsu, Japan Daiki Ohba Saitama, Japan

Nithiwat Vatanavicharn Bangkok, Thailand Ishwar Verma Delhi, India Ulrika Voss Stockholm, Sweden Louise Wilson Great Ormond Street Hospital London, UK Takahiro Yamada Sapporo, Japan Haesung Yoon Seoul, South Korea

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xii Paediatricians Paul Arundel Sheffield Children’s NHS Foundation Trust Sheffield, UK Paolo Bianchi Ospedali Riuniti di Bergamo Bergamo, Italy Nicholas Bishop Sheffield Children’s NHS Foundation Trust UK Simon Roth Barnet Hospital London, UK

Contributors Manuel Parrón Madrid, Spain Anna Marzoli IRCCS G. Gaslini Genova, Italy Valérie Mayne Melbourne, Australia Amada Sampson Royal Women’s Hospital Melbourne, Australia Lal Taor Cincinnati Children’s Hospital Medical Center Ohio, USA

Anastasia Konstantindou National University of Athens Greece Esin Kotiloglu Cambridge University Hospital UK Nick Ostjovic Birmingham Women’s Hospital UK Jan Pyman Royal Women’s Hospital Melbourne, Australia Ricardo Palma-Dias Royal Women’s Hospital Melbourne, Australia

Fetal Pathology and Medicine Giulia Tuo IRCCS G. Gaslini Genova, Italy Radiologists Noriko Aida Yokohama, Japan Lorenzo Bacigalupo Ente Ospedaliero Ospedali Galliera Genova, Italy Alistair Calder Great Ormond Street Hospital London, UK Joanna Fairhurst Southampton Children’s Hospital UK Hwa Kim Seoul, South Korea Beth Kline-Fath Cincinnati Children’s Hospital Medical Center Ohio, USA

Virginia Billson Melbourne, Australia Alessandro Cecchi Centro Unico Regionale ASUR Diagnosi Prenatale di II livello Loreto, Italy Elisa Carboni Centro Unico Regionale ASUR Diagnosi Prenatale di II livello Loreto, Italy Marta Cohen Sheffield Children’s Hospital UK

Rosemary Scott University College Hospital London, UK K Subapriya Chennai, India Anita Whitehead Cambridge University Hospital UK Josephine Wyatt-Ashmead Imperial College London UK Medical Libraries Bristol Skeletal Dysplasia Registry

Thomas Jaques Great Ormond Street Hospital London, UK Iona Jeffrey St George’s Hospital London, UK

Margherita Corona Medical Library ‘Ospedali Galliera’ Ente Ospedaliero Ospedali Galliera Genoa, Italy

Authors

Christine M Hall was a founding member of the International Skeletal Dysplasia Society in 1999 and was President in 2000 and 2001. She hosted an international meeting for this society in Oxford in 2001 and was also Chairman of the Committee for the International Nomenclature and Classification of Constitutional Disorders of Bone. She was a founding member of the Skeletal Dysplasia Society for Teaching and Research (SDG) UK in 1978 and is actively involved with this group, which has a membership of about 300. In 2004, Professor Hall was awarded Honorary Membership in the European Society of Paediatric Radiology for services to paediatric radiology. In 2019, Professor Hall was awarded Honorary Membership in the International Skeletal Dysplasia Society. Amaka C Offiah is the first black and female Managing Editor of the journal Pediatric Radiology, convener of the Skeletal Dysplasia Group for Teaching and Research, Chairperson of the European Society of Paediatric Radiology Child Abuse Taskforce and Co-Chair for the North-East Region of the Experts in the Family Justice System Committee. Francesca Forzano is the current Chair of the Public and Professional Policy Committee of the European Society of Human Genetics (ESHG) and a member of the Scientific Programme Committee of the ESHG annual conference. She has been Co-Director of the European Course in Genetic Counseling in Practice for the past 15 years.

Mario Lituania is a retired consultant obstetrician and gynaecologist from Galliera Hospital, Genova, Italy. From 2003, he was director of the Fetal and Perinatal Medicine Unit at Galliera Hospital and a Contract Professor at the Graduate School of Medical Genetics at the University of Genova (since 1991). Gen Nishimura is a semi-retired paediatric radiologist who is currently assigned as a Visiting Professor at the Center for Intractable Diseases, Saitama Medical University Hospital, Japan; Adjunct Professor in Paediatrics at the University of Utah, Utah, USA; and consultant at the K1 Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden. He has also contributed to recent revisions of the International Nosology and Classification of Genetic Skeletal Disorders (2006, 2010, 2015, 2019, 2023 revisions). Valérie Cormier-Daire is a medical geneticist (MD, PhD) and Professor of Genetics (Université Paris Centre). An active member of the European Society of Human Genetics and of the International Skeletal Dysplasia Society, she is a partner in eight industrial projects on clinical trials and is the owner of two patents.

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Part 1 Normal Fetal Skeletal Growth and Development

Skeletal Patterning, Bone Cell Differentiation and Bone Growth The fetal skeleton comprises three embryonic origins: (1) the neural crest, (2) sclerotome and (3) lateral mesoderm, which give rise to (1) the craniofacial bones and clavicle, (2) axial skeleton – skull base (basiocciput), ribs, spine and sternum and (3) appendicular skeleton – shoulder girdle, pelvic girdle and tubular bones, respectively. Fetal bone development begins with condensation of undifferentiated mesenchymal cells. Formation of skeletal primordia is regulated by way of two distinctive, but synchronous, steps: patterning and differentiation. The former determines the position, number and shape of the primordial template. The latter refers to transition of the immature mesenchymal cells into bone cells (osteoblasts and osteocytes) and cartilage cells (chondroblasts and chondrocytes), which play a pivotal role in intramembranous ossification and endochondral ossification, respectively. These basic processes are almost completed during the early embryonic stage (8–12 weeks of gestation). At the end of the first trimester, most skeletal components are ossified and identifiable on postmortem radiograph. Afterward, the principal process is growth and maturation. Individual bones enlarge and mature according to the prenatal and postnatal timetables. Disruption of patterning leads to bone malformation (abnormally shaped bones) termed ‘dysostosis’. Impairment of differentiation results in generalised stunting of bone associated with disease-specific bone deformities, termed ‘bone dysplasia’.

Different Mechanisms of Ossification Bone formation is governed by two different mechanisms, intramembranous ossification and endochondral ossification, which have different roles in bone formation. For embryonic development of primary ossification centres, the former contributes to ossification of the neural crest–derived bones (calvarium, facial bones, clavicles) and external surface (cortex) of the sclerotome/lateral mesoderm-derived bones (axial and appendicular skeleton), while the latter to the internal structure (spongiosa or cancellous bone) of the axial and appendicular skeleton. After primary ossifications centres are established, endochondral ossification occurs only at the epiphyseal cartilage (secondary ossification centre) and growth plate or growth plate equivalent of tubular bones, ribs, spine and flat bones. In the appendicular skeleton, and to a certain extent in the axial skeleton, endochondral bone formation contributes to longituDOI: 10.1201/9781003166948-1

dinal (directional) bone growth, while intramembranous bone formation contributes to radial (circumferential) bone growth.

Intramembranous Ossification Intramembranous ossification is a relatively simple process. In neural crest–derived bones, undifferentiated mesenchymal cells condense as a primordium via cellular proliferation. Then, the mesenchymal cells evolve into osteoprogenitor cells and ultimately into osteoblasts that secrete the bone matrix proteins (e.g., type 1 collagen). The initial processes proceed in an avascular environment. Subsequently, vascular invasion into the bone anlagen occurs and induces matrix mineralisation. The initial small foci of mineralisation coalesce into a scaffold of immature trabeculae, into which osteoblasts are entrapped and differentiated into mature osteocytes. The immature bone (woven bone) is gradually remodelled into mature bone (lamellar bone) via repeated cycles of bone resorption and new bone formation. Defective ossification of neural crest–derived bones is clinically observed in cleidocranial dysplasia due to loss-of-function mutations in the RUNX2 gene (Figure 1.1a–c). Intramembranous ossification is also essential in external or cortical bone formation of the axial and appendicular skeleton, which is closely linked to internal or cancellous bone formation through endochondral ossification.

Endochondral Ossification Internal structures of the axial and appendicular skeleton are created by a complex process termed endochondral ossification, in which a cartilage intermediate plays an essential role. As with intramembranous ossification, the first step of endochondral ossification is condensation of undifferentiated mesenchymal cells to a primordium. The primitive condensation predetermines the position, size and shape of bone (patterning). Then, the mesenchymal cells differentiate into chondroblasts in an avascular environment. Simultaneously, the periphery of the condensation evolves into the perichondrium composed of immature perichondral cells. Perichondral cells retain chondrogenic potential, adding chondrocytes into the periphery of cartilage templates and contributing to their radial growth. Chondroblasts further differentiate into chondrocytes, which undergo centrifugal maturation, developing into proliferating chondrocytes and differentiating into hypertrophic chondrocytes with their columnar formation. Chondrocytes secret cartilage matrix proteins (i.e., type 2 collagen and aggrecan). Hypertrophic 1

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Fetal and Perinatal Skeletal Dysplasias

(b)

(a)

(c)

FIGURE 1.1  (a–c): Cleidocranial dysplasia. Note wide fontanelles with multiple Wormian bones and hypoplastic clavicles. The medial segment of both clavicles is formed. However, the right distal segment is missing, and the left is rudimentary along with pseudoarthrosis.

chondrocytes progress to the stage of terminal differentiation and undergo apoptosis. The subsequent processes are matrix mineralisation, vascular invasion and matrix absorption. Then, endochondral bone formation begins with deposition of immature osteoid. The woven bones are subsequently remodelled into mature bones via consecutive bone resorption and new bone apposition. While chondrocyte maturation proceeds, the perichondrium begins with intramembranous ossification for radial or circumferential growth of bone collars. External intramembranous ossification and internal endochondral ossification are linked to each other. External perichondral intramembranous ossification begins at the hypertrophic zone of the inner template. During fetal growth, centrifugal endochondral ossification continues toward bone ends and ultimately forms growth plates (physes) and secondary ossification centres (epiphyses). The periphery of growth plates remains outlined by the perichondrium (perichondral ring), which probably adds chondrocytes to the growth plate. Endochondral bone growth at the growth plates follows the development of primary ossification centres. From the third trimester, epiphyseal ossification starts and continues to proceed postnatally. The timing of growth plates formation is assumed to be programmed in advance. In fact, the growth plates are distant from bone ends, along with vertically long epiphyses in disorders with delayed terminal differentiation of chondrocytes (e.g., metaphyseal dysplasia Jansen type due to gain-in-function mutations of the PTHLH gene and cleidocranial dysplasia due to loss-of-function mutations in the RUNX2 gene) (Figure 1.2a). Growth plates are scooped or cupped in shape in disorders with premature cessation of the terminal differentiation (e.g., achondroplasia due to gain-in-function mutations in the FGFR3 gene). The finding is attributable to a relatively normal

growth potential in chondrocytes that are newly added from the perichondrium to the growth plate (Figure 1.2b).

Embryonal Stage The human skeleton originates from cells derived partially from paraxial mesenchyme and partially from the neural crest (part of the cranial vault and the viscerocranium). Bone tissue forms through a process involving ossification of a primordial cartilage model, which arises from mesenchyme. This process is defined as indirect or endochondral ossification and occurs in most bones. The bones of the cranial vault, part of the viscerocranium and the clavicle, form through a process known as direct or intramembranous ossification, in which bone develops from specialised regions of mesoderm, parts of which differentiate into osteoblasts and osteoclasts. Morphogenesis is determined by a web of molecular programmes that overlap and regulate processes concerning position, differentiation, modelling, proliferation, apoptosis and cell renewal. Bone tissue forms and develops through a modelling process involving production of bone matrix by osteoblasts and resorption by osteoclasts. Osteoblasts derive from multipotential mesenchymal cells and further differentiate into bone-lining cells and osteocytes. Osteoclasts originate from haematopoietic precursor cells in common with monocytes and macrophages. Ossification starts in the eighth gestational week and continues postnatally until the mid-20s are reached. The human skeletal system is divided into two principal groups: the axial skeleton and the appendicular skeleton. The axial skeleton consists of the vertebral column, the thoracic cage and the skull. The appendicular skeleton consists of the pectoral girdles, the upper limbs, the pelvic girdles and the lower limbs.

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Normal Fetal Skeletal Growth and Development

(a)

 

(b)

FIGURE 1.2  (a) A 3-year-old child with metaphyseal dysplasia Jansen type. Note wide growth plates, metaphyseal irregularities and mega-epiphyses. (b) A 3-year-old child with achondroplasia. Note metaphyseal cupping, metaphyseal flaring and small epiphyses.

Vertebral Column During the third gestational week, the paraxial mesoderm condenses into spherical structures called somites, which are paired on either side of the neural groove and form in a craniocaudal direction. Within each somite are three distinct and temporally transient structures forming in a dorsoventral (DV) pattern: (1) the dermomyotome, (2) the myotome and (3) the sclerotome. The sclerotome forms bone tissue (i.e., the vertebral column). The myotome is a precursor for muscular structures, while the dermomyotome produces the progenitor cells of the dermis. The sclerotome undergoes a process known as ‘epithelio-mesenchymal transition’. This differentiation is regulated by a number of surrounding tissues including the notochord, neural tube, lateral plate mesoderm and myotome. Later differentiation of the vertebrae and intervertebral discs involves remodelling of the initial segmentation in which a half-somite shifts caudally. Within the somites, it is possible to identify alternating loose and dense tissues that do not mix; the loose, cephalic tissue is the precursor of the centrum, while the dense, caudal tissue is the precursor of the intervertebral disc. The centrum encloses the notochord and gives rise to most of the vertebral body. The neural processes extend dorsally on each side of the neural tube, and later right and left processes unite to complete the neural arch. Therefore, cells derived from two adjacent somites form each vertebra.

The segmentation process is genetically controlled by an oscillating ‘segmentation clock’, which is determined by pulses of signalling of Notch, Wnt and fibroblast growth factor (FGF). The Notch pathway is particularly important for proper patterning of the developmental axes and vertebral modelling, and many components of this pathway have been identified (DLL1, DLL3, LFNG, MIB1, POFUT1, PSEN1, CSL/RBPJ), as well as some of the target genes (HES7, MESP2, LFNG). HOX genes play a fundamental role both in axial skeletal patterning and in the proper development and modelling of the vertebrae, but the molecular net they rule is still largely unknown. The vertebral column forms as a cartilaginous template that is later converted into bone by endochondral ossification. Ossification is incomplete, with an articular cartilage remnant adjacent to the intervertebral disc. The intervertebral disc then differentiates into a fibrocartilaginous disc. The vertebral body ossifies before the vertebral arch, which partially surrounds the spinal cord (a dorsal opening is closed by the dorsal ligament) to allow further growth of the spinal cord. The ossification process starts at the ninth gestational week. At birth, the majority of the vertebrae show three ossification centres, one for the centrum and one for each lateral process.

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Ribs At the side of the vertebrae of the neck and trunk, close to the vertebral arches, small condensations of mesenchyme develop to form the costal processes. The ribs arise solely from the costal processes of the thoracic vertebrae. They start to develop on day 35, and by day 45 the first seven ribs fuse ventrally to the sternum. The other five ribs do not connect directly with the sternum and therefore are defined as false ribs. At the end of the embryonal stage, the cartilage model of the thoracic cage is complete. Around the sixth week an ossification centre appears at the angle of each rib. Other ossification centres will appear around puberty in the tubercles and head of each rib. The costal processes of the cervical vertebrae will form the anterior part of the transverse foramina, through which the vertebral arteries pass, while the costal processes of the lumbar vertebrae will form the transverse processes. At the sacral level, the costal processes take part in the formation of the alae.

Fetal and Perinatal Skeletal Dysplasias followed by the basioccipital region. The process moves from the base of the cranium to the parietal region, and by the end of the embryonal stage, formation of the cartilaginous templates of the skull is complete. The bones of the cranial vault have large, flexible, fibrous joints (sutures: coronal, lambdoid, metopic, sagittal, squamous temporal), which allow the skull remarkable flexibility, enabling the head to pass through the birth canal and allowing postnatal growth of the brain. The sutures gradually fuse at different postnatal times – first the metopic suture in infancy, then followed by the others much later. Ossification continues through puberty until the mid-20s. In old age, the sutures separating the vault plates are often completely ossified. Recent studies have shown that noggin (a bone morphogenetic protein [BMP] antagonist) is involved in closure of the sutures. Ephrin, FGF2, FGFR2 and Twist-related protein 1 (TWIST1) also regulate the timing of sutural closure. Abnormal premature fusion (synostosis) of any of the sutures will lead to a number of different skull shape deformities.

Sternum The sternum develops from two condensed structures of mesenchymal cells in the ventral body wall known as sternal bars. It fuses with the cartilaginous tissue of the ribs in a craniocaudal direction. By the ninth week the cartilaginous model of the sternum is complete. Ossification proceeds in a craniocaudal direction until the fifth postnatal month.

Skull The skull has distinctive features that make it a unique structure within the skeletal system: an embryonal origin from neural crest cells in addition to formation via an intramembranous ossification process. The bones of the skull are divided into two groups: (1) the viscerocranium, which includes the bones of the face and originates from neural crest cells, and (2) the cranial vault or neurocranium, which originates from the occipital somites. The bones of the cranial vault develop through intramembranous ossification, while the bones that form the base of the skull are formed by endochondral ossification. The viscerocranium arises from the first two branchial arches. The first arch gives rise to the maxilla, zygomatic bone, temporal bone (dorsal portion), mandible and sphenomandibular ligament (ventral portion or Meckel cartilage). The second arch gives rise to the incus, malleus and stapes, which are the first bones to be fully ossified (4 months). The face develops between the fourth and tenth gestational weeks by fusion of five structures: the frontonasal process, a pair of maxillary swellings and a pair of mandibular swellings. Two nasal placodes, formed by condensed ectodermal tissue, form and develop over the frontonasal process and contribute to the nasal structures, the philtrum and the primary palate. The external auditory meatus and the tympanic cavity derive from the first pharyngeal cleft and pouch, respectively. The cranial vault starts its development around the membranous labyrinth. The first structure to appear is the otic capsule

Limbs The first sign of the limbs is a small protrusion at the flank of the embryonal body. These limb buds arise from mesenchymal cells derived from the lateral plate mesoderm and are covered by an ectodermal layer that forms the apical ectodermal ridge (AER). The posterior half of the bud encompasses a region known as the zone of polarising activity (ZPA). The ZPA has a central and unique function in normal limb bud development, controlling survival and differentiation of the mesenchyme along the anteroposterior (AP) axis. The upper limb buds appear around day 24 at the cervicothoracic transition point, and the lower limb buds appear around day 28 at the lumbosacral transition point. The precise point in which the bud shows up along the AP axis is probably determined by the expression of HOX genes. The limb bud grows and elongates in a proximal-to-distal direction and develops through stages that include mesenchymal condensation, differentiation into cartilage, creation of a cartilage anlage and endochondral ossification. The condensation of the mesenchyme produces three different elements in chronological sequence: (1) stylopod (proximal), (2) zeugopod (intermediate) and (3) autopod (distal). The patterning of the developing limb is also established in relation to the anteroposterior (AP) and dorsoventral (DV) axes. In the upper limb, the first primordial bone to appear is the humerus, followed by the radius, ulna, metacarpals and phalanges. The tip of the developing buds acquires a flattened shape and is defined as the hand plate (day 32) or the foot plate (day 36). The mesenchyme then condenses to form a radial chondrogenic structure that represents the blueprint of the fingers. The digital rays are linked by a mesenchymal membrane, which progressively disappears by apoptosis to enable shaping of individual digits (days 46–49). The cartilaginous template of the limb bones is completed around the eighth week, following which the ossification process

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Normal Fetal Skeletal Growth and Development slowly begins. Cartilage, bones, tendons and skin derive from the mesenchyme within the limb buds. Muscles, nerves and vessels originate from the myotome and migrate progressively within the limb buds. The formation of the limb – from the first sign to the completion of the cartilaginous limb – takes 4 weeks. At the sixth week the limbs rotate anteriorly, so that the elbows and knees point laterally, and the palms and soles point medially toward the trunk. At the seventh week the limbs undergo another torsion, 90° along the longitudinal axis, so that the elbows are directed caudally and the knees cranially. At the eighth week a third counter clockwise rotation completes the positioning. Limb morphogenesis and three-dimensional patterning are coordinated by interactions between the centres of different limb regions through the molecules that they produce: (1) AER – FGFs, (2) ZPA – sonic hedgehog (SHH) and (3) dorsal ectoderm (WNT7A). Abnormal coordination between these centres is responsible for abnormalities of the three-dimensional development of the limb – namely, reduction defects and duplications.

Proximal-Distal Axis: Fibroblast Growth Factors Growth along the proximal-distal axis is dependent on the AER, a specialised epithelial layer set on the tip of the limb bud. The FGFs, four of which are specifically expressed within the AER, are the key molecular players of this specialised region. Removal of the AER in the chick embryo results in the loss of formation of adjacent skeletal structures: early in the limb bud phase, it results in the complete loss of the limb, while in later stages it results in the normal formation of proximal structures with loss of the more distal elements.

Anteroposterior Axis: Sonic Hedgehog The posterior mesenchyme of the limb bud, the ZPA, has been linked to limb morphogenesis along the AP axis. SHH is the key signalling molecule of the ZPA: the addition of SHH proteins to the distal portions of the limb bud of the chick embryo triggers the development of mirror-image digital duplication, while the removal of SHH results in loss of skeletal elements in the AP axis. SHH regulates the expression of GLI3, which is an important regulator of the AP patterning of the distal portion of the limb bud. GLI3 and dHAND are expressed early in the limb bud in the anterior and posterior portions, respectively, and their expression appears to be mutually exclusive. Although they are interconnected, the expression of dHAND seems to be independent of the SHH pathway. dHAND is essential for establishing the normal AP patterning of the proximal structures (stylopod and zeugopod).

Dorsoventral Axis: WNT7A DV patterning is dependent on signals derived from the ectoderm overlying the limb bud. At a very early stage of limb budding, WNT7A is expressed in the dorsal ectoderm and induces the transcription factor LMX1B, which is necessary for dorsal morphology of the target cells, particularly in the autopod. WNT7A expression is repressed in the ventral ectoderm by the transcription factor Engrailed (EN1), which is induced by

BMP through activation of the receptor BMPR1A. The absence of WNT7A expression determines a biventral pattern of the autopod, while the absence of ENL or BMP expression causes a bidorsal pattern.

Fetal Stage Up until the 14th week, development of the skeleton is relatively fast. Beyond 14 weeks, development is much slower and involves growth and modelling of the segments. There is good correlation between overall fetal development and femoral growth and modelling.

BIBLIOGRAPHY Dreyer SD, Zhou G, Lee B. The long and the short of it: Developmental genetics of the skeletal dysplasias. Clin Genet. 1998; 54: 464–73. Dunwoodie SL. The role of notch in patterning the human vertebral column. Curr Opin Genet Dev. 2009; 19: 329–37. Eurin D, Narcy F, LeMerrer M et al. Atlas Radiographique du squelette foetal normal. Paris: Flammarion MédecineScience; 1993. Goodman FR. Limb malformations and the human HOX genes. Am J Med Genet. 2002; 112: 256–65. Grzeschik KH. Human limb malformations: An approach to the molecular basis of development. Int J Dev Biol. 2002; 46: 983–91. Hinchliffe JR. Developmental basis of limb evolution. Int J Dev Biol. 2002; 46: 835–45. Karsenty G. The complexities of skeletal biology. Nature. 2003; 423: 316–18. Krakow D. The dysostoses. In: Rimoin DL, Connor JM, Pyeritz RE, et al. Emery and Rimoin’s Principles and Practice of Medical Genetics. London: Churchill Livingstone; 2002. pp. 4160–81. Larsen WJ. Human Embryology. 2nd ed. New York, NY: Churchill Livingstone; 1997. McLean W, Olsen BR. Mouse models of abnormal skeletal development and homeostasis. Trends Genet. 2001; 17: S38–43. Moore KL. The Developing Human: clinically oriented embryology. 2nd ed. Philadelphia, PA: Saunders Company; 1977. Morriss-Kay GM, Wilkie AO. Growth of the normal skull vault and its alterations in craniosynostosis: Insight from human genetics and experimental studies. J Anat. 2005; 207: 637–53. Nissim S, Tabin C. Development of limbs. In: Epstein CJ, Erickson RP, Wynshaw-Boris A, editors. Inborn Errors of Development: the molecular basis of clinical disorders of morphogenesis. Oxford: Oxford University Press; 2004. pp. 148–67. Niswander L. Pattern formation: Old models out on a limb. Nat Rev Genet. 2003; 4: 133–43. Sadler TW, editor. Langman’s Medical Embryology. 6th ed. Baltimore, MD: Williams & Wilkins; 1990. Saunders JWJR, Gasseling MT. Ectodermal-mesodermal interactions in the origin of limb symmetry. In: Fleischmajer R, Billingham RE, editors. Epithelial-Mesenchymal Interactions. Baltimore, MD: Williams & Wilkins; 1968. pp. 78–97.

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Fetal and Perinatal Skeletal Dysplasias

Superti-Furga A, Bonafé L, Rimoin DL. Molecular-pathogenetic classification of genetic disorders of the skeleton. Am J Med Genet. 2001; 106: 282–93. 2002; 112112 Tickle C. Molecular basis of vertebrate limb patterning. Am J Med Genet

Warren SM, Brunet LJ, Harland RM et al. The BMP antagonist noggin regulates cranial suture fusion. Nature. 2003; 422: 625–9. Wellik DM. Hox patterning of the vertebrate axial skeleton. Dev Dyn. 2007; 23: 2454–63.

NORMAL FETAL RADIOGRAPHS These images next should be consulted in conjunction with the synopsis of fetal development in Part 1. 11–14 weeks (11, 12 and 14 weeks):

   

   

At 11 weeks of gestation, only the clavicles, scapulae, ilia and tubular bones are ossified. The short tubular bones are partly ossified. At 12 weeks, the thoracic and lumbar spine are ossified. At 14 weeks, the cervical spine and sacrum are partly ossified. All short tubular bones are ossified, but ossification of the middle phalanges is still incomplete.

Normal Fetal Skeletal Growth and Development 15–17 weeks (15, 16 and 17 weeks):

At 16 weeks, the ischia are ossified. 19–21 weeks (19 weeks, 20 weeks and 1 days and 21 weeks):

Ossification of all primary ossification centres, other than the pubic bones, is complete.

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Fetal and Perinatal Skeletal Dysplasias

22–26 weeks (22 weeks, 24 weeks and 6 days and 26 weeks):

     25 weeks (24 weeks and 6 At days), pubic ossification is seen. At 26 weeks, the calcanei are ossified.

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Normal Fetal Skeletal Growth and Development 26 and 27 weeks:

    27–30 weeks (27 weeks and 30 weeks):

  At 27 weeks, ossification of the calcanei and tali is seen.

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Fetal and Perinatal Skeletal Dysplasias

32–35 weeks (32 weeks and 2 days and 35 weeks):

  The calcanei and tali are well ossified at these gestational ages. 38–40 weeks (38 weeks and 2 days and 39 weeks and 3 days):

 

Normal Fetal Skeletal Growth and Development 41–42 weeks (41 weeks and 41 weeks and 3 days):

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Part 2 Diagnosis of Fetal Skeletal Dysplasias

Imaging Strategies: Prenatal Skeletal dysplasias are a group of heterogeneous and complex, largely genetic disorders affecting bone growth and development and resulting in abnormalities of bone size, shape and density. Despite recent advances in imaging modalities and molecular genetics, accurate in utero diagnosis may be difficult. Some of the factors that make diagnosis difficult are: • The large number of conditions (there are more than 771 skeletal dysplasias and many more syndromes with significant skeletal involvement) • Phenotypic variability within an individual condition • Overlapping features between conditions • In utero evolution of changes • Lack of a systematic approach

Radiography In the past, prior to the use of ultrasound in medicine, skeletal abnormalities were only rarely recognised in utero, usually by serendipity. Occasionally skeletal dysplasias were diagnosed in the third trimester using prenatal radiographs, which were performed if there was an abnormal lie of the fetus or polyhydramnios. In utero radiographs of the fetus suspected of having a skeletal dysplasia were still used to confirm the ultrasound findings in the days of static B scanning and the early days of real-time scanning so as to optimise counselling and management.

Ultrasound Today, ultrasound evaluation of the fetus for detection of congenital anomalies has become standard practice. Advances in ultrasound technology with two-dimensional (2D) and threedimensional (3D) ultrasound, particularly in conjunction with transvaginal ultrasound, now allow an accurate examination of the fetus in the first trimester. The fetal skeleton is readily visualised using 2D and 3D ultrasound by 12 weeks of gestation, and measurements of the fetal femora and humeri are considered part of any basic mid-trimester evaluation. The National and International Society of Ultrasound has provided the medical ultrasound community with updated practice parameters and recommendations for the performance and recording of DOI: 10.1201/9781003166948-2

high-quality ultrasound examinations. The standard diagnostic obstetric ultrasound examination is considered the minimum criteria for a complete fetal examination. The detailed diagnostic examination is an extension of the standard sonographic fetal assessment. It is an indication-driven examination performed for a known or suspected fetal anatomic abnormality, genetic disorder or in families with increased risk of a fetal anatomic or genetic abnormality. The detailed obstetric ultrasound examination may be applied with specific, appropriate and standardised protocols in the first trimester (11 weeks 6 days and 13 weeks 6 days) and in the second and third trimester. 3D ultrasound is currently accepted as a complementary technique to conventional 2D ultrasound in the prenatal diagnosis of congenital anomalies. It has proven useful in the evaluation of facial dysmorphic features, postural and structural anomalies of the hands and feet and rib and vertebral anomalies and for evaluation of abnormal cranial sutures. In cases of suspected bone disease, an organised, systematic and sequential diagnostic approach is necessary.

Long Bones All the long bones should be examined and measured. If limb shortening is present, the number of bones and the shortened segment must be identified (rhizo-, meso-, acro-, acromeso- or micromelic shortening). The shape, degree of mineralisation, any fracture and angulation should also be recorded. The shape of the metaphyses may be difficult to demonstrate and is evaluated more accurately by 3D than 2D ultrasound. Abnormal epiphyseal calcification should also be looked for, but it may be difficult to identify when subtle. Joint deformity, contractures, subluxations and dislocations should be excluded.

Hands and Feet The hands and feet should be examined to exclude gross abnormalities such as acheiria, apodia and oligo/polydactyly. Both hands should be examined with longitudinal views while in an open configuration. Fixed postural deformities affecting the wrists or digits include: • Clenched hand: trisomy 18, fetal akinesia deformation sequence (FADS) • Camptodactyly: trisomies 18 and 13, FADS • Clinodactyly: trisomy 21 13

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Fetal and Perinatal Skeletal Dysplasias • Clubhand: aneuploidy, thromobcytoponia absent radius (TAR) syndrome, Fanconi anaemia, Aase syndrome, Holt-Oram syndrome and VACTERL association • Clubhand with radial angulation characterises the spectrum of ‘radial ray’ anomalies

Thumb anomalies include: • Hypoplasia: radial hypoplasia sequence • Triphalangeal thumb: trisomy 13, Fanconi anaemia, Holt-Oram syndrome, Poland sequence, VACTERL association and tibial hemimelia-polydactyly-triphalangeal thumb (Werner mesomelic dysplasia) • Broad thumb: acrocephalosyndactylies (Apert, Carpenter and Pfeiffer syndromes) • ‘Hitchhiker’ deformity: diastrophic dysplasia Foot length should be measured, and the femur/foot length ratio nomogram [the mean (±SD) value is (0.99 ± 0.06)] is a useful parameter to help differentiate dysplastic (disproportionate) limb reduction from constitutional factors or intrauterine growth retardation (IUGR): • Positional deformities include talipes equinovarus and rocker-bottom feet. Abnormalities of the number of digits: • Postaxial polydactyly is more frequent than preaxial polydactyly. This malformation may be an isolated finding with an autosomal dominant inheritance. However, postaxial polydactyly may also be associated with various syndromes (e.g., Ellis-van Creveld, short rib-polydactyly syndromes, Meckel-Gruber syndrome, Bardet-Biedl syndrome, Smith-LemliOpitz syndrome). • Preaxial polydactyly may be present in Holt-Oram and Carpenter syndromes. • Mesoaxial polydactyly: this is seen in chondroectodermal dysplasia. • Isolated syndactyly may be difficult to diagnose in utero, but when affecting more than two fingers, as in Apert syndrome, the hand has a specific appearance, described as ‘mitten-shaped’ because the fingers are not well individualised. • Ectrodactyly (split hand/foot deformity) is the result of a longitudinal deficiency of the central digits and may be associated with syndactyly, aplasia or hypoplasia of the medial and lateral phalanges and metacarpals/ metatarsals. A split hand deformity may be isolated or associated with syndromes such as ectrodactyly-ectodermal dysplasia-cleft lip or palate (EEC) syndrome.

circumference that is less than the fifth centile for gestational age has been proposed as a basic indicator of pulmonary hypoplasia. A small thorax secondary to rib shortening may be associated with lung hypoplasia, respiratory distress and neonatal death. The shape of the thorax, the number and integrity of the ribs and the presence and size of the scapulae should be established. The shape and length of the clavicles should be assessed.

Skull and Face Measurements of biparietal diameter (BPD) and head circumference (HC) should routinely be performed to identify cranial abnormalities such as macrocephaly (e.g., achondroplasia and thanatophoric dysplasia). Facial dysmorphism can be better depicted by 3D than by 2D ultrasound. Facial clefts, frontal bossing, micrognathia and abnormally shaped ears are identifiable. The binocular and interocular diameter should be measured in order to identify hypotelorism or hypertelorism. The shape, mineralisation and degree of ossification of the skull should be assessed. Abnormally high definition of the intracranial structures in association with cranial vault distortion on mild pressure of the probe on the maternal abdomen indicates bone demineralisation (osteogenesis imperfecta, achondrogenesis, hypophosphatasia). Abnormalities of shape (cloverleaf skull deformity, brachycephaly, scaphocephaly and turricephaly) and other syndromic craniosynostoses are better detected late in the second and third trimesters by 3D sonography.

Spine An algorithmic sequential approach may be applied when disproportion seems to affect the spine. The following questions should be addressed: • Is spine alignment normal? • Is the spine shorter because of missing parts (caudal dysgenesis: unilateral, partial or total sacral agenesis; spondylocostal dysplasia)? • Is it shorter because of abnormal curvature or fusions (formation/segmentation anomalies, hemivertebrae, ‘butterfly vertebrae’; Klippel-Feil syndrome)? • Is platyspondyly or vertebral collapse present (thanatophoric dysplasia, osteogenesis imperfecta type II/ III, spondyloepiphyseal dysplasia congenita)? • Are all parts of the spine equally ossified (deficient ossification of vertebral bodies; achondrogenesis types I and II or of neural arches; hypophosphatasia)? • Is the spinal canal of normal width (wide: spinal dysraphism; narrow: vertebral dislocation)? • Is there an abnormal position of the conus medullaris?

Thorax

Pelvis

The thoracic circumference and the cardiothoracic ratio are measured at the level of the four-chamber heart view. A chest

The shape of the pelvis and individual pelvic bones may be important in the diagnosis of certain dysplasias and

15

Diagnosis of Fetal Skeletal Dysplasias dysostoses. The presence of the three ossification points (iliac, pubic and ischial bones) should be confirmed. On sonography, the nucleus of the first sacral segment (S1) is visualised from 12 weeks of gestation, S2 from 14 weeks, S3 from 18 weeks, S4 from 21 weeks and S5 from 24 weeks. S1 can be located at the level of the iliac crest in the coronal plane. Sacral nuclei can be better visualised with the use of multiplanar imaging. Prenatal diagnosis of caudal dysgenesis should prompt screening for a large spectrum of associated malformations. Fetal caudal dysgenesis represents a set of urinary, anorectal and spinal cord malformations (Currarino syndrome, sirenomelia, OEIS complex, VACTERL association and closed spinal cord dysraphism with a low-lying tethered cord, sacral agenesis with spinal lipoma and sacral agenesis with a truncated conus medullaris). The conus medullaris (CM) position is important because abnormal position may be associated with tethered cord syndrome. The method for evaluating the position of the CM is by quantitative measurement of the CM–S1 distance, which is feasible and easy using 2D and/or 3D ultrasound. In fetuses with skeletal dysplasia and shortened trunk, the CM–S1 distance is shorter than in the normal population (low position of the CM), while in fetuses with skeletal dysplasia but a normal trunk size, it is normal.

Diagnostic Accuracy of Sonographic Evaluation in Skeletal Dysplasias

deviations below the mean and/or with a head circumference greater than the 75th centile should be evaluated in a centre with expertise in the recognition of skeletal dysplasias. An extensive retrospective analysis of 1500 cases of prenatalonset skeletal dysplasia (International Skeletal Dysplasia Registry) pointed out that in most cases (70%), the skeletal abnormality was recognised in the second trimester, and many of these prior to 20 weeks’ gestation (40%). For the remaining 30%, the skeletal dysplasia was recognised by ultrasound performed after the 24th week of pregnancy. This retrospective analysis showed a diagnostic accuracy of 41%. Accurate prenatal diagnosis informs the management of the index case and genetic counselling. Prenatal diagnosis is easier in the presence of a positive family history with a precise description of the phenotype. Data on prenatal diagnosis of skeletal dysplasias are shown in Table 2.1 – the false positives are mainly fetuses with dysmorphic syndromes or IUGR. The two most common lethal skeletal dysplasias (thanatophoric dysplasia and osteogenesis imperfecta type 2/3) are diagnosed correctly in 88% and 90% of cases, respectively. The prenatal diagnosis of these conditions is possible late in the first and early in the second trimester, whereas achondroplasia is not detectable on ultrasound before 20–23 weeks’ gestation.

Prognosis

Diagnosis The analysis of skeletal anomalies requires expertise and intimate knowledge of the normal developing fetus. The majority of skeletal dysplasias are first suspected during routine sonographic examination after short-long bones or other skeletal anomalies are observed. Fetuses with long bone measurements less than the fifth centile or more than three standard

The discrimination between lethal and non-lethal forms of skeletal dysplasias is of major clinical importance. Prenatal ultrasound correctly predicts the prognosis in 91–100% of cases. A femur length/abdominal circumference ratio below 0.16 indicates a lethal outcome. The presence of pulmonary hypoplasia secondary to a small thorax and/or concomitant visceral abnormalities suggests a poor outcome.

TABLE 2.1 Diagnostic Accuracy of Prenatal Ultrasound in Skeletal Dysplasias Author

Single/Multicentre

Cases (n)

Correct US Diagnosis (%)

False Positive (n)

False Negative (n)

Tretter et al.a (1998)

Single

 27

48

1

0

Gaffney et al. (1998)

Single

 35

31

3

ND

Hersch et al. (1998)

Single

 27

50

ND

ND

Doray et al. (2000)

Multi

 47

60

5

ND

Parilla et al. (2003)

Single

 31

65

2

0

Witters et al. (2008)

Single

 38

66

0

0

Schramm et al. (2009)

Single

162

68

12

2

Yeh et al. (2011)

Single

 40

70

ND

ND

Khalil et al.c,d (2011)

Single

 15

40

ND

ND

b

Included only lethal skeletal dysplasias. b In this series, 25% of cases are consanguineous. c By 14 weeks. d Four cases with positive family history of skeletal dysplasia. Abbreviations: ND: data not given; US: ultrasound. a

16

Fetal and Perinatal Skeletal Dysplasias

Pulmonary Hypoplasia Thoracic circumference is measured at the level of the fourchamber view of the heart. When disproportion mainly affects the thorax, the following questions should be addressed: • Is the thorax extremely small (thanatophoric dysplasia)? • Is the thorax long and narrow (Jeune syndrome)? • Are the ribs extremely short (short rib-polydactyly syndromes)? • Are there rib fractures (osteogenesis imperfecta type II)? • Are there gaps within the ribs (cerebro-costo-mandibular syndrome)? • Are there fused ribs (spondylocostal dysplasia)? • Is there clavicular aplasia, hypoplasia or pseudarthrosis (cleidocranial dysplasia)? • Are the scapulae abnormal (hypoplasia or absence in Campomelic dysplasia)? A small thorax is detected in many skeletal dysplasias such as thanatophoric dysplasia, achondrogenesis, osteogenesis imperfecta, short rib-polydactyly syndromes, hypophosphatasia, Campomelic dysplasia and chondroectodermal dysplasia and results in pulmonary hypoplasia, which is the main cause of neonatal death in the lethal skeletal dysplasias. Lethal conditions are almost always characterised by severe micromelia or pulmonary hypoplasia resulting from a small thorax. Many parameters have been proposed for the evaluation of lung hypoplasia and prediction of lethality (see Appendix 2). • Thoracic circumference below the fifth centile • Thoracic circumference/abdominal circumference below 0.6 (normal = 0.89) • Rib cage perimeter/thoracic circumference ratio (normal = 0.67 ± 0.004) Various techniques for measuring in utero fetal lung volumes have been described, including 2D sonography, virtual organ computer-aided analysis (VOCAL) and total fetal lung volume (TFLV) using MRI.

Nuchal Translucency The measurement of fetal nuchal translucency (NT) at 11–13+6 weeks of gestation (CRL 45–84 mm) has been established as a sensitive, accurate and effective method of screening for chromosomal abnormalities. Increased NT may also be associated with congenital heart defects, other structural defects and genetic syndromes. International Society of Ultrasound in Obstetrics and Gynaecology (ISUOG) and American Institute of Ultrasound in Medicine (AIUM) guidelines include first-trimester evaluation of fetal anatomy at the time of NT aneuploidy screening. An increased NT may be a non-specific sign when seen in isolation;

in association with limb anomalies, it can be indicative of an underlying skeletal dysplasia, dysostosis, metabolic bone disorder, congenital limb deficiencies or aneuploidy. An increased NT is seen in 85% of fetuses with a lethal skeletal dysplasia. Nuchal skin thickening may progress to generalised skin oedema and hydrops. Reported advantages of first-trimester fetal screening include early detection or exclusion of many major anomalies, early reassurance to at-risk mothers, early genetic diagnosis and an easier pregnancy termination if appropriate. However, limitations are linked to late expression of the phenotype or late development of some anatomical assessment structures and pathologies. Suggested anatomical assessment at the time of the 11–13+6week scan includes, among other structures, the spine (longitudinal and axial scan views to show normal vertebral alignment and integrity) and thorax and limb/extremities (hands and feet with normal orientation). The phalanges of the hands may be visible at 11 weeks, especially on transvaginal scanning. A routine 11–13+6-week scan, carried out according to a standardised protocol, can identify many severe skeletal abnormalities. However, to improve prenatal detection of abnormalities, routine additional scans in both the second and third trimester are necessary using standardised protocols (Table 2.2) and adequately trained sonographers with expertise in fetal medicine and clinical genetics. The first-trimester detection rate of skeletal abnormalities in the two papers in Table 2.2 was 29.8% and 33.8%, respectively. The overall detection rate of the first and the second trimester was 84.44 and 67.96%, respectively. These studies demonstrate that although first-trimester ultrasound screening cannot replace second-trimester ultrasound screening, it may advance the detection time of severe skeletal structural anomalies during early pregnancy using a standardised protocol. Sonographic phenotyping of fetal congenital malformations and anatomic variants in combination with next-generation sequencing (NGS) and other genomic technologies is transforming prenatal diagnosis of fetal genetic disorders. First, chromosomal microarray (CMA) and then NGS brought technology capable of more detailed genomic evaluation to prenatal genetic screening and diagnosis. Accurate identification of craniofacial dysmorphology and limb abnormalities may be the keystone of syndrome identification. For this reason, fetal dysmorphology is an important practical approach for non-invasive prenatal diagnosis (NIPT) based on analysis of cell-free fetal DNA (cffDNA) in maternal plasma. NIPT offers safe and accurate molecular and rapid confirmation of FGFR3-related skeletal dysplasias (achondroplasia and thanatophoric dysplasia). If fetal sonographic features are non-specific or the differential diagnosis is broad, then it may be more appropriate to choose a broader first-line investigation, such as rapid fetal exome sequencing from chorionic villi or amniocytes. For fetuses with severe skeletal dysplasias, rapid fetal exome sequencing may enable the assessment of many candidate genes in a single test, facilitating faster diagnosis.

17

Diagnosis of Fetal Skeletal Dysplasias TABLE 2.2 Diagnosis of Fetal Skeletal Dysplasias, Skeletal Abnormalities, Congenital Limb Deficiencies (CLDs) and Postural Deformities in Pregnancies Undergoing Routine Ultrasound Examination at 11–13 Weeks’ Gestation Author

Skeletal Dysplasias Congenital Limb Deficiencies (CLDs) Postural Deformities Skeletal Abnormalities

Total Cases (n)

First Trimester % (n)

Second Trimester % (n)

Third Trimester % (n)

Postnatal % (n)

Syngelaki et al. (2019)

Data from 100 997 singleton pregnancies carried out according to a standardised protocol at a routine 11–13-week scan.

225

29.8 (67)

58.7 (132)

4.4 (10)

7.1 (16)

Liao et al. (2021)

Data from 53 349 singleton pregnancies carried out according to a predefined protocol for standardised views at 11–13+6-week scan.

231

33.8 (78)

34.2 (79)

0.9 (2)

31.2 (72)

Ultrasound Checklist • Measure the number and length of all long bones (femora, humeri, radii, ulnae, tibiae, fibulae, and clavicles) • Compare with other segments and classify the limb shortening as: • Rhizomelic • Mesomelic • Acromelic • Acromesomelic • Micromelic • Qualitative assessment of long bones: • Shape (straight, curved, angulated, bilateral or unilateral) • Echogenicity (well mineralised, poorly mineralised) • Fractures • Appearance of the metaphyseal ends (flared, cupping, spikes, irregularities) • Evaluate hands and feet: • Digits: number and shape of digits (polydactyly, oligodactyly, ectrodactyly, syndactyly) • Foot size and shape • Femur/Foot length ratio • Positional deformities (abnormal posturing of the extremities) • Evaluate the cranium: • Size (macrocranium, microcranium) • Facial profile (frontal bossing, micrognathia) • Hypertelorism/hypotelorism • Mineralisation and shape of the cranium (brachycephaly, scaphocephaly) • Evaluation of cranial sutures and fontanelles (3D) (craniosynostosis) • Facial clefts

• Examination of the thorax: • Measure chest dimensions and lung biometry • Size and shape of scapulae • Size and shape of clavicles • Examination of the spine: • Curvature of the spine (scoliosis, kyphosis): • Poor mineralisation • Platyspondyly/collapse (fractures) • Segmentation defects and clefts • Evaluate structural anatomy of internal organs • Echocardiography • Assess fetal movements • Assess amniotic fluid volume • Doppler ultrasound (may be used to differentiate IUGR from skeletal dysplasia)

Computed Tomography Low-dose volumetric fetal CT is a relatively uncommon procedure, although it is becoming an increasingly accepted tool for the further evaluation of the fetus with a suspected skeletal dysplasia. Unlike ultrasound, CT scan images the entire fetal skeleton in a single view. 3D and 2D reconstructions provide information similar, and sometimes superior to, postnatal radiography. Fetal 3D CT can also identify fetal skeletal dysplasias more accurately (73–94%) than standard ultrasonography. Maximum intensity projection (MIP) and 3D volume rendering (3D VR) are the image-processing techniques most used in current 3D CT imaging. 3D VR is helpful in observing the overall structure of the skeleton. On the other hand, MIP is useful in the precise demonstration of each bone, with detail like postnatal radiographs. The use of both techniques is recommended since this approach results in exquisite imaging and therefore more reliable interpretation. Two-dimensional multiplanar reformatted imaging (MPR) may also be performed to avoid overlooking

18 subtle findings. Note that image smoothing associated with image processing may underestimate certain skeletal changes, such as deformity of vertebral bodies. 3D CT has been shown effective in the accurate prenatal diagnosis of many dysplasias, including platyspondylic dysplasia Torrance type, chondrodysplasia punctata, Kniest dysplasia and short rib-polydactyly syndrome 3, Verma-Naumoff type. It has also proven useful in the simultaneous assessment of twins discordant for fetal skeletal abnormalities. The main perceived drawback is the radiation exposure to the fetus. The consensus threshold level of radiation with negligible risk to the fetus is 50 mGy, with ‘actionable’ levels lying above 150 mGy. With the use of appropriate parameters, the fetal dose can be kept around 3.5 mGy – well below quoted risk thresholds. When CT is used for imaging the fetus, it is not usually performed before 30 weeks’ gestational age. The reasons for this include the perceived increased risk from radiation, relative undermineralisation of the skeleton and increased fetal movement, which can cause an imaging artefact. Advances in ultrasonographic imaging and genetics have increased the capability of prenatal diagnosis. The use of lowdose fetal CT affords detailed depiction of the fetal bones, and protocol modification has allowed marked decreases in radiation dose, leading to improvement in prenatal diagnosis over that achieved with ultrasound. Limitations of this imaging technique are linked to its relative late use in pregnancy and subsequent management issues related to the pregnancy.

Magnetic Resonance Imaging MRI is an important diagnostic tool for the further assessment of suspected fetal anomalies. It is used mainly for further imaging of the fetal brain, although it is also useful in evaluating the thoracic and abdominal viscera. There is consensus that fetal MRI is indicated following an expert ultrasound examination in which the diagnostic information about an abnormality is incomplete. Under these circumstances, MRI may provide important information that may confirm or complement the ultrasound findings and alter or modify patient management. Fetal MRI examination performed before 18 weeks does not usually provide additional information to that obtained with an ultrasound examination. Fetal MRI may be a useful diagnostic tool for skeletal dysplasias only in limited circumstances: temporal lobe migration abnormalities in thanatophoric dysplasia, hypochondroplasia, achondroplasia and Apert and Pfeiffer syndromes and follow-up of the spine and shape, length and position of bones, fingers and toes. However, the increased contrast resolution allows visualisation of the unossified cartilage, which is not visible on either ultrasound or CT. This has promise for future applications in assessing the fetus with a suspected skeletal dysplasia.

Fetal and Perinatal Skeletal Dysplasias

Imaging Strategies: Postnatal Surviving Infants The precise diagnosis of a prenatally detected skeletal dysplasia is usually made postnatally. Clinical examination of the infant will identify dysmorphic features, disproportion and deformity. Radiological imaging includes either: • AP and lateral image of the infant (babygram) plus one hand and foot, or: • Skeletal survey (symmetrical condition) • AP and lateral skull • Lateral thoracolumbar spine • AP chest and abdomen (to include the symphysis pubis) • AP one upper limb (left or right) • AP one lower limb (left or right) • DP one hand and foot • Skeletal survey (asymmetrical condition) • As for symmetrical conditions, but image both (left and right) upper and lower limbs Specific complications related to the final diagnosis may warrant further radiographic or cross-sectional imaging such as lateral cervical spine, brain MRI or 3D CT skull for suspected craniosynostosis. Tailored molecular studies may confirm the accuracy of suggested radiographic and/or clinical diagnoses.

Fetal and Perinatal Death Radiographic Skeletal Survey This can be technically difficult, especially in very small fetuses. Images should be obtained in true orthogonal planes (anteroposterior and lateral). High spatial and high contrast resolution radiographic techniques (mammographic or Faxitron equipment) will help delineate the skeleton, especially in very young fetuses. Dedicated views of the extremities may be required. Image manipulation allows detailed evaluation of internal bone architecture and measurement of often very small skeletal structures. Familiarity with the normal appearances and biometry of the developing fetal skeleton during gestation, especially in the second trimester, allows the accurate recognition of developmental anomalies.

Interpretation of the Skeletal Survey (See Chapter 1 on normal development of the fetal skeleton.) 1. Measure and compare the lengths of the long bones to known standards for gestational age and ethnicity where available (see Part 1) 2. Assess skeletal maturity compared to gestational age 3. Consider the normal degree of ossification for gestational age

19

Diagnosis of Fetal Skeletal Dysplasias 4. Assess the morphology of individual bones: confirm ultrasound findings and in addition bone density, fractures, structure, shape, and number. Note the following: • Skull – Calvarial mineralisation – Sutures (including Wormian bones and fontanelles) – Craniofacial proportion – Shape (brachycephaly, turricephaly, cloverleaf deformity) • Spine – Vertebral body shape (flat, ‘pear’, anisospondyly) – Vertebral body ossification (absent, segmentation defects) – Pedicles (absent, wide/narrow interpedicular distance) • Thorax – Shape (narrow, long, ‘bell’) – Ribs (short, broad, missing, ‘beaded’, ‘coat-hanger’) – Clavicles (hypoplastic, absent, hooked) – Scapulae (hypoplastic) • Pelvis – Iliac crests (‘lace-like’) – Iliac wings (square, flared, ‘horns’) – Acetabula (horizontal, trident, sloping) – Ischia (absent) – Pubic rami (absent, short) – Symphysis pubis (wide) • Long and short tubular bones – Epiphyses (cone-shaped, absent ossification, advanced ossification, stippled)

(1)

 

(2a)

– Metaphyses (flared, irregular, spurred, smooth) – Diaphyses (slender, wide, concertina, bowed, angulated, periosteal new bone) • Hands and feet – Shape (trident, ‘mitten’, ‘sock’) – Number (polydactyly, oligodactyly, ectrodactyly, syndactyly) – Joints – Alignment (dislocation, camptodactyly, talipes) – Fusion

Computed Tomography Volumetric CT with 2D and 3D reconstruction can provide complementary information to radiographs with respect to the ossified skeleton. In the postmortem setting, there are no doserelated considerations, and high doses can be used to optimise resolution. CT can overcome artefacts such as radiographic foreshortening and provide a good 3D overview of the entire skeleton and may therefore be superior to conventional radiographic examination. However, it does not provide the anatomical or architectural detail of individual bones that can be obtained with high-detail radiography. Because of the lack of intrinsic soft tissue contrast, postmortem CT provides rudimentary information about the brain and viscera.

Magnetic Resonance Imaging Postmortem MRI is a complementary tool to autopsy, particularly when consent has been declined. However, it is not yet in routine clinical use. High-contrast resolution allows evaluation of soft tissue structures and unossified cartilage, including the epiphyses, joints and vertebral bodies. It is also suitable for identifying a suspected intracranial abnormality because postmortem examination of the fetal brain is often limited by advanced early tissue autolysis.

 

(2b)

CASE 1: In utero fetal radiograph close to term. There is marked curvature of the spine and a narrow thorax of normal length, the prenatal appearance of asphyxiating thoracic dysplasia. CASE 2a: Prenatal radiograph at 30 weeks of a fetus with Caffey disease. There is irregular cortical thickening with an indistinct appearance (arrows point to tibia and fibula). CASE 2b: Neonatal radiograph of the lower limbs of the same case. Arrows identify hyperostosis of the long bones.

20

Fetal and Perinatal Skeletal Dysplasias

(3)

(4)

(5)

 

(6a)

 

(6b)

CASE 3: Physiological pregnancy at 7+5 weeks. 3D US: the embryo sections are, respectively, lateral, dorsal, and frontal. Embryo with appendicular structures: the upper limbs have caudally directed elbows and the lower limbs cranially directed knees. Embryonal annexes are clearly visible: yolk sac, its pedicle and umbilical cord. CASE 4: Pregnancy at 10+5 weeks. 3D US: the fetus shows pathological nuchal translucency (NT) (4.3 mm). Note the upper and lower limbs and their extremities: all normal with respect to position and morphology. CASE 5: Physiological pregnancy at 22 weeks. 3D US: normal fetal position, visualisation of the face and upper limb, hand, and fingers (partially flexed). CASE 6a: Physiological pregnancy at 22 weeks: 2D US (top): 3D US (bottom): normal position and morphology of fetal feet. CASE 6b: 2D US: visualisation of the soles, metatarsals, and toes from below.

21

Diagnosis of Fetal Skeletal Dysplasias

(7)

 

(9)

 

(8)

(10)

(11) CASE 7: Physiological pregnancy at 31 weeks. Surface rendered 3D US showing the normal position of the fetal hand in various projections. CASE 8: Pregnancy at 30 weeks: 3D US. Arthrogryposis multiplex congenita, showing talipes with the feet fixed in front of the fetal face. CASE 9: Pregnancy at 30 weeks: 2D US: arthrogryposis multiplex congenita. The leg is extended on the thigh, and there was lack of joint movement. CASE 10: Pregnancy at 30 weeks: 3D US: volume-contrast imaging and OmniView: arthrogryposis multiplex congenita. It is possible to obtain multiple section planes with different orientations tocontemporaneously evaluate the abnormal foot positions (bilateral equinovarus). CASE 11: Pregnancy at 30 weeks: 3D US, multiplanar mode: TUI system application (tomographic ultrasound imaging): arthrogryposis multiplex congenita. This technique shows automated visualisation of the scan planes on the same image. The reference plane may be axial, sagittal, or frontal. In this case, from a sagittal plane (top left), it is possible to obtain axial sections of the clubfoot as on a CT scan.

22

Fetal and Perinatal Skeletal Dysplasias

(12)

(13a)

(13b)

CASE 12: Pregnancy at 24+1 weeks. 3D US, multiplanar mode and rendering showing isolated clubfeet. CASE 13a: Pregnancy at 24+1 weeks: 3D US with surface rendering showing isolated clubfoot. CASE 13b: Section from the back shows the thigh, leg, and clubfoot.

23

Diagnosis of Fetal Skeletal Dysplasias

(14a)

 

(14b)

(15)

(16) CASE 14a: Pregnancy at 29+4 weeks: 3D US with volume-contrast imaging (VCI) and OmniView. Both techniques show the dorsum of the foot, which reaches the anterior part of the leg. CASE 14b: Pregnancy at 29+4 weeks: 2D US: vertical talus. CASE 15: Scan at 30 weeks. 3D and 2D US: echographic appearance of talus valgus and abducted foot. CASE 16: Fetal akinesia deformation sequence, or Pena-Shokeir syndrome. Pregnancy at 29 weeks: polyhydramnios. The hallux overlaps the second toe, and there is a rocker-bottom appearance. The neonatal radiograph confirms the echographic finding.

24

Fetal and Perinatal Skeletal Dysplasias

(17)

(18)

(19)

 

CASE 17: Normal clavicles at 16 weeks. CASE 18: Normal appearance of the pelvic bones, femur and hip joint at 20 weeks in the sagittal plane (4D US, VCI-C). CASE 19: Normal pelvic bones and caudal part of the spine in the coronal plane (20 weeks) and a view from the back (4D US, VCI-C).

25

Diagnosis of Fetal Skeletal Dysplasias

(20)

 

(21)

 

(23)

(25)

 

 

(26)

(22)

(24)

 

CASE 20: Normal spine and pelvis on a sagittal section at 20 weeks (3D US, VCI-C). CASE 21: Normal vertebral column and pelvis in the coronal plane at 21 weeks (4D US, VCI-C). CASE 22: Vertebral column and intervertebral discs at 21 weeks (4D US, VCI-C). On this section it is possible to measure the heights of the vertebral bodies and discs. CASE 23: Visualisation of the thorax at 21 weeks (4D US) showing the morphology and number of ribs. CASE 24: A 25-week fetus shows the scapula on 3D US, VCI and OmniView. CASE 25: Incarcerated hemivertebra (arrow). Longitudinal scan of the fetal spine at 18 weeks: no signs of scoliosis in utero. CASE 26: Hemivertebra (arrow) at 25 weeks on a longitudinal section of the vertebral column. Incarcerated hemivertebrae are triangular or ovoid in shape. The term incarcerated (or invaginated) refers to the configuration of the adjoining endplates, which accommodate the shape of the hemivertebra.

26

Fetal and Perinatal Skeletal Dysplasias

(27)

 

(28)

 

(29)

(30)

 

(31)

 

CASE 27: Hemivertebra at 25 weeks. 3D US shows the hemivertebra and surrounding vertebrae as a closed structure (arrows). The incarcerated hemivertebra is accommodated in a niche in the neighbouring vertebrae. CASE 28: Fetal kyphoscoliosis at 21 weeks. Anomalies of formation and segmentation represent the main cause of fetal spinal deformities. CASE 29: Mild femoral angulation (unilateral) in a case of isolated focal femoral hypoplasia (3D US) at 18 weeks. CASE 30: Wide femoral curvature at 28 weeks. Deformability, fractures and bone angulations suggest a diagnosis of osteogenesis imperfecta. CASE 31: Oligodactyly of the foot (arrows) at 14 weeks.

27

Diagnosis of Fetal Skeletal Dysplasias

(32)

(33)

(35a)

 

(34)

 

CASE 32: Unilateral split hand malformation with syndactyly detected at 22 weeks (3D US) compared with the contralateral normal hand. CASE 33: Besides syndactyly, note fusion between fourth and fifth metacarpals: 3D image with VCI-C. CASE 34: Postnatal radiographs confirm syndactyly and 4–5 metacarpal fusion. CASE 35a: A 16-week fetus affected by multiple anomalies. There is longitudinal hemimelia of the upper limbs and one single finger (straight arrow). The right lower limb shows longitudinal hemimelia involving the tibial ray; there is a rudimentary fibula, the foot is upwardly rotated (curved arrow). On the right, the pathological findings are confirmed.

28

Fetal and Perinatal Skeletal Dysplasias

(35b)

 

(35c)

(35d)

(36)

 

 

CASE 35b: Longitudinal hemimelia of upper limb with monodactyly. CASE 35c: Oligodactyly of left foot (absent second toe). CASE 35d: Comparison of echographic appearance, gross anatomy, and 3D CT. CASE 36: A 12-week fetus affected by atypical phocomelia; rudimentary humerus and forearm and oligodactyly (3D US).

29

Diagnosis of Fetal Skeletal Dysplasias

(37)

(38a)

 

(38b) CASE 37: Atypical phocomelia of upper limbs with bilateral oligodactyly. CASE 38a: Pregnancy at 21 weeks showing curved tibia (unilateral), clubfoot and preaxial polydactyly (bifid first toe) (3D US). CASE 38b: Preaxial polydactyly and clubfoot detected at 21weeks (3D US) and radiographic correlation after birth.

30

Fetal and Perinatal Skeletal Dysplasias

(38c)

(39) CASE 38c: Curved tibia (with preaxial polydactyly) diagnosed at 21 weeks (3D US) and correlation with radiographs after birth. CASE 39: A 24-week fetus with short limbs and craniosynostosis. Bidimensional image on the left shows a cranial silhouette typical for premature coronal suture fusion. On the right, the metopic suture is abnormal with a marked U-shaped widening.

BIBLIOGRAPHY Cassart M. Suspected fetal skeletal malformations or bone diseases: How to explore. Pediatr Radiol. 2010; 40: 1046–51. Dückelmann AM, Kalache DK. Three-dimensional ultrasound in evaluating the fetus. Prenat Diagn. 2010; 30: 631–8. Khalil A, Pajkrt E, Chitty L. Early prenatal diagnosis of skeletal anomalies. Prenat Diagn. 2011; 31: 115–24. Offiah AC, Hall CM. Radiological diagnosis of the constitutional disorders of bone: As easy as A, B, C? Pediatr Radiol. 2003; 33: 153–61.

Thayyil S, De Vita E, Sebire NJ et al. Postmortem cerebral magnetic resonance imaging T1 and T2 in fetuses, newborns and infants. Eur J Radiol. 2011. doi: 10.1016/j.ejrad. 2011.01.105 Ulla M, Aiello H, Paz Cobos M et al. Prenatal diagnosis of skeletal dysplasias: Contribution of three-dimensional computed tomography. Fetal Diagn Ther. 2011; 29: 238–47. Vergani P, Andreani M, Greco M et al. Two- or three-dimensional ultrasonography: Which is the best predictor of pulmonary hypoplasia? Prenat Diagn. 2010; 30: 834–8.

Diagnosis of Fetal Skeletal Dysplasias Wada R, Sawai H, Nishumura G, et al. Prenatal diagnosis of Kneist dysplasia with three- dimensional helical computed tomography. J Matern Fetal Neonatal Med. 2011 doi: 10.3109/14767058.2010.545903 Yamada T, Nishumura G, Nishida K et al. Prenatal diagnosis of short-rib polydactyly syndrome type 3 (Verma-Naumoff

MOLECULAR DIAGNOSIS OF FETAL SKELETAL DYSPLASIAS Genetic and Genomic Tests The 11th revision of genetic skeletal disorders recognises 771 entities associated with 552 genes, reflecting improvement in molecular delineation of new disorders thanks to advances in DNA sequencing technology. Genetic or genomic tests are therefore very often offered for diagnostic purposes. A genetic test is a test that targets one or more genes in order to find a change in the gene which can be associated with a health problem. A genomic test is a test that targets a segment or the entirety of the genome, which includes but is not limited to the genes to find a change which can be associated with a health problem. These two terms are often used interchangeably. Several molecular diagnostic techniques can be used for the diagnosis of fetal skeletal dysplasias. The choice of molecular diagnostic technique will depend on the specific clinical scenario and the suspected diagnosis. These include: 1. Next-generation sequencing (NGS) technologies: This is a high-throughput sequencing technology that can rapidly sequence large amounts of DNA. NGS can be used to analyse a panel of genes associated with skeletal dysplasias or for whole-exome (WES) or whole-genome sequencing (WGS) to identify pathogenic variants. 2. Sanger sequencing: This is a traditional sequencing technique that can be used to sequence individual genes. Sanger sequencing can be used as a standalone or first-line test or as second-line test to confirm variants identified by NGS or to sequence specific genes that are not included in NGS panels. 3. Copy number variant (CNV) analysis: this analysis can detect the dosage of chromosomes or chromosome segments, even very small. Extra copies are called duplications; reduced numbers of copies are called deletions. CNV analysis can be performed using microarrays: array comparative genomic hybridisation (aCGH) or SNP array.

31 type) by three-dimensional helical computed tomography. J Obstet Gynaecol Res. 2011; 37: 151–5. Yazici Z, Kline-Fath BM, Laor T et al. Fetal MR imaging of Kneist dysplasia. Pediatr Radiol. 2010; 40: 348–52.

All the changes, or mutations, of the DNA are currently defined collectively as ‘variants’. Variants can be classified as pathogenic, likely pathogenic, uncertain significance, likely benign or benign. Pathogenic and likely pathogenic variants are associated with the development of the disease and are considered diagnostic. Variants of uncertain significance refers to a genetic change that the laboratory cannot interpret. Sometimes it might require further investigation to determine their clinical significance – for instance, segregation in the family or functional studies. Likely benign and benign variants are not associated with disease development and can be considered variants within the normal range. Interpretation of variants is a critical step in the molecular diagnosis of fetal skeletal dysplasias. The interpretation of variants requires expertise in molecular genetics, bioinformatics, and clinical genetics. Genetic counselling should be offered to affected families to discuss the implications of the variant and the risk of recurrence in future pregnancies. Once a mutation has been identified, it is possible to offer a specific and timely prenatal diagnosis in further pregnancies of the parents. In these instances, the diagnosis can be confirmed by CVS as early as 11 gestational weeks – well before the fetal phenotype can be detected by sonography. For the same reason, it is important to encourage adults affected by a skeletal dysplasia and who want to have children of their own to undergo molecular testing themselves before they embark on a pregnancy. Prenatal molecular diagnosis is also offered in cases of sporadic dominant disorders because gonadal mosaicism and even parental constitutional mosaicism have been reported in a few disorders. For example, achondroplasia and thanatophoric dysplasia, caused by mutations in the FGFR3 gene, have a recurrence risk of up to 5% because of gonadal mosaicism (often of paternal origin). When the skeletal anomalies are secondary to a metabolic syndrome and no molecular test is available, biochemical markers on chorionic villi or amniocytes may be analysed and used to make a diagnosis.

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Prenatal Ultrasound assessment of the fetus may detect many abnormalities and patterns that are associated with skeletal dysplasias or are even typical of a specific disorder, thus allowing an accurate prenatal diagnosis. However, in many instances, either the features are subtle and common to many different disorders, or the clinical picture is incomplete at that gestational age or at any time prenatally. Fetal skeletal dysplasias can present with a wide range of clinical manifestations, including short limbs, abnormal skull shape and spinal abnormalities. In some cases, fetal skeletal dysplasias can be lethal, while in other cases, they may result in significant morbidity and disability. Accurate diagnosis of fetal skeletal dysplasias is critical for appropriate prenatal counselling and management. To maximise the possibility of making a specific diagnosis, it is important to combine all investigations and tools, including clinical genetic assessment and the offer of specific genetic testing, when available. Molecular diagnostic techniques have greatly improved our ability to diagnose these conditions. These include microarrays, single gene tests or NGS-based tests – prenatal exome or whole-genome sequencing can be proposed in some situations, although it may not be widely available or covered by national healthcare systems or insurance. The genetic test may be performed on a fetal DNA sample obtained through chorionic villus (CVS) sampling or amniocentesis. Non-invasive prenatal diagnosis (NIPD) refers to a set of techniques used to detect genetic abnormalities in a developing fetus without invasive procedures such as amniocentesis or CVS. Instead, NIPD relies on analysing fetal DNA that is present in the mother’s blood (cell-free fetal DNA [cffDNA] or ffDNA). This technique is most effective for disorders caused by a single gene mutation, such as achondroplasia, where the mother is not affected – for instance, to exclude a recurrence of a paternal condition or of a de novo mutation in a previous child via gonadal mosaicism. However, it is important to note that NIPD for skeletal dysplasia is still a developing technology and has limitations. False negatives and false positives can occur, and confirmatory testing with invasive procedures may still be necessary in some cases. In addition, NIPD for skeletal dysplasia is currently only available at a limited number of specialised centres. In practice, although the vast majority of skeletal dysplasias are genetic and inherited according to specific modes, in many instances, they occur in families with no significant history of skeletal disorders, either because the patient is a carrier of a

Fetal and Perinatal Skeletal Dysplasias new dominant mutation or they represent the first within the family having inherited the condition. In the absence of any specific ultrasound feature, the usefulness of molecular analysis may be discussed for prognostic and pregnancy management purposes. However, it is important for parents to discuss the benefits and limitations of prenatal exome sequencing with their healthcare provider and genetic counsellor and to make an informed decision based on their individual circumstances and preferences. Following termination of pregnancy or stillbirth, it is extremely important to undertake a thorough examination of the fetus, including a full postmortem examination, fetal imaging (as mentioned earlier) and tissue or DNA storage for subsequent or future genetic testing. Ideally a multidisciplinary team, including the clinical geneticist, radiologist, pathologist, obstetrician and neonatologist, should examine the fetus. In a subset of cases, the fetal phenotype might partially overlap with that present in some chromosomal abnormalities, and hence standard fetal karyotyping may be indicated.

Postnatal Even when abnormal fetal features are detected on prenatal ultrasound, a precise diagnosis is not often made until postnatal evaluation and follow-up. The diagnostic path of a neonate affected by a skeletal disorder should start with a detailed pregnancy and family history – this may often allow the diagnosis, or at least the inheritance pattern, to be established. A physical examination should include the assessment of all body segments and (if possible) the measurements of each. Upper segment to lower segment ratio and arm span to height ratio are particularly useful for identifying disproportion between trunk and limbs. Imaging studies have a fundamental role and have been described earlier. By this stage, a clinical diagnosis or a set of differential diagnoses will have been reached, and appropriate laboratory testing may confirm or exclude a diagnosis. Usually this will be targeted panel or NGS analysis, but occasionally might include biochemical testing (e.g., measurement of plasma very long-chain fatty acid [VLCFA] levels in Zellweger syndrome, calcium, phosphate and hormones and vitamins associated with their homeostasis in neonatal hyperparathyroidism). The confirmation of a clinical diagnosis by genetic testing is important not only for family planning counselling but also to accurately define the diagnosis, understand the natural history of the disorder and determine the most appropriate follow-up plan, especially in cases where the phenotype overlaps with other disorders, is subtle or evolves with time.

Diagnosis of Fetal Skeletal Dysplasias

BIBLIOGRAPHY Cho SY, Song MJ, Jin DK et al. Molecular diagnosis of fetal skeletal dysplasia using targeted exome sequencing: A singlecenter experience. J Matern Fetal Neonatal Med. 2021; 34: 2124–31. Forzano F, Lituania M, Viassolo V et al. A familial case of achondrogenesis type II caused by a dominant COL2A1 mutation and ‘patchy’ expression in the mosaic father. Am J Med Genet A. 2007; 143A: 2815–20. Krakow D, Lachman RS, Rimoin DL. Guidelines for the prenatal diagnosis of fetal skeletal dysplasias. Genet Med. 2009; 11: 127–33.

33 Natacci F, Baffico M, Cavallari U et al. Germline mosaicism in achondroplasia detected in sperm DNA of the father of three affected sibs. Am J Med Genet A. 2008; 146A: 784–6. Unger S. A genetic approach to the diagnosis of skeletal dysplasia. Clin Orthop Relat Res. 2002; 401: 32–8. Unger S, Ferreira CR, Mortier GR et al. Nosology of genetic skeletal disorders: 2023 revision. Am J Med Genet A. 2023; 191: 1164–1209. Yang X, Jin S, Wei X et al. Molecular diagnosis of fetal skeletal dysplasia by targeted next-generation sequencing in a Chinese cohort. Prenat Diagn. 2020; 40: 958–67.

Part 3 Individual Conditions Grouped According to the International Nosology and Classification of Genetic Skeletal Disorders* Christine M Hall Consultant Paediatric Radiologist (retired), Emeritus Professor of Paediatric Radiology Amaka C Offiah HEFCE Clinical Senior Lecturer, Honorary Consultant Radiologist Francesca Forzano Consultant Clinical Geneticist Mario Lituania Director, Fetal and Perinatal Medicine Unit Michelle Fink Paediatric Radiologist Deborah Krakow Obstetrician-Gynecologist, Maternal- Fetal Medicine Specialist, Medical Geneticist Great Ormond Street Hospital for Children Institute of Child Health, University of London University of Sheffield/Sheffield Children’s Hospital Galliera Hospital, Genoa Royal Children’s Hospital and the Royal Women’s, Hospital Fetal Medicine Unit, Melbourne University of California at Los Angeles

*

Unger S, Ferreira CR, Mortier GR et al. Nosology of genetic skel etal disorders: 2023 revision. Am J Med Genet A. 2023; 191: 1164–1209.

DOI: 10.1201/9781003166948-3

35

1 Thanatophoric Dysplasia, Types 1 and 2, FGFR3-Related

Synonyms: TD Confirmation of diagnosis: identification of pathogenic variants in fibroblast growth factor receptor-3 (FGFR3) with appropriate clinical and radiographic findings. Frequency: between 1/20,000 and 1/50,000 for both types of thanatophoric dysplasia (TD). TD type 1 is more frequent than TD type 2. Genetics: TD is caused by heterozygous pathogenic variants in the gene FGFR3, which result in a gain in function of the tyrosine kinase activity of the receptor. It is an autosomal dominant condition, usually de novo, with complete penetrance. The recurrence risk for couples who have had a previously affected fetus is higher than in the general population due to possible gonadal mosaicism and is about 2%. Age/Gestational age of manifestation: usually detectable by ultrasound during the second trimester (12–18 weeks). Clinical features: • Micromelia with redundant skin folds • Narrow thorax, short ribs, relatively normal trunk length • Macrocephaly, distinctive facial features (prominent forehead, depressed nasal bridge, protruding eyes) • Type 1: bowed femora, occasionally cloverleaf skull deformity (kleeblattschädel) • Type 2: straight femora, moderate to severe cloverleaf skull deformity • Brachydactyly, trident hand • Hypotonia • Brain anomalies: hydrocephalus, temporal lobe neuronal migration abnormalities, brain stem hypoplasia, encephalocoele Prenatal ultrasound features: TD may present with increased nuchal translucency thickness in the first trimester (at 11–13 weeks). In the late first and early second trimester, diagnosis may be suspected on the basis of severe micromelia. The femora are usually bowed in type 1, with a ‘telephone receiver’ – like shape, and straight in type 2. The fibulae appear shorter than the tibiae. The thorax is of almost normal length, but narrow, with short ribs showing flared anterior extremities, and there is platyspondyly. Early in the second trimester there is 36

relative macrocrania, with frontal and sometimes parietal bossing. A flat or depressed nasal bridge can be identified on median sagittal section, and bulging eyes may already be present. In TD type 2, a cloverleaf-shaped skull may be visualised with a tri-lobed appearance in coronal views (kleeblattschädel). Common findings in both TD types are small hands, brachydactyly, ‘trident hand’, small dysmorphic scapulae and abducted limbs. In the second trimester the skin, which grows normally despite progressive relative shortening of the long bones, is redundant and forms creases and rings around the limbs. In the late second and in the third trimester, polyhydramnios may appear due to a combination of oesophageal compression (small thorax) and impaired swallowing (disproportion of maxilla and tongue). Occasional associated anomalies: ventriculomegaly, hydrocephalus, heart defects, renal anomalies and radioulnar synostosis. Developmental brain anomalies occur early and can be seen from 18 weeks. These include temporal lobe hyperplasia, increased folding of the cortex on the medial temporal surface and hippocampal dysplasia. Radiographic features: TD type 1 shows relative macrocephaly with severe micromelia, trident acetabula, short ribs and platyspondyly. The vertebral bodies are described as ‘wafer-thin’ on the lateral projection and have an ‘H’ configuration on the anteroposterior projection. The intervertebral spaces are wide, resulting in the appearance of a long trunk. The pelvis has trident acetabula with medial and lateral spurs, squared ilia and short sacrosciatic notches. The ribs are uniformly short, resulting in a ‘barrel-shaped’ thorax, and their anterior ends are flared. The femora are bowed, giving the socalled appearance of ‘telephone receivers’ and have a proximal oval radiolucency. There is variable bowing of the other long bones. TD type 2 has a ‘cloverleaf’ skull deformity as a result of premature intrauterine closure of sagittal, coronal and lambdoid sutures causing pronounced frontal and biparietal prominences. Other changes are similar to TD type 1 but milder. There is mild platyspondyly and shortening of the ribs, but with more normal flaring of the base of the thorax (‘bellshaped’ rather than ‘barrel-shaped’). The long bones are usually straight and micromelia is less severe. The acetabula are trident in shape. Prognosis: TD is usually lethal in the perinatal period. Even with intensive medical care, affected infants rarely survive for more than a few months. They are usually ventilator-dependent and show severe intellectual disability, seizures, bilateral hearing loss, kyphosis, joint hypermobility and contractures. DOI: 10.1201/9781003166948-4

Thanatophoric Dysplasia, Types 1 and 2, FGFR3-Related

37

Differential diagnosis: allelic conditions (different variants in the gene FGFR3): achondroplasia (p. 46); homozygous achondroplasia (p. 46). Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) is an extremely rare condition caused by a specific dominant mutation (p.Lys650Met). Unlike TD, it may be viable.

Short, bowed long bones: osteogenesis imperfecta types 2 and 3 (p. 429); Campomelic dysplasia (p. 302); hypophosphatasia (p. 452); Stüve-Wiedemann dysplasia (p. 311).

Narrow thorax: platyspondylic dysplasia, Torrance type (p. 67); short rib–polydactyly syndromes (p. 182–222); asphyxiating thoracic dystrophy (Jeune) (p. 196); chondroectodermal dysplasia (p. 203).

Trident acetabula: short rib-polydactyly syndromes (p. 182– 222); asphyxiating thoracic dystrophy (Jeune) (p. 196); chondroectodermal dysplasia (p. 203); odontochondrodysplasia (p. 235).

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Cloverleaf skull deformity: some cases of Pfeiffer syndrome (p. 491); osteocraniostenosis (p. 328).

 

 

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CASE 1: Prenatal diagnosis of TD1 at 16 weeks of gestation. (a, b) Lower limbs viewed with two-dimensional and four-dimensional ultrasound. There is marked shortening and bowing of the long bones with the classical ‘telephone receiver’ appearance of the femur and anterior bowing of the tibia. (c) Three-dimensional surface rendering, advanced volume contrast imaging (VCI) and OmniView show brachydactyly and a trident hand. (d, e) There is a narrow fetal thorax. The vertebral bodies appear rounded and flattened with wide intervertebral disc spaces. On the two-dimensional ultrasound, there is a relatively long trunk compared to the three-dimensional CT.

38

Fetal and Perinatal Skeletal Dysplasias

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CASE 1: (f, g) Three-dimensional fetal ultrasound of the pelvis and anteroposterior pelvic radiograph of the aborted fetus. The pelvic configuration is short and broad; spikes on either side of the short sacrosciatic notch (arrows) produce the ‘trident acetabulum’. (h, i) Postmortem three-dimensional anteroposterior and lateral CT.

Thanatophoric Dysplasia, Types 1 and 2, FGFR3-Related

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CASE 2: Fetus with TD1 at 16 + 5 weeks’ gestation. (a) Three-dimensional CT shows macrocephaly, small narrow thorax, micromelia and bowed femora. (b) Longitudinal ultrasound scan of the fetal spine shows intervertebral spaces that are wider than the height of the vertebral bodies (parallel lines). (c, d) Volume-rendered ultrasound image of the thorax, ribs and vertebral bodies show platyspondyly, small thorax and irregular vertebral endplates. (e) Lateral sonogram of the thorax shows short ribs with wide anterior ends. CASE 3: Fetus with TD1. (a–d) In utero fetal three-dimensional ultrasound at 18 + 6 weeks’ gestation in maximum mode high definition (HD) live shows macrocephaly, prominent forehead and depressed nasal bridge.

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Fetal and Perinatal Skeletal Dysplasias

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CASE 3: (e, f) Two-dimensional ultrasound scan of the fetal head shows occipitotemporal hyperplasia with aberrant sulci. (g–i) Two-dimensional ultrasound and three-dimensional ultrasound maximum mode show platyspondyly, short ribs with narrow thorax and a small dysmorphic scapula. (j–l) Three-dimensional ultrasound with VCI, maximum mode and HD live show macrocephaly, micromelia (arrows in j) and short ribs (arrows in k). (m–o) Correlation between radiographic and CT features of TD1.

Thanatophoric Dysplasia, Types 1 and 2, FGFR3-Related

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CASE 4: A 20-week fetus with TD1. (a) Prenatal three-dimensional HD live of the fetal head shows prominent forehead and depressed nasal bridge. (b, c) Three-dimensional CT correlation with and without soft tissue overlay (postmortem). (d, e) Anteroposterior and lateral postmortem radiographs and (f) three-dimensional CT show the typical skeletal features.

42

Fetal and Perinatal Skeletal Dysplasias

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CASE 5: In utero images at 21 weeks’ gestation. (a, b) Ultrasound images show abnormal sulcation of the posterior and medial lobes. (c–h) MRI shows extensive malformation of the cerebral mantle and abnormal deep horizontal sulci in the medial temporal and occipital lobes. CASE 6: Postmortem images at 22 weeks’ gestation; (a, b) postmortem maximum intensity projection (MIP) CT images; (c, d) three-dimensional CT images; (e) surfacerendered CT image; (f, g) anteroposterior and lateral babygrams.

Thanatophoric Dysplasia, Types 1 and 2, FGFR3-Related

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CASES 7, 8: Anteroposterior and lateral babygrams show the cloverleaf skull and straight femora that are typical of TD2. Other features are as seen in TD1. CASE 9: TD2 at 20 weeks of gestation; (a–c) coronal view of the head shows a cloverleaf skull deformity with hydrocephalus; three-dimensional ultrasound shows cloverleaf skull deformity with frontal bossing; (d) micromelia with straight femora; (e, f) prenatal three-dimensional helical CT; (g) postmortem anteroposterior babygram.

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CASE 10: The ‘common’ thanatophoric dysplasia type 2 mutation, p.Lys650Glu, was identified.

 

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Thanatophoric Dysplasia, Types 1 and 2, FGFR3-Related

BIBLIOGRAPHY Chen CP, Chang TY, Lin TW et al. Prenatal diagnosis of hydranencephaly and enlarged cerebellum and cisterna magna in a fetus with thanatophoric dysplasia type II and a review of prenatal diagnosis of brain anomalies associated with thanatophoric dysplasia. Tai J Obstet Gynecol. 2018; 57: 119–22. Chen SW, Chen CP, Wang LK et al. Perinatal imaging findings and molecular genetic analysis of thanatophoric dysplasia type 1 in a fetus with a c.2419T>G (p.Ter807Gly) (X807G) mutation in FGFR3. Tai J Obstet Gynecol. 2017; 56: 87–92. Chitty LS, Khalil A, Barrett AN et al. Safe, accurate, prenatal diagnosis of thanatophoric dysplasia using ultrasound and free fetal DNA. Prenat Diagn. 2013; 33: 416–23.

45 Chitty LS, Mason S, Barrett AN et al. Non-invasive prenatal diagnosis of achondroplasia and thanatophoric dysplasia: Next-generation sequencing allows for a safer, more accurate, and comprehensive approach. Prenat Diagn. 2015; 35: 656–62. Sahin S, Ograg H, Aslan E et al. A thanatophoric dysplasia type 1 case with a FGFR3 p.R248c mutation and survival beyond the neonatal period. Genet Couns. 2016; 27: 513–7. Wang DC, Shannon P, Toi A et al. Temporal lobe dysplasia: A characteristic sonographic finding in thanatophoric dysplasia. Ultrasound Obstet Gynecol. 2014; 44: 588–94.

2 Achondroplasia, FGFR3-Related

Includes homozygous achondroplasia and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN). Synonyms: ACH. Confirmation of diagnosis: identification of the pathogenic variant in FGFR3 with appropriate clinical and radiographic findings. Frequency: 1/15,000–1/40,000; it is the most frequent viable form of short-limb dysplasia. Genetics: caused by a recurrent (G380R or G1138A) heterozygous pathogenic variant in the gene FGFR3 (fibroblast growth factor receptor-3) that results in a gain in function of the tyrosine kinase activity of the receptor. Rarely, ACH may be caused by other FGFR3 heterozygous pathogenic variants. It is an autosomal dominant condition, usually de novo, with complete penetrance. The recurrence risk for couples who have had a previously affected fetus is higher than in the general population due to possible gonadal mosaicism and is estimated to be 5%. Homozygous ACH can occur when both parents are affected with achondroplasia: this is an extremely rare condition. Age/Gestational week of manifestation: usually detectable by ultrasound during the second or third trimester (23–30 weeks). The homozygous form can be detected during the second trimester (14–23 weeks).

in lethal skeletal dysplasias (50%). Limb length is preserved until around 22 weeks’ gestation, after the time of the routine fetal anomaly scan. The reduced growth profile is apparent by 24–26 weeks, when the limb lengths become less than the 2.5th centile. Prenatal diagnosis usually occurs only in the third trimester. Two-dimensional ultrasound shows rhizomelic shortening, mildly bowed femur, relatively large skull vault, frontal bossing and depressed nasal bridge, resulting in a saddle nose deformity. The hands are broad with short digits (brachydactyly) with the ‘trident hand’ sign (an increased interspace between the third and the fourth digits). Three-dimensional ultrasound may confirm the diagnosis and improve the visualisation of abnormalities. Three-dimensional ultrasound may demonstrate caudal narrowing of the lumbar interpedicular distances, rather than the normal widening of the lumbar canal. Prenatal three-dimensional ultrasound and three-dimensional helical computed tomography both identify fetal bone abnormalities. Specific signs of achondroplasia may be seen at the proximal femoral metaphysis with the ultrasound transducer positioned at a 45° angle to the diaphyseal axis. There is relative overgrowth of the periosteum, creating ‘the collar hoop’ sign. The collar hoop sign appears at the upper end of the diaphysis as a small, highly echogenic hook, usually seen after 29 weeks’ gestation. The proximal metaphyseal-epiphyseal interface is much more rounded and has a wide angle at its connection with the diaphysis; the mean measurement of this angle is 98.5° (standard deviation [SD] 6.8°) at 22 weeks’ gestation and 105.6° (SD 7.3°) at 32 weeks’ gestation. A detailed ultrasound examination of the proximal femur is indicated whenever the femoral length is below the fifth centile. Rarely a fetus may present with a combined achondroplasia and multiple craniosynostosis phenotype.

Clinical features: • Rhizomelic limb shortening (extremely severe to micromelia in case of homozygous ACH) • Redundant skin folds along the limbs • Macrocephaly, distinctive facial features (prominent forehead, midface hypoplasia, depressed nasal bridge), occasionally hydrocephalus • Brachydactyly, trident hand • Hypotonia • Occasional respiratory distress due to a small thorax Prenatal ultrasound features: there may be increased nuchal translucency in the first trimester, but this is more common

46

In homozygous achondroplasia, femoral lengths below the third centile compared with the biparietal diameter (BPD) at 17 weeks’ BPD age and which also show progressive shortening at 20 and 23 weeks’ BPD age establish the diagnosis. Short femora compared to BPD will not be demonstrated until after 17 weeks in heterozygous achondroplasia. At the 26week BPD age scan, the femoral length will not exceed 34 mm. Other findings overlap with those seen in heterozygous achondroplasia (p. 46) and thanatophoric dysplasia (p. 36). There is relative macrocephaly, mid-face hypoplasia, frontal bossing, platyspondyly and brachydactyly with trident configuration hands. Early in the third trimester there is significant lung hypoplasia suggesting a lethal condition. Polyhydramnios may develop in the third trimester.

DOI: 10.1201/9781003166948-5

Achondroplasia, FGFR3-Related

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SADDAN is an extremely rare condition, which may be viable, and is caused by a specific dominant pathogenic variant (p.Lys650Met). Radiographic features: the skull vault is disproportionately large with prominence of the frontal bone. The long bones are short. There is delayed ossification of the epiphyses at the knees. The proximal femora show an oval transradiancy due to sloping metaphyses and a reduced thickness of bone. This metaphyseal sloping is often apparent also at the knees. The thorax is narrow with some rib shortening. In the spine there is mild platyspondyly, and the intervertebral spaces are wide. The vertebral bodies do not yet have the characteristic ‘bullet’ shape of later childhood (posterior scalloping and rounded anterior borders). In the neonate a narrow interpedicular distance may not be apparent, becoming more obvious during early childhood. Thoracolumbar kyphosis may develop during infancy. The iliac bones are squared and the acetabula horizontal with medial and lateral spurs (trident acetabula), and the sacrosciatic notches are narrow and spurred. In the hands the tubular bones are short and broad (bullet shaped) and they are held in a ‘trident’ or ‘starfish’ position. Homozygous achondroplasia has an overlapping radiographic phenotype with both heterozygous achondroplasia and thanatophoric dysplasia, and there is micromelia with bowed long bones. SADDAN shows a severe radiological phenotype similar to thanatophoric dysplasia, but without the cloverleaf skull/craniosynostosis.

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Prognosis: viable – affected individuals usually have normal intellect and life span; however, a number of complications can develop. The reduced size of the skull base and the foramen magnum can predispose to cervicomedullary compression, hydrocephalus and obstructive sleep apnoea. Unexpected death can occur in 2%–5% of patients during the first years of life. Frequent middle ear infections can lead to deafness. Crowded teeth are secondary to the relatively reduced jaw size. Hypotonia can lead to lumbar kyphosis in the first months of life. Later, lumbar hyperlordosis and genu varum are usually present. Lumbar spinal stenosis occurs. Mean adult height is 124–130 cm. Vosoritide, a C-type natriuretic peptide (CNP) analogue, is the first medication approved for children with achondroplasia from age 2 years until growth plates close; it has been demonstrated that treatment will increase the height, but there are not yet data on its effect on other complications. The homozygous form of achondroplasia is lethal. Death results from respiratory insufficiency as a result of a small thorax and neurologic deficit from hydrocephalus. Differential diagnosis: Other FGFR3-related conditions: hypochondroplasia (p. 54); thanatophoric dysplasia (p. 36). Trident acetabulum and narrow thorax: asphyxiating thoracic dystrophy (p. 196); chondroectodermal dysplasia (p. 203); short rib polydactyly syndrome type 1/3 (pp. 182–222).

 

(1c)

CASE 1: (a–c) Frontal bossing, depressed nasal bridge and mild midface hypoplasia on two- and three-dimensional prenatal US.

 

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CASE 1: (d) Short fingers (trident hand); (e, f) on two-dimensional US, the fetal vertebral bodies appear small and bullet-shaped with platyspondyly (parallel red lines); (g, h) narrow thorax, squared iliac wings with flat, trident acetabula and a radiolucent appearance of the upper femoral metaphyses. CASE 2: Comparison of third-trimester three-dimensional US profiles of fetuses with achondroplasia showing frontal bossing, depressed nasal bridge and flattened midface. CASE 3: Three-dimensional US images of the face in profile, also displaying brachydactyly with flexion of the digits.

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CASE 4: Two- (4a) and three (4b)-dimensional US images of the hand show the characteristic ‘trident’ configuration of the digits and brachydactyly. CASE 5: Three-dimensional US of the short and curved femur. CASE 6: Two-dimensional US image of the femur. The arrow points to the ‘collar hoop sign’ at the upper end of the diaphysis, seen as a small echogenic hook, which is considered a relative overgrowth of the periosteum; normal twodimensional US appearance of upper femoral metaphysis. CASE 7: Double de novo mutations in a fetus with achondroplasia and Muenke syndrome. There were mutations in exon 10 and exon 7 of the FGFR3 gene. In addition to features of achondroplasia, including frontal bossing, low nasal bridge, ‘trident hand’ and rhizomelic shortening, there is premature fusion of the coronal sutures (arrows).

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CASE 8: Termination of pregnancy at 34 weeks’ gestation with cerebral decompression. The skeletal survey shows sloping proximal femoral and humeral metaphyses; spurred acetabula (trident), also trident or splayed appearance of the fingers; mild platyspondyly with some thoracolumbar kyphosis; small thorax.

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CASE 9: Typical radiological findings of achondroplasia but also showing stippling of the proximal tibial epiphysis (9d) and tarsus (9j) and some coronal cleft vertebral bodies and midline sagittal notches suggestive of a form of chondrodysplasia punctata. There had been four previous normal pregnancies.

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CASE 10: Homozygous achondroplasia. (a, b) Two-dimensional ultrasound of the lateral chest and profile at 12 weeks (a) with an arrow pointing to a normal-appearing lateral chest and profile and at 27 weeks (b) showing significant depression (arrow) and small size relative to the abdomen. (c) Twodimensional ultrasound at 27 weeks showing frontal bossing, midface hypoplasia and rounded nose – very similar findings to thanatophoric dysplasia; (d) three-dimensional ultrasound of the hand showing significant brachydactyly and trident configuration; (e) four-dimensional X-ray mode image showing flattened lumbar vertebrae (platyspondyly) at 32 weeks (arrow); (f) postnatal radiograph – small thorax, short ribs, short bowed long bones, platyspondyly, trident acetabula squared ilia, redundant folds of skin.

Achondroplasia, FGFR3-Related

BIBLIOGRAPHY Chan ML, Qi Y, Larimore K, Cherukuri A et al. Pharmacokinetics and exposure-response of vosoritide in children with achondroplasia. Clin Pharmacokinet. 2022; 61: 263–80. Chitty LS, Griffin DR, Meaney C et al. New aids for the noninvasive prenatal diagnosis of achondroplasia: Dysmorphic features, charts of fetal size and molecular confirmation using cell free fetal DNA in maternal plasma. Ultrasound Obstet Gynecol. 2011; 37: 283–9. Coi A, Santoro M, Pierini A et al. Epidemiology of achondroplasia: A population-based study in Europe. Am J Med Genet A. 2019; 179: 1791–8. Hatzaki A, Sifakis S, Apostolopoulou D et al. FGFR3 related skeletal dysplasias diagnosed prenatally by ultrasonography and molecular analysis: Presentation of 17 cases. Am J Med Genet A. 2011; 155: 2426–35. Mellis R, Chandler N, Jenkins L et al. The role of sonographic phenotyping in delivering an efficient noninvasive prenatal diagnosis service for FGFR3-related skeletal dysplasias. Obstet Gynecol Soc. 2020; 75: 90–102.

53 Savarirayan R, Tofts L, Irving M et al. Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: A randomised, double-blind, phase 3, placebo-controlled, multicentre trial. Lancet. 2020; 396: 684–92. Savarirayan R, Irving M, Maixner W et al. Rationale, design, and methods of a randomized, controlled, open-label clinical trial with open-label extension to investigate the safety of vosoritide in infants, and young children with achondroplasia at risk of requiring cervicomedullary decompression surgery. Sci Prog. 2021 doi: 10.1177/00368504211003782. Vivanti AJ, Cordier AG, Benachi et al. Optimal non-invasive diagnosis of fetal achondroplasia combining ultrasonography with circulating cell-free fetal DNA analysis. Ultrasound Obstet Gynecol. 2019; 53: 87–94.

3 Hypochondroplasia, FGFR3-Related

Synonyms: HCH Confirmation of diagnosis: identification of monoallelic pathogenic variants in the FGFR3 gene. Frequency: the frequency of HCH is probably underestimated; it may approach the prevalence of achondroplasia (1/15 000 to 1/40 000 live births). Genetics: HCH is an autosomal dominant disorder due to heterozygous, gain-in-function variants in FGFR3 mapped on chromosome 4p16.3 and encoding fibroblast growth factor receptor 3. Mutations are dispersed in FGFR3. However, there are two common mutations in the intracellular tyrosine kinase domain of FGFR3 (c.1620C>A and c.1620C>G), both of which result in substitution of asparagine for lysine at codon 540 (p.Lys540Asp) in exon 10. About 70% of affected individuals have p.Lys540Asp, which causes more severe manifestations than those of other rare mutations. Age/Gestational age of manifestation: seldom made at birth unless a prior family history exists. However, short limbs may be detectable by ultrasound during the second or third trimester (23–30 weeks); early diagnosis may become more common. Most affected individuals present with short stature as toddlers or young school-age children. Clinical features: The phenotype is similar to, but milder than, that of achondroplasia; birth weight and length are often within the normal range, and the disproportion in limb-to-trunk length is often mild and easily overlooked during infancy.

utero and in infancy. Deviation of the fetal growth curve of femur length from the normal values, in conjunction with a normal growth curve of the biparietal diameter, has been suggested to be a useful indication for prenatal non-lethal skeletal dysplasia. Second-trimester ultrasound findings consistent with a diagnosis of a non-lethal skeletal dysplasia include a decreased rate of development of the femora (femur length less than the fifth centile) after 23 weeks’ gestation, while biparietal diameter, abdominal circumference and foot length are all within normal limits. In these cases, prenatal diagnosis relies on targeted molecular studies. The combination of ultrasound and a molecular genetic approach is helpful for establishing an accurate diagnosis of HCH in utero. A ‘normal’ third-trimester ultrasound examination is not sufficient to rule out a diagnosis of HCH. Radiographic features: long bone shortening with mild metaphyseal flare (especially femora and tibiae); shortening and scooping of the femoral neck; a shallow ‘chevron’ deformity of the distal femoral metaphysis; mild to moderate brachydactyly; elongation of the distal fibula, with the fibular growth plate appearing to lie distal to the ankle mortice; shortening of the distal ulna with a long ulnar styloid; iliac hypoplasia (squared, short ilia with narrowing of the greater sciatic notch and some flattening of the acetabular roof); narrowing, or failure to widen in the normal manner of the lumbar interpedicular distances; short (anteroposterior) lumbar pedicles with mild posterior scalloping of the vertebral bodies and a pronounced lumbar lordosis. Iliac hypoplasia and ovoid radiolucency of the femoral neck due to scooping are diagnostic clues in the neonatal period.

• Short stature, stocky build • Large head (macrocephaly) with relatively normal facies • Short proximal segments of the limbs with broad, short hands and feet (brachydactyly) • Limitation of elbow extension • Generalised, but mild, joint laxity • Other less common musculoskeletal findings: scoliosis, lumbar lordosis, genu varum • Seizures from dysgenesis of the temporal lobe (seldom) • Acanthosis nigricans (seldom)

Prognosis: viable – affected individuals usually have normal intellect and life span. Motor milestones are usually not significantly delayed. Hypochondroplasia, unlike achondroplasia, does not show symptoms resulting from spinal cord compression at the foramen magnum and lumbar spine (apnoea/quadriparesis and cauda equina syndrome). Genu varum is usually transient and rarely requires surgical intervention. Adult height is generally between 128 and 165 cm. The prevalence of intellectual disability is thought to be slightly higher than in the general population and can be related to temporal dysgenesis and intractable seizures. Acanthosis nigricans can occur rarely. Many affected individuals present with no symptoms other than mild short stature. They may not seek medical intervention, nor may they have an accurate diagnosis.

Prenatal ultrasound features: prenatal sonographic detection of HCH is difficult due to the absence of specific sonographic markers because many of the subtle signs are not present in

Differential diagnosis: other FGFR3-related conditions: thanatophoric dysplasia; achondroplasia; homozygous achondroplasia,

54

DOI: 10.1201/9781003166948-6

Hypochondroplasia, FGFR3-Related

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and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), a rare, usually lethal condition due to a specific variant (p.Lys650Met) (p. 46). Somatic mosaicism of FGFR3 variants usually associated with thanatophoric dysplasia may cause phenotypes resembling hypochondroplasia. In middle and late childhood, hypochondroplasia should be differentiated from disorders with short limbs but normal trunk, such as metaphyseal chondrodysplasias Schmid type,

caused by dominant pathogenic variants in COL10A1 and characterised by short, bowed limbs, coxa vara and moderate short stature and dyschondrosteosis (Leri-Weill) due to dominant mutations or deletion of SHOX characterised by disproportionate, mesomelic short stature and characteristic Madelung wrist deformity. The mildest end of hypochondroplasia may be difficult to distinguish from constitutional (non-syndromic) short stature.

(1c)

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CASE 1: A patient with p.Lys540Asp. Babygram (a–c) shows iliac hypoplasia and ovoid radiolucency of the femoral neck. Fetal CT at 30 weeks of gestation (d, e) displays iliac hypoplasia and scooping of the femoral neck.

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(3d) CASE 2: An affected neonate. Radiographs (a–c) show iliac hypoplasia and ovoid radiolucency of the femoral neck. The vertebral bodies appear somewhat ovoid. The long bones show mild metaphyseal flaring. CASE 3: A 31-week-gestation fetus of an affected mother; (a) the biparietal diameter and head circumference are greater than the 90th centile for 36 weeks; (b) two-dimensional US of the femur demonstrating rhizomelic shortening and an arrow pointing to mild metaphyseal flaring at the distal end; (c) two-dimensional US of the tibia showing mild mesomelic shortening (fifth centile) relative to the more severe rhizomelic shortening; (d) two-dimensional US of the foot showing that the foot-to-femur ratio is altered (ratio 0.88), which is less than the expected 1:1 ratio.

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CASE 3: (e) Two-dimensional US of the hand showing a normal appearance without overt trident appearance; (f) three-dimensional US of the facies showing mild flattening of the nasal bridge; (g) three-dimensional US of the profile. The metopic region is prominent, the nasal bridge is flat and the nasal tip is rounded, characteristic of the achondroplasia-hypochondroplasia spectrum.

BIBLIOGRAPHY Arenas MA, Pino Del Fano M et al. FGFR3-related hypochondroplasia: Longitudinal growth in 57 children with the p.Asn540Lys mutation. Pediatr Endocrinol Metab. 2018; 31: 1279–84. Couser NL, Pande CK, Turcott CM et al. Mild achondroplasia/ hypochondroplasia with acanthosis nigricans, normal development, and a p.Ser348Cys FGFR3 mutation. Am J Med Genet A. 2017; 173: 1097–101. Hyland VJ, Robertson SP, Flanagan S et al. Somatic and germline mosaicism for a R248C missense mutation in FGFR3, resulting in a skeletal dysplasia distinct from thanatophoric dysplasia. Am J Med Genet A. 2003; 120A: 157–68. Karadimas C, Sifakis S, Valsamopoulos P et al. Prenatal diagnosis of hypochondroplasia: Report of two cases. Am J Med Genet A. 2006; 140A: 998–1003.

Linnankivi T, Mäkitie O, Valanne L et al. Neuroimaging and neurological findings in patients with hypochondroplasia and FGFR3 N540K mutation. Am J Med Genet A. 2012; 158A: 3119–25. Muguet Guenot L, Aubert H, Isidor B et al. Acanthosis nigricans, hypochondroplasia, and FGFR3 mutations: Findings with five new patients, and a review of the literature. Pediatr Dermatol. 2019; 36: 242–6. Sabir AH, Sheikh J, Singh A et al. Earlier detection of hypochondroplasia: A large single-center UK case series and systematic review. Am J Med Genet A. 2021; 185: 73–82. Saito T, Nagasaki K, Nishimura G et al. Criteria for radiologic diagnosis of hypochondroplasiain neonates. Pediatr Radiol. 2016; 46: 513–8.

4 Achondrogenesis Type 2/Hypochondrogenesis, COL2A1-Related

Synonyms: ACG2; achondrogenesis Langer-Saldino type; chondrogenesis imperfecta. Confirmation of diagnosis: identification of pathogenic variants in COL2A1 with appropriate clinical and radiographic features. Frequency: 1 in 40,000 for all the types of achondrogenesis. Genetics: autosomal dominant, caused by pathogenic variants in the gene COL2A1. Achondrogenesis type 2/hypochondrogenesis is regarded as a continuum, but in view of the disparity in severity at the ends of the phenotypic range, these conditions are recognised as separate phenotypic entities. Other disorders with progressively milder phenotypes caused by COL2A1 mutations include spondyloepiphyseal dysplasia congenita, spondyloepimetaphyseal dysplasia Strudwick type, platyspondylic dysplasia Torrance type, Kniest dysplasia, Stickler syndrome, osteoarthritis with mild chondrodysplasia, spondyloepiphyseal dysplasia Namaqualand type, spondyloepiphyseal dysplasia with precocious osteoarthritis, multiple epiphyseal dysplasia with myopia and conductive deafness, spondyloperipheral dysplasia and some cases of otospondylomegaepiphyseal dysplasia. Recurrence of achondrogenesis type 2/hypochondrogenesis within a family is the result of germline or somatic mosaicism.

• Cystic hygroma, hydrops • Micrognathia and cleft palate • Rarely polydactyly and cardiac malformations Prenatal ultrasound features: both of these perinatally lethal conditions show a spectrum ranging from severe (achondrogenesis type 2) to less severe (hypochondrogenesis) and then merging with the surviving spondyloepiphyseal dysplasia congenita. Short long bones can be identified in the second trimester. Also there is a small thorax with slender, short ribs but normal ossification of the skull. The vertebral bodies are largely unossified throughout in achondrogenesis, but in hypochondrogenesis there is absent ossification of only the sacrum and cervical spine. A cystic hygroma with multiple septa may be present. There is polyhydramnios.

Age/Gestational week of manifestation: can be detected by ultrasound during the first to second trimester (11–16 weeks).

Radiographic features: in achondrogenesis type 2 the skull is disproportionately large and well ossified. The tubular bones are short and the humeri and femora over-modelled with flared metaphyses. The fibulae are short. The thorax is small with short, horizontal ribs. In the pelvis the acetabula are concave and the sacrosciatic notches wide. There is no ossification of the pubic rami. In the spine the vertebral bodies are unossified or barely ossified. There is delayed (or absent) ossification of epiphyses. The changes in hypochondrogenesis are milder with less severe micromelia and disproportion and absent ossification of vertebral bodies affecting only the cervical and sacral regions. In the pelvis the ilia are rounded with horizontal acetabula. The ossified vertebrae have a pear-shaped configuration and show anisospondyly, with L1 being significantly larger than L5. These same changes are found in spondyloepiphyseal dysplasia congenita.

Clinical features:

Prognosis: lethal.

COL2A1 encodes collagen type II, a fundamental component of the cartilaginous extracellular matrix, the nucleus pulposus and the vitreous of the eye.

• Severe micromelia • Large head, short neck, short trunk, protuberant abdomen • Flat nasal bridge, short nose with anteverted nostrils

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Differential diagnosis: Achondrogenesis type 1A and 1B (p. 106 and p. 205); thanatophoric dysplasia (p. 36); Schneckenbecken dysplasia (p. 260); SEDC (p. 73); Kniest dysplasia (p. 82); platyspondylic dysplasia; Torrance type (p. 67).

DOI: 10.1201/9781003166948-7

Achondrogenesis Type 2/Hypochondrogenesis, COL2A1-Related

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CASES 1–4: Fetal radiographs. Fetuses of between 16 and 22 weeks’ gestation. Disproportionately large skull vaults. Absent ossification of vertebral bodies throughout and ossification of pedicles in the cervical and thoracic regions mainly. Short ilia, crescent-shaped acetabular roofs and wide sacrosciatic notches; short ribs and long bones with cupped metaphyses.  

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CASE 9: A 17-week-gestation fetus with general soft tissue oedema, and the head is relatively large. There is absent ossification of the vertebral bodies, with early ossification of the neural elements in the cervical spine only. All the long bones are short with flared, cupped metaphyses. The chest is barrel shaped with short ribs. The ilia are small and have crescent-shaped medial and inferior margins. There is absent ossification of the ischial bones.

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CASE 10: Prenatal sonography and postnatal radiograph show extreme micromelia with metaphyseal cupping, poor ossification of the vertebral bodies and short ribs. CASE 11: US scans and radiograph of a fetus at 16 weeks showing a large, septated nuchal cystic hygroma with hydrops. All long bones are short.

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CASE 12: US scan at 28 weeks. Note redundant, thickened skin and a relatively narrow thorax in the axial section at the level of the four-chamber view. Coronal section of the fetal trunk shows shortening with a bell- shaped thorax. Sagittal section of the spine shows platyspondyly (arrows). CASE 13: US scan at 28 weeks of pregnancy; (a) sagittal view of fetal face profile shows marked micrognathia (arrows); (b) sagittal view of fetal neck and thorax identifies thick, redundant skin (arrows). CASE 14: A 17-week-gestation fetus; (a) absent ossification of vertebral bodies with ossification only of pedicles in the cervical region; short long bones with cupped metaphyses; concave acetabular roofs and medial borders; absent ossification of phalanges; (b) MRI shows bulky cartilaginous epiphyses. Early ossific nuclei are seen in the lumbar spine. The cartilaginous non-ossified portions of the inferior ilia and ischia are seen.

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CASES 1–5: Fetal radiographs from 18 to 24 weeks’ gestation.  

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CASES 6, 7 were both perinatal deaths; (6c, 7b) notice the anisospondyly with a progressive decrease in size of the lumbar vertebral bodies.

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CASE 8: An 18-week fetus. CASE 9 survived until 4 months. Absent ossification of cervical vertebral bodies; platyspondyly and anisospondyly; horizontal acetabular roofs with square iliac wings; wide sacrosciatic notch; squared-off ends of the long tubular bones; small thorax. CASE 10: A 17-week-gestation fetus: micrognathia; high arched palate; central cleft.

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BIBLIOGRAPHY Bisht RU, Belthur MV, Singletom IM et al. Hypochondrogenesis: A pictorial assay combining ultrasound, MRI and low-dose computerized tomography. Clin Imaging. 2021; 69: 363–8. Bruni V, Spoleti CB, La Barbera A et al. A novel splicing variant of COL2A1 in a fetus with achondrogenesis type II: Interpretation of pathogenicity of in-frame deletions. Genes (Basel). 2021; 12: 1396. Dogan P, Varal IG, Gorukmez O et al. Achondrogenesis type 2 in a newborn with novel mutation on the COL2A1 gene. Balkan J Med Genet. 2019; 22: 89–94.

Fetal and Perinatal Skeletal Dysplasias Handa A, Grigelioniene G, Nishimura G. Radiologic features of type II and type XI collagenopathies. Radiographics. 2021; 41: 192–209. Kobayashi Y, Ito Y, Taniguchi K et al. Novel missense COL2A1 variant in a fetus with achondrogenesis type II. Hum Genome Var. 2022; 9: 40. Wang W, Wu Q, Zhong X et al. Diagnosis of prenatal-onset achondrogenesis type II by a multidisciplinary assessment: A retrospective study of 2 cases. Case Rep Obstet Gynecol 2019: 7981767.

5 Platyspondylic Dysplasia, Torrance Type, COL2A1-Related

Synonyms: lethal short-limbed platyspondylic dwarfism, Torrance type; thanatophoric dysplasia, Torrance variant; also includes platyspondylic lethal skeletal dysplasia, Luton type, PLSDL, thanatophoric dysplasia, Luton variant. Confirmation of diagnosis: identification of pathogenic variants in COL2A1 with appropriate clinical and radiological findings. Frequency: unknown. Genetics: autosomal dominant, due to pathogenic variants in the gene COL2A1 encoding for collagen II, the major cartilage matrix protein. PLSDT is caused by mutations in the C-propeptide domain of COL2A1, which determines the biosynthesis of an altered collagen chain. Allelic disorders are achondrogenesis type 2, hypochondrogenesis, spondyloepiphyseal dysplasia congenita, Kniest dysplasia, spondyloepiphyseal dysplasia Strudwick type, Stickler syndrome, osteoarthritis with mild chondrodysplasia, spondyloepiphyseal dysplasia Namaqualand type, spondyloepiphyseal dysplasia with precocious osteoarthritis, multiple epiphyseal dysplasia with myopia and conductive deafness, spondyloperipheral dysplasia and some cases of otospondylomegaepiphyseal dysplasia. Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester (21 weeks). Clinical features: • • • • • •

Polyhydramnios Micromelia Thoracic hypoplasia Protuberant abdomen Macrocephaly Short neck, coarse facial features, depressed nasal bridge

Prenatal ultrasound features: polyhydramnios may be the presenting feature. Severe long bone shortening (–5 to –8 standard

DOI: 10.1201/9781003166948-8

deviations [SD]) with some radial bowing can be identified by 24 weeks. This is in contrast to the relative macrocephaly. In addition the thorax is hypoplastic with short ribs and lung hypoplasia and a relatively prominent abdomen, and there is severe platyspondyly. Dysmorphic features include a depressed nasal bridge and small nose. These findings are similar to those seen in thanatophoric dysplasia, and a precise diagnosis is rarely made prenatally. However, the femora are not bowed as in thanatophoric dysplasia. No visceral abnormalities are present. 3D CT: this has been used to establish the correct diagnosis at 26 weeks of gestation. The specific findings are wafer-thin platyspondyly, short ribs with cupped anterior ends, short ilia, absent ossification of the pubic bones, short long bones with irregular and cupped metaphyses and bowed radii. Radiographic features: the skull vault is disproportionately large with a prominent frontal bone. The thorax is small due to short ribs, which show anterior cupping. There is marked platyspondyly, with the vertebral bodies in the thoracic region being barely ossified. In the pelvis the ilia are short, the sacrosciatic notches wide and the acetabula horizontal. The pubic rami and ischia are broad. There is marked shortening of the tubular bones with some widening and bowing, especially of the radii, with flared, cupped metaphyses. Prognosis: the disease is generally perinatally lethal. A subset of patients with a milder form can survive until adulthood and develop a Kniest-like dysplasia, showing short tubular bones and marked metaphyseal flaring, but no vitreoretinal degeneration or hearing impairment. Differential diagnosis: platyspondylic lethal disorders: thanatophoric dysplasia (p. 36); three types of achondrogenesis (p. 58, 105, 256); schneckenbecken dysplasia (p. 260); spondylometaphyseal dysplasia type Sedaghatian (p. 262). Allelic disorders: spondyloepiphyseal dysplasia congenita (p. 73); Kniest dysplasia (p. 82).

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CASES 1–3: Disproportionately large head, small thorax, prominent abdomen and short limbs. There is marked platyspondyly with wide intervertebral spaces. The ilia are small with horizontal acetabular roofs and wide sacrosciatic notches. The superior pubic rami are not ossified. The long bones are short with squared-off or cupped metaphyses.  

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CASE 4: There was severe respiratory distress at birth. Small thorax, marked platyspondyly, short long bones with irregular metaphyses, absent ossification of the pubic rami and knee epiphyses.

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CASE 5: One previously affected fetus was terminated on the suspicion of achondrogenesis. There was a further intrauterine death at 25 weeks. (a–c) Fetal CT at 28 weeks’ gestation; (d) postnatal radiographic appearances. Disproportionately large skull; small thorax with short ribs; short long bones with cupped metaphyses. The ilia are short with horizontal acetabula. There is no ossification of the pubic rami or knee epiphyses at birth.

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CASE 6: Neonate. (a, c) Small thorax and short ribs; short long bones with flared metaphyses; absent ossification of the pubic rami and epiphyses at the knees. (b) Marked platyspondyly; (d) the lateral view of the cervical spine shows absent ossification of most of the vertebral bodies.

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BIBLIOGRAPHY Désir J, Cassart M, Donner C et al. Spondyloperipheral dysplasia as the mosaic form of platyspondylic lethal skeletal dysplasia Torrance type in mother and fetus with the same COL2A1 mutation. Am J Med Genet A. 2012; 158A: 1948–52. Handa A, Grigelioniene G, Nishimura G. Radiologic features of type II and type XI collagenopathies. Radiographics. 2021; 41: 192–209.

Fetal and Perinatal Skeletal Dysplasias Okamoto T, Nagaya K, Asai H et al. Platyspondylic lethal dysplasia Torrance type with a heterozygoud mutation in the triple helical domain of COL2A1 in two sibs from phenotypically normal parents. Am J Med Genet A. 2012; 158A: 1953–6. Tamaru S, Kikuchi A, Takagi K et al. Prenatal diagnosis of platyspondylic skeletal dysplasia Torrance type with threedimensional helical computed tomography. Prenat Diagn. 2009; 29: 1282–4.

6 Spondyloepiphyseal Dysplasia Congenita and Spondyloepimetaphyseal Dysplasia (SEMD) Strudwick Type, COL2A1-Related

Synonyms: SEDC; SED congenita. Confirmation of diagnosis: identification of pathogenic variants in COL2A1 with appropriate clinical and radiographic findings. Frequency: 1 in 100,000. Genetics: autosomal dominant, due to pathogenic variants in the gene COL2A1 encoding for collagen II, the major cartilage matrix protein. Mutations are generally missense, but occasionally can be in-frame small intragenic deletions or duplications. Allelic disorders are achondrogenesis type 2, hypochondrogenesis, Kniest dysplasia, spondyloepiphyseal dysplasia Strudwick type, platyspondylic dysplasia Torrance type, Stickler syndrome, osteoarthritis with mild chondrodysplasia, spondyloepiphyseal dysplasia Namaqualand type, spondyloepiphyseal dysplasia with precocious osteoarthritis, multiple epiphyseal dysplasia with myopia and conductive deafness, spondyloperipheral dysplasia and some cases of otospondylomegaepiphyseal dysplasia. Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester of gestation (16–23 weeks). Clinical features: • • • • • •

Short stature, short trunk and neck, shortened limbs Pectus carinatum Flat face, malar hypoplasia, cleft palate Myopia, nystagmus, congenital cataracts, glaucoma Coxa vara, clubfoot Hearing loss

Prenatal ultrasound features: specific prenatal findings are not well described. The features and the changes may be the same as those seen in spondyloepiphyseal dysplasia congenita. Prenatal ultrasound may reveal mild shortening of the femur

DOI: 10.1201/9781003166948-9

and humerus during the second trimester (16 weeks), and at the end of the second trimester all fetal long bones are short. Platyspondyly, anisospondyly and lumbar lordosis may be detected in utero. Three-dimensional ultrasound can reveal additional findings, including facial dysmorphism: malar flattening, hypertelorism, micrognathia and cleft palate. Polyhydramnios may be present. Radiographic features: at birth, there is absent (or delayed) ossification of the epiphyses of the knees and pubic rami. The long bones are short with squared and sometimes irregular metaphyseal ends. The thorax is small, short and ‘bell’ shaped, and the abdomen appears relatively protuberant. The acetabular roofs are horizontal. In the spine there is anisospondyly (a difference in the size and shape of the vertebral bodies), with L1 appearing larger than L5. The vertebral bodies appear oval, and in the thoracic region there is some posterior constriction giving a ‘pear’-shaped appearance. These neonatal appearances are indistinguishable from spondyloepimetaphyseal dysplasia type Strudwick (p. 80). During childhood marked coxa vara develops and there is delayed ossification of the capital femoral epiphyses. In the spine there is platyspondyly. There may be odontoid hypoplasia and deficient ossification of the anterior part of one or more cervical vertebral bodies, resulting in cervical kyphosis which may require stabilisation. There is pectus carinatum. Prognosis: viable, although occasionally perinatally lethal due to respiratory distress. Length can sometimes be normal at birth, but becomes progressively reduced in the first years of life; final stature is approximately 84–128 cm. Decreased joint mobility and arthritis often develop early in life. Surgical intervention may be required for stabilisation of the cervical spine. Intellect is usually normal. Differential diagnosis: other type 2 collagen disorders: hypochondrogenesis (p. 58); Kniest dysplasia (p. 82); Stickler syndrome (p. 89); OSMED (p. 98); dyssegmental dysplasia Rolland-Desbuquois (p. 166); Morquio disease, MPS type 4. Although the clinical habitus is similar, radiology will differentiate these two conditions.

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CASE 1: This full-term infant had short limbs, bilateral talipes equinovarus and a cleft palate. The chest is narrow with a prominent abdomen. Apart from feeding problems related to the cleft palate, the neonatal period was uneventful. The pubic rami and the epiphyses at the knees are unossified. The femoral necks are short. The spine shows anisospondyly, with L1 being much larger than L5. The hand is normal, and there is bilateral talipes equinovarus.

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CASES 2–3: Neonates. There is no ossification of the pubic rami or epiphyses at the knees. The long bones are short.

 

 

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CASES 4–5: All the spines show the characteristic small body of L5. (5b) A coronal cleft of L1. (5a) Short femoral necks. The unossified femoral heads are located within the acetabula, and there is no hip dislocation.

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CASES 6–7: The spine shows typical anisospondyly with a difference in shape and size between the vertebral bodies. There is delayed ossification of the pubic rami and knee epiphyses.

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CASE 8: (a) This shows a radiograph of the maternal abdomen (historical image). CASE 9: (9a) US of the spine at 31 weeks showing flattened, ovoid vertebral bodies (arrows) and also showing anisospondyly (large L1 and small L5). (b–d) Images as a neonate and at 6 months.

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CASE 10: A 23-week fetus; (a) two-dimensional US image showing platyspondyly. The lateral processes are well seen, but the arrow points to a barely visible vertebral body in the lumbar region, with faint vertebral bodies seen cranially. (b) Two-dimensional US of the lateral chest with an arrow pointing to the hypoechoic space superior to the heart showing the absence of the normal five sternal ossification centres normally seen by 23 weeks. (c) Three-dimensional US; lateral image of the ankle showing the distal tibia and metatarsals: the arrow points to the heel showing no ossification of a calcaneum. (d) Two-dimensional US of the normal-sized and -appearing hand. (e) Three-dimensional US of the facial profile showing a flattened nasal bridge and micrognathia.

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BIBLIOGRAPHY Chitty LS, Tan AW, Nesbit DL et al. Sonographic diagnosis of SEDC and double heterozygote of SEDC and achondroplasia — a report of six pregnancies. Prenat Diagn. 2006; 26: 861–5. Cui YX, Xia XY, Bu Y et al. Rapid molecular prenatal diagnosis of spondyloepiphyseal dysplasia congenita by PCR-SSP assay. Genet Test. 2008; 12: 533–6. Handa A, Grigelioniene G, Nishimura G. Radiologic features of type II and type XI collagenopathies. Radiographics. 2021; 41: 192–209. Saleem S, Anwar A, Iftikhar PM et al. Spondyloepiphyseal dysplasia congenita: A rare cause of respiratory distress. Cureus 2019; 11: e5101. doi: 10.7759/cureus.5101. Turner LM, Steffensen TS, Leroy J, Gilbert-Barness E. Spondyloepiphyseal dysplasia congenita. Fetal Pediatr Pathol. 2010; 29: 57–62. Xia XY, Cui YX, Huang YF et al. Molecular prenatal diagnosis in 2 pregnancies at risk for spondyloepiphyseal dysplasia congenita. Clin Chim Acta. 2008; 387: 153–7.

SPONDYLOEPIMETAPHYSEAL DYSPLASIA (SEMD) STRUDWICK TYPE COL2A1-RELATED Synonyms: SEMD, Strudwick type; SEMDC; spondylometaepiphyseal dysplasia congenita, Strudwick type; SMED, Strudwick type; SMED, type I; Strudwick syndrome; dappled metaphysis syndrome; spondylometaphyseal dysplasia; SMD. Confirmation of diagnosis: identification of pathogenic variants in COL2A1. Frequency: unknown. Genetics: autosomal dominant, due to mutations in the gene COL2A1, encoding for collagen II, the major constituent of hyaline cartilage and vitreous humour. Allelic disorders are achondrogenesis type 2, hypochondrogenesis, Kniest dysplasia, spondyloepiphyseal dysplasia congenita, platyspondylic dysplasia Torrance type, Stickler syndrome, osteoarthritis with mild chondrodysplasia, spondyloepiphyseal dysplasia Namaqualand type, spondyloepiphyseal dysplasia with precocious osteoarthritis, multiple epiphyseal dysplasia with myopia and conductive deafness, spondyloperipheral dysplasia and some cases of otospondylomegaepiphyseal dysplasia.

Prenatal US features: prenatal findings have not been described. The changes would be the same as those seen in spondyloepiphyseal dysplasia congenita. The earliest sonographic findings would be mild shortening of the femur and humerus at 16 weeks and by 27 weeks all fetal long bones would be moderately short. Anomalies of the vertebrae would not be detected in utero. Increased nuchal translucency thickness and hypomineralisation of the spine has been noted on the 11 week scan in a family at risk of SEDC. Additional findings may include polyhydramnios and some facial dysmorphism with hypertelorism and malar flattening, cleft palate and micrognathia. Radiographic features: at birth, there is absent (delayed) ossification of the epiphyses at the knees. There is also absent ossification of the pubic rami. The long bones are short with squared and sometimes irregular metaphyseal ends. The thorax is small, short and ‘bell’ shaped with pectus carinatum and the abdomen appears relatively protuberant. The acetabular roofs are horizontal. In the spine there is anisospondyly (a difference in size/shape of the vertebral bodies) with L1 appearing larger than L5. The vertebral bodies appear oval and in the thoracic region there is some posterior constriction giving a ‘pear’ shaped appearance. These neonatal appearances are indistinguishable from spondyloepiphyseal dysplasia congenita. During childhood, marked coxa vara develops and there is delayed ossification of the capital femoral epiphyses. In the spine there is platyspondyly. There may be odontoid hypoplasia and deficient ossification of the anterior part of one or more cervical vertebral bodies resulting in cervical kyphosis. The metaphyses show the characteristic changes of expansion, irregularity and dappled or flocculent ossification with areas of patchy sclerosis and lysis and the appearance of corner fractures. Prognosis: viable. Respiratory distress can be present at birth. Early orthopaedic complications include atlantoaxial instability, hip subluxation, coxa vara and talipes equinovarus. In late childhood and/or early adulthood the main problems are severe scoliosis, cord compression, premature hip osteoarthritis and myopia, which can be severe and lead to retinal detachment. Final stature is significantly reduced. Intellect is normal. Differential diagnosis:

Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester (16–20 weeks).

Allelic conditions: at birth is generally indistinguishable from SEDC (p.); Kniest dysplasia (p. 82); Stickler syndrome (p. 89).

Clinical features:

Other forms of spondylometaphyseal dysplasia can be differentiated by the specific features of each type, the retinitis pigmentosa in Megarbane type, hypogammaglobulinaemia and striated metaphyses in SPONASTRIME: rhizomelic shortening, cardiac and brain anomalies in the more severe Sedaghatian type (p. 262) and the rounded vertebral bodies in Sutcliffe type. Kozlowski type has more severe platyspondyly. Caused by mutations in TRPV4.

• • • • •

Short stature, short trunk and neck, shortened limbs Pectus carinatum Flat face, malar hypoplasia, cleft palate Coxa vara, clubfoot Inguinal hernia

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The mother of CASE 1: with a height of 122 cm had SEMD type Strudwick with marked irregularity and fragmentation/flocculation of the metaphyses. The radiographs of the neonate are indistinguishable from SEDC.

BIBLIOGRAPHY Amirfeyz R, Taylor A, Smithson SF et al. Orthopaedic manifestations and management of spondyloepimetaphyseal dysplasia Strudwick type. J Pediatr Orthop B. 2006; 15: 41–4.

Walter K, Tansek M, Tobias ES et al. COL2A1-related skeletal dysplasias with predominant metaphyseal involvement. Am J Med Genet A. 2007; 143: 161–7.

7 Kniest Dysplasia, COL2A1-Related

Synonyms: none. Confirmation of diagnosis: identification of pathogenic variants in COL2A1 with appropriate clinical and radiographic findings.

platyspondyly. The fetal face shows a flat forehead, hypertelorism, prominent eyes, a low nasal bridge and a small, flattened nose. Cleft palate and cataracts may be present. Straight or bowed long bones, absence or presence of polyhydramnios and a normal to mildly hypoplastic thorax are variable among reported cases.

Frequency: unknown. Genetics: autosomal dominant, due to pathogenic variants in the gene COL2A1 encoding for collagen II, the major cartilage matrix protein. The mutations associated with Kniest dysplasia cause in-frame deletions in type II collagen, generally located between exons 12 and 24, either by small intragenic deletions or splice site alterations. These deletions lead to shorter monomers of collagen type II. Splicing variants can be associated with a higher risk for ophthalmologic complications and hearing loss. Other disorders caused by pathogenic variants in the same gene are achondrogenesis type 2, hypochondrogenesis, spondyloepiphyseal dysplasia congenita, spondylometaepiphyseal dysplasia Strudwick type, platyspondylic dysplasia Torrance type, Stickler syndrome, osteoarthritis with mild chondrodysplasia, spondyloepiphyseal dysplasia Namaqualand type, spondyloepiphyseal dysplasia with precocious osteoarthritis, multiple epiphyseal dysplasia with myopia and conductive deafness, spondyloperipheral dysplasia and some cases of otospondylomegaepiphyseal dysplasia. Age/Gestational week of manifestation: can be detected by ultrasound during the second to third trimester (24–27 weeks). Clinical features: • Disproportionate short stature, short limbs with prominent knees • Short neck, narrow chest • Specific facial features: flat forehead, depressed nasal bridge, small nose with anteverted nares, long upper lip, micrognathia, cleft palate • Myopia, cataracts, hearing loss • Clubfoot Prenatal ultrasound features: a prenatal diagnosis of Kniest dysplasia has only been reported in five cases. With 2D and 3D ultrasound, an accurate diagnosis of this dysplasia is difficult before 23 weeks of pregnancy. Sonography reveals shortening of the limbs (mild to moderate) with wide metaphyses, but the hands and feet may appear disproportionately large. There may be talipes equinovarus. The thorax may be short and slightly hypoplastic, and sagittal scans of the fetal spine may demonstrate 82

Prenatal CT and MRI features: a precise diagnosis may be made using three-dimensional helical CT and/or fetal MRI early in the third trimester. 3D CT performed for a fetus at 28 weeks of gestation revealed dumbbell-shaped femora and platyspondyly with coronal clefts of the lumbar vertebral bodies. Fetal MRI may facilitate the prenatal diagnosis, delineating the fetal cartilage abnormalities. MRI findings include significantly enlarged hyaline cartilaginous structures with abnormally high T2 signal intensity (the epiphyses of the humeral head, ankle, knee and hips; also the sternum, intervertebral discs and cartilaginous portions of the ribs and scapulae), delayed ossification of the pubic and ischial bones and platyspondyly. Lung volumes are reduced. Radiographic features: a disproportionately large skull, with short, over-modelled long bones and wide metaphyses (dumbbell appearance). The thorax is wide and short. In the pelvis the ilia are small and flared with sloping acetabula. There is absent or poor ossification of the pubic bones. The spine shows mild platyspondyly, multiple coronal clefts and thoracolumbar kyphosis. There may be hypoplasia of the odontoid peg leading to instability in the cervical spine. In the hands the distal ends of the proximal phalanges are large, and there may be pseudoepiphyses here – in other words, epiphyses at both ends of the proximal phalanges. Most epiphyses show delayed ossification, but later in childhood they appear large. There is talipes equinovarus. Prognosis: viable. Respiratory problems and tracheolaryngomalacia in the neonatal period are common. Hypoplasia of the dens can lead to cervical instability and spinal cord compression. Motor milestones are usually delayed, and intelligence is normal. Scoliosis and thoracic kyphosis develop early; the joints are progressively enlarged and stiff. There might be early-onset arthrosis. Other problems include severe myopia, which might lead to retinal detachment, and sensorineural deafness. Final adult height is usually 106–145 cm. Differential diagnosis: spondyloepiphyseal dysplasia congenita (p. 73); OSMED/Weissenbacher-Zweymuller dysplasia (p. 98); dyssegmental dysplasia Rolland-Desbuquois type (p. 166); Schwartz-Jampel syndrome type 1 or myotonic chondrodysplasia (p. 172); metatropic dysplasia (p. 176); achondrogenesis type 2/hypochondrogenesis (p. 58). DOI: 10.1201/9781003166948-10

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CASES 1–2: Fetuses. In the spine there are pear-shaped vertebrae with a relatively large L1 compared with L5; the thorax is short and wide; the ilia are small; the long bones are short with a dumbbell appearance due to flared metaphyses.

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CASE 3: Fetuses. In the spine there are pear-shaped vertebrae with a relatively large L1 compared with L5; the thorax is short and wide; the ilia are small; the long bones are short with a dumbbell appearance due to flared metaphyses. CASES 4, 5: Neonates: short, broad thorax; platyspondyly with coronal clefts in CASE 5. Small ilia with sloping acetabula and short or absent superior pubic rami. Short, dumbbell-shaped long bones.

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CASE 6: Fetal MRI: (a) sagittal body and lower limb showing large cartilaginous epiphyses at the knee; (b) sagittal upper limb also showing large cartilaginous epiphyses. CASE 7: Broad metaphyses, sloping acetabular roofs; delayed ossification of epiphyses at the knee. Kyphosis with hypoplastic vertebral body at the thoracolumbar junction; oval vertebral bodies; small thorax.

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CASE 8: Termination of pregnancy at 25 weeks’ gestation. Short long bones with wide metaphyses; broad thorax; small, wide iliac bones; multiple coronal clefts in the lumbar spine.

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BIBLIOGRAPHY Gilligan LA, Calvo-Garcia MA, Weaver KN et al. Fetal magnetic resonance imaging of skeletal dysplasias. Pediatr Radiol. 2020; 50: 224–33.

Wada R, Sawai H, Nishimura G et al. Prenatal diagnosis of Kniest dysplasia with three-dimensional helical computed tomography. J Matern Fetal Neonatal Med. 2011; 24: 1181–4. Yazici Z, Kline-Fath BM, Laor T et al. Fetal MR imaging of Kniest dysplasia. Pediatr Radiol. 2010; 40: 348–52.

8 Stickler Syndrome, COL2A1-Related

Synonyms: Stickler syndrome, vitreous type 1; Stickler syndrome, membranous vitreous type; arthro-ophthalmopathy, hereditary progressive; AOM. Confirmation of diagnosis: identification of pathogenic variants in COL2A1 with appropriate clinical and radiographic appearances. Frequency: 1 in 7,500–9,000. Genetics: autosomal dominant, caused by pathogenic variants in COL2A1 encoding for collagen II, the major constituent of hyaline cartilage and vitreous humour. Mutations are loss-offunction and lead to haploinsufficiency of the gene. Other disorders caused by COL2A1 pathogenic variants are achondrogenesis type 2, hypochondrogenesis, Kniest dysplasia, spondyloepiphyseal dysplasia congenita, platyspondylic dysplasia Torrance type, spondyloepimetaphyseal dysplasia Strudwick type, osteoarthritis with mild chondrodysplasia, spondyloepiphyseal dysplasia Namaqualand type, spondyloepiphyseal dysplasia with precocious osteoarthritis, multiple epiphyseal dysplasia with myopia and conductive deafness, spondyloperipheral dysplasia and some cases of otospondylomegaepiphyseal dysplasia. Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester (20 weeks). Clinical features: • Pierre Robin sequence (30%) • Midface hypoplasia, depressed nasal bridge, anteverted nares, micrognathia • Cleft palate, bifid uvula • Congenital myopia, cataract, membranous vitreous anomaly, retinal detachment • Sensorineural or conductive hearing loss • Joint hypermobility, premature osteoarthritis Prenatal ultrasound features: an abnormal facial profile with retromicrognathia may be identified as a result of the Pierre Robin sequence, underdevelopment of the maxilla and flat or depressed nasal bridge. Polyhydramnios occurs as a result of abnormal swallowing of the amniotic fluid. Cleft palate (open cleft, submucous cleft or bifid uvula) may be detected from 19 weeks by 2D and 3D ultrasound. These findings in an at-risk family have suggested the diagnosis. DOI: 10.1201/9781003166948-11

Radiographic features: the neonatal expression of Stickler syndrome type 1 is referred to as Weissenbacher-Zweymuller syndrome and is also seen in otospondylomegaepiphyseal dysplasia (OSMED), which results from mutations in type 11 collagen. In the neonate the long bones are short with wide metaphyses, almost a ‘dumbbell’ appearance. In the spine there is mild platyspondyly. During infancy these changes gradually normalise, and between the ages of about 2 and 5 years skeletal abnormalities are absent. Thereafter there is the development of platyspondyly, which may be localised only; scoliosis; and some minor epiphyseal changes, predominantly flattening of the capital femoral epiphyses associated with broad femoral necks and leading to premature osteoarthritis. Prognosis: viable. Tracheostomy might be needed at birth in the case of a severe Pierre Robin sequence. Cleft palate requires surgical repair. Eye anomalies and hearing function need careful monitoring from birth. Orthodontic treatments to correct malocclusion are generally necessary. Joint laxity can be seen in a proportion of young individuals and disappears with age. The arthropathy is usually mild, although early-onset arthritis may be severe, requiring surgical joint replacement as early as the third decade of life. Mitral valve prolapse has been reported. Final stature is generally within the normal range. Intellect is normal. Differential diagnosis: other forms of Stickler syndrome: all of them are much rarer. Stickler syndrome COL11A1-related presents with a ‘beaded’ vitreous anomaly; Stickler syndrome COL11A2-related does not include abnormalities of the eyes; autosomal recessive forms of Stickler syndrome are associated with pathogenic variants in the genes COL9A1, COL9A2 or COL9A3. (p. 98). Other disorders caused by pathogenic variants in the gene COL2A1: spondyloepiphyseal dysplasia congenita (SED congenita) (p. 73); spondyloepimetaphyseal dysplasia (SEMD) Strudwick type (p. 80) and Kniest dysplasia (p. 82) are all much more severe, presenting with disproportionate short stature from birth. Spondyloperipheral dysplasia also shows brachydactyly type E. Other syndromes with Pierre Robin sequence: 22q11.2 deletion syndrome: shows a wide phenotypic spectrum, typical facial features, conotruncal cardiopathy, hypoplastic thymus and parathyroid glands, mild mental retardation, psychiatric disorders, short stature. Skeletal anomalies are uncommon, apart from scoliosis; Catel-Manzke syndrome (p. 293).

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CASE 1: Child was born at 38 weeks with a birth weight of 3.0 kg. He had micrognathia and a cleft palate and was highly myopic, as was his father, brother and sister. The sister also had a cleft palate. Genetic studies confirmed a linkage to COL2A1. (b–d) Broad femoral necks; flared metaphyses; flattened proximal tibial epiphysis. CASE 2: Child was delivered after a normal pregnancy at 42 weeks’ gestation. There were dysmorphic facial features including proptosis, a flat midface, a cleft palate and micrognathia, high myopia and mixed hearing loss. (a–c) Broad femoral necks; flared metaphyses; flattened epiphyses. CASE 3: Child had micrognathia, a large cleft palate, a flat midface and depressed nasal bridge, causing respiratory and feeding difficulties. (a, b) Flat proximal tibial epiphysis and small mandible.

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CASE 4: Weissenbacher-Zweymüller phenotype with flared metaphyses; mild platyspondyly. A COL2A1 mutation was confirmed.

 

 

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CASE 5: (e–h) Wide femoral necks. Small, flattened epiphyses at the knees. (h) Mild platyspondyly. CASE 6: Type 2 collagen (COL2A1) mutation; (a) two-dimensional sagittal view of the fetus at 13 weeks’ gestation. Normal fetal US parameters and significant micrognathia (arrow); (b) threedimensional US (13 weeks’ gestation) with arrow pointing to micrognathia; (c) follow-up three-dimensional image (14 weeks’ gestation) with severe micrognathia (arrow).

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BIBLIOGRAPHY Davies A, Davies A, Wren Y et al. Syndromes associated with Robin sequence: A national prospective cohort study. Arch Dis Child. 2023; 108: 42–6. Gueneuc A, Spaggiari E, Millischer AE et al. Contribution of three-dimensional ultrasound and three-dimensional helical computed tomography to prenatal diagnosis of Stickler syndrome. Ultrasound Obstet Gynecol. 2019; 54: 279–80. Handa A, Grigelioniene G, Nishimura G. Radiologic features of type II and type IX collagenopathies. Radiographics. 2021; 41: 192–209. Hoornaert KP, Vereecke I, Dewinter C et al. Stickler syndrome caused by COL2A1 mutations: Genotype-phenotype

Fetal and Perinatal Skeletal Dysplasias correlation in a series of 100 patients. Eur J Hum Genet. 2010; 18: 872–80. Nixon TRW, Alexander P, Richards A et al. Homozygous type IX collagen variants (COL9A1, COL9A2, and COL9A3) causing recessive Stickler syndrome — expanding the phenotype. Am J Med Genet A. 2019; 179: 1498–1506. Richards AJ, McNinch A, Martin H et al. Stickler syndrome and the vitreous phenotype: Mutations in COL2A1 and COL11A1. Hum Mutat. 2010; 31: E1461–1471. Shapiro MJ, Blair MP, Solinski MA et al. The importance of early diagnosis of Stickler syndrome: Finding opportunities for preventing blindness. Taiwan J Ophthalmol. 2018; 8: 189–95.

9 Fibrochondrogenesis, COL11A1- and COL11A2-Related

Synonyms: FCG. Confirmation of diagnosis: identification of biallelic pathogenic variants in the COL11A1 gene or biallelic or monoallelic pathogenic variants in the COL11A2 gene. Frequency: very rare – fewer than 30 cases reported. Genetics: FCG is a heterogeneous disorder that can result from autosomal recessive loss-of-function mutations in COL11A1 mapped on 1p21.1 or from either recessive or dominant mutations in COL11A2 mapped on 6p21.32. COL11A1 and COL11A2 encode the proα1(11) chain and the proα2(11) chain of type 11 collagen, respectively. FCG is the severest end of the spectrum of type XI collagenopathy. Type 11 collagen is a heterotrimer composed of three different proα-chains: proα1(11), proα2(11) and proα1(2), alternatively termed proα3(11). Thus, there is phenotypic overlap between type 11 and type 2 collagenopathies. Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester (14–20 weeks). Clinical features: • Perinatal lethality in most cases; longer survival is rare • Hydrops fetalis • Facial abnormalities: flat midface, protuberant eyes, flat nasal bridge and flat small nose with anteverted nares, low-set ears, small mouth with long upper lip, cleft palate, micrognathia • Narrow chest, protuberant abdomen • Markedly short limbs (rhizomelic shortening), occasionally clubfeet • Severe myopia and hearing impairment in long-term survivors • Occasionally omphalocele • Central nervous system abnormalities (dilated ventricles, cerebral atrophy, polymicrogyria) • Unique histological changes of the cartilage: fibroblastic dysplasia of chondrocytes with interwoven fibrous septa

DOI: 10.1201/9781003166948-12

Prenatal ultrasound features: in the second trimester the findings include severe micromelia, predominantly in a rhizomelic distribution, wide metaphyses (dumbbell-shaped long bones), pear-shaped vertebral bodies, platyspondyly, small thorax with short ribs, a relatively prominent abdomen and talipes equinovarus. Fetal head biometry detects a large biparietal diameter, and ventriculomegaly may be present, usually due to dilatation of the posterior parts of the lateral ventricles. 3D ultrasound allows visualisation of protuberant eyes, small nose and flat face. In the second and third trimesters a mild polyhydramnios may be present. Radiographic features: the skull is disproportionately large with a wide biparietal diameter. The thorax is small, and the ribs are short with cupped anterior ends. The clavicles are relatively long. The vertebral bodies are flat and least ossified in the cervical spine and have a distinctive shape with posterior constriction and round anterior parts (pear-shaped or pinched). A sagittal midline cleft may be present in many vertebral bodies, and the interpedicular distances are wide throughout. The iliac bones are small, rounded and broad. The sacrosciatic notches are small, and the acetabula have a caudally directed hump bordered by spurs. The ischia are wide. The long bones are stubby with very broad metaphyses, giving rise to a ‘dumbbell’ appearance. The metaphyses are mildly irregular with peripheral spur formation. There may be ectopic ossifications at the metadiaphyseal junction. The tarsal bones are large, and talipes equinovarus is common. Prognosis: usually perinatally lethal. The children who survived beyond the first years presented later with global developmental delay, short limbs with contractures of the large joints, a narrow chest with severe pectus carinatum, dorsal kyphosis, bilateral sensorineural hearing loss, severe myopia and bilateral cataracts. Differential diagnosis: neonatal skeletal dysplasia with dumbbell deformity, including Schneckenbecken dysplasia (p. 260), Kniest dysplasia (p. 82), perlecanopathies (p. 166, 172) and metatropic dysplasia (p. 176).

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CASES 1, 2: Stillbirths. Radiographs show dumbbell-shaped long bones, a narrow thorax with shortening and anterior cupping of the ribs, rounded ilia with narrow sacrosciatic notches, wide ischia, wide interpedicular distances and platyspondyly with posterior constriction and sagittal clefts of the vertebral bodies. CASE 3: A terminated fetus at 21 weeks of gestation. Postmortem radiographs (a–d) and postmortem CT (e) showed a phenotype that is essentially the same as, but milder than, those of Cases 1 and 2.  

Fibrochondrogenesis, COL11A1- and COL11A2-Related

BIBLIOGRAPHY Akawi N, Al-Gazali L, Ali B. Clinical and molecular analysis of UAE fibrochondrogenesis patients expands the phenotype and reveals two COL11A1 homozygous null mutations. Clin Genet. 2012; 82: 147–56. Al-Gazali LI, Bakalinova D, Bakir M et al. Fibrochondrogenesis: Clinical and radiological features. Clin Dysmorphol. 1997; 6: 157–63. Bekdache GN, Begam MA, Chedid F, Al-Gazali L et al. Fibrochondrogenesis: Prenatal diagnosis and outcome. J Obstet Gynaecol. 2013; 33: 663–8. Hunt NCA, Vujanic GM. Fibrochondrogenesis in a 17-week fetus: A case expanding the phenotype. Am J Med Genet. 1998; 75: 326–9. Randrianaivo H, Haddad G, Roman H et al. Fetal fibrochondrogenesis at 26 weeks’ gestation. Prenat Diagn. 2002; 22: 806–10. Erratum in: Prenat Diagn. 2002; 22: 1242.

97 Rosemberg S, Rodriques CJ, Sibley R et al. Fibrochondrogenesis: Lethal, autosomal recessive chondrodysplasia with distinctive cartilage histopathology. Am J Med Genet. 1984; 19: 265–75. Stembalska A, Dudarewicz L, Śmigiel R. Lethal and life-limiting skeletal dysplasias: Selected prenatal issues. Adv Clin Exp Med. 2021; 30: 641–7. Tompson SW, Bacino CA, Safina NP et al. Fibrochondrogenesis results from mutations in the COL11A1 type XI collagen gene. Am J Hum Genet. 2010; 87: 708–12. Tompson SW, Faqeih EA, Ala-Kokko L et al. Dominant and recessive forms of fibrochondrogenesis resulting from mutations at a second locus, COL11A2. Am J Med Genet A. 2012; 158A: 309–14.

10 Otospondylomegaepiphyseal Dysplasia, Recessive and Dominant Types, COL11A2-Related

Synonyms: OSMED; Stickler syndrome type 3; STD3; Weissenbacher-Zweymüller syndrome (WZS); Nance-Insley syndrome; Nance-Sweeney chondrodysplasia.

• Vitreoretinal degeneration with myopia and occasionally cataract (STD2 and Marshall syndrome, but not OSMED)

Includes: Stickler syndrome COL11A1-related; Stickler syndrome COL11A2-related; Stickler dysplasia type 2; STD2; Marshall syndrome.

Prenatal ultrasound features: there have been no reports of prenatal diagnosis in the literature. The facial profile with micrognathia and cleft palate and relative proptosis together with moderate limb shortening in the third trimester may be suggestive.

Confirmation of diagnosis: identification of monoallelic or biallelic pathogenic variants of COL11A2 associated with typical clinical and radiological features. Frequency: fewer than 1 in 1,000,000. Genetics: OSMED is either due to heterozygous or homozygous/compound heterozygous pathogenic variants in COL11A2 mapped on 6p21.32. When affected children with OSMED show remarkable catch-up growth during early childhood, the phenotype may be termed WZS. Type 11 collagenopathies are a continuum which also includes Stickler syndrome COL11A2-related, Stickler syndrome COL11A1-related and Marshall syndrome, all dominantly inherited, and the more severe fibrochondrogenesis. COL11A1 and COL11A2 encode the proα1(11) chain and proα2(11) chain of type 11 collagen, respectively. Type 11 collagen is a heterotrimer composed of three different proα-chains, proα1(11) and proα2(11) and proα1(2), alternatively termed proα3(11). Thus, there is phenotypic overlap between type 11 and type 2 collagenopathies. Age/Gestational week of manifestation: rhizomelic shortening and cleft palate may be detected by ultrasound during the third trimester (30 weeks). Clinical features: • Short stature, rhizomelic shortening • Pierre Robin sequence, cleft palate • Flat face, protruding eyes, hypertelorism, depressed nasal bridge, anteverted nares, long philtrum • Enlarged joints • Sensorineural hearing loss

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Radiographic features: the skull is disproportionately large, and facial bones are hypoplastic. In severe cases, the craniofacial deformity may be attributed to premature fusion of the coronal sutures, in that the anterior cranial fossa is short and the middle cranial fossa is deep. The mandible is hypoplastic as well. The vertebral bodies show mild to moderate platyspondyly associated with multiple coronal clefts. The ilia may be mildly broad. The long bones are stubby with metaphyseal widening, giving rise to a dumbbell appearance. Severity of dumbbell deformity is variable. Megaepiphyses become manifest with age. The short tubular bones may show mild dumbbell deformity. Prognosis: feeding difficulties and respiratory problems are common in infancy. There is often a catch-up growth after 3 years of age, but final stature is frequently significantly short. The joints become enlarged over time and lead to reduced mobility, joint pain and osteoarthritis, which may require early joint replacement. Differential diagnosis: Marshall syndrome is radiologically very similar to Stickler syndrome COL11A1-related but has severe facial abnormalities. OSMED and Stickler syndrome COL11-related share many clinical and radiological features with Stickler syndrome COL2A1-related (p. 89) and Kniest dysplasia (p. 82). In general, facial abnormalities, platyspondyly and dumbbell deformity of the long bones are much more severe in OSMED than in STD1. However, there is significant phenotypic overlap between both disorders. The final diagnosis rests on the clinical manifestation and molecular analysis. Kniest dysplasia shows more severe platyspondyly and elongated vertebral bodies. Coronal clefts are localised at the thoracolumbar junction in Kniest dysplasia, while they tend to be diffuse in OSMED and Stickler syndrome COL11-related.

DOI: 10.1201/9781003166948-13

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(2d) CASES 1, 2: Siblings born to consanguineous parents with probable autosomal recessive OSMED. A stillborn (1a) and an affected young child (2a–d) show modest platyspondyly, broad ilia and dumbbell deformity of the long bones. Case 2 shows megaepiphyses.  

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CASE 3: A neonate with autosomal dominant OSMED. Radiographs show short, broad thorax; mild platyspondyly with multiple coronal clefts; mildly broad ilia; and dumbbell deformity of the long bones.

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CASE 4: A neonate with severe Stickler type 2. Radiographs show shortening of the anterior cranial fossa; micrognathia; short, broad thorax; mild platyspondyly with multiple coronal clefts; mildly broad ilia; dumbbell deformity of the long bones; and large tali and calcanei.

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CASE 5: A neonate with mild Stickler type 2. Radiographs show short anterior cranial fossa, micrognathia, mild modification with remnants of the vertebral bodies, mildly wide ilia, mild dumbbell deformity of the long bones and large tali and calcanei.

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CASE 6: An infant with Marshall syndrome at 2 months of age. The skeletal changes are almost identical to those of Case 1. However, the skull shows a box-like appearance. The anterior cranial fossa is severely short, and the orbital roofs show a harlequin-like appearance. These findings are likely to represent craniosynostosis. On the other hand, vertebral changes are much milder than that of Case 1. Defective vertebral ossification may have rapidly caught up in this infant.

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BIBLIOGRAPHY Acke FR, Malfait F, Vanakker OM et al. Novel pathogenic COL11A1/COL11A2 variants in Stickler syndrome detected by targeted NGS and exome sequencing. Mol Genet Metab. 2014; 113: 230–5. Harel T, Rabinowitz R, Hendler N et al. COL11A2 mutation associated with autosomal recessive Weissenbacher-Zweymuller syndrome: Molecular and clinical overlap with otospondylomeg-aepiphyseal dysplasia (OSMED). Am J Med Genet A. 2005; 132A: 33–5. Melkoniemi M, Brunner HG, Manouvrier S et al. Autosomal recessive disorder otospondylom-egaepiphyseal dysplasia is associated with loss-of-function mutations in the COL11A2 gene. Am J Hum Genet. 2000; 66: 368–77. Micale L, Morlino S, Schirizzi A et al. Exon-trapping assay improves clinical interpretation of COL11A1 and COL11A2 intronic variants in Stickler syndrome type 2 and otospondylomegaepiphyseal dysplasia. Genes (Basel). 2020; 11: 1513. Richards AJ, Fincham GS, McNinch A et al. Alternative splicing modifies the effect of mutations in COL11A1 and results in

Fetal and Perinatal Skeletal Dysplasias recessive type 2 Stickler syndrome with profound hearing loss. J Med Genet. 2013; 50: 765–71. Robin NH, Moran RT, Ala-Kokko L. Stickler Syndrome. 2000 [updated 2021]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Mirzaa GM, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022. Selvam P, Singh S, Jain A et al. Novel COL11A2 pathogenic variants in a child with autosomal recessive otospondylomegaepiphyseal dysplasia: A review of the literature. J Pediatr Genet. 2020; 9: 117–20. Van Steensel MA, Buma P, de Waal Malefijt MC et al. Otospondylo-megaepiphyseal dysplasia (OSMED): Clinical description of three patients homozygous for a missense mutation in the COL11A2 gene. Am J Med Genet. 1997; 70: 315–23. Winter RM, Baraitser M, Laurence KM et al. The WeissenbacherZweymüller, Stickler, and Marshall syndromes: Further evidence for their identity. Am J Med Genet. 1983; 16: 189–99.

11 Achondrogenesis (Type 1B), SLC26A2-Related

Synonyms: ACG1B; achondrogenesis, Fraccaro type Confirmation of diagnosis: identification of pathogenic variants in SLC26A2. Frequency: 1 in 40,000 for all achondrogenesis subtypes. Genetics: autosomal recessive, caused by pathogenic variants in SLC26A2 (solute carrier family 26 A2), encoding a sulphate transporter involved in the sulphation of proteoglycans in cartilage matrix. This gene is also known as DTDST. Pathogenic variants in the transmembrane domain or nonsense variants usually result in achondrogenesis type 1B, whereas other pathogenic variants can cause less severe allelic phenotypes such as atelosteogenesis type 2, diastrophic dysplasia and autosomal recessive multiple epiphyseal dysplasia. Age/Gestational age of manifestation: can be detected by ultrasound during the first to second trimester (11–16 weeks). Clinical features: • Severe micromelia and clubfeet • Large head, short trunk, hypoplasia of the thorax, protuberant abdomen • Flat nasal bridge, short nose with anteverted nostrils

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• Short neck and cystic hygroma, hydrops • Often umbilical or inguinal herniae Prenatal ultrasound features: routine studies may identify very short fetal limbs, a small thorax and polyhydramnios. In low-risk pregnancies the diagnosis is not usually made until the second trimester. In a high-risk pregnancy, transvaginal ultrasound can establish a diagnosis at 14–15 weeks’ gestation. Radiographic features: the skull is disproportionately large. The orbits extend laterally and superiorly. There is severe micromelia with all the long bones extremely short. There may be some tapering of the distal humeri. The short tubular bones of the hands and feet may be unossified, and there is talipes equinovarus. The thorax is small, and the ribs short and slender but with expanded and cupped lateral (anterior) ends. The scapulae are small with irregular contours. The vertebral bodies are barely ossified or unossified, although the pedicles are well seen. There is significant widening of the interpedicular distances in both the cervical and lumbar regions, giving the ‘cobrahead’ appearance. The ilia are short and have a crescentic appearance with a concave inferior border; ischia are usually unossified. Prognosis: lethal. Differential diagnosis: atelosteogenesis type 2 (p. 108); achondrogenesis type 1A (p. 256); achondrogenesis type 2 (p. 58); hypophosphatasia (p. 452); diastrophic dysplasia (p. 111).

 

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ALL CASES show well-ossified pedicles with widening of the interpedicular distances in the cervical and lumbar regions – the so-called ‘cobra-head’ appearance. The vertebral bodies are barely ossified. The ilia are short with a ‘crescentic’ appearance. CASE 3: Multiple skeletal anomalies identified by prenatal US at 20 weeks’ gestation. At autopsy, the fetus was hydropic with a depressed nasal bridge and cleft palate. There was severe micromelia. The thorax was narrow and the abdomen prominent.

DOI: 10.1201/9781003166948-14

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CASE 4: There is a pronounced cystic hygroma and generalised hydrops. CASE 5: A 20-week-gestation fetus with a DTDST (SLC26A2) mutation; (a) Two-dimensional US of the humerus showing an extremely short, subjectively thickened bone. (b) Two-dimensional US of the hand demonstrating the ‘hitchhiker’ position of the thumb. (c) Two-dimensional US of the lumbar spine and sacrum showing lumbar scoliosis and skin oedema; (d) Twodimensional US of the lower extremity in the characteristic position with a clubfoot. (e) Two-dimensional image of the foot with the arrow pointing to plantar oedema.

Achondrogenesis (Type 1B), SLC26A2-Related

BIBLIOGRAPHY Dwyer E, Hyland J, Modaff P et al. Genotype-phenotype correlation in DTDST dysplasias: Atelosteogenesis type II and diastrophic dysplasia variant in one family. Am J Med Genet A. 2010; 152A: 3043–50. Superti-Furga A, Hästbacka J, Wilcox WR et al. Achondrogenesis type IB is caused by mutations in the diastrophic dysplasia sulphate transporter gene. Nat Genet. 1996; 12: 100–2.

107 Superti-Furga A, Rossi A, Steinmann B et al. A chondrodysplasia family produced by mutations in the diastrophic dysplasia sulfate transporter gene: Genotype/phenotype correlations. Am J Med Genet. 1996; 63: 144–7.

12 Atelosteogenesis (Type 2), SLC26A2-Related

Synonyms: AO2; AOII; neonatal osseous dysplasia I; de la Chapelle dysplasia, McAlister dysplasia Confirmation of diagnosis: identification of pathogenic variants in SLC26A2 together with the appropriate phenotype. Frequency: unknown. Genetics: autosomal recessive, caused by pathogenic variants in SLC26A2, which is also known as DTDST (diastrophic dysplasia sulphate transporter gene), encoding a sulphate transporter involved in the sulphation of proteoglycans in cartilage matrix. Mutations in the same gene have also been associated with diastrophic dysplasia (DTD), autosomal recessive multiple epiphyseal dysplasia and achondrogenesis type 1B (ACG1B). A genotype-phenotype correlation exists. Transmembrane domain or nonsense mutations usually result in achondrogenesis type 1B, the most severe associated phenotype, whereas ‘milder’ mutations (missense, located outside the transmembrane domain) or combinations of one severe and one milder mutation cause less severe phenotypes such as atelosteogenesis type 2, DTD and recessive multiple epiphyseal dysplasia. Impaired activity of the sulphate transporter in chondrocytes and fibroblasts results first in the synthesis of insufficiently sulphated proteoglycans and ultimately in abnormal extracellular matrix and endochondral bone formation. Age/Gestational week of manifestation: can be detected by ultrasound during the first to second trimester (11–20 weeks). Clinical features: • • • • • • • •

Micromelia with predominant rhizomelic limb shortening Small thorax, protuberant abdomen ‘Hitchhiker’ thumbs Typical facial features: midface hypoplasia, depressed nasal bridge, micrognathia Cleft palate Gap between the first and second toes Clubfoot Polyhydramnios

Prenatal ultrasound features: sonographic examination at 12 weeks of pregnancy may show a wide pathological nuchal translucency. All limbs are severely shortened. ‘Hitchhiker’ thumbs and bilateral clubfeet can be observed. Mid-trimester fetal US scan (18–22 weeks) may demonstrate severe micromelia, more affect108

ing the proximal segments, with a large discrepancy between the fetal head and long bones measurements: abnormal femur-to-head (0.08) and femur-to-abdomen ratios (0.09). Long bone measurements of at least three standard deviations below reference ranges, along with abnormalities of the feet and hands, are important clues for the sonographic diagnosis. Both femurs may be curved inwards and have rounded proximal metaphyses. Ultrasound examination of the lower extremities can reveal marked talipes equinovarus, with the plantar aspects of the feet facing each other and wide separation between the first and second toes. The proximal humerus has wide metaphyses, while the distal segment is narrow and tapered. The short, abducted thumbs (‘hitchhiker’) can be detected. The hands are short with hypoplastic phalanges and have ulnar deviation resulting from shortening of the ulna. Deformities of the cervical and lumbosacral regions have been identified. Longitudinal scan of the fetal spine may demonstrate coronal clefts at the lumbar level with a horizontal angulation of the sacrum. Polyhydramnios may be present. These same features have been identified on prenatal MRI at 22 weeks. Differentiation between atelosteogenesis type 2 and DTD with imaging can still be difficult. Radiographic features: the long bones are short and bowed with wide metaphyses. The distal end of the humerus may be tapered or bifid and the distal end of the ulna short and tapered, with bowing of the proximal end. There are dislocations of the radial heads and knees. The tubular bones of the hands and feet are short or absent with the second and third metacarpals less severely affected. There may be accessory phalanges or large pseudoepiphyses between the metacarpals and the proximal phalanges. There is talipes equinovarus. In the spine there is cervical kyphosis due to hypoplasia of several cervical vertebral bodies, some platyspondyly, kyphoscoliosis and pronounced lumbosacral lordosis. There is widening of the interpedicular distances in the cervical and lumbar spine (‘cobra-head’ appearance) also seen in other conditions with SLC26A2 mutations. The ischia are vertical. Prognosis: perinatally lethal. Differential diagnosis: other disorders caused by pathogenic variants in SLC26A2 (allelic disorders): achondrogenesis type 1B (ACG1B) (p. 105); diastrophic dysplasia (p. 111); recessive multiple epiphyseal dysplasia (EDM4) is milder, viable and in half of the cases not recognisable at birth; pseudodiastrophic dysplasia (p. 133). Other subtypes of atelosteogenesis: atelosteogenesis types 1/3 (p. 156, 162). Other lethal disorders with micromelia: thanatophoric dysplasia (p. 36). DOI: 10.1201/9781003166948-15

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CASE 1: Note dislocated elbows with tapered distal ends of the humeri; ectopic ossification around the elbows; short distal ulna. In the hands there are accessory phalanges/pseudoepiphyses between the proximal phalanges and metacarpals. In the spine there is mild platyspondyly, hypoplasia of L2 with kyphosis and a pronounced cervical kyphosis due to hypoplasia of the bodies of C5 and C6.

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CASE 2: (a) Two-dimensional US of the spine in a 26-week fetus. An arrow points to severe lumbar kyphoscoliosis. (b) Three-dimensional US (skeletal mode) of the ribs and spine with arrows pointing to shortened ribs and lumbar scoliosis. (c) Three-dimensional image of the arm with top arrow pointing to short first metacarpal and lower arrow to bifid humerus. (d, e) Profile showing flattened nasal bridge and arrow pointing to micrognathia. (f) Short femur. (g) Three-dimensional US of the lower extremities showing bilateral equinovarus (left arrow, equinovarus; right arrow, deviated hallux). (h) Term: anteroposterior radiograph showing lumbar scoliosis and upper limb rhizomelia with bifid humerus. (i) Term: anteroposterior radiograph showing hypoplastic pubis, dislocated femoral heads, sloping acetabular roof, mesomelia and bilateral clubfoot.

BIBLIOGRAPHY Hästbacka BL, de la Chapelle A et al. A novel mutation in the sulfate transporter gene SLC26A2 (DTDST) specific to the Finnish population causes de la Chapelle dysplasia. J Med Genet. 2008; 45: 827–31. Fernandez-Aguilar S, Noël JC, Van Regemorter N et al. Diagnosis of atelosteogenesis type II after a routine echography at 12 weeks’ pregnancy. Prenat Diagn. 2005; 25: 717–8. Maeda K, Miyamoto Y, Sawai H et al. A compound heterozygote harboring novel and recurrent DTDST mutations with intermediate phenotype between atelosteogenesis type II and diastrophic dysplasia. Am J Med Genet A. 2006; 140: 1143–7.

Miller E, Blaser S, Miller S et al. Fetal MR imaging of atelosteogenesis type II (AO-II). Pediatr Radiol. 2008; 38: 1345–9. Rossi A, Superti-Furga A. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance. Hum Mutat. 2001; 17: 159–71. Superti-Furga A, Hästbacka J, Rossi A et al. A family of chondrodysplasias caused by mutations in the diastrophic dysplasia sulfate transporter gene and associated with impaired sulfation of proteoglycans. Ann N Y Acad Sci. 1996; 785: 195–201.

13 Diastrophic Dysplasia, SLC26A2-Related

Synonyms: DD; DTD; includes diastrophic dysplasia, broad bone-platyspondylic variant Confirmation of diagnosis: identification of biallelic pathogenic variants in the SLC26A2 gene correlated with clinical and radiographic features. Frequency: about 1 in 100,000. Genetics: autosomal recessive, caused by mutations in the gene SLC26A2, also known as DTDST. The mutation detection rate exceeds 90%, and five common mutations account for 65% of the cases. The gene encodes for a sulphate transporter expressed in chondrocytes and fibroblasts. The reduced or abolished activity of this protein causes an under-sulphation of proteoglycans in the cartilage matrix, impaired proteoglycan deposition within the matrix and ultimately impaired endochondral bone formation. Age/Gestational age of manifestation: can be detected by ultrasound at the end of the late first trimester or during the second trimester (14–22 weeks). Clinical features: • • • •

Severely short limbs Kyphoscoliosis Contractures (shoulders, elbows, hip, knee, talipes) ‘Hitchhiker’ thumb, brachydactyly, ulnar deviation of fingers • Neonatal appearance of cystic lesions of the pinnae, hypertrophic auricular cartilage • Laryngotracheal stenosis • Rarely congenital heart defects Prenatal ultrasound features: first-trimester ultrasound may show increased nuchal translucency. Subtle findings on sonography may be detected in the first trimester (11–13 weeks); however, the diagnosis can be made with more accuracy at 14–15 weeks, and reliability is operator-dependent. The prenatal detection of diastrophic dysplasia is usually made in the routine mid-trimester fetal ultrasound scan. The main features include severe shortening of the long bones, brachydactyly with abducted ‘hitchhiker’ thumb, normal-sized skull with a small nose and severe micrognathia, cleft palate in a proportion of cases (25%), slight truncal shortening, talipes equinovarus

DOI: 10.1201/9781003166948-16

and abduction of the halluces. Facial dysmorphism, cleft palate and ‘hitchhiker’ thumb are better visualised with three-­ dimensional ultrasound. Additional ultrasound features include coronal clefts in the lumbar and lower thoracic vertebrae, exaggerated lumbar lordosis and thoracic scoliosis. Radiographic features: there is marked micrognathia associated with a cleft palate. The long bones are short, predominantly in a rhizomelic distribution. There are mild bowing deformities. There may be dislocation of the radial heads and sometimes other large joints. The thumbs are abducted and proximally placed as a result of short, sometimes oval, first metacarpals. There is irregular shortening of metacarpals and phalanges. Similar changes are present in the feet, and in addition there is marked talipes equinovarus. The thorax is small. In the spine there is mild platyspondyly and some vertebral endplate irregularity. Scoliosis may develop. There may be a cervical kyphosis resulting from hypoplasia of cervical vertebral bodies. Instability here may require surgical stabilisation to prevent cord compression. During childhood the epiphyses and metaphyses appear irregular and wide. An inverted Vshaped deformity (‘chevron’ deformity) sometimes develops at the distal ends of the long bones. Prognosis: usually viable according to the severity of the phenotype. Respiratory insufficiency can occur due to a small rib cage and tracheobronchomalacia. Neurologic complications are related to cervical kyphosis. Joint contractures and spine deformity tend to worsen with age. Average adult stature is around 120 cm. Intellect is usually normal. Differential diagnosis: allelic conditions, SLC26A2-related: there is a phenotypic continuum within a broad spectrum, at the most severe end of which lie atelosteogenesis type 2 (p. 108) and achondrogenesis type 1B (p. 105), both lethal. Autosomal recessive multiple epiphyseal dysplasia is at the milder end of the spectrum, with fewer than half of affected cases showing prenatal abnormalities, usually clubfoot or contractures. Short limbs and contractures: many forms of distal arthrogryposis. Stüve-Wiedemann syndrome (p. 311). Pseudodiastrophic dysplasia (p. 133). Otopalatodigital syndromes: the most severe form, also known as fronto-oto-palato-digital osteodysplasia, can show skeletal dysplasia, arthrogryposis and multiple malformations. Desbuquois dysplasia (p. 121); omodysplasia (p. 273).

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CASES 1, 2: Fetuses. CASE 3: Neonate. They show short long bones with some bowing; dislocated radial heads and lateral clavicular hooks; short first metacarpals resulting in abduction of the thumbs. There is cervical kyphosis in Case 3 with some minor cord compression on MRI.

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CASE 4: Shows short long bones with some bowing; dislocated radial heads and lateral clavicular hooks; short first metacarpals resulting in abduction of the thumbs. There is cervical kyphosis. Talipes equinovarus.

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CASE 5: Short long bones with some bowing; dislocated radial heads and lateral clavicular hooks; short proximal phalanx of the middle finger; cervical kyphosis. CASE 6: A 17-week fetus of an obese mother. (a, b) Radiographic appearances: short long bones and mandible; abducted thumbs (‘hitchhiker’ thumbs) and halluces, talipes equinovarus, distal tapering of the humeri with elbow dislocation.

Diastrophic Dysplasia, SLC26A2-Related

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CASE 7: (a, b) Talipes equinovarus. CASE 8: Dislocated radial heads with curved proximal ulnae; talipes equinovarus; small thorax and micrognathia.

116

BIBLIOGRAPHY Barbosa M, Sousa AB, Medeira A et al. Clinical and molecular characterization of diastrophic dysplasia in the Portuguese population. Clin Genet. 2011; 80: 550–7. Canto MJ, Buixeda M, Palau J et al. Early ultrasonographic diagnosis of diastrophic dysplasia at 12 weeks of gestation in a fetus without previous family history. Prenat Diagn. 2007; 27: 976–8. Dawson PA. Sulfate in fetal development. Semin Cell Dev Biol. 2011; 22: 653–9. De Souza Lima T, Ferreira BG, Loureiro Souza CW et al. Prenatal diagnosis of diastrophic dysplasia in the second trimester of pregnancy: Two-and three-dimensional ultrasonographic findings. Turk J Obstet Gynecol. 2021; 18: 258–63. Dwyer E, Hyland J, Modaff P et al. Genotype-phenotype correlation in DTDST dysplasias: Atelosteogenesis type II and diastrophic dysplasia variant in one family. Am J Med Genet A. 2010; 152A: 3043–50. Härkönen H, Loid P, Mäkitie O. SLC26A2-associated diastrophic dysplasia and rMED — clinical features in affected Finnish children and review of the literature. Genes (Basel). 12: 714. Honório JC, Bruns RF, Gründtner LF et al. Diastrophic dysplasia: Prenatal diagnosis and review of the literature. Sao Paolo Med J. 2013; 131: 127–32. Maeda K, Miyamoto Y, Sawai H et al. A compound heterozygote harbouring novel and recurrent DTDST mutations with intermediate phenotype between atelosteogenesis type II and diastrophic dysplasia. Am J Med Genet A. 2006; 140: 1143–7.

Fetal and Perinatal Skeletal Dysplasias Miyake A, Nishimura G, Futami T et al. A compound heterozygote of novel and recurrent DTDST mutations results in a novel intermediate phenotype of Desbuquois dysplasia, diastrophic dysplasia, and recessive form of multiple epiphyseal dysplasia. J Hum Genet. 2008; 53: 764–8. Panzer KM, Lachman R, Modaff P et al. A phenotype intermediate between Desbuquois dysplasia and diastrophic dysplasia secondary to mutations in DTDST. Am J Med Genet A. 2008; 146A: 2920–4. Rossi A, Superti-Furga A. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance. Hum Mutat. 2001; 17: 159–71. Silveira C, da Costa Silveira K, Lacarrubba-Flores MD et al. SLC26A2/DTDST spectrum: A cohort of 12 patients associated with a comprehensive review of the genotype-phenotype correlation. Mol Syndromol. 2023; 13: 485–95. Unger S, Superti-Furga A. Diastrophic dysplasia. 2004 [Updated 2021 Dec 23]. In Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews ® [Internet] Seattle (WA): University of Washington, Seattle; 1993–2022. Zechi-Ceide RM, Moura PP, Raskin S et al. A compound heterozygote SLC26A2 mutation resulting in robin sequence, mild limbs shortness, accelerated carpal ossification, and multiple epiphyseal dysplasia in two Brazilian sisters. A new intermediate phenotype between diastrophic dysplasia and recessive multiple epiphyseal dysplasia. Am J Med Genet A. 2013; 161A: 2088–94.

14 Chondrodysplasia with Congenital Joint Dislocations (Recessive Larsen Syndrome), CHST3-Related

Synonyms: CHST3-CD; chondrodysplasia with congenital joint dislocations, CHST3 type recessive Larsen syndrome; humerospinal dysostosis; spondyloepiphyseal dysplasia (SED) Omani type, spondyloepiphyseal dysplasia with congenital joint dislocations; SEDCJD Confirmation of diagnosis: identification of biallelic pathogenic variants in the CHST3 gene. Frequency: rare. About 30 disease-associated variants in CHST3 have been found in about 50 patients. Large affected families are known in Oman, India and Pakistan. Genetics: CHST3-CD is an autosomal recessive disorder due to homozygous or compound heterozygous loss-of-function pathogenic variants in CHST3 located on chromosome 10q22.1 and encoding carbohydrate sulphotransferase or chondroitin 6-O-sulfotransferase-1 (C6ST-1). The gene defects impair biosynthesis of chondroitin sulphate proteoglycans. The gene spans only three exons, and the pathogenic variants are scattered throughout, although the majority have currently been identified in the sulphotransferase domain. A few founder variants are known in families of similar ethnic background. Age/Gestational age of manifestation: onset is usually prenatal and can be detected as early as the 16th week of pregnancy. Clinical features: • Prenatal onset of short stature with short limbs • Congenital joint dislocations/subluxations of the large joints, especially radial head and hips; clubfeet • Normal facial features • Occasionally cardiac valve dysplasia with insufficiency • Hearing impairment rarely reported Prenatal ultrasound features: the most frequently involved joints are the knee and elbow, starting at 16 weeks of pregnancy by ultrasound. Talipes equinovarus, vertebral irregularity, platyspondyly and short trunk are common findings. A

DOI: 10.1201/9781003166948-17

broad forehead, hypertelorism and small ears can be visualised with 3D ultrasound. Rhizomelia, brachydactyly and camptodactyly may be present. Bifurcated distal humeri is rare. Cardiac anomalies can be present and include ventricular septal defects, mitral and tricuspid defects and aortic regurgitation. Oligohydramnios and/or polyhydramnios may be present. Radiographic features: the diagnostic features in neonates include multiple coronal clefts of the lumbar spine; wide interpedicular distance from T12 to L2; bifurcation of the distal humeri; elbow dislocation, genu recurvatum and hip dislocation; and undertubulation of the long bones. The unique combination of multiple coronal clefts and bifid distal humeri led to the disease name humerospinal dysostosis. With age, affected individuals develop kyphoscoliosis with narrow intervertebral spaces, severe degenerative joint diseases with joint restriction and occasionally supernumerary carpal bones. The late manifestation was termed SED Omani type. Large, round epiphyses of the long bones, particularly of the knee, may be seen in childhood prior to the development of joint degeneration. Prognosis: joint dislocations might require surgical intervention, which may be difficult. There is progressive degenerative joint disease and spondylosis. During childhood, kyphosis of the cervical spine will progressively develop, less commonly scoliosis. Adult height ranges from 110 cm to 140 cm. Intellect is normal. Differential diagnosis: CHST3-CD may be confused with Larsen dysplasia Reunion Island type caused by B4GALT7 pathogenic variants, also known as autosomal recessive Larsen syndrome, and also with autosomal dominant Larsen syndrome (p. 151), which has a characteristic ‘dish’ facies. The differential diagnosis comprises a group of bone dysplasias with joint dislocations, including SEMDJL Beighton type (p. 129), pseudodiastrophic dysplasia (p. 111), Desbuquois dysplasia (p. 121), diastrophic dysplasia and SEMDJL Hall type (p. 127). A lethal form of recessive Larsen syndrome has been described as a combination of the Larsen phenotype and pulmonary hypoplasia and is associated with pathogenic variants in the gene B3GAT3.

117

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CASE 1: (a) A neonate presented with genu recurvatum and elbow, knee and hip dislocation. (b–d) There is widening of the interpedicular distance of the upper lumbar spine, incomplete coronal clefts of the lumbar spine and bifurcation of the distal humerus. (e) The long bones show mild undertubulation. (f) Kyphosis of the cervical spine is noted.

Chondrodysplasia with Congenital Joint Dislocations (Recessive Larsen Syndrome), CHST3-Related

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CASE 2: Radiographs at age 3 months (a, b, c, d) and at age 10 months (e, f) show the same pattern as Case 1. Bifurcation of the distal humeri is more clearly seen.

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BIBLIOGRAPHY Albuz B, Çetin GO, Özhan B et al. A novel nonsense mutation in CHST3 in a Turkish patient with spondyloepiphyseal dysplasia, Omani type. Clin Dysmorphol. 2020; 29: 61–4. Dubail J, Cormier-Daire V. Chondrodysplasias with multiple dislocations caused by defects in glycosaminoglycan synthesis. Front Genet. 2021; 12: 642097. Duz MB, Topak A. Recurrent c.776T>C mutation in CHST3 with four other novel mutations and a literature review. Clin Dysmorphol. 2020; 29: 167–72. Hermanns P, Unger S, Rossi A et al. Congenital joint dislocations caused by carbohydrate sulfotransferase 3 deficiency in recessive Larsen syndrome and humero-spinal dysostosis. Am J Hum Genet. 2008; 82: 1368–74. Srivastava P, Pandey H, Agarwal D et al. Spondyloepiphyseal dysplasia Omani type: CHST3 mutation spectrum and phenotypes in three Indian families. Am J Med Genet A. 2017; 173: 163–8.

Fetal and Perinatal Skeletal Dysplasias Superti-Furga A, Unger S. CHST3-Related Skeletal Dysplasia. 2011 Sep 1 [updated 2019 Jan 31]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2020. Thiele H, Sakano M, Kitagawa H et al. Loss of chondroitin 6-O-sulfotransferase-1 function results in severe human chondrodysplasia with progressive spinal involvement. Proc Natl Acad Sci U S A. 2004; 101: 10155–60. Unger S, Lausch E, Rossi A et al. Phenotypic features of carbohydrate sulfotransferase 3 (CHST3) deficiency in 24 patients: Congenital dislocations and vertebral changes as principal diagnostic features. Am J Med Genet A. 2010; 152A: 2543–9. van Roij MH, Mizumoto S, Yamada S et al. Spondyloepiphyseal dysplasia, Omani type: Further definition of the phenotype. Am J Med Genet A. 2008; 146A: 2376–84.

15 Desbuquois Dysplasia, CANT1-Related Synonyms: DBQD; micromelic dwarfism with vertebral and metaphyseal abnormalities and advanced carpotarsal ossification Confirmation of diagnosis: identification of pathogenic variants in one of the associated genes with appropriate clinical and radiographic findings. Frequency: very rare – fewer than 50 cases reported in the literature. Genetics: autosomal recessive condition. Two types have been recognised depending on the presence or not of an accessory ossification centre on the second digit and/or a delta phalanx or bifid distal phalanx of the thumb. DBQ type 1 is caused by pathogenic variants in the gene coding calcium-activated nucleotidase-1 (CANT1), an extracellular enzyme which preferentially hydrolyses di/tri-phosphate nucleotides, particularly UDP and GDP. CANT1-specific variants have also been identified in a distinct form with no extra ossification centre distal to the second metacarpal but with short metacarpals and long phalanges (Kim variant) and in multiple epiphyseal dysplasia. DBQ type 2 (also called Baratela-Scott syndrome) is caused by mutations in the gene encoding xylosyltransferase 1 (XYLT1), which is the initiating enzyme in the biosynthesis of the glycosaminoglycan (GAG) linkage region. It catalyses the transfer of D-xylose from UDP-D-xylose to specific serine residues of the core protein. In DBQ type 1 and 2, reduced GAG synthesis has been demonstrated in patient fibroblasts. DBQ is part of the group of chondrodysplasias with multiple dislocations, which has been associated with pathogenic variants in genes encoding proteins implicated in GAG biosynthesis. They have been classified as defects in the linker region biosynthesis (XYLT1, B4GALT7, B3GALT6, B3GAT3, FAM20B), defects in GAG chain elongation or epimerisation (CSGALNACT1, CHSY1, DSE), defects in GAG sulfation (SLC26A2, CHST3, CHST11, CHST14, IMPAD1, SLC36B2) and defects in the activity of transporters and other Golgi proteins (SLC35A3, SLC10A7, CANT1, TMEM165). Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester (20 weeks). Clinical features: • Marked rhizo-mesomelic shortening of prenatal onset • Occasionally fetal hydrops

DOI: 10.1201/9781003166948-18

• • • • •

Severe generalised joint laxity Prominent eyes, flat nasal bridge, micrognathia Cleft palate Short and narrow thorax, pectus carinatum, kyphoscoliosis Possible associated anomalies: cardiac anomalies (septal defects, aortic coarctation), pulmonary hypoplasia, exomphalos, polyhydramnios

Prenatal ultrasound features: hydrops has been identified from 17 weeks, together with rhizomelic and mesomelic shortening. Dysmorphic features, especially micrognathia and proptosis, are present. Cleft palate can be detected early in the second trimester by 3D ultrasound. Specific sonographic signs are bilateral knee dislocations and severe bilateral genu recurvatum with talipes equinus. Abnormal hand positioning and/ or deformities of fingers in the hands may be detected in the second trimester. Distinctive features include an extra ossification centre distal to the second metacarpal (at the base of the proximal phalanx of the index) and bifid phalanx of the thumb. Lung hypoplasia is a predictor of a poor outcome. Radiographic features: the ‘monkey wrench’ or ‘Swedish key’ appearance of the proximal femur is due to a prominent lesser trochanter. The greater trochanter is high, and there is coxa valga. The acetabular roof is horizontal, and the ilia are small. There is proximal fibular overgrowth. Hand changes include either an extra ossification centre distal to the second metacarpal and/or a delta phalanx (longitudinal bracket epiphysis) of the thumb, sometimes with a bifid distal phalanx of the thumb (46% of cases) – type 1 – or no changes (54%) – type 2. In both types there is advanced carpal and tarsal bone maturation, small joint dislocations and short distal phalanges due to premature fusion of the epiphyses. Other findings in type 1 include large joint dislocations/subluxations, kyphoscoliosis in older children and coxa valga. In type 2, there may be coxa vara. Findings occasionally seen in both types include a small thorax, wide metaphyses and flat epiphyses of the knees, delayed ossification of epiphyses, coronal and sagittal clefts of the vertebral bodies, cervical spine abnormalities, wide anterior ribs, medial deviation of the feet and enlarged first metatarsals with bifid distal phalanges. In addition to the two documented types there is an apparently distinct variant with no extra ossification centre distal to the second metacarpal but with short metacarpals and long phalanges (Kim variant). Prognosis: can be viable, although respiratory distress due to narrow thorax and obstructive apnoea may be severe and lead to neonatal or early death. Affected patients show marked short

121

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stature (average adult height is 114 cm) and disabling joint laxity. Severe precocious osteoarthritis of the hands and spine is a major manifestation of the Kim variant. There may be intellectual impairment, obesity and glaucoma in the course of the disease.

diastrophic dysplasia (p. 111); pseudodiastrophic dysplasia (p. 133); other chondrodysplasias with multiple dislocation (CHST3-related) (p. 117); Ehlers-Danlos syndrome spondylodysplastic type and Larsen syndrome la Réunion type B4GALT7. The combination of hand features, growth failure severity and radiological aspects of long bones and of vertebrae allow discrimination among the different conditions.

Differential diagnosis: Larsen syndrome (FLNB) and OPD syndromes (p. 145, 148, 151); Catel-Mantzke syndrome (p. 293);

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CASE 1: Ultrasonic findings at 16 weeks showed bilateral short femora and humeri (at third percentile), radii, ulnae, tibiae and fibulae (less than third centile). Ultrasound demonstrated hyperextended knees, bilateral knee dislocations and severe bilateral ‘genu recurvatum’ with talipes equinus. (a) 2D-US, (b, c) 3D and 3D-HD live US at 16 weeks and 4 days gestation. (d) 3D-US maximum mode shows knee dislocation with fixed hyperextension and wide anterior ribs. (e) 3D-US HD live demonstrates the fetal hand with an apparent gap at the base between the second and third finger (white arrow). (f) Abnormal posture (clino-camptodactyly) with other characteristic hand changes, including an extra ossification centre distal to the second metacarpal (white arrow).

Desbuquois Dysplasia, CANT1-Related

123

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CASE 1: (g, h) Round face and midface hypoplasia with 3D CT scan correlation (19 GW). (i) 2D CT scan (19 GW) shows the cleft palate. (j, k) Fetal skeletal survey (19 GW) and, (l) lateral view showing prominent lumbar coronal clefts (red arrows). Postmortem 3D CT: different modalities of fetal 3D CT reconstruction.

124

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CASE 2: (a, d) Multiple dislocations (hips, knees and radial heads) and prominent lesser trochanters with ‘monkey wrench’ appearance of the proximal femora; (b, c) coronal clefts in the spine. (e) Advanced ossification of carpal bones. Extra ossification centre at the base of the middle proximal phalanx.

Desbuquois Dysplasia, CANT1-Related

125

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CASE 2: (f) Dolichocephaly. CASE 3: Dislocated knees and elbows. CASE 4: (a) Dislocated knees; prominent lesser trochanters; fusion of second, third and fourth right metatarsals; hypoplastic right hallux; (b) Multiple coronal clefts. (c) Dislocated elbows and curved proximal ulnae. (d) Duplication of proximal phalanges of the thumbs and hyperphalangy of index and middle fingers.

126

BIBLIOGRAPHY Balasubramanian K, Li B, Krakow D et al. MED resulting from recessively inherited mutations in the gene encoding calcium-activated nucleotidase CANT1. Am J Med Genet A. 2017; 173: 2415–21. Bui C, Huber C, Tuysuz B et al. XYLT1 mutations in Desbuquois dysplasia type 2. Am J Hum Genet. 2014; 94: 405–14. Dubail J, Cormier-Daire V. Chondrodysplasias with multiple dislocations caused by defects in glycosaminoglycan synthesis. Front Genet. 2021; 16(12): 642097. Furuichi T, Dai J, Cho TJ et al. CANT1 mutation is also responsible for Desbuquois dysplasia, type 2 and Kim variant. J Med Genet. 2011; 48: 32–7.

Fetal and Perinatal Skeletal Dysplasias Huber C, Oules B, Bertoli M et al. Identification of CANT1 mutations in Desbuquois dysplasia. Am J Hum Genet. 2009; 85: 706–10. Laccone F, Schoner K, Krabichler B et al. Desbuquois dysplasia type I and fetal hydrops due to novel mutations in the CANT1 gene. Eur J Hum Genet. 2011; 19: 1133–7. LaCroix AJ, Stabley D, Sahraoui R et al. GGC repeat expansion and exon 1 methylation of XYLT1 is a common pathogenic variant in Baratela-Scott syndrome. Am J Hum Genet. 2019; 104: 35–44. Ranza E, Huber C, Levin N et al. Chondrodysplasia with multiple dislocations: Comprehensive study of a series of 30 cases. Clin Genet. 2017; 91: 868–80.

16 SEMD with Joint Laxity (SEMD-JL, Hall Type), KIF22-Related

Synonyms: SEMDJL2; SEMDJL2, leptodactylic type; spondyloepimetaphyseal dysplasia with multiple dislocations, Hall type; spondyloepimetaphyseal dysplasia with joint laxity type 2 Confirmation of diagnosis: identification of missense pathogenic variants in KIF22. Frequency: rare. About 35 cases have been reported. Genetics: autosomal dominant, caused by pathogenic variants in KIF22 located on chromosome 16p11. The protein encoded by KIF22 is a member of the kinesin-like protein family, microtubule-dependent molecular motors that transport organelles within cells and move chromosomes during cell division. Age/Gestational age of manifestation: may be suspected in affected families based on facial dysmorphism and knee malposition in the third trimester. Clinical features: • Depressed nasal bridge; short, upturned nose; midface hypoplasia • Short stature • Ligamentous laxity • Congenital hip dislocation • Laryngotracheomalacia Prenatal ultrasound features: prenatal findings have not been well described. Suggestive facial features may be identified in

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affected families. Polyhydramnios and short long bones in the third trimester have been reported. Radiographic features: radiographic characteristics include significantly retarded epiphyseal ossification that evolves into epiphyseal dysplasia (small, irregular epiphyses) and precocious osteoarthritis, metaphyseal irregularities and vertical, longitudinal striations; constricted, tapered, beaked femoral necks; slender metacarpals and metatarsals; and mild thoracolumbar kyphosis or scoliosis with normal or mild platyspondyly. The most distinctive features for the differential diagnosis of SEMDJL2 are the slender metacarpals and phalanges and the small irregular carpal bones and reduced size of the overall carpus; however, these features are evident only in young children. Prognosis: viable. In infancy, respiratory obstruction due to laryngotracheomalacia may require tracheostomy. Joint laxity with subluxation or occasionally frank dislocation leads to mobility difficulty. The generalised epiphyseal abnormality progresses to severe precocious osteoarthritis. Cognitive development is normal. Differential diagnosis: other conditions with joint laxity or dislocations. B3GAT3-related phenotypes (p. 133), BGAIL7related phenotypes (EDSSD1 and Larsen dysplasia Reunion Island type); Larsen dysplasia (autosomal dominant and autosomal recessive) (p. 151); Desbuquois dysplasia (types 1 and 2) (p. 121); diastrophic dysplasia (p. 111); and SEMDJL1 (Beighton type) (p. 129). Differentiation is also needed from other conditions with severe epiphyseal dysplasia, such as many of the type 2 collagenopathies (p. 58–89). Sponastrime dysplasia has vertical/longitudinal striations in the metaphyses but is associated with severe platyspondyly in infancy and early childhood.

 

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CASE 1: (a, b) Undermodelled long bones, medial ‘beaking’ of the femoral necks and delayed ossification of the knee epiphyses; (c) biconvex vertebral endplates with some posterior constriction of the vertebral bodies.

DOI: 10.1201/9781003166948-19

127

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CASE 2: (a, b) Undermodelled long bones, medial beaking of the femoral necks and delayed ossification of the knee epiphyses; (c) platyspondyly with oval-shaped vertebral bodies and posterior constriction.

BIBLIOGRAPHY Beighton P, Kozlowski K. Spondylo-epi-metaphyseal dysplasia with joint laxity and severe, progressive kyphoscoliosis. Skeletal Radiol. 1980; 5: 205–12. Boyden ED, Campos-Xavier AB, Kalamajski S et al. Recurrent dominant mutations affecting two adjacent residues in the motor domain of the monomeric kinesin KIF22 result in skeletal dysplasia and joint laxity. Am J Hum Genet. 2011; 89: 767–72. Hall CM, Elcioglu NH, MacDermot KD et al. Spondylo­ epimetaphyseal dysplasia with multiple dislocations (hall type): Three further cases and evidence of autosomal dominant inheritance. (Letter) J Med Genet. 2002; 39: 666–70. Hall CM, Elcioglu NH, Shaw DG. A distinct form of spondyloepimetaphyseal dysplasia with multiple dislocations. J Med Genet. 1998; 35: 566–72. Holder-Espinasse M, Fayoux P, Morillon S et al. Spondylo­ epimetaphyseal dysplasia (hall type) with laryngeal stenosis: A new diagnostic feature? Clin Dysmorph. 2004; 13: 133–5. Kim O-H, Cho T-J, Song H-R et al. A distinct form of spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL)leptodactylic type: Radiological characteristics in seven new patients. Skeletal Radiol. 2009; 38: 803–11. Megarbane A, Ghanem I, Le Merrer M. Spondyloepimetaphyseal dysplasia with multiple dislocations, leptodactylic type:

Report of a new patient and review of the literature. Am J Med Genet. 2003; 122A: 252–6. Min B-J, Kim N, Chung T et al. Whole-exome sequencing identifies mutations of KIF22 in spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type. Am J Hum Genet. 2011; 89: 760–6. Nishimura G, Honma T, Shiihara T et al. Spondyloepimetaphyseal dysplasia with joint laxity leptodactylic form: Clinical course and phenotypic variations in four patients. Am J Med Genet. 2003; 117A: 147–53. Nishimura G, Mikawa M, Fukushima Y. Another observation of Langer-type sponastrime dysplasia variant. (Letter). Am J Med Genet. 1998; 80: 288–90. Park S-M, Hall CM, Gray R et al. Persistent upper airway obstruction is a diagnostic feature of spondyloepimetaphyseal dysplasia with multiple dislocations (hall type) with further evidence for dominant inheritance. Am J Med Genet. 2007; 143A: 2024–8. Rossi M, De Brasi D, Hall CM et al. A new familial case of spondylo-epi-metaphyseal dysplasia with multiple dislocations hall type (leptodactylic form). Clin Dysmorph. 2005; 14: 13–8. Tüysüz B, Yılmaz S, Erener-Ercan T et al. Spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type: Longitudinal observation of radiographic findings in a child heterozygous for a KIF22 mutation. Pediatr Radiol. 2015; 45: 771–6.

17 SEMD with Joint Laxity (SEMD-JL, Beighton Type), B3GALT6-Related

Synonyms: SEMDJL1; Ehlers-Danlos syndrome spondylodysplastic (progeroid) type 2 (EDSSPD2; EDSP2) Diagnostic confirmation: identification of biallelic pathogenic variants in the B3GAL6 gene. Frequency: rare. More than 50 affected individuals have been known. The disorder is more prevalent in the Afrikaner population living in South Africa due to a founder mutation. Genetics: autosomal recessive due to homozygous or compound heterozygous pathogenic variants in B3GALT6 mapped on chromosome 1q36.33 and encoding a key enzyme (beta-1,3-galactosyltransferase 6) for the biosynthesis of the glycosaminoglycan (GAG) linker region. SEMDJL belongs to a group of disorders with impairment of the GAG linker, collectively termed linkeropathies. Founder mutations are known in the Afrikaner population living in South Africa (c.235A>G; p.Thr79Ala) and in the East Asian population (c.1A>G; p.Met1? and c.694C>T; p.Arg232Cys). Age/Gestational age of manifestation: mild shortening of the limbs can be detected in the third trimester. Clinical features: • Short limbs, usually proportionate • Congenital or early-onset kyphoscoliosis, progressive • Elbow contracture secondary to radial head hypoplasia/ subluxation • Joint laxity especially prominent in the finger joints • Often hip dislocation and clubfeet • Occasionally mild facial dysmorphisms (oval face, protuberant eyes, blue sclera, long philtrum, cleft palate) • Soft elastic skin • Spatulated fingertips Prenatal ultrasound features: the abnormal skeletal features are usually visible during late pregnancy. Currently, 2D and 3D ultrasound can detect non-specific signs of the disease, including facial dysmorphism, as proptosis, flattened nasal bridge, flat face, micrognathia and cleft palate. Short long bones may be associated with talipes equinovarus. Routine

DOI: 10.1201/9781003166948-20

mid-trimester fetal ultrasound scan can detect cardiac septal defects and abnormalities of the kidneys and urinary tracts (unilateral renal agenesis, pyelectasis, double collecting system and ureterocoele). Scoliosis has been rarely suspected in affected fetuses. Radiographic features: the findings include moderate platyspondyly with anterior projection of the vertebral bodies at an early age and later less pronounced platyspondyly; progressive kyphoscoliosis develops in early childhood and rapidly deteriorates during the preschool age; wide, short ilia with narrowing of the greater sciatic notch; metaphyseal flaring of the long bones; hypoplasia and subluxation of the radial head; relative shortening of the metacarpals and relative elongation of the phalanges; mildly advanced carpal skeletal age. Platyspondyly and iliac changes are already evident in the neonatal period. Prognosis: viable. In newborns and in infants the main features are more related to the connective tissue involvement, while skeletal features evolve progressively postnatally. Progressive kyphoscoliosis can cause neurological compromission and even cardiorespiratory failure due to severe thoracic deformity. Since the spinal malalignment is refractory to conservative management, early surgical intervention may be required. Anomalies of dentition have been reported. In a proportion there can be developmental delay and cognitive disability. Differential diagnosis: SEMDJL1 should be differentiated from other linkeropathies; B3GAT3-associated phenotypes, including B4GALT7-associated phenotypes (EDSSD1 and Larsen dysplasia Reunion Island type) (p. 133); and other bone dysplasias with multiple dislocation, including Larsen dysplasia (autosomal dominant and autosomal recessive) (p. 151), Desbuquois dysplasia (types 1 and 2) (p. 121), diastrophic dysplasia (p. 111) and SEMDJL type 2 (Hall type) (p. 127). Multiple joint dislocation and contracture, iliac dysplasia and metaphyseal flaring in these disorders resemble those of SEMDJL1. However, these disorders, unlike SEMDJL1, are not associated with overt platyspondyly, but with only mild or even absent spondylar dysplasia. On radiological grounds, SEMDJL1 is most similar to mild cases of metatropic dysplasia (p. 176). Striking metaphyseal flaring or dumbbell deformity of the long bones in metatropic dysplasia is distinguishable from mild metaphyseal flaring in SEMDJL1.

129

130

Fetal and Perinatal Skeletal Dysplasias

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(1e)

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CASE 1: Radiographs at age 3 days (a–f) show mild platyspondyly, wide ilia with narrowing of the greater sciatic notch, mild metaphyseal flaring of the long bones, mild malalignment of the elbow joint, relative shortening of the metacarpals and mild clubfoot. Fetal CT at age 33 weeks of gestation.

SEMD with Joint Laxity (SEMD-JL, Beighton Type), B3GALT6-Related

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(1j)

131

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CASE 1: (g, h) Demonstrates mild platyspondyly and wide ilia with narrowing of the greater sciatic notch, as does skeletal survey in the neonatal period. Radiographs at age 6 months (i–l) more apparently show platyspondyly, iliac deformity and metaphyseal flaring. The right hip shows subluxation. The proximal radius is hypoplastic, suggesting proximal radioulnar subluxation.

132

Fetal and Perinatal Skeletal Dysplasias

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CASE 2: Radiographs at age 4 months (a–f) show platyspondyly with anterior vertebral projection; wide, short ilia and metaphyseal flaring of the long bones; and hypoplasia of the proximal radius.

BIBLIOGRAPHY Caraffi SG, Maini I, Ivanovski I et al. Severe peripheral joint laxity is a distinctive clinical feature of spondylodysplastic-Ehlers-Danlos syndrome (EDS)-B4GALT7 and spondylodysplastic-EDS-B3GALT6. Genes (Basel). 2019; 10: 799. Chimusa ER, Beighton P, Kumuthini J et al. Detecting genetic modifiers of spondyloepimetaphyseal dysplasia with joint laxity in the Caucasian Afrikaner community. Hum Mol Genet. 2019; 28: 1053–63. Christianson AL, Beighton P. Spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL) in three neonates. Genet Couns. 1996; 7: 219–25. Dubail J, Cormier-Daire V. Chondrodysplasias with multiple dislocations caused by defects in glycosaminoglycan synthesis. Front Genet. 2021; 12: 642097.

Honey EM. Spondyloepimetaphysealdysplasia with joint laxity (Beighton type): A unique South African disorder. S Afr Med J. 2016; 106: S54–6. Malfait F, Kariminejad A, Van Damme T et al. Defective initiation of glycosaminoglycan synthesis due to B3GALT6 mutations causes a pleiotropic Ehlers-Danlos-syndromelike connective tissue disorder. Am J Hum Genet. 2013; 92: 935–45. Nakajima M, Mizumoto S, Miyake N et al. Mutations in B3GALT6, which encodes a glycosaminoglycan linker region enzyme, cause a spectrum of skeletal and connective tissue disorders. Am J Hum Genet. 2013; 92: 927–34. Vorster AA, Beighton P, Ramesar RS. Spondyloepimetaphyseal dysplasia with joint laxity (Beighton type); mutation analysis in eight affected South African families. Clin Genet. 2015; 87: 492–5.

18 Multiple Joint Dislocations, Short Stature, Craniofacial Dysmorphisms and Skeletal Dysplasia, with or without Heart Defects (Pseudodiastrophic Dysplasia), B3GAT3-Related

Synonyms: JDSCD (multiple joint dislocations, short stature and craniofacial dysmorphism with or without congenital heart defects; B3GAT3 deficiency), PPD, pseudodiastrophic dysplasia Diagnostic confirmation: identification of biallelic pathogenic variants in the B3GAT3 gene together with clinical and radiological findings. Frequency: very rare. Approximately a dozen affected individuals have been reported. However, the disorder may be more prevalent than currently believed. PDD is likely to be a phenotypic variation of JDSCD. Over two dozen affected individuals with JDSCD have been known. Genetics: PDD is an autosomal recessive disorder due to homozygous or compound heterozygous pathogenic variants in B3GAT3, mapped on chromosome 11q12.3 and encoding beta-1,3-glucurosyltransferase 3, essential for biosynthesis of the glycosaminoglycan (GAG) linker region. PDD belongs to a group of disorders with impairment of the GAG linker, collectively termed linkeropathy. Meanwhile, it is reported that siblings with a similar or identical phenotype had biallelic pathogenic variants in CANT1 (a disease-causing gene for Desbuquois dysplasia). Thus, it is postulated that PDD is not a disease entity, but only a severe manifestation seen in a heterogeneous group of disorders with abnormal proteoglycan biosynthesis. Age/Gestational age of manifestation: short limbs of affected fetuses are discernible in the late second trimester. Some affected fetuses show severe bowing of the long bones. The clinical and radiological manifestations are full-blown as neonates. Clinical features: the clinical hallmarks comprise maldevelopment of bone and joints. Early lethality is not uncommon as a result of thoracic hypoplasia with pulmonary hypoplasia and major airway compromise. Cardiac anomalies may be responsible for the early demise. • Short stature with rhizomelic shortening and bowing of the limbs • Hyperextensibility and/or contracture of joints • Dislocation of the large joints, particularly of the elbow and hip joints • Clubfeet

DOI: 10.1201/9781003166948-21

• Long fingers with interphalangeal subluxation; spatulate fingertips • Short, narrow chest; short neck; abnormal curvature of the spine • Craniofacial dysmorphism (relatively large head, hypertelorism, midface hypoplasia, protuberant eyes, blue sclera, full cheeks, long philtrum, small mouth, micrognathia with cleft palate) • Occasionally congenital cardiac defects (valvular incompetence and structural anomalies). Prenatal ultrasound features: the long bones are identified as short and sometimes bowed in the second trimester. These findings are usually not distinctive enough to allow diagnosis. Radiographic features: the findings include craniofacial disproportion (relatively large head and small facial bones); short, narrow thorax; mild to moderate platyspondyly with ovoid vertebral bodies; wide, flared ilia commonly associated with supraacetabular notch as a result of hip dislocation; striking metaphyseal broadening of the long bones, particularly of the proximal femora, proximal humeri and distal radii; commonly elbow and hip dislocation; bowing of the long bones, commonly of the femur and radius/ulna; elongation of the metacarpals and phalanges with interphalangeal dislocation. There is a report of affected sibling fetuses with severe bowing of the long bones, which spontaneously ameliorated with progression of gestational age. Prognosis: PDD is a semi-lethal disorder. Most affected individuals manifest with respiratory distress in the neonatal period and require respiratory support. The majority die from cardiorespiratory compromise in infancy. PDD does not show the hallmarks of diastrophic dysplasia, such as the ‘hitchhiker thumb’ and cystic swelling of the pinnae. Clubfeet in PDD is reported to respond well to the standard management, but not in diastrophic dysplasia. Differential diagnosis: distinction between PDD and JDSCD is difficult. In JDSCD, however, skin elasticity and/or cutis laxa is prominent, radioulnar synostosis is common and bone fragility may be present. PDD shares many features with other linkerpathies, particularly SEMDJL1 (p. 129) and EDSSPD1. PDD is also differentiated from other bone dysplasias with multiple joint dislocations, such as Larsen dysplasia (p. 151), diastrophic dysplasia (p. 111) and Desbuquois dysplasia (p. 121).

133

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Fetal and Perinatal Skeletal Dysplasias

(1a)

(1d)

 

 

(1e)

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(1f )

(1c)

 

 

CASE 1: Radiographs as a neonate (a–f) show a broad thorax; wide, flared ilia; mild platyspondyly with ovoid vertebral bodies; metaphyseal widening of the long bones; mild bowing of the femora, tibiae and fibulae; twisting of the radii and ulnae; elbow subluxation; clubfeet; and arachnodactyly with interphalangeal subluxation.

Multiple Joint Dislocations, Short Stature, Craniofacial Dysmorphisms and Skeletal Dysplasia

135

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(2b)

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CASE 2: Radiographs as a neonate (a–d) Show a broad thorax; wide, flared ilia; mild platyspondyly; hip and knee dislocations; femoral bowing; clubfeet; and arachnodactyly. CASE 3: A stillbirth. A postmortem radiograph shows metaphyseal widening of the limbs, elbow dislocation, bowing of the ulnae and femora, clubfeet and arachnodactyly with interphalangeal subluxation. CASE 4: The neonatal radiographs demonstrate dislocations of the hips and elbows and subluxations of the fingers. There is mild bowing of the radii and ulnae.

136

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Fetal and Perinatal Skeletal Dysplasias

 

BIBLIOGRAPHY Byrne AB, Mizumoto S, Arts P et al. Pseudodiastrophic dysplasia expands the known phenotypic spectrum of defects in proteoglycan biosynthesis. J Med Genet. 2020; 57: 454–60. Canki-Klain N, Stanescu V, Bebler P et al. Pseudodiastrophic dysplasia evolution with age and management. Report of two new cases and review of the literature. Ann Genet. 1990; 33: 129–36. Colman M, Van Damme T, Steichen-Gersdorf E et al. The clinical and mutational spectrum of B3GAT3 linkeropathy: Two case reports and literature review. Orphanet J Rare Dis. 2019; 14: 138. Eteson DJ, Beluffi G, Burgio GR et al. Pseudodiastrophic dysplasia: A distinct newborn skeletal dysplasia. J Pediatr. 1986; 109: 635–41.

(4d)

Jones KL, Schwarze U, Adam MP et al. A homozygous B3GAT3 mutation causes a severe syndrome with multiple fractures, expanding the phenotype of linkeropathy syndromes. Am J Med Genet A. 2015; 167A: 2691–6. Ritelli M, Cinquina V, Giacopuzzi E et al. Further defining the phenotypic spectrum of B3GAT3 mutations and literature review on linkeropathy syndromes. Genes (Basel). 2019; 10: 631. Yap P, Liebelt JE, Amor DJ et al. Pseudodiastrophic dysplasia: Two cases delineating and expanding the pre and postnatal phenotype. Am J Med Genet A. 2016; 170A: 1363–6. Yauy K, Tran Mau-Them F, Willems M et al. B3GAT3-related disorder with craniosynostosis and bone fragility due to a unique mutation. Genet Med. 2018; 20: 269–74.

19 Frontometaphyseal Dysplasia, FLNA-, MAP3K7- and TAB2-Related

Synonyms: FMD; frontometaphyseal dysplasia 1; FMD1; frontometaphyseal dysplasia 2; FMD2 Confirmation of diagnosis: identification of pathogenic variants in FLNA, MAP3K7 or TAB2 with the appropriate clinical and radiographic features. Frequency: unknown. FMD1 is the most common, while only about 20 cases of FMD2 have been reported, and very few are TAB2-related. Genetics: FMD1 is an X-linked recessive disorder caused by gain-in-function pathogenic variants in FLNA encoding filamin A, a cytoplasmic protein which binds the actin cytoskeleton and links it to membrane receptors, and is therefore crucial for signal transduction and membrane stability. FMD is part of a group of disorders caused by gain-in-function mutations in FLNA defined as the ‘otopalatodigital syndrome spectrum disorders’, which also includes OPD1, OPD2 and Melnick-Needles syndrome (MNS). There is a well-defined genotype-phenotype correlation: mutations associated with FMD are scattered throughout the gene; mutations in exons 3, 4 or 5, which encode the distal portion of the actinbinding domain, lead to OPD1 or OPD2; females affected by OPD2 might also carry a mutation in exons 11, 28 or 29; only three mutations in exon 22 are currently associated with MNS. Penetrance of mutations related to the OPD syndrome spectrum disorders is complete in males and incomplete in females. Females usually present with a milder phenotype. Loss-of-function FLNA pathogenic variants can cause periventricular nodular heterotopia. FMD2 is an autosomal dominant disorder caused by heterozygous missense pathogenic variants in the MAP3K7 gene encoding TGF-β-activated kinase 1 (TAK1). A few cases of FMD have been reportedly associated with heterozygous variants in the gene TAB2, whose product binds TAK1. FMD1 is considered to be caused by overexpression of TAK1. Age/Gestational week of manifestation: can be detected by ultrasound during the second to third trimester (after 20 weeks). Clinical features: • Prominent supraorbital ridges, down-slanting palpebral fissures, prominent eyes, hypertelorism, full cheeks, oligohypodontia • Limb bowing • Joint limitation at the wrists, elbows, knees, ankles

DOI: 10.1201/9781003166948-22

• Urethral and ureteric stenosis, cardiac anomalies (septal defects, pulmonary stenosis, vascular aneurysms), prominent keloid formation in type 2 • Laryngeal stenosis • Congenital and non-progressive muscular hypoplasia • Small mandible, rarely cleft palate Prenatal ultrasound features: many of the manifestations may be visualised, although the gestational age at which various anomalies can be detected differs. A cardiac anomaly or urinary tract severely dilated by obstruction may be visible from very early in the second trimester. In contrast, the skeletal dysplasia with its associated limb bowing and thoracic hypoplasia may be visible only after 20 weeks’ gestation. The diagnosis is only suggested prenatally in at-risk families. Radiographic features: in the skull there is localised supraorbital thickening of the frontal bone. The skull vault is thickened with some sclerosis, and pronounced convolutional markings and craniosynostosis may occur. The base is sclerotic with lack of pneumatisation of the mastoid air cells and frontal sinuses, and the mandible is small. Fusion of vertebral bodies (especially the second to fourth cervical vertebral bodies) and deficiency of the posterior vertebral arches are common, and scoliosis develops. There is pronounced widening of the interpedicular distances in the lumbar spine. In the thorax the ribs are wavy and distorted. The iliac bones are flared. The long bones are bowed with a characteristic S-shaped bowing of the tibiae. The metaphyses are wide and undermodelled, giving the ‘Erlenmeyer flask’ appearance of the distal femora. There may be advanced ossification of the femoral and tibial epiphyses and coxa valga with hip dislocation. The metacarpals, metatarsals and phalanges are elongated and poorly modelled. The distal phalanges of the thumbs and halluces are hypoplastic. There are progressive flexion contractures of the hand over the first two decades resulting in marked limitation of movement at the interphalangeal and metacarpophalangeal joints. Carpal and tarsal fusions are common. Erosion of the carpal bones has been observed in adolescence and adulthood. Affected females have a milder phenotype. Prognosis: perinatal death is common in the more severely affected males. Tracheal malformations may cause recurrent infections. Mixed hearing loss is present in almost all individuals. Males do not have a progressive skeletal dysplasia, but often develop secondary complications, especially progressive joint contractures, which are particularly disabling in the hands over the first two decades. Progressive scoliosis has

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Fetal and Perinatal Skeletal Dysplasias

been described in both males and females. Intellect is generally normal in FLNA-related FMD, while there can be intellectual disability in MAP3K7-related FMD. Keloid formation and cervical fusions have also been reported in FMD2. Urinary tract dilatation from stenoses may occur.

(1a)

(1b)

(1d)

  (1e)

 

Differential diagnosis: Shprintzen-Goldberg syndrome (p. 504). Other otopalatodigital syndrome spectrum disorders: these include OPD1 (p. 145), OPD2 (p. 148), osteodysplasty or Melnick-Needles syndrome (p. 141).

(1c)

 

(1f )

CASE 1: (a, b) Neonatal films. Undermodelled, broad short tubular bones with short metacarpals and absent ossification of the middle phalanges of the toes; (c–f) at 9 months of age. Characteristic supracetabular notch with flared iliac wings and coxa valga; narrow pedicles with widening of the interpedicular spaces; slender mildly wavy ribs. (g, h) Pronounced supraorbital ridge, large skull vault and pronounced skull markings.

Frontometaphyseal Dysplasia, FLNA-, MAP3K7- and TAB2-Related

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139

 

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CASE 2: Healthy normal-height parents; no family history of any similar condition. (a, f) At birth ‘funny fingers and toes’, full cheeks and prominent eyes were noted; (c) Thickened supraorbital ridge; sclerotic skull base and short mandible; (d) Undermodelled, bowed long bones with wide metaphyses; wide lumbar interpedicular distances; flared narrow ilia; vertical ischia; dislocated hip; (e) Bowed tibiae; wide metaphyses; (h, i) CT head at 1 year for an unusually shaped head, prominent eyes and global moderate delay.

140

(2g)

BIBLIOGRAPHY Clark AR, Sawyer GM, Robertson SP et al. Skeletal dysplasias due to filamin A mutations result from a gain-of-function mechanism distinct from allelic neurological disorders. Hum Mol Genet. 2009; 18: 4791–800. Robertson SP, Filamin A. Phenotypic diversity. Curr Opin Genet Dev. 2005; 15: 301–7. Robertson SP. Otopalatodigital syndrome spectrum disorders: Otopalatodigital syndrome types 1 and 2, frontometaphyseal dysplasia and Melnick-Needles syndrome. Eur J Hum Genet. 2007; 15: 3–9.

Fetal and Perinatal Skeletal Dysplasias

   

(2h)

Robertson SP, Jenkins ZA, Morgan T et al. Frontometaphyseal dysplasia: Mutations in FLNA and phenotypic diversity. Am J Med Genet A. 2006; 140A: 1726–36. van Woerden GM, Senden R, de Konink C et al. The MAP3K7 gene: Further delineation of clinical characteristics and genotype/phenotype correlations. Hum Mutat. 2022; 43: 1377–95. Wade EM, Daniel PB, Jenkins ZA et al. Mutations in MAP3K7 that alter the activity of the TAK1 signalling complex cause frontometaphyseal dysplasia. Am J Hum Genet. 2016; 99: 392–406.

20 Melnick-Needles Syndrome (Osteodysplasty), FLNA-Related

Synonyms: Melnick-Needles syndrome; MNS; osteodysplasty Confirmation of diagnosis: identification of gain-in-function pathogenic variants in FLNA with the appropriate clinical and radiographic findings. Frequency: rare; fewer than 1:100,000 people. Genetics: MNS is an X-linked dominant disorder caused by pathogenic variants in the gene FLNA encoding filamin A, a cytoplasmic protein which binds the actin cytoskeleton and links it to membrane receptors, and is therefore crucial for signal transduction and membrane stability. MNS is part of a group of disorders caused by gain-in-function mutations in FLNA defining the ‘otopalatodigital syndrome spectrum disorders’, also including OPD1, OPD2 and frontometaphyseal dysplasia. There is a well-defined genotype-phenotype correlation: almost all (>90%) individuals with MNS have pathogenic variants in exon 22 of FLNA (mostly p.Ala1188Thr or p.Ser1199Leu); rarely, variants have been identified in exons 6 and 23. Variants in exons 3, 4 or 5, which encode the distal portion of the actin-binding domain, lead to OPD1 or OPD2; variants in exons 11, 28 and 29 have been detected in females affected by OPD2; variants associated with FMD are scattered throughout the gene. Penetrance of mutations related to the OPD syndrome spectrum of disorders is complete in males and incomplete in females. Females affected by MNS have been reported to have almost complete skewed inactivation of the chromosome X carrying the mutation. Somatic mosaicism has been reported in some cases. Loss-of-function FLNA variants can cause periventricular nodular heterotopia. Three specific missense variants in the N-terminal third of the gene have been found in myxomatous cardiac valvular dystrophy. Age/Gestational week of manifestation: can be detected by ultrasound late in the first trimester or during the second trimester (14–20 weeks) in the case of a male fetus; females are usually undetected. Clinical features – Females: • Prominent lateral borders of the supraorbital ridges, proptosis, full cheeks, micrognathia, facial asymmetry, oligohypodontia • Limb bowing, joint subluxation • Narrow thorax, scoliosis • Long digits DOI: 10.1201/9781003166948-23

• Hydronephrosis secondary to ureteric obstruction • Conductive deafness, hoarse voice Clinical features – Males: • Indistinguishable from severe OPD2 (p. 148) • Multiple organ malformations: urethral atresia, megacystis, prune belly sequence, tetralogy of Fallot, atrioventricular canal defects, malrotation of the gut Prenatal ultrasound features: many of the manifestations can be visualised prenatally, although the gestational age at which various anomalies can be detected differs. An exomphalos or urinary tract severely dilated by obstructive uropathy may be visible from very early in the second trimester. In contrast, severe micrognathia, skeletal changes with limb bowing, scoliosis and thoracic hypoplasia may be detected with accuracy between 16 and 20 weeks. A lethally affected male fetus may be identified prenatally from 13 weeks in a woman with MNS. Oligohydramnios or polyhydramnios may be present. Findings may include decreased ossification of the skull vault, periventricular nodular heterotopia, hypertelorism, proptosis, ‘prune belly–like’ abdominal wall, cardiac abnormalities (tetralogy of Fallot, atrioventricular canal defect), bowel malrotation and positional deformities of the hands and feet. Radiographic features: affected females show considerable variability in severity. There is delayed closure of the fontanelles and sclerosis of the skull base with mild thickening of the vault and sometimes pronounced convolutional markings. There is underpneumatisation of the frontal sinuses and mastoid air cells. The clavicles show cortical irregularity with some medial widening, and there is an irregular contour to the ribs (ribbon-ribs). The thorax is narrow. The long bones are bowed with an S-shape and with cortical irregularity and show metaphyseal widening. There is angulation of the neck of the radius. The metacarpals, metatarsals and phalanges are elongated, but the distal phalanges are short. Joint subluxations develop. The vertebral bodies are tall with wide interpedicular distances, and scoliosis develops. The iliac wings are flared with inferior hypoplasia and supra-acetabular constriction. Affected males exhibit severe malformations similar to those observed in individuals with OPD2 (p.), resulting in prenatal lethality or death in the first few months of life. Prognosis: almost all males die early prenatally or perinatally. At term, the male phenotype is identical to OPD2. MNS is the

141

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most severe phenotype within the ‘otopalatodigital syndrome spectrum disorders’ in males. Females show a wide phenotypic variability, with some patients presenting only with subtle features and others having a reduced life span (death in the second to third decade) due to respiratory failure. Short stature and mixed deafness are common. There is no intellectual disability.

Frank-ter Haar syndrome presents with similar, although milder, skeletal features, but also shows macrocornea and glaucoma. Serpentine fibula-polycystic kidney disease also presents with cystic kidney disease and elongated and curved fibulae and does not show metaphyseal anomalies, bowing of the tibiae or cortical irregularities. Shprintzen-Goldberg syndrome (p. 504); affected male fetuses of women with osteopathia striata with cranial sclerosis (p. 421).

Differential diagnosis: other otopalatodigital syndrome spectrum disorders (pp. 137, 145, 148).

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CASE 1: Short distal phalanges, metatarsus adductus; undermodelled short tubular bones; slender ribs, bowed tibiae, vertical ischia and constricted inferior ilia.

Melnick-Needles Syndrome (Osteodysplasty), FLNA-Related

(2a)

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(2b)

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(3b)

(3a)

143

 

(3e)

CASE 2: Abnormal course of NJ tube demonstrating small bowel malrotation due to exomphalos; narrow pedicles with wide lumbar interpedicular distances; wavy long bones; dislocated elbow. CASE 3: Bowing of long bones, wide metaphyses; undermodelled short tubular bones; short distal phalanges; anterior concavity of thoracic vertebral bodies; constricted pelvic outlet; vertical ischia; supra-acetabular notch with flared iliac wings.

144

Fetal and Perinatal Skeletal Dysplasias

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CASE 4: Bowed long bones; dislocated radial heads; absent glenoid fossae; constricted bases of the ilia, vertical ischia; wide interpedicular distances in the lumbar spine.

BIBLIOGRAPHY Clark AR, Sawyer GM, Robertson SP et al. Skeletal dysplasias due to filamin A mutations result from a gain-of-function mechanism distinct from allelic neurological disorders. Hum Mol Genet. 2009; 18: 4791–800. Foley C, Roberts K, Tchrakian N et al. Expansion of the spectrum of FLNA mutations associated with Melnick-Needles syndrome. Mol Syndromol. 2010; 1: 121–6. Naudion S, Moutton S, Coupry I et al. Fetal phenotypes in otopalatodigital spectrum disorders. Clin Genet. 2016; 89: 371–7.

Robertson SP. Otopalatodigital syndrome spectrum disorders: Otopalatodigital syndrome types 1 and 2, frontometaphyseal dysplasia and Melnick-Needles syndrome. Eur J Hum Genet. 2007; 15: 3–9. Robertson SP. Filamin a: Phenotypic diversity. Curr Opin Genet Dev. 2005; 15: 301–7. Von Oeyen P, Holmes LB, Trelstad RL et al. Omphalocele and multiple severe congenital anomalies associated with osteodysplasty (Melnick-Needles syndrome). Am J Med Genet. 1982; 13: 453–63.

21 Otopalatodigital Syndrome Type 1, FLNA-Related

Synonyms: OPD1; OPD I syndrome; OPD syndrome 1; frontooto-palato-digital osteodysplasia; Taybi syndrome Confirmation of diagnosis: identification of pathogenic variants in FLNA with the appropriate clinical and radiographic findings. Frequency: unknown. Genetics: OPD1 is an X-linked dominant disorder caused by pathogenic variants in the gene FLNA encoding filamin A, a cytoplasmic protein which binds the actin cytoskeleton and links it to membrane receptors, and is therefore crucial for signal transduction and membrane stability. OPD1 is part of a group of disorders caused by gain-in-function mutations in FLNA defining the ‘otopalatodigital syndrome spectrum of disorders’, which also includes OPD2, frontometaphyseal dysplasia (FMD) and Melnick-Needles syndrome (MNS). There is a well-defined genotype-phenotype correlation: variants in exons 3, 4 or 5, which encode the distal portion of the actin-binding domain, lead to OPD1 or OPD2; females affected by OPD2 might also carry variants in exons 11, 28 and 29; a few variants in exon 22 (mostly p.Ala1188Thr or p.Ser1199Leu) and rarely variants in exons 6 and 23 are associated with MNS; variants associated with FMD are scattered throughout the gene. Penetrance of variants related to the OPD syndrome spectrum of disorders is complete in males and incomplete in females. Gonadal mosaicism has been reported in OPD1 families. Loss-of-function FLNA variants can cause periventricular nodular heterotopia. Three specific missense variants in the N-terminal third of the gene have been found in myxomatous cardiac valvular dystrophy. Age/Gestational week of manifestation: birth; cleft palate can be detected by ultrasound during the second to third trimester Clinical features: • Prominent supraorbital ridges, downslanting palpebral fissures, hypertelorism, broad nasal bridge and tip, hypodontia, oligodontia • Cleft palate • Limited elbow extension, knee flexion and wrist abduction

DOI: 10.1201/9781003166948-24

• Mild bowing of long bones • Digital anomalies: short and proximally placed thumbs, ‘spatulate’ tips of the fingers, hypoplastic halluces, long second toe, wide sandal gap • Pectus excavatum Prenatal ultrasound features: the diagnosis is usually only established at birth. Prenatal ultrasound diagnosis is challenging, not only for clinical overlap with other entities but also because only subtle skeletal abnormalities may be present. 2D and 3D ultrasound examination at 18–22 weeks of gestation may detect dysmorphic features including hypertelorism, cleft secondary palate, cleft lip/primary palate, broad nasal bridge, micrognathia and low-set ears. When combined with bowed long bones and abnormal digits, the diagnosis can be suspected. Chest deformities and a wide sandal gap between the first and second toes may be present. Radiographic features: there is sclerosis of the skull base, thickening of the vault and underdevelopment of the frontal sinuses. The mastoid air cells are not pneumatised, and the angle of the mandible is obtuse. The neural arches can fail to fuse, particularly in the cervical spine. The long bones are mildly bowed, and there is dislocation of the radial heads. In the hands a pseudoepiphysis at the base of the second metacarpal is characteristic. The second digits are long. Short, broad first metacarpals and distal phalangeal hypoplasia most marked in the thumb is also characteristic. There is camptodactyly and a wide space between the second and third fingers. Accessory carpal bones and fusion of carpal and tarsal bones can also be present. The pelvis is narrow with a lack of normal flaring of the ilia. Prognosis: viable – OPD1 represents the mildest phenotype in males within the OPD spectrum of disorders. Mixed deafness is always present. Final height can be mildly reduced in a proportion of cases. Intellectual development is normal. Life span is not reduced; no long-term significant complications are reported. Females can have the same severity as males, but frequently have only mild manifestations. The OPD1 phenotype in females may be indistinguishable from OPD2. Differential diagnosis: Larsen syndrome (p. 151). Other otopalatodigital syndrome spectrum disorders (p. 137, 141, 148).

145

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CASE 1: (a, c, d) Neonatal films; (b, e, f) at 9 months of age. He had a cleft palate and conductive hearing loss with the characteristic pugilistic face and a wide sandal gap between the first and second toes. Short metacarpals, metatarsals and distal phalanges; attempted duplication distal phalanges of thumbs, index fingers, big toes and second toes; advanced carpal bone age; pseudoepiphysis base of left second metatarsal; metatarsus adductus; steep clivus; coxa valga; flared iliac bones.

Otopalatodigital Syndrome Type 1, FLNA-Related

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147

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BIBLIOGRAPHY Clark AR, Sawyer GM, Robertson SP et al. Skeletal dysplasias due to filamin A mutations result from a gain-of-function mechanism distinct from allelic neurological disorders. Hum Mol Genet. 2009; 18: 4791–800. Joksic I, Cuturilo G, Jurisic A et al. Otopalatodigital syndrome type I: Novel characteristics and prenatal manifestations in two siblings. Balkan J Med Genet. 2019; 22: 83–8. Kusajima EG, Maeda T, Murao N et al. Cleft lip in oto-palatodigital syndrome type I. Congenit Anom (Kioto). 2021; 61: 103–4.

Naudion S, Moutton S, Coupry I et al. Fetal phenotypes in otopalatodigital spectrum disorders. Clin Genet. 2016; 89: 371–7. Robertson SP. Otopalatodigital syndrome spectrum disorders: Otopalatodigital syndrome types 1 and 2, frontometaphyseal dysplasia and Melnick-Needles syndrome. Eur J Hum Genet. 2007; 15: 3–9.

22 Otopalatodigital Syndrome Type 2, FLNA-Related

Synonyms: OPD2; OPD II syndrome; OPD syndrome 2; cranio-oro-digital syndrome; facio-palato-osseous syndrome; FPO Confirmation of diagnosis: identification of pathogenic variants in FLNA with appropriate clinical and radiographic findings. Frequency: unknown, but very rare. Genetics: OPD2 is an X-linked dominant disorder caused by pathogenic variants in the gene FLNA encoding filamin A, a cytoplasmic protein which binds the actin cytoskeleton and links it to membrane receptors, and is therefore crucial for signal transduction and membrane stability. OPD2 is part of a group of disorders caused by gain-in-function mutations in FLNA defined as the ‘otopalatodigital syndrome spectrum of disorders’, which also includes OPD1, frontometaphyseal dysplasia (FMD) and Melnick-Needles syndrome (MNS). There is a well-defined genotype-phenotype correlation: variants in exons 3, 4 or 5, which encode the distal portion of the actin-binding domain, lead to OPD1 or OPD2; females affected by OPD2 might also carry variants in exons 11, 28 and 29; a few variants in exon 22 (mostly p.Ala1188Thr or p.Ser1199Leu) and rarely variants in exons 6 and 23 are associated with MNS; variants associated with FMD are scattered throughout the gene. Penetrance of variants related to the OPD syndrome spectrum of disorders is complete in males and incomplete in females. Gonadal mosaicism has been reported in OPD1 families. Loss-of-function FLNA variants can cause periventricular nodular heterotopia. Three specific missense variants in the N-terminal third of the gene have been found in myxomatous cardiac valvular dystrophy. Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester (18 weeks). Clinical features: • Prominent forehead, downslanting palpebral fissures, hypertelorism, midface hypoplasia, flat nasal bridge, oligodontia, Pierre Robin sequence, low-set and posteriorly rotated ears • Cleft palate • Bowed long bones • Scoliosis • Narrow thorax • Hypoplastic thumbs and halluces, absent halluces, camptodactyly 148

• Affected males may also show exomphalos, hydronephrosis, ureteric obstruction, hypospadias; • cardiac anomalies: septal defects, right ventricular outflow tract obstruction; • brain anomalies: hydrocephalus, cerebellar hypoplasia, encephalocele, myelomeningocele Prenatal ultrasound features: from about 18 weeks, long bone shortening and bowing, absent or hypoplastic fibulae, abnormal digits, platyspondyly and coronal clefts may be identified. Characteristic facial features can be detected by 2D and 3D ultrasound, such as frontal bossing, flat and broad nasal bridge, hypertelorism, prominent eyes, midface hypoplasia, micrognathia, cleft lip/palate and low-set ears. Omphalocele is the most striking defect in male fetuses. The thorax is small with lung hypoplasia. Other findings include brain anomalies (hydrocephalus, Dandy-Walker malformation and neuronal migration disorders), cardiac defects and obstructive uropathy. There may be oligohydramnios secondary to bladder outflow obstruction or polyhydramnios. Radiographic features: the skull vault may be hypomineralised in the neonatal period, the anterior fontanelle is large and there is pronounced skull base sclerosis with hypoplastic facial bones. The thorax is hypoplastic with angulated, ribbonlike ribs and widened posterior ribs. There may be 11 pairs of ribs. The long bones are bowed with wide metaphyses, the radii short with dislocated heads and there is absent ossification of the fibulae. In the hands the metacarpals and phalanges are short and broad, and the second metacarpal has a characteristic half-moon or delta appearance. The thumbs are short with absent (or bifid) distal phalanges. The fingers show camptodactyly and syndactyly, and there is a wide gap between the index and middle fingers. In the feet several metatarsals may be unossified and the phalanges hypoplastic. The halluces are absent or broad and short. The interpedicular distances are wide, and extensive spinal dysraphism or coronal clefting may be present. In the pelvis the iliac wings are flared, inferior iliac bones constricted, acetabula horizontal, pubic bones unossified and ischia vertical. Female carriers have a subclinical bone dysplasia and facial dysmorphism but may occasionally manifest a more severe phenotype. Prognosis: males usually die within the first year of life, often secondary to thoracic hypoplasia with resulting pulmonary insufficiency. Survivors require respiratory support and assistance with feeding and usually have neurodevelopmental DOI: 10.1201/9781003166948-25

Otopalatodigital Syndrome Type 2, FLNA-Related

149

delay and mixed deafness. Females are less severely affected, often presenting only with a subclinical phenotype; rarely, they can manifest a phenotype similar in severity to that of males. Craniofacial features are the most common findings; conductive hearing loss has been reported. Females affected by OPD1 and OPD2 show almost the same phenotype.

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Differential diagnosis: other otopalatodigital syndrome spectrum disorders (p. 137, 141, 145); atelosteogenesis type 3 (p. 162); Larsen syndrome (p. 151); Yunis-Varon syndrome (p. 488). Bowed limbs, narrow thorax and cleft palate: Campomelic dysplasia (p. 302); dyssegmental dysplasia: (p. 166).

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CASE 1: Small chest, bowing of the long bones; dislocated elbow; vertical ischia, flared iliac wings; absent fibulae. CASE 2: Bowing of long bones; dislocated elbows; narrow pedicles; brachycephaly, small posterior fossa, steep clivus; flared iliac wings and narrow pelvic outlet.

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BIBLIOGRAPHY Clark AR, Sawyer GM, Robertson SP et al. Skeletal dysplasias due to filamin A mutations result from a gain-of-function mechanism distinct from allelic neurological disorders. Hum Mol Genet. 2009; 18: 4791–800. Kaissi AA, Kraschi R, Kaulfersch W et al. Extended phenotypes in a boy and his mother with oto-palato-digital-syndrome type II. Clin Case Rep. 2015; 3: 762–6. Mariño-Enríquez A, Lapunzina P, Robertson SP et al. Otopalatodigital syndrome type 2 in two siblings with A novel filamin A 629G>T mutation: Clinical, pathological, and molecular findings. Am J Med Genet A. 2007; 143A: 1120–5.

Naudion S, Moutton S, Coupry I et al. Fetal phenotypes in otopalatodigital spectrum disorders. Clin Genet. 2016; 89: 371–7. Robertson SP. Otopalatodigital syndrome spectrum disorders: Otopalatodigital syndrome types 1 and 2, frontometaphyseal dysplasia and Melnick-Needles syndrome. Eur J Hum Genet. 2007; 15: 3–9.

23 Larsen Syndrome, FLNB-Related

Synonyms: LRS Confirmation of diagnosis: identification of pathogenic variants in FLNB with appropriate clinical and radiographic findings. Frequency: 1 in 100,000. Genetics: Larsen syndrome is an autosomal dominant disorder caused by a heterozygous pathogenic variant in FLNB encoding the cytoskeletal protein filamin B. FLNB-related disorders are a spectrum which spans from milder forms, such as Larsen syndrome and spondylocarpotarsal synostosis (SCT) syndrome to severe conditions such as atelosteogenesis types I (AOI) and III (AOIII) and Piepkorn osteochondrodysplasia (POCD). The variants associated with Larsen syndrome, atelosteogenesis types 1 and 3 and Boomerang dysplasia, are either missense or small in-frame deletions and result in the expression of an abnormal protein. Larsen syndrome can also be associated with somatic mosaicism for an FLNB mutation. Variants associated with Larsen syndrome are predominantly located in exons 2–5 and 27–33. Frameshift or nonsense mutations, associated with loss of protein expression, are associated with spondylocarpotarsal synostosis syndrome, which is inherited in a recessive fashion. Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester (16 weeks). Clinical features: • Multiple large joint congenital dislocations; joint hypermobility • Specific facial features: prominent forehead, flat profile, flat nasal bridge, hypertelorism • Cleft palate (15%), hearing loss • Cylindrical fingers, spatulate distal phalanges, particularly thumbs • Talipes equinovarus • Occasionally congenital heart defects and neurological abnormalities Prenatal ultrasound features: the definitive diagnosis is usually made postnatally, with antenatal diagnosis reported more often in at-risk families. Limb abnormalities include rhizomelic micromelia of the upper limbs with distal humeral tapering or short humeri, with asymmetrical shortening of the forearm and leg bones. Joint dislocations occur with hyperextension (genu recurvatum) of the knees, dislocation of the hip, flexion deDOI: 10.1201/9781003166948-26

formities of the elbows and fixed flexion of the fingers. The fingers may be thickened. Talipes equinovarus occurs. The thorax is small. Three-dimensional ultrasound demonstrates a dysmorphic facies with a prominent and high forehead, hypertelorism, flat nasal bridge and midface, low-set ears and micrognathia with a prominent upper lip. Vertebral coronal clefts can be noted in the cervical and lumbar spine. Four-dimensional ultrasound may be useful in confirming large joint laxity. Polyhydramnios can occur during the second trimester. Radiographic features: the thorax may be small and bellshaped. There are multiple large and small joint dislocations. The humeri may be short and tapered distally. The short tubular bones are variably short and broad with rounded or domed metaphyses. Supernumerary carpal and tarsal bones are present. There may be talipes equinovarus. In the spine there may be cervical spine instability and cervical kyphosis. Various segmentation defects may occur as well as coronal clefts. In the pelvis the pubic rami are short with a wide symphysis pubis. The capital femoral epiphyses can show premature ossification. Prognosis: viable – neonatal or early death can rarely occur due to respiratory problems secondary to laryngotracheomalacia. Cervical spine instability is common and should be monitored and ideally pre-emptively stabilised. Patients with cervical spine problems have a higher anaesthetic risk. Dysplasia of the vertebral laminae and hypoplasia of the lateral processes of all cervical vertebrae may be present. Individuals with Larsen syndrome and cervical spine dysplasia are at significant risk for cervical cord myelopathy and secondary tetraparesis. Other skeletal complications include talipes equinovarus, dislocations or subluxations of the large joints, scoliosis and cervical kyphosis. Hearing loss is common due to malformations of the auditory ossicles. Oral problems include malocclusion, periodontitis, gingival hyperplasia and hypodontia. Stature is generally within the normal range. Intellect is usually normal, although neurodevelopmental delay has been reported in a minority of cases. Differential diagnosis: the so-called ‘recessive Larsen syndrome’, also including the Reunion Island form of Larsen syndrome, is radiographically different. Spondyloepiphyseal dysplasia (SED) Omani type or humerospinal dysostosis can be similar to Larsen syndrome at birth, but later develops progressive spondylodysplasia, epiphyseal dysplasia and rhizomelic limb shortening. It is caused by mutations in CHST3; omodysplasia (p. 273). Some overlap with FLNB-related disorders, in particular atelosteogenesis type 1/3 (p. 156, 162) and FLNA-related 151

152

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disorders, particularly otopalatodigital syndrome type1 (p. 145). Other disorders with multiple congenital dislocations: Desbuquois dysplasia (p. 121), diastrophic dysplasia (p. 111), pseudodiastrophic dysplasia (p. 133). Ehlers-Danlos syndromes comprise a heterogeneous group of connective tissue disorders also characterised by skin hyperextensibility,

(1a)

(1c)

abnormal wound healing, hypotonia, easy bruising and vascular complications including spontaneous rupture of large arteries. Fetal akinesia deformation sequence consists of a combination of anomalies secondary to poor fetal movements, such as multiple joint contractures, facial anomalies, pulmonary hypoplasia and polyhydramnios.

(1b)

(1d)

CASE 1: Dislocated hips, knees and elbows; (c) short metacarpals and broad phalanges with rounded metaphyses (‘tombstone’-like); (d) short, distally tapered humerus.

Larsen Syndrome, FLNB-Related

153

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CASE 2: Dislocated hips and knees. CASE 3: Short, distally tapered humeri; dislocated elbows and knees. CASE 4: Multiple dislocations; coronal cleft vertebrae; short metacarpals.

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Fetal and Perinatal Skeletal Dysplasias

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(5g) CASE 5: Dislocated knees, hips and elbows. Multiple coronal clefts in the spine. Short, distally tapered humerus. Severe cervical kyphosis.

Larsen Syndrome, FLNB-Related

BIBLIOGRAPHY Becker R, Wegner RD, Kunze J et al. Clinical variability of Larsen syndrome: Diagnosis in a father after sonographic detection of a severely affected fetus. Clin Genet. 2000; 57: 148–50. Bicknell LS, Farrington-Rock C, Shafeghati Y et al. A molecular and clinical study of Larsen syndrome caused by mutations in FLNB. J Med Genet. 2007; 44: 89–98. De La Rocha A, Birch JG, Schiller JR. Precocious appearance of the capital femoral ossific nucleus in Larsen syndrome. J Bone Joint Surg Am. 2012; 94: e551–4. Hickey SE, Koboldt DC, Mosher TM et al. Novel in-frame FLNB deletion causes Larsen syndrome in a three-generation pedigree. Cold Spring Harb Mol Case Stud. 2019; 5: a004176.

155 S UK, Sankar S, Younes S et al. Deciphering the role of filamin B calponin-homology domain in causing the Larsen syndrome, boomerang dysplasia, and atelosteogenesis type I spectrum disorders via a computational approach. Molecules. 2020; 25: 5543. Shih JC, Peng SS, Hsiao SM et al. Three-dimensional ultrasound diagnosis of Larsen syndrome with further characterization of neurological sequelae. Ultrasound Obstet Gynecol. 2004; 24: 89–93. Winer N, Kyndt F, Paumier A et al. Prenatal diagnosis of Larsen syndrome caused by a mutation in the filamin B gene. Prenat Diagn. 2009; 29: 172–4.

24 Atelosteogenesis Type 1 (Includes Boomerang Dysplasia), FLNB-Related Synonyms: AO1, AOII, giant cell chondrodysplasia, spondylohumerofemoral hypoplasia; includes boomerang dysplasia and Piepkorn dysplasia Confirmation of diagnosis: identification of missense pathogenic variants or small in-frame deletions in FLNB. Frequency: unknown for AO1, but rare; fewer than 20 cases of boomerang dysplasia reported. Genetics: boomerang dysplasia, Piepkorn dysplasia and atelosteogenesis types 1 and 3 are part of a continuous pathological spectrum caused by dominant pathogenic variants in FLNB encoding the cytoskeletal protein filamin B. Allelic disorders are Larsen syndrome and spondylocarpotarsal synostosis. The variants associated with Larsen syndrome, atelosteogenesis types 1 and 3 and Boomerang dysplasia, are either missense or small in-frame deletions and result in the expression of an abnormal protein. Larsen syndrome can also be associated with somatic mosaicism for an FLNB mutation. Variants associated with Larsen syndrome are predominantly located in exons 2–5 and 27–33. Frameshift or nonsense mutations associated with loss of protein expression are associated with spondylocarpotarsal synostosis syndrome, which is inherited in a recessive fashion. Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester between the 13th and 16th week of pregnancy. Clinical features: • Polyhydramnios • Short stature, severe limb shortening and bowing • Absence of long bones (humerus, femora, fibulae, metacarpals) • Dislocated hips, knees, elbows, clubfeet • Brachydactyly • Cleft palate, hypertelorism, flat nasal bridge, midface hypoplasia, micrognathia • Laryngeal stenosis • Thoracic hypoplasia, narrow pelvis In boomerang dysplasia: • Encephalocele, exomphalos • Limb rigidity 156

In Piepkorn dysplasia: • Syndactyly, polydactyly, mitten-like hands with small nubbins of tissue for the toes • Craniosynostosis with widely open anterior fontanelle • Occasionally cardiac and genitourinary defects Prenatal ultrasound features: AO1 can present as a hydropic fetus with micromelia and features which can be evocative of a lethal disorder. The clinical hallmarks, early in the second trimester, include severe shortening and deficient ossification of the long bones, especially the femora and humeri. The humerus may be distally tapered or absent; radii, ulnae and tibiae are bowed with hypoplastic or absent fibulae; and talipes equinovarus deformity is present. Dislocations of the hip, knee and elbow may be present. Sagittal scan of the spine shows reduced echogenicity of the vertebral bodies and of the posterior neural arches; coronal clefts may be present at the level of the lumbar vertebrae. The thorax is narrow with a relatively protuberant abdomen. 2D and 3D ultrasound can detect hypertelorism, depressed nasal bridge, midface hypoplasia, micrognathia and cleft palate. Short metacarpal/metatarsals with broad and flat distal phalanges determine a particular form of brachydactyly in the hands and feet: ‘paddle shaped with spatulate fingers’. The distal phalanges, well ossified, are detected by ultrasound, whereas the middle and proximal phalanges appear absent because of underossification. In boomerang dysplasia there is severe micromelia and absent ossification of many long bones. Short fingers and toes may be associated with oligosyndactyly or polysyndactyly. One of the most typical features is that only one of the three tubular bones may be identified in each limb, which is bowed (‘boomerang’like). Humeri and femora might not be visible either because they are absent or unossified. The elbows and knee joints cannot be identified, and talipes equinovarus may be present. The dysmorphic features include a flat face with hypertelorism and severe micrognathia. The thorax appears small and bellshaped, whereas the abdomen is protuberant. The spine and skull vault are poorly ossified. Omphalocele can rarely be present. Polyhydramnios can occur after 20 weeks of gestation. Radiographic features: in AO1 the humerus is hypoplastic and tapers distally and the femur is hypoplastic. There is platyspondyly with coronal clefts and incomplete vertebral ossification in the thoracic region. There are absent or hypoplastic carpals, tarsals, metacarpals, metatarsals and proximal DOI: 10.1201/9781003166948-27

Atelosteogenesis Type 1 (Includes Boomerang Dysplasia), FLNB-Related and middle phalanges, and the ossified short tubular bones have bizarre shapes. Various long bones, especially the fibulae, may be absent. This forms part of an overlapping phenotype with boomerang dysplasia. This has multiple joint dislocations. In the spine there is platyspondyly, scoliosis, coronal and sagittal clefts and segmentation defects. There may be cervical spine anomalies with instability and kyphosis and pronounced lordosis. The humeri are short with distal tapering as in AO1, and other long bones are short with smooth, rounded metaphyses. There are abnormalities of the short tubular bones. In the hands the proximal phalanges are relatively large and evenly ossified with convex ends, and sometimes with a distal notch. The middle phalanges are round and hypoplastic and the distal phalanges short and broad. There is talipes equinovarus. In boomerang dysplasia a well-ossified bone in the shape of a boomerang is seen in the position of the tibia with absent fibula. The femora, humeri, radii and ulnae may be variably absent. Other long bones are short, bowed and undermodelled. The skull vault is undermineralised with large fontanelles and may show an ossification defect if an encephalocele is present.

157

In the spine ossification is deficient, especially of the vertebral bodies, and the metacarpals and proximal and middle phalanges might also be absent. Other phalanges may show convex, rounded metaphyses, giving a ‘tombstone’ appearance. The pelvis is characteristic, with rounded and flared iliac wings, which taper and are hypoplastic inferiorly with no acetabula. The ischia are well developed, but the pubic rami are unossified. There may be talipes equinovarus. Prognosis: boomerang dysplasia and Piepkorn dysplasia are prenatally lethal; AO1 is perinatally lethal. These disorders form a continuous spectrum. Differential diagnosis: atelosteogenesis type 2 (p. 108), Larsen syndrome (p. 151), otopalatodigital syndrome type 2 (p. 148). Other disorders with poor skeletal ossification: osteogenesis imperfecta (p. 429); hypophosphatasia (p. 452); achondrogenesis, all types (p. 58, 105, 256). Other lethal disorders with micromelia: thanatophoric dysplasia (p. 36), Grebe dysplasia (p. 283). Mitten-­like hands typical of Piepkorn syndrome can also be found in Apert syndrome (p. 496), albeit here polydactyly is rare and there is no micromelia, while there is craniosynostosis.

(1) CASE 1: Multiple joint dislocations; distal tapering of humeri; absent fibulae.

 

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CASE 2: Absent ossification of humeri and some metacarpals and phalanges of the hands and feet; rhizomelic shortening; incomplete ossification of the thoracic vertebral bodies with absent pedicles of the lumbar and sacral; absent fibulae. CASE 3: Atelosteogenesis 1/3 (26-week gestation); three-­dimensional image of the lower extremities showing severe flexion deformity with bilateral clubfeet; (c) two-dimensional US of the right hand showing marked brachydactyly with almost absent mineralisation of the metacarpals and phalanges, with an arrow pointing to a broad thumb; (d, e) three-­dimensional US of the facies, torso and upper extremities showing flat facies with a small, upturned nose and micromelia with ulnar deviation of the hands.

Atelosteogenesis Type 1 (Includes Boomerang Dysplasia), FLNB-Related

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(3j) CASE 2: (f) Very short tibia with arrow pointing to area of absent/deficient fibula. (g) Two-dimensional image of the vertebral column with poor ossification of the cervical vertebrae. The arrows point to a hypoechoic space with two lateral white lines that represent the spinal cord, not normally seen at 26 weeks’ gestation. CASE 3: (h) Two-dimensional US of the profile showing small, upturned nose and micrognathia. (i) Three-dimensional image of the facies. Note the very flat nasal bridge and upturned nares; (j) radiographic appearances at term.

160

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(4g) CASE 4: Dislocated hips and elbows. Scoliosis and multiple coronal cleft vertebrae. Short humerus with distal tapering. Bowed radius and ulna. Short broad phalanges and metacarpals. Absent ossification of proximal and middle phalanges of the toes. Short superior pubic rami and sloping acetabula.

Atelosteogenesis Type 1 (Includes Boomerang Dysplasia), FLNB-Related

161

BOOMERANG DYSPLASIA, FLNB-RELATED

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CASES 1–3: Postmortem radiographs and fetal CT show absent ossification of many of the long bones. The few long bones that are ossified are short and bowed, resembling boomerangs. Poorly ossified vertebral bodies.

BIBLIOGRAPHY Bicknell LS, Morgan T, Bonafé L et al. Mutations in FLNB cause boomerang dysplasia. J Med Genet. 2005; 42: e43. Farrington-Rock C, Firestein MH, Bicknell LS et al. Mutations in two regions of FLNB result in atelosteogenesis I and III. Hum Mutat. 2006; 27: 705–10. Kumar SU, Sankar S, Younes S et al. Deciphering the role of filamin B calponin-homology domain in causing the Larsen syndrome, boomerang dysplasia, and atelosteogenesis type I spectrum disorders via a computational approach. Molecules. 2020; 25: 5543. Odent S, Loget P, Le Marec B et al. Unusual fan shaped ossification in a female fetus with radiological features of boomerang dysplasia. J Med Genet. 1999; 36: 330–2. Schultz C, Langer LO, Laxova R et al. Atelosteogenesis type III: A long-term survival, prenatal diagnosis, and evidence for dominant transmission. Am J Med Genet. 1999; 83: 28–42.

Stern HJ, Graham JM Jr, Lachman RS et al. Atelosteogenesis type III: A distinct skeletal dysplasia with features overlapping atelosteogenesis and oto-palato-digital syndrome type II. Am J Med Genet. 1990; 36: 183–95. Tsutsumi S, Maekawa A, Obata M et al. A case of boomerang dysplasia with a novel causative mutation in filamin B: Identification of typical imaging findings on ultrasonography and 3D-CT imaging. Fetal Diagn Ther. 2012; 32: 216–20. Ueno K, Tanaka M, Miyakoshi K et al. Prenatal diagnosis of atelosteogenesis type I at 21 weeks’ gestation. Prenat Diagn. 2002; 22: 1071–5. Wessels A, Wainwright HC, Beighton P. Atelosteogenesis type I: Autopsy findings. Pediatr Dev Pathol. 2011; 14: 496–500.

25 Atelosteogenesis Type 3, FLNB-Related

Synonyms: AO3, AOIII Confirmation of diagnosis: identification of pathogenic variants in FLNB with appropriate clinical and radiographic findings. Frequency: about 25 cases have been identified. Genetics: atelosteogenesis types 1 and 3, boomerang dysplasia and Piepkorn dysplasia, are part of a continuous pathological spectrum caused by dominant pathogenic variants in FLNB encoding the cytoskeletal protein filamin B. Allelic disorders are Larsen syndrome and spondylocarpotarsal synostosis. The variants associated with Larsen syndrome, atelosteogenesis types 1 and 3 and Boomerang dysplasia, are either missense or small in-frame deletions and result in the expression of an abnormal protein. Larsen syndrome can also be associated with somatic mosaicism for an FLNB mutation. Variants associated with Larsen syndrome are predominantly located in exons 2–5 and 27–33. Frameshift or nonsense mutations associated with loss of protein expression are associated with spondylocarpotarsal synostosis syndrome, which is inherited in a recessive fashion. Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester (16–20 weeks). Clinical features: • • • •

Polyhydramnios Short stature, severe limb shortening and bowing Dislocated hips, knees, elbows, clubfeet Cleft palate, hypertelorism, flat nasal bridge, short nose, micrognathia • Broad distal phalanges, syndactyly, camptodactyly • Thoracic hypoplasia • Laryngotracheomalacia Prenatal ultrasound features: in AO3, ultrasonography at 20 weeks can detect rhizomelic shortness of the limbs and talipes

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equinovarus, with other biometric values within normal limits. The humerus may be markedly short, with rounding and flaring of the proximal metaphysis and distal tapering giving a ‘drumstick’ appearance. 3D ultrasound can detect craniofacial abnormalities: hypertelorism, depressed nasal bridge, micrognathia and a cleft palate. Later in pregnancy, broad distal phalanges, coronal clefts in the thoracolumbar vertebral bodies and platyspondyly can be visualised. Short and bowed tibiae can be demonstrated; polyhydramnios may develop during the third trimester. Radiographic features: AO3 has multiple joint dislocations. In the spine there is platyspondyly, scoliosis, coronal and sagittal clefts and segmentation defects. There may be cervical spine anomalies with instability and kyphosis and pronounced lordosis. The humeri are short with distal tapering, as in AO1, and other long bones are short with smooth, rounded metaphyses. There are abnormalities of the short tubular bones. In the hands the proximal phalanges are relatively large and evenly ossified with convex ends, and sometimes with a distal notch. The middle phalanges are round and hypoplastic and the distal phalanges short and broad. There is talipes equinovarus. Prognosis: AO3 is milder than AO1 and can be viable; however, intensive neonatal care is generally required because of respiratory failure due to laryngotracheomalacia and thoracic hypoplasia. Cervical spine instability may cause cord compression. Developmental delay has been reported in a proportion of AO3 cases and attributed to consequences of oxygen depletion from respiratory complications. As a result of orthopaedic abnormalities, there is delayed development of motor skills such as standing and walking. Differential diagnosis: atelosteogenesis type 2 (p. 108). Allelic disorders: boomerang dysplasia and AO1 (p. 156) represent the severest end of the phenotypical spectrum of FLNB-related disorders, while Larsen syndrome (p. 151) is at the milder end. Other disorders with poor skeletal ossification: osteogenesis imperfecta (p. 429); hypophosphatasia (p. 452); achondrogenesis, all types (p. 58, 105, 256). Other lethal disorders with micromelia: thanatophoric dysplasia (p. 36).

DOI: 10.1201/9781003166948-28

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CASE 1: (a) Bilateral calcaneovalgus. (c) Short third metacarpal, ‘tombstone’ phalanges. (e) Dislocated knees. (f) Hypoplasia of posterior vertebral bodies. (g) Tapered distal humerus. (h, i) Absence/hypoplasia of cervical bodies/neural arches; wide gap between C1 and C2 with atlanto-occipital fusion; spondylolysis of C4; indentation of the inferoposterior occiput with prominence superiorly.

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CASE 2: Presented at birth with a cleft palate and breathing and feeding difficulties. There were multiple joint dislocations, and the limbs showed rhizomelic shortening. The dysmorphic features included a broad forehead, depressed nasal bridge and hypertelorism. Radiographs show tapered distal humeri and short, broad metacarpals and phalanges. CASE 3: Hypoplastic cervical vertebral bodies and spondylolysis. Prominent occiput. CASE 4: Knee dislocations; short, tapered humeri; short metacarpals and middle phalanges.

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CASE 5: Short, distally tapered humeri; dislocated elbows, hips, knees and ankles; short first and third metacarpals and short, wide middle phalanges; hypoplastic cervical vertebral bodies.

BIBLIOGRAPHY Farrington-Rock C, Firestein MH, Bicknell LS et al. Mutations in two regions of FLNB result in atelosteogenesis I and III. Hum Mutat. 2006; 27: 705–10. Sarikaya IA, Gorgun B, Erdal OA. Atelosteogenesis type III: Orthopedic management. J Ped Orthopaedics B. 2017; 26: 546–51.

Schultz C, Langer LO, Laxova R et al. Atelosteogenesis type III: A long-term survival, prenatal diagnosis, and evidence for dominant transmission. Am J Med Genet. 1999; 83: 28–42. Stern HJ, Graham JM Jr, Lachman RS et al. Atelosteogenesis type III: A distinct skeletal dysplasia with features overlapping atelosteogenesis and oto-palato-digital syndrome type II. Am J Med Genet. 1990; 36: 183–95.

26 Dyssegmental Dysplasia, HSPG2-Related

Synonyms: anisospondylic camptomicromelic dwarfism; dyssegmental dysplasia (DD) is classified into two subtypes: severe Silverman-Handmaker type (DDSH) and mild RollandDesbuquois type (DDRD) Confirmation of diagnosis: identification of biallelic pathogenic variants in the HSPG2 gene. Frequency: fewer than 1 in 1,000,000. Genetics: DDSH, DDRD and Schwartz-Jampel syndrome (SJS) encompass a continuous spectrum of autosomal recessive disorders. DDSH and SJS are due to biallelic pathogenic variants in HSPG2, mapped on 1p36.12 and encoding heparan sulphate proteoglycan 2, alternatively termed perlecan. DDSH variants are associated with complete loss of function, while SJS-associated variants cause partial loss of function. Perlecan is a unique heparan sulphate proteoglycan that binds to the basement membrane proteins (e.g., collagen IX and laminin-1) and acts as a coreceptor for FGF2. Perlecan is involved in the cartilage matrix structure and has a pivotal role in chondrocyte proliferation. Perlecan deficiency interferes with bone growth and leads to secondary acetylcholine-esterase deficiency at the neuromuscular junction and ultimately myotonia. Age/Gestational age of manifestation: the fetal manifestation can usually be detected by ultrasound during the second trimester (14–18 weeks), with the most severe forms by the 12th week. Clinical features: • • • • • • • •

Polyhydramnios Severe short stature Midface hypoplasia, cleft palate, pursed lips Narrow chest with respiratory distress Microcampomelia Reduced joint movements, clubfeet Hirsutism Occipital encephalocele (DDSH)

Prenatal ultrasound features: polyhydramnios is a common finding. Scalp oedema, cystic hygroma, ascites and sometimes

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hydrops can be present in the fetus. The long bones are all short and bowed; in contrast, the skull measurements are normal. Micromelia is pronounced, and the thorax is small. There is marked spinal disorganisation, coronal clefting and scoliosis. There is talipes equinovarus. Occipital encephalocele may be identified in DDSH. Radiographic features: DDSH and DDRD share the same radiological pattern but show different severities. The hallmarks include moderate platyspondyly, anisospondyly, bowing of the long bones, dumbbell deformity of the tubular bones and broad ilia. Anisospondyly refers to abnormally increased variability in size of the vertebral bodies that have either single or multiple ossification centres. In severe cases, some vertebral bodies are extremely large, while others have totally absent ossification. In milder cases, the vertebral bodies have multiple coronal clefts or mild variability in an ossification pattern. The presence of the gigantic vertebral bodies causes increased interpedicular distances in the spine. Anisospondyly may be restricted to the thoracolumbar junction in DDRD, while it is more extensive in DDSH. Bowing of the long bones is variable. The femora show either posteromedial or anterolateral bowing. Lateral bowing is the rule in the tibiae and fibulae. The radii and ulnae may show mild bowing. Dumbbell deformity is milder in DDRD. The ilia are broad and round. The greater sciatic notches are short, but the acetabula are sloping. It is noteworthy that the upper cervical spine, particularly of C2–C3, shows defective vertebral ossification, which may cause kyphotic deformity. Prognosis: DDSH is inevitably perinatally lethal. Neonates with DDRD invariably show respiratory failure that may lead to perinatal lethality. However, survival beyond the neonatal period with respiratory support is more frequently reported. Longer-term survivors may develop myotonic facies but not overt myotonia. Differential diagnosis: the combination of dumbbell deformity with coronal clefts in DDRD is like that of Kniest dysplasia (p. 82). Anisospondyly in DDSH is so unique that the definitive diagnosis is readily made. DDRD may be confused with metatropic dysplasia (p. 176). However, metatropic dysplasia shows more severe platyspondyly but not overt anisospondyly.

DOI: 10.1201/9781003166948-29

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CASES 1–3: Stillbirths: All fetuses show a small thorax with short ribs, striking anisospondyly, wide interpedicular distances of the lumbar spine, round ilia with short sciatic notches and broad ischia. The long bones are short, curved and dumbbell shaped. There is bilateral talipes equinovarus. CASE 4: A stillbirth at an early gestational age. Retarded ossification of the vertebral bodies does not allow identification of anisospondyly. Wide interpedicular distances support the diagnosis. Medial bowing of the femora is common in dyssegmental dysplasia, Silverman-Handmaker type.

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CASES 5, 6: Neonates. Both patients show the same phenotypes, including striking anisospondyly, broad ilia and mild dumbbell deformity and bowing of the long bones. Fetal CT (5c) illustrates the postnatal manifestations. CASE 7: Radiographs in the neonatal period (a, b) show severe dumbbell deformity and bowing of the long bones but mild anisospondyly. Radiographs at age 4 years and 8 months (c–e) show severe narrowing of the upper thorax and persistent bowing of the long bones.

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CASES 8, 9: Neonates. Both patients show mild dumbbell deformity and bowing of the long bones. Anisospondyly is more severe in Case 8 than in Case 9. Ossification of the cervical spine is defective in both.

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BIBLIOGRAPHY Anderson PE, Hauge M, Bang J. Dyssegmental dysplasia in siblings: Prenatal ultrasonic diagnosis. Skeletal Radiol. 1988; 17: 29–31. Arikawa-Hirasawa E, Wilcox WR, Le AH et al. Dyssegmental dysplasia, Silverman-Handmaker type, is caused by functional null mutations of the perlecan gene. Nat Genet. 2001; 27: 431–4. Arikawa-Hirasawa E. Impact of the heparan sulfate proteoglycan perlecan on human disease and health. Am J Physiol Cell Physiol. 2022; 322: C1117–C1122. Basalom S, Trakadis Y, Shear R et al. Dyssegmental dysplasia, Silverman-Handmaker type: A challenging antenatal diagnosis in a dizygotic twin pregnancy. Mol Genet Genomic Med. 2018; 6: 452–6. Ladhani NN, Chitayat D, Nezarati MM et al. Dyssegmental dysplasia, Silverman-Handmaker type: Prenatal ultrasound findings and molecular analysis. Prenat Diagn. 2013; 33: 1039–43.

171 Martinez JR, Dhawan A, Farach-Carson MC. Modular proteoglycan perlecan/HSPG2: Mutations, phenotypes, and functions. Genes (Basel). 2018; 9: 5. Rieubland C, Jacquemont S, Mittaz L et al. Phenotypic and molecular characterization of a novel case of dyssegmental dysplasia, Silverman-Handmaker type. Eur J Med Genet. 2010; 53: 294–8. Wax JR, Albanese J, Smith R et al. Prenatal sonographic features of dyssegmental dysplasia Rolland-Desbuquois type. J Clin Ultrasound. 2011; 39: 480–3. Wu WJ, Ma GC, Chang TY et al. Hydrops in first trimester as unreported prenatal finding of dyssegmental dysplasia confirmed by exome sequencing. Ultrasound Obstet Gynecol. 2021; 58: 318–20.

27 Myotonic Chondrodystrophy (Schwartz-Jampel Syndrome), HSPG2-Related

Synonyms: SJS; SJS type 1; chondrodystrophic myotonia; myotonic, dwarfism, chondrodystrophy and ocular and facial abnormalities; Burton dysplasia Confirmation of diagnosis: identification of biallelic pathogenic variants in the HSPG2 gene.

distinctively decreased, with limitation of joint movements due to contractures, more evident at the elbows (limited extension). Coronal clefts of the spine may be identified. Micrognathia is well demonstrated with 3D ultrasound. Radiographic features: the manifestation is ‘Kniest-like dysplasia with congenital bowing’.

Frequency: more than 130 cases have been described. Genetics: SJS is an autosomal recessive disorder due to homozygous or compound heterozygous pathogenic variants in HSPG2 mapped on 1p36.12 and encoding heparan sulphate proteoglycan 2, alternatively termed perlecan. Perlecan is a unique heparan sulphate proteoglycan that binds to the basement membrane proteins (e.g., collagen 9 and laminin-1) and acts as a coreceptor for FGF2. Perlecan is involved in cartilage matrix structure and plays a role in chondrocyte proliferation. Perlecan deficiency impairs endochondral ossification and leads to secondary acetylcholine-esterase deficiency at the neuromuscular junction. SJS is allelic to dyssegmental dysplasia, severe DDSH (Silverman-Handmaker type) and mild DDRD (Roland-Desbuquois type). The three disorders encompass a continuous spectrum of disorders. SJS type 2, alternatively called Stüve-Wiedemann syndrome, is a different disorder. Age/Gestational age of manifestation: the fetal manifestation may be detected by ultrasound during the third trimester. Clinical features: • • • • •

Joint contractures Bowing of the long bones Microcampomelia Short stature, usually postnatal Midface hypoplasia with micrognathia and pursed lips in infancy; later myotonic facies with blepharophimosis and microstomia • Cataract, occasionally microcornea • Myotonia Prenatal ultrasound features: bilateral camptodactyly with overlapping fingers can be present as early as 16–17 weeks of gestation. There is typically mild shortening and bowing of the lower extremities, particularly the femora and tibiae, and bilateral positional talipes equinovarus. Fetal motor activity is 172

The hallmarks include moderate platyspondyly, occasionally with coronal clefts, moderate dumbbell deformity of the tubular bones, bowing of the long bones and broad ilia. Bowing of the long bones is usually lateral bowing of the femora and/or of the tibiae and fibulae, but rarely posteromedial bowing of the femora is seen. The ilia are broad and round with shortening of the greater sciatic notches and sloping acetabula. The upper cervical spine, particularly of C2–C3, may show defective vertebral ossification with kyphotic deformity. Prognosis: the manifestation of SJS is diverse. Some affected children come to medical attention because of myotonia and/or short stature within the first 2 years of life, while others show severe short stature in the neonatal period. Myotonia and myotonic facies, particularly blepharophimosis, becomes apparent in early childhood. Myotonia is initially associated with muscular hypertrophy, but later muscular wasting. Joint contractures are present from birth and progress postnatally. Kyphosis of the cervical spine may cause myelopathy. Affected individuals are at risk for malignant hyperthermia with anaesthesia. Furthermore, tracheal intubation is difficult due to a combination of micrognathia, limited mouth opening and cervical kyphoscoliosis. A minority of children will have intellectual disability. The disease is usually progressive until adolescence, when it usually stabilises. If complications can be managed successfully, the condition may not affect the life span. Differential diagnosis: the combination of dumbbell deformity with coronal clefts in SJS may lead to a misdiagnosis of Kniest dysplasia (p. 82). The differential diagnosis may be difficult, but the presence or absence of limb bowing gives a diagnostic clue. The distinction between SJS and DDRD (p. 166) is somewhat arbitrary. Freeman-Sheldon syndrome is a severe form of distal arthrogryposis, and microstomia is typical, giving the so-called ‘whistling-face’; however, long bones are usually not bowed, and there are no ocular issues besides strabismus. Marden-Walker syndrome is characterised by arthrogryposis, DOI: 10.1201/9781003166948-30

Myotonic Chondrodystrophy (Schwartz-Jampel Syndrome), HSPG2-Related a mask-like face with blepharophimosis, micrognathia and kyphoscoliosis, but often there is also a cleft palate, and in some there are cardiac, cerebral and/or urinary malformations. In the

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cases where skeletal features are milder and muscular features more prominent, also myotonic dystrophy type 1 and the congenital forms of myotonia may be suspected.

 

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CASE 1: Neonate. Radiographs show a broad thorax, moderate platyspondyly, remnants of coronal clefts of the lumbar spine, broad ilia, sloping acetabula, mild dumbbell deformity and bowing of the long bones, and defective ossification of the vertebral body of C2.

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CASES 2, 3: Neonates. The findings are like those of Case 1; however, coronal clefts of the lumbar spine are more pronounced. Case 2 shows medial bowing of the femora, while case 3 lateral bowing. Metaphyseal flaring and cupping is seen in Case 3.

 

Myotonic Chondrodystrophy (Schwartz-Jampel Syndrome), HSPG2-Related

BIBLIOGRAPHY Arikawa-Hirasawa E, Le AH, Nishino I et al. Structural and functional mutations of the perlecan gene cause SchwartzJampel syndrome, with myotonic myopathy and chondrodysplasia. Am J Hum Genet. 2002; 70(5): 1368–75. Das Bhowmik A, Dalal A, Matta D et al. Identification of a novel splice site HSPG2 mutation and prenatal diagnosis in Schwartz Jampel syndrome type 1 using whole exome sequencing. Neuromuscul Disord. 2016; 26(11): 809–814. Echaniz-Laguna A, Rene F, Marcel C et al. Electrophysiological studies in a mouse model of Schwartz-Jampel syndrome demonstrate muscle fiber hyperactivity of peripheral nerve origin. Muscle Nerve. 2009; 40(1): 55–61. Martinez JR, Dhawan A, Farach-Carson MC. Modular proteoglycan perlecan/HSPG2: Mutations, phenotypes, and functions. Genes (Basel). 2018; 9 (11): 556.

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Mathur N, Ghosh PS. Schwartz-Jampel syndrome. Pediatr Neurol. 2017; 68: 77–78. Nicole S, Davoine CS, Topaloglu H et al. Perlecan, the major proteoglycan of basement membranes, is altered in patients with Schwartz-Jampel syndrome (chondrodystrophic myotonia). Nat Genet. 2000; 26(4): 480–3. Spranger J, Hall BD, Häne B et al. Spectrum of Schwartz-Jampel syndrome includes micromelic chondrodysplasia, kyphomelic dysplasia, and burton disease. Am J Med Genet. 2000; 94(4): 287–95. Stum M, Davoine CS, Vicart S et al. Spectrum of HSPG2 (perlecan) mutations in patients with Schwartz-Jampel syndrome. Hum Mutat. 2006; 27(11): 1082–91.

28 Metatropic Dysplasia, TRVP4-Related (Various Forms)

Synonyms: metatropic dwarfism; MTD Confirmation of diagnosis: typical clinical and radiological features, associated with pathogenic variants in the gene TRPV4. Frequency: rare, fewer than 250 cases reported. Genetics: autosomal dominant, caused by pathogenic variants in the gene TRPV4 on 12q24. The condition is allelic to brachyolmia type 3, spondylometaphyseal dysplasia Kozlowski type, spondyloepimetaphyseal dysplasia Maroteaux type and familial digital arthropathy with brachydactyly. Three neuromuscular disorders are also associated with pathogenic variants in the gene TRPV4: Charcot-Marie-Tooth disease type 2C, scapuloperoneal spinal muscular atrophy and congenital distal spinal muscular atrophy. The TRPV4 gene encodes a cation channel protein that regulates intracellular calcium concentration and exerts a crucial role in growth plate development. Functional studies suggest that TRPV4 pathogenic variants may cause a gain in channel function, except for those associated with familial digital arthropathy-brachydactyly (FDAB), which would cause a loss of channel function. Age/Gestational age of manifestation: can be detected by ultrasound during the second trimester (16–20 weeks). Clinical features: • • • • •

Short limbs Narrow, long trunk Long coccyx, impression of a coccygeal ‘tail’ Prominent joints, reduced mobility In the newborn a flat face with a prominent forehead and squared-off jaw can be present

mobility and joint contractures. Severe metaphyseal enlargement is a misleading finding because it might be misinterpreted as limb bowing (‘pseudo-bowing’), particularly in the femur and humerus. The face shows hypertelorism, proptosis and a small, flat nose. If these features are detected in the second trimester, there is a high probability of a severe form. In the third trimester the limbs are disproportionately short. In a subset of patients, there can be fetal akinesia syndrome, particularly in cases of specific TRPV4 variants also associated with the neurological phenotype. In the third trimester, fetal MRI and CT scan can be integrated to better capture the skeletal abnormalities. Radiographic features: the thorax is narrow, with short ribs showing expanded anterior and posterior ends. There is severe platyspondyly with wide intervertebral spaces but narrow interpedicular distances and odontoid hypoplasia. The long bones are short, with striking expansion of the metaphyses giving a dumbbell appearance. The ends of the metaphyses show sclerosis. They are sometimes irregular or domed, and the short tubular bones are cupped. There is irregular ossification of the calcanea and tali. In the pelvis the ilia are short, the sacrosciatic notches wide and the acetabula horizontal (‘halberd’ shaped). There is progressive kyphoscoliosis throughout childhood resulting in significant truncal shortening. There is delayed ossification of the carpal bones. Prognosis: the condition has a spectrum according to the severity, from perinatally lethal, usually due to respiratory failure, to milder surviving forms. In the surviving cases, the phenotype changes over time (the Greek ‘metatropos’ means ‘changing pattern’), with an inversion of proportions, developing a short, kyphoscoliotic trunk with relatively longer limbs. Intellect is normal; final stature is around 120 cm. Differential diagnosis: allelic condition related to TRPV4 variants: spondylometaphyseal dysplasia Kozlowski type: similar spine abnormalities, milder limb involvement.

Prenatal ultrasound features: the biparietal diameter may be enlarged; the thorax is relatively long and narrow with short ribs; there is platyspondyly with sagittal and coronal cleft of the vertebral bodies.

Narrow chest and short limbs: short rib-polydactyly syndromes including asphyxiating thoracic dystrophy (Jeune) (p. 196) and chondroectodermal dysplasia (Ellis-van Creveld syndrome) (p. 203); thanatophoric dysplasia (p. 36).

A severe shortening of long bones with extremely flared metaphyses (dumbbell appearance) can be detected early in pregnancy, while the digits are disproportionately long. Later in the second trimester the joints become prominent with restricted

Short dumbbell-shaped long bones and platyspondyly: fibrochondrogenesis (p. 95); Kniest dysplasia (p. 82); Stickler syndrome (p. 89); otospondylomegaepiphyseal dysplasia and Weissenbacher-­Zweymüller syndrome (p. 98).

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DOI: 10.1201/9781003166948-31

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CASES 1–4: Fetuses – short dumbbell-shaped tubular bones; platyspondyly; disproportionately large hands and feet.

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CASE 5: Neonate aged 3 days. CASE 6: Clinically this neonate had respiratory distress, dysmorphic facial features and some obvious joint abnormalities. His hips were fixed in flexion/abduction, and the femora and tibiae appeared to be short and bowed. Below the knees there were marked bony prominences. CASE 7: There is marked , ‘wafer thin’ platyspondyly and expansion of the metaphyses of the long bones.

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CASE 8: Short ‘dumbbell’-shaped tubular bones; relatively dense metaphyses; severe (‘wafer-thin’) platyspondyly; narrow thorax; short ribs with anterior cupping; cupped metaphyses of short tubular bones. CASE 9: Short dumbbell appearance of long bones; narrow interpedicular distances with sagittal cleft vertebral bodies; severe platyspondyly with long sacrum (‘tail’); gross hyperostosis, particularly of ribs, iliac crests and metaphyses.

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CASE 10: Hypertrophic form of metatropic dysplasia. (a, b) Hyperostosis of the flared metaphyses, iliac crests and costochondral junctions; marked platyspondyly, long sacrum (tail) and narrow interpedicular distances. (c, d) US at 16 weeks and 21 weeks showing short femur and short tibia and fibula, both with flared metaphyses. CASE 11: A 25-week-gestation fetus with a pre-termination of pregnancy diagnosis of thanatophoric dysplasia. (a, b) Short long bones with flared, sclerotic metaphyses; short ribs with sclerotic anterior and posterior ends; disproportionately large hands and feet; narrow interpedicular distances.

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BIBLIOGRAPHY Andreucci E, Aftimos S, Alcausin M et al. TRPV4 related skeletal dysplasias: A phenotypic spectrum highlighted by clinical, radiographic, and molecular studies in 21 new families. Orphanet J Rare Dis. 2011; 6: 37. Geneviève D, Le Merrer M, Feingold J et al. Revisiting metatropic dysplasia: Presentation of a series of 19 novel patients and review of the literature. Am J Med Genet A. 2008; 146A: 992–6. Hall CM, Elcioglu N. Lethal metatropic dysplasia variants. Pediatr Radiol. 2004; 34: 66–74. Kozlowski K, Campbell J, Anderson B et al. Metatropic dysplasia and its variants (analysis of 14 cases). Australas Radiol. 1988; 32: 325–37. Krakow D, Vriens J, Camacho N et al. Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia. Am J Hum Genet. 2009; 84: 307–15.

Loukin S, Su Z, Kung C. Increased basal activity is a key determinant in the severity of human skeletal dysplasia caused by TRPV4 mutations. PLoS One. 2011; 6: e19533. Nemec SF, Cohn DH, Krakow D et al. The importance of conventional radiography in the mutational analysis of skeletal dysplasias (the TRPV4 mutational family). Pediatr Radiol. 2012; 42: 15–23. Nilius B, Voets T. The puzzle of TRPV4 channelopathies. EMBO Rep. 2013; 14: 152–63. O’Sullivan MJ, McAllister WH, Ball RH et al. Morphologic observations in a case of lethal variant (type I) metatropic dysplasia with atypical features: Morphology of lethal metatropic dysplasia. Pediatr Dev Pathol. 1998; 1: 405–12. Unger S, Lausch E, Stanzial F et al. Fetal akinesia in metatropic dysplasia: The combined phenotype of chondrodysplasia and neuropathy? Am J Med Genet A. 2011; 155A: 2860–4.

29 Short Rib-Polydactyly Syndrome Type 1 and 3, IFT80-, DYNC2H1-, WDR34-, WDR60- and DYNC2L11-Related

Synonyms: SRPS; includes SRPS type I; SRP1; SaldinoNoonan syndrome; polydactyly with neonatal chondrodystrophy, type I; SRPS, type III; SRP3; Verma-Naumoff syndrome; polydactyly with neonatal chondrodystrophy, type III Confirmation of diagnosis: characteristic radiographic and clinical findings with suggestive genetic mutation. Incidence: very rare, precise incidence unknown. Genetics: autosomal recessive. In patients affected by the subtype SRP3 (Verma- Naumoff), pathogenic variants in the genes IFT80, DYNC2H1, WDR34, WDR60 and DYNC2LI1 have been found. IFT80 is a component of the anterograde intraflagellar transport (IFT) complex B and is crucial to the development and maintenance of motile and sensory cilia. DYNC2H1 (dynein, cytoplasmic 2, heavy chain 1) encodes a subunit of a cytoplasmic dynein complex. The same genes have also been found to be mutated in asphyxiating thoracic dystrophy (ATD); this finding emphasises that these conditions are part of a common clinical spectrum and are included among the ciliopathies. Age/Gestational week of manifestation: can be detected by ultrasound during the first trimester (12–14 weeks). Clinical features: • Extremely narrow thorax, pulmonary hypoplasia, short limbs, short neck • Generalised oedema or hydrops • Postaxial polydactyly • Prominent forehead, depressed nasal bridge, flat occiput • Urogenital and anorectal anomalies, including polycystic kidneys, imperforate anus, vaginal atresia, cloacal abnormalities, ambiguous genitalia and situs abnormalities • Cardiac malformations Prenatal ultrasound features: SRPS has been associated with increased nuchal translucency; typical findings in all

182

types are micromelia with or without polydactyly. Other signs include a narrow thorax with short, horizontally oriented ribs, a protuberant abdomen, and multiple anomalies of major organs. The overlapping phenotypes add to the difficulty in obtaining a precise ultrasound diagnosis. Prenatal diagnosis of SRPS1 has been performed at 13 weeks’ gestation. It is characterised by marked micromelia (flipper-like extremities), polydactyly of the hands and sometimes of the feet and occasionally absent fibulae. Associated anomalies include congenital heart defects, renal anomalies (aplasia/hypoplasia, renal cysts), anal atresia and ambiguous genitalia. SRPS3 is similar, although milder, than SRPS1. Prenatal diagnosis has been reported in the second and third trimester. There is postaxial polydactyly and brachydactyly of the hands and feet. The incidence of congenital heart disease and gastrointestinal and genitourinary anomalies is lower than in type 1. Both may show fetal oedema, cystic hygroma, hydrops, situs inversus and platyspondyly with increased intervertebral disc spaces. The phenotypes of SRPS may also overlap with those of nonlethal short rib-polydactyly syndromes, and more accurate differentiation is feasible using both ultrasound and threedimensional helical CT. Radiographic features: short ribs result in a narrow thorax. The pelvis has short ilia with spurred (trident) acetabula. There may be mild platyspondyly. The long bones are short with irregular, spurred metaphyses. There is pre- and postaxial polydactyly. Prognosis: perinatally lethal. Differential diagnosis: other short rib-polydactyly syndromes: the SRP group includes lethal disorders classified as type 1 and 3 (Saldino-Noonan/Verma-Naumoff), type 2 (Majewski) and type 4 (Beemer-Langer); SRP2 (p. 186, 191) and SRP4 (p. 191); asphyxiating thoracic dysplasia (Jeune) (p. 196); chondroectodermal dysplasia (Ellis-van Creveld syndrome) (p. 203). Other lethal disorders with narrow thorax: Campomelic dysplasia (p. 302); thanatophoric dysplasia (p. 36); achondrogenesis, all types (p. 58, 105, 256); paternal UPD 14 (p. 528).

DOI: 10.1201/9781003166948-32

183

Short Rib-Polydactyly Syndrome Type 1 and 3

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CASES 1, 2: Very short ribs and small thorax and short long bones with irregular metaphyses; trident acetabula. (2b) Mild platyspondyly. CASES 3–5: Very short ribs and long bones with irregular metaphyses, trident acetabula and mild platyspondyly.

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CASES 6, 7: Both cases show short long bones and ribs with a small narrow thorax. There are trident acetabula. (7a, b) Prenatal US shows postaxial polydactyly of the foot, confirmed postnatally. Case 7 was a 23-week fetus.

185

Short Rib-Polydactyly Syndrome Type 1 and 3

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CASES 8, 9: Both cases show short ribs, a narrow thorax, short long bones, trident acetabula and mild platyspondyly.

BIBLIOGRAPHY Badiner N, Taylor SP, Forlenza K et al. Mutations in DYNC2H1, the cytoplasmic dynein 2, heavy chain 1 motor protein gene, cause short-rib polydactyly type I, Saldino-Noonan type. Clin Genet. 2017; 92: 158–65. Cavalcanti DP, Huber C, Le Quan Sang KH et al. Mutation in IFT80 gene in a foetus with a phenotype of Verma-Naumoff provides molecular evidence for the Jeune-Verma-Naumoff dysplasia spectrum. J Med Genet. 2011; 48: 88–92. Chen CP, Chern SR, Chang TY et al. Prenatal diagnosis and molecular genetic analysis of short rib-polydactyly syndrome type III (Verma-Naumoff) in a second-trimester fetus with a homozygous splice mutation in intron 4 in the NEK1 gene. Taiwan J Obstet Gynecol. 2012; 51: 266–270. Cheng C, Li X, Zhao S et al. Compound heterozygous variants in DYNC2H1 in foetus with type III short rib-polydactyly syndrome and situs inversus totalis. BMC Med Genomics. 2022; 15: 55. doi: 10.1186/s12920-022-01205-z Dagoneau N, Goulet M, Geneviève D et al. DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III. Am J Hum Genet. 2009; 84: 706–11.

Deng L, Cheung SW, Schmitt ES et al. Targeted gene panel sequencing prenatally detects two novel mutations of DYNC2H1 in a fetus with increased biparietal diameter and polyhydramnios. Birth Defects Res. 2018; 110: 364–71. Huber C, Wu S, Kim AS et al. WDR34 mutations that cause shortrib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-kB pathway in cilia. Am J Hum Genet. 2013; 93: 926–31. Kumru P, Aka N, Köse G et al. Short rib polydactyly syndrome type 3 with absence of fibula (Verma-Naumoff syndrome). Fetal Diagn Ther. 2005; 20: 410–14. Xia CL, Xiao SQ, Yang X et al. Radiological and histopathological features of short rib-polydactyly syndrome type III and identification of two novel DYNC2H1 variants. Mol Med Rep. 2021; 23: 426. doi: https://doi.org/10.3892/ mmr.2021.12065 Yamada T, Nishimura G, Nishida K. Prenatal diagnosis of shortrib polydactyly syndrome type 3 (Verma-Naumoff type) by three-dimensional helical computed tomography. J Obstet Gynaecol Res. 2011; 37: 151–5.

30 Short Rib-Polydactyly Syndrome Type 2 (Majewski), NEK1-, DYNC2H1-, IFT81- and IFT154-Related

Synonyms: SRPS, type II; SRP2; Majewski syndrome; polydactyly with neonatal chondrodystrophy, type II Confirmation of diagnosis: identification of pathogenic variants in NEK1, DYNC2H1, IFT81 or IFT154 with the appropriate radiographic findings. Incidence: unknown, very rare. Genetics: autosomal recessive inheritance caused by homozygous mutations in the NEK1 gene or DYNC2H1. Digenic biallelic mutation in the NEK1 and DYNC2H1 genes has also been reported in one case. Homozygous mutations in IFT81 or in IFT154 have been reported in one case. Age/Gestational week of manifestation: can be detected by ultrasound during the first trimester (12–14 weeks). Clinical features: • • • • • •

Extremely narrow thorax, pulmonary hypoplasia Short limbs, short neck Generalised oedema or hydrops Pre- and postaxial polydactyly Large head, prominent forehead, flat nose, micrognathia Midline cleft of the upper lip, cleft palate, cleft or lobulated tongue • Hypoplastic epiglottis, malformed larynx • Other malformations: polycystic kidneys, small bowel malrotation, ambiguous genitalia, brain anomalies Prenatal ultrasound features: prenatal diagnosis of SRPS2 may be performed late in the first or early in the second

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trimester. Characteristic features are marked micromelia, particularly distally; polysyndactyly; a narrow thorax with short, horizontally oriented ribs; protuberant abdomen; and the variable association of anomalies in other organs, including cystic renal dysplasia, genital abnormalities and cerebellar and brain anomalies. Pre- and/or postaxial polysyndactyly is reportedly associated with brachydactyly of the hands. Fetal biometry of long bones shows micromelia with extremely short, hypoplastic, ‘ovoid’ tibiae, shorter than the fibulae. Facial anomalies detectable by ultrasound include a prominent forehead, depressed nasal bridge, cleft lip/palate and micrognathia. SRPS2 may present with fetal oedema and a hydropic appearance in utero and at birth. Three-dimensional ultrasound may help to identify some key features that can lead to the correct diagnosis. Radiographic features: the ribs are short with a narrow thorax. All the long bones are short, but the appearance of the tibiae is striking, being extremely short and oval. The metaphyses are smooth and convex. In the hands and feet there is pre- and/ or postaxial polydactyly. Typically, the spine and pelvis appear normal. Prognosis: perinatally lethal. Differential diagnosis: OFD type 4 (Mohr-Majewski syndrome) (p. 209). Other short rib-polydactyly syndromes: SRP1/3 (p. 182), SRP4 (p. 191), asphyxiating thoracic dysplasia (Jeune) (p. 196) and chondroectodermal dysplasia (Ellis-van Creveld syndrome) (p. 203). Other lethal disorders with a narrow thorax: Campomelic dysplasia (p. 302), thanatophoric dysplasia (p. 36), achondrogenesis, all types (p. 58, 105, 256) and paternal UPD 14 (p. 528).

DOI: 10.1201/9781003166948-33

187

Short Rib-Polydactyly Syndrome Type 2 (Majewski)

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(1b)

 

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CASE 1: Termination of pregnancy at 14 weeks’ gestation. At postmortem there were wide set eyes; broad-based nose with anteverted nostrils; cleft of right lip and midline cleft of posterior soft palate, small chin and low-set ear canals; short limbs; polydactyly (nine right fingers with two thumbs, eight left fingers with two thumbs and ten toes on each foot with two halluces bilaterally); small chest and lungs. Occipital bone with midline defect. CASE 2: Miscarriage of an Asian male fetus at 15 weeks’ gestation. At postmortem there was pulmonary hypoplasia. The left arm had seven short digits and soft tissue syndactyly 3–5; the right arm had six digits (double second one), and each foot had six digits, with soft tissue syndactyly 3–6 on the left. In addition, there was fetal hydrops, bilateral pleural effusion and ascites, accessory (double) spleen, situs inversus, unilobed lungs, cystic-dysplastic kidneys and exomphalos. Note the relative hypoplasia of the tibiae.

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CASE 3: A stillborn boy was born after the mother’s ninth pregnancy, including four miscarriages. He had a narrow chest and polysyndactyly. (a) Small bowel malrotation; polysyndactyly.

189

Short Rib-Polydactyly Syndrome Type 2 (Majewski)

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CASE 4: The sibling of Case 3 was born after the mother’s 10th pregnancy, during which oligohydramnios and dysplastic fetal kidneys were identified. He had a narrow chest and short limbs with polysyndactyly of both hands and feet. The craniofacial features included a cleft palate, micrognathia and low-set ears. He also had cryptorchidism and a hypoplastic penis and scrotum. (3a, 4b) Advanced ossification of proximal humeral epiphyses. CASES 5–7: Short ribs, polydactyly, smooth metaphyses and hypoplastic, oval tibiae. (7a) Early advanced ossification of the proximal humeral epiphyses.

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BIBLIOGRAPHY Chen CP, Chang TY, Chen CY et al. Short rib-polydactyly syndrome type II (Majewski): Prenatal diagnosis, perinatal imaging findings and molecular analysis of the NEK1 gene. Taiwan J Obstet Gynecol. 2012; 51: 100–5. El Hokayem J, Huber C, Couvé A et al. NEK1 and DYNC2H1 are both involved in short rib-polydactyly Majewski type but not in Beemer Langer cases. J Med Genet. 2012; 49: 227–33. Naki MM, Gür D, Zemheri E et al. Short rib-polydactyly syndrome. Arch Gynecol Obstet. 2005; 272: 173–5.

Fetal and Perinatal Skeletal Dysplasias Sirichotiyakul S, Tongsong T, Wanapirak C, Chanprapaph P. Prenatal sonographic diagnosis of Majeweski syndrome. J Clin Ultrasound. 2002; 30: 303–7. Thiel C, Kessler K, Giessl A et al. NEK1 mutations cause shortrib polydactyly syndrome type Majewski. Am J Hum Genet. 2011; 88: 106–14. Viora E, Sciarrone A,, Bastonero S et al. Three-dimensional ultrasound evaluation of short-rib polydactyly syndrome type II in the second trimester: A case report. Ultrasound Obstet Gynecol. 2002; 19: 88–91.

31 Short Rib-Polydactyly Syndrome Type 4 (Beemer), IFT80-Related

Synonyms: SRPS, type IV; SRP4; Beemer-Langer syndrome; short rib syndrome, Beemer type Confirmation of diagnosis: detection of biallelic pathogenic variants in the gene IFT80 associated with suggestive clinical and radiological features. Frequency: very rare; a high incidence (1 in 2,000) has been reported in the Hungarian Roma population. Genetics: autosomal recessive inheritance, associated with biallelic pathogenic variants in the gene IFT80, a component of the anterograde intraflagellar transport (IFT) complex B and crucial to the development and maintenance of motile and sensory cilia. DYNC2H1 (dynein, cytoplasmic 2, heavy chain 1) encodes a subunit of a cytoplasmic dynein complex. The same genes have also been found to be mutated in ATD; this finding emphasises that these conditions are part of a common clinical spectrum and are included among the ciliopathies. Age/Gestational week of manifestation: can be detected by ultrasound during the first trimester (12–14 weeks). Clinical features: • • • • • •

• •

Extremely narrow thorax, pulmonary hypoplasia Very short limbs, short neck Generalised oedema or hydrops Large cranium, flat face, flat nasal bridge, occasionally anophthalmia, small or atretic auditory canals Midline cleft lip and palate, accessory frenulum High incidence of brain anomalies (62%), including holoprosencephaly, Dandy-Walker malformation, hydrocephalus, agenesis or hypoplasia of the corpus callosum, encephalocele, anencephaly Occasionally pre- and postaxial polydactyly Cystic dysplasia variably involving the kidneys, liver and pancreas

DOI: 10.1201/9781003166948-34

• Cardiac malformations • Exomphalos • Ambiguous genitalia, absent internal genitalia Prenatal ultrasound features: short long bones and a narrow thorax (all below the fifth centile) can be identified by transvaginal ultrasound from about 12 weeks in an at-risk fetus. The head circumference and biparietal diameter have normal measurements. The diagnosis may be made on routine scan at 20 weeks. Typically, the tibia is longer than the fibula (unlike short rib-polydactyly syndrome type 2, Majewski). Pre- and/or postaxial polydactyly may be present. Other skeletal abnormalities include bowed ulnae and radii, small scapulae and small ilia. Nuchal oedema and hydrops may be present. There may be exomphalos and dysmorphic features, including a prominent forehead, hypertelorism, a midline cleft lip/palate, micrognathia, abnormal ears and cardiac abnormalities. Intracerebral abnormalities may be identified and include agenesis or hypoplasia of the corpus callosum, Dandy-Walker malformation, hypothalamic hamartoma or hamartoblastoma, occipital bone defects with encephalocele, holoprosencephaly, anencephaly or hydrocephaly. Radiographic features: similar to SRP type 2, but the tibiae are not short and oval. The ribs are short with a narrow thorax. The metaphyses are smooth and rounded. There may or may not be pre- or postaxial polydactyly. Bending of the long bones, and especially the radii and ulnae, is common. The spine and pelvis are morphologically normal. Prognosis: perinatally lethal. Differential diagnosis: Other short rib-polydactyly syndromes: SRP1/3 (p. 182) and SRP2 (p. 186); asphyxiating thoracic dysplasia (Jeune) (p. 196); Ellis-van Creveld syndrome (p. 203). Other lethal disorders with narrow thorax: thanatophoric dysplasia (p. 36); achondrogenesis, all types (p. 58, 105, 256); paternal UPD 14 (p. 528). Oral-facial-digital syndrome type 4 (p. 209).

191

192

Fetal and Perinatal Skeletal Dysplasias

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(3a)

(3d)

 

 

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CASE 1: Fetus. CASE 2: A relatively large head; flat nasal bridge; clinically narrow chest and short limbs. The parents were first cousins. CASE 3: (a) Axial US; head through the posterior fossa. (b) Parasagittal US; ribs. (c) Sagittal US; body; ultrasound at 20 weeks of gestation showed in the brain an absent vermis and a posterior fossa cyst, 13.9 × 12.5 mm. There was nuchal thickening and mild generalised oedema. The thorax was narrow and pear-shaped. (d–l) Prenatal MRI at 22 weeks of gestation. Multiplanar HASTE imaging of the fetal brain and body. Axial T2 star and diffusion-weighted imaging of the fetal brain. Thick slab imaging of the uterus and fetus. The brain malformations consist of a classic Dandy-Walker malformation, agenesis of the corpus callosum, abnormality of migration and sulcation, hypothalamic hamartoma and focal occipital dysraphism. The chest is small and bell-shaped.

Short Rib-Polydactyly Syndrome Type 4 (Beemer), IFT80-Related

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(3j)

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(3n)

193

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CASE 3: Postmortem demonstrated a posterior cleft palate. Postmortem imaging of a 23-week-gestation fetus: (m–p) Radiographs show short, bowed long bones with smooth metaphyses. The ribs are short and horizontal. There is abnormal supra-acetabular notching of the ilia. The calcaneal ossification centres are relatively advanced. The occipital bone demonstrates a bony spur at the site of the occipital dysraphism. (s, t) MRI demonstrates focal occipital dysraphism.

194

Fetal and Perinatal Skeletal Dysplasias

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CASE 4: Short ribs with a narrow thorax; short long bones with rounded metaphyses; note that the fibulae are shorter than the tibiae (unlike type 2). The acetabula and spine are normal (unlike types 1 and 3).

Short Rib-Polydactyly Syndrome Type 4 (Beemer), IFT80-Related

BIBLIOGRAPHY Bizaoui V, Huber C, Kohaut E et al. Mutations in IFT80 cause SRPS type IV. Report of two families and review. Am J Med Genet A. 2019; 179: 639–44. Elcioglu NH, Hall CM. Diagnostic dilemmas in the short Rib– Polydactyly syndrome group. Am J Med Genet. 2002; 111: 392–400. El Hokayem J, Huber C, Couvé A et al. NEK1 and DYNC2H1 are both involved in short rib-polydactyly Majewski type but not in Beemer Langer cases. J Med Genet. 2012; 49: 227–33. Kova´cs N, Sa´rka´ny I, Mohay G et al. High incidence of short rib-polydactyly syndrome type IV in a Hungarian Roma subpopulation. Am J Med Genet. 2006; 140A: 2816–8.

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Silveira KC, Moreno CA, Cavalcanti DP. Beemer-Langer syndrome is a ciliopathy due to biallelic mutations in IFT122. Am J Med Genet A. 2017; 173: 1186–9. Taori KB, Sharbidre KG, Krishnan V et al. Diagnosis of short rib polydactyly syndrome type IV (Beemer-Langer syndrome) with cystic hygroma: A case report. J Clin Ultrasound. 2009; 37: 406–9. Yamaguchi K, Sfiimizu K, Suzumura H. Short rib-polydactyly syndrome: Lethal chondrodysplasia associated with brain malformations in a 35-week-gestation infant. Clin Neuropathol. 2006; 25: 128–33.

32 Short Rib-Thoracic Dysplasia (Jeune)

DYNC2H1-, DYNC2LI1-, WDR34-, TCTEX1D2-, WDR60-, WDR19-, IFT140-, TTC21B-, IFT122-, WDR35-, IFT43-, IFT80-, IFT172-, IFT81-, IFT52-, CFAP410-, CEP120- AND KIAA0753-RELATED Synonyms: ATD; asphyxiating thoracic dystrophy; Jeune syndrome; thoracic-pelvic-phalangeal dystrophy; includes ATD1, ATD2, ATD3, ADT4 and ADT5 Confirmation of diagnosis: characteristic radiographic and clinical findings with suggestive pathogenic variants. Frequency: 1–5 in 500,000. Genetics: autosomal recessive, genetically heterogeneous. Referred to as skeletal ciliopathies. Many of the genes involved in this spectrum of disorders encoded proteins involved in the biosynthesis and/or function of primary cilia. Ciliary proteins are selectively transported into the cilium by intraflagellar transport (IFT). Anterograde IFT by the IFT-B complex travels from the cytoplasm to the ciliary tip through the use of a kinesin-II motor. The IFT-B anterograde complex consists of nine core components (IFT22, IFT25, IFT27, IFT46, IFT52, IFT70, IFT74, IFT81 and IFT88) and several peripheral subunits (IFT20, IFT54, IFT57, IFT80, IFT172, IFT38 and IFT56). Cargo may be unloaded along the cilium and at the tip, and molecules are conveyed back to the cytoplasm by retrograde transport using the IFT-A complex, which is catalysed by the dynein 2 complex molecular motor. The IFT-A complex consists of six primary components (IFT43, WDR35, IFT122, TTC21B, IFT140 and WDR19) and other ancillary proteins. The dynein-2 motor complex is composed of three light chains (LCs) that are shared with other dyneins, as well as a unique LC (TCTEX1D2), a light intermediate chain (DYNC2LI1) and two intermediate chains (WDR34 and WDR60) and the heavy chain (DYNC2H1). More than 20 different genes have been identified so far as responsible for ATD: IFT52, IFT172 and IFT80; IFT154 (TRAF3IP1), involved in anterograde intraflagellar transport); DYNC2H1, TCTEX1D2, DYNC2LI1, WDR34 and WDR60 (cytoplasmic dynein motor); IFT43, IFT140, WDR35, WDR19 and TTC21B (retrograde intraflagellar transport); and CEP120, KIAA0586, KIAA0753 and CFAP410 (centrosomal, centriolar and basal body proteins). Additional locus heterogeneity in these disorders results from mutations in proteins involved in planar cell polarity (INTU) or in GRK2, by impairing hedgehog and canonical Wnt signalling. Allelic 196

heterogeneity in a number of the genes results in phenotypes along a spectrum of skeletal severity ranging from isolated nephronophthisis to SRPS. DYNC2H1 is the major gene responsible for ATD, accounting for more than 50% of cases. Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester (16 weeks). Clinical features: • • • •

Short stature, short limbs Short, narrow thorax Postaxial polydactyly in about 10% of cases Associated anomalies: renal cysts, pancreatic cysts, bile duct proliferation, liver cirrhosis, Hirschsprung disease, retinitis pigmentosa, Joubert syndrome

Prenatal ultrasound features: increased nuchal translucency at 14 weeks’ gestation on routine sonography has been identified, with a diagnosis of asphyxiating thoracic dysplasia made at 22 weeks’ gestation. Diagnosis has been reported at 14 weeks’ gestation in a high-risk pregnancy, while the earliest prenatal diagnosis in a low-risk pregnancy was made at 16 weeks’ gestation. The major ultrasound findings of the severe, lethal forms are polyhydramnios, a bell-shaped or a long and narrow thorax and short ribs; the thorax is small in transverse and anteroposterior diameters and a left deviation of the cardiac axis has been described. On the sagittal scan, there is a narrow thorax compared with a protruding abdomen. Respiratory movements may not be detected. The long bones show mild rhizomelia and mesomelia with short hands and feet. Brachydactyly ranges from moderate to severe. An inconstant feature is postaxial hexadactyly of the hands and feet. Some affected fetuses may have cystic dysplastic kidneys with increased echogenicity or dilated pelvicalyceal systems. When associated with Joubert syndrome, ultrasound may demonstrate hypoplasia of the vermis and enlarged extra-axial cerebrospinal fluid spaces. Radiographic features: short ribs result in a narrow thorax. In the pelvis there are trident acetabula and short iliac bones. The long bones are short, predominantly in the mesomelic segments, and may show some mild bowing and metaphyseal spurring. The radius and ulna sometimes show the ‘chicken drumstick’ appearance in which the proximal end of the ulna and distal end of the radius are widened. In the hands the tubular bones are short and associated with multiple cone-shaped epiphyses that show advanced ossification. Postaxial polydactyly of the DOI: 10.1201/9781003166948-35

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Short Rib-Thoracic Dysplasia (Jeune) hands and feet is present in about 10% of patients. There is also advanced ossification of the capital femoral epiphyses, which may be seen at birth (not normally ossified until about 6 months of age). Typically, the spine is normal. In Joubert syndrome, MRI findings include the ‘molar tooth’ sign on axial views because of thickened and elongated superior cerebellar peduncles, a deep interpeduncular fossa and hypoplasia of C1, resulting in narrowing of the cerebrospinal space at this level and enlargement of the subarachnoid spaces caudally. Prognosis: often lethal within the first year of life because of respiratory insufficiency. Intrafamilial variability has been reported, and milder clinical forms exist. In the postnatal period patients may develop in the course of the disease renal insufficiency, hepatic dysfunction and retina alteration. In selected patients, corrective surgery of the thorax resulting in expan-

(1)

(4)

 

 

sion of the chest can improve the prognosis. Some patients have been described with associated Joubert syndrome, which is also a spectrum of ciliary disorders, that results in apnoea, ataxia, cognitive impairment and abnormal eye movements. Differential diagnosis: short rib-polydactyly group (SRP) (p. 182–222); Ellis-van Creveld syndrome (p. 203); cranioectodermal dysplasia (p. 212); thoracolaryngopelvic dysplasia (Barnes syndrome) (p. 222). Shwachman-Diamond syndrome (p. 229) may present in the neonatal period with a narrow thorax and short ribs with prominent anterior ends. Later in childhood the characteristic metaphyseal irregularity, predominantly of the proximal femora, develops. It may be differentiated by the normal acetabula, absence of long bone bowing, mesomelic shortening and phalangeal shortening; thanatophoric dysplasia (p. 36); Pat UPD14 (p. 528).

(2)

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CASES 1–4: Fetal examples all showing short ribs with a narrow thorax, mild femoral bowing, some metaphyseal cupping and horizontal acetabula with medial and lateral spurs. CASE 5: Short ribs were recognised in this baby by prenatal US at 28 weeks’ gestation. He was delivered at 36 weeks and died after a few hours. The facial features were normal, but the chest was narrow, and he had bilateral postaxial polydactyly of the hands.

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Fetal and Perinatal Skeletal Dysplasias

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CASES 6–9: Fetuses showing rib shortening with a narrow thorax. The femora are mildly bowed, and there are trident acetabula.

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Short Rib-Thoracic Dysplasia (Jeune)

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CASE 10: There is four-limb postaxial polydactyly. The thorax is narrow due to short ribs. The metaphyses are cupped with some spurring. There are trident acetabula.

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CASE 11: A 30-week-gestation fetus. (a, b) Post-termination of pregnancy radiographs. (c) Fetal MRI (coronal section) shows the narrow thorax, small lungs and mild bilateral dilatation of the pelvicalyceal systems. (d) Two-dimensional US longitudinal scan of the fetal thorax from behind: the thorax is long and narrow. CASE 12: This child had severe respiratory distress from birth and remained ventilation dependent until he died in early infancy; (b) note the bowed femora; (c) trident acetabula; (d) postaxial polydactyly and ‘chicken drumstick’ appearance of the radius and ulna. CASE 13: A neonate with a narrow thorax, trident acetabula and mildly bowed femora. CASE 14: At delivery at 38 weeks’ gestation, birth weight was 3.15 kg. He breathed spontaneously but was noted to have a narrow chest, a relatively long body, short limbs and short stubby fingers. At 3 months he had feeding difficulties and tachypnoea. Weight was 3.3 kg (third centile) and length was 52.0 cm (50th centile). There was a 3-cm hepatomegaly and a left renal mass due to medullary cystic disease. There was nystagmus with abnormal visually evoked potentials, and vision was limited. He acquired a chest infection and had a cardiopulmonary arrest after which he was ventilated for 8 days. He had a prolonged metabolic acidosis due to impaired renal function, recurrent chest infections and eventually died at 6 months.

201

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CASE 15: (a, b) Neonate. (c, d) Age 7 months. Note advanced carpal bone maturation. CASE 16: (a) Pregnancy at 20 weeks. Sagittal scan: 3D US maximum mode shows the narrow rib cage that limits the cardiopulmonary space (red arrows). The width of the chest is narrow compared with the abdomen. (b) Oblique and coronal posterior view of the spine and the rib cage. 3D US maximum mode. The thorax appears bell-shaped.

202

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CASE 16: (c, d) Post-termination radiographs. (e–g): Postmortem 3D CT anteroposterior, posteroanterior and lateral views. Short ribs, narrow thorax, a relatively long trunk and rhizomelic shortening of upper and lower limbs.

BIBLIOGRAPHY Agarwal A, Agarwal S. Fetal micromelia, thoracic dysplasia and polydactyly revisited: A case-based antenatal sonographic approach. Ultrasound. 2019; 27: 196–201. Chen SH, Chung MT, Chang FM. Early prenatal diagnosis of Jeune syndrome in a low-risk pregnancy. Prenat Diagn. 2003; 23: 606–7. Dagoneau N, Goulet M, Geneviève D et al. DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short ribpolydactyly syndrome, type III. Am J Hum Genet. 2009; 84: 706–11. Davies JT, Long FR, Adler BH et al. Lateral thoracic expansion for Jeune syndrome: Evidence of rib healing and new bone formation. Ann Thorac Surg. 2004; 77: 445–8. Den Hollander NS, Robben SGF, Hoogeboom AJM et al. Early sonographic diagnosis and follow-up of Jeune syndrome. Ultrasound Obstet Gynecol. 2001; 18: 378–83. Huang L-X, Lu X-G, Liu J-X et al. Case report and a brief review: Analysis and challenges of prenatal imaging phenotypes

and genotypes of Joubert syndrome. Front Genet. 2022; 13: 1038274. doi: 10.3389/fgene.2022.1038274 Schramm T, Gloning KP, Minderer S et al. Prenatal sonographic diagnosis of skeletal dysplasias. Ultrasound Obstet Gynecol. 2009; 34: 160–70. Simonini C, Fröschen EM, Nadal J et al. Prenatal ultrasound in fetuses with polycystic kidney appearance – Expanding the phenotype. Arch Gynecol Obstet. 2022 doi: 10.1007/ s00404-022-06814-8 Simonini C, Floeck A, Strizek B et al. Fetal ciliopathies: A retrospective observational single-center study. Arch Gynecol Obstet. 2022; 306: 71–83. Tüysüz B, Barış S, Aksoy F et al. Clinical variability of asphyxiating thoracic dystrophy (Jeune) syndrome: Evaluation and classification of 13 patients. Am J Med Genet. 2009; 149A: 1727–33. Zhang W, Taylor SP, Ennis HA et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018; 39: 152–66.

33 Chondroectodermal Dysplasia (Ellis-van Creveld), EVC1-, EVC2-, WDR35-, DYNC2LIL-, GLIL- and SMO-Related Synonyms: EVC; Ellis-van Creveld syndrome Confirmation of diagnosis: identification of pathogenic variants in any of the responsible genes with clinical and radiographic features. Frequency: rare, around 200 cases reported; more common among the Amish community. Genetics: autosomal recessive, caused by mutations in the genes EVC or EVC2, located in a head-to-head configuration on chromosome 4p16 and which share a common promoter region. Mutations in the same genes can also cause Weyers acrofacial dysostosis (Curry-Hall syndrome), an autosomal dominant disorder allelic to EVC. Whereas EVC and EVC2 are the major genes responsible for EVC, genes involved in the hedgehog pathways have been recently identified as causative in EVC: WDR35, GLI1, DYNC2LI1 and SMO. Age/Gestational week of manifestation: can be detected by ultrasound during the first trimester (13 weeks). Clinical features:

rounded metaphyses, postaxial polydactyly (all affected individuals have polydactyly of the hands and approximately 10% have polydactyly of the feet) and cardiac defects in 60% of cases (most commonly ASD, single atrium or atrioventricular septal defect). Radiographic features: typically, the skull and spine are normal. The thorax is narrow due to short ribs. In the pelvis the ilia are short and there are trident acetabula with medial and lateral spurs. The long bones are short, predominantly in the mesomelic segments, and bowing is not a major feature. The metaphyses are smooth and convex. The proximal humeri demonstrate a pronounced slope laterally. There may be advanced ossification of specific epiphyses – the proximal femora and humeri. In the hands and feet there is postaxial polydactyly. Syndactyly and synostosis of the carpal bones may occur. The middle phalanges and proximal phalanx of the thumb are short and relatively broad, and the distal phalanges are hypoplastic, being both short and narrow. Depending on the stage of gestation, there may be absent ossification of the distal phalanges. Prognosis: viable – prognosis depends on the respiratory difficulties in the first months of life due to the narrow thorax and cardiac malformations. Cognitive development is normal. The average adult height is 110–160 cm. Orthopaedic and orthodontic follow-up is needed.

• Narrow thorax, short limbs, postaxial polydactyly, talipes, short stature • Hidrotic ectodermal dysplasia: dysplastic hair, fingernails and teeth, neonatal teeth • Heart defects: atrial septal defect (ASD), persistent left superior vena cava, pulmonary venous connection abnormalities, common atrium, hypoplastic left heart • Multiple oral frenula, midline cleft lip and alveolar ridge • Cryptorchidism, hypospadias

Differential diagnosis: Short rib-polydactyly group (SRP) (pp. 182–222); Mohr-Majewski syndrome (p. 209); asphyxiating thoracic dystrophy (Jeune) (p. 196); cranioectodermal dysplasia (p. 212); Kaufman-McKusick syndrome (p. 599); Weyers acrodental dysostosis: allelic disorder, caused by heterozygous mutations in the genes EVC1 or EVC2; it is less severe, showing moderate short stature because of short limbs, postaxial polydactyly and ectodermal dysplasia. Heart defect and thoracic narrowing are not present; PatUPD 14 (p. 528).

Prenatal ultrasound features: may be diagnosed by ultrasound in the late first trimester (usually in affected families) and in the second and third trimesters. Increased nuchal translucency thickness has been described at 13 weeks’ gestation and at 18+5 weeks. The diagnosis is based on the association of a narrow thorax, short ribs, short and bowed long bones,

There are overlapping features with cardioacrofacial dysplasia, characterised by congenital cardiac defects, primarily a common atrium or atrioventricular septal defect; limb anomalies, including short limbs, brachydactyly and postaxial polydactyly; and dysmorphic facial features caused by heterozygous germline or mosaic variants in PRKACA or PRKAC.

DOI: 10.1201/9781003166948-36

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CASE 1: Short ribs and trident acetabula, mildly bowed humeri; (c) postaxial polydactyly; hypoplastic middle phalanges and absent ossification of the distal phalanges. CASE 2: Had short limbs on ultrasound scan at 20 weeks’ gestation. At postmortem the fetus had short limbs and bilateral postaxial polydactyly with 5/6 syndactyly of the hands. In the feet there were bilateral talipes equinovarus and postaxial polydactyly with 3/4 and 5/6 syndactyly. The ribs were short and broad at the costochondral junctions. CASE 3: This fetus was found to have short limbs and polydactyly at 20 weeks’ gestation. At postmortem there was postaxial polydactyly of the hands and feet, a narrow chest and hypoplastic lungs; there was also intestinal malrotation and large kidneys, which demonstrated microcystic change.

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CASE 4: Antenatal ultrasound showed short limbs with polydactyly of the hands, a ventricular septal defect and hypoplastic left heart. The baby was stillborn at full term. Parents were first cousins, and another consanguineous marriage in the extended family resulted in a similarly affected infant. CASES 5, 6: Neonates. Sloping upper humeral metaphyses – note advanced ossification of the capital femoral epiphyses and proximal humeral epiphyses in Case 6.

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CASE 7: Normal pregnancy – at birth there was a narrow chest, but respiratory function was normal; there was a midline cleft in the upper lip, polydactyly of the hands and small dysplastic nails; sloping, smooth lateral upper humeral metaphyses and humeral bowing, short tibiae and fibulae. CASE 8: Term delivery; six fingers and toes bilaterally; narrow chest; long body with relatively short limbs and three natal teeth. At 2 years marked genu valgum with an intermalleolar distance of 12.0 cm; unusual dentition; tethered gums to the lips (oral frenulae); broad stubby hands and 10° of recurvatum at both elbows. The nails were dysplastic, and there was an ostium primum cardiac defect; notice the ‘chicken drumstick’ appearance of the radius and ulna with wide distal radius and proximal ulna. CASE 9: Termination of pregnancy at 22 weeks. Bilateral upper limb postaxial polydactyly; narrow thorax with short ribs, trident acetabula, smooth metaphyses, sloping proximal metaphyses of the humeri and bilateral talipes equinovarus. CASE 10: Bowed humeri and femora, narrow thorax with short ribs, medial and lateral spurs on acetabula, disproportionately short tibiae, postaxial polydactyly.

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CASE 11: Termination of pregnancy at 22 weeks. Postaxial polydactyly of the hands, bowed humeri. CASE 12: US at 16 weeks’ gestation; small, narrow thorax; postaxial polydactyly; post-termination of pregnancy skeletal survey at 18 weeks’ gestation. CASE 13: Pregnancy at 15 weeks and 6 days. (a, b) Apical four-chamber views in color Doppler in a fetus with atrioventricular septal defect (AVSD) during diastole. (c) Color and pulsed Doppler at the four-chamber view in a fetus with AVSD. Note the presence of atrioventricular valve regurgitation.

208

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CASE 13: (d, e) Postaxial polydactyly of the hands. Surface mode, 3D-US HD-live. Fetal right hand (front view and from above). 3D volume acquisition of the right fetal hand at 156 weeks displayed with HD-live and silhouette effect (palmar view of the hand). There is postaxial polydactyly that appears as a cutaneous appendage. (f) 3D acquisition of the right hand with maximum mode rendering. Postaxial polydactyly with two minuscule bone elements at the level of the proximal phalanx of the fifth ray (white arrow) at 175 weeks’ gestation. (g, h) 2D-US detects shortening of the long bones. Femoral and humeral measurements are at the third percentile for gestational age, with increased curvature.

BIBLIOGRAPHY Aubert-Mucca M, Huber C, Baujat, et al. Ellis-van Creveld syndrome: Clinical and molecular analysis of 50 individuals. J Med Genet. 2022 Aug 4; 0:1–9. doi: https://doi.org/10.1136/ jmg-2022-108435 Caparrós-Martín JA, De Luca A, Cartault F et al. Specific variants in WDR35 cause a distinctive form of Ellis-van Creveld syndrome by disrupting the recruitment of the EvC complex and SMO into the cilium. Hum Mol Genet. 2015; 24: 4126–37. Djenoune L, Berg K, Brueckner M, et al. A change of heart: New roles for cilia in cardiac development and disease. Nat Rev Cardiol. 2021; Dec 3. doi: 10.1038/s41569-021-00635-z. Online ahead of print. Handa A, Voss U, Hammarsjö A et al. Skeletal ciliopathies: A pattern recognition approach. Jpn J Radiol. 2020; 38: 193–206. Le TL, Sribudiani Y, Dong X et al. Bi-allelic variations of SMO in humans cause a broad spectrum of developmental anomalies due to abnormal hedgehog signaling. Am J Hum Genet. 2020; 106: 779–92.

Niceta M, Margiotti K, Digilio MC et al. Biallelic mutations in DYNC2LI1 are a rare cause of Ellis-Van Creveld syndrome. Clin Genet. 2018; 93: 632–9. Palencia-Campos A, Aoto PC, Machal EMF et al. PRKACA/ PRKACB germline and mosaic variants in PRKACA and PRKACB cause a multiple congenital malformation syndrome. Am J Hum Genet. 2020; 107: 977–88. Palencia-Campos A, Ullah A et al. GLI1 inactivation is associated with developmental phenotypes overlapping with Ellis-van Creveld syndrome. Hum Mol Genet. 2017; 26: 4556–71. Sergi C, Voigtländer T, Zoubaa S et al. Ellis-van Creveld syndrome: A generalized dysplasia of enchondral ossification. Pediatr Radiol. 2001; 31: 289–93. Zaka A, Shahzad S, Rao HZ et al. An intrafamilial phenotypic variability in Ellis-van Creveld syndrome due to a novel 27 bps deletion mutation. Am J Med Genet A. 2021; 185: 2888–94. Zhang W, Taylor SP, Ennis HA et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018; 39: 152–66.

34 Orofaciodigital Syndrome Type 4, TCTN3-Related

Synonyms: Mohr-Majewski syndrome; OFD4; OFDS IV; OFD syndrome, Baraitser-Burn type; Baraitser-Burn syndrome; OFD syndrome with tibial defects Frequency: very rare, fewer than 30 cases reported. Genetics: autosomal recessive inheritance. Heterogeneous condition. TCTN3 pathogenic variants have been identified in an extreme form of OFD associated with bone dysplasia, tibial defect, cystic kidneys and brain anomalies in unrelated fetal cases with overlapping Meckel and OFD IV syndromes and in a family with Joubert syndrome. No mutations were identified in typical nonfetal OFD IV syndrome cases. TCTN3 is necessary for transduction of the sonic hedgehog (SHH) signalling pathway, as revealed by abnormal processing of GLI3 in patient cells. In a consanguineous family with two affected siblings with an atypical form of OFD IV (limb defects, growth retardation, scaphocephaly and seizures), exome sequencing analysis revealed a novel homozygous splice site variant in TCTN3 that segregated with disease. Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester (11–13 weeks). Increased nuchal translucency can be seen at 10–12 weeks’ gestation. Clinical features: • • • • • • •

•

Mesomelic shortening of the limbs Pre/postaxial polysyndactyly of hands and feet Talipes equinovarus Midline cleft lip and palate, multiple oral frenula, tongue lobulation or hamartomas, micrognathia Hypoplasia of larynx and epiglottis, hamartomatous larynx, midline clefts of the epiglottis Brain anomalies: Dandy-Walker malformation, cerebral atrophy, polymicrogyria, absent olfactory bulbs Heart defects: single atrium, ventricular septal defect (VSD), anomalous pulmonary venous drainage, tetralogy of Fallot, hypoplastic left heart syndrome Other possible associated anomalies: abnormal lung lobation, anal atresia, malrotated bowel, liver and kidney cysts, hepatic fibrosis, hypoplastic or ambiguous genitalia

Prenatal ultrasound features: increased nuchal translucency may be identified from 10 weeks, and the specific anomalies allow diagnosis by 13 weeks. In the skeletal system there is mesomelic shortening with specific shortening of the ulnae and tibiae leading to ulnar deviation of the hands and talipes equinovarus. There is mild bowing of the femora and tibiae. There is upper and lower DOI: 10.1201/9781003166948-37

limb pre- and/or postaxial polydactyly with syndactyly. Cardiac malformations include hypoplastic left heart and atrioventricular septal defect (AVSD). The cranium has an abnormal configuration (scaphocephaly, turricephaly). Intracerebral abnormalities include schizencephaly, single ventricle and encephalocele. Dysmorphic features may be identified (prominent forehead, hypertelorism, micrognathia and midline cleft or notch of the upper lip). Radiographic features: the skull vault may show turricephaly or scaphocephaly, and a midline occipital defect may be associated with encephalocele. The mandible is short. There is mesomelic shortening. In the upper limbs there is striking disproportionate shortening of the ulnae with ulnar deviation of the hands. There may be postaxial polydactyly, soft tissue syndactyly and short middle phalanges. In the lower limbs there is talipes equinovarus and pre- and postaxial polydactyly of the feet. The tibiae are disproportionately short, and this may result in knee and ankle joint deformities and instability. The thorax is small, mainly as a result of reduced height with only minor shortening of the ribs. Prognosis: viable – failure to thrive and recurrent infections have been reported. Survival may be reduced because of the severity of associated malformations. Patients usually show developmental delay and short stature. Conductive hearing loss may be present. Differential diagnosis: OFD4 shows transitional features between Mohr syndrome (OFD 2) and Majewski syndrome (short rib-polydactyly syndrome type 2). All the oral-facial-digital syndromes (OFDS), including OFD4, share some features; namely, hand anomalies, such as polydactyly, and orofacial anomalies, such as lobulation and hamartomas of the tongue, multiple frenula and midline clefts. OFD1 also has polycystic kidney disease, abnormal dentition and Xlinked dominant inheritance; OFD2 is characterised by polydactyly, bifid nasal tip and absence of polycystic kidney disease; OFD3 presents with ‘seesaw winking’ (alternate winking of the eyes) and myoclonic jerks; OFD5 has only polydactyly and median cleft lip, without other associated features; OFD6 has cerebellar anomalies, postaxial or central polydactyly in the hands and preaxial polydactyly in the feet; OFD7 shows clinodactyly instead of polydactyly and hydronephrosis; OFD8 is inherited as an X-linked recessive trait and comprises tibial and radial defects; OFD9 has retinal abnormalities. Polydactyly and brain anomalies are also present in Meckel syndrome (p. 217), short rib-polydactyly syndrome type 4 (p. 191), asphyxiating thoracic dysplasia (p. 196), chondroectodermal dysplasia (p. 203), Pallister-Hall syndrome (p. 587) and hydrolethalus syndrome. 209

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CASE 1: First affected child of consanguineous Pakistani parents. Clinically there were sublingual hamartoma, posterior cleft palate, micrognathia, low-set ears, congenital conductive hearing loss, proptosis and oculomotor apraxia. Skeletal problems included lower limb mesomelic shortening due to short tibiae and dislocated knees, severe talipes, hand postaxial polydactyly with short middle phalanges and camptodactyly and pre- and postaxial polydactyly in the feet. CASE 2: Younger sibling of Case 1. Clinical findings were the same as in the older sibling. Hypoplastic tibiae; postaxial polydactyly of hand; pre- and postaxial polydactyly of feet with attempted duplication of the broad first metatarsals with three distal phalanges of the left foot; talipes equinovarus.

Orofaciodigital Syndrome Type 4, TCTN3-Related

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CASE 3: Historical radiographs; short tibiae and postaxial polydactyly of the hands and pre- and postaxial polydactyly of the feet.

BIBLIOGRAPHY Kahl P, Heukamp LC, Buettner R et al. Orofaciodigital syndrome type IV (Mohr-Majewski syndrome): Report of a family with two affected siblings. Pediatr Dev Pathol. 2007; 10: 239–43. Ozdemir-Karatas M, Oxdemir-Ozenen D, Hart PS, Hart TC. Craniodentofacial manifestations in a rare syndrome: Orofaciodigital type IV (Mohr-Majewski syndrome). Case Rep Dent. 2014. doi: 10.1155/2014/605892

Rösing B, Kempe A, Berg C et al. Orofaciodigital syndrome type IV (Mohr-Majewski): Early prenatal diagnosis in siblings. Ultrasound Obstet Gynecol. 2008; 31: 457–60. Thomas S, Legendre M, Saunier S et al. TCTN3 mutations cause Mohr-Majewski syndrome. Am J Hum Genet. 2012; 91: 372–8.

35 Cranioectodermal Dysplasia (Levin-Sensenbrenner), IFTI22-, WDR35-, WDR19-, IFT40- and IFT43-Related

Synonyms: CED; includes CED1, 2, 3 and 4 Confirmation of diagnosis: identification of biallelic pathogenic mutations in IFT122, IFT121, IFT43 and IFT144 together with the appropriate clinical and radiographic findings. Frequency: very rare – fewer than 50 cases reported. Genetics: CED is an autosomal recessive disorder belonging to the group of skeletal ciliopathies. Four genes have been currently associated with the disease: IFT122, which causes CED1; WDR35 (IFT121), which causes CED2; IFT43, which causes CED3; and WDR19, which encodes IFT144 and causes CED4. IFT122 is a component of the intraflagellar transport complex A and is involved in retrograde ciliary transport and in the assembly and maintenance of cilia and flagella. WDR35 is a WD40 domain–containing protein and is also implicated in intraflagellar transport. IFT144 and IFT43 are also members of the intraflagellar transport complex. All these genes are associated with the ATD spectrum. WDR19 is also associated with isolated nephronophthisis, Mainzer-Saldino syndrome and Senior-Loken syndrome. Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester (19 weeks). Clinical features: • Short limbs, joint laxity, narrow and short thorax, pectus excavatum, protuberant abdomen • Dolichocephaly, craniosynostosis • High forehead, epicanthic folds, telecanthus, broad nasal bridge, anteverted nares, high arched palate, low-set prominent ears, everted lower lip • Brachydactyly, syndactyly • Ectodermal anomalies: abnormally shaped teeth, sparse hair, dystrophic nails, skin laxity, bilateral inguinal herniae • Occasionally other malformations can be present involving the heart, brain and eye (retinitis pigmentosa) • Tubulo-interstitial nephropathy, hepatic fibrosis Prenatal ultrasound features: prenatal diagnosis has only been made in at-risk fetuses. Growth parameters are normal

212

during the first and early second trimester, although there is increased nuchal translucency. At 20 weeks, measurements of the mesomelic segments and foot length fall below the fifth centile, with the ulnae and tibiae being shortest. Brachydactyly may be demonstrated. The biparietal diameter is reduced, but there is no evidence of sagittal craniosynostosis even though this may be present at term. Enlargement of the cisterna magna and posterior fossa cysts may be visualised. The facial profile is flat and the thorax mildly small. The kidneys may be small and show heterogeneous hyperechogenicity with pelvic dilatation. Radiographic features: at birth there may be dolichocephaly as a result of sagittal craniosynostosis and a narrow biparietal diameter. There is a generalised decrease in bone density. The thorax is narrow as a result of short ribs, which show angulation in the midaxillary line. There is acromesomelic shortening. The long bones are bowed with smooth, domed metaphyses. There is striking expansion of the proximal ulnae and some expansion of the distal radii, giving a ‘chicken drumstick’ appearance. The distal ulnae are short. There is a long, sloping proximal humerus. The hands and feet occasionally show postaxial polydactyly. The tubular bones are short, and the middle and distal phalanges are severely hypoplastic or absent. The spine and pelvis appear normal. Prognosis: viable – intrauterine growth retardation has been reported, although growth parameters at birth are often normal. In childhood there is progressive growth retardation and cranial enlargement. Sagittal suture synostosis might require early surgical correction. Intellectual development is normal. Roughly half of cases develop chronic renal failure secondary to progressive tubulo-interstitial nephritis. In some cases, retinal anomalies have also been described. Differential diagnosis: involvement of skeletal and ectodermal systems: chondroectodermal dysplasia (Ellis-van Creveld) (p. 203); CDPX2 (p. 352); cartilage-hair hypoplasia (p. 224); tricho-dento-osseous syndrome, which shows kinky hair and osteosclerosis; GAPO syndrome, an acronym for growth retardation, alopecia, pseudo-anodontia and progressive optic atrophy, which also presents with diffuse visceral organs fibrosis. Hepatorenal fibrocystic syndromes: Meckel-Gruber syndrome (p. 217); asphyxiating thoracic dysplasia (p. 196); short rib-polydactyly syndrome type 1/3 (p. 182). Small thorax: patUPD14. (p. 528).

DOI: 10.1201/9781003166948-38

Cranioectodermal Dysplasia (Levin-Sensenbrenner), IFTI22-, WDR35-, WDR19-, IFT40- and IFT43-Related

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CASE 1: There is sagittal craniosynostosis. The thorax is narrow due to short, angulated ribs. Bowed humeri and ‘chicken drumstick’ appearance of the radius and ulna. Short tibiae and fibulae. Normal pelvis and spine.

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CASES 2, 3: Both are 21-week fetuses. They show short tibiae and fibulae with an unusual angulation of the upper tibiae. The thorax is narrow due to short, angulated ribs. Case 2 has short, bowed radii and ulnae and postaxial polydactyly. Case 3 shows pronounced craniosynostosis.

Cranioectodermal Dysplasia (Levin-Sensenbrenner), IFTI22-, WDR35-, WDR19-, IFT40- and IFT43-Related

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CASE 4: Neonate. There is sagittal craniosynostosis and dolichocephaly. (c) There is the ‘chicken drumstick’ appearance of the radius and ulna. (d) Short tibia and fibula. (e) Small thorax. CASE 5: (a) Narrow thorax with short, angulated ribs.

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CASE 5: (c, d) Short tibia and tibia. (e) The proximal humerus is sloping. (f, g) Hypoplastic distal and middle phalanges.

BIBLIOGRAPHY Gilissen C, Arts HH, Hoischen A et al. Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome. Am J Hum Genet. 2010; 87: 418–23. Konstantinidou AE, Fryssira H, Sifakis S et al. Cranioectodermal dysplasia: A probable ciliopathy. Am J Med Genet A. 2009; 149A: 2206–11. Lin AE, Traum AZ, Sahai I et al. Sensenbrenner syndrome (cranioectodermal dysplasia): Clinical and molecular analyses of 39 patients including two new patients. Am J Med Genet A. 2013; 161A: 2762–76.

Walczak-Sztulpa J, Eggenschwiler J, Osborn D et al. Cranioectodermal dysplasia, Sensenbrenner syndrome, is a ciliopathy caused by mutations in the IFT122 gene. Am J Hum Genet. 2010; 86: 946–9. Walczak-Sztulpa J, Wawrocka A, Leszczynska B et al. Prenatal genetic diagnosis of cranioectodermal dysplasia in a Polish family with compound heterozygous variants in WDR35. Am J Med Genet A. 2020; 182A: 2417–25. Zaffanello M, Diomedi-Camassei F, Melzi ML et al. Sensenbrenner syndrome: A new member of the hepatorenal fibrocystic family. Am J Med Genet A. 2006; 140A: 2336–40.

36 Meckel Syndrome, TMRM67-, CEP290-, RPGRIP1L-, CC2D2A MKS1-, TMEM216-, NPHP3-, TCTN2-, B9D1-, B9D2-, TMEM231-, KIF14-, TMEM107- and TXNDC15-Related

Synonyms: Meckel syndrome type 1–14; MKS; MKS1–14; MES; Meckel-Gruber syndrome; dysencephalia splanchnocystica; Gruber syndrome; type 4: Meckel-like cerebrorenodigital syndrome; type 7: renal-hepatic-pancreatic dysplasia with Dandy-Walker cyst or Goldston syndrome; type 10: Joubert syndrome 34; type 13: Joubert syndrome 29

a member of the kinesin superfamily of microtubule-associated motors; TMEM107 (MKS13); and TXNDC15 (MKS14).

Confirmation of diagnosis: detection of pathogenic variants in the associated genes combined with congruent clinical features. In 40–50% of cases the diagnosis remains clinical.

Clinical features:

Frequency: 1–10 in 140,000 worldwide; 1/38,500 in Europe; 1 in 9,000 in Finland; 1 in 3,500 in Kuwaiti Bedouin populations; 1/1,300 in Gujarati Indians; 1 in 5,000 in Qatar. Genetics: Meckel syndrome is genetically heterogeneous and autosomal recessive for which at least 14 different genes have been identified, all encoding proteins that are structural or functional components of the primary cilium, usually at the transition zone, a region between the basal body and ciliary axoneme, which is critical in regulating the diffusion of proteins. Quite a few of these genes are also associated with Joubert syndrome, which is considered either an allelic condition or part of a larger ciliopathy spectrum of which Meckel syndrome represents the most severe end. The gene most frequently involved is TMEM67 (MKS3), encoding meckelin, a transmembrane protein required for proper ciliary structure and function. Other genes are MKS1 (MKS1), encoding a component of the flagellar apparatus basal body proteome; TMEM216 (MKS2), encoding a transmembrane protein interacting with TMEM67, which is needed for cellular polarisation and centrosomal apical docking; CEP290 (MKS4) or nephrocystin 6, which promotes ciliogenesis; RPGRIP1L (MKS5), or nephrocystin 8; CC2D2A (MKS6); NPHP3 (MKS7), or nephrocystin 3; TCTN2 (MKS8), or Tectonic2, which is a paralog of Tectonic1, known to modulate mouse sonic hedgehog signalling and contributes to the composition of a multiprotein complex localised at the transition zone; B9D1 (MKS9) and B9D2 (MKS10) encode proteins which connect the basal body and transition zone membrane; TMEM231 (MKS11), a critical component of a ring-like macromolecule in the transition zone, which acts as a barrier of protein diffusion between plasma and ciliary membranes; KIF14 (MKS12),

DOI: 10.1201/9781003166948-39

Age/Gestational age of manifestation: can be detected by ultrasound during the first trimester (11–14 weeks). Elevated amniotic alpha-fetoprotein is common and due to encephalocele.

• Occipital encephalocele, microcephaly, hydrocephaly or anencephaly, polymicrogyria, absent olfactory lobes, cerebral and cerebellar dysgenesis • Anophthalmia or microphthalmia • Cleft lip and palate • Postaxial polydactyly (55%), rarely preaxial • Polycystic kidneys, hepatic fibrosis, and cysts • Other associated anomalies include urethral atresia, heart malformations and ambiguous genitalia Prenatal ultrasound features: features can be present as early as 11 weeks. There can be increased nuchal translucency (NT). Transvaginal or transabdominal ultrasound between 12+5 weeks and 13+2 weeks can reveal the first pathologic findings if a systematic ultrasound examination of the fetal skull, brain, kidneys, bladder, hands and feet is performed. There is often a protuberant abdomen. At this stage, there is a normal amount of amniotic fluid. In the second-trimester ultrasound, there is usually a protuberant abdomen due to large cystic echogenic kidneys (biometry > 95° centile) showing an unusual heterogeneous cortico-medullary differentiation, with small cystic lesions in the medulla surrounded by hyperechoic cortex (microcysts). Postaxial polydactyly is reported in up to 83% of cases. The central nervous system anomalies may range from a bony defect in the occipital vault with a protrusion of a small meningoencephalocele to a large meningoencephalocystocoele. Ventriculomegaly and cerebellar dysgenesis may be present and rarely anencephaly and craniorachischisis. The fetal bladder may or may not be visualised. Craniofacial defects detectable by ultrasound include microcephaly, sloping forehead, hypertelorism, cleft lip/palate and micrognathia. Skeletal malformations comprise shortening and bowing of long tubular bones and talipes equinovarus. Congenital heart defects and genital anomalies may occur. Oligohydramnios

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makes the visualisation more difficult in the second trimester, and in cases of severe oligo-anhydramnios, fetal MRI can be used as an alternative and to define the brain abnormalities associated with an encephalocele.

and renal anomalies but is characterised more specifically by hypoplasia of the cerebellar vermis, the characteristic neuroradiological ‘molar tooth sign’, abnormal neurological development and, rarely, occipital myelomeningocele.

Radiographic features: in the skull there is an occipital encephalocele and poor ossification of the vault. There may be microcephaly or even macrocephaly because of hydrocephalus. Postaxial and, more rarely, preaxial polydactyly may be present. Bowing and shortening of the long bones and talipes equinovarus have been reported.

Chromosomal anomalies – namely, trisomy 13 and trisomy 18 – might present some overlap with Meckel syndrome as well as amniotic band syndrome. Polycystic kidneys, liver and lung anomalies can also be present in ARPKD, but in this condition there are no skeletal defects. Zellweger syndrome (p. 528); asphyxiating thoracic dysplasia (Jeune) (p. 196); Cumming syndrome: a lethal disorder characterised by tetramelic campomelia, short long bones and variable other anomalies, including cervical lymphocele, polycystic kidneys, polycystic or fibrotic pancreas and liver, polysplenia, heterotaxia, lung hypoplasia, short bowel and neurological malformations. Dandy-Walker malformation; Arnold-Chiari II malformation; spina bifida.

Prognosis: perinatally lethal due to respiratory and renal insufficiency. Differential diagnosis: Joubert syndrome is a heterogeneous group of disorders which can present with retinal dystrophy

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CASE 1: Deficient ossification of skull vault; encephalocele and micrognathia.

 

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(2c) CASE 2: Postaxial polydactyly.

 

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CASE 3: Ultrasound examination at 12 weeks’ gestation shows occipital encephalocele (indicated by straight and curved arrows) and the fetal hand with postaxial polydactyly. (c) US at 14 weeks; axial section of fetal abdomen showing a large abdomen filled by enlarged hyperechogenic kidneys (K) (indicated by arrows). CASE 4: (a) An axial scan of the fetal head shows an occipital defect of the skull with an encephalocele (arrow). (b) A coronal view of the abdomen shows enlarged echogenic kidneys (arrows) and severe oligohydramnios.

Meckel Syndrome

BIBLIOGRAPHY Aydin Ozturk P, Asena M, Katar S et al. Meckel-Gruber syndrome: A case who lived for 5 months. Pediatr Neurosurg. 2019; 54: 277–80. Dąbkowska S, Kucińska-Chahwan A, Beneturska A et al. Prenatal diagnosis and clinical significance of cephaloceleA single institution experience and literature review. Prenat Diagn. 2020; 40: 612–17. Pauta M, Martinez-Portilla RJ, Borrell A. Prenatal exome sequencing in recurrent fetal structural anomalies: Systematic review and meta-analysis. J Clin Med. 2021; 10: 4739. Peng M, Han S, Sun J et al. Evaluation of novel compound variants of CEP290 in prenatally suspected case of Meckel syndrome through whole exome sequencing. Mol Genet Genomic Med. 2022; 10: e1935. Ridnõi K, Šois M, Vaidla E et al. A prenatally diagnosed case of Meckel-Gruber syndrome with novel compound heterozygous pathogenic variants in the TXNDC15 gene. Mol Genet Genomic Med. 2019; 7: e614.

221 Stembalska A, Rydzanicz M, Pollak A et al. Prenatal versus postnatal diagnosis of Meckel-Gruber and Joubert syndrome in patients with TMEM67 mutations. Genes (Basel). 2021; 12: 1078 doi: 10.3390/genes12071078. Turkyilmaz A, Geckinli BB, Alavanda C et al. Meckel-Gruber syndrome: Clinical and molecular genetic profiles in two fetuses and review of the current literature. Genet Test Mol Biomarkers. 2021; 25: 445–51. Yaqoubi HNA, Fatema N. Meckel Gruber syndrome associated with anencephaly – An unusual reported case. Oxf Med Case Reports. 2018; 2018: omx092. Zhang R, Chen S, Han P et al. Whole exome sequencing identified a homozygous novel variant in CEP290 gene causes Meckel syndrome. J Cell Mol Med. 2020; 24: 1906–16.

37 Thoracolaryngopelvic Dysplasia (Barnes)

Synonyms: TLPD, Barnes syndrome, thoracic dysostosis Confirmation of diagnosis: identification of clinical and radiographic findings with no genetic mutations in other short rib dysplasias. Frequency: very rare. Genetics: autosomal dominant; the causative gene has not yet been identified. Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester (16–20 weeks). Clinical features: • A small, rigid, bell-shaped thorax • Normal stature, asthenic build, some limb asymmetry • Abnormal laryngeal cartilage configuration with hypoplasia and stenosis also affecting the proximal trachea • Palpable liver and spleen Prenatal ultrasound features: the thorax is small in transverse and anteroposterior diameters and the ribs are short. On the sagittal scan, there is a narrow thorax compared to a

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protruding abdomen. Respiratory movements may not be detected. Polyhydramnios may be present. Radiographic features: short horizontal ribs result in a long, narrow thorax. The ribs may be wide throughout their length, or the widening may affect only the anterior ends (costochondral junctions). The clavicles are high and straight. In the pelvis the iliac bones are small with some inferior hypoplasia. The pelvic inlet is small. Bone modelling is otherwise normal, although there may be some long bone asymmetry. Prognosis: viable – intrafamilial variability has been reported, and milder clinical forms exist. TLPD can result in severe respiratory distress and death either in the neonatal period or later in childhood as a result of recurrent respiratory tract ­infections. There can be anaesthetic difficulties with intubation due to laryngeal stenosis and reduced lung volumes. Corrective surgical procedures to expand the thorax result in some improvement. The reduced size of the pelvis results in obstruction during labour. Differential diagnosis: other disorders with a small thorax: asphyxiating thoracic dysplasia (p. 196); short rib-­polydactyly syndrome type 1/3 (p. 182); Ellis-van Creveld syndrome (p. 203); cranioectodermal dysplasia (p. 212); Shwachman-­Diamond syndrome (p. 229); Pat UPD14 (p. 528).

 

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  DOI: 10.1201/9781003166948-40

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CASE 1: A 23-week-gestation fetus. (a, b) Two-dimensional image of the thorax with two arrows pointing to a long, narrow chest; (c) three-­dimensional image of the chest and abdomen with an arrow pointing to a short, narrow chest relative to the abdomen; (d) two-dimensional image of the femur showing normal configuration and length, differentiating it from asphyxiating thoracic dystrophy; (e, f) radiographs of the lower extremity and lateral chest of the fetus.

BIBLIOGRAPHY Marik I, Grochova J, Kozlowski K. Thoracic-pelvic dysostosis. Clin Dysmorphol. 2000; 9: 285–7. Miller TL, Cox T, Blackson T et al. Pulmonary function assessment in an infant with Barnes syndrome: Proactive evaluation for surgical intervention. Pediatrics. 2006; 118. doi: https://pubmed.ncbi.nlm.nih.gov/16950944/#:~:text= 10.1542/peds.2006%2D0135.

Patel SH, Banzali FM Jr, Post RJ et al. Parturient with Barnes syndrome (thoracolaryngopelvic dysplasia) undergoing caesarean delivery of a neonate with Barnes syndrome: A case report. A Pract. 2018; 11: 151–4.

38 Cartilage-Hair Hypoplasia/Anauxetic Dysplasia Spectrum, RMRP-Related

Synonyms: CHH; metaphyseal chondrodysplasia, McKusick type; anauxetic dysplasia; thanatophoric dysplasia variant, type Glasgow; metaphyseal dysplasia without hypotrichosis; MDWH

Prenatal ultrasound features: short, bowed long bones and a small thorax may be identified on fetal ultrasonography as early as 12 weeks, but a specific diagnosis is not usually made unless in an at-risk family.

Confirmation of diagnosis: identification of pathogenic variants in RMRP.

Radiographic features: in the fetus, the long bones are short and bowed, the thorax small and there is mild platyspondyly. In infancy there may be quite pronounced bowing of the femora with disproportionately large and rounded distal femoral epiphyses. Also, there is mild cupping of the bases of the metacarpals and phalanges and later cone-shaped or delta-shaped epiphyses here. In early childhood the metaphyses are flared and irregular with the most pronounced changes being at the knees. There is brachydactyly and sometimes a prominent angulation of the sternum resulting in pectus carinatum.

Frequency: rare worldwide, except in Finland (1 in 23,000) and in Amish groups (1–2 in 1,000). Genetics: autosomal recessive disorders due to pathogenic variants in RMRP, encoding the untranslated RNA subunit of the ribonucleoprotein endoribonuclease (RNase MRP); CHHassociated mutations lead to decreased cell growth by impairing ribosomal assembly and by altering cyclin-dependent cell cycle regulation. Anauxetic dysplasia is also autosomal recessive and caused by mutations in either RMRP or POP1. Age/Gestational week of manifestation: usually at birth; early prenatal diagnosis in at-risk families has been rarely made on ultrasound from short, bowed long bones. Clinical features: • Disproportionate short stature, short limbs and hands • Reduced birth length, postnatal progressive shortening, more marked in anauxetic dysplasia • Hyperlaxity, chiefly at hands, wrists and feet • Fine, sparse, blond hair; baldness, but normal hair in a group of patients with CHH and in anauxetic dysplasia • Deficient erythropoiesis and immunodeficiency in CHH but not in anauxetic dysplasia • Occasionally oesophageal atresia or Hirschsprung disease • Occasionally intellectual impairment in anauxetic dysplasia

224

Prognosis: viable, but may be severe or fatal during childhood. The median adult height is 131 cm in males and 123 cm in females. There is a moderate increase of infection rate in infancy, but not in adults. Susceptibility to varicella is common. Cases of severe aplastic anaemia have been reported, as well as an increased risk for malignancies, particularly Hodgkin and nonHodgkin lymphomas; leukaemias; and solid tumours affecting the skin, liver, eyes, and testicles. Differential diagnosis: other syndromes with metaphyseal dysplasia: Shwachman-Bodian-Diamond syndrome (p. 229). Omenn syndrome: severe disorder characterised by reticuloendotheliosis with eosinophilia, generalised erythroderma, diarrhoea, failure to thrive and hepatosplenomegaly. Metaphyseal dysplasia Jansen type (p. 461). Other syndromes with bowed bones: Schmid dysplasia: a mild form of metaphyseal dysplasia with short, bowed limbs, lumbar lordosis and waddling gait; Campomelic dysplasia (p. 302); kyphomelic dysplasia (p. 313); Stüve-Wiedemann syndrome (Schwartz-Jampel syndrome type 2) (p. 311); osteogenesis imperfecta (p. 429); Antley-Bixler syndrome (p. 500); hypophosphatasia (p. 452).

DOI: 10.1201/9781003166948-41

Cartilage-Hair Hypoplasia/Anauxetic Dysplasia Spectrum, RMRP-Related

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CASE 1: A 16-week fetus with abnormalities on the 12-week US scan. There were three affected sibling fetuses, all with RMPR mutations. CASE 2: A 31-week fetus with some metaphyseal flaring and irregularity. Both cases show short bowed long bones, a small thorax and mild platyspondyly.

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(3c) CASE 3: A neonate with short, bowed long bones and a small thorax.

 

 

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CASE 4: A neonate with short, bowed long bones, especially marked in the femora. The thorax is small. There is mild cupping of the metaphyses of the proximal and middle phalanges. In the pelvis the sacrosciatic notches are short. The distal femoral epiphyses are large and rounded. There is also an oval transradiancy of the proximal femora, mimicking conditions caused by FGFR3 mutations. CASE 5: A 6-month-old boy. The long bones are short and bowed, the thorax small and the distal femoral epiphyses relatively large.

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BIBLIOGRAPHY Crahes M, Saugier-Veber P, Patrier S et al. Foetal presentation of cartilage hair hypoplasia with extensive granulomatous inflammation. Eur J Med Genet. 2013; 56: 365–70. Hall CM, Liu B, Haworth A, Reed L, Pryce J, Mansour S. Early prenatal presentation of the cartilage-hair hypoplasia/ anauxetic dysplasia spectrum of disorders mimicking recurrent thanatophoric dysplasia. Eur J Med Genet. 2021; 64: 104162. Makitie O, Kaitila I, Savilahti E. Susceptibility to infections and in vitro immune functions in cartilage-hair hypoplasia. Eur J Pediatr. 1998; 157: 816–20. Sulisalo T, Sillence D, Wilson M et al. Early prenatal diagnosis of cartilage-hair hypoplasia (CHH) with polymorphic DNA markers. Prenat Diagn. 1995; 15: 135–40.

Thiel CT, Horn D, Zabel B et al. The molecular basis of the cartilage-hair hypoplasia-anauxetic dysplasia spectrum. Best Pract Res Clin Endocrinol Metab. 2011; 25: 131–42. Thiel CT, Mortier G, Kaitila I et al. Type and level of RMRP functional impairment predicts phenotype in the cartilage hair hypoplasia-anauxetic dysplasia spectrum. Am J Hum Genet. 2007; 81: 519–29. Zweier C, Schmitt ME, Reis A et al. Severely incapacitating mutations in patients with extreme short stature identify RNA-processing endoribonuclease RMRP as an essential cell growth regulator. Am J Hum Genet. 2005; 77: 795–806.

39 Metaphyseal Dysplasia with Pancreatic Insufficiency and Cyclical Neutropenia (Shwachman-Bodian-Diamond Syndrome, SBDS), SBDS-, EFL1-, DNAJC21- and SRP54-Related

Synonyms: Shwachman syndrome; Shwachman-Diamond syndrome; SDS; SDS1; SDS2; Shwachman-Bodian syndrome; SBS; SBDS; pancreatic insufficiency and bone marrow dysfunction; lipomatosis of pancreas, congenital Confirmation of diagnosis: identification of biallelic pathogenic variants in SBDS, EFL1 or DNAJC21 or heterozygous pathogenic variants in SRP54 with appropriate clinical and radiographic findings. Frequency: about 1/77,000. Genetics: the majority of cases are related to biallelic pathogenic variants in the Shwachman-Bodian-Diamond syndrome (SBDS) gene, encoding for a ribosomal protein essential for the correct assembly of the 80S eukaryotic ribosome. Although 90% of individuals affected with SBDS have one pathogenic variant in this gene, the detection rate of two pathogenic variants is only 62%. Three SBDS variants are relatively common (c.183_184delinsCT, detectable in about 55% of patients; c.258+2T>C; and c.[183_184delinsCT; 258+2T>C]). Other genes associated with SBDS include EFL1 and DNAJC21, both with recessive inheritance, and SRP54, with dominant inheritance. Since all these genes are involved in ribosome biogenesis, SBDS has been classified as a ribosomopathy. Age/Gestational age of manifestation: the specific diagnosis has not been made prenatally. Clinical features: • • • •

Short stature, growth failure Recurrent infections Hepatomegaly Exocrine pancreatic dysfunction; malabsorption; malnutrition • Hematologic abnormalities; anaemia; neutropoenia; thrombocytopaenia; myelodysplasia; acute myeloid leukaemia

DOI: 10.1201/9781003166948-42

Prenatal ultrasound features: currently, there are only a few reported cases of SBDS in neonates – early diagnosis is even more challenging in the prenatal period. Rarely, the skeletal involvement is predominant, and the first manifestation may be detected at the anomaly scan (18–22 weeks) as shortening of the upper and lower extremities and metaphyseal anomalies. Radiographic features: As a neonate, the thorax is small due to short ribs with prominent anterior ends. In infancy there are metaphyseal changes with irregularities that get progressively worse. These initially affect the proximal femora. Bone maturation is delayed. There is generalised osteopenia, and vertebral compression fractures may occur. Skeletal manifestations of SBDS may range from clinically asymptomatic to severe and can evolve or progress over time. Pancreatic imaging studies with ultrasonography or CT may reveal small size for age. MRI may reveal pancreatic lipomatosis with retained ductal and islet components. Prognosis: viable. Potential complications need ongoing assessment and management. Neonates have short stature, but might not show typical skeletal features at birth, which might evolve over time, while the clinical problems are dominated by recurrent infections, often severe, growth failure and haematological anomalies. Persistent or intermittent neutropenia is a common feature, followed by single-line or multilineage cytopenias and susceptibility to myelodysplasia syndrome (MDS) and acute myelogenous leukaemia (AML). Exocrine pancreatic dysfunction, a hallmark of this condition, can cause malabsorption and malnutrition. Hepatomegaly is common. Other features might include cardiac defects, ear malformations and hearing loss and ichthyosis. Children often present with intellectual disabilities and behavioural problems. Differential diagnosis: cystic fibrosis, but this shows increased sweat chloride levels and has no bone marrow failure. JohansonBlizzard syndrome (JBS) UBR1-related, but this has no haematological abnormalities. Blackfan-Diamond syndrome has no pancreatic insufficiency. Fanconi anaemia has normal pancreatic function (p. 573). Cartilage-hair-hypoplasia, RMRP-related (p. 224); other conditions with primary immune deficiency.

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CASE 1: (a–d) The metaphyses are irregular and cupped. The ribs are short and the thorax narrow. There is delayed ossification of the pubic rami and epiphyses at the knees.

Metaphyseal Dysplasia with Pancreatic Insufficiency and Cyclical Neutropenia

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BIBLIOGRAPHY Hashmi SK, Allen C, Klaassen R et al. Comparative analysis of Shwachman-Diamond syndrome to other inherited bone marrow failure syndromes and genotype-phenotype correlation. Clin Genet. 2011; 79: 448–58. Joyce CE, Saadatpour A, Ruiz-Gutierrez M et al. TCF-beta signaling underlies hematopoietic dysfunction and bone marrow failure in Shwachman-Diamond syndrome. J Clin Invest. 2019; 129: 3821–6. Kerr EN, Ellis L, Dupuis A et al. The behavioral phenotype of school-age children with Shwachman-Diamond syndrome indicates neurocognitive dysfunction with loss of Shwachman-Bodian-Diamond syndrome gene function. J Pediatr. 2010; 156: 433–8.

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Myers KC, Bolyard AA, Otto B et al. Variable clinical presentation of Shwachman-Diamond syndrome: Update from the North American Shwachman-Diamond syndrome registry. J Pediatr. 2014; 164: 866–70. Stepensky P, Chacon-Flores M, Kim KH et al. Mutations in ELF1, an SBDS partner, are associated with infantile pancytopenia, exocrine pancreatic insufficiency and skeletal anomalies in a Shwachman-Diamond like syndrome. J Med Genet. 2017; 54: 558–66. Venturi G, Montanaro L. How altered ribosome production can cause or contribute to human disease: The spectrum of ribosomopathies. Cells. 2020; 9: 2300.

40 Metaphyseal Anadysplasia, MMP13- and MMP9-Related

Synonyms: MANDP1; MANDP2; spondyloepimetaphyseal dysplasia, Missouri type (SEMDM); metaphyseal dysplasia Spahr type (MDST) Confirmation of diagnosis: identification of pathogenic variants in the MMP13 or MMP9 gene. Frequency: very few cases have been reported. However, the disorder may be more common than currently known, as clinical manifestations can be mild and undiagnosed. Genetics: metaphyseal anadysplasia type 1 is an autosomal dominant disorder caused by pathogenic variants in MMP13, while metaphyseal anadysplasia type 2 is an autosomal recessive disorder caused by pathogenic variants in MMP9. SEMDM is the severest phenotypic end of MANDP1. MDST is an autosomal recessive disorder due to biallelic MMP13 pathogenic variants. MMP13 is mapped on chromosome 11q22.2 and encodes matrix metalloproteinase 13 (collagenase 3). MMP9 is mapped on 20q13.12 and encodes matrix metalloproteinase 13 (collagenase type V). These matrix metalloproteinases play a pivotal role in cartilage collagen degradation. Impairment of the collagen degradation interferes with endochondral ossification. MMP13 and MMP9 interact with each other. MMP13 mutations interfere with MMP9 function. Age/Gestational age of manifestation: features of metaphyseal anadysplasia type 2 have been demonstrated at the 14th to 15th week of pregnancy. Metaphyseal anadysplasia type 1 has only been described postnatally. Clinical features: • • • •

Mild short stature or normal height Rhizomelic shortening of the limbs Bowed legs Rarely rachitic rosary-like thoracic deformity

Prenatal ultrasound features: in rare cases, mild shortening of the long bones and bowing can be detected after the 14th week.

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Radiographic features: metaphyseal dysplasia of the long bones is most severe in the neonatal period. Endochondral ossification of the growth plate is defective, which gives rise to rickets-like metaphyseal irregularities and metaphyseal flaring, as well as very wide separation of the bone ends. Defective endochondral ossification of the vertebral bodies presents as multiple coronal clefts in the lumbar spine. The metaphyseal dysplasia becomes very mild in early childhood. Severely delayed vertebral ossification in SEMDM manifests as ovoid vertebral bodies that persist throughout childhood. Metaphyseal dysplasia of MDST is indistinguishable from that of metaphyseal dysplasia Schmid type. Prognosis: viable, favourable outcome. Affected neonates are usually only slightly shorter than their unaffected siblings, but generally within the normal range They might present with mild rhizomelic shortening, particularly of the lower limbs. Limb shortening is seen in infancy and early childhood and may be associated with mild bowing of the femora and tibiae and genu varum. Flaring of the anterior rib ends may be likened to rachitic rosary. All physical findings spontaneously regress during childhood. The regressive course is the origin of the disease name. ‘Ana’ is the prefix referring to ‘return’. MDST, unlike MANDP, does not show regression of physical or radiological abnormalities. Children with MDST develop short stature and bowed legs in early childhood. Differential diagnosis: MANDP should be distinguished from metaphyseal dysplasia (MD) that radiologically manifests in the neonatal period and in young infancy, including MD Jansen type (p. 461), severe phenotypes of MD McKusick type (cartilage hair hypoplasia) and anauxetic dysplasia (p. 224). However, differentiation is straightforward, because short stature is severe in these disorders. Jansen type also shows generalised demineralisation as a result of increased PTH/PHTrP-PTHR1 signalling. Rachitic changes of the metaphyses may be seen in neonates with vitamin D–dependent rickets. Vitamin dependency shows generalised osteopenia, while MANDP has normal mineralisation. Laboratory data aid in differentiation.

DOI: 10.1201/9781003166948-43

Metaphyseal Anadysplasia, MMP13- and MMP9-Related

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CASE 1 (A younger sibling of Case 2): Radiographs as a neonate (a–e) show flaring and cupping of the anterior rib ends, multiple coronal clefts of the lumbar spine and severe metaphyseal dysplasia of the long bones. A radiograph at age 2 years (f) shows regression of metaphyseal dysplasia.

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CASE 2 (An older sibling of Case 1): Radiographs at age 1 month (a–d) show almost the same skeletal changes as those of Case 1. Radiographs at age 2 years (e) and 6 years (f) show progressive alleviation of metaphyseal dysplasia with age.

BIBLIOGRAPHY Bonafé L, Liang J, Gorna MW et al. MMP13 mutations are the cause of recessive metaphyseal dysplasia, Spahr type. Am J Med Genet A. 2014; 164: 1175–9. Lausch E, Keppler R, Hilbert K et al. Mutations in MMP9 and MMP13 determine the mode of inheritance and the clinical spectrum of metaphyseal anadysplasia. Am J Hum Genet. 2009; 85: 168–78. Li D, Weber DR, Deardorff MA et al. Exome sequencing reveals a nonsense mutation in MMP13 as a new cause of autosomal recessive metaphyseal anadysplasia. Eur J Hum Genet. 2015; 23: 264–6. Merrer L, Maroteaux MP. Metaphyseal anadysplasia type II: A new regressive metaphyseal dysplasia. Pediatr Radiol. 1998; 28: 771–5.

Maroteaux P, Verloes A, Stanescu V et al. Metaphyseal anadysplasia: Ametaphyseal dysplasia of early onset with radiological regression and benign course. Am J Med Genet. 1991; 39: 4–10. Sharony R, Borochowitz Z, Cohen L et al. Prenatal course of metaphyseal anadysplasia associated with homozygous mutation in MMP9 identified by exome sequencing. Clin Genet. 2017; 92: 645–8. Song C, Li N, Hu X et al. A de novo variant in MMP13 identified in a patient with dominant metaphyseal anadysplasia. Eur J Med Genet. 2019; 62: 103575.

41 Odontochondrodysplasia, TRIP11-Related

Synonyms: ODCD; spondylometaphyseal dysplasia with dentinogenesis imperfecta; Goldblatt syndrome Confirmation of diagnosis: identification of biallelic pathogenic variants in the TRIP11 gene with clinical correlation. Frequency: rare. Over 15 affected individuals have been reported. Genetics: ODCD is an autosomal recessive disorder due to homozygous or compound heterozygous pathogenic variants in TRIP11, alternatively called GMAP-210, mapped on 14q32 and encoding thyroid hormone receptor interactor 11 (Golgiassociated microtubule-binding protein 210; GMAP-210). GMAP-210 is related to Golgi-associated vesicle transport and also interacts with intraflagellar transport 20 (IFT20; a molecule for ciliary trafficking process). ODCD is allelic to achondrogenesis type 1A (ACG1A): the former is related to hypomorphic mutations, while the latter to biallelic null mutations. Most hypomorphic mutations are splice mutations, leading to variable splicing and phenotypes. In the same family, some affected individuals present with ODCD, while others with ACG1A. Age/Gestational age of manifestation: prenatal (limb shortening). Clinical features: the unique combination of chondrodysplasia with dentinogenesis imperfecta pinpoints the diagnosis ­after primary dentition. • Prenatal short stature • Short limbs that may be initially proportional but become mesomelic with age • Thoracic hypoplasia • Generalised joint laxity

DOI: 10.1201/9781003166948-44

• Dentinogenesis imperfecta affecting both deciduous and permanent teeth • Mild facial dysmorphism (frontal bossing, prominent eyes, midface hypoplasia, micrognathia) Prenatal ultrasound features: specific diagnosis is possible during the second trimester (18–21 weeks) only in families at risk for this disorder. In patients apparently not at risk, the routine mid-trimester fetal ultrasound scan may reveal limb shortening, whereas platyspondyly may be detected with more accuracy later (from 22 weeks). During the third trimester all long bones may show a biometry lower than 2 standard deviations (SD), associated with enlarged metaphyses. Radiographic features: the skeletal changes are classified as severe spondylometaphyseal dysplasia (SMD). The findings include severe platyspondyly with multiple coronal clefts (ossification catches up with age); progressive metaphyseal dysplasia (irregular, cupped, ragged metaphyses) of the long bones; severe brachydactyly (short, broad phalanges and metacarpals) with cone-shaped epiphyses; elongation and constriction of the femoral neck with coxa valga; broad ilia with trident acetabula; and occasionally lace-like iliac crests. Prognosis: the outcome is variable. Some affected individuals succumb to respiratory difficulties as neonates, while others survive without any respiratory compromise into adulthood. Kyphoscoliosis may manifest with age. Final short stature is severe (an affected woman was 109 cm at age 17 years). Differential diagnosis: ODCD should be differentiated from severe SM(E)D: opsismodysplasia (p. 266), SMED short limbs-abnormal calcification type (p. 241), SMD Sedaghatian type (p. 262), MAGMAS (PAM16)-related SMD, spondylometaphyseal dysplasia with cone-rod dystrophy and platyspondylic skeletal dysplasia Torrance type (p. 67). The differential diagnosis may be difficult at an early age.

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CASE 1: A terminated fetus at 22 weeks’ gestation (younger sibling; a, b) and a young infant (older sibling; c–f). The manifestation of the younger sibling indicates a severe form of platyspondylic chondrodysplasia; however, the hallmarks of ODCD have not developed yet. The constellation of multiple coronal clefts of the vertebral bodies; broad, short ilia; metaphyseal cupping with round epiphyses of the long bones; and short metacarpals in the older sibling warrants the diagnosis of ODCD.

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CASE 2: A terminated fetus in the late second trimester. The skeletal changes merely suggest a severe form of platyspondylic skeletal dysplasia, but not the precise diagnosis. Platyspondyly is very severe. The ilia are broad. The ischia manifest as tiny ossification centres. The proximal and middle phalanges are mildly short and broad.

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CASE 3: Third-trimester ultrasound performed at 34 weeks (24-year-old patient, primigravida, healthy, non-consanguineous Albanian couple). (a–b) 2D US, 3D US, maximum mode showing short femur (less than third centile) with enlarged metaphyses. The other long bones are short (G; p.(Tyr89Cys) in ERF Frequency: rare – fewer than 20 cases have been reported Genetics: this condition results from the recurrent heterozygous missense variant NM_006494.2:c.266A>G; p.(Tyr89Cys) in ERF on chromosome 19q13.2, encoding the ETS2 repressor factor (ERF) protein. Other mutations in ERF result in craniosynostosis. Age/Gestational week of manifestation: the eponymous case was diagnosed at birth.

Prenatal ultrasound features: the specific diagnosis has not been made antenatally; however, bilateral index finger hyperphalangy and abnormality of the great toes may be identified in the second trimester. Radiographic features: prominent frontal bone; in the hands, the index fingers are short and there are extra phalanges positioned at the base of the proximal phalanges of the index fingers. These are vertically oriented and on the radial side, resulting in ulnar angulation of the index fingers. In the feet there is pronounced hallux valgus due to a medially positioned, small, triangular proximal phalanx. Prognosis: viable – only a few infants have been reported to date, and no long-term follow-up is currently available. Psychomotor development in the first 6 months of life was reported as normal.

Clinical features: Differential diagnosis: Catel-Manzke syndrome (p. 293); Desbuquois dysplasia (p. 121); brachydactyly, Temtamy type (p. 298); brachydactyly type C (p. 288). ERF variants have previously been associated with complex craniosynostosis. In contrast, none of the patients with the c.266A>G p.(Tyr89Cys) variant have craniosynostosis.

• Frontal bossing, synophrys, hypertelorism, long philtrum, short nose, full lips • Ulnar deviation of the index fingers, syndactyly, hallux valgus • Bronchomalacia • Other possible findings: umbilical hernia, hypospadias, cardiac septal defects • Polyhydramnios

 

 

 

CASE 1: First child of non-consanguineous healthy Caucasian parents. Dysmorphic features included hypertelorism, blue-grey sclerae and a flat nasal bridge; (a–c) small accessory phalanges at the bases of the index fingers (hyperphalangism) resulting in ulnar angulation of the index fingers; proximally placed thumbs; (d) short halluces due to hypoplastic, triangular or delta-shaped, medially placed proximal phalanges; hallux valgus with lateral angulation of the distal phalanges of the halluces.   

300

DOI: 10.1201/9781003166948-63

Hyperphalangism, Characteristic Facies, Hallux Valgus and Bronchomalacia (Chitayat Syndrome), ERF-Related

BIBLIOGRAPHY Balasubramanian M, Lord H, Levesque S et al. Chitayat syndrome: Hyperphalangism, characteristic facies, hallux valgus and bronchomalacia results from a recurrent c.266A>G p.(Tyr89Cys) variant in the ERF gene. J Med Genet. 2017; 54: 157–65. Caro-Contreras A, Alcántara-Ortigoza MA, Ahumada-Pérez JF et al. Molecular analysis provides further evidence that Chitayat syndrome is caused by the recurrent p.(Tyr89Cys) pathogenic variant in the ERF gene. Am J Med Genet A. 2019; 179: 118–22. Chitayat D, Haj-Chahine S, Stalker HJ et al. Hyperphalangism, facial anomalies, hallux valgus, and bronchomalacia: A new syndrome? Am J Med Genet. 1993; 45: 1–4. Low K, Smith J, Lee S, Newbury-Ecob R. A mother and daughter with a novel phenotype of hand and foot abnormalities and severe pectus excavatum. Am J Med Genet. 2013; 161A: 2056–9.

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Puri RD, Phadke SR. Catel-Manzke syndrome without cleft palate: A case report. Clin Dysmorphol. 2003; 12: 279–81. Shin SH, StJoseph E, Mannan K, Khan K. Radiography of Chitayat syndrome in an infant male. Radiol Case Rep. 2019; 14: 448–51. Suter AA, Santos-Simarro F, Toerring PM et al. Variable pulmonary manifestations in Chitayat syndrome: Six additional affected individuals. Am J Med Genet. A. 2020; 182: 2068–76. Tanaka Y, Matsuo N, Nishimura G et al. Broad proximal phalanx, facial anomalies, hallux valgus, and bronchomalacia: Additional case [letter]. Am J Med Genet. 1994; 50: 211–12.

61 Campomelic Dysplasia, SOX9-Related

Synonyms: CMPD; CMD1; CMPD1; camptomelic dysplasia; Campomelic dysplasia with autosomal sex reversal; CMPD1/ SRA1; acampomelic campomelic dysplasia; acampomelic campomelic dysplasia with autosomal sex reversal Confirmation of diagnosis: identification of pathogenic variants in SOX9 with typical clinical and radiographic findings Frequency: 1 in 120,000 to 1.6 in 10,000 Genetics: caused by heterozygous pathogenic variants in the gene SOX9. Molecular analysis provides a 95% detection rate, and penetrance is complete. Usually sporadic, recurrence risk can be due to gonadal mosaicism. Chromosomal rearrangements or variants in SOX9 regulatory regions do not have complete penetrance and might display a milder phenotype. SOX9 is a transcription factor involved in the regulation of chondrocyte differentiation and development and function of the testis, inner ear and abdominal organs (pancreas, heart, gut). Age/Gestational age of manifestation: increased nuchal translucency can be detected in the first trimester. Ultrasound diagnosis is possible between the first and second trimester (13–16 weeks). Clinical features: • Short, bowed lower limbs, sometimes with skin dimples • Clubfeet • Flat face and nasal bridge, possible cleft palate • Abnormal male genitalia to sex reversal in fetuses having a male karyotype • Tracheobronchomalacia; cervical spine instability can lead to severe respiratory distress Prenatal ultrasound features: late in the first trimester there can be increased nuchal translucency or cystic hygroma; short, bowed femora; severe micromelia; punctiform tibiae and fibulae; and micrognathia. The retronasal triangle (RNT) view and maxillary gap might allow early diagnosis of cleft palate and micrognathia at 11–14 weeks. In the second trimester, a sagittal scan of the face shows a flat nasal bridge, elongated philtrum and micrognathia. There is symmetrical

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anterior bowing of the lower extremities, with hypoplasia of fibulae and talipes equinovarus. The short femora show symmetrical anterolateral bending or mild angulation at the proximal third; the short tibiae show an anterolateral diaphyseal angulation of the distal third. The long bones of upper extremities have normal length or only mild shortening. Other sonographic features include cleft palate, hypoplastic scapulae, a bell-shaped chest and 11 pairs of ribs, better diagnosed with 3D ultrasound. Central nervous system, cardiac and renal anomalies, including mild hydronephrosis, have also been described. Radiographic features: in the skull there is dolichocephaly, relative macrocephaly and a small mandible with a pronounced antegonal notch. There is absent ossification of the pedicles of the vertebral bodies in the thoracic region, and there may be a cervical kyphosis with instability due to ­hypoplastic vertebral bodies. The scapulae have absent ossification of the wings. There are usually 11 pairs of ribs. The pelvis has tall, narrow, vertically orientated iliac bones with shallow acetabula. The hips are dislocated. The femora show mild angulation at the junction of the upper third with the lower two-thirds. In the lower legs there is angulation of the tibiae at the junction of the upper two-thirds with the lower third. The fibulae are hypoplastic, and there is talipes equinovarus. In the upper limbs there may be dislocation of the radial heads. The first metacarpals are short, and middle ­phalanges may also be short. Prognosis: usually lethal in the perinatal period. Long-term survivors have been reported who may develop short stature, progressive kyphoscoliosis, cervical spine anomalies, hearing loss and mild intellectual impairment. Survivors, phenotypically females with 46,XY karyotype, might be at increased risk of developing gonadoblastoma. Differential diagnosis: more than 40 distinct disorders can present prenatally with bowed or angulated femora. The more common conditions considered in the differential diagnosis are osteogenesis imperfecta (p. 429), hypophosphatasia (p. 452), thanatophoric dysplasia (p. 36), asphyxiating thoracic dystrophy (Jeune) (p. 196), Stüve-Wiedemann syndrome (p. 311), Antley-Bixler syndrome (p. 500), Cousin syndrome (p. 548) and scapulo-iliac dysostosis: symmetrical hypoplasia of scapulae, iliac wings, acetabular roofs, dislocated hips, narrow ilia, and lordosis. Short stature and eye abnormalities may also be present.

DOI: 10.1201/9781003166948-64

Campomelic Dysplasia, SOX9-Related

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CASE 1: There is mesomelic shortening and marked angulation of the tibia with an anterior spur. Post-termination of pregnancy skeletal survey. There are angulated femora and tibiae with marked shortening of the fibulae. The ischia are widely spaced and vertical, the ilia narrow and the pubic rami absent.

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CASE 2: (a–c) Prenatal US showing angulation of the femur (junction of upper one-third with lower two-thirds) and of the tibia (junction of upper two-thirds with lower one-third) and marked micrognathia. Skeletal survey; absence of pedicles in the thoracic spine.

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CASE 3: Prenatal fetal US at 20 weeks’ gestation showing kyphosis. Post-termination of pregnancy MRI at 22 weeks’ gestation showing micrognathia, absent ossification of cervical vertebral bodies, deficient ossification of thoracic vertebral bodies with sagittal clefts, scoliosis and a small thorax. Skeletal survey, in addition, shows dislocated hips, angulated femora and tibiae and very short fibulae. The dislocated right radial head is seen and the associated right lateral clavicular hook. There are 11 pairs of ribs and absent ossification of the pubic rami.

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CASE 4: A 24-week-gestation fetus. CASE 5: A 21-week-gestation fetus. CASES 6, 7: Neonates. Notice that the lower-limb long bone angulations become less pronounced with increasing gestational age. Short tibiae and fibulae. The lateral skull views show a steep clivus, dolichocephaly with unusual prominence of the occipital bone and antegonial notching of the mandible and absent ossification of the wings of the scapulae and the thoracic vertebral pedicles.

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CASE 8: Prominent occiput and antegonial notching of the mandible. Absent thoracic pedicles and narrow vertical ilia with dislocated hips. Short angulated tibiae and fibulae. CASE 9: Short angulated lower limbs were detected in this fetus by prenatal US at 20 weeks’ gestation. At postmortem examination the fetus also had a posterior cleft palate and ambiguous external genitalia, although the internal reproductive organs were female. The fetal karyotype was 46,XX. CASE 10: At 36 weeks’ gestation birth weight was 3.0 kg (75th centile) and head circumference 38 cm (greater than the 97th centile). There was hypotonia, a small jaw and a cleft soft palate; short limbs; and bowing of the lower legs with bilateral talipes equinovarus. There was severe respiratory distress due to tracheobronchomalacia, treated with a tracheostomy at 3 weeks old. Convulsions occurred in the neonatal period and death at the age of 9 months. Notice the cervical kyphosis and absent ossification of cervical vertebral bodies.

Campomelic Dysplasia, SOX9-Related

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CASE 11: This termination of pregnancy was identified with very short limbs with bowing and a narrow thorax on the 20-week scan. Postmortem examination showed additionally a cleft palate and bilateral talipes equinovarus. CASE 12: A 24-week ultrasound; (a) three-dimensional US showing a flat face and angulation of the femur. Skeletal survey day 1; 12 pairs of ribs; hypoplastic scapulae and thoracic pedicles; bowed femora; narrow ilia; talipes equinovarus; short tibia and fibula and middle phalanges of the fingers; dislocated radial head; prominent occiput and antegonial notch of the mandible.

310

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BIBLIOGRAPHY Alanay Y, Krakow D, Rimoin DL et al. Angulated femurs and the skeletal dysplasias: Experience of the international skeletal dysplasia registry (1988–2006). Am J Med Genet A. 2007; 143A: 1159–68. Gentilin B, Forzano F, Bedeschi MF et al. Phenotype of five cases of prenatally diagnosed Campomelic dysplasia harboring novel mutations of the SOX9 gene. Ultrasound Obstet Gynecol. 2010; 36: 315–23. Normann EK, Pedersen JC, Stiris G et al. Campomelic dysplasia: An underdiagnosed condition? Eur J Pediatr. 1993; 152: 331–3. Pazzaglia UE, Beluffi G. Radiology, and histopathology of the bent limbs in Campomelic dysplasia: Implications in the aetiology of the disease and review of theories. Pediatr Radiol. 1987; 17: 50–5.

Promsonthi P, Wattanasirichaigoon D. Prenatal diagnosis of Campomelic dysplasia with three-dimensional ultrasound. Ultrasound Obstet Gynecol. 2006; 27: 583–7. Pryde PG, Zelop C, Paulo RM. Prenatal diagnosis of isolated femoral bent bone skeletal dysplasia: Problems in differential diagnosis and genetic counselling. Am J Med Genet A. 2003; 117A: 203–6. Waratani M, Ito F, Tanaka Y et al. Prenatal diagnosis of fetal skeletal dysplasia using 3-dimensional computed tomography: A prospective study. BMC Musculoschelet Disord. 2020; 21: 662. Zhen L, Xu LL, Li DZ. Cystic hygroma and micromelic lower limbs: First trimester sonographic markers of Campomelic dysplasia. Eur J Obstet Gynecol Reprod Biol. 2019; 238: 191–3.

62 Stüve-Wiedemann Dysplasia, LFR-Related

Synonyms: STWS, SWS, Schwartz-Jampel syndrome, type 2; SJS2 Confirmation of diagnosis: identification of two pathological variants in LIFR Frequency: very rare, a few dozen patients reported (0.5–3.5 per 10,000) Genetics: SWS is an autosomal recessive disorder caused by pathological variants in LIFR (leukaemia inhibitory factor receptor), locus 5p13. The lack of the LIFR protein results in alterations in the JAK/STAT3 signalling pathway and affects osteoclast differentiation and activation. Homozygous mutations in ILS6T (interleukin 6 cytokine family signal transducer, gp130) have been identified in three families, resulting in complete absence of signalling by the IL6 cytokine family, including LIF. Age/Gestational week of manifestation: usually detectable by ultrasound during the second or third trimester in at-risk families (16–30 weeks). Clinical features: • • • •

Short, bowed limbs, clubfeet Contractures, camptodactyly Prenatal-onset neuromuscular disorder Specific dysmorphic features, including facial myotonia, squared face with midface hypoplasia, short nose and micrognathia with pursed lips • Dysautonomia, episodic hyperthermia • Tongue ulceration, absent corneal reflex • Scoliosis Prenatal ultrasound features: there is mild to moderate micromelia. The lower-limb long bones are bowed, the tibiae more than the femora. The fibulae are spared. The scapulae and clavicles are normal. There is camptodactyly and talipes equinovarus, which are important discriminators from other causes of bent bones. Growth restriction may be identified by biometry late in the second trimester, but normal Doppler of the umbilical artery can exclude intrauterine growth retardation as a result of placental insufficiency, and the thoracic dimensions are normal. Oligohydramnios is present in one-half of cases.

DOI: 10.1201/9781003166948-65

A normal mid-trimester study does not exclude the diagnosis, which is usually made postnatally. Prenatal diagnosis is more readily made in at-risk families with a positive family history. Radiographic features: at birth there are contractures of the elbows and knees and camptodactyly with ulnar deviation of the fingers. Positional deformities of the feet may be present. The skull is dolichocephalic and the mandible hypoplastic. There is bowing of the long bones, particularly the femora and tibiae, and this is associated with medial cortical thickening at the concavity of the curves. The metaphyses are wide, and longitudinal translucencies, or a coarsening of the trabecular pattern, with relative radiolucency, are present. The ribs may be slender, the ilia are relatively small and narrow and the pubic rami and ischia are relatively broad. During childhood the posterior and anterior borders of the vertebrae are concave, scoliosis develops and there is coxa vara with shortening of the femoral necks. There may be avascular necrosis of the capital femoral epiphyses. Prognosis: usually lethal in the neonatal period due to respiratory and feeding distress or hyperthermia. Respiratory distress is due to muscular hypotonia, not lung hypoplasia. Surviving patients develop short stature, progressive scoliosis and fractures; autonomic nervous system dysfunction becomes more prominent. Specific signs include lack of corneal and patellar reflexes, poor dentition with dappled enamel and decreased pain perception. Differential diagnosis: bowed limbs: Campomelic dysplasia (p. 302); osteogenesis imperfecta (p. 429); kyphomelic dysplasia (p. 313); cartilage-hair hypoplasia (p. 224); otopalatodigital group of disorders (p. 145, 148); hypophosphatasia (p. 452). Cousin syndrome (p. 548); scapulo-iliac dysostosis: symmetrical hypoplasia of scapulae, iliac wings, acetabular roofs, dislocated hips, narrow ilia and lordosis. Short stature and eye abnormalities may also be present. Antley-Bixler syndrome (p. 500); Cumming syndrome: cervical lymphocele, polycystic kidneys, short gut, polysplenia, recessive inheritance. Femoral hypoplasia unusual facies syndrome (p. 560). Muscular contractions: Crisponi syndrome – congenital muscular contractions, peculiar contraction of the facial muscles in response to tactile stimuli or during crying, arthrogryposis, severe feeding and respiratory difficulties, hyperthermia. Caused by recessive pathogenic variants in the cytokine-like factor 1 gene (CRLF1) or cardiotrophin-like cytokine factor 1 (CLCF1).

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(2) CASE 1: Bowed femora and tibiae with cortical thickening of the medial aspects of the mid-diaphyses; relative metaphyseal widening and radiolucency; camptodactyly. Straight fibulae and upper-limb long bones. CASE 2: US at 21 weeks, 6 days gestation: mild-to-moderate micromelia, bowing of the lower bones and positional talipes, with sparing of the fibula and the upper limb bones. The clavicles, scapulae and thoracic dimensions were normal. (a) 2D US. Both curved femora are shown with the flared metaphyses laterally.

BIBLIOGRAPHY Begam MA, Alsafi W, Bekdache GN et al. Stuve-Wiedemann syndrome: A skeletal dysplasia characterised by bowed long bones. Ultrasound Obstet Gynecol. 2011. doi: 10.1002/ uog.8967 Chen YH, Grigelioniene G, Newton PT et al. Absence of GP130 cytokine receptor signaling causes extended ­Stüve-Wiedemann syndrome. J Exp Med. 2020; 217: e20191306. Cormier-Daire V, Superti-Furga A, Munnich A et al. Clinical homogeneity of the Stüve-Wiedemann syndrome and overlap with the Schwartz-Jampel syndrome type 2. Am J Med Genet. 1998; 78: 146–9. Dagoneau N, Scheffer D, Huber C et al. Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/

Schwartz-Jampel type 2 syndrome. Am J Hum Genet. 2004; 74: 298–305. Di Rocco M, Stella G, Bruno C et al. Long-term survival in StuveWiedemann syndrome: A neuro-myo-skeletal disorder with manifestations of dysautonomia. Am J Med Genet A. 2003; 118A: 362–8. Jung C, Dagoneau N, Baujat G et al. Stüve-Wiedemann syndrome: Long-term follow-up and genetic heterogeneity. Clin Genet. 2010; 77: 266–72. Sigaudy S, Moncla A, Fredouille C et al. Congenital bowing of the long bones in two fetuses presenting features of StuveWiedemann syndrome and Schwartz-Jampel syndrome type 2. Clin Dysmorphol. 1998; 7: 257–62.

63 Kyphomelic Dysplasia with Facial Dysmorphism, KIF5B-Related and Other Forms

Synonyms: bowing, congenital, with short bones Confirmation of diagnosis: typical combination of clinical and radiological features. In a small proportion, identification of heterozygous pathogenic variants in KIF5B Frequency: extremely rare Genetics: kyphomelic dysplasia is a heterogeneous group of conditions of unknown cause in most cases, possibly autosomal recessive. One type results from heterozygous pathogenic variants in KIF5B, encoding kinesin-1 heavy chain. Kinesins (a group of motor proteins involved in the transport of molecules along the microtubules) are essential for mitosis and trafficking of vesicles and organelles. All pathogenic variants reported involved conserved amino acids in or close to the ATPase ­activity–related motifs in the catalytic motor domain of the KIF5B protein. Age/Gestational week of manifestation: detectable by ultrasound at the end of the first trimester. Clinical features: • Short and stubby long bones, rhizo-mesomelic shortening, sharp anterolateral angulation of femora and humeri • Typical facial features, including flat face with high forehead, flat nasal bridge, micrognathia and low-set ears • Cleft lip and palate • Pterygia • Occasionally osteoporosis with fractures • Narrow thorax

DOI: 10.1201/9781003166948-66

Prenatal ultrasound features: ultrasound diagnosis may be suspected when there are short limbs, marked laterally bowed femora, often anteriorly bowed tibiae and fibulae with no foot deformity. Humeri, ulnae and radii may be straight or slightly curved. Cranial size and shape are normal. Micrognathia may be evaluated by the jaw index. A narrow chest with short ribs may be identified. The scapulae are of normal shape and size. Joint movements may be limited by pterygia. Radiographic features: the long bones show rhizomelic shortening and severe metaphyseal broadening. Mild metaphyseal irregularities may exist. Sharp lateral angulation is seen in the femora and to a lesser extent in the humeri. The tibiae and fibulae show mild posteromedial bowing. The radii and ulnae may be mildly bowed or straight. The short tubular bones are not short. The thorax is mildly narrow and elongated. The spine may be normal, but mild platyspondyly is common. Bone mineralisation appears normal as neonates, but osteoporosis becomes manifest in early childhood. Prognosis: viable – but respiratory distress is possible in the neonatal period. The bowing of the long bones improves with age, but disproportionate short stature persists. Intellect is usually normal, but some cases with neurodevelopmental disorders have been described, particularly in cases that are KIF5Brelated. Differential diagnosis: bowed limbs: Campomelic dysplasia (p. 302); Stüve-Wiedeman syndrome (p. 311); ShwartzJampel syndrome (p. 172); cartilage-hair hypoplasia (MCD McKusick type) (p. 224); LBR-related spondylometaphyseal dysplasia (p. 253); hypophosphatasia (p. 452); osteogenesis imperfecta (p. 429); Antley-Bixler syndrome (p. 500); bent bone dysplasia FGFR2-related (p. 319).

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CASE 1: Pregnancy at 12 weeks’ gestation. (a) 4D US showing short, bowed lower limbs and micrognathia. (b) 2D US shows the anteriorly bent tibiae and fibulae (10th centile) without foot deformity. Postmortem CT of the aborted fetus at 14 weeks. (c) Soft tissue overlay images demonstrate micrognathia and short and curved lower limbs. (d) Partial transparency of soft tissues showing underlying skeletal appearance. There is micrognathia; the scapulae appear of normal shape. Long bones of lower limbs are short, angulated and/or bowed. (e) Skeletal appearance: upper long bones are straight with normal biometry. Femora are very short and angulated; tibiae are short and posteriorly curved.

Kyphomelic Dysplasia with Facial Dysmorphism, KIF5B-Related and Other Forms

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CASE 2: At birth there were dysmorphic facial features and micrognathia. (a) The lower limbs were bowed with bilateral fixed flexion deformities at the hips. Ultrasound confirmed hip dislocations. (b) Narrow thorax. CASE 3: Unilateral cleft lip and palate; dysmorphic features including micrognathia, a flat nasal bridge and malar region. There was bilateral talipes equinovarus; marked shortening, abduction and angulation of the femora; shallow, sloping acetabula and flared iliac wings. The ribs were mildly short with a small thorax.

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CASE 4: A neonate. Fetal CT in the third trimester (a) and postnatal radiographs (b–d) show mild platyspondyly, a narrow thorax and metaphyseal broadening of long bones with sharp anterolateral angulation of the femora and mild posterior bowing of the tibiae and fibulae.

Kyphomelic Dysplasia with Facial Dysmorphism, KIF5B-Related and Other Forms

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CASE 5: A neonate. (a–c) Radiographs show the skeletal changes similar to those of Case 1.

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CASE 5: (d–h) Follow-up radiographs at age 2 years show development of osteoporosis and improvement of bowing of long bones.

BIBLIOGRAPHY Cormier-Daire V, Geneviève D, Munnich A et al. New insights in congenital bowing of the femora. Clin Genet. 2004; 66: 169–76. Flex E, Albadri S, Radio FC et al. Dominantly acting KIF5B variants with pleiotropic cellular consequences cause variable clinical phenotypes. Hum Mol Genet. 2023; 32: 473–88. Guala A, Biroli E, Bassini P et al. Prenatal diagnosis of kyphomelic dysplasia. Prenat Diagn. 2001; 21: 1146–9. Hall BD, Spranger JW. Familial congenital bowing with short bones. Radiology. 1979; 132: 611–14.

Itai T, Wang Z, Nishimura G et al. De novo heterozygous variants in KIF5B cause kyphomelic dysplasia. Clin Genet. 2022; 102: 3–11. Le Merrer M, Cormier Daire V, Maroteaux P. Re-evaluation of kyphomelic dysplasia. Am J Med Genet A. 2003; 120: 289–91. Paladini D. Fetal micrognathia: Almost always an ominous finding. Ultrasound Obstet Gynecol. 2010; 35: 377–84. Pryde PG, Zelop C, Paulo RM. Prenatal diagnosis of isolated femoral bent bone skeletal dysplasia: Problems in differential diagnosis and genetic counselling. Am J Med Genet A. 2003; 117A: 203–6.

64 Bent Bone Dysplasia, FGFR2-Related

Synonyms: FGFR2-BBD; BBDS Diagnostic confirmation: identification of disease-specific pathogenic variants in the FGFR2 gene together with appropriate radiographic findings Frequency: rare. Only 16 affected individuals have been reported, 2 of which were described as osteoglophonic dysplasia. Genetics: FGFR2-BBD is attributed to two disease-specific, dominant pathogenic variants of the FGFR2 gene, mapped on chromosome 10q26.13 and encoding fibroblast growth factor receptor 2 (C.1172T>G, p. Met391Arg; c.1141T>G, p. Tyr381Asp). The mutations that reside in the transmembrane domain of FGFR2 substitute polar amino acid residues for conserved hydrophobic amino acid residues and create pleiotropic malfunctions (decreased responsiveness to extracellular FGFs and increased responsiveness to intracellular FGFs). Increased or decreased FGFR2 signalling may vary among different tissues. Age of manifestation: some features are identifiable from the early second trimester. Clinical features: most clinical features represent the combination of craniosynostosis and defective ossification of the skeleton. • Short stature (variable, rarely normal birth length) • Coronal craniosynostosis presenting with turribrachycephaly or turridolichocephaly with large fontanelles • Facial dysmorphism: hypertelorism, exophthalmos, midface hypoplasia, short nose, small mouth, protruding tongue, micrognathia, sometimes natal teeth, low-set ears • Thoracic hypoplasia with respiratory failure • Bent limbs, more prominent in the lower than in the upper extremities • Brachydactyly • Hirsutism • Occasionally clitoromegaly in affected girls and hypospadias in affected boys • Hepatosplenomegaly Prenatal ultrasound features: nuchal oedema or cystic hygroma can be detected as early as 17 weeks of gestation. There is bowing and significant shortening of all long bones, more DOI: 10.1201/9781003166948-67

marked in the lower limbs. The skull is poorly ossified. The thorax is narrow and bell-shaped, with short wavy ribs and short clavicles (moustache-shaped), and the middle third of the clavicle is thickened. Femoral fractures have been reported. Craniofacial features include flattened midface, hypertelorism, proptosis, depressed nasal bridge, anteverted nares, macroglossia and protrusion of the tongue and low-set dysplastic ears. Polyhydramnios may be present in the third trimester. Radiographic features: craniosynostosis is variable in severity. Most affected individuals manifest with mild turricdolichocephaly or turribrachycephaly, while some have a severe cloverleaf skull. Craniosynostosis may not be radiologically apparent in the early gestational period. Calvarial ossification is defective, particularly at an early age. The axial and appendicular skeleton shows generalised demineralisation with coarse trabeculae. The ribs are short, twisted and wavy. The thorax is narrow. The inner pelvic rim is deep as a result of ossification defects. The long bones, particularly the femora and tibiae, are bowed and slender. The femoral shaft is sometimes sharply angulated and even fractured. The skeletal changes of the clavicle and short tubular bones are pathognomonic of FGFR2-BBD: moustacheshaped clavicles (markedly short clavicles with a thick, sometimes bulbous, medial segment and tapered distal segment) and angel-shaped phalanges and metacarpals due to cortical excrescence of the mid-shaft and/or scooping out of the outer bone end. Scooping out may also be seen in the long bones. Prognosis: stillbirth is common. Affected neonates inevitably show severe respiratory distress requiring ventilatory support and commonly succumb during infancy despite intensive medical intervention. Even long-term survivors need prolonged respiratory support and are susceptible to respiratory failure. Craniosynostosis may cause increased intracranial pressure and tonsillar herniation (Arnold-Chiari malformation). The longer-term survivors show intellectual disabilities; however, it remains questionable whether the mental deficit is primary or secondary to postnatal illness. Differential diagnosis: there have been reports of affected individuals with FGFR2-BBD who were misdiagnosed with osteoglophonic dysplasia (FGFR1-related craniosynostosis syndrome associated with metaphyseal fibrous defects, platyspondyly and cone-shaped epiphyses of the phalanges) or Cole-Carpenter syndrome (p. 450). Prenatal bowing of the limbs: Antley-Bixler syndrome (p. 500), Campomelic dysplasia (p. 302), kyphomelic dysplasia (p. 313), hypophosphatasia (p. 452), neonatal hyperparathyroidism (p. 457) and osteogenesis imperfecta (p. 429). 319

320

Fetal and Perinatal Skeletal Dysplasias

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CASE 1: Radiographs as a neonate (a–f) show wide fontanelles, turricephaly with a harlequin appearance of the orbital rims, moustache-shaped clavicles, twisted ribs, defective ossification of the inner pelvic rim, bowing of the femora and tibiae and angel-shaped phalanges and metacarpals. Generalised demineralisation with a coarse trabecular pattern is seen.

Bent Bone Dysplasia, FGFR2-Related

321

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CASE 2: Radiographs as a neonate (a–g) show almost the same skeletal changes as those of Case 1. However, moustache-shaped clavicles and angelshaped phalanges are less prominent than those of Case 1.

322

Fetal and Perinatal Skeletal Dysplasias

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Bent Bone Dysplasia, FGFR2-Related

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CASE 3: A terminated fetus at 20 weeks of gestation. Postmortem radiographs (a–d) show the skeletal changes identical with those of Cases 1 and 2. However, it is difficult to ascertain craniosynostosis. Fetal CT at 19 weeks identifies the changes seen on the radiographs.

324

BIBLIOGRAPHY Azoury SC, Reddy S, Shukla V et al. Fibroblast growth factor receptor 2 (FGFR2) mutation related syndromic craniosynostosis. Int J Biol Sci. 2017; 13: 1479–88. Handa A, Okajima Y, Izumi N et al. Bent bone dysplasia (BBD)FGFR2 type: The radiologic manifestations in early gestation. Pediatr Radiol. 2016; 46: 296–9. Krakow D, Cohn DH, Wilcox WR et al. Clinical and radiographic delineation of bent bone dysplasia-FGFR2 type or bent bone dysplasia with distinctive clavicles and angel-shaped phalanges. Am J Med Genet A. 2016; 170: 2652–61.

Fetal and Perinatal Skeletal Dysplasias Merrill AE, Sarukhanov A, Krejci P et al. Bent bone dysplasiaFGFR2 type, a distinct skeletal disorder, has deficient canonical FGF signaling. Am J Hum Genet. 2012; 90: 550–7. Neben CL, Tuzon CT, Mao X et al. FGFR2 mutations in bent bone dysplasia syndrome activate nucleolar stress and perturb cell fate determination. Hum Mol Genet. 2017; 26: 3253–70. Scott RH, Meaney C, Jenkins L et al. The postnatal features of bent bone dysplasia-FGFR2 type. Clin Dysmorphol. 2014; 23: 8–11. Stichelbout M, Dieux-Coeslier A, Clouqueur E et al. A new case of bent bone dysplasia-FGFR2 type and review of the literature. Am J Med Genet A. 2016; 170: 785–9.

65 3M Syndrome, CUL7-, OBSL1- and CCDC9-Related

Synonyms: Le Merrer syndrome, gloomy face syndrome or Yakut short stature syndrome First described by Miller, McKusick and Malvaux. Confirmation of diagnosis: a combination of pre- and postnatal growth retardation with relatively large head circumference Frequency: very rare, approximately 100 affected individuals have been reported Genetics: autosomal recessive inheritance. Due to biallelic pathogenic variants in CUL7 (cullin 7), OBSL1 (obscurinlike 1) or CCDC8 (coiled-coil domain-containing protein 8). CUL7 assembles an E3 ubiquitin ligase complex, and functional studies suggest that impaired ubiquitination may have a role in the pathogenesis of intrauterine growth retardation in humans, this being a cardinal feature of 3M syndrome. In affected individuals with Yakut short stature syndrome, homozygosity for a founder mutation in the CUL7 gene has been identified. OBSL1 mutations result in complete loss of OBSL1. Knockdown of OBSL1 via siRNAs in HEK cells led to a decrease in CUL7 levels, suggesting a role for OBSL1 in the maintenance of normal levels of CUL7. These findings suggested that the two proteins work in the same pathway that affects cell proliferation and human growth. There is a strong correlation ­between the tissue distribution of CCDC8 and that of OBSL1 and CUL7. OBSL1 may act as an adaptor protein linking CUL7 and CCDC8. Age/Gestational week of manifestation: usually at birth; prenatal growth retardation may be identified, contrasting with a relatively large head.

DOI: 10.1201/9781003166948-68

Clinical features: • Short stature of prenatal onset, height –5.0 standard deviation score (SDS) below the mean, final height 120–130 cm; proportionate short stature • Characteristic facial features, which vary with time; relatively large head, dolichocephaly, midface retrusion, long philtrum, full lips, triangular face with pointed chin • Musculoskeletal features: short broad neck, deformed sternum, short thorax, square shoulders, hyperlordosis, clinodactyly of the fifth fingers, joint hypermobility, prominent heels and pes planus • Genitourinary anomalies in males: hypogonadism and hypospadias • Intelligence: normal Prenatal ultrasound features: intrauterine growth retardation. Radiographic features: may appear in the course of the d­ isease. The long bones are slender with diaphyseal constriction and flared metaphyses. The vertebral bodies are tall with reduced anterior-posterior and transverse diameter (especially in the lumbar region), anterior wedging of the thoracic vertebral bodies and mildly irregular upper and lower endplates; thoracic kyphoscoliosis; spina bifida occulta. The thorax is relatively broad with slender, horizontal ribs. Bone maturation is slightly delayed. There is a high metacarpal index. Other findings include dolichocephaly, pseudoepiphyses of the second metacarpal bone, dislocated hips and a prominent talus. Prognosis: proportionate short stature. Differential diagnosis: other forms of intrauterine growth retardation syndromes like Silver-Russell syndrome.

325

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Fetal and Perinatal Skeletal Dysplasias

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CASE 1: A 33-week termination of pregnancy. Intrauterine growth retardation. Dolichocephaly and vertebrae with a reduced AP diameter. CASE 2: Neonate with tall vertebral bodies with a reduced AP diameter. The thorax is broad.

3M Syndrome, CUL7-, OBSL1- and CCDC9-Related

BIBLIOGRAPHY Al-Dosari MS, Al-Shammari M, Shaheen R et al. 3M syndrome: An easily recognizable yet underdiagnosed cause of proportionate short stature. J Pediatr. 2012; 161: 139–45. Badina A, Pejin Z, Odent T et al. Hip dislocation in 3-M syndrome: Risk of misdiagnosis. Clin Dysmorphol. 2011; 20: 114–6. Hanson D, Murray PG, O’Sullivan J et al. Exome sequencing identifies CCDC8 mutations in 3-M syndrome, suggesting that CCDC8 contributes in a pathway with CUL7 and OBSL1 to control human growth. Am J Hum Genet. 2011; 89: 148–53. Hanson D, Murray PG, Sud A et al. The primordial growth disorder 3-M syndrome connects ubiquitination to the cytoskeletal adaptor OBSL1. Am J Hum Genet. 2009; 84: 801–6. Huber C, Delezoide A-L, Guimiot F et al. A large-scale mutation search reveals genetic heterogeneity in 3M syndrome. Eur J Hum Genet. 2009; 17: 395–400. Huber C, Dias-Santagata D, Glaser A et al. Identification of mutations in CUL7 in 3-M syndrome. Nat Genet. 2005; 37: 1119–24.

327 Huber C, Munnich A, Cormier-Daire V. The 3M syndrome. Best Pract Res Clin Endocrinol Metab. 2011; 25: 143–51. Lugli L, Bertucci E, Mazza V et al. Pre- and post-natal growth in two sisters with 3-M syndrome. Eur J Med Genet. 2016; 59: 232–6. Maksimova N, Hara K, Miyashia A et al. Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: New population isolate in Asia. J Med Genet. 2007; 44: 772–8. Meo F, Pinto V, D’Addario V. 3-M syndrome: A prenatal ultrasonographic diagnosis. Prenat Diagn. 2000; 20: 921–3. Simsek-Kiper PO, Taskiran E, Kosukcu C et al. Further expanding the mutational spectrum and investigation of genotypephenotype correlation in 3M syndrome. Am J Med Genet A. 2019; 179: 1157–72. Van der Wal G, Otten BJ, Brunner HG et al. 3-M syndrome: Description of six new patients with review of the literature. Clin Dysmorphol. 2001; 10: 241–52.

66 Osteocraniostenosis, FM111A-Related

Synonyms: OCS; gracile bone dysplasia; skeletal dysplasia, lethal, with gracile bones; osteocraniosplenic syndrome; habrodysplasia Confirmation of diagnosis: identification of pathogenic variants in FAM111A with concordant clinical and radiological findings Frequency: very rare – fewer than 30 cases reported in the literature Genetics: osteocraniostenosis results from heterozygous mutations in the FAM111A gene and is allelic to the non-lethal, dominant disorder Kenny-Caffey syndrome (KCS). KCS patients are characterised by hypoparathyroidism and hypocalcaemia; low calcium levels have also been detected in OCS cases, supporting the hypothesis of a parathormone (PTH) ­dysfunction underlying both conditions. Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester (20 weeks). Clinical features: • Large fontanelles, cloverleaf skull • Short limbs, short halluces, slender long bones, multiple fractures • Typical facial features: prominent forehead, hypertelorism but narrow palpebral fissures, flat face, depressed nasal bridge, short flat nose with anteverted nares, short philtrum, inverted V-shaped mouth, low-set ears • Absent or hypoplastic spleen • Hypogonadism • Ophthalmological abnormalities: microphthalmia, aniridia, cataract Prenatal ultrasound features: short, slender long bones, bowed radius and ulna, platyspondyly and a cloverleaf skull deformity with a wide biparietal diameter may be identified

328

during the second trimester. Intrauterine growth restriction (IUGR), severely shortened long bones and occasionally intrauterine bone fractures with callus formation. The thinness and the markedly delayed ossification of the cranial vault allow clear visualisation of the intracranial structures. The characteristic facial dysmorphic features, including high and broad forehead, frontal and parietal bossing, mild hypertelorism, depressed nasal bridge, flat nasal tip, and low-set ears, may be demonstrated on three-dimensional ultrasound. Skin oedema, pericardial effusion, ascites, hydrops and hepatomegaly may be present. Coronal and sagittal scans of the trunk may show thin ribs and flat vertebral bodies. An irregular appearance of the ribs may be due to multiple healing fractures. The long bones are short and straight with slender diaphyses, although they can be bowed and sometimes deformed from fractures. Radiographic features: there is craniosynostosis, leading to a mild cloverleaf skull appearance. The skull is poorly ossified. The long bones, clavicles and ribs are slender and sclerotic. The long bones are overmodelled with flared metaphyses, and fractures may be present. There is brachydactyly of the hands with absent or hypoplastic distal phalanges, and the radius and ulna may be bowed. The first metacarpal is short and square. The vertebral bodies are mildly flattened and sclerotic. Prognosis: lethal – although survival has been reported; these patients showed global developmental delay and possibly represent different entities. Differential diagnosis: thanatophoric dysplasia type 2 (p. 36). Gracile bones: Kenny-Caffey syndrome; fetal akinesia deformation sequence – usually secondary to oligohydramnios or a neuromuscular disease; also shows limb deformities, contractures and pulmonary hypoplasia. Yunis-Varon syndrome (p. 488); Hallermann-Streiff syndrome (p. 333). Secondary to oligohydramnios: Potter face (flat face, micrognathia, flattened and posteriorly rotated ears), redundant skin. Secondary to neuromuscular disease: polyhydramnios due to lack of swallowing, low birth weight. Multiple fractures: osteogenesis imperfecta (p. 429).

DOI: 10.1201/9781003166948-69

Osteocraniostenosis, FM111A-Related

(1a)

(1d)

329

 

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CASE 1: This neonate had a shunt for hydrocephalus and died at 1 month.

(1c)

330

Fetal and Perinatal Skeletal Dysplasias

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(2d) CASE 2: Very slender and overmodelled long bones with increased bone density and fractures; short first metacarpals and hypoplastic distal phalanges; platyspondyly; craniosynostosis with cloverleaf skull deformity.

Osteocraniostenosis, FM111A-Related

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CASE 3: First child of non-consanguineous parents. Dysmorphic with small mouth, hypoplastic nails, micropenis and asplenia. Generalised increase in bone density; hypoplastic first metacarpal and terminal phalanges; mild platyspondyly; slender overmodelled long bones with bowing of left radius; slender ribs; poorly ossified skull vault with wide biparietal parameter; absent ossification of pubic rami.

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BIBLIOGRAPHY Brennan P, Hall C. Osteocraniostenosis in a fetus with a 46, XX/46, XY karyotype. Clin Dysmorphol. 2002; 11: 57–61. Elliott AM, Wilcox WR, Spear GS et al. Osteocraniostenosishypomineralized skull with gracile long bones and splenic hypoplasia: Four new cases with distinctive chondro-osseous morphology. Am J Med Genet A. 2006; 140A: 1553–63. Müller R, Steffensen T, Krstić N et al. Report of a novel variant in the FAM111A gene in a fetus with multiple anomalies including gracile bones, hypoplastic spleen, and hypomineralized skull. Am J Med Genet A. 2021; 185: 1903–7. Pemberton L, Barker R, Cockell A et al. Case report: Targeted whole exome sequencing enables the first prenatal diagnosis of the lethal skeletal dysplasia osteocraniostenosis. BMC Med Genet. 2020; 21: 7.

Fetal and Perinatal Skeletal Dysplasias Rosato S, Unger S, Campos-Xavier B et al. Clinical and molecular diagnosis of osteocraniostenosis in fetuses and newborns: Prenatal ultrasound, clinical, radiological and pathological features. Genes (Basel). 2022; 13: 261. Spear GS. Parietal bone agenesis with gracile bones and splenic hypoplasia/aplasia: Clinicopathologic report and differential diagnosis with review of cranio-gracile bone syndromes, “osteocraniostenosis” and Kleeblattschädel. Am J Med Genet Part A. 2006; 140A: 2341–8. Thomas JA, Rimoin DL, Lachman RS et al. Gracile bone dysplasia. Am J Med Genet. 1998; 75: 95–100. Unger S, Górna MV, Le Béchec A et al. FAM111A mutations result in hypoparathyroidism and impaired skeletal development. Am J Hum Genet. 2013; 92: 990–5. Verloes A, Narcy F, Grattagliano B et al. Osteocraniostenosis. J Med Genet. 1994; 31: 772–8.

67 Hallermann-Streiff Syndrome, GJA1-Related

Synonyms: HSS; Francois dyscephalic syndrome; oculomandibulo-dyscephaly Confirmation of diagnosis: identification of pathogenic variants in GJA1 together with clinical and radiographic findings Frequency: at least 200 cases reported Genetics: all reported cases have been sporadic. In some cases, pathogenic recessive variants in the gene GJA1 (gap junction protein, 43-KD), encoding connexion 43, have been found. Pathogenic variants in the same gene cause both the dominant and recessive forms of oculo-dento-digital syndrome. Age/Gestational week of manifestation: usually at birth; rarely associated malformations can be detected by ultrasound by the second trimester (20 weeks). Clinical features: • Typical facial features: frontal bossing, malar hypoplasia, sparse eyebrows and eyelashes, microphthalmia, thin pointed nose, microstomia, hypoplastic mandible • Skin atrophy, hypotrichosis, hypodontia, occasionally neonatal teeth • Congenital cataract, coloboma of iris, choroid or optic disc, strabismus • Proportionate short stature, more commonly of postnatal onset • Occasionally genitourinary anomalies, congenital heart defects and tracheomalacia Prenatal ultrasound features: this condition is not normally diagnosed by prenatal ultrasound. A case has been reported of a fetus with fusion of the placental end of the umbilical artery which postnatally was diagnosed with Hallermann-Streiff syndrome. Radiographic features: the skull is poorly ossified with a thinned vault, wide sutures and fontanelles and Wormian bones. There is brachycephaly, but the frontal bone and sometimes the parietal bones are prominent. There may be platybasia,

DOI: 10.1201/9781003166948-70

a depressed pituitary fossa and small orbits. The mandibular rami are small with obtuse mandibular angles, and the condyles may be absent with anteriorly placed temporomandibular joints. The long bones and ribs are slender. The long bones are overmodelled with relatively flared metaphyses, diaphyseal endosteal thickening and medullary narrowing. There is mild bowing of the radius and ulna and mild platyspondyly. Prognosis: viable – in the neonatal period, feeding and respiratory problems can occur, owing to the small jaw, small nose and tracheomalacia. Sleep apnoea and increased anaesthetic risks can be present. Intellectual disability is not typical, but it is reported in roughly 15% of cases. Seizures and choreoathetosis have also been described. Final stature is around 150–157 cm. Differential diagnosis: Caffey-Kenny syndrome; osteocraniostenosis (p. 328) also have slender long bones but are clinically quite distinct. Oculo-dento-digital dysplasia: similar facial features although milder, hypoplastic phalanges and IV–V ­syndactyly, ocular anomalies (microphthalmia, microcornea, glaucoma, cataract). Two forms are known, autosomal recessive and dominant, both caused by pathogenic variants in GJA1. The recessive form shows a more severe ocular phenotype than the dominant form. Other progeroid syndromes: Hutchinson-Gilford progeria – a rare disorder which shows postnatal premature ageing, alopecia, loss of subcutaneous fat, early-onset arteriosclerosis, osteoporosis and osteolysis. Eye anomalies and intellectual disability are not present. Caused by dominant pathogenic variants in the lamin A gene (LMNA). Recessive mutations in the same gene cause mandibuloacral dysostosis, characterised by postnatal growth retardation, craniofacial anomalies, particularly marked mandibular hypoplasia, skeletal abnormalities, progressive osteolysis of the distal phalanges and clavicles, skin atrophy with mottled pigmentation and lipodystrophy. Pseudoprogeria-Hallermann-Streiff syndrome (PHS): one single report with similar facial features, but besides intellectual disability also presents with progressive and severe spastic quadriplegia. Wiedemann-Rautenstrauch syndrome has thin arms and legs, abnormally large hands and feet and impaired intellectual and psychomotor development.

333

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(1e) CASE 1: Slender ribs and long bones; (c, d) brachycephaly with wide open anterior fontanelle; thin skull vault; hypoplastic mandible with obtuse mandibular angle; frontal bossing.

Hallermann-Streiff Syndrome, GJA1-Related

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CASE 2: Neonate with natal teeth and cataracts (a). Wide biparietal diameter, prominent frontal bone and hypoplastic mandible. The sutures and fontanelles are wide and the skull vault thin (b–d).

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(2g) CASE 2: (e–h) The ribs are slender and long bones slender with flared metaphyses.

 

 

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Hallermann-Streiff Syndrome, GJA1-Related

BIBLIOGRAPHY Chen CL, Peng J, Jia XG et al. Hallermann-Streiff syndrome with bilateral microphthalmia, pupillary membranes and cataract absorption. Int J Ophthalmol. 2017; 10: 1016–18. Dulong A, Bornert F, Gros CI et al. Diagnosis and innovative multidisciplinary management of Hallermann-Streiff syndrome: 20-year follow-up of a patient. Cleft Palate Craniofac J. 2018; 55: 1458–66. Elliott AM, Wilcox WR, Spear GS et al. Osteocraniostenosis– Hypomineralized skull with gracile long bones and splenic hypoplasia. Four new cases with distinctive chondro-osseous morphology. Am J Med Genet A. 2006; 140A: 1553–63. Godzieba A, Smektała T, Dowgierd K et al. Diagnosis, early care, and treatment of Hallermann-Streiff syndrome: A review of the literature. Pediatr Ann. 2021; 50: e227–e231. Jimenez-Armijo A, Oumensour K, Bousfiha B et al. A novel homozygous variant in GJA1 causing a Hallermann-Streiff/ Oculodentodigital dysplasia overlapping phenotype: A clinical

337 report. Front Dent Med. 04 June 2021; https://doi.org/10.3389/ fdmed.2021.675130 Mirshekari A, Safar F. Hallermann-Streiff syndrome: A case review. Clin Exp Dermatol. 2004; 29: 477–9. Pizzuti A, Flex E, Mingarelli R et al. A homozygous GJA1 gene mutation causes a Hallermann-Streiff/ODDD spectrum phenotype. Hum Mutat. 2004; 23: 286. Schmidt J, Wollnik B. Hallermann-Streiff syndrome: A missing molecular link for a highly recognizable syndrome. Am J Med Genet C Semin Med Genet. 2018; 178: 398–406. Sepulveda W, Dezerega V, Carstens E et al. Fused umbilical arteries: Prenatal sonographic diagnosis and clinical significance. J Ultrasound Med. 2001; 20: 59–62. Srivasan LP, Viswanathan J. Hallermann-Streiff syndrome: Difficulty in airway increases with increasing age. J Clin Anesth. 2018; 50: 1.

68 Microcephalic Osteodysplastic Primordial Dwarfism Types 1 and 3, RNU4ATAC-Related Synonyms: MOPD; MOPD1; MOPD I; MOPD3; MOPD III; osteodysplastic primordial dwarfism, type I; brachymelic primordial dwarfism; Taybi-Linder syndrome; TALS; cephaloskeletal dysplasia; low-birth-weight dwarfism with skeletal dysplasia; osteodysplastic primordial dwarfism, type III; MOPD, Caroline Crachami type; MOPD, Sicilian fairy type

Prenatal ultrasound features: early prenatal diagnosis is possible by sonographic monitoring of the fetal head circumference, abdominal circumference and femur length. Intrauterine growth retardation is severe enough (between −5 and −9 standard deviations) to be detected unequivocally before the 18th week of gestation. There may be oligohydramnios.

Confirmation of diagnosis: identification of biallelic pathogenic variants in RNU4ATAC together with the appropriate clinical findings

Radiographic features: the skull shows microcephaly with a sloping frontal bone and a prominent occiput (bathrocephaly). The orbits are relatively large and the skull base steep and sclerotic. The anterior fontanelle is small or closed. The limbs have short, mildly bowed and undermodelled long bones with wide metaphyses. The fingers are short, with fifth finger clinodactyly and a short first metacarpal. There are elongated clavicles, 11 pairs of ribs and some posterior constriction of the ribs. In the spine there are cleft cervical neural arches, coronal clefts and some thoracolumbar platyspondyly. In the pelvis the iliac wings are rounded with horizontal acetabular roofs and medial spurs on the ischia. There are contractures of the shoulders, elbows, hips and knees, and there may be dislocations of the hips and radial heads. There is delayed epiphyseal ossification with no knee epiphyses at birth and poor ossification of the sternum. Intracranial abnormalities have been described (lissencephaly, hypoplastic frontal lobes, agenesis of the corpus callosum, agenesis of cerebellar vermis), and CT or MRI may demonstrate these.

Frequency: very rare – fewer than 50 cases reported in the literature Genetics: MOPD types 1 and 3 were originally described as two separate disorders, mainly on the basis of radiological criteria, and were subsequently identified as a single entity. Inheritance is autosomal recessive. A candidate region has been mapped on 2q14.2-q14.3. Biallelic mutations have been identified in the RNU4ATAC gene, which encodes U4atac, a small nuclear RNA that is a crucial component of the minor spliceosome and required for the proper excision of the U12dependent class of introns. Mutations in the RNU4ATAC gene have also been identified in Roifman and Lowry-Wood syndromes. Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester (18 weeks). Clinical features: • Severe intrauterine growth deficiency • Severe microcephaly • Specific facial features: sloping forehead, protruding eyes, prominent nose with flat nasal bridge, micrognathia, short neck • Sparse hair and eyebrows, dry and hyperkeratotic skin • Short limbs, dislocation of elbows and hips, relatively broad hands and feet • Brain anomalies: lissencephaly, hypoplastic frontal lobes, agenesis of the corpus callosum, agenesis of cerebellar vermis • Possible associated anomalies: cardiac (tetralogy of Fallot, atrial septal defect, coarctation of aorta), renal (hypoplasia, cysts), genital (micropenis, hypospadias, cryptorchidism) • Oligohydramnios 338

Prognosis: usually lethal within the first year of life. Developmental delay and seizures are constant features. Death has often been reported as secondary to infectious disease. Differential diagnosis: other diseases characterised by significant intrauterine growth restriction (IUGR) and prenatal-onset microcephaly include MOPD type 2: relatively proportionate head size at birth, postnatal progression to severe microcephaly, progressive skeletal dysplasia, dislocated joints, characteristic facies, dysplastic or missing dentition. No brain abnormalities, but a proportion can show cerebral aneurysms and moya moya disease. Patients display a sociable personality and a high squeaky voice. Autosomal recessive, with mutations in PCNT2, have been identified. Seckel syndrome: proportionate prenatal-onset dwarfism, absence of skeletal dysplasia. Patients develop severe developmental delay and sometimes haematological abnormalities. Autosomal recessive, genetically heterogeneous, three loci identified, type 1 is caused by pathogenic variants in ATR. Fetal alcohol syndrome: the more severe cases can show intrauterine growth retardation, microcephaly, cardiac abnormalities (septal defects, tetralogy of Fallot), brain DOI: 10.1201/9781003166948-71

Microcephalic Osteodysplastic Primordial Dwarfism Types 1 and 3, RNU4ATAC-Related abnormalities (microcephaly, agenesis of corpus callosum, cavum septum pellucidum, ventriculomegaly). Facial features are very typical and include short palpebral fissures, smooth and underdeveloped philtrum with a thin upper lip. Epiphyseal stippling has been reported, as well as short distal phalanges and

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transverse limb defects. Dubowitz syndrome: typical facial features, which consist of telecanthus, ptosis, blepharophimosis, prominent epicanthic folds, broad nasal tip, micrognathia. Ears are often dysplastic, occasionally cleft palate. Other features include sparse hair and eczema on the face and flexural areas.

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CASE 1: A neonate. Radiographs show severe microcephaly, long clavicles, mildly delayed vertebral ossification, flat acetabula and lack of normal metaphyseal flaring (modelling failure). MRI shows severe pachygyria.

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CASE 2: A 5-month-old infant. The skeletal changes are similar to those of Case 1. However, modelling failure of long bones is much milder. The ilia are short, and acetabula are flat.

Microcephalic Osteodysplastic Primordial Dwarfism Types 1 and 3, RNU4ATAC-Related

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CASE 3: A neonate. Modelling failure of long bones is severe. Ossification of the vertebral bodies and pubic bones is mildly delayed.

BIBLIOGRAPHY Abdel-Salam GM, Miyake N, Eid MM et al. A homozygous mutation in RNU4ATAC as a cause of microcephalic osteodysplastic primordial dwarfism type I (MOPD I) with associated pigmentary disorder. Am J Med Genet A. 2011; 155A: 2885–96. Benoit-Pilven C, Besson A, Putoux A et al. Clinical interpretation of variants identified in RNU4ATAC, a non-coding spliceosomal gene. PLoS One. 2020; 15: e0235655. Eason J, Hall CM, Trounce JQ. Renal tubular leakage complicating microcephalic osteodysplastic primordial dwarfism. J Med Genet. 1995; 32: 234–5. He H, Liyanarachchi S, Akagi K et al. Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I. Science. 2011; 332: 238–40.

Meinecke P, Passarge E. Microcephalic osteodysplastic primordial dwarfism type I/III in sibs. J Med Genet. 1991; 28: 795–800. Meinecke P, Schaefer E, Wiedemann HR. Microcephalic osteodysplastic primordial dwarfism: Further evidence for identity of the so-called types I and III. Am J Med Genet. 1991; 39: 232–6. Nagy R, Wang H, Albrecht B et al. Microcephalic osteodysplastic primordial dwarfism type I with biallelic mutations in the RNU4ATAC gene. Clin Genet. 2012; 82(2): 140–6. Putoux A, Pinson AA et al. Refining the phenotypical and mutational spectrum of Taybi-Linder syndrome. Clin Genet. 2016; 90: 550–5. Sigaudy S, Toutain A, Moncla A et al. Microcephalic osteodysplastic primordial dwarfism Taybi-Linder type: Report of four cases and review of the literature. Am J Med Genet. 1998; 80: 16–24.

69 Saul-Wilson Syndrome, COG4-Related

Synonyms: microcephalic osteodysplastic dysplasia; SWS; SWILS Confirmation of diagnosis: a combination of pre- and postnatal growth retardation with typical clinical and radiographic findings and heterozygous, pathogenic variants in COG4 Frequency: fewer than 20 cases have been reported in the medical literature Genetics: Saul-Wilson syndrome is caused by heterozygous pathogenic variants in COG4, resulting in the substitution of p.Gly516Arg, which confers a gain in function. COG4 encodes a subunit of the conserved oligomeric Golgi (COG) complex, a hetero-octameric protein complex that regulates vesicular trafficking between the Golgi apparatus and the endoplasmic reticulum (ER). Almost all the cases reported were de novo, with one familial case secondary to parental gonadal mosaicism. Age/Gestational week of manifestation: usually at birth, although prenatal growth retardation may be identified. Clinical features: • Marked short stature, usually of prenatal onset • Low birth weight, microcephaly • Distinctive progeroid features: large anterior fontanelle, prominent forehead, visible scalp veins, prominent eyes, narrow nasal bridge with a beaked appearance and long columella, micrognathia • Sparse hair and eyebrows • Short distal phalanges of the hands and feet • Clubfeet • Blue sclerae Prenatal ultrasound features: no prenatal diagnoses have been reported, but usually there is specific intrauterine growth restriction and bilateral talipes equinovarus. Radiographic features: there is enlargement and delayed closure of the anterior fontanelle, and the sutures are wide with some Wormian bones. In the spine there is hypoplasia of the odontoid process leading to cervical instability and cord compression. There is mild platyspondyly with irregular vertebral endplates. Some patients have hypoplasia of L1 leading to kyphosis and sometimes scoliosis. The long bones are overmodelled with narrow diaphyses and flared metaphyses, and 342

the epiphyses are large and rounded. At the hips there is coxa valga, and there is bilateral talipes equinovarus. The hands and feet show short tubular bones with some cone-shaped epiphyses and significantly short distal phalanges (brachytelephalangism). Ivory epiphyses of the distal phalanges are present. Prognosis: viable. The combination of pre- and postnatal growth restriction results in an average final adult height of 107 cm. Developmental milestones are delayed, but intellect is usually normal. Sensorial problems are common and typically develop in infancy or childhood and include hearing loss, lamellar cataract and rod/cone dystrophy. Intermittent neutropenia is detectable in all patients after the first months of life. Asymptomatic elevation of liver transaminases is very frequent. Skeletal complications include possible subluxation of the cervical spine and cord compression, bone fragility and osteoarticular pain. Differential diagnosis: Caffey-Kenny syndrome; osteocraniostenosis (p. 328). Prenatal IUGR: Silver-Russell syndrome usually presents with macrocephaly and asymmetry, and there are no abnormalities of skeletal morphology. Caused by epigenetic abnormalities on chromosome 11p15.5 or 7. Microcephalic osteodysplastic primordial dwarfism type 2 is a recessive disorder caused by pathogenic variants in PCNT. There is usually a more pronounced microcephaly, without frontal prominence; there are often cerebral vascular abnormalities, and shortening of distal phalanges is lacking. Microcephalic osteodysplastic primordial dwarfism type 1/3 (p. 338). Floating-Harbor syndrome; peculiar facial features; there is no microcephaly; dominant pathogenic variants in the gene SRCAP. Osteogenesis imperfecta (p. 429). Other progeroid syndromes: HutchinsonGilford progeria – a rare disorder caused by dominant mutations in the lamin A gene (LMNA) which develops in childhood, while children are usually normal at birth. Recessive pathogenic variants in the same gene or in ZMPSTE24 cause mandibuloacral dysostosis, characterised by postnatal growth retardation, craniofacial anomalies, particularly marked mandibular hypoplasia, skeletal abnormalities, progressive osteolysis of the distal phalanges and clavicles, skin atrophy with mottled pigmentation and lipodystrophy. Hallermann-Streiff syndrome (p. 333). Pseudoprogeria-Hallermann-Streiff syndrome (PHS): one single report, similar facial features, but also presents with progressive and severe spastic quadriplegia. Wiedemann-Rautenstrauch syndrome, caused by recessive variants in the gene POLR3A, does not involve hands and feet; affected individuals will develop intellectual disability; GorlinChaudhry-Moss syndrome can be differentiated by the presence of craniosynostosis and hypertrichosis. DOI: 10.1201/9781003166948-72

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CASE 2: A 3-month-old infant. Both patients show craniofacial disproportion with a large anterior fontanel, modest platyspondyly with pear-shaped vertebral bodies, slender ribs, slender tubular bones and brachydactyly with cone-shaped phalanges. Large epiphyses of the knee seen in Case 2 warrant a definitive diagnosis at this age.

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CASE 3: A young infant. The skeletal changes are identical to those of Cases 1 and 2. Megaepiphyses of the knee along with slender bones give the clue to the radiological diagnosis.

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Saul-Wilson Syndrome, COG4-Related

BIBLIOGRAPHY Blackburn JB, D’Souza Z, Lupashin VV. Maintaining order: COG complex controls Golgi trafficking, processing, and sorting. FEBS Lett. 2019; 593: 2466–87. Ferreira C. Saul-Wilson Syndrome. 2020 Feb 20. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2021. Available from http://www.ncbi.nlm.nih.gov/books/NBK554080/ Ferreira CR, Xia ZJ, Clément A et al. A recurrent de novo heterozygous COG4 substitution leads to Saul-Wilson syndrome, disrupted vesicular trafficking, and altered proteoglycan glycosylation. Am J Hum Genet. 2018; 103: 553–67. Ferreira CR, Zein WM, Huryn LA et al. Defining the clinical phenotype of Saul-Wilson syndrome. Genet Med. 2020; 22: 857–66.

347 Koruga N, Pušeljić S, Tomac V et al. Severe cranio-cervical stenosis in a child with Saul-Wilson syndrome: A case report. Children (Basel). 2022; 9: 532. Saul RA, Wilson WG. Commentary — The Saul-Wilson syndrome from its early days until now. Am J Med Genet A. 2019; 179: 159–60. Xia ZJ, Zeng XI, Tambe M et al. A dominant heterozygous mutation in COG4 causes Saul-Wilson syndrome, a primordial dwarfism, and disrupts zebrafish development via Wnt signalling. Front Cell Dev Biol. 2021; 9: 720688. Zafra I, Nebenfuehr B, Golden A. Saul-Wilson syndrome missense allele does not show obvious Golgi defects in a C. elegans model. MicroPubl Biol. 2021; 2021: 10.17912/ micropub.biology.000373. Corrigendum: Saul-Wilson syndrome missense allele does not show obvious Golgi defects in a C. elegans model. MicroPubl Biol. 2021; 2021: 10. 17912/micropub.biology.000379.

70 Mucolipidosis II (I-Cell Disease), GNPTAB-Related

Synonyms: ML2; MLII; ML II alpha/beta; I-cell disease; ICD; Leroy I-cell disease; Pacman dysplasia; epiphyseal stippling with osteoclastic hyperplasia Confirmation of diagnosis: identification of pathogenic variants in GNPTAB with appropriate clinical and radiographic findings Frequency: ranges from 1:123  500 to 1:625  500; there is a particularly high prevalence of around 1:6000 in the FrenchCanadian population. Genetics: ML2 is an autosomal recessive lysosomal storage disease due to N-acetylglucosaminyl 1-phosphotransferase deficiency, which leads to defective lysosomal targeting of many lysosomal enzymes. The enzyme is formed by three polypeptide subunits encoded by two genes: the gene coding for the alpha/beta subunits, GNPTAB, causes ML2 and ML3 alpha/ beta (a milder form); the gene coding for the gamma subunits, GNPTG, causes ML3 gamma. Patients affected by ML2 show inclusions in the fibroblasts; hence the name of the disease (‘inclusion cell disease’). Age/Gestational age of manifestation: may be suspected by ultrasound during the second to third trimester (25–32 weeks) or at birth.

metaphyses are frayed and irregular, and metaphyseal fractures result in deformities. The skull vault is small and brachycephalic. The thorax is often small and deformed with slender ribs. In the spine the lumbar vertebral bodies have a reduced anteroposterior diameter. The acetabula are shallow, sometimes resulting in dislocation of the hips, and the iliac wings flared with narrow iliac bases. Stippled tarsal bones are often present. The previously named ‘Pacman dysplasia’ is the prenatal form of mucolipidosis II with hyperparathyroidism and stippling of epiphyses and the coccygeal and sacral vertebral region. Prognosis: lethal in the perinatal period, in infancy or by 10 years of age, depending on the type. The most common cause of death is from cardiorespiratory complications. I­ nfants develop a number of features which progressively worsen over years: coarse facial features; hypertrophic gingiva and ­macroglossia; intellectual disability; thick, tight and hirsute skin; deformities and contractures; dysostosis multiplex; hepatosplenomegaly; thickening and insufficiency of the cardiac valves; ventricular hypertrophy; corneal opacities; and conductive hearing loss.

Prenatal ultrasound features: antenatal manifestations may be variable, highly nonspecific and appear late in the second to third trimester. Femora are short, sometimes bowed, and increased echogenicity around the periosteum (periosteal cloaking) may be detected, which might look like elevation of the periosteum. Polyhydramnios is often present, while rarely there can be oligohydramnios.

Differential diagnosis: stippling: chondrodysplasia punctata (pp. 352–367). Hyperparathyroidism: this group includes many conditions, ranging from rickets due to vitamin D deficiency to neonatal severe primary hyperparathyroidism (p. 457). Dysostosis multiplex, lysosomal storage disorders: MPS I-H – also known as Hurler disease, more common than ML2, presents with more marked clinical signs of ‘storage’ and less severe d­ ysostosis multiplex on radiographs; due to deficiency of the enzyme alpha-L-iduronidase (IDUA). GM1gangliosidosis type 1: similar features, usually lethal in the first years of life, extensive Mongolian blue spots on the skin and retinal cherry red spots; caused by deficiency of betagalactosidase-1 (GLB1). Infantile galactosialidosis: the earlyonset form may show ­fetal hydrops, ascites, visceromegaly, macular cherry red spot, early death; caused by recessive mutations in the gene CTSA (cathepsin A). Infantile sialic acid storage disease (ISSD): severe organ involvement (hepatosplenomegaly, cardiomegaly, nephrotic syndrome), hydrops, ascites, early death. Caused by recessive pathogenic variants in the gene SLC17A5.

Radiographic features: there is generalised osteopenia with a coarse trabecular pattern. In the neonatal period the long bones show striking periosteal reactions (periosteal cloaking). The

Hypophosphatasia (p. 452), Caffey disease (p. 411), dysplastic cortical hyperostosis (Kozlowski-Tsuruta) (p. 416), lethal neonatal short limb dysplasia (Al-Gazali) (p. 418), Raine dysplasia (p. 403).

Clinical features: • Short limbs, short hands and fingers • Hip dislocation, long bone deformities, clubfoot • Full round cheeks, flat midface, shallow orbits, depressed nasal bridge, gingival hypertrophy • Inguinal and umbilical herniae • Redundant skin folds

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DOI: 10.1201/9781003166948-73

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CASE 1: A neonate. Radiographs show generalised osteopenia with a coarse trabecular pattern, thick long bones with periosteal cloaking, tarsal stippling and metaphyseal fractures. The skull shows mild microbrachycephaly. CASE 2: Periosteal cloaking, fractures and tarsal stippling are pronounced.

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CASES 3, 4: Two affected siblings. They died in the neonatal period. Short long bones and bowed femora were seen on US at 20 weeks of gestation. Parathormone levels were increased. The skeletal changes are identical to those seen in neonatal hyperparathyroidism. The manifestation is much more severe in Case 3 than in Case 4.

Mucolipidosis II (I-Cell Disease), GNPTAB-Related

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CASE 5: Periosteal cloaking of the humerus is striking. Tall vertebral bodies are seen in Cases 4 and 5.

BIBLIOGRAPHY Lees C, Homfray T, Nicolaides KH. Prenatal ultrasound diagnosis of Leroy I cell disease. Ultrasound Obstet Gynecol. 2001; 18: 275–6. Saul RA, Proud V, Taylor HA et al. Prenatal mucolipidosis type II (I-cell disease) can present as Pacman dysplasia. Am J Med Genet. 2005; 135A: 328–32. Unger S, Paul DA, Nino MC et al. Mucolipidosis II presenting as severe neonatal hyperparathyroidism. Eur J Pediatr. 2005; 164: 236–43.

Yuksel A, Kavserili H, Gungor F. Short femurs detected at 25 and 31 weeks of gestation diagnosed as Leroy I-cell disease in the postnatal period: A report of two cases. Fetal Diagn Ther. 2007; 22: 198–202. Wongkittichote P, Upchurch GM, Dehner LP et al. Placental pathology in an unsuspected case of mucolipidosis type II with secondary hyperparathyroidism in a premature infant. Mol Genet Metab Rep. 2021; 27: 100747.

71a Chondrodysplasia Punctata X-Linked Recessive, Brachytelephalangic Type, ARSE-Related

Synonyms: CDPX1; CDP-BT Confirmation of diagnosis: on clinical and radiological grounds and identification of pathogenic variants in the ARSE gene

• Hypoplastic distal phalanges (brachytelephalangy) with short nails • Occasionally cervical myelopathy • Mild intellectual disability in CDPX1

Frequency: unknown. Most common subtype in CDP Genetics: the terms CDPX1 and CDP-BT are commonly used interchangeably; however, this is not appropriate. CDPX1 ­accounts for only half of males with CDP-BT. The cause remains unknown in most individuals with CDP-BT. CDPX1 is an X-linked recessive disorder due to mutations in ARSE mapped on Xp22.3 and encoding arylsulfatase E (ARSE). ARSE has a heat-labile arylsulfatase activity and localises to the Golgi apparatus; however, its precise biological role remains unknown. There is a cluster of arylsulfatase genes with significant homology in Xp22.3, including ARSD, ARSE and ARSF. However, neither ARSD nor ARSF mutations have been found in individuals with CDP-BT. Multiple sulphatase deficiency, an autosomal recessive disorder due to mutations in SUMF1 (sulphatasemodifying factor 1), may cause CDP-BT as well as dysostosis multiplex (the skeletal phenotype of mucopolysaccharidosis). Microdeletion spanning Xp22.3 may cause not only CDP-BT but also Kallmann syndrome and steroid sulphatase deficiency (X-linked ichthyosis). CDP-BT is also seen in a group of genetic diseases related to vitamin K metabolism, including Keutel syndrome due to mutations in MGP (matrix Gla protein), mutations in VKORG1 (a subunit of vitamin K epoxide reductase) and mutations in GGCX (gamma-glutamyl carboxylase) and a subset of children with mutations in FMM20C (a causative gene for Raine syndrome). Maternal vitamin K deficiency (mainly due to severe hyperemesis gravidarum), warfarin embryopathy and maternal systemic lupus erythematosus (SLE)/mixed connective tissue disease give rise to a phenocopy of CDP-BT. Even chromosome aberration (e.g., trisomy 21) may rarely present with CDP-BT. Age/Gestational age of manifestation: facial and skeletal abnormalities can be detected from the second to third trimester. Clinical features: • Severe nasomaxillary hypoplasia (Binder phenotype) with depressed nasal bridge and a short, flat nose, often with a deep groove between the ala nasi and nasal tip, occasionally associated with stenosis of the nasal passage • Mild pre- and postnatal growth failure 352

Prenatal ultrasound features: significant fetal facial dysmorphism during a routine ultrasound examination at 19–22 weeks can be noticed: there is a flattened profile with verticalised nasal bones and an abnormally increased nasofrontal angle. A combination of 2D and 3D imaging provides a better assessment and enables measurement of facial angles. Long bone shortening is variable. Stippling is usually symmetric and involves the epiphyses of the long bones, tarsus, hips and costochondral junctions. Stippling along the spine is often visualised better on transversal sections and 3D maximum-mode ultrasound scans. Vertebral anomalies are common, even though, compared with other types, CDPX1 has milder manifestations. Vertebrae can be dysplastic and hypoplastic, with coronal cleft and disc dislocation. Sagittal ultrasound view of the fetal spine can detect changes in physiological curvature, kyphosis and stenosis of the spinal canal. 3D ultrasound imaging may prove useful when looking for spinal canal stenosis. MRI can reveal cervical and/or cervicothoracic canal stenosis with subsequent spinal cord compression – an important prognostic factor. Identification of brachytelephalangy is difficult and requires careful analysis of all the fingers in extension. Hypoplasia of the distal phalanx on both hands has been detected by ultrasound at 30 weeks of age and confirmed by helical computed tomography (3D-HCT). Fetal skeletal CT can detect calcifications in the upper airways. Polyhydramnios is often present. Radiographic features: the radiological hallmark is brachytelephalangy. The distal phalanges are short along with wide tufts and narrow bases. The combination of distal broadening and proximal tapering gives rise to a unique V-shaped configuration of the distal phalanges. The fifth distal phalanx is usually unaffected. Other short tubular bones, particularly the proximal phalanx of the index finger, may be short. Ossification of the cervical vertebral bodies is defective and occasionally associated with atlantoaxial instability and canal stenosis at the craniovertebral junction, causing cervical myelopathy. The thoracolumbar vertebral bodies may show defective ossification with coronal clefts. Puncta or stippled epiphyses are usually confined to the tarsal region, cervical spine and lumbosacrococcygeal region, but are sometimes more generalised, involving epiphyses of long bones, thoracic vertebrae, costochondral DOI: 10.1201/9781003166948-74

Chondrodysplasia Punctata X-Linked Recessive, Brachytelephalangic Type, ARSE-Related junctions and laryngeal and tracheal cartilage. The nasal bones and anterior nasal spine of the maxilla are hypoplastic. Prognosis: viable. Most affected individuals are healthy, other than facial abnormalities and brachytelephalangy. However, cervical myelopathy is a severe and even life-threatening morbidity. Regular monitoring and early surgical intervention for stenosis at the craniovertebral junction are required.

 

Differential diagnosis: severe phenotypes of CDP-BT may be misdiagnosed with CDP Conradi-Hünermann type CDPX2, (p. 357). Keutel syndrome is associated with peripheral pulmonary stenosis, hearing impairment and auricular calcifications. VKORG1 and GGCX mutations are accompanied by reduced vitamin K–dependent coagulation factors. CDPX1 may manifest with only nasomaxillary hypoplasia but not puncta.

 

 

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CASE 1: A neonate. Skeletal survey shows multiple puncta in the lumbosacral spine, proximal femora, calcanei and cervical spine. Ossification of the cervical vertebral bodies is defective. Atlantoaxial instability is seen. Brachytelephanagy is seen in the first to fourth fingers of the hand.

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CASES 2, 3: Two neonates. Case 2 shows brachytelephalangy, defective ossification with puncta of the cervical vertebral bodies and craniovertebral junction stenosis. Case 3 shows only brachytelephalangy and subtle puncta in the lower lumbar spine.

Chondrodysplasia Punctata X-Linked Recessive, Brachytelephalangic Type, ARSE-Related

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CASE 4: A neonate. Brachytelephalangy is seen in the first to fourth fingers of the hand. The first proximal phalanx and second to fourth middle phalanges are defective in ossification and appear angel-shaped. Puncta are prominent at the metacarpal bases. Ossification of the cervical vertebral bodies is defective along with atrophy of the upper cervical spinal cord. The thyroid cartilage shows multiple puncta. The nasal bone is hypoplastic. CT shows puncta throughout the spine. Puncta are also seen in the tarsal bones.

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CASE 5: A neonate. Ossification of the lumbar vertebral bodies is defective. Puncta are seen in the lumbosacral spine and coccyx, sternum, hips, knees and carpotarsal regions. Brachytelephalangty of the hand is seen only in the first, third and fourth fingers.

BIBLIOGRAPHY Blask AR, Rubio EI, Chapman KA et al. Severe nasomaxillary hypoplasia (binder phenotype) on prenatal US/MRI: An important marker for the prenatal diagnosis of chondrodysplasia punctata. Pediatr Radiol. 2018; 48: 979–91. Boulet S, Dieterich K, Althuser M et al. Brachytelephalangic chondrodysplasia punctata: Prenatal diagnosis and postnatal outcome. Fetal Diagn Ther. 2010; 28: 186–90. Casarin A, Rusalen F, Doimo M et al. X-linked brachytelephalangic chondrodysplasia punctata: A simple trait that is not so simple. Am J Med Genet A. 2009; 149A: 2464–8. Eash DD, Weaver DD, Brunetti-Pierri N et al. Cervical spine stenosis and possible vitamin k deficiency embryopathy in an unusual case of chondrodysplasia punctata and an updated classification system. Am J Med Genet A. 2003; 122A: 70–5. Fraldi A, Biffi A, Lombardi A et al. SUMF1 enhances sulfatase activities in vivo in five sulfatase deficiencies. Biochem J. 2007; 403: 305–12.

Franco B, Meroni G, Parenti G et al. A cluster of sulfatase genes on Xp22.3: Mutations in chondrodysplasia punctata (CDPX) and implications for warfarin embryopathy. Cell. 1995; 81: 15–25. Gupta N, Ghosh M, Shukla R et al. Brachytelephalangic chondrodysplasia punctata: A case series to further delineate the phenotype. Clin Dysmorphol. 2012; 21: 113–7. Horikoshi T, Kikuchi A, Tamaru S et al. Prenatal findings in a fetus with contiguous gene syndrome caused by deletion of Xp22.3 that includes locus for X-linked recessive type of chondrodysplasia punctata (CDPX1). Obstet Gynaecol Res. 2010; 36: 671–5. Sheffield LJ, Osborn AH, Hutchison WM et al. Segregation of mutations in arylsulphatase E and correlation with the clinical presentation of chondrodysplasia punctata. J Med Genet. 1998; 35: 1004–8. Toriello HV, Erick M, Alessandri JL et al. Maternal vitamin K deficient embryopathy: Association with hyperemesis gravidarum and Crohn disease. Am J Med Genet A. 2013; 161A: 417–29.

71b Chondrodysplasia Punctata X-Linked Dominant Type, Conradi-Hünermann Type, EBP-Related

Synonyms: CDPX2; CDP Conradi-Hünermann-(Happle) type Confirmation of diagnosis: identification of pathogenic variants in the EBP gene Frequency: fewer than 1 in 400,000 newborns; the second most common disorder after CDP brachytelephalangic type (CDP-BT) in the CDP group Genetics: CDPX2 is an X-linked dominant disorder due to mutations in EBP mapped on Xp11.23 and encoding emopamilbinding protein with 3-beta-hydroxysteroid-delta(8)-­delta(7)isomerase activity that is essential for cholesterol biosynthesis. Hemizygous males are usually lethal in utero, and rare longterm survival is attributed to postzygotic mosaicism. MEND (male EBP disorder with neurologic defects) is an X-linked mental retardation syndrome allelic to CDPX2. Age/Gestational age of manifestation: affected fetuses may be detected by prenatal ultrasound. Clinical features: • Flat face with a depressed nose • Skin changes usually following Blaschko lines: transient congenital ichthyosiform erythroderma (disappears within the first few months); linear hyperkeratosis and follicular atrophoderma; coarse, lusterless hair and cicatricial alopecia • Cataracts • Asymmetric limb shortening • Short stature, variable in severity • Scoliosis

DOI: 10.1201/9781003166948-75

Prenatal ultrasound features: prenatal diagnosis is difficult because of marked phenotypic variation. Dysmorphic flattened facies with a hypoplastic nose, kyphoscoliosis with irregular vertebral ossification, asymmetric shortening of the long bones and epiphyseal and paravertebral stippling may be found. Premature or multicentric ossifications of the talus and calcaneus may be early findings. Radiographic features: puncta or stippled epiphyses are usually widespread in the spine, ribs, scapulae, pelvic bones, tubular bones, tarsal and carpal regions and occasionally the laryngeal cartilage. Vertebral ossification is often very irregular, resulting in anisospondyly and progressive kyphoscoliosis. There is asymmetric shortening of the long bones with metaphyseal flaring and sometimes bowing. The short tubular bones are variably short. Prognosis: the prognosis of affected females depends on the pattern of X chromosome inactivation, ranging from in utero lethality to healthy individuals with mild short stature. In general, however, affected individuals who survive early infancy have a normal life expectancy. The common postnatal morbidity is kyphoscoliosis due to dysplastic vertebral ossification, which may require surgical intervention. Differential diagnosis: affected individuals may present with severe limb asymmetry and asymmetric skin changes, which may be misdiagnosed as CHILD syndrome (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) that is another X-linked disorder of abnormal cholesterol biosynthesis due to NSDHL mutations. Limb defects in CHILD syndrome are the results of abnormal patterning, such as oligodactyly, meromelia and amelia, while those in CDPX2 are only asymmetric limb shortening and simple abnormal patterning, such as postaxial polydactyly. CDPX2 may present with severe rhizomelic shortening, which may be mistaken for rhizomelic CDP (p. 362).

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CASES 1–5: Aborted or stillborn fetuses: All fetuses show a variable pattern of limb shortening and asymmetry, spondylar dysplasia and puncta in the cartilage.

Chondrodysplasia Punctata X-Linked Dominant Type, Conradi-Hünermann Type, EBP-Related

 

 

 

 

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CASE 6: US (a–d) at 22 weeks’ gestation shows asymmetric shortening of the limbs and epiphyseal stippling in the long bones: (a) right humerus – 33 mm; (b) left humerus – 31.5 mm; (c) right femur – 34.5 mm; (d) left femur – 36.1 mm; US for the spine (e, f) shows sagittal cleft vertebrae; postmortem spinal MRI (g, h) and skeletal survey (i–l) at 25 weeks’ gestation recapitulate the US findings.

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  CASE 7: US for a female fetus. Two-dimensional images of the humerus and femur (a, b) show shortening of the shafts with epiphyseal stippling (arrows); facial profile (c) shows a small, upturned nose and hypoplastic nasal bone. The mother and maternal aunt are affected with CDPX2.

Chondrodysplasia Punctata X-Linked Dominant Type, Conradi-Hünermann Type, EBP-Related

 

361

 

  CASE 8: A neonate. Radiographs show irregular ossifications of the vertebral bodies with juxtaspinal puncta, puncta of the ischiopubic junction and asymmetry of the lower limbs with epiphyseal stippling. The upper limbs are not affected. The nasal bone is very short.

BIBLIOGRAPHY Arnold AW, Bruckner-Tuderman L, Has C et al. ConradiHünermann-Happle syndrome in males vs. MEND syndrome (male EBP disorder with neurological defects). Br J Dermatol. 2012; 166: 1309–13. Horinouchi T, Morisada N, Uemura H et al. Male CDPX2 patient with EBP mosaicism and asymmetrically lateralized skin lesions with strict midline demarcation. Am J Med Genet A. 2019; 179: 1315–8.

Lefebvre M, Dufernez F, Bruel AL et al. Severe X-linked chondrodysplasia punctata in nine new female fetuses. Prenat Diagn. 2015; 35: 675–84. Pacault M, Vincent M, Besnard T et al. New splicing pathogenic variant in EBP causing extreme familial variability of Conradi-Hünermann-Happle syndrome. Eur J Hum Genet. 2018; 26: 1784–90. Rossi M, Hall CM, Bouvier R et al. Radiographic features of the skeleton in disorders of post-squalene cholesterol biosynthesis. Pediatr Radiol. 2015; 45: 965–76.

71c Rhizomelic Type Chondrodysplasia Punctata, PEX7-, DHPAT-, AGP5-, FAR1- and PEX5-Related

Synonyms: RCDP Confirmation of diagnosis: identification of biallelic pathogenic variants in the PEX7, GNPAT or AGPS gene Frequency: less than 1/100,000 Genetics: RCDP is a phenotypically homogeneous, but genetically heterogeneous, group of disorders inherited as an autosomal recessive trait and caused by abnormal peroxisome biogenesis or single peroxisomal enzyme deficiency. RCD is classified into types 1, 2 and 3. RCDP1 is related to biallelic mutations in PEX7 mapped on 6q23.3, RCDP2 to those in GNPAT on 1q42 and RCDP3 to those in AGPS on 2q31. PEX7 belongs to a group of the pexin (PEX) genes and encodes the peroxisomal type 2 targeting signal (PTS2) receptor. PEX7 is essential for assembly of PTS2-dependent peroxisomal proteins, while a majority of PEX genes are responsible for assembly of PTS1 proteins and for Zellweger syndrome. RCDP2 is related to a deficiency of dihydroxyacetone-phosphate acyltransferase, and RCDP3 to alkyl-dihydroxyacetone-phosphate synthase. These enzymes are important for the plasmalogen synthesis. Recently, it has been proposed that a deficiency of peroxisomal fatty acyl-CoA reductase-1 (FAR1) and PEX5 causes RCDP4 and RCDP5, respectively. However, the phenotypes of these disorders remain unclearly elucidated. Age/Gestational age of manifestation: affected fetuses can be detected by prenatal ultrasonography during the second trimester (16–22 weeks). Clinical features:

Prenatal ultrasound features: first-trimester ultrasound screening may show increased nuchal translucency (NT). Prenatal detection of RCDP is possible during the fetal morphological scan. The pattern is based on the combination of symmetric rhizomelic bone shortening, metaphyseal flaring and epiphyseal stippling Sonographic features include short long bones predominantly affecting the femora and/or humeri with punctate calcification in the regions of epiphyses and in periarticular cartilage. Sagittal scan of the spine can visualise a coronal cleft of vertebral bodies. Facial dysmorphism is characterised by a low nasal bridge and flat face. The ultrasound detection of bilateral cataracts is a sign associated with RCDP. Recently, the presence of prefrontal oedema has been described as an ultrasound sign associated with RCDP. Sometimes polyhydramnios may be present. Radiographic features: RCDP 1, 2 and 3 are indistinguishable on radiological grounds. The radiological hallmarks include symmetrical shortening of the humeri and, to a lesser extent, of the femora with flared metaphyses and multiple coronal clefts in all or most thoracic and lumbar vertebral bodies. The vertebral bodies are normal in height. Puncta, or stippled calcifications, are striking in the epiphyses of the long bones and pelvic and shoulder bones, while they are absent or very mild in the spine. Patellar puncta are particularly striking, as they are in Zellweger syndrome. Prognosis: affected children are severely disabled and commonly die in infancy and early childhood.

• • • • •

Differential diagnosis: severe cases with CDP tibia-metacarpal (TM) type (p. 367) are sometimes associated with humeral shortening, the phenotype of which is commonly misdiagnosed as RCDP. However, CDP-TM shows striking vertebral puncta and platyspondyly, while RCDP has subtle vertebral puncta and multiple coronal clefts in RCDP. CDPX2 (p. 357) may show rhizomelic shortening, but the disorder manifests with limb asymmetry and severe spondylar dysplasia.

362

DOI: 10.1201/9781003166948-76

Flat face with a depressed nose Rhizomelic shortening of the limbs Cataracts Ichthyosiform skin lesions Severe developmental delay with abnormal cerebral myelination • Joint contracture

Rhizomelic Type Chondrodysplasia Punctata, PEX7-, DHPAT-, AGP5-, FAR1- and PEX5-Related

 

 

 

 

 

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CASES 1–3: Three neonates with RCDP type 1 show the same pattern of skeletal changes in varying severities, including rhizomelic shortening with metaphyseal widening of the long bones and multiple coronal clefts of the vertebral bodies. Epiphyseal puncta are striking in the long bones, pelvic bones and patella, but minimal in the spine.

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  CASE 4: An infant with RCDP type 2. Rhizomelic shortening and metaphyseal widening of the long bones are the same as those of RCDP type 1. However, this infant showed only subtle puncta in the proximal humerus (c). CASE 5: Rhizomelic shortening with epiphyseal stippling was seen at 27 weeks of gestation; (a) the facial profile demonstrating a very small upturned nose and mild micrognathia; (b) severe shortening of the humerus with epiphyseal stippling (arrows).

Rhizomelic Type Chondrodysplasia Punctata, PEX7-, DHPAT-, AGP5-, FAR1- and PEX5-Related

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  CASE 5: (c) Shortening of the humerus relative to the ulna with epiphyseal puncta (arrow); (d) the femur that is short for gestational age with epiphyseal puncta (hand arrows); (e) two-dimensional image of the biparietal diameter and head circumference showing relative microcephaly for gestational age; (f) two-dimensional sagittal view of the chest and abdomen showing a narrow chest (hand arrows) and protuberant abdomen (long arrow). CASE 6: A 30-day-old infant. (a) Flat face; (b, c) symmetrical shortening of the humeri and femora, flared metaphyses; punctate calcific deposits are clearly visible in the periarticular and epiphyseal regions (red circles). (d) Coronal clefts are present in the thoracic and lumbar vertebrae. (e) The radius is shorter than the ulna.

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BIBLIOGRAPHY Bams-Mengerink AM, Koelman JH, Waterham H et al. The neurology of rhizomelic chondrodysplasia punctata. Orphanet J Rare Dis. 2013; 8: 174. Barøy T, Koster J, Strømme P et al. A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform. Hum Mol Genet. 2015; 24: 5845–54. Braverman N, Chen L, Lin P et al. Mutation analysis of PEX7 in 60 probands with rhizomelic chondrodysplasia punctata and functional correlations of genotype with phenotype. Hum Mutat. 2002; 20: 284–97. Buchert R, Tawamie H, Smith C et al. A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency. Am J Hum Genet. 2014; 95: 602–10.

Erdogdu E, Dilek N, Arisoy R et al. Prenatal diagnosis of rhizomelic chondrodysplasia punctata. Genet Couns. 2016; 27: 533–35. Itzkovitz B, Jiralerspong S, Nimmo G et al. Functional characterization of novel mutations in GNPAT and AGPS, causing rhizomelic chondrodysplasia punctata (RCDP) types 2 and 3. Hum Mutat. 2012; 33: 189–97. Muratoğlu Şahin N, Bilici ME et al. Type 1 rhizomelic chondrodysplasia punctata with a homozygous PEX7 mutation. J Pediatr Endocrinol Metab. 2017; 30: 889–92. Rossi M, Hall CM, Bouvier R et al. Radiographic features of the skeleton in disorders of post-squalene cholesterol biosynthesis. Pediatr Radiol. 2015; 45: 965–76.

71d Chondrodysplasia Punctata Tibia-Metacarpal Type

Synonyms: CDP-TM Confirmation of diagnosis: on clinical and radiological grounds Frequency: unknown Genetics: the cause remains unknown. A subset of children with warfarin embryopathy or born from mothers affected with systemic lupus erythematosus (SLE)/mixed connective tissue disease can manifest as CDP-TM. This phenotype may not be the result of a Mendelian disorder, but a polygenic and/or acquired condition. Age/Gestational age of manifestation: shortened limbs may be visualised during the second trimester (16–21 weeks). Clinical features: the clinical phenotype is like, but more ­severe than, that of CDP brachytelephalangic type (CDP-BT). • Moderate to severe pre- and postnatal growth failure • Mesomelic or rhizomesomelic shortening of the limbs • Brachytelephalangy with generalised brachydactyly • Severe nasomaxillary hypoplasia (Binder phenotype) • Occasionally short, broad thorax Prenatal ultrasound features: generalised shortening of the long bones, with bowing of the femora and tibiae, has been detected at 16 weeks’ gestation. Sonographic views of the fetal profile may detect a flattened midface with vertical nasal bone, depressed nasal bridge, abnormally increased nasofrontal angle

DOI: 10.1201/9781003166948-77

(normal angle: 128° ± 7°) and retrusion of the maxilla. There may be severe thoracic hypoplasia, platyspondyly and coronal clefts of the vertebral bodies. The rhizomelic shortening and bowing of the limbs are associated with calcific stippling in the epiphyseal cartilage of the humeri and femora, carpal bones and paravertebral region. The tibiae are much shorter than the fibulae. In the third trimester, multidetector CT (MDCT) with three-dimensional (3D) CT reconstructions may provide a useful contribution to confirm punctate calcifications and to detect other stippled calcifications at the shoulders, elbows and knees. Polyhydramnios may be present. Radiographic features: the tibiae are shorter than the fibulae, and the fibulae may be bowed. Likewise, ulnar shortening and radial bowing may be seen. Humeral shortening may be pronounced. The metacarpals are irregularly short. The distal phalanges are commonly hypoplastic and V-shaped in appearance, as seen in CDP-BT. The proximal and middle phalanges may be severely involved and sometimes ‘angel-shaped’ due to bracket pseudoepiphyses. Generalised platyspondyly may be seen with multiple coronal clefts. Puncta or stippled epiphyses variably manifest, but tend to be more extensive than seen in CDP-BT. Prognosis: most affected individuals are healthy, other than facial abnormalities and micromelia. However, severely affected neonates may present with respiratory failure due to thoracic hypoplasia and tracheomalacia. Differential diagnosis: affected individuals with severe humeral shortening may be misdiagnosed with rhizomelic type CDP (p. 362), while those with severe spondylar dysplasia may be mistaken for Conradi-Hünermann type CDP (p. 357).

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CASE 1: A stillbirth. The tibiae are shorter than the fibulae. The fibulae are posteriorly bowed. The first and fourth metacarpals and second proximal phalanx are short. Multiple coronal clefts are seen in the thoracolumbar spine. Puncta are seen in the cervical spine and tarsal region. CASE 2: A neonate. The tibiae are shorter than the fibulae. The humeri are also short and bowed. The vertebral bodies show platyspondyly. The metacarpals are short. The proximal and middle phalanges are dysplastic, and the proximal phalanges are angel-shaped. The distal phalanges are broad and short (brachytelephalangy). Puncta are more extensive than those of Case 1, involving the long bone epiphyses, carpals and tarsals, laryngeal cartilage and spine.

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Chondrodysplasia Punctata Tibia-Metacarpal Type

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CASE 3: A neonate. The tibiae are shorter than the fibulae. The femora are medially bowed. The ulnae are radially bowed. The metacarpals are short. The second proximal phalanx is triangular in shape. Brachtelephalangy is evident. Subtle puncta are seen in the calcanei and proximal and distal phalanges. CASE 4: A neonate. This case shows severe tibial shortening, humeral shortening, striking spondylar dysplasia, angel-shaped proximal and middle phalanges, brachytelephalangy and striking puncta in the long bones, carpals, tarsals and spine. Spondylar dysplasia causes a short trunk.

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CASES 5–7: Two stillbirths and one neonate show the phenotypic spectrum of severe CDP T-M. All cases show shortening of the tibiae and other long bones, spondylodysplasia and extensive puncta in varying degrees.

BIBLIOGRAPHY Argo KM, Toriello HV, Jelsema RD et al. Prenatal findings in chondrodysplasia punctata, tibia-metacarpal type. Ultrasound Obstet Gynecol. 1996; 8: 350–4. Borochowitz Z. Generalized chondrodysplasia punctata with shortness of humeri and brachymetacarpy: Humerometacarpal (HM) type: Variation or heterogeneity? Am J Med Genet. 1991; 41: 417–22. Fryburg JS, Kelly TE. Chondrodysplasia punctata, humerometacarpal type: A second case. Am J Med Genet. 1996; 64: 493–6. Miyazaki O, Nishimura G, Sago H et al. Prenatal diagnosis of chondrodysplasia punctata tibia-metacarpal type using multidetector CT and three-dimensional reconstruction. Pediatr Radiol. 2007; 37: 1151–4.

Rittler M, Menger H, Spranger J. Chondrodysplasia punctata, tibia-metacarpal (MT) type. Am J Med Genet. 1990; 37: 200–8. Savarirayan R, Boyle RJ, Masel J et al. Long-term follow-up in chondrodysplasia punctata, tibia-metacarpal type, demonstrating natural history. Am J Med Genet A. 2004; 124A: 148–57. Shukla A, Phadke SR. Chondrodysplasia punctata tibia metacarpal type: Report of a 1.5-year-old child with severe short stature and extensive calcific stippling. Clin Dysmorphol. 2015; 24: 118–21.

72 Greenberg Dysplasia, LBR-Related

Synonyms: GRBGD; hydrops-ectopic calcification-motheaten (HEM) skeletal dysplasia; moth-eaten skeletal dysplasia; dappled diaphyseal dysplasia Confirmation of diagnosis: identification of biallelic pathogenic variants in the LBR gene Frequency: about two dozen cases have been reported in the literature Genetics: GRBGD is an autosomal recessive disorder caused by biallelic pathogenic variants in LBR mapped on 1q42.12. Biallelic pathogenic variants in LBR are also responsible for other skeletal dysplasias (i.e., LBR-related spondylometaphyseal dysplasia and LBR-related achondrogenesis type 1A-like dysplasia). Moreover, biallelic or monoallelic pathogenic variants in LBR cause an isolated anomaly of granulocytes (i.e., PelgerHuët anomaly) (PHA; hypolobulated nuclei and abnormal chromatin structure of granulocyte). LBR encodes the lamin B receptor that is involved in two different processes: cholesterol biosynthesis by operating as 3-beta-­hydroxysterol delta(14)reductase and preservation of the chromatin structure by promoting heterochromatin binding to the inner nuclear membrane. It is assumed that the former is related to the skeletal dysplasias and the latter to the granulocyte anomaly. Age/Gestational age of manifestation: can be detected by ultrasound during the second trimester (17 weeks). Clinical features: • Polyhydramnios • Hydrops fetalis • Narrow thorax, marked rhizo-mesomelic limb shortening • Broad, but relatively long, hands; sometimes polydactyly • Facial dysmorphism: severely hypoplastic and retracted midface, markedly depressed nasal bridge • Extraskeletal anomalies: pulmonary hypoplasia, incomplete lung lobation, intestinal malrotation, extramedullary haematopoiesis

DOI: 10.1201/9781003166948-78

Prenatal ultrasound features: there is a cystic hygroma, hydrops fetalis (scalp oedema and extensive ascites) and severe micromelia. The skull vault is very poorly ossified, allowing clear visualisation of the internal fetal brain. The contours of the long bones are abnormal, and there are unusual irregular hypo- and hyperechoic areas within the bones. The vertebrae are flattened (platyspondyly), and there is irregular hyperechogenicity of the vertebral bodies. The iliac bones show an irregular contour, and the iliac wings are short. The thorax is small and the ribs short with pronounced irregular hyperechoic foci. The scapulae are irregular with hypo- and hyperechoic areas. The hands are not severely short as compared with the proximal and middle segments of the limbs. Postaxial polydactyly may be present. Radiographic features: the skull vault is poorly ossified and appears disproportionately large, while the skull base appears sclerotic. There is hypoplasia of the maxilla and mandible. The laryngeal cartilages show punctate premature calcifications. The clavicles are relatively long and almost normally modelled. The spine shows marked platyspondyly with irregular, dense ossifications of the vertebral bodies. The thorax is narrow and barrel shaped. The ribs are short and irregular, showing a beaded appearance. There is extensive ectopic calcification of the costal cartilages, giving rise to hook-like projections. The scapulae, ilia, pubic rami, ischia and long bones are dense and irregular, with fragmented ossification, giving rise to a ‘moth-eaten’ appearance. All the long bones are extremely short and bowed. The epiphyses show puncta or stippled calcifications. The short tubular bones are relatively long and broad. There may be absent ossification of the distal phalanges. Postaxial polydactyly is sometimes seen. Prognosis: usually lethal in utero. Differential diagnosis: GRBGD should be differentiated from severe forms of chondrodysplasia punctata, including CDPX2 (p. 357), CDP-TM type (p. 367) and RCDP (p. 362). In particular, the most severe phenotype of CDPX2 may present with a moth-eaten appearance of the bones; however, CDPX2 shows limb asymmetry, while GRBGD does not. A moth-eaten appearance is not seen in CDP-TM or RCDP. The relation between GRBGD and Astley-Kendall dysplasia (p. 386) remains unclear. If a moth-eaten appearance is milder, GRBGD may be misdiagnosed as achondrogenesis (p. 105, 256) or Blomstrand dysplasia (p. 464).

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CASES 1–3: Three terminated fetuses with severe fetal hydrops, thoracic narrowing, protuberant abdomen and severe micromelia. The pregnancy was interrupted in the second trimester in all (at 18 weeks of gestation in Case 2 and at 15 weeks in Case 3). Case 2 had postaxial polydactyly of the hands, and the parents had the Pelger-Huët anomaly. Case 3 also had postaxial polydactyly and showed portal fibrosis on histological grounds. All fetuses show severe platyspondyly, epiphyseal puncta, a ‘moth-eaten’ appearance of primary ossification centres and puncta of the costal and laryngeal cartilages.

Greenberg Dysplasia, LBR-Related

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  CASES 4, 5: Terminated fetuses with less conspicuous puncta. Both cases show epiphyseal puncta, spondylodysplasia and severe shortening of the long bones. However, the primary ossification centres of the long bones are only mildly fragmented in Case 4 and almost normally ossified in Case 5. These cases may fall into the intermediate between typical Greenberg dysplasia and LBR-related achondrogenesis type 1A-like phenotype. The lumbar spine of Case 4 was broken during delivery. Epiphyseal stippling of Case 5 is well delineated in post-autopsy images (b and c).

BIBLIOGRAPHY Clayton P, Fischer B, Mann A et al. Mutations causing Greenberg dysplasia but not Pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein. Nucleus. 2010; 1: 354–66. Giorgio E, Sirchia F, Bosco M et al. A novel case of Greenberg dysplasia and genotype-phenotype correlation analysis for LBR pathogenic variants: An instructive example of one gene-multiple phenotypes. Am J Med Genet A. 2019; 179: 306–11.

Gregersen PA, McKay V, Walsh M et al. A new case of Greenberg dysplasia and literature review suggest that Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley-Kendall dysplasia are allelic disorders. Mol Genet Genomic Med. 2020; 8: e1173. Konstantinidou A, Karadimas C, Waterham HR et al. Pathologic, radiographic and molecular findings in three fetuses diagnosed with HEM/Greenberg skeletal dysplasia. Prenat Diagn. 2008; 28: 309–12.

374 Madazli R, Aksoy F, Ocak V et al. Detailed ultrasonographic findings in Greenberg dysplasia. Prenat Diagn. 2001; 21: 65–7. Offiah AC, Mansour S, Jeffrey I et al. Greenberg dysplasia (HEM) and lethal X linked dominant Conradi-Hünermann chondrodysplasia punctata (CDPX2): Presentation of two cases with overlapping phenotype. J Med Genet. 2003; 40: e129. Rossi M, Hall CM, Bouvier R et al. Radiographic features of the skeleton in disorders of post-squalene cholesterol biosynthesis. Pediatr Radiol. 2015; 45: 965–76.

Fetal and Perinatal Skeletal Dysplasias Trajkovski Z, Vrcakovski M, Saveski J et al. Greenberg dysplasia (hydrops-ectopic calcification- moth-eaten skeletal dysplasia): Prenatal ultrasound diagnosis and review of literature. Am J Med Genet. 2002; 111: 415–19. Waterham HR, Koster J, Mooyer P et al. Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3 betahydroxysterol delta 14-reductase deficiency due to mutations in the Lamin B receptor gene. Am J Hum Genet. 2003; 72: 1013–17.

73 Warfarin Embryopathy

Synonyms: chondrodysplasia punctata due to warfarin teratogenicity; fetal warfarin syndrome Confirmation of diagnosis: on clinical and radiological grounds Frequency: rare – occurs in only a minority of fetuses exposed to warfarin Genetics: the disorder is an acquired condition caused by in utero exposure to warfarin, a coumarin derivative commonly used as an oral anticoagulant. Warfarin is a vitamin K antagonist that blocks vitamin K epoxide reductase, a key enzyme for vitamin K–dependent carboxylation, an essential posttranslational modification for the biological functions of certain proteins, including clotting factors, osteocalcin and matrix Gla protein (MGP), the latter two of which are required for chondrocyte differentiation and matrix mineralisation during endochondral ossification. Disruption of vitamin K activation also impairs activity of arylsulfatase E that is related to X-linked recessive chondrodysplasia punctata (CDPX1). The teratogenic effect is dose dependent, with the highest risk for doses ≤5 mg/day and gestational weeks dependent, with the highest susceptibility between 6 and 12 weeks. Embryonic teratogenicity determines abnormal organogenesis, while fetal teratogenicity is more often secondary to haemorrhages and abnormal vascularisation. Age/Gestational age of manifestation: affected fetuses can be detected by ultrasound during the second trimester (16–18 weeks). Clinical features: • • • • •

First trimester exposure Hydrops Intrauterine growth retardation Polyhydramnios Severe hypoplasia of the nose, sometimes choanal atresia • Brachydactyly, particularly hypoplasia of the distal phalanges • Extraskeletal abnormalities: hydrocephalus and brain malformations, particularly midline dysplasias (agenesis of the corpus callosum, Dandy-Walker anomaly, atrophy of the cerebellar vermis); eye anomalies (corneal opacities, cataract, optic atrophy, DOI: 10.1201/9781003166948-79

microphthalmia); skin and hair abnormalities; other possible anomalies (cleft lip and/or palate, pelviureteric junction obstruction, cardiac malformations, gastroschisis) Prenatal ultrasound features: nasal malformation is the only consistent clinical feature: there is a flattened nose in the midsagittal plane (flat naso-frontal angle), vertical nasal bones and retraction of the maxilla. 2D ultrasound scan detects nasomaxillary hypoplasia; however, 3D ultrasound may be required for a more accurate assessment of facial dysmorphism: short nose, flat nasal bridge and squared appearance of the alveolar ridge. Cleft lip and/or palate may be present. Epiphyseal stippling may not readily be detected. Intrauterine growth restriction and polyhydramnios are common. Central nervous system anomalies have been reported: partial agenesis of the corpus callosum, Dandy-Walker malformation, hydrocephalus, microcephaly. Intracranial bleeding, porencephalic lesions and ventriculomegaly have been demonstrated at 26 weeks’ gestation. Radiographic features: the radiological spectrum of warfarin embryopathy may be variable depending on the warfarin dose. In most cases, however, the skeletal phenotype is a phenocopy of CDP brachytelephalangic type (CDP-BT). Brachytelephalangy (short distal phalanges with broad tufts and tapered ­bases) is distinctive; shortening of the proximal and middle phalanges and metacarpals is sometimes seen; ossification of the cervical vertebral bodies is defective and associated with atlantoaxial instability and stenosis at the craniovertebral junction; abnormal ossification of the thoracolumbar vertebral bodies with occasional coronal clefts may be seen. Puncta or stippled epiphyses show a predilection for the cervical spine, lumbosacrococcygeal region and tarsal region; however, they may be extensive in some cases or very mild in others. Calcification of the laryngeal and tracheal cartilage may cause laryngeal stenosis and tracheomalacia. Prognosis: the prognosis depends on the gestational age at the time of exposure and on the dose. Exposure in the first trimester has no effect in roughly 60% of cases, spontaneous abortions or stillbirths in 15–20% and liveborn fetuses with warfarin embryopathy in 15–20%. Exposure in the second and third trimesters is not usually associated with skeletal defects but with adverse neurological outcome and other extraskeletal morbidities. Airway management for stenosis of the nasal airway and laryngotracheal abnormalities is frequently required in the neonatal period. Affected neonates with a severe skeletal 375

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phenotype may have thoracic hypoplasia. Central nervous system complications usually cause a poor outcome. Differential diagnosis: warfarin embryopathy should be differentiated from a group of CDP, particularly from CDPX1 (p. 352), as well as from VKORG1 deficiency and GGCX deficiency. Other conditions with stippling: Smith-Lemli-Opitz syndrome – caused by a defect in the enzyme 3 beta-hydroxysterol-delta 7-reductase; this converts 7-dehydrocholesterol to cholesterol (gene DHCR7). This more complex syndrome has characteristic facial traits (bitemporal narrowing, ptosis, broad nasal bridge, short nasal root, anteverted nares, micrognathia), cleft palate, brain anomalies (microcephaly, agenesis of the corpus callosum, holoprosencephaly) and anomalies of the genital, cardiovascular and gastrointestinal systems. Skeletal anomalies include rhizomelia, postaxial polydactyly, syndactyly of the second and third toes and short, proximally placed thumbs. Zellweger syndrome (p. 382); Keutel syndrome is a very rare recessive disorder characterised by diffuse and progressive calcification of cartilage (nasal, ear and respiratory tract), dysmorphic facial features and peripheral pulmonary stenosis. It

 

is caused by pathogenic variants in the vitamin K–dependent matrix Gla protein (MGP). Stippling is occasionally present in neonatal hypothyroidism: osteopenia, Wormian bones, wide anterior fontanelle; GM1 gangliosidosis – findings are similar to I-cell disease, and it is also a storage disorder; mucolipidosis type 2 (I-cell disease) (p. 348); Cornelia de Lange syndrome (p. 540); trisomy 18, trisomy 21 and fetal exposure to hydantoins and alcohol. Maternal autoimmune disorders, particularly systemic lupus erythematosus (p. 378) and Sjögren syndrome, have been associated with fetal stippling. A phenotype similar to although much more complex and severe than warfarin embryopathy is described in multiple sulphatase deficiency, a recessive condition caused by mutations in the sulphatase-modifying factor-1 gene (SUMF1), responsible for the activation of all the sulphatase enzymes in the cell. CHILD syndrome: an acronym for congenital hemidysplasia with ichthyosiform erythroderma and limb defects, a very rare condition which shows unilateral involvement with joint contractures, limb hypoplasia and a wide range of organ malformations (cardiac, genitourinary, endocrine, cerebral).

 

CASE 1: A terminated fetus at 28 weeks of gestation. The mother had a high dose of warfarin at the early gestational period. Postmortem radiographs show very large puncta in the hips, knees and tarsal regions. Fine stippling is also seen in the cervical spine.

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  CASE 2: The mother was taking long-term warfarin prophylaxis after surgery for congenital heart disease. Fetal ultrasonography revealed skeletal abnormalities at 23 weeks’ gestation. The postmortem features of the fetus included a hypoplastic depressed nose, rhizomelic shortening of the limbs and a narrow thorax as well as mild ventriculomegaly of the brain. A postmortem radiograph shows stippling in the spine and epiphyses of the long bones. There is marked platyspondyly.

BIBLIOGRAPHY Basu S, Aggarwal P, Kakani N et al. Low-dose maternal warfarin intake resulting in fetal warfarin syndrome: In search for a safe anticoagulant regimen during pregnancy. Birth Defects Res A Clin Mol Teratol. 2016; 106: 142–7. Ferreira S, Costa R, Malveiro D et al. Warfarin embryopathy: Balancing maternal and fetal risks with anticoagulation therapy. Pediatr Neonatol. 2018; 59: 534–5. Gupta P, Kumar S, Roy KK et al. Prenatal diagnosis of warfarin embryopathy using three-dimensional ultrasound. Int J Gynaecol Obstet. 2010; 111: 184–5.

Mehndiratta S, Suneja A, Gupta B et al. Fetotoxicity of warfarin anticoagulation. Arch Gynecol Obstet. 2010; 282: 335–7. Silveira DB, da Rosa EB, de Mattos VF et al. Importance of a multidisciplinary approach and monitoring in fetal warfarin syndrome. Am J Med Genet A. 2015; 167: 1294–9. Sousa R, Barreira R, Santos E. Low-dose warfarin maternal anticoagulation and fetal warfarin syndrome. BMJ Case Rep. 2018; 2018: bcr2017223159. Wainwright H, Beighton P. Warfarin embryopathy: Fetal manifestations. Virchows Arch. 2010; 457: 735–9.

74 Maternal Systemic Lupus Erythematosus

Synonyms: maternal lupus syndrome Confirmation of diagnosis: suggestive clinical and serology findings, congruent maternal history Frequency: unknown. Occurs in only a minority of fetuses born to mothers with systemic lupus erythematosus (SLE) or mixed connective tissue disease Genetics: this is an acquired condition that is caused by transplacental passage of a maternal antibody (or antibodies), which impairs a protein (proteins) related to vitamin K recycling and vitamin K–dependent gamma-carboxylation. However, it remains elusive what the causative antibody and target protein are. The causative antibody could be different from anti-Ro (anti-SSA) and anti-La (anti-SSB) commonly seen in neonatal lupus erythematosus. Age/Gestational age of manifestation: affected fetuses can be detected by ultrasound during the second trimester (18–24 weeks). Clinical features: • • • •

Intrauterine and postnatal growth retardation Nasomaxillary hypoplasia, variable and may be mild Short limbs; brachydactyly The manifestation of neonatal lupus erythematosus (skin rashes and heart block) is less common

Prenatal ultrasound features: the findings are indistinguishable from those of chondrodysplasia punctata brachytelephalangic type (CDPX1) and include polyhydramnios, nasomaxillary hypoplasia and stippled epiphyses with variable long bone shortening. Intrauterine growth restriction (IUGR) can be detected. Prenatal diagnosis is not always possible – normal antenatal ultrasound findings were reported in a male infant born at 36 weeks’ gestation with classic clinical and radiologic findings.

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Radiographic features: the changes are similar to those of CDP-BT or CDP-TM. Puncta or stippled epiphyses are variable. Stippling tends to be confined to the tarsal regions, cervical spine and lumbosacrococcygeal region in CDP-BT– like phenotypes, while they may more extensively involve the long bones and spine in CDP-TM–like phenotypes. The distal phalanges are short along with wide tufts and narrow bases, sometimes associated with stippling. There may be variable shortening and stippling of the proximal and middle phalanges and the metacarpals and metatarsals. Ossification of the cervical vertebral bodies is defective and may be associated with stenosis of the craniovertebral junction and atlantoaxial instability. Thoracolumbar spinal changes may be severe with defective ossification of the vertebral bodies and coronal clefts. Generalised platyspondyly may be present along with striking puncta. Tibial and humeral shortening may be pronounced. There may be laryngeal cartilage calcification. Prognosis: usually viable. There is an increased risk of preeclampsia and prematurity, which can affect prognosis. Thirddegree atrioventricular (AV) block is irreversible and can lead to fetal demise in 5–20% of cases. Second-degree AV block can be reversible. Skin, liver and haematological anomalies are usually transient. The prognosis related to the facial anomalies is like that of CDP-BT or CDP-TM. A small subset of ­affected individuals shows neonatal respiratory failure because of thoracic hypoplasia and/or airway stenosis. The presence or absence of cervical myelopathy determines the physical morbidities of affected children. The nasomaxillary hypoplasia becomes less pronounced with age. Somatic growth failure tends to be modest. Differential diagnosis: this condition should be differentiated from CDP-BT or CDP-TM, including CDPX1 (p. 352, 367, 357), Keutel syndrome, warfarin embryopathy (p. 375) and deficiency of VKORG1 and GGCX. Atypical cases may be like disorders in other types of CDP.

DOI: 10.1201/9781003166948-80

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CASE 1: The manifestation of the fetus is a phenocopy of CDP-BT. Stippling is seen at the metacarpal bases and tarsal region. CASE 2: The sibling fetus of Case 1. Note the extensive anterior spinal ligament calcification in addition to puncta at the proximal femora. Both cases show striking spinal dysplasia.

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Fetal and Perinatal Skeletal Dysplasias

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CASES 3, 4: A neonate and terminated fetus. The manifestations of these cases correspond to those of CDP-TM. Both patients show generalised stippling, spinal dysplasia, tibial shortening and brachytelephalangy. Case 4 also shows humeral shortening. Postmortem CT (c) clearly delineates the distribution of puncta.

BIBLIOGRAPHY Alkhunaizi E, Unger S, Shannon P et al. Maternal SLE and brachytelephalangic chondrodysplasia punctata in a patient with unrelated de novo RAF1 and SIX2 variants. Am J Med Genet A. 2020; 182: 1807–11.

Chitayat D, Keating S, Zand DJ et al. Chondrodysplasia punctata associated with maternal autoimmune diseases: Expanding the spectrum from systemic lupus erythematosus (SLE) to mixed connective tissue disease (MCTD) and scleroderma: Report of eight cases. Am J Med Genet A. 2008; 146A: 3038–53.

Maternal Systemic Lupus Erythematosus Elçioglu N, Hall CM. Maternal systemic lupus erythematosus and chondrodysplasia punctata in two sibs: Phenocopy or coincidence? J Med Genet. 1998; 35: 690–4. Grika-Marton M, Szukiewicz D, Teliga-Czajkowska J et al. An overview of neonatal lupus with anti-Ro characteristics. Int J Mol Sci. 2021; 22: 9281. Kozlowski K, Basel D, Beighton P. Chondrodysplasia punctata in siblings and maternal lupus erythematosus. Clin Genet. 2004; 66: 545–9. Limaye MA, Buyon JP, Cuneo BF et al. A review of fetal and neonatal consequences of maternal systemic lupus erythematosus. Prenat Diagn. 2020; 40: 1066–76. Nayak SS, Adiga PK, Rai L et al. Severe rhizomelic chondrodysplasia punctata in a fetus due to maternal mixed connective tissue disorder. Genet Couns. 2012; 23: 487–91.

381 Shanske AL, Bernstein L, Herzog R. Chondrodysplasia punctata and maternal autoimmune disease: A new case and review of the literature. Pediatrics. 2007; 120: e436–41. Tardif ML, Mahone M. Mixed connective tissue disease in pregnancy: A case series and systematic literature review. Obstet Med. 2019; 12: 31–37. Tim-aroon T, Jaovisidha S, Wattanasirichaigoon D. A new case of maternal lupus-associated chondrodysplasia punctata with extensive spinal anomalies. Am J Med Genet A. 2011; 155A: 1487–91. Zuppa AA, Riccardi R, Frezza S et al. Neonatal lupus: Follow-up in infants with anti-SSA/Ro antibodies and review of the literature. Autoimmun Rev. 2017; 16: 427–32.

75 Cerebro-Hepato-Renal (Zellweger) Syndrome

Synonyms: ZWS; Zellweger syndrome, cerebro-hepato-renal syndrome; PBD-A (peroxisome biogenesis disorder-A). Confirmation of diagnosis: suggestive clinical and biochemical characteristics and/or identification of pathogenic variants in the PEX genes. Frequency: 1 in 50,000 to 1 in 500,000

• Brain malformation (polymicrogyria, heterotopia, callosal hypoplasia, etc.) • Hepatosplenomegaly, jaundice, abnormal liver function; renal cortical cysts • Other features: talipes equinovarus, camptodactyly, single palmar crease, patent ductus arteriosus (PDA), ventricular septal defect (VSD)

Genetics: ZWS encompasses a group of the most severe phenotype of peroxisome biogenesis disorders (PBDs) inherited as an autosomal recessive trait. Zellweger spectrum disorder (ZSD) is a phenotypic continuum ranging from severe forms, clinically defined as Zellweger syndrome or PBDA, to mild forms, such as neonatal adrenoleukodystrophy and infantile Refsum disease, also defined as PBDB, and rhizomelic chondrodysplasia punctata (RCDP) associated with variants in PEX7. The condition is genetically heterogeneous and is caused by biallelic pathogenic variants in one of the 13 pexin (PEX) genes, including PEX1 (PBD1A, most common), PEX5 (PBD2A), PEX12 (PBD3A), PEX6 (PBD4A), PEX2 (PBD5A), PEX10 (PBD6A), PEX26 (PBD7A), PEX16 (PBD8A), PEX3 (PBD10A), PEX13 (PBD11A), PEX19 (PBD12A), PEX14 (PBD13A) and PEX11B (PBD14B). PEX genes encode a group of proteins essential for the assembly of peroxisomes. Variants which abolish activity of the gene correlate with the most severe phenotype, while missense variants which allow retention of function, albeit reduced, correlate with a milder phenotype. Peroxisomes are single-membrane-bound ubiquitous intracellular organelles which catalyse various metabolic pathways including β-oxidation of very long-chain fatty acids, degradation of phytanic acid and the synthesis of plasmalogen.

Prenatal ultrasound features: increased nuchal translucency thickness can be detected in the first trimester. The routine midtrimester fetal ultrasound scan (18–22 weeks) can demonstrate hyperechoic, enlarged kidneys bilaterally and expression of multiple microcysts. Fetal echogenic bowel may be present. Followup ultrasound may visualise periventricular pseudocysts, mild asymmetric ventriculomegaly, thin corpus callosum or corpus callosum dysgenesis. Fetal MR imaging reveals ZS-characteristic abnormal cortical gyral patterns (polymicrogyria, pachygyria), confirming the presence of periventricular pseudocysts. Dysmorphic craniofacial features including hypertelorism, prominent and high forehead, broad nasal bridge, flat face and micrognathia may be detected. Talipes equinovarus may be associated. Growth restriction and fetal hypokinesia are more evident in the third trimester. Bilateral cataracts and nystagmoid eye movements have been documented after 37 weeks’ gestation. Persistent hyperplastic primary vitreous may be present.

Age/Gestational age of manifestation: may be diagnosed in the first trimester (10–14 weeks) in an at-risk pregnancy.

Prognosis: affected individuals show severe neurological abnormalities and rarely survive beyond the first year. However, several long-term survivors and mildly affected individuals have recently been reported. Hepatosplenomegaly and renal microcysts can be present on postnatal ultrasound.

Clinical features: • Characteristic facial features: expressionless facies, large fontanelles, high forehead, flat occiput, hypoplastic supraorbital ridges, hypertelorism, epicanthic folds, upward slanting palpebral fissures • Severe hypotonia • Cryptorchidism, hypospadias, prominent clitoris • Cataracts, retinal pigmentary changes, Brushfield spots, hypoplasia of the optic disc

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Radiographic features: stippled calcifications of the patella are characteristic and typically manifest as crescent-shaped calcifications. Puncta may be seen in the triradiate cartilage, hip and shoulder. There is a large anterior fontanelle with macrocephaly and dolichocephaly.

Differential diagnosis: ZWS should be clinically (and molecularly) differentiated from PBDB, as it is relevant for prognosis (neonatal adrenoleukodystrophy and infantile Refsum), and single peroxisomal enzyme deficiency (e.g., D-bifunctional protein deficiency), which may show mild patellar puncta. Patellar puncta are prominent in RCDP (p. 362), but this disorder shows severe shortening of the humeri and femora, while ZWS has almost normal long bones.

DOI: 10.1201/9781003166948-81

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Cerebro-Hepato-Renal (Zellweger) Syndrome Epiphyseal stippling: note that patellar stippling is not predominant in other subtypes of CDP. chondrodysplasia punctata (pp. 352–367); warfarin embryopathy (p. 375); congenital hypothyroidism – osteopenia, Wormian bones and wide anterior fontanelle. Keutel syndrome is a very rare recessive disorder characterised by diffuse and progressive calcification of cartilage (nasal, ear and respiratory tract), dysmorphic facial features, hypoplastic terminal phalanges and peripheral pulmonary stenosis. It is caused by pathogenic variants in the vitamin K–dependent matrix Gla protein (MGP). Smith-Lemli-Opitz syndrome: caused by a defect in the enzyme 3 beta-hydroxysterol-delta 7-reductase; this converts 7-dehydrocholesterol to cholesterol (gene DHCR7). This more complex syndrome has characteristic facial traits (bitemporal narrowing, ptosis, broad nasal bridge, short nasal root, anteverted nares, micrognathia), cleft palate, brain anomalies (microcephaly, agenesis of the corpus callosum, holoprosencephaly) and anomalies of the genital, cardiovascular and gastrointestinal systems. Skeletal anomalies include rhizomelia, postaxial polydactyly, syndac-

(1a)

 

(1b)

CASES 1, 2: Both cases show striking stippling in the patellar region.

tyly of the second and third toes and short, proximally placed thumbs. Stippling is occasionally present in GM1 gangliosidosis: mucolipidosis type II (I-cell disease) (p. 348); Cornelia de Lange syndrome (p. 540); trisomy 18 and trisomy 21 and fetal exposure to hydantoins and alcohol. Maternal autoimmune disorders, particularly systemic lupus erythematosus (p. 378) and Sjögren syndrome, have been associated with fetal stippling. Hypotonia: Prader-Willi syndrome – a UPD15 disorder with severe hypotonia and gradual development in childhood of morbid obesity. Spinal muscular atrophy: SMN1 and SMN2 mutations cause degeneration of anterior horn cells with progressive muscle weakness. Poor weight gain, scoliosis and contractures. Congenital myotonic dystrophy: caused by expansion of a CTG trinucleotide repeat in the non-coding region of DMPK. Cataract; skeletal and smooth muscle involvement; reduced life span. X-linked myotubular myopathy: pathogenic variants in the gene MTM1; affected male pregnancies show prenatal polyhydramnios and reduced fetal movement; ventilator dependent.

 

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CASE 2: Presents with distinctive craniofacial dysmorphism, including hypoplastic supraorbital ridges, tall forehead and hypertelorism. CASE 3: A neonate. Stippling is seen in the patellar region, triradiate cartilage, proximal humeral epiphyses and coracoid process of the scapulae.

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Cerebro-Hepato-Renal (Zellweger) Syndrome

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CASE 4: A neonate with deficiency of bifunctional protein. Patellar stippling is less pronounced than those typically seen in Zellweger syndrome. Subtle stippling is also seen in the triradiate cartilage.

BIBLIOGRAPHY Berendse K, Engelen M, Ferdinandusse S et al. Zellweger spectrum disorders: Clinical manifestations in patients surviving into adulthood. J Inherit Metab Dis. 2016; 39: 93–106. Cheillan D. Zellweger syndrome disorders: From severe neonatal disease to atypical adult presentation. Adv Exp Med Biol. 2020; 1299: 71–80. Ebberink MS, Mooijer PA, Gootjes J et al. Genetic classification and mutational spectrum of more than 600 patients with a Zellweger syndrome spectrum disorder. Hum Mutat. 2011; 32: 59–69. Johnson JM, Babul-Hirji R, Chitayat D. First-trimester increased nuchal translucency and fetal hypokinesia associated with Zellweger syndrome. Ultrasound Obstet Gynecol. 2001; 17: 344–6.

Klouwer FC, Berendse K, Ferdinandusse S et al. Zellweger spectrum disorders: Clinical overview and management approach. Orphanet J Rare Dis. 2015; 10: 151. Kumar S, Suthar R, Sharda S et al. Zellweger syndrome: Prenatal and postnatal growth failure with epiphyseal stippling. J Pediatr Endocrinol Metab. 2014; 27: 185–8. Rosewich H, Ohlenbusch A, Gärtner J. Genetic and clinical aspects of Zellweger spectrum patients with PEX1 mutations. J Med Genet. 2005; 42: e58. Smitthimedhin A, Otero HJ. Scimitar-like ossification of patellae led to diagnosis of Zellweger syndrome in newborn: A case report. Clin Imaging. 2018; 49: 128–130. Ventura MJ, Wheaton D, Xu M et al. Diagnosis of a mild peroxisomal phenotype with next-generation sequencing. Mol Genet Metab Rep. 2016; 9: 75–78.

76 Astley-Kendall Dysplasia

Synonyms: none Confirmation of diagnosis: on clinical and radiological grounds Frequency: only three affected families (five affected individuals) have been reported Genetics: the cause is still unknown. It may be sporadic or autosomal recessive. A family with three affected female siblings born to the consanguineous parents has been reported (Nairn and Chapman, 1989). Age/Gestational age of manifestation: can be detected by ultrasound during the first trimester (11–13+6 weeks). Clinical features: • Early-onset extremely short limbs • Virtually absent ossification of the cranial vault, which is represented by a thick membranous tissue • Very narrow thorax due to short ribs Prenatal ultrasound features: this rare, lethal neonatal skeletal dysplasia has been detected by ultrasound at 18 weeks of pregnancy. There is absent or decreased ossification of the vault with Wormian bones visible using 3D ultrasound on maximum mode rendering. The long bones appear short and bowed or angulated with wide, sclerotic diaphyses due to callus from healing fractures. Hands and feet are normal. Multifocal punctate calcification may be identified involving the axial skeleton, carpus and tarsus. In the spine there is marked platyspondyly and poor or absent ossification of vertebral bodies. The thorax

386

is narrow and the ribs deformed because of fractures. Polyhydramnios may be present. Radiographic features: the skull is disproportionately large with absent ossification. The thorax is small and narrow. The ribs are short, broad and deformed due to fractures. The spine shows marked platyspondyly with extensive stippling. The thoracic vertebral bodies may be missing. The ilia are short and flared. Stippled calcification affects the carpus and tarsus and may involve the scapulae, proximal femora, pubic bones and ischia. The long bones are short, broad and angulated from fractures along with metaphyseal broadening. However, the appearance of the femora was variable among affected individuals. The original case of Astley and Kendall showed an almost normal trabeculation with dumbbell-like metaphyseal splaying. The sporadic case of Elçioglu and Hall and two siblings of Nairn and Chapman had diaphyseal sclerosis and undermodelling, giving the appearance of callus formation. The third sibling showed diaphyseal fragmentation resembling that of Greenberg dysplasia. Prognosis: lethal in utero or at birth. Differential diagnosis: the combination of multiple fractures and defective calvarial ossification may lead to a diagnosis of lethal osteogenesis imperfecta (p. 429), achondrogenesis type 1A (p. 256), lethal hypophosphatasia (p. 452) or I-cell disease (p. 348). The differentiation between Astley-Kendall dysplasia and Greenberg dysplasia (p. 371) may be difficult; however, puncta are much more extensive in Greenberg dysplasia. Other conditions with ectopic stippled calcification: chromosomal abnormalities, disruption of vitamin K metabolism, such as warfarin (p. 375) or maternal autoimmune disorders, particularly systemic lupus erythematosus (p. 378).

DOI: 10.1201/9781003166948-82

387

Astley-Kendall Dysplasia

 

  CASE 1: Stillbirth at 34 weeks’ gestation. Postmortem radiographs show osteopaenia and fractures of the long bones and ribs. The ribs are beaded, and the tibiae are angulated. Puncta are seen in the spine, ilia, ischia, proximal femoral epiphyses and tarsal areas. The calvarium shows reduced ossification; the vertebral bodies show marked platyspondyly with absent ossification of the thoracic vertebral bodies.  

BIBLIOGRAPHY Astley R, Kendall AC. A bone dysplasia for diagnosis. Ann Radiol (Paris). 1980; 23: 121–3. Elçioglu N, Hall CM. A lethal skeletal dysplasia with features of chondrodysplasia punctata and osteogenesis imperfecta: An example of Astley-Kendall dysplasia. Further delineation of a rare genetic disorder. J Med Genet. 1998; 35: 505–7.

Gregersen PA, McKay V, Walsh M et al. A new case of Greenberg dysplasia and literature review suggest that Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley-Kendall dysplasia are allelic disorders. Mol Genet Genomic Med. 2020; 8: e1173. Nairn ER, Chapman S. A new type of lethal short-limbed dwarfism. Pediatr Radiol. 1989; 19: 253–7.

77 Osteopetrosis, Neonatal or Infantile Forms, TCRG1-, CLCN7- and SNX10-Related: Osteopetrosis, Infantile Form with Nervous System Involvement, OSTM1-Related

Synonyms: infantile malignant osteopetrosis; autosomal recessive osteopetrosis (ARO), osteopetrosis-B (OPTB; B refers to autosomal recessive, while OPTA refers to autosomal dominant osteopetrosis), marble bone disease autosomal recessive, Albers-Schonberg disease autosomal recessive (note: Albers-Schonberg disease refers to autosomal dominant osteopetrosis) Confirmation of diagnosis: identification of biallelic pathogenic variants in a number of genes, cited later Frequency: 1:250 000 Genetics: infantile osteopetrosis encompasses a heterogeneous group of autosomal recessive disorders (ARO). They are histologically divided into osteoclast-rich and osteoclast-poor types. Osteoclast-rich ARO is caused by osteoclast dysfunction, particularly impaired acidification of the osteoclast resorption lacunae, including OPTB1 (disease-causing gene: TCIRG1; the most common and over 50% in ARO, OPTB4 (CLCN7; 17%), OPTB5 (OSTM1; 5%) and OPTB8 (SNX10). TCIRG1 encodes an osteoclast-specific subunit of the vacuolar proton pump (V-ATPase). CLCN7 and OSTM1 proteins together form a molecular complex localised in late endosomes and lysosomes in the ruffled border of osteoclasts. SNX10 encodes an interactor of V-ATPase. It should be emphasised that CLCN7-OPTB and OSTM1-OTPB are neuropathic forms of ARO. Milder forms of osteoclast-rich ARO comprise OPTB3 (CA2 encoding carbonic anhydrase II) and OPTB6 (PLEKHM1). These are not associated with bone marrow failure. CA2OPTB is associated with brain calcification and renal tubular acidosis. Osteoclast-poor OPTB is caused by impaired osteoclastogenesis (osteoclast differentiation), including OPTB2 caused by mutations in TNFSF11 encoding RANKL (ligand for RANK) (2% in OPTB) and OPTB7 by mutations in TNFRSF11A encoding RANK (receptor activator of NF-kappa-B) (4.5% in OPTB). RANK-OPTB is associated with hypogammaglobulinemia.

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Other rare subtypes are related to mutations in FERMT3, MITF and LRRK1 and a large deletion spanning RAG1, RAG2 and TRAF6. FERMT3-OPTB is associated with leukocyte adhesion deficiency type III; MITF-OPTB with coloboma, microphthalmia, macrocephaly, albinism, and deafness; and RAG1, RAG2 and TRAF6 deletion with severe combined immunodeficiency. X-linked osteopetrosis caused by NEMO mutations presents as an immunodeficiency disorder rather than a sclerosing bone disease. Age/Gestational week of manifestation: onset is usual prenatal and can be detected as early as 14–18 weeks of pregnancy. Clinical features: • Large head, proptosis, cranial nerve compression, hydrocephalus • Hypocalcaemia due to osteoclast dysfunction • Bone marrow failure (hepatosplenomegaly, extramedullary haematopoiesis, pancytopenia) • Bone fragility that becomes a medical concern after infancy • Neuropathic forms: primary neurodegeneration, including optic and retinal atrophy Prenatal ultrasound features: in pregnancies at risk, suspicious signs may appear early in the second trimester. Although the structural brain malformations are typically not considered to be a part of the clinical spectrum of osteosclerosis, most of the cases detected in the prenatal period in at-risk and not at-risk pregnancies occur in association with structural brain malformations. Ultrasonographic features of the affected fetus detected on a routine morphology scan include brain abnormalities with ventriculomegaly, macrocephaly, prominent forehead, hypertelorism, depressed nasal bridge, wide metaphyses of the femora and talipes equinovarus. Polyhydramnios may be present in the third trimester. Hydrocephalus can cause thinning of the cerebral mantle, there can be agenesis of the corpus callosum with interhemispheric cyst, small posterior fossa with cerebellar hypoplasia and a thin brain stem with pontine hypoplasia. There is increased bone density of the tubular bones, metaphyseal irregularities and small vertebral bodies with increased density.

DOI: 10.1201/9781003166948-83

Osteopetrosis, Neonatal or Infantile Forms, TCRG1-, CLCN7- and SNX10-Related Radiographic features: affected neonates show homogeneous osteosclerosis at birth. However, the metaphyseal ends may be relatively radiolucent with fraying or irregularities (osteopetrorickets). The diaphyses of the long bones may be outlined by radiolucent bands (periosteal reaction–like). The metaphyses of the long bones may show striking undermodelling (Erlenmeyer flask deformity). Since osteoclast abnormalities in osteopetrosis fluctuate after birth, the initial uniform osteosclerosis evolves into transverse alternating sclerotic and lucent bands in the metaphyses of the tubular bones, concentric alternating sclerotic changes in the ilia and a rugger ­jersey ­appearance of the vertebral bodies. The long bones and vertebral bodies may show a ‘bone-in-bone’ appearance. The sclerotic areas of the tubular bones are wider than the lucent areas. The sclerotic bone is fragile and susceptible to fractures. The calvarium and skull base are sclerotic. When bone marrow failure occurs, the diploic spaces of the calvarium become very thick with a hair-on-end appearance. The vertebral bodies may show prominence of the nutritional vascular canals. Bone marrow

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transplantation (BMT) or hematopoietic stem cell transplantation (HSCT) augments a normal bone marrow, and bone density gradually normalises over the course of a few months after transplantation. Prognosis: bone marrow failure is potentially lethal in infancy – if untreated, usually fatal by 10 years of age. HSCT can be curative for bone marrow failure as well as osteosclerosis, but not for neurodegeneration. HSCT should be undertaken as soon as possible after diagnosis, ideally in the first few months of life. Affected individuals also may show progressive deafness, blindness, dental abnormalities and increased risk of mandibular osteomyelitis. Differential diagnosis: neonates with normal (physiological) neonatal osteosclerosis may be misdiagnosed with ARO. In the neonatal period, ARO is indistinguishable from dysosteosclerosis (p. 398). Pycnodysostosis (p. 394) shows generalised osteosclerosis but no metaphyseal fraying or undermodelling.

 

 

 

CASES 1–5: All cases show generalised osteosclerosis. Metaphyseal undermodelling is seen in Cases 2–5, particularly prominent in Case 4. Metaphyseal irregularities (osteopetrorickets) are seen in Cases 3 and 5. Case 3 shows a bone-in-bone appearance and periosteal reaction–like changes. Case 4 shows notching of the anterior vertebral bodies (prominence of the nutritional vascular canal).

390

Fetal and Perinatal Skeletal Dysplasias

 

 

 

 

 

 

Osteopetrosis, Neonatal or Infantile Forms, TCRG1-, CLCN7- and SNX10-Related

 

391

 

 

 

 

 

 

CASE 6: A neonate with TCIRG1 mutations. There is generalised osteosclerosis and a ragged appearance of the metaphyses of the long bones.

392

Fetal and Perinatal Skeletal Dysplasias

 

 

 

 

CASE 7: A neonate with biallelic mutation in CLCN7 (neuropathic osteopetrosis). Skeletal survey (a–d) shows generalised osteosclerosis but not metaphyseal undermodelling. MR images (e, f: T1 imaging at 1 month and FLAIR imaging at 2 months) show a signal change (T1 high intensity) in the white matter anterior to the anterior horn of the lateral ventricle and progressive brain atrophy.

BIBLIOGRAPHY Aker M, Rouvinski A, Hashavia S et al. An SNX10 mutation causes malignant osteopetrosis of infancy. J Med Genet. 2012; 49: 221–6. Besbas N, Draaken M, Ludwig M et al. A novel CLCN7 mutation resulting in a most severe form of autosomal recessive osteopetrosis. Eur J Pediatr. 2009; 168: 1449–54. Boudin E, Van Hul W. Sclerosing bone dysplasias. Best Pract Res Clin Endocrinol Metab. 2018; 32: 707–23.

George A, Zand DJ, Hufnagel RB et al. Biallelic mutations in MITF cause coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness. Am J Hum Genet. 2016; 99: 1388–94. Iida A, Xing W, Docx MK et al. Identification of biallelic LRRK1 mutations in osteosclerotic metaphyseal dysplasia and evidence for locus heterogeneity. J Med Genet. 2016; 53: 568–74.

Osteopetrosis, Neonatal or Infantile Forms, TCRG1-, CLCN7- and SNX10-Related Pangrazio A, Cassani B, Guerrini MM et al. RANK-dependent autosomal recessive osteopetrosis: Characterization of five new cases with novel mutations. J Bone Miner Res. 2012; 27: 342–51. Penna S, Capo V, Palagano E et al. One disease, many genes: Implications for the treatment of osteopetroses. Front Endocrinol (Lausanne). 2019; 10: 85. Stark Z, Savarirayan R. Osteopetrosis. Orphanet Journal of Rare Diseases. 2009; 4: 5.

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Villa A, Guerrini MM, Cassani B et al. Infantile malignant, autosomal recessive osteopetrosis: The rich and the poor. Calcif Tissue Int. 2009; 84: 1–12. Wu CC, Econs MJ, DiMeglio LA et al. Diagnosis and management of osteopetrosis: Consensus guidelines from the osteopetrosis working group. J Clin Endocrinol Metab. 2017; 102: 3111–23.

78 Pycnodysostosis, CTSK-Related

Synonyms: pycnodysostosis PYCD, Maroteaux-Lamy syndrome Confirmation of diagnosis: identification of biallelic pathogenic variants in the CTSK gene Frequency: fewer than 1 in 100,000 Genetics: PYCD is an autosomal recessive disease caused by mutations in CTSK, mapped on 1q21.3 and encoding cathepsin K, a lysosomal enzyme secreted by osteoclasts belonging to the cysteine protease family and necessary for the degradation of the bone matrix. Age/Gestational week of manifestation: affected individuals usually present in late infancy and early childhood. Fetal and perinatal diagnosis is uncommon, occasionally detectable by ultrasound during the second trimester (20 weeks).

normal lengths in the second trimester without modification of bone shape. Mild, non-specific long bone shortening may be visualised in the third trimester. Radiographic features: there is generalised bone sclerosis with bone fragility. Pathological fractures may lead to spondylolysis of the lumbar spine. The skull shows wide sutures and fontanelles with multiple Wormian bones. The facial bones are small. The mandible is straight with an obtuse mandibular angle. The clavicles are short and laterally hypoplastic. There is notching of the anterior borders of the vertebral bodies (prominent nutritional canals). The long bones are overmodelled and slender with relatively wide metaphyses. The ilia show a supra-acetabular indentation. Acro-osteolysis becomes manifest in later infancy and early childhood. In the neonatal period the distal phalanges are pointed. Craniosynostosis has been reported.

• Craniofacial dysmorphism (wide skull, persistence of the anterior fontanelle, exophthalmos, blue sclerae, pinched nose, anteverted nares, obtuse mandibular angle) • Short stature • Bone fragility • Short and bulbous distal phalanges with hypoplastic nails, not apparent as neonates

Prognosis: the disease is not usually progressive, and the prognosis is favourable. The main medical problems are short stature (135–150 cm in the adult), susceptibility for fractures, predisposition to osteomyelitis (often of the mandible) and dental abnormalities (delayed tooth eruption, persistence of deciduous teeth, decayed and abnormally shaped teeth). Haematological problems have been reported but are extremely rare. Upper airway obstruction is a common feature in pycnodysostosis and may cause obstructive sleep apnoea. Continuous positive airway pressure (CPAP) may be needed in a few cases. Spondylolisthesis, scoliosis and obesity have been described in the course of the disease.

Prenatal ultrasound features: prenatal diagnosis has not been reported. The clinical hallmarks that are potentially detectable, but not diagnosable, in the second trimester include craniofacial disproportion due to underdeveloped facial bones, micrognathia and prominence of the frontal and parietal bones associated with wide cranial sutures and fontanelles. These are better detected by three-dimensional ultrasound. Careful evaluation may identify clavicular hypoplasia. Limb bones have

Differential diagnosis: the combination of generalised osteosclerosis, delayed closure of the cranial sutures and acro-osteolysis is so unique that the diagnosis is straightforward. However, PYCD may be misdiagnosed as osteopetrosis (p. 394) before the development of acro-osteolysis. The combination of wide sutures with acro-osteolysis or hypoplasia of the terminal phalanges is seen in cleidocranial dysplasia (p. 482), Hajdu-Cheney syndrome (p.) and mandibuloacral dysplasia. However, these disorders do not show osteosclerosis.

Clinical features:

394

DOI: 10.1201/9781003166948-84

Pycnodysostosis, CTSK-Related

395

 

 

 

 

CASE 1: An infant. Skeletal survey shows generalised osteosclerosis, overmodelling of the tubular bones, supra-acetabular constriction, pronounced anterior notches of vertebral bodies, a large anterior fontanelle, straight mandibular angle and hypoplastic distal phalanges (a–f). He underwent bone marrow transplantation at age 6 months, which normalised bone densities at 17 months (g, h).

396

Fetal and Perinatal Skeletal Dysplasias

 

 

 

 

  CASE 2: The younger sibling of Case 1. CASE 3: An 8-month-old infant. The radiological features resemble those of Cases 1 and 2. Acro-osteolysis is manifest in the distal phalanges of the index fingers (d, e).

Pycnodysostosis, CTSK-Related

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  CASE 4: A fetus. There is generalised osteosclerosis, overmodelled long bones and supra-acetabular constriction.

BIBLIOGRAPHY Araujo TF, Ribeiro EM, Arruda AP et al. Molecular analysis of the CTSK gene in a cohort of 33 Brazilian families with pycnodysostosis from a cluster in a Brazilian northeast region. Eur J Med Res. 2016; 21: 33. Arman A, Bereket A, Coker A et al. Cathepsin K analysis in a pycnodysostosis cohort: Demographic, genotypic and phenotypic features. Orphanet J Rare Dis. 2014; 9: 60. Bizaoui V, Michot C, Baujat G et al. Pycnodysostosis: Natural history and management guidelines from 27 French cases and a literature review. Clin Genet. 2019; 96: 309–16. Doherty MA, Langdahl BL, Vogel I et al. Clinical and genetic evaluation of Danish patients with pycnodysostosis. Eur J Med Genet. 2021; 64: 104135.

Ihde LL, Forrester DM, Gottsegen CJ et al. Sclerosing bone dysplasias: Review and differentiation from other causes of osteosclerosis. Radiographics. 2011; 31: 1865–82. Khirani S, Amaddeo A, Michot C et al. Sleep-disordered breathing in children with pycnodysostosis. Am J Med Genet A. 2020; 182: 122–9. Novinec M, Lenarčič B. Cathepsin K: A unique collagenolytic cysteine peptidase. Biol Chem. 2013; 394: 1163–79. Thomas GPL, Magdum SA, Saeed NR et al. Multisuture craniosynostosis and papilledema in pycnodysostosis: A paradox? J Craniofac Surg. 2019; 30: 110–114. Xue Y, Cai T, Shi S et al. Clinical and animal research findings in pycnodysostosis and gene mutations of cathepsin K from 1996 to 2011. Orphanet J Rare Dis. 2011; 6: 20.

79 Dysosteosclerosis, SLC29A3-, TNFRSF11A- and CSF1R-Related

Synonyms: DOS; brain abnormalities neurodegeneration and dysosteosclerosis (BANDDOS) Confirmation of diagnosis: identification of biallelic pathogenic variants in the SLC29A3, CSF1R and RANK genes and rarely those in the RANKL and TCIRG1 genes Frequency: fewer than 30 cases reported in the literature Genetics: DOS encompasses a genetically heterogenous group of autosomal recessive disorders. The disease-causing genes include SLC29A3, CSF1R, TNFRSF11A (encoding RANK), TNFSF11 (encoding RANKL) and TCIRG1. SLC29A3 is mapped on 10q22.1 and encodes a lysosomal nucleoside transporter termed ENT3. Mutations in SLC29A3 are responsible not only for DOS but also hereditary histiocytosis (histiocytosis-lymphadenopathy-plus syndrome). CSF1R is mapped on 5q32 and encodes a tyrosine kinase growth factor receptor for colony-stimulating factor 1. The biallelic mutations are related to BANDDOS, while monoallelic mutations are related to a neurodegenerative disorder (hereditary diffuse leukoencephalopathy with spheroids). RANK and RANKL are well-known molecules that play a pivotal role in osteoclastogenesis, and they are responsible for subtypes of autosomal recessive osteopetrosis (OPTB7 and OPTB2, where OPTB refers to osteopetrosis autosomal recessive, while OPTA refers to osteopetrosis autosomal dominant). TCIRG1 is a disease-causing gene for the most common autosomal recessive osteopetrosis (OPTB1). Partial loss-of-function mutations in TCIRG1 seem to be responsible for DOS. Age/Gestational week of manifestation: generally perinatal. Prenatal diagnosis is difficult, can be potentially detected by ultrasound during the second to third trimester (20–27 weeks). Clinical features: • Short stature • Bone fragility • Dental anomalies (impaired eruption of both deciduous and permanent teeth, malaligned teeth, enamel hypoplasia)

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• Optic atrophy either due to optic canal stenosis or neurodegeneration • Neurodegeneration and developmental delay: neurodegeneration may represent a consequence of BANDDOS, but mild developmental delay is reported in SLC29A3 mutations • Patchy skin atrophy: this manifestation is likely to be a result of SLC29A3 mutations Prenatal ultrasound features: the diagnosis by prenatal ultrasound has not been reported. Short, bowed long bones in the second to third trimester may suggest the diagnosis in the fetus of a mother with a previously affected child; platyspondyly is unlikely to be identified on prenatal ultrasound. Radiographic features: the skeletal manifestations are indistinguishable from infantile osteopetrosis, other than the presence of mild platyspondyly. In most cases, platyspondyly develops during infancy and early childhood. Platyspondyly is usually modest. Increased bone density is generalised in the neonatal period. However, osteosclerosis may improve with age. The pattern of osteosclerosis evolves from initial homogeneous sclerosis, through a distinctive pattern of alternating sclerotic and lucent zones (sclerosis of the epimetaphysis – osteopenia in the metadiaphyseal junction – sclerosis of the diaphysis), to localised sclerosis confined to the metaphysis. The metaphyses show striking widening with undermodelling (Erlenmeyer flask deformity). The vertebral bodies initially show uniform sclerosis and later endplate sclerosis (sandwich vertebrae or ‘rugger jersey’ vertebrae). Prognosis: the prognosis is guarded. Affected individuals develop short stature, progressive deformity with increased bone fragility and dental anomalies. Neurodegeneration in BANDDOS is variable, ranging from rapid regression in early childhood to late onset in adulthood. Bone marrow failure is not common but can occur. Other than optic atrophy, cranial nerve palsy is uncommon. Differential diagnosis: the differential diagnosis between DOS and infantile osteopetrosis (p. 388) may be impossible in the neonatal period and early infancy.

DOI: 10.1201/9781003166948-85

Dysosteosclerosis, SLC29A3-, TNFRSF11A- and CSF1R-Related

399

 

 

 

 

 

CASE 1: An infant with blindness, developmental delay, failure to thrive, dysplastic pulmonary valves and pulmonary hypertension. CT and MRI scans of the brain confirmed ventriculomegaly, and a ventriculoperitoneal shunt was inserted. She died of an overwhelming respiratory infection at age 2 years. Radiographs in the neonatal period (a–c, g) show sclerosis and frayed metaphyses, but not platyspondyly. Radiographs at 9 months (d–f, h) show generalised sclerosis with transverse striations, expansion of the metaphyses and minimal vertebral flattening with anterior notching of the vertebral bodies.

400

Fetal and Perinatal Skeletal Dysplasias

 

 

 

CASE 2: An 11-month-old boy with osteosclerosis, and there are alternating sclerotic and lucent bands at the metadiaphyseal junctions of the long bones. The long bones show metaphyseal undermodelling. There is platyspondyly with coronal clefts of the lumbar spine. CASE 3: A child with BANDDOS. (a) At birth, the skeleton is uniformly sclerotic, and the metaphyses of the long bones are ragged. (b–f) At 4 years, the metaphyses are sclerotic, while the diaphyses are radiolucent. There is metaphyseal undermodelling (club shaped) and platyspondyly. CT shows ventriculomegaly and periventricular calcifications.

Dysosteosclerosis, SLC29A3-, TNFRSF11A- and CSF1R-Related

 

401

 

 

 

 

CASE 4: A 4-month-old boy with TNFSF11 mutations. Osteosclerosis is almost uniform. However, the metaphyses of the long bones show irregularity and alternating sclerotic and lucent transverse bands. Mild platyspondyly is seen. The pubic rami are fractured.

402

Fetal and Perinatal Skeletal Dysplasias

 

 

BIBLIOGRAPHY Campeau PM, Lu JT, Sule G et al. Whole-exome sequencing identifies mutations in the nucleoside transporter gene SLC29A3 in dysosteosclerosis, a form of osteopetrosis. Hum Mol Genet. 2012; 21: 4904–9. Elcioglu NH, Vellodi A, Hall CM. Dysosteosclerosis: A report of three new cases and evolution of the radiological findings. J Med Genet. 2002; 39: 603–7. Guo L, Elcioglu NH, Karalar OK et al. Dysosteosclerosis is also caused by TNFRSF11A mutation. J Hum Genet. 2018; 63: 769–74. Guo L, Bertola DR, Takanohashi A et al. Bi-allelic CSF1R mutations cause skeletal dysplasia of dysosteosclerosis-Pyle disease spectrum and degenerative encephalopathy with brain malformation. Am J Hum Genet. 2019; 104: 925–35.

Howaldt A, Nampoothiri S, Quell LM et al. Sclerosing bone dysplasias with hallmarks of dysosteosclerosis in four patients carrying mutations in SLC29A3 and TCIRG1. Bone. 2019; 120: 495–503. Kobayashi K, Goto Y, Kise H et al. A case report of dysosteosclerosis observed from the prenatal period. Clin Pediatr Endocrinol. 2010; 19: 57–62. Whyte MP, Wenkert D, McAlister WH et al. Dysosteosclerosis presents as an “osteoclast-poor” form of osteopetrosis: Comprehensive investigation of a 3-year-old girl and literature review. J Bone Miner Res. 2010; 25: 2527–39. Xue JY, Wang Z, Smithson SF et al. The third case of TNFRSF11Aassociated dysosteosclerosis with a mutation producing elongating proteins. J Hum Genet. 2021; 66: 371–7.

80 Raine Dysplasia, FAM20C-Related

Synonyms: RNS; osteosclerotic bone dysplasia, lethal; osteomalacia, sclerosing, with cerebral calcification; CSOCC Confirmation of diagnosis: identification of biallelic pathogenic variants in the FAM20C gene Frequency: very rare, less than 1 in 1,000,000 Genetics: RNS is an autosomal recessive disorder due to homozygous or compound heterozygous pathogenic variants in FAM20C (family with sequence similarity 20, member C), also known as DMP4 (a dentin matrix protein). FAM20C is a Golgilocalised protein kinase that plays a pivotal role in phosphorylation of more than 100 secreted proteins, including bone proteins, and is essential for mineralisation of bone. Pathogenic variants cause either mislocalisation of the protein or kinase domain loss of function. Hypophosphorylation of FAM20C targets is the cause of both lethal and non-lethal phenotypes. In milder phenotypes, the protein would preserve its folding and secretion properties but would have a diminished kinase activity. Age/Gestational week of manifestation: can be suspected on ultrasound during the second trimester. Clinical features: affected individuals show severe skull deformities, distinctive facial appearance and brain malformation. The craniofacial dysmorphism is partly accounted for by craniosynostosis. • Microcephaly, calvarial deformities (brachycephaly, turribrachycephaly, turridolichocephaly, cloverleaflike skull); wide sutures and fontanelles • Facial abnormalities: markedly depressed nasal bridge, severe midface hypoplasia, severe proptosis, hypertelorism, nasal hypoplasia, low-set ears • Choanal atresia • Cleft palate, gum hypertrophy • Brain abnormalities: intracerebral calcifications, hydrocephalus, hypoplastic posterior fossa, small cerebellum, encephalocele • Hypoplastic lungs

DOI: 10.1201/9781003166948-86

Prenatal ultrasound features: ultrasound in the second trimester, particularly if 3D, may show facial dysmorphism with hypertelorism, prominent eyes, depressed nasal bridge, a flat profile, a small and pointed nose, bowed and everted lips, a small triangular mouth associated with microretrognathia and low-set ears. Cleft palate may be visualised early in the second trimester, mostly with the use of 3D ultrasound and volume contrast imaging and OmniView ultrasound technologies. Later, at the end of the second trimester, turricephaly and frontal bossing, cloverleaf-shaped skull, cataract and intracerebral calcification become apparent. Widespread focal cerebral ­calcifications (punctiform hyperechogenicity) are mainly identified in the basal ganglia and periventricular white matter. The cerebellum looks ill-defined with a small cisterna magna as a consequence of a hypoplastic posterior fossa. Osteosclerosis is present with variable severity, identified by sonography as ‘cotton flakes’ of the long bones. Irregular periosteal thickenings are present along the diaphyses of the long bones, clavicles, scapulae and ribs resembling pseudofractures. Polyhydramnios may develop in the third trimester. Fetal MRI and fetal CT scan may confirm the ultrasound findings, revealing other anomalies not detectable by ultrasound. Radiographic features: the hallmarks include generalised osteosclerosis with mild metaphyseal undermodelling and variable amounts of periosteal new bone formation affecting the long bones, mandible, ribs and clavicles. The periosteal hyperostosis is well remodelled and only mildly irregular in the late gestation, while it may manifest as speculated sclerosis in the early gestation. Craniosynostosis leads to variable skull deformities ranging from brachycephaly through turribrachycephaly and turridolichocephaly to severe cloverleaf-like deformity and causes ventriculomegaly. The cranial sutures and fontanelles are widely open, which may be associated with meningocele and encephalomeningocele. The skull base and facial bones are sclerotic. The mandible shows an obtuse angle. Intracranial calcifications are a diagnostic clue to RNS. Punctate calcifications in the cartilage and brachytelephalangy may be present. Prognosis: there are two main phenotypes, one lethal and one non-lethal. The former is usually lethal perinatally due to respiratory failure as a result of the combination of choanal atresia and pulmonary hypoplasia. The latter is a milder form, which is associated with osteosclerosis and possible osteomalacia and osteonecrosis and respiratory problems. Intellectual disability

403

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Fetal and Perinatal Skeletal Dysplasias

is common, although normal development is reported in some young children. Other common issues include hearing and visual impairment, dysphagia and amelogenesis imperfecta. Differential diagnosis: RNS should be differentiated from prenatal/perinatal sclerosing dysplasias: Caffey disease pre/perinatal presentation (p. 411); dysplastic cortical hyperostosis (Kozlowski-Tsuruta) (p. 416); lethal neonatal short limb dysplasia (AlGazali) (p. 418); osteopetrosis (p. 388); pyknoachondrogenesis

(a lethal osteochondrodysplasia-like achondrogenesis but associated with the additional feature of extreme sclerosis of bones). Blomstrand dysplasia (p. 464); desmosterolosis (a rare disorder of cholesterol biosynthesis); Lenz-Majewski syndrome (p. 426). Spiculated periosteal bone formation in the early gestation may be like that of mucolipidosis II (I-cell disease) (p. 348). The combination of punctate calcification and brachytelephalangy may lead to a misdiagnosis of CDPX1 (p. 352), but the presence of brain calcification helps with differentiation.

 

  CASE 1: This baby was the third child of unrelated parents with no significant family history. He was born at 37 weeks’ gestation but died within 24 hours of respiratory failure. He showed marked brachycephaly with wide fontanels and sutures and facial dysmorphism, including a flat midface and prominent eyes. Radiographs (a–f) show generalised increased bone density with mild metaphyseal undermodelling and diaphyseal cortical irregularities. The skull is brachycephalic with wide sutures. The skull base and facial bones are sclerotic. The mandibular angle is obtuse.

Raine Dysplasia, FAM20C-Related

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CASE 2: A longer survivor. Clinically there is severe craniofacial dysmorphism (turribrachycephaly, depressed nasal bridge, hypertelorism, proptosis, downslanting palpebral fissures, short nose, long philtrum, downturned corners of the mouth and micrognathia). Radiographs in infancy (b–h) show craniofacial sclerosis, diaphyseal sclerosis with some cortical irregularities, metaphyseal radiolucency (trophic changes due to postnatal illness) and brachytelephalangy. (i) Brachytelephalangy is clearly seen on the radiograph at age 2 years. (d) Cranial CT shows brain calcifications and meningocele protruding through wide fontanelles.

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Fetal and Perinatal Skeletal Dysplasias

 

 

CASE 3: A neonate. Radiographs (a, b) show generalised sclerosis and metadiaphyseal cortical irregularity of the long bones. Three-dimensional CT and coronal CT (c, d) show severe turridolichocephaly wide fontanelles, meningoencephalocele, ventriculomegaly and faint brain calcifications. CASE 4: A 24-week-gestation fetus had dysmorphic facies with proptosis and everted lower eyelids. The postmortem radiograph shows spiculated periosteal new bone affecting most of the skeleton (a manifestation in the early gestational age of RNS).

Raine Dysplasia, FAM20C-Related

BIBLIOGRAPHY Chitayat D, Shannon P, Keating S et al. Raine syndrome: A rare lethal osteosclerotic bone dysplasia. Prenatal diagnosis, autopsy, and neuropathological findings. Am J Med Genet A. 2007; 143A: 3280–5. Elalaoui SC, Al-Sheqaih N, Ratbi I et al. Non lethal Raine syndrome and differential diagnosis. Eur J Med Genet. 2018; 59: 577–83. Faundes V, Castillo-Taucher S, Gonzalez-Hormazabal P et al. Raine syndrome: An overview. Eur J Med Genet. 2014; 57: 536–42. Fradin M, Stoetzel C, Muller J et al. Osteosclerotic bone dysplasia in siblings with a FAM20C mutation. Clin Genet. 2011; 80: 177–83. Hülskamp G, Wieczorek D, Rieder H et al. Raine syndrome: Report of a family with three affected sibs and further delineation of the syndrome. Clin Dysmorphol. 2003; 12: 153–60. Koob M, Doray B, Fradin M et al. Raine syndrome: Expanding the radiological spectrum. Pediatr Radiol. 2011; 41: 389–93. Mameli C, Zichichi G, Mahmood N et al. Natural history of nonlethal Raine syndrome during childhood. Orphanet J Rare Dis. 2020; 15: 93.

407 Palma-Lara I, Pérez-Ramirez M, García Alonso-Thermann P et al. FAM20C overview: Classic and novel targets, pathogenic variants and Raine syndrome phenotypes. Int J Mol Sci. 2021; 22: 8039. Simpson MA, Hsu R, Keir LS et al. Mutations in FAM20C are associated with lethal osteosclerotic bone dysplasia (Raine syndrome), highlighting a crucial molecule in bone development. Am J Hum Genet. 2007; 81: 906–12. Simpson MA, Scheuerle A, Hurst J et al. Mutations in FAM20C also identified in non-lethal osteo-sclerotic bone dysplasia. Clin Genet. 2009; 75: 271–6. Tamai K, Tada K, Takeuchi A et al. Fetal ultrasonographic findings including cerebral hyperechogenicity in a patient with non-lethal form of Raine syndrome. Am J Med Genet A. 2018; 176: 682–6. Whyte MP, McAlister WH, Fallon MD et al. Raine syndrome (OMIM #259775), caused by FAM20C mutation, is congenital sclerosing osteomalacia with cerebral calcification (OMIM 259660). J Bone Miner Res. 2017; 32: 757–69. Wang X, Wang S, Li C et al. Inactivation of a novel FGF23 regulator, FAM20C, leads to hypophosphatemic rickets in mice. PLoS Genet. 2012; 8: e1002708.

81 Caffey Disease (Including Infantile and Attenuated Forms), COL1A1-Related

Synonyms: infantile cortical hyperostosis (ICH) Confirmation of the diagnosis: characteristic clinical and radiological findings and identification of the specific pathogenic variant (c.3040C>T) in the COL1A1 gene Frequency: unknown. However, over 1,000 cases have been reported Genetics: autosomal dominant disorder due to a disease-specific, heterozygous, pathogenic variant in the COL1A1 gene (c.3040C>T; p.Arg1014Cys). The penetrance is incomplete, and expressivity is variable. COL1A1 is mapped on 17q21.33 and encodes the α-1 chain of type 1 collagen. Type 1 collagen is the major collagen of skin, tendons and bone. Age/Gestational week of manifestation: can occasionally be detected prenatally by ultrasound during the late third trimester; sometimes at birth; more commonly between 6 weeks and 6 months of age. Clinical features: • Deformity and occasionally bowing of the affected bones due to diaphyseal hyperostosis • Bowed tibia • Prominent mandible due to mandibular hyperostosis • Hot, tender swelling of involved bones with increased acute reactants (ERR, CRP, WBC) Prenatal ultrasound features: prenatal cortical/periosteal hyperostosis manifests as thickened, irregular diaphyses with increased echogenicity and floccular outline. Even if mild, forms may be suspected at the end of the second trimester, but prenatal diagnosis is challenging. Radiographic features: polyostotic periosteal new bone formation and eventual hyperostosis affecting the diaphyses of

408

various long bones but sparing the metaphyses: asymmetric bone involvement in the classic and COL1A1 forms contrasts with symmetric involvement in the prenatal form. However, a single case with prenatal onset of COL1A1 form had symmetric bone involvement. New bone formation also affects the mandible, scapulae, ribs and clavicles. These bones as well as the ulnae are commonly affected in the classic form. By contrast, the scapulae, ribs and clavicles are rarely involved in the COL1A1 form. Prognosis: viable. Usually appears perinatally to early infancy and resolves spontaneously by 2 years of age. The acute inflammatory feature spontaneously resolves over a few weeks. Symptoms are acute, mainly represented by pain and swelling, often located in the lower limbs or jaw, sometimes accompanied by fever and irritability. Diaphyseal hyperostosis usually disappears before the age of 1–2 years, while bowing gradually remodels during early childhood. The mandible is almost always affected. Occasionally long-term complications can occur, particularly cross-fusion of the paired long bones (radius/ulna and tibia/fibula) when involved. Asymmetry of the limbs and scoliosis rarely occur. Recurrence of periosteal bone formation in later life has been described, and in one case tumoral calcinosis has been reported after repeated inflammatory events. Differential diagnosis: ICH should be differentiated from disorders with periosteal new bone formation as neonates or in infancy: lethal Caffey, a more severe condition which usually has an earlier onset in the second to third trimester of pregnancy; non-accidental childhood injury; prostaglandin-E osteopathy; congenital syphilis; neonatal lysosome storage diseases: mucolipidosis type II (I-cell disease) (p. 348) and GM1 gangliosidosis; FGF23-related hyperphosphatemic hyperostosis/tumoral calcinosis, a rare, heterogeneous recessive disorder associated with pathogenic variants in the genes FGF23, GALNT3 and KL; chronic recurrent multifocal osteomyelitis; marrow infiltrative disorders. There is a single case report that fetuin A deficiency caused ICH.

DOI: 10.1201/9781003166948-87

Caffey Disease (Including Infantile and Attenuated Forms), COL1A1-Related

 

 

 

 

409

 

 

 

 

 

 

 

CASE 1: A child with a family history of an affected mother, maternal grandfather and great uncle. A mutation of p.Arg836Cyts in COL1A1 was found. Radiographs at age 2 days show severe diaphyseal hyperostosis and bowing of the tibiae (a–c). Radiographs at age 7 months reveal rapid remodelling of hyperostosis and involvement of the radii and ulna. CASE 2: A 2-month-old-infant with p.Arg836Cys in COL1A (a–f). The mandible, clavicles, scapulae and ribs are normal. Diaphyseal hyperostosis is seen in the left femur, right tibia and both ulnae. The right tibia is laterally bowed.

410

BIBLIOGRAPHY Chapman T, Menashe SJ, Taragin BH. Radiographic overlap of recurrent Caffey disease and chronic recurrent multifocal osteomyelitis (CRMO) with considerations of molecular origins. Pediatr Radiol. 2020; 50: 618–27. Darmency V, Thauvin-Robinet C, Rousseau T et al. Contribution of three-dimensional computed tomography in prenatal diagnosis of lethal infantile cortical hyperostosis (Caffey disease). Prenat Diagn. 2009; 29: 892–4. Guerin A, Dupuis L, Mendoza-Londono R. Caffey Disease. 2012 Aug 2 [updated 2019 Jun 13]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2020. Gensure RC, Mäkitie O, Barclay C et al. A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders. J Clin Invest. 2005; 115: 1250–7. Issa El Khoury F, Kreichati G, Kharrat K, Ghanem I. Tumoral calcinosis of the cervical spine and its association with Caffey disease in a 4-month-old boy: Case report and review of the literature. J Pediatr Orthop B. 2012; 21: 286–91.

Fetal and Perinatal Skeletal Dysplasias Kamoun-Goldrat A, Martinovic J, Saada J et al. Prenatal cortical hyperostosis with COL1A1 gene mutation. Am J Med Genet A. 2008; 146A: 1820–4. Lee DY, Kim WJ, Kim B, et al. Differential diagnosis between child abuse and infantile cortical hyperostosis: A case report and literature review. Int J Environ Res Public Health. 2021; 22; 18: 12269. Merdler-Rabinowicz R, Grinberg A, Jacobson JM et al. Fetuin-A deficiency is associated with infantile cortical hyperostosis (Caffey disease). Pediatr Res. 2019; 86: 603–7. Nemec SF, Rimoin DL, Lachman RS. Radiological aspects of prenatal-onset cortical hyperostosis [Caffey dysplasia]. Eur J Radiol. 2012; 81: e565–72. Nistala H, Mäkitie O, Jüppner H. Caffey disease: New perspectives on old questions. Bone. 2014; 60: 246–51. Shandilya R, Gadre KS, Sharma J et al. Infantile cortical hyperostosis (Caffey disease): A case report and review of the literature–Where are we after 70 years? J Oral Maxillofac Surg. 2013; 71: 1195–201.

82 Caffey Dysplasia (Severe Lethal Variant)

Synonyms: prenatal onset of cortical hyperostosis (PCH) Confirmation of diagnosis: on clinical and radiological grounds Frequency: very rare, fewer than 50 cases reported Genetics: although the causal gene is currently unknown, it is presumed that it might be a monogenic autosomal recessive disorder on the grounds of reports of affected siblings born to healthy parents. It is not completely excluded that a subset of affected individuals may have in utero acquired conditions. In only one case, the specific COL1A1 variant (c.3040C>T; p.Arg1014Cys) associated with infantile cortical hyperostosis was detected. Age/Gestational week of manifestation: the manifestations may be detected by ultrasound during the second trimester (14–20 weeks). Clinical features: • Polyhydramnios; hydrops; hepatosplenomegaly • Deformity of the affected bones due to diaphyseal hyperostosis • Occasionally severe bowing and shortening of affected long bones • In utero systemic inflammation: cord blood with leucocytosis, neutrophilia, increased levels of hepatic enzymes Prenatal ultrasound features: PCH can be severe (with onset before 35 weeks’ gestation) or mild (with onset after 35 weeks). Most fetuses with the severe type are detected mainly from associated anomalies or complications of polyhydramnios (from 14 weeks of gestation, but on average around the 27th week), fetal hydrops, skin oedema and hepatosplenomegaly. The earliest ultrasound signs of limb bowing and shortening have been reported at 14 weeks of gestation in an at-risk pregnancy. The long bones appear short and bowed/angulated, showing an ab-

DOI: 10.1201/9781003166948-88

normal irregular diaphyseal thickening. Increased echogenicity and swollen, floccular contour of the long bones (periosteal hyperostosis) represent typical signs of the disease. In severe cases, also the ribs, mandible, scapulae and clavicles are involved. Large abdomen with or without ascites. Fetal movements may be reduced. The combination of ultrasound and fetal radiographs (including 3D CT) is diagnostic. Radiographic features: PCH, unlike classic Caffey disease, manifests with symmetrical periosteal new bone formation of the diaphyses. The long bones usually show irregular diaphyseal expansion. The irregular periosteal hyperostosis can be well remodelled with age, and later the long bones may be short, bowed, undermodelled and smooth in outline. The short tubular bones are relatively unaffected. The scapulae are overgrown and sclerotic. The clavicles are seldom affected. The ribs are wide. The ilia are rounded with some central sclerosis. The skull is brachycephalic with wide sutures. There is sclerosis and overgrowth of the skull base, facial bones and mandible. The spine appears normal. Prognosis: usually prenatally lethal. Intensive neonatal care is required for surviving individuals, who might show nearly complete remodelling of diaphyseal hyperostosis and bowing. Differential diagnosis: PCH should be differentiated from disorders with prenatal diaphyseal hyperostosis or prenatal bowing. The former includes Raine syndrome (p. 403), dysplastic cortical hyperostosis, Kozlowski-Tsuruta type (p. 416), lethal neonatal short limb dysplasia, al-Gazali type (p. 418), prenatal storage disease – mucolipidosis type 2 (I-cell disease) (p. 348) and GM1 gangliosidosis. Infantile Caffey disease (p. 411) may appear prenatally but usually much later in pregnancy or after birth; the mandible is almost always affected, while it is usually spared in the lethal form. The latter (prenatal long bone bowing) comprise osteogenesis imperfecta (p. 429), hypophosphatasia (p. 452) and Campomelic dysplasia (p. 302). Combination of irregular hyperostosis with diaphyseal expansion in utero tends to be misdiagnosed as multiple rib fractures and accordion-like long bones seen in severe osteogenesis imperfecta.

411

412

Fetal and Perinatal Skeletal Dysplasias

 

 

 

 

  CASE 1: US at 25 weeks of gestation. Referred because of polyhydramnios. (a) There was placental oedema, increased placental thickness and hyperechoic bowel. Fetal biometry showed an abdominal circumference on the 95th centile and long bones on the 3rd centile; (b) the unusual facial profile is the result of proptosis; (c) the fingers have a flocculent outline; (d) the humerus is short and thickened with irregular echogenicity and angulation – this could simulate callus secondary to fracturing (pseudofracture); (e) the tibia and fibula are short, bowed and thickened with irregular echogenicity; (f) the femur is short, straight and thickened; (g) intrauterine radiograph. The bones of the lower extremity are short, bowed and thickened; (h–j) skeletal survey showing periosteal cloaking of the mandible, scapulae, ribs and long bones.

413

Caffey Dysplasia (Severe Lethal Variant)

 

 

 

 

 

 

 

CASE 2: Periosteal new bone formation affecting the long bones and ribs in a symmetrical manner. The mandible is also involved. CASE 3: Severe hydrops and perinatally lethal. Symmetrical periosteal thickening involves the radii and ulnae (paired bones) and the mandible.

414

Fetal and Perinatal Skeletal Dysplasias

 

 

 

 

 

 

 

CASES 4, 5: Note short, broad, angulated long bones; thickened ribs; clavicles and scapulae; sclerotic, overgrown mandible; and sclerotic facial bones and skull base. The ilia are rounded with central sclerosis. The spine is spared. In contrast, Case 1 shows natal teeth, fractured humerus and coronal cleft vertebrae.

Caffey Dysplasia (Severe Lethal Variant)

BIBLIOGRAPHY Burton KR, Glanc P. Prenatal presentation of lethal variant infantile cortical hyperostosis (Caffey disease). Ultrasound Q. 2016; 32: 338–41. Darmency V, Thauvin-Robinet C, Rousseau T et al. Contribution of three-dimensional computed tomography in prenatal diagnosis of lethal infantile cortical hyperostosis (Caffey disease). Prenat Diagn. 2009; 29: 892–4. Drinkwater BM, Crino JP, Garcia J et al. Recurrent severe infantile cortical hyperostosis (Caffey disease) in siblings. Prenat Diagn. 1997; 17: 773–6. Kamoun-Goldrat A, Martinovic J, Saada J et al. Prenatal cortical hyperostosis with COL1A1 gene mutation. Am J Med Genet A. 2008; 146A: 1820–4.

415 Lécolier B, Bercau G, Gonzalès M et al. Radiographic, haematological, and biochemical findings in a fetus with Caffey disease. Prenat Diagn. 1992; 12: 637–41. Nemec SF, Rimoin DL, Lachman RS. Radiological aspects of prenatal-onset cortical hyperostosis [Caffey dysplasia]. Eur J Radiol. 2012; 81: e565–72. Schweiger S, Chaoui R, Tennstedt C et al. Antenatal onset of cortical hyperostosis (Caffey disease): Case report and review. Am J Med Genet A. 2003; 120A: 547–52. Wright JR, Van den Hof MC, Macken MB. Prenatal infantile cortical hyperostosis (Caffey’s disease): A ‘hepatic myeloid hyperplasia-pulmonary hypoplasia sequence’ can explain the lethality of early onset cases. Prenat Diagn. 2005; 25: 939–44.

83 Dysplastic Cortical Hyperostosis, Kozlowski-Tsuruta Type

Synonyms: none Confirmation of diagnosis: on clinical and radiological grounds Frequency: extremely rare – only two cases have been reported in the literature Genetics: the cause is unknown; parental consanguinity has been reported, and therefore autosomal recessive inheritance is a possibility Age/Gestational week of manifestation: can be detected by ultrasound during the second to third trimester.

Radiographic features: the long bones are short. There is striking symmetrical cortical thickening with cortical irregularity affecting the long bones, ribs and clavicles, giving the appearance of increased bone density. The mandible, scapulae, pelvis and spine do not show this new bone formation. Normal metaphyseal flaring of the long bones is relatively preserved. The skull is relatively small. The ribs are short, giving a small thorax. The ribs are irregularly expanded, while their posterior ends appear constricted. The metacarpals show proximal pointing. Ossification of the vertebral bodies is retarded. The vertebral bodies are mildly flat, and the lumbar spine may show multiple coronal clefts. Prognosis: prenatally or perinatally lethal.

Clinical features: • • • •

Polyhydramnios Hydrops Short trunk Rhizomelic limb shortening

Prenatal ultrasound features: the specific diagnosis has not been made prenatally. However, hydrops fetalis with a small chest and rhizomelic limb shortening have been reported at 25 weeks’ gestation. Bilateral pleural effusion, hepatomegaly and polyhydramnios were present. Findings include extensive cortical thickening of the long bones, ribs, clavicles and scapulae. There were coronal clefts of the lumbar vertebrae.

 

 

Differential diagnosis: Kozlowski-Tsuruta dysplastic cortical hyperostosis should be differentiated from prenatal severe sclerosing bone dysplasias: Raine syndrome (p. 403); desmosterolosis (rhizomelic limb shortening and generalised osteosclerosis, but also ambiguous genitalia, hypoplastic nasal bridge, cleft palate, thick alveolar ridges and gingival nodules); Caffey disease, infantile and lethal types (p. 411); lethal neonatal short limb dysplasia (Al-Gazali) (p. 418). Irregular cortical thickening may be mistaken for prenatal dysostosis multiplex: mucolipidosis 2 (I-cell disease) (p. 348); GM1-gangliosidosis type 1 (similar features to mucolipidosis 2; usually lethal in the first years of life, extensive Mongolian blue spots on the skin and retinal cherry red spots; caused by deficiency of beta-galactosidase-1 [GLB1]).

 

 

CASE 1: A fetus was terminated at 26 weeks’ gestation for ultrasound findings of hydrops, short limbs and a small thorax. The parents were Asian and first cousins. In addition, the mother’s parents were first cousins and the father’s parents second cousins. At postmortem there was a small thorax with lung hypoplasia, rhizomelic limb shortening, pleural effusions and a large left lobe of the liver. Note irregular cortical thickening of the clavicles, ribs and long bones. Normal metaphyseal flaring of the long bones is relatively preserved, except for the radius. Ossification of the vertebral bodies is mildly retarded. The lumbar spine shows multiple coronal clefts of vertebral bodies.

416

DOI: 10.1201/9781003166948-89

417

Dysplastic Cortical Hyperostosis, Kozlowski-Tsuruta Type

 

 

 

CASES 2: A stillbirth at 27 weeks of gestation was the second affected fetus of a consanguineous couple. There were microtia and wide fontanelles. CASE 3: A stillbirth at 22 weeks of gestation. Both fetuses show severe hydrops. They show irregular cortical hyperostosis of the clavicles, ribs and long bones. Ossification of the thoracic and lumbar vertebral bodies is defective in Case 2, while it is mild in Case 3.

BIBLIOGRAPHY Boudin E, Van Hul W. Sclerosing bone dysplasias. Best Pract Res Clin Endocrinol Metab. 2018; 32: 707–23. Kozlowski K, Tsuruta T. Dysplastic cortical hyperostosis: A new form of lethal neonatal dwarfism. Br J Radiol. 1989; 62: 376–8.

Suri M, Garret C, Winter RM et al. Dysplastic cortical hyperostosis (Kozlowski-Tsuruta syndrome): A report of a second case. Clin Dysmorphol. 2002; 11: 267–70.

84 Dysplastic Cortical Hyperostosis, Al-Gazali Type, ADAMTSL2-Related

Synonyms: Al-Gazali skeletal dysplasia Confirmation of diagnosis: identification of biallelic pathogenic variants in the ADAMTSL2 gene Frequency: extremely rare; only a few affected families are known, some unpublished Genetics: Al-Gazali skeletal dysplasia is an autosomal recessive disorder caused by homozygous or compound heterozygous mutations in ADAMTSL2, mapped on chromosome 9q34.2 and encoding the ADAMTSL2 protein. Mutations in the ADAMTSL2 gene are also responsible for autosomal recessive geleophysic dysplasia. It may be that Al-Gazali dysplasia is the severest phenotypic end of AR-geleophysic dysplasia on molecular and phenotypic grounds. ADAMTSL2 interacts with latent TGF-beta-binding protein-1. Dysregulation of TGF-beta signalling is partly responsible for the skeletal abnormalities of Al-Gazali and geleophysic dysplasias. Recurrence in a consanguineous family has been reported, and therefore autosomal recessive inheritance is most likely.

Prenatal ultrasound features: large biparietal diameter, brachycephaly, enlarged anterior fontanelle with widened sutures and Wormian bones, depressed nasal bridge and low-set ears can be detected by 2D and 3D ultrasound in the second trimester, as well as short long bones, very small hands and feet with brachydactyly and bilateral talipes equinovarus. Short ribs, small thorax and platyspondyly can be detected late in the second trimester. All these signs, even if correctly identified, are not sufficiently specific to allow a precise diagnosis. Radiographic features: there is generalised osteosclerosis. The long bones are short and undermodelled with smooth, rounded metaphyses. The skull is disproportionately large with widely open fontanelles and sutures and multiple Wormian bones. There is a wide biparietal diameter. The ribs and clavicles are short, resulting in a small thorax. The ribs are wide. There is delayed ossification of the pubic rami. The first metacarpals are short. There is bilateral talipes equinovarus. Prognosis: lethal. However, a longer-term survivor is known.

Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester. Clinical features: • Corneal clouding, short nose with depressed bridge, thin lips, low-set ears, atretic auditory canals • Polyhydramnios • Micromelia; short neck • Large head with wide anterior fontanelle and wide biparietal diameter • Severe brachydactyly; clubfeet

418

Differential diagnosis: dysplastic cortical hyperostosis (Kozlowski-Tsuruta) (p. 416); Caffey disease, lethal severe variant (p. 411); mucolipidosis 2 (I-cell disease) (p. 348). GM1gangliosidosis type 1: similar features to mucolipidosis 2, usually lethal in the first years of life, extensive Mongolian blue spots on the skin and retinal cherry red spots; caused by deficiency of beta-galactosidase-1 (GLB1). Raine dysplasia (p. 403). However, Al-Gazali dysplasia shows milder osteosclerosis and distinctive brachydactyly.

DOI: 10.1201/9781003166948-90

Dysplastic Cortical Hyperostosis, Al-Gazali Type, ADAMTSL2-Related

 

 

419

 

 

CASE 1: The parents of this fetus were double first cousins. The fetus had a large head with short limbs and short fingers and toes. There was bilateral talipes equinovarus and dysmorphic features consisting of a short nose with a depressed nasal bridge, atretic auditory canals and low-set ears. There was corneal clouding. There is generalised bone sclerosis; the long bones are short and undermodelled with smooth rounded metaphyses; large vault with wide sutures and multiple Wormian bones; broad ribs; delayed pubic ossification; short first metacarpal.

420

Fetal and Perinatal Skeletal Dysplasias

 

 

CASE 2: A neonate. The radiological changes of Cases 2 and 3 are identical to those of Case 1. Note severe brachydactyly with bullet-shaped phalanges and a triangular appearance of the first metacarpal. CASE 3: A stillbirth at 26 weeks of gestation.

BIBLIOGRAPHY Al-Gazali LI, Devadas K, Hall CM. A new lethal neonatal short limb dwarfism. Clin Dysmorphol. 1996; 5: 159–64.

Grigelioniene G, Papadogiannakis N, Conner P et al. Extending the phenotype of lethal skeletal dysplasia type Al Gazali. Am J Med Genet A. 2011; 155A: 1404–8.

85 Osteopathia Striata with Cranial Sclerosis, AMER1-Related

Synonyms: OSCS; hyperostosis generalisata with striations Confirmation of diagnosis: identification of heterozygous or hemizygous pathogenic variants (mutations) in the WTX gene Frequency: fewer than 100 cases Genetics: OSCS is an X-linked dominant disorder due to mutations in WTX, alternatively termed AMER1, mapped on Xq11 and encoding WTX (Wilms tumour X), alternatively termed APC (adenomatous polyposis coli) membrane recruitment protein 1. WTX is a repressor for Wnt/beta-catenin signalling and ultimately increases osteogenesis. It also collaborates in the binding of APC with the plasma membrane and the microtubular cytoskeleton. Somatic WTX mutations are associated with Wilms tumour. Age/Gestational age of manifestation: may be detected by ultrasound between the 14th and 22nd weeks of gestation related to the severity of the abnormalities. Clinical features: males present with more severe phenotypes than females. • Craniofacial dysmorphism (macrocephaly, frontal bossing, broad nasal bridge, hypertelorism, flat midface, cleft palate, micrognathia, malpositioned teeth) • Conductive hearing loss; occasionally cranial nerve compression • Intellectual disability, mild in affected females and severe in affected males • Other associated anomalies in severely affected females and affected males include hydrocephalus, brain malformation (hydrocephalus, hypoplasia of the corpus callosum), craniosynostosis, Pierre Robin sequence, laryngotracheomalacia, cleft lip, congenital heart defects, genitourinary anomalies, gastrointestinal anomalies (malrotation of the midgut, omphalocele, anal malformations, Hirschsprung disease), myopathy, vertebral anomalies, digital patterning defects, clubfoot Prenatal ultrasound features: prenatal diagnosis has been reported in only a few cases, mostly because of a positive family history, especially if the mother was affected. The ultrasound examination performed early in the second trimester or at 18– 22 weeks of gestation may detect multiple anomalies, including macrocephaly, craniofacial dysmorphism (prominent forehead, DOI: 10.1201/9781003166948-91

hypertelorism, flat nasal bridge, cleft palate, micro-retrognathia and glossoptosis), brain anomalies (ventriculomegaly, corpus callosum hypoplasia, cerebellar vermis agenesis), limb and acral anomalies (short femora, bilateral fibular aplasia/hypoplasia, clubfeet, ‘rocker bottom’ deformation, large thumbs from duplication of the distal phalanx), heart defects, gastrointestinal anomalies (intestinal malrotations, omphalocele anal atresia) and enlarged, hyperechogenic, poorly differentiated kidneys. Some malformations present in males are not very specific, for instance, Pierre Robin sequence, cardiac defects and gastrointestinal anomalies. Fetal or postmortem CT scan can demonstrate generalised osteosclerosis. Radiological features: affected females typically show overgrowth and sclerosis of the calvarium, skull base and to a lesser degree, the facial bones. There are sclerotic, longitudinal striations in the metadiaphyses of the long bones and radiating fanlike striations in the ilia and scapulae. The striations become more apparent during childhood. Severely affected females and affected males show generalised sclerosis, variable spinal involvement (cervical kyphosis, kyphoscoliosis), fibular aplasia/hypoplasia and digital patterning defects (e.g., polybracydactyly of the index finger, syndactyly of the middle and ring fingers, postaxial polydactyly, broad thumbs). There is wide intrafamilial variability. Prognosis: most affected males are stillborn or perinatally lethal. Longer-term survivors are severely retarded and require multidisciplinary medical care for their complex malformations as well as social support. Affected females show less severe, but highly variable, phenotypes. Laryngotracheomalacia is associated with a poor prognosis. Cranial osteosclerosis can cause severe headaches and cranial nerve compression, resulting in hearing loss, facial paralysis and visual impairment. Dental problems are also common. Intellectual impairment is present in a minority of cases. Final stature may be reduced. It is postulated that individuals with OSCS may be susceptible to Wilms tumour. Differential diagnosis: the severe phenotype with generalised sclerosis should be differentiated from some of the prenatal sclerosing bone dysplasias: Raine syndrome (p. 403), severe lethal variant of Caffey disease (p. 411), Al-Gazali dysplasia (p. 418) and osteopetrosis (p. 388). The combination of generalised sclerosis and digital malformation may be mistaken for osteosclerotic Robinow syndrome (p. 276) and sclerosteosis, which shows syndactyly of the fingers. Osteopathia striata is a syndromic component of Goltz syndrome. 421

422

Fetal and Perinatal Skeletal Dysplasias

(1a)

(1d)

(2a)

  (1b)

 

(1e)

 

 

  (2b)

(1c)

(1f )

  (2c)

CASE 1: An affected mother had a large head (OFC: 63 cm), photosensitive epilepsy and persistent deciduous teeth. Prenatal ultrasound revealed exomphalos at 12–14 weeks of gestation. Intrauterine death occurred at 18 weeks of gestation. Radiographs of the mother (a–c) show calvarial hyperostosis and mild metaphyseal striations. The male fetus showed exomphalos, bilateral cleft lip and palate, bowed legs and hypoplasia of the left kidney. A postmortem radiograph of the stillborn (d) shows generalised osteosclerosis, a narrow thorax and tibial bowing with fibular aplasia. This fetus had duplication of the distal phalanx of the left index finger.

Osteopathia Striata with Cranial Sclerosis, AMER1-Related

 

(2d)

(2g)

(3c)

 

 

 

(2h)

(3d)

423

(2e)

 

(3a)

 

 

(2f )

 

 

(3b)

(3e)

CASE 2: An affected male. His mother had macrocephaly and mild hearing impairment, and she had undergone cleft palate repair. Radiographs and cranial CT as a neonate (a–e) show craniofacial disproportion, generalised osteosclerosis, aplasia of the fibula and brachydactyly with brachymesophanagy of the index finger. Fetal CT at 31 weeks of gestation (f) shows the findings of postnatal radiographs. Prenatal ultrasound (g, h) revealed clubfeet and a large head with frontal bossing. CASE 3: Two affected male fetuses (younger sibling: a–c; older sibling: d, e). Postmortem radiographs show cranial sclerosis, generalised osteosclerosis and multiple coronal clefts (b). Both fetuses have fibular aplasia, broad thumbs, brachymesophalangy and duplication of the index fingers. There is bowing of the tibiae and radii.

424

Fetal and Perinatal Skeletal Dysplasias

 

 

 

 

 

 

CASE 4: An affected mother shows calvarial hyperostosis and mild metaphyseal striations (a–c). Her affected daughter shows macrocephaly, generalised osteosclerosis and hypoplasia of the proximal fibula (d–i). She required intensive care in the neonatal period.

Osteopathia Striata with Cranial Sclerosis, AMER1-Related

BIBLIOGRAPHY Bach A, Mi J, Hunter M, Halliday BJ et al. Wilms tumor in patients with osteopathia striata with cranial sclerosis. with osteopathia striata with cranial sclerosis. Eur J Hum Genet. 2021; 29: 396–401. Hague J, Delon I, Brugger K et al. Male child with somatic mosaic osteopathia striata with cranial sclerosis caused by a novel pathogenic AMER1 frameshift mutation. Am J Med Genet A. 2017; 173: 1931–5. Heikoop D, Brick L, Chitayat D et al. The phenotypic spectrum of AMER1-related osteopathia striata with cranial sclerosis: The first Canadian cohort. Am J Med Genet A. 2021; 185: 3793–803. Herman SB, Holman SK, Robertson SP et al. Severe osteopathia striata with cranial sclerosis in a female case with whole WTX gene deletion. Am J Med Genet A. 2013; 161A: 594–9.

425 Holman SK, Daniel P, Jenkins ZA et al. The male phenotype in osteopathia striata congenita with cranial sclerosis. Am J Med Genet A. 2011; 155A: 2397–408. Jenkins ZA, van Kogelenberg M, Morgan T et al. Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis. Nat Genet. 2009; 41: 95–100. Tomita Y, Chong PF, Yamamoto T et al. Sequential radiologic findings in osteopathia striata with cranial sclerosis. Diagn Interv Imaging. 2019; 100: 529–31. Vasiljevic A, Azzi C, Lacalm A et al. Prenatal diagnosis of osteopathia striata with cranial sclerosis. Prenat Diagn. 2015; 35: 302–4.

86 Lenz-Majewski Hyperostotic Dysplasia, PTDSS1-Related

Synonyms: LMHD Confirmation of diagnosis: identification of monoallelic pathogenic variants in the PTDSS1 gene Frequency: extremely rare – fewer than 20 cases reported Genetics: LMHD is an autosomal dominant disorder due to heterozygous, activating variants in PTDSS1, mapped on chromosome 8q22 and encoding phosphatidylserine synthase 1. LMHD-related variants increase synthesis of phosphatidylserine that is a component of cell membrane phospholipids. Disruption of phosphatidylserine metabolism impairs bone mineralisation and brain development. Age/Gestational week of manifestation: birth. Clinical features: • Intrauterine growth retardation (but may be normal), postnatal growth failure • Craniofacial dysmorphism (relatively large head, large fontanelles, hypertelorism, choanal atresia, nasolacrimal duct obstruction, cleft palate, macrostomia, enamel dysplasia, large floppy ears) • Progeroid appearance, loose and wrinkled skin, prominent veins • Short fingers, partial skin syndactyly, proximal symphalangism • Hypospadias, cryptorchidism in males • Intellectual disability; dysgenesis of the corpus callosum, mild white matter atrophy Prenatal ultrasound features: there have been no reports of prenatally diagnosed or identified cases. It may be possible to demonstrate intrauterine growth retardation from biometric parameters, brachydactyly and hypoplasia/absence of the corpus callosum.

426

Radiographic features: the radiological changes are descriptively termed craniodiaphyseal dysplasia. The skull, facial bones and mandible show progressive sclerosis and overgrowth. The sutures and fontanelles appear large with delayed closure. The clavicles and ribs are strikingly wide and sclerotic. The tubular bones show diaphyseal hyperostosis and metaphyseal osteopenia. The diaphyseal equivalents of the spine and flat bones are sclerotic, while the metaphyseal equivalents are osteopenic. The middle phalanges may be short along with progressive proximal symphalangism. Mild shortening of the metacarpals and osseous syndactyly of the postaxial metacarpal bases may be seen. Bone maturation is delayed. The trabecular pattern becomes progressively coarser with increasing age. Prognosis: viable, although death in infancy or childhood has been repeatedly reported. Choanal atresia may cause respiratory failure as neonates. There is severe growth retardation and progressive skeletal sclerosis. Hyperostosis of the skull base may cause stenosis of the craniovertebral junction and hydrocephalus. The facial features become increasingly coarse over time. All patients have neurodevelopmental delay; some have deafness. Differential diagnosis: LMHD should be differentiated from other craniotubular dysplasias, such as craniometaphyseal and craniodiaphyseal dysplasia. Given the distinctive facial and cutaneous abnormalities in LMHD, the differential diagnosis is not difficult. LMHD may be confused with other progeroid syndromes. However, sclerotic skeletal changes in LMHD are distinctive from the osteoporosis seen in some progeroid syndromes, such as autosomal recessive cutis laxa syndromes types 2A and 2B (ATP6V0A2 mutations and PYCR1 mutations) and geroderma osteodysplasticum (GORAB mutations). It is postulated that SCARF syndrome shares some features with LMHD (Koppe R, et al., 1989).

DOI: 10.1201/9781003166948-92

Lenz-Majewski Hyperostotic Dysplasia, PTDSS1-Related

427

 

 

 

 

 

CASE 1: Clinically the neonate showed soft tissue syndactyly, blue sclerae with features of a connective tissue disorder and failure to thrive. There is sclerosis of the skull vault, base and facial bones. The diaphyses of the long bones are sclerotic with thickening of the cortex, and the metaphyses are relatively radiolucent. The ribs and clavicles are wide and sclerotic, but there is a radiolucent flare at the posterior ends of the ribs. There is sclerosis of the central parts of the scapulae, ilia and ischia.

428

BIBLIOGRAPHY Koppe R, Kaplan P, Hunter A et al. Ambiguous genitalia associated with skeletal abnormalities, cutis laxa, craniostenosis, psychomotor retardation, and facial abnormalities (SCARF syndrome). Am J Med Genet. 1989; 34: 305–12. Piard J, Lespinasse J, Vlckova M et al. Cutis Laxa and excessive bone growth due to de novo mutations in PTDSS1. Am J Med Genet A. 2018; 176: 668–75. Saraiva JM. Dysgenesis of corpus callosum in Lenz-Majewski hyperostotic dwarfism. Am J Med Genet. 2000; 91: 198–200.

Fetal and Perinatal Skeletal Dysplasias Sohn M, Balla T. Lenz-Majewski syndrome: How a single mutation leads to complex changes in lipid metabolism. J Rare Dis Res Treat. 2016; 2: 47–51. Sousa SB, Jenkins D, Chanudet E et al. Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome. Nat Genet. 2014; 46: 70–6. Tamhankar PM, Vasudevan L, Bansal V et al. Lenz-Majewski syndrome: Report of a case with novel mutation in PTDSS1 gene. Eur J Med Genet. 2015; 58: 392–9.

87 Osteogenesis Imperfecta

Synonyms: OI types I-IX, OI 1-9 Confirmation of diagnosis: clinical and radiological suggestive features associated with pathogenic variants in the related gene Frequency: considering all types together, the incidence is 6–7:100,000. OI types 2 and 3, the forms usually detected prenatally, have an incidence of 2:100,000. Genetics: OI types 1–5 are inherited in an autosomal dominant manner and are caused by pathogenic variants in the genes COL2A1 and COL2A2. Almost 60% of individuals with mild OI have de novo variants (detection rate in this group is 100%); virtually 100% of individuals with lethal (type 2) OI or with severe (type 3) OI have a de novo pathogenic variant (detection rate in this group: 60–98%). Penetrance of COL2A1 or COL2A2 pathogenic variants is complete, but expression can be variable. OI types 7–9 are inherited in an autosomal recessive manner and caused by pathogenic variants in the gene CRTAP (OI 7 and a small proportion of cases of OI 2/3), LEPRE (OI 8) and PPIB (OI 9). Mutations within these genes cause decreased collagen 3-prolyl hydroxylation. Recently, pathogenic variants in the genes FKBP10 and SERPINH1 have also been found as causing severe recessive forms of OI: both these genes encode for chaperone proteins whose deficiency causes impairment of type 1 procollagen folding and secretion. OI types 7–9 may be grouped together as autosomal recessive OI. Age/Gestational week of manifestation: severe forms can be detected by ultrasound during the first or second trimester (11–16 weeks). Mutation identification facilitates prenatal diagnosis. In pregnancies at risk of OI type 2, prenatal diagnosis can be performed as early as 13 weeks’ gestation by analysis of DNA (chorionic villus sampling [CVS]) and sonography (2D and 3D transvaginal sonography, 2D and 3D transabdominal sonography). Clinical features (severe forms): • Generalised osteoporosis, fractures • Short limbs, often bowed long bones • Large, soft skull, wide fontanelles

DOI: 10.1201/9781003166948-93

• Barrel chest, callus formation (ribs) • Hyperlaxity • Blue sclerae, prominent eyes, small beaked nose, triangular face • Increased nuchal thickness may be seen at 12 weeks’ gestation • Some have dentinogenesis imperfecta Prenatal ultrasound features: findings in affected fetuses are variable and depend on the severity of the disease. The phenotypic severity of OI ranges from perinatal death (type 2) to relatively mild forms (types 1 and 4) with few bone fractures throughout life. The prenatal appearance of the less severe nonlethal OI forms is variable and ranges from multiple skeletal deformities to a normal sonogram. Prenatal sonomorphology correctly identifies 89% of more severe OI at the first diagnostic examination. Type 1: the onset of limb deformities in OI type 1 may occur after birth; less frequently, short, curved femora may be detected in the third trimester. Type 2: this may present in the first trimester of pregnancy with increased nuchal translucency (NT) thickness. It is rarely accompanied by other major anomalies, although associations with ventriculomegaly and with encephalocele have been reported in the first trimester. There is severe bone fragility and undermineralisation. There are bowing and fracturing of the tubular bones occurring as a result of fetal movement. Bone healing results in limb shortening, angulation, widening and a wrinkled appearance caused by multiple fractures and callus formation. The femora may be asymmetric in size and shape as a result of asymmetric fractures. Early in the second trimester, decreased ossification of the skull enables an unusually high-quality evaluation of the fetal brain in the near field with abnormal clarity of intracranial structures. The skull shape appears deformed, and the vault is compressible with light transducer pressure. Other phenotypic features include a small, bell-shaped thorax (longitudinal-coronal view), deformed ribs (beaded) due to fractures and flattened vertebrae.

429

430

Fetal and Perinatal Skeletal Dysplasias

TABLE 87.1 Summary of Clinical Features of the Different Types of OI OI Type

Inheritance

Gene

1

AD

COL1A1 COL1A2

2

AD AR

COL1A1 COL1A2 CRTAP P3H1, PPIB

3

AD AR

COL1A1 COL1A2 IFITM5 SERPINF1 CRTAP, P3H1, PPIB, SERPINH1, FKPB10, TMEM38B, BMP1, WNT1, CREB3LI, SPARC, TENT5A, MBTPS2, MESD, KDELR2, SP7, CCD134 CRTAP P3H1

4

AD

5

AD

6

AR

7

AR

CRTAP

8

AR

9 Others

Prognosis

Clinical Features

Viable, mild

Mild, non-deforming, blue sclerae; normal or mild short stature; hearing loss in 50% of cases; no DI (type IA), DI (type IB)

Perinatally lethal

Multiple fractures at birth; soft skull, short stature, severe deformities, dark blue sclera, DI

Viable, severe

Severely deforming, very short stature, triangular face, blue sclerae, DI, hearing loss

COL1A1 COL1A2

Viable, mild to moderate

Moderately deforming and short, no DI (IVA), DI (IVB), white sclerae

IFITM5

Viable, moderately deforming

Moderate short stature, ossification of interosseous membrane, hyperplastic callus, white sclerae, no DI, elbow dislocation

Viable, moderate to severe

Moderately short, scoliosis, accumulation of osteoid in bone tissue, osteomalacia; no DI; white sclerae

Viable, moderately deforming

Normal birth length, short final stature, moderate-severe bone fragility, fracture frequency decreases postpuberty; bluish sclerae, no DI, normal hearing

P3H1

Perinatally lethal, when viable severely deforming

Multiple fractures, present at birth, severe osteopenia, soft skull, severe deformations, no DI, white sclerae

AR

PPIB

Perinatally lethal, when viable severely deforming

Multiple fractures present at birth, short limbs, DI, blue sclerae

AR

FKBP10 SERPINH1

Perinatally lethal, when viable severely deforming

Abbreviation: DI, dentinogenesis imperfecta.

Type 3: affected fetuses have marked deformity of the long bones and skull, usually present at birth. Type 3 may be identified on ultrasound in the second and third trimester with findings similar to OI type 2 or may appear less severe than type 2. Type 4: has findings overlapping in severity between type 1 and type 3. Fractures may occur at birth or may not be evident until childhood. Radiographic features: those of the autosomal dominant (AD) forms of OI are described. The autosomal recessive types are mainly limited by the region of origin and fall into the OI type 2 or 3 phenotypes. Prognosis: the most severe forms, which can be seen prenatally, are usually lethal in the perinatal period due to pulmonary insufficiency (small thorax, rib fractures, flail chest). Survival beyond 1 year is very rare and usually requires intensive support.

Infants who survive this period generally have normal intelligence, unless there have been intracerebral haemorrhages, but do not walk without assistance because of severe bone fragility and deformity. Growth is minimal; adult stature may be less than 1 meter. Hearing loss is common. Basilar invagination can cause brain stem compression, obstructive hydrocephalus, syringomyelia, sleep apnoea and death. Differential diagnosis: the key features requiring differentiation are poorly ossified skull vault; small thorax; short bowed or angulated tubular bones. Hypophosphatasia (p. 452), Bruck syndrome (p. 447), Menkes disease (p. 602), thanatophoric dysplasia (p. 36), Campomelic dysplasia (p. 302), achondrogenesis (all types) (p. 58, 105, 256), hyperparathyroidism – severe form (p. 457), Astley-Kendall dysplasia (p. 386), parvovirus infection. Maternal and fetal infection with parvovirus results in osteopenia, areas of patchy sclerosis and fractures. In neonates, multiple fractures require differentiation from physical abuse (non-accidental injury).

431

Osteogenesis Imperfecta TABLE 87.2 Summary of the Radiographic Features of the Different Forms of AD OI OI Type

Radiographic Features

1

At birth: rarely presents with fractures. Mildly bowed femora may be present. Multiple Wormian bones. Osteopenia and fractures start during early childhood. The frequency of fracturing diminishes after adolescence. Mild deformity only.

2A

Perinatally lethal. Largely unossified skull vault and generalised severe osteopenia. At birth the femora are short and crumpled (concertina-like) due to multiple intrauterine fractures, without differentiation into metaphyses and diaphyses. The tibiae and fibulae are short and acutely angulated and other long bones deformed. The thorax is small and the ribs broad due to healing fractures along their lengths. The vertebral bodies are collapsed. Prenatal diagnosis and termination of pregnancy before term will result in a different picture because of fewer fractures. The ribs may be slender with multiple healing fractures (beaded), the femora less crumpled and the vertebral bodies of more normal height.

2B

The least severe form of perinatally lethal OI with some overlap with type 3. Generalised osteopenia and poorly ossified skull vault. Slender long bones and ribs with multiple healing fractures. Angulated tibiae and fibulae.

2C

Severe, perinatally lethal. Totally unossified skull vault with resultant deformity. Unusual bone density with multiple small sclerotic foci, sclerotic metaphyses and sclerotic rims of the scapulae within a generally osteopenic skeleton, presumably a response to multiple healing micro-fractures. Slender long bones and ribs with multiple fractures. Angulated tibiae and fibulae. Abnormal modelling of the ilia with hypoplasia inferiorly. The femora may be abnormally modelled with pointing proximally or distally. Typically, the vertebral bodies are not collapsed.

3

Severe deforming type. Presents at birth or prenatally with a poorly ossified skull vault with multiple Wormian bones and generalised osteopenia. Rib and long bone fractures may be present at birth but progress postnatally, resulting in severe deformity. Multiple vertebral body collapse results in kyphoscoliosis.

4

Falls into a spectrum overlapping between type 1 and type 3. At birth femoral bowing may be the only feature. Platybasia and basilar invagination is a complication in older patients. Wormian bones in the skull vault are a variable feature.

5

Generalised osteopenia but with sclerotic metaphyses. In the neonate the metaphyses are sclerotic, frayed, wide and flared. Cupped, expanded anterior rib ends. Interosseous membrane ossification. Fractures with exuberant callus formation. Dislocated radial heads.

87A. OSTEOGENESIS IMPERFECTA, NON-DEFORMING (SILLENCE TYPE 1)

 

 

 

 

CASE 1: An infant. Radiographs show generalised decreased osteoporosis, multiple Wormian bones in the posterior part of the sagittal suture, slender ribs, healing fractures of the left sixth posterior rib and right femur and mild bowing of the left femur and both tibiae. CASE 2: An infant. Radiographs show slender ribs, femoral bowing, left femoral fracture and Wormian bones.

432

Fetal and Perinatal Skeletal Dysplasias

 

 

CASE 3: An infant. Wormian bones are well depicted on 3D CT. The femora, tibiae and fibulae are slender and mildly bowed.

87B. OSTEOGENESIS IMPERFECTA, SEVERE PERINATAL FORM (SILLENCE TYPE 2A AND B)

 

 

 

CASES 1–4: Stillbirths. CASES 1, 2: Radiographs show beaded ribs and crumpled long bones due to multiple healing fractures and deficient ossification of the calvarium.

433

Osteogenesis Imperfecta

 

 

CASES 3, 4: The ribs show defective ossification and multiple fractures. The long bones are thick and crumpled.

 

 

 

 

 

 

CASE 5: A 20-week-gestation fetus. (a–c) 2D US of the skull shows lack of ossification of the vault with good visualisation of the fetal brain. The fetal skull appears easily compressible with transducer pressure. (d) 2D US at the level of the four-chamber view shows a narrow thorax with mild pericardial effusion. Heart circumference is at the 50th centile and chest circumference below the 5th centile, indicating pulmonary hypoplasia. (e–h) 2D US of the limbs shows micromelia and bowed, broad long bones due to intrauterine fractures.

434

Fetal and Perinatal Skeletal Dysplasias

 

 

 

 

 

 

 

CASE 5: (m–q) Postmortem 3D CT reveals a narrow thorax with multiple rib fractures and mildly flat vertebral bodies. (m) The surface rendering mode of 3D CT captures the physical manifestations as well.

435

Osteogenesis Imperfecta 87C. OSTEOGENESIS IMPERFECTA, SEVERE PERINATAL FORM (SILLENCE TYPE 2C)

 

 

 

 

 

 

CASES 1–3: Stillbirths. All cases show severely defective calvarial ossification; thin, beaded ribs; and slender long bones with diaphyseal fractures and metaphyseal splaying and sclerosis. Despite severe deformity of the ribs and long bones, the vertebral bodies are not collapsed. Fetal CT captures the skeletal changes of postmortem radiographs in Case 3.

436

Fetal and Perinatal Skeletal Dysplasias

87D. OSTEOGENESIS IMPERFECTA, SEVERE NONLETHAL FORM (SILLENCE TYPE 3)

 

 

 

 

CASE 1: A stillbirth. CASE 2: A terminated fetus at 23 weeks of gestation. CASE 3: A terminated fetus shortly after identification of short, bowed and fractured femora at 20 weeks of gestation. CASE 4: A neonate delivered at 38 weeks’ gestation who died 1 hour after birth. Crumpled long bones are indistinguishable from those of lethal osteogenesis imperfecta (type 2 OI). However, the ribs are less severely affected. The calvarium is better ossified.

437

Osteogenesis Imperfecta

 

 

 

 

 

 

 

 

 

 

CASE 5: A neonate. (a–d) Radiographs show defective calvarial ossification, rib fractures and crumpled long bones. (e–i) At 28 weeks of gestation, 2D US showed decreased calvarial ossification with deformity, with compression of the transducer probe. The femora, tibiae and fibulae were deformed, while the right humerus was straight. (j–l) 3D US showed rib fractures and frontal bossing and depressed nasal bridge. (m, n) 2D US and axial MRI showed a small collapsed thorax due to rib fractures.

438

Fetal and Perinatal Skeletal Dysplasias

 

 

 

 

 

 

 

CASE 6: A stillbirth. Postmortem radiographs and CT show skeletal changes similar to those of Case 5. CASE 7: A terminated fetus. Antenatal US and postmortem radiographs and CT show defective calvarial ossification and bowed long bones. The ribs are not fractured.

439

Osteogenesis Imperfecta

 

 

 

 

  CASE 8: Based on prenatal US findings, a tentative diagnosis of lethal OT was made. However, despite severe deformity of the limbs, the baby survived the neonatal period. Radiographs at age 1 month show thick, crumpled long bones and a narrow thorax with thin ribs. The ribs are not fractured.

440

Fetal and Perinatal Skeletal Dysplasias

87E. OSTEOGENESIS IMPERFECTA, RECESSIVE, UNLINKED TO COL1A1 AND COL1A2

 

 

 

 

 

 

 

 

CASE 1: Radiological findings are consistent with those of type 3 OI. There were affected siblings born to consanguineous Asian parents. CASE 2: The parents of this fetus were first cousins. At 23 weeks of gestation, bowing of the long bones was identified by prenatal US. At postmortem examination, the head was relatively large and the cranium soft with islands of bony ossification. The palate was highly arched. The limbs were short and the legs angulated due to intrauterine fractures. CASE 3: A neonate with CRTAP mutations. (a–d) Radiographs show deficient calvarial ossification; thin ribs with fractures; crumpled femora, tibiae and fibulae; and a fracture with some callus of the right humerus. Generalised osteoporosis is evident.

441

Osteogenesis Imperfecta

  

 

 

 

CASE 3: (e–i) At 20 weeks of gestation, 2D US showed some mineralisation of the calvarium, but arrows pointing to areas of diminished echogenicity suggested poor mineralisation. Other US findings included thin ribs and bilateral bowed femora and mild bowing of the tibiae. The abdominal circumference was normal. The chest to abdominal circumference ratio was 0.89, which was near normal and not in the lethal range.

442

Fetal and Perinatal Skeletal Dysplasias

 

 

 

 

 

CASE 4: A fetus in a family with recurrence of OI. (a–d) At 22 weeks of gestation, 2D US showed a thin, irregularly shaped rib (arrow) and a bent, fractured femur. The spine, radius and ulna were normal. CASE 5: A neonate with PPIB mutations. The skeletal phenotype is consistent with that of type 3 OI. The ribs are thin and associated with multiple fractures. The vertebral bodies are not collapsed. The femora and tibiae are thick and crumpled as a result of intrauterine fractures. The fibulae are severely deformed.

OSTEOGENESIS IMPERFECTA TYPE 4

  CASE 1: A neonate with slim long bones along with severe bowing of the femora.

 

443

Osteogenesis Imperfecta

 

 

 

 

CASE 2: A neonate. The ribs and long bones are slim along with multiple fractures. CASE 3: Radiographs at birth, 7 months and 12 months. The neonatal manifestation is indistinguishable from that of type 3 OI. However, the long bones are well remodelled with age.

444

Fetal and Perinatal Skeletal Dysplasias

OSTEOGENESIS IMPERFECTA TYPE 5

 

 

 

 

 

 

CASE 1: (a–h) Radiographs at birth show multiple Wormian bones, acute fractures of the left tibia and left ulna and a healing fracture of the right fibula. The metaphyses of the long bones are mildly dense. The distal femora are ragged (an unusual finding). The mother of this neonate was also affected.

445

Osteogenesis Imperfecta

 

 

 

 

 

 

 

 

 

 

 

CASE 1: (i–l) Radiographs at 5 months show multiple rib fractures, dense metaphyses and diaphyseal osteoporosis of the long bones and ossification of the interosseous membrane of the forearm. CASE 2: An infant. CASE 3: A 7-month-old infant. In both infants, metaphyseal sclerosis is apparent, and the ribs are directed downward. Hyperostosis of the femoral shafts and forearm is seen in Case 3.

446

BIBLIOGRAPHY Aerts M, Van Holsbeke C, De Ravel T, Devlieger R. Prenatal diagnosis of type II osteogenesis imperfecta, describing a new mutation in the COL1A1 gene. Prenat Diagn. 2006; 26: 393–4. Ayadi ID, Hamida EM, Rebeh RB et al. Perinatal lethal type II osteogenesis imperfecta: A case report. Pan Afr Med J. 2015; 21: 11. doi: 10.11604/pamj.2015.21.11.6834 Borg SA, Bishop NJ. New diagnostic modalities and emerging treatments for neonatal bone disease. Early Hum Dev. 2018; 126: 32–7. Chen CP, Su YN, Lin SP et al. Favourable outcome in a pregnancy with concomitant maternal and fetal osteogenesis imperfecta associated with a novel COL1A2 mutation. Prenat Diagn. 2006; 26: 188–90. Cho FN, Kan YY, Chen SN et al. Osteogenesis imperfecta associated with first-trimester ventriculomegaly as an early ultrasound sign. Prenat Diagn. 2005; 25: 519–20. Chryczyk MM. Imaging of osteogenesis imperfecta prebirth to adolescence. Radiol Technol. 2016; 87: 690–7.

Fetal and Perinatal Skeletal Dysplasias Gilligan LA, Calvo-Garcia MA, Weaver KN, Kline-Fath BM. Fetal magnetic resonance imaging of skeletal dysplasias. Pediatr Radiol. 2020; 50: 224–33. Kamoun-Goldrat A, Martinovic J, Saada J et al. Prenatal cortical hyperostosis with COL1A1 gene mutation. Am J Med Genet. 2008; 146A: 1820–4. Ngo C, Viot G, Aubry C et al. First-trimester ultrasound diagnosis of skeletal dysplasia associated with increased nuchal translucency thickness. Ultrasound Obstet Gynecol. 2007; 30: 221–6. Pyott SM, Pepin MG, Schwarze U et al. Recurrence of perinatal lethal osteogenesis imperfecta in sibships: Parsing the risk between parental mosaicism for dominant mutations and autosomal recessive inheritance. Genet Med. 2011; 13: 125–30. Storoni S, Verdonk SJE, Zhytnik L et al. From genetics to clinical implications: A study of 675 Dutch osteogenesis imperfecta patients. Biomolecules 2023; 13: 281. doi: 10.3390/ biom13020281

88 Bruck Syndrome, FKBP10- and PLOD2-Related

Synonyms: Bruck syndrome 1; BRKS1; Kuskokwim disease; arthrogryposis-like disorder; Bruck syndrome 2; BRKS2; osteogenesis imperfecta with congenital joint contractures Confirmation of diagnosis: clinical and radiological suggestive features associated with pathogenic variants in the related gene Frequency: very rare Genetics: autosomal recessive condition. BRKS1 is associated with pathogenic variants in the FKBP10 gene, which encodes the chaperone protein FKBP65,involved in collagen cross-linking. BRKS2 is caused by pathogenic variants in the PLOD2 gene, which encodes telopeptide lysyl hydroxylase. Age/Gestational week of manifestation: onset is usually prenatal and can be detected as early as the 16th week of pregnancy. Clinical features: • • • • • • •

Postnatal short stature Severe limb deformity Congenital contractures Pterygia Fractures Progressive scoliosis Pectus carinatum

Prenatal ultrasound features: Bruck syndrome combines features of osteogenesis imperfecta and arthrogryposis multiplex congenita. Prenatal ultrasound may detect bowed short femurs and multiple joint contractures early in the second trimester (15–16 weeks of pregnancy); sometimes, fetal anomalies are observed during the third trimester. Clinical manifestations include elbows and knees fixed in flexion/extension, while the wrists may be found fixed in extension. Malposition of the feet may be associated. Intrauterine manifestation of fractures of long bones is not constant; the fractures are often of postnatal onset. Other prenatal features include brachycephaly, facial dysmorphia with retrognathia and polyhydramnios.

DOI: 10.1201/9781003166948-94

Radiographic features: the long bones are short and slender and may be bowed. There are multiple joint contractures. Contractures can be appreciated on prenatal imaging, are fixed and may be bilateral. The bones are osteopenic, and therefore there are multiple fractures. Prenatal ultrasound may show retrognathia. Scoliosis may occur. Congenital cardiac disease and pulmonary haemorrhage have been described. Prognosis: viable. Children develop progressive postnatal short stature, scoliosis and possible deformities related to osteopenia and multiple fractures. Notably, metaphyseal corner fractures and posterior rib fractures have been reported in affected neonates. Teething and hearing are normal. There are no cognitive disabilities. Differential diagnosis: other causes of bone fragility: osteogenesis imperfecta all types (p. 429), hypophosphatasia (p. 452) and Menkes disease (p. 602). In neonates, multiple fractures require differentiation from physical abuse (non-accidental injury). Other causes of joint contractures: arthrogryposis multiplex congenita. Loeys-Dietz syndrome can also show thin skin, hypertelorism, bifid uvula, cleft palate and dilatation of the aortic root or other arteries. Heterogeneous condition (associated with genes SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1 and TGFBR2). Stickler syndrome (p. 89) presents with midfacial flattening, cleft palate, early-onset and rapidly progressive myopia, hearing loss and spondyloepiphyseal dysplasia (associated with genes COL2A1, COL9A1, COL9A2, COL9A3, COL11A1, and COL11A2). Marfan syndrome (p. 471) is rarely symptomatic at birth; affected neonates can show severe hypotonia, valvular anomalies and/or aortic root dilatation. Typically they show or develop lens (sub)luxation and high myopia. Caused by dominant pathogenic variants in the gene FBN1. Homocystinuria also presents with arachnodactyly and lens subluxation; it also shows a predisposition to thromboembolism and typical biochemical anomalies; caused by pathogenic variants in the gene CBS.

447

448

Fetal and Perinatal Skeletal Dysplasias

(1a)

 

(1d)

 

(2c)

 

(2a)

(2d)

(1b)

 

 

(1c)

(2b)

 

(2e)

CASE 1: A neonate with FKBP10 mutations. The right femur shows severe bowing. However, other long bones are normal. The skull, spine, ribs and shoulder and pelvic girdles are unremarkable. CASE 2: A 6-month-old infant with PLOD2 mutations. There are multiple Wormian bones, rib fractures and bowing of the right tibia. However, osteopenia is mild. The neonatal and infantile manifestations tend to be mild in cases with FKBP10 and PLOD2 mutations.

Bruck Syndrome, FKBP10- and PLOD2-Related

BIBLIOGRAPHY Berg C, Geipel A, Noack F et al. Prenatal diagnosis of Bruck syndrome. Prenat Diagn. 2005; 25: 535–8. Bobyn A, Jetha M, Frohlich B, et al. Metaphyseal and posterior rib fractures in osteogenesis imperfecta: Case report and review of the literature. Bone Rep. 2022; 8: 16:101171. Cuillier F, Alessandri JL, Lemaire P et al. Bruck syndrome: Second antenatal diagnosis. Fetal Diagn Ther. 2007; 22: 23–8. Moravej H, Karamifar H, Karamizadeh Z et al. Bruck syndrome – A rare syndrome of bone fragility and joint contracture and novel homozygous FKBP10 mutation. Endokrynol Pol. 2015; 66: 170–4.

449 Mumm S, Gottesman GS, Wegkehrt D et al. Bruck syndrome 2 variant lacking congenital contractures and involving a novel compound heterozygous PLOD2 mutation. Bone 2020 doi: 10.1016/j.bone.2019.115047 Otaify GA, Abdel-Hamid MS, Hassib NF et al. Bruck syndrome in 13 new patients: Identification of five novel FKBP10 and PLOD2 variants and further expansion of the phenotypic spectrum. Am J Med Genet A. 2022; 188: 1815–25. Sandy JL, Perez D, Goh S et al. Expanding the phenotype of Bruck syndrome: Severe limb deformity, arthrogryposis, congenital cardiac disease and pulmonary hemorrhage. Am J Med Genet A. 2023; 191: 265–70. Tran CT, Smet M-E, Forsey J et al. Bruck syndrome: Beyond the obvious. Fetal Diagn Ther. 2022; 49: 479–85.

89 Osteogenesis Imperfecta with Craniosynostosis (Cole-Carpenter Syndrome), P4HB- and SEC24D-Related

Synonyms: Cole-Carpenter syndrome 1; CLCRP1; bone fragility with craniosynostosis, ocular proptosis, hydrocephalus and distinctive facial features; Cole-Carpenter syndrome 2; CLCRP2 Confirmation of diagnosis: clinically and radiologically suggestive features associated with pathogenic variants in the related genes Frequency: very rare Genetics: CLCRP1 is an autosomal dominant condition associated with pathogenic variants in the P4HB gene, encoding the beta subunit of prolyl 4-hydroxylase. Prolyl 4-hydroxylase is a tetramer consisting of two alpha and two beta subunits: in the tetrameric form, it catalyses the formation of 4-hydroxyproline in collagen. The pathogenic variants might exhibit a gain in function. CLCRP2 is an autosomal recessive disorder caused by biallelic pathogenic variants in the gene SEC24D, encoding a component of the structural proteins of the vesicles involved in the transport of proteins from the endoplasmic reticulum. Age/Gestational week of manifestation: can be detected from 18 weeks of gestation. Clinical features: • Short stature, more commonly postnatal and progressive • Bone fragility, fractures • Craniosynostosis, particularly coronal and lambdoid • Skull ossification defects • Marked frontal bossing, ocular proptosis, midface hypoplasia and micrognathia • Hydrocephalus

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Prenatal ultrasound features: prenatal ultrasound may reveal ventriculomegaly in pregnancy and hydrocephalus at birth. Disproportionately short limbs and bowed lower and upper limbs are due to multiple intrauterine fractures. Craniofacial findings can be detected by 2D and 3D ultrasound: there is hypertelorism, with or without proptosis, and micrognathia. Detailed ultrasound examination at the 20th and 23rd weeks can reveal multiple fractures of the long bones, mildly bent extremities and a thin, poorly ossified skull. Moreover, the presence of some rib fracture and the thorax not being severely hypoplastic can suggest that the skeletal dysplasia is a non-lethal type. Radiographic features: the skeletal phenotype is that of type 3 osteogenesis imperfecta with osteopenia, multiple fractures and progressive deformity of the long bones. In addition, there may be craniosynostosis, with premature fusion of sutures. Wormian bones and hydrocephalus occur in some patients. It has been suggested that there is phenotype-genotype correlation, with patients with mutations in P4HB having unusual crumpling and fractures, with sclerosis at the metadiaphyseal junctions of the long bones. Prognosis: viable. Multiple fractures can cause deformities and can impair autonomous mobility over time. Craniosynostosis and hydrocephalus might require surgical interventions. There can be dentinogenesis imperfecta. There is postnatal short stature. Intellectual development is normal. Differential diagnosis: other causes of bone fragility: osteogenesis imperfecta all types (p. 429), hypophosphatasia (p. 452). In neonates, multiple fractures require differentiation from physical abuse (non-accidental injury). Other causes of craniosynostosis: Apert syndrome (p. 496), Antley-Bixler syndrome (p. 500), Pfeiffer syndrome (p. 491) and Shprintzen-Goldberg syndrome (p. 504) are unlikely to be confused with Cole-Carpenter because of the absence of long bone fractures.

DOI: 10.1201/9781003166948-95

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CASE 1: A stillbirth at 14 weeks of gestation. There is generalised osteopenia. The long bones are severely deformed and crumpled. The scapulae are distorted. Bitemporal bulging of the skull probably represents craniosynostosis.

BIBLIOGRAPHY Balasubramanian M, Padidela R, Pollitt RC et al. P4HB recurrent missense mutation causing Cole-Carpenter syndrome. J Med Genet. 2018; 55: 158–65. Balasubramanian M, Pollitt RC, Chandler KE et al. CRTAP mutation in a patient with Cole-Carpenter syndrome. Am J Med Genet A 2015; 167(A): 587–91. Cotrina-Vinagre FJ, Rodríguez-García ME, Martín-Hernández E et al. Characterization of a complex phenotype (feverdependent recurrent acute liver failure and osteogenesis imperfecta) due to NBAS and P4HB variants. Mol Genet Metab. 2021; 133: 201–10.

Ouyang L, Lang F. Cole-Carpener syndrome-1 with a de novo heterozygous deletion in the P4HB gene in a Chinese girl: A case report. Medicine (Baltimore). 2017; 96: e9504. Porntaveetus T, Theerapanon T, Srichomthong C, Shotelersuk V. Cole-Carpenter syndrome in a patient from Thailand. Am J Med Genet A. 2018; 176: 1706–10. Rauch F, Fahiminiya S, Majewski J et al. Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB. Am J Hum Genet. 2015; 96: 425–31.

90 Hypophosphatasia, Perinatal Lethal and Infantile Forms, ALPL-Related

Synonyms: HOPS, hypophosphatasia perinatal lethal Confirmation of diagnosis: clinically and radiologically suggestive features associated with pathogenic variants in ALPL Frequency: 1 in 100,000 Genetics: caused by pathogenic variants in the gene ALPL encoding the tissue-non-specific alkaline phosphatase (TNAP). Detection rate of mutations in severe (perinatal and infantile) hypophosphatasia is around 95%. Serum alkaline phosphatase (AP) activity is markedly reduced in hypophosphatasia, while urinary phosphoethanolamine (PEA) is increased. Variable clinical expression ranges from a lethal prenatal type to lateonset short stature or only premature shedding of teeth. Six clinical forms are currently recognised: perinatal (lethal), prenatal benign, infantile, childhood, adult and odontohypophosphatasia. The inheritance pattern is variable, and incomplete penetrance has been reported. The prenatal form is usually inherited as an autosomal recessive trait; the rare benign variant is autosomal dominant. Age/Gestational week of manifestation: usually detectable by ultrasound during the second trimester (14–20 weeks). Clinical features: • Fractures • Short, deformed limbs; bony spurs protruding from the long bones (diagnostic sign) • Small thoracic cage, short ribs • Soft cranium, wide sutures, later craniosynostosis • Polyhydramnios • Biochemical anomalies: hypercalcemia, hypercalciuria, phosphoethanolaminuria, elevated plasma and urine inorganic pyrophosphate (PPi), decreased tissue and serum alkaline phosphatase Prenatal ultrasound features: the lethal perinatal form shows marked undermineralisation in utero; however, severe in utero presentation has also been reported to result postnatally in a mild hypophosphatasia phenotype with good clinical outcome. In the prenatal benign form, the initial severe findings improve during the third trimester and after birth; these clinical subtypes

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overlap in the prenatal period. Increased nuchal translucency (NT) is variably present. Prenatal scans of severe forms show markedly impaired mineralisation of the skeleton resulting in caput membranaceum, hypomineralisation or absent ossification of vertebral bodies with a sharp demarcation between ossified and unossified vertebrae and short, bowed long bones with cupped and ‘hyperechoic metaphyses with no acoustic shadowing’, particularly in the femora, a consequence of a heterogeneous and poorly mineralised metaphyseal hypertrophic cartilage. This is a newly identified ultrasound sign of hypophosphatasia. Occasionally fractures may be present. Affected fetuses may sometimes have skin-covered osteochondral spurs protruding from the forearms or legs. The ribs may be short and beaded and the thorax narrow, with a small thoracic cage. The head is large, with a thin cranial vault and consequent increased echogenicity of intracranial structures. 3D sonography contributes to the evaluation of craniofacial dysmorphism: enlargement of the metopic suture and cleft lip and palate (rare in this disorder). 3D helical CT may improve accuracy and provide additional details of the abnormal bones. Radiographic features: there is a spectrum of abnormality, which ranges from almost normal bone density and ossified skull vault (with wide sutures and a large anterior fontanelle) to severe generalised osteopenia with complete absence of ossification of the skull vault. There may be deficient or absent ossification of the facial bones, vertebral bodies (and neural arches), ribs, long tubular bones (predominantly ulna and fibula) and pelvic bones – any of these bones may be involved in any combination. There may be bowing, angulation and bony diaphyseal spurs of the tibiae and radii. The metaphyses may be flared and irregular. Lytic defects can affect the metaphyses, iliac bones and anterior rib ends. Long bone and rib fractures are a feature. Prognosis: lethal. Rare perinatal benign variants do exist, in which there is spontaneous progressive improvement in mineralisation and skeletal deformity over the course of the third trimester of pregnancy and postnatally. Differential diagnosis: osteogenesis imperfecta types 2 and 3 (p. 429), achondrogenesis type 1a, 1b and 2 (p. 58, 105, 256), thanatophoric dysplasia (p. 36), SMD type Sedeghatian (p. 262), cleidocranial dysplasia (p. 482), Campomelic dysplasia (p. 302).

DOI: 10.1201/9781003166948-96

Hypophosphatasia, Perinatal Lethal and Infantile Forms, ALPL-Related

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CASE 1: A stillbirth with lethal hypophosphatasia at 20 weeks of gestation. Postmortem radiographs and 3D CT images show unossified calvarial bones except for the frontal bones; short, slender, irregular and incompletely ossified ribs; ossification of only two lumbar and two sacral vertebral bodies; absent ossification of the neural arches; short and angulated long bones; and ossification defects of the metaphyses and iliac crests. Prenatal 2D and 3D ultrasound captures the findings seen on radiographs. Brain structures are unusually well visualised because of defective calvarial ossification. CASE 2: A stillbirth with lethal hypophosphatasia. Mineralisation defects are milder than those of Case 1. Prenatal ultrasound showed metaphyseal defects of the femur and underossified hand.

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CASES 3–7: Variable patterns of ossification defects in lethal or infantile types. The ossification defects have a random pattern. Examples include better-ossified vertebral bodies than neural arches (Cases 3–7), better ossified ulnae than radii (Cases 5 and 6) and better ossified frontal bones than other calvarial bones (Case 7). CASE 8: A neonate with infantile type. The axial skeleton and humerus are relatively well ossified. The ulna and radius show severe ossification defects. The metaphysis of the distal radius shows a deep ossification defect. The second metacarpal, fifth proximal phalanx and all distal phalanges are missing. The metaphysis of the fourth middle phalanx shows a deep ossification defect.

Hypophosphatasia, Perinatal Lethal and Infantile Forms, ALPL-Related

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CASE 9: A neonate with mild infantile type. The skeleton is relatively well ossified. However, metaphyseal bone defects are conspicuous in the proximal humerus and distal radius. Longitudinal radiolucencies are seen in the distal femora and proximal tibiae. The long bones are bowed. The right fibula shows a Bowdler spur. In this case, skeletal changes identified on ultrasound at 20 weeks of gestation became milder at birth (36 weeks of gestation). CASE 10: A neonate with prenatal benign type. The skeletal changes include sharp bowing of the femora and radii and ulnae and mild bowing of the humeri. Metaphyseal bone defects are absent. The right ulna shows a Bowdler spur. Prenatal US showed severe bowing of the femora (g) and mild bowing of the humeri (h).

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BIBLIOGRAPHY Brasseur-Daudruy M, Ickowicz V, Degre S et al. Hyperechoic metaphyses in hypophosphatasia: What does it mean? Pediatr Radiol. 2008; 38: 340–2. Comstock C, Bronsteen R, Lee W, Vettraino I. Mild hypophosphatasia in utero. J Ultrasound Med. 2005; 24: 707–9. Guguloth A, Aswani Y, Anandpara KM. Prenatal diagnosis of hypophosphatasia congenita using ultrasonography. Ultrasonography. 2016; 35: 83–6. Offiah AC, Vockley J, Munns CF, Murotsuk J. Differential diagnosis of perinatal hypophosphatasia: Radiologic perspectives. Pediatr Radiol. 2019; 49: 3–22. Simon-Bouy B, Taillandier A, Fauvert D et al. Hypophosphatasia: Molecular testing of 19 prenatal cases and discussion about genetic counselling. Prenat Diagn. 2008; 28: 993–8.

Fetal and Perinatal Skeletal Dysplasias Stevenson DA, Carey JC, Coburn SP et al. Autosomal recessive hypophosphatasia manifesting in utero with long bone deformity but showing spontaneous postnatal improvement. J Clin Endocrinol. 2008; 93: 3443–8. Watanabe A, Yamamasu S, Shinagawa T et al. Prenatal genetic diagnosis of severe perinatal (lethal) hypophosphatasia. J Nippon Med Sch. 2007; 74: 65–9. Witters I, Moerman P, Mornet E, Fryns JP. Positive maternal serum triple test screening in severe early onset hypophosphatasia. Prenat Diagn. 2004; 24: 494–7. Zankl A, Mornet E, Wong S. Specific ultrasonographic features of perinatal lethal hypophosphatasia. Am J Med Genet A. 2008; 146A: 1200–4.

91 Neonatal Hyperparathyroidism, Severe Form, CASR-Related

Synonyms: NSPH; NHPT; hyperparathyroidism – neonatal familial Confirmation of diagnosis: identification of biallelic pathogenic variants in CASR Frequency: unknown, rare Genetics: generally secondary to homozygous loss-offunction pathogenic variants in the CASR gene, which encodes the calcium-sensing receptor (CaSR), a member of the subfamily of G protein–coupled transmembrane receptors. CaSR controls parathormone (PTH) secretion and calcium urinary excretion in response to variations in serum calcium levels. Carriers of heterozygous mutations of the gene are affected by familial hypocalciuric hypercalcemia (FHH). It is reported that if the mutation is inherited from the father, NSHPT results; in contrast if the mutation is inherited from the mother, then neonatal hypoparathyroidism occurs. Sporadic forms of NSHPT have also been reported and associated with heterozygous de novo pathogenic variants in the CASR gene. Age/Gestational week of manifestation: usually manifests at birth or soon after. Clinical features: • At birth: hypotonia, respiratory distress, irritability • First few months: polyuria, dehydration, constipation, failure to thrive

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DOI: 10.1201/9781003166948-97

 

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• Multiple fractures, reduced mineralisation of the skeleton • Rib cage deformities • Biochemical characteristics: severe hypercalcemia, elevated alkaline phosphatase, marked hyperparathyroidism, relative hypocalciuria Prenatal ultrasound features: prenatal diagnosis has not been reported. Patients with severe neonatal hyperparathyroidism have been reported who were delivered at term after uneventful pregnancies. Prenatal diagnosis may therefore not be possible. Radiographic features: there is generalised osteopenia with long bone diaphyseal and metaphyseal fractures. The metaphyses are cupped and frayed. There may be subperiosteal bone resorption. Multiple rib fractures are also a feature. The thorax may be ‘bell-shaped’. The skull is poorly mineralised. Prognosis: lethal if untreated. The control of hypercalcemia can be obtained through the use of bisphosphonates and dialysis, but parathyroidectomy is generally indispensable. Differential diagnosis: other conditions with reduced bone mineralisation: osteogenesis imperfecta (p. 429); hypophosphatasia (p. 452); congenital rickets: short stature, craniotabes, hypotonia, hypocalcaemia, elevated serum alkaline phosphatase, ­secondary hyperparathyroidism, decreased 25-hydroxyvitamin D and normal 1,25-dihydroxyvitamin D serum levels. Treatment with calcium and vitamin D is necessary and sufficient in the main for the normalisation of the biochemical profile and clinical anomalies; mucolipidosis type II (p. 348).

 

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CASE 1: A neonate born prematurely at 30 + 5 weeks. (a–d) Antenatal US imaging showed bilateral shortening of the femora and humeri. Radiographs in the neonatal period show generalised osteopenia, poor ossification of the skull vault, multiple rib deformities and constriction of the proximal femora indicative of subperiosteal resorption. (e–h) Radiographs in infancy show slender, bowed long bones with metaphyseal irregularities and alleviated subperiosteal resorption.

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CASE 2: An infant. Radiographs show generalised osteopenia, rib deformities and slender, bowed long bones with metaphyseal constriction and destruction and large epiphyses. CASE 3: A neonate. The skeletal changes are similar to those of Case 2. Fetal CT shows defective skull ossification and slender long bones.

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BIBLIOGRAPHY Al-Kahalaf FA, Ismail A, Soliman AT et al. Neonatal severe hyperparathyroidism: Further clinical and molecular delineation. Eur J Pediatr. 2011; 170: 625–31. Al Nassar H, Machmouchi M, Alnosair A. Familial hyperparathyroidism: A diagnostic challenge and treatment challenge in Saudi Arabia. Cureus. 2022; 14: e28434. doi: 10.7759/ cureus.28434 Aubert-Mucca M, Dubucs C, Groussolles M et al. Prenatal features and neonatal management of severe hyperparathyroidism caused by the heterozygous inactivating calcium-sensing receptor variant, Arg185Gln: A case report and review of the literature. Bone Rep. 2021; 15: 101097. doi: 10.1016/j.bonr.2021.101097

Fetal and Perinatal Skeletal Dysplasias Hassan SS, Kempers M, Lugtenberg D et al. Challenges in diagnosis and management of neonatal hyperparathyroidism in a resource-limited country: A case series from a Sudanese family. Pan Afr Med J. 2021; 40: 105. doi: 10.11604/ pamj.2021.40.105.29527 Obermannova B, Banghova K, Sumnik Z et al. Unusually severe phenotype of neonatal primary hyperparathyroidism due to a heterozygous inactivating mutation in the CASR gene. Eur J Pediatr. 2009; 168: 569–73. Waller S, Kurzawinski T, Spitz L et al. Neonatal severe hyperparathyroidism: Genotype/phenotype correlation and the use of pamidronate as rescue therapy. Eur J Pediatr. 2004; 163: 589–94.

92 Metaphyseal Dysplasia, Jansen Type, PTHR1-Related

Synonyms: JMC; Jansen metaphyseal chondrodysplasia; ­Jansen metaphyseal dysostosis; metaphyseal chondrodysplasia Murk Jansen type; MCDJ Confirmation of diagnosis: identification of heterozygous gain-in-function PTHR1 variants with a combination of radiographic and biochemical abnormalities Frequency: rare; about 30 patients reported Genetics: autosomal dominant due to pathogenic variants in the gene PTHR1, which encodes the PTH/PTHrP receptor (both these hormones activate the receptor with equal efficiency and efficacy). PTHR1 belongs to the G protein–­coupled transmembrane receptor family. It activates the adenine ­cyclase and phospholipase C, thereby regulating the calcium ion homeostasis in the body. Pathogenic variants associated with MCDJ are gain-in-function and lead to a constitutional activation of the PTH/PTHrP receptor, causing hypercalcemia, hypophosphatemia and delayed chondrocyte differentiation. Age/Gestational week of manifestation: skeletal anomalies may be detected at 20+1 weeks of gestation. Clinical features: • Postnatal short stature, short limbs • Bell-shaped thorax • Facial dysmorphism, protruding eyes, high-arched palate, micrognathia, choanal stenosis, nephrocalcinosis • Severe hypercalcaemia, hypercalciuria, mild hypophosphatemia, normal PTH or PTHrP: usually asymptomatic Prenatal ultrasound features: ultrasound at 20 weeks may reveal a bell-shaped thorax and small chest circumference.

DOI: 10.1201/9781003166948-98

Transverse scan of the thorax and surface view of the ribs can show an abnormal wave-shape of the ribs with the concavity of the central portion. The facial profile shows microretrognathia. Overall fetal size, movements, bone mineralisation, shape of the cranium and vertebral bodies are usually normal. Radiographic features: radiographic features observed during infancy include diffuse demineralisation, sometimes with fractures; rickets-like metaphyseal changes; and erosion of the bone cortex and subperiosteal resorption. Cupping and fraying of the metaphyses, present from birth, becomes more apparent during childhood. These findings are associated with failure of the long bones to grow normally, resulting in severely reduced adult height. Sclerosis of the base of the skull is typically recognised in infancy, although the vault is undermineralised. There is marked mandibular hypoplasia. Prognosis: viable. Skeletal anomalies are very mild at birth, but are rapidly progressive postnatally, resulting in deformity and short stature. Neonates present with biochemical anomalies (hypercalcaemia, hypophosphatemia, hyperphosphaturia, high levels of 1,25-dihydroxyvitamin D3, high serum alkaline phosphatase, low to undetectable PTH and PTHrP), which can be initially completely asymptomatic. They often have feeding difficulties, vomiting, dehydration and respiratory distress. Teeth eruption is delayed. Over time, waddling gait, bowed legs, contracture deformities and expansion of the joints gradually develop. The sclerosis of the base of the skull may result in deafness and blindness. There may be premature fusion of the cranial sutures, requiring surgery. Instability in the cervical spine has been reported. Differential diagnosis: other causes of rickets, even though the biochemical findings are inconsistent with this diagnosis. Other metaphyseal dysplasias: metaphyseal dysplasia, McKusick type (p. 224).

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CASE 1: PTH was low. Slender, deformed ribs and a narrow thorax. Coarse trabecular pattern with demineralisation and frayed, irregular metaphyses and wide growth plates.

Metaphyseal Dysplasia, Jansen Type, PTHR1-Related

BIBLIOGRAPHY Gorvin CM. Genetic causes of neonatal and infantile hypercalcaemia. Pediatr Nephrol. 2022; 37: 289–301. Khan R, Oakes P, Fisahn C et al. Skull base and cervical spine involvement in Jansen syndrome: Case report. Pediatr Neurosurg. 2017; 52: 140–3. Nampoothiri S, Fernández-Rebollo E, Yesodharan D et al. Jansen metaphyseal chondrodysplasia due to heterozygous H223RPTH1R mutations with or without overt hypercalcemia. J Clin Endocrinol Metab. 2016; 101: 4283–9. Noda H, Guo J, Khatri A et al. An inverse agonist ligand of the PTH receptor partially rescues skeletal defects in a mouse model of Jansen’s metaphyseal chondrodysplasia. J Bone Miner Res. 2020; 35: 540–9.

463 Onuchic L, Ferraz-de-Souza B, Mendonca BB et al. Potential effects of alendronate on fibroblast growth factor 23 levels and effective control of hypercalciuria in an adult with Jansen’s metaphyseal chondrodysplasia. J Clin Endocrinol Metab. 2012; 97: 1098–103. Saito H, Noda H, Gatault P et al. Progression of mineral ion abnormalities in patients with Jansen metaphyseal chondrodysplasia. J Clin Endocrinol Metab. 2018; 103: 2660–9. Savoldi G, Izzi C, Signorelli M et al. Prenatal presentation and postnatal evolution of a patient with Jansen metaphyseal dysplasia with a novel missense mutation in PTH1R. Am J Med Genet A. 2013; 161: 2614–9.

93 Blomstrand Dysplasia, PTHR1-Related

Synonyms: chondrodysplasia Blomstrand type; BOCD Diagnostic confirmation: identification of biallelic pathogenic variants in the PTHR1 gene with compatible radiology Frequency: very rare. Approximately two dozen affected families have been reported. Genetics: autosomal recessive, caused by loss-of-function pathogenic variants in the gene PTHR1 mapped on chromosome 3p21.31 and encoding parathyroid hormone receptor-1 (PTHR1). PTHR1 binds PTH and PTHrP. PTH signalling through PTHR delays the hypertrophic differentiation of proliferating chondrocytes in normal growth plates; PTHrP signalling through PTHR1 regulates endochondral bone development and epithelial-mesenchymal interactions in the formation of the mammary glands and teeth. Loss of function of PTHR1 causes osteosclerosis, accelerated skeletal maturation and malformation of the breasts and teeth. Eiken dysplasia is a recessive, allelic disorder of BOCD. Heterozygous PTHR1 variants can be responsible for primary failure of tooth eruption. Activating dominant mutations of the same gene can cause metaphyseal chondrodysplasia Jansen type and a small proportion of cases of Ollier enchondromatosis. Age/Gestational week of manifestation: fetal abnormalities can be found by ultrasound during the first or early second trimester (11–14 weeks). The skeletal phenotype is fully blown in the second trimester. Clinical features: • • • •

Polyhydramnios, fetal hydrops Long narrow thorax with pulmonary hypoplasia Severe micromelia Facial abnormalities (proptosis, depressed nasal bridge, micrognathia, marked macroglossia) • Absent breasts and nipples • Malformed and impacted teeth • Preductal aortic coarctation and intestinal malrotation have been reported Prenatal ultrasound features: can be diagnosed as early as 12 weeks’ gestation, but more commonly early in the second

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trimester. Easy detectability by transvaginal ultrasound has been demonstrated in a family at risk, but there is intra- and interfamilial variability of the disorder. The extreme micromelia with broad metaphyses and short ribs is associated with increased bone density and short ribs. In contrast, the size of the hands and feet is nearly normal. The fetal abdomen is protuberant because of the small thorax, fetal ascites and/or hydrops. There is a large skull vault with underdevelopment of the skull base with hypoplasia of the face. As a result of this there is proptosis, micrognathia and apparent macroglossia due to the small oral cavity. Polyhydramnios may be present. Radiographic features: the triad of the skeletal phenotype include generalised osteosclerosis, metaphyseal undermodelling and, most distinctively, premature ossification of cartilage (advanced skeletal maturation). The skull vault is large with a prominent frontal bone. The skull base is short and sclerotic. The facial bones are small with a short mandible. There is premature ossification of the thyroid and hyoid cartilage. The thorax is narrow due to marked rib shortening, and the ribs are broad. The spine is normal in shape. The long bones are all severely short, while the hands and feet appear disproportionately large. The long bones show striking metaphyseal broadening and mid-diaphyseal narrowing. The radii and ulnae are bowed, and the radial heads dislocated. The carpal and tarsal bones show strikingly advanced ossification. Prognosis: lethal. Preterm delivery of a stillborn baby is common. No long-term survival has been known. Differential diagnosis: BOCD should be differentiated from other lethal/semi-lethal sclerosing bone dysplasias: Raine dysplasia (p. 403); prenatal-onset Caffey disease (p. 411); dysplastic cortical hyperostosis (Kozlowski-Tsuruta) (p. 416); lethal neonatal short limb dysplasia (Al-Gazali) (p. 418); infantile osteopetrosis (p. 388); pycnoachondrogenesis (achondrogenesis-like bone dysplasia associated with diffuse sclerosis of bones); desmosterolosis (a rare disorder of cholesterol biosynthesis). However, awareness of advanced skeletal age seen in BOCD facilitates the differential diagnosis. On prenatal ultrasound and prenatal CT, BOCD may be misdiagnosed with skeletal dysplasias, with severe metaphyseal broadening, such as Kniest dysplasia (p. 82) and fibrochondrogenesis (p. 95). Absence of platyspondyly in BOCD helps with the distinction.

DOI: 10.1201/9781003166948-99

Blomstrand Dysplasia, PTHR1-Related

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CASES 1–4: Generalised osteosclerosis; short tubular bones with wide metaphyses; narrow thorax, short, wide ribs, straight clavicles; dislocated radial heads. (b). Note advanced carpal ossification and protruding tongue (macroglossia) (b). Advanced ossification of the hyoid bone. CASES 5, 6: Generalised osteosclerosis; short tubular bones with wide metaphyses; narrow thorax, short, wide ribs, straight clavicles; dislocated radial heads; advanced carpal ossification.

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BIBLIOGRAPHY den Hollander NS, van der Harten HJ et al. First-trimester diagnosis of Blomstrand lethal osteochondrodysplasia. Am J Med Genet. 1997; 73: 345–50. Duchatelet S, Ostergaard E, Cortes D et al. Recessive mutations in PTHR1 cause contrasting skeletal dysplasias in Eiken and Blomstrand syndromes. Hum Mol Genet. 2005; 14: 1–5. Galera MF, de Silva Patrício FR, Lederman HM et al. Blomstrand chondrodysplasia: A lethal sclerosing skeletal dysplasia. Case report and review. Pediatr Radiol. 1999; 29: 842–5. Jobert AS, Zhang P, Couvineau A et al. Absence of functional receptors for parathyroid hormone and parathyroid hormone-related peptide in Blomstrand chondrodysplasia. J Clin Invest. 1998; 102: 34–40. Loshkajian A, Roume J, Stanescu V et al. Familial Blomstrand chondrodysplasia with advanced skeletal maturation: Further delineation. Am J Med Genet. 1997; 71: 283–8.

Fetal and Perinatal Skeletal Dysplasias Oostra RJ, van der Harten JJ, Rijnders WP et al. Blomstrand osteochondrodysplasia: Three novel cases and histological evidence for heterogeneity. Virchows Arch. 2000; 436: 28–35. Risom L, Christoffersen L, Daugaard-Jensen J et al. Identification of six novel PTH1R mutations in families with a history of primary failure of tooth eruption. PLoS One. 2013; 18;8(9): e74601. Wysolmerski JJ, Cormier S, Philbrick WM et al. Absence of functional type 1 parathyroid hormone (PTH)/PTH-related protein receptors in humans is associated with abnormal breast development and tooth impaction. Clin Endocrinol Metab. 2001; 86: 1788–94.

94 Hajdu-Cheyney Syndrome Including Serpentine Fibula Syndrome, NOTCH2-Related

Synonyms: serpentine fibula polycystic kidney syndrome, SFPKS; Hajdu-Cheney syndrome (HJCYS); arthrodentoosteodysplasia; acro-osteolysis with osteoporosis and changes in skull and mandible Confirmation of diagnosis: identification of heterozygous pathogenic variant in NOTCH2 associated with congruent clinical features Frequency: rare; about 100 cases of HJCYS have been reported, but its prevalence is likely to be higher. SFPKS is much rarer. Genetics: SFPKS is an autosomal dominant condition, and it represents the most severe end of the phenotypic spectrum of HJCYS. It is caused by heterozygous pathogenic variants in exon 34 of the gene NOTCH2, encoding a single-pass transmembrane protein belonging to the evolutionarily conserved NOTCH receptor family, which is activated through cell-cell contact. The mutations cause an impairment of the PEST degradation domain, which leads to a gain in function of the receptor. Notch signalling can lead to intercellular interactions, which enable groups of cells to function as a large congruous structure, with mechanisms of ‘lateral inhibition’ or ‘lateral induction’, which are pivotal in embryonic development and postnatal cellular maintenance. Age/Gestational age of manifestation: some craniofacial and limb abnormalities and heart and kidney anomalies can be detected in the second trimester (19–25 weeks). Clinical features: • Short stature • Shield thorax with wide-spaced nipples • Short neck with low posterior hairline; pterygium colli • Peculiar facial features: arched eyebrows, downward-slanting palpebral fissures, telecanthus, midface hypoplasia with full cheeks, low-set ears, microretrognathia • Joint laxity • Bowing of the leg and forearm; dislocation of the elbow

DOI: 10.1201/9781003166948-100

• • • •

Brachydactyly Cystic kidney Cataract Congenital heart anomalies (aortic coarctation, ventricular septal defect, valve abnormalities)

Prenatal ultrasound features: 2D and 3D ultrasound allow the detection of craniofacial dysmorphism including hypertelorism, prominent eyes, micrognathia, cleft lip/palate, bifid uvula and Wormian bones. Shortened and slightly bowed femora and ulnae may be present alongside bowed forearms and Sshaped fibulae. The symmetry of the changes of the long bones suggests these deformations are not the result of fractures. The kidneys may show increased parenchymal echogenicity and multiple cysts; cardiovascular anomalies (ventricular septal defects, aortic coarctation) may also be present. Radiographic features: the fontanelles and cranial sutures are wide. The ribs are thin, and the vertebral bodies may be tall (dolichospondyly). The long and short tubular bones show overtubulation. The fibulae show serpentine (S-shaped) bowing. The proximal radii are sharply angulated and may be associated with spur-like bone projections. The ulnae and femora may also be (mildly) bowed. With age, the SFPKS skeletal features evolve into those of classic HJCYS, including bathrocephaly with multiple Wormian bones, basilar invagination, generalised osteoporosis with vertebral compression fractures and acro-osteolysis. The age-dependent evolution of the SFPKS skeletal phenotype remains elusive. However, it is known that development of acro-osteolysis is much earlier in SFPKS than in classic HJCYS (early childhood vs. mid-childhood). Prognosis: lethal in infancy in the more severe cases, mostly secondary to respiratory distress. Survivors may show failure to thrive in infancy. The manifestations of affected children in late childhood seem to be indistinguishable from those of classic HJCYS, which comprise osteoporosis, hearing loss, clubbed fingers (acro-osteolysis) and premature loss of teeth. Craniofacial anomalies can include open sutures, platybasia and basilar invagination, which can cause severe neurological complications, including central respiratory arrest and sudden death. Osteoporotic fractures can cause bone deformities.

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Differential diagnosis: Alagille syndrome type 2 is allelic to HJCYS; like Alagille syndrome type 1, it may present with cholestatic liver disease and posterior embryotoxon. Melnick-Needles syndrome (p. 141) has metaphyseal undermodelling and not overtubulation of the tubular bones. Bowing of the fibulae and radii resembles that of mesomelic

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dysplasia Reardon-Kozlowski type (p. 281), yet broadening of the long bones in Reardon-Kozlowski contrasts with overtubulation in SFPKS. SFPKS should be differentiated from other disorders with congenital bowing, such as osteogenesis imperfecta (p. 429), hypophosphatasia (p. 452) and Campomelic dysplasia (p. 302).

 

 

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CASE 1: A neonate. Radiographs show wide fontanelles and overtubulation of the long and short tubular bones. The radii and ulnae, tibiae and fibulae are disproportionately short. The fibulae are narrow and serpentine in appearance. The proximal radii are slender and show sharp lateral angulation. The ulnae are mildly bowed, and the elbows dislocated.

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CASE 2: A neonate. The fontanelles are wide. The ribs are slender, and the vertebral bodies are tall. The tubular bones show overtubulation. The serpentine appearance of the fibulae and radii are more pronounced than seen in Case 1. The elbows are dislocated. The femora also show sharp lateral angulation. CASE 3: A neonate (a–c). Two years of age (e–g). Radiographs show overtubulation of the tubular bones with femoral bowing and serpentine fibulae and radii. The radii show spur-like bone projections at the apex of bending. Multiple renal cysts are seen on US. At age 2 years, there is acro-osteolysis of the index and little fingers (d).

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BIBLIOGRAPHY Canalis E, Zanotti S. Hajdu-Cheney syndrome: A review. Orphanet J Rare Dis. 2014; 9: 200. Currarino G. Hajdu-Cheney syndrome associated with serpentine fibulae and polycystic kidney disease. Pediatr Radiol. 2009; 39: 47–52. Gray MJ, Kim CA, Bertola DR et al. Serpentine fibula polycystic kidney syndrome is part of the phenotypic spectrum of Hajdu-Cheney syndrome. Eur J Hum Genet. 2012; 20: 122–4. Isidor B, Le Merrer M, Exner GU et al. Serpentine fibula-polycystic kidney syndrome caused by truncating mutations in NOTCH2. Hum Mutat. 2011; 32: 1239–42. Mašek J, Andersson ER. The developmental biology of genetic notch disorders. Development. 2017; 144: 1743–63.

Fetal and Perinatal Skeletal Dysplasias Martin BM, Ivanova MH, Sarukhanov A et al. Prenatal and postnatal findings in serpentine fibula polycystic kidney syndrome and a review of the NOTCH2 spectrum disorders. Am J Med Genet A. 2014; 164A: 2490–5. Narumi Y, Min BJ, Shimizu K et al. Clinical consequences in truncating mutations in exon 34 of NOTCH2: Report of six patients with Hajdu-Cheney syndrome and a patient with serpentine fibula polycystic kidney syndrome. polycystic kidney syndrome Am J Med Genet A. 2013; 161A: 518–26. Sjöqvist M, Andersson ER. Do as I say, Not(ch) as I do: Lateral control of cell fate. Dev Biol. 2019; 447: 58–70. Swan L, Gole G, Sabesan V et al. Congenital glaucoma: A novel ocular manifestation of Hajdu-Cheney syndrome. Case Rep Genet. 2018; 2018: 2508345.

95 Marfan Syndrome, FBN1-Related

Synonyms: MFS Diagnostic confirmation: identification of pathogenic variants in the FBN1 gene Frequency: while MFS is relatively common (1–2 in 10,000), neonatal MFS is very rare Genetics: MFS is an autosomal dominant disorder caused by pathogenic variants in FBN1 mapped on 15q21.1 and encoding fibrillin-1. Fibrillin-1 is a major constituent of extracellular microfibrils, which has wide distribution in both elastic and non-elastic connective tissues. Neonatal MFS is the severest variation of MFS, in which FBN1 mutations are grouped in exons 23–32, called the neonatal region. Age/Gestational week of manifestation: can be detected by ultrasound from the second trimester (22 weeks), but more commonly in the third trimester Clinical features (early-onset type): the diagnosis of MFS is based on the revised Ghent criteria, comprising the presence or absence of affected family members and a set of major and minor manifestations in different body systems. Other findings include skeletal changes (e.g., dolichostenomelia, arachnodactyly), facial features (e.g., dolichocephaly, micrognathia) and skin, lung, dura, eye, and cardiac valvular abnormalities. Neonatal MFS shares the cardinal features with classic MFS; however, the neonatal form shows several distinctive findings. Findings overlapping with the neonatal manifestation in classic MFS: • Ectopia lentis (cardinal feature) • Aortic dilatation, annuloaortic ectasia, aortic regurgitation (cardinal feature) • Mitral valve prolapse • Dolichostenomelia, muscle hypoplasia, loose skin • Arachnodactyly; camptodactyly • Pectus carinatum or excavatum; large joint contracture or laxity • Dolichocephaly, micrognathia • Findings distinctive in neonatal MFS: • Severe mitral and/or tricuspid valvular insufficiency • Congenital pulmonary emphysema • Progeroid face DOI: 10.1201/9781003166948-101

Prenatal ultrasound features: the major prenatal findings are related to the cardiovascular system, including dilatation of the aortic root; aortic, pulmonary, mitral and tricuspid regurgitation; and cardiomegaly. Skeletal abnormalities include increased length of the long bones and hyperflexed hands and feet. Radiographic features: in the neonatal period, severe arachnodactyly, thin ribs and overtubulation of the long bones are evident. The thorax is long and narrow. The long bones may be mildly bowed. Later, dolichospondyly (increased height of the vertebral bodies), posterior scalloping of the vertebral bodies as a result of dural ectasia and scoliosis may develop. Prognosis: neonatal MFS is a potentially lethal condition as a result of cardiopulmonary failure within the first few years of life. However, there may be a wide phenotypic spectrum, and a subset of affected individuals may survive when adequate management is provided. The prognosis is substantially dependent on the degree of cardiovascular involvement. Longer-term survivors may develop ocular problems (ectopia lentis, myopia, glaucoma and cataract) and musculoskeletal complications (scoliosis, pectus excavatum or pectus carinatum and joint laxity and/or contracture). Differential diagnosis: neonatal MFS should be distinguished from congenital syndromes with marfanoid habitus and/or vascular fragility: Shprintzen-Goldberg syndrome (p. 504); Beals syndrome – congenital contractual arachnodactyly also has crumpled ears and a pathogenic variant in FBN2; Loeys-Dietz syndrome has clubfeet, cleft palate and craniostenosis and heterozygouspathogenic variants in SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1 or TGFBR2; Ehlers-Danlos syndrome vascular type has clubfoot, hip dislocation or limb deficiency and a heterozygous pathogenic variant in COL3A1 or on biochemical analysis of type III procollagen from cultured fibroblasts; Ehlers-Danlos syndrome kyphoscoliotic type has joint hypermobility, severe hypotonia at birth, progressive kyphoscoliosis and fragility of the sclera and is caused by mutations in the PLOD1 gene or the FKBP14 gene, and it is inherited in an autosomal recessive manner; homocystinuria has widening of epiphyses and metaphyses of long bones, and the vertebral bodies are flattened.

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CASE 1: A neonate. Skeletal survey shows cardiomegaly, a long narrow thorax with thin ribs, overtubulation of the long bones and arachnodactyly. CASE 2: A male infant with a missense mutation in exon 25 of FBN1. Radiographs show a narrow thorax with thin ribs, prominent lesser trochanters and mild bowing of the femora.

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CASE 3: A neonate. Radiographs show thin ribs; mildly bowed, overtubulated long bones; and arachnodactyly. Cardiac US shows dilatation of the root of the aorta. CASE 4: A neonate. Radiographs show a narrow thorax with very thin, wavy ribs; overtubulation of the long bones with mild bowing; and severe arachnodactyly.

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BIBLIOGRAPHY Buntinx IM, Willems PJ, Spitaels SE et al. Neonatal Marfan syndrome with congenital arachnodactyly, flexion contractures, and severe cardiac valve insufficiency. J Med Genet. 1991; 28: 267–73. Dean JC. Marfan syndrome: Clinical diagnosis and management. Eur J Hum Genet. 2007; 15: 724–33. Gavilian C, Herraiz I, Granados MA et al. Prenatal diagnosis of neonatal Marfan syndrome. Prenat Diagn. 2011; 31: 610–13. Loeys BL, Dietz HC, Braverman AC et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010; 47: 476–85.

Fetal and Perinatal Skeletal Dysplasias Ramaswamy P, Lytrivi ID, Nguyen K et al. Neonatal Marfan syndrome: In utero presentation with aortic and pulmonary artery dilatation and successful repair of an acute flail mitral valve leaflet in infancy. Pediatr Cardiol. 2006; 27: 763–5. Stadié R, Geipel A, Heep A et al. Prenatal diagnosis of Marfan syndrome. Ultrasound Obstet Gynecol. 2007; 30: 119–22. Tognato E, Perona A, Aronica A, et al. Neonatal Marfan syndrome. Am J Perinatol. 2019; 36 (S02): S74–S76.

96 Marshall-Smith Syndrome, NFIX-Related

Synonyms: MRSHSS Diagnostic confirmation: identification of a monoallelic pathogenic variant in the NFIX gene Frequency: over 60 affected individuals have been described Genetics: MRSHSS is an autosomal dominant disorder caused by frameshift mutations, splice-site mutations or small deletions through exons 6–10 in NFIX, mapped on 19p13.1 and encoding a transcription factor belonging to the nuclear factor 1 (NFI) family. MRSHSS mutations escape nonsense-mediated messenger RNA (mRNA) decay and give rise to dominant negative effects. Hypomorphic mutations (mostly missense mutations and deletions) of NFIX affecting the DNA-binding/ dimerisation domain are responsible for a different clinical phenotype termed a Sotos-like overgrowth syndrome (Sotos syndrome 2 or Malan syndrome). Age/Gestational age of manifestation: affected individuals present with full-blown clinical and radiological features at birth. Facial dysmorphism may be identified on prenatal ultrasound in the third trimester. Clinical features: • Craniofacial dysmorphism (prominent forehead, hypertrichosis and bushy eyebrows, shallow orbits with prominent eyes, blue sclerae, depressed nasal bridge with upturned nose, low-set ears and micrognathia) • Prenatal accelerated skeletal maturation • Postnatal failure to thrive with growth parameters below the third centile • Upper airway obstruction due to micrognathia, choanal stenosis and laryngomalacia • Psychomotor retardation • Bone fragility and progressive scoliosis in older patients

DOI: 10.1201/9781003166948-102

Prenatal ultrasound features: fetal anomaly scan of the second trimester could detect unusual facial features, including a broad forehead with frontal bossing, depressed nasal bridge, anteverted nares, hypertelorism, proptosis and low-set posteriorly rotated ears. Microretrognathia and cleft palate can be present. Ventriculomegaly, corpus callosum agenesis/dysgenesis, septa pellucida absence with septo-optic dysplasia and cerebellar hypoplasia have been described. Omphalocele may be an occasional anomaly associated with Marshall-Smith syndrome. Polyhydramnios can occur in the third trimester. A multisuture craniosynostosis may represent a further complication of Marshall-Smith syndrome. Radiographic features: accelerated skeletal maturation (estimated bone age ranging from 3 years to 4 years in the neonatal period); broadening of the proximal and middle phalanges with pointed distal ends (bullet-shaped phalanges) and to a lesser extent of the metacarpals; hypoplasia of the facial bones and unusual downward protrusion of the supraoccipital bone behind the foramen magnum; osteosclerosis of the orbital rims and skull base; mild thoracic hypoplasia and mildly narrow ilia; overtubulation of the long bones (progressive with age). Prognosis: prenatal growth acceleration may have been described in MRSHSS, but it is not common. Postnatal failure to thrive is pronounced. Airway obstruction causes high mortality as neonates or infants; however, modern respiratory management allows survival into adulthood. Severe proptosis prevents the eyes from closing and may require surgical intervention. Overtubulation of the long bones with osteoporosis and bone fragility becomes apparent in childhood. Intellectual disability is variable and may be of the low-normal range. The distinctive phalangeal broadening and accelerated skeletal age become less prominent with age, which makes the diagnosis difficult in older affected children. Differential diagnosis: MRSHSS should be differentiated from other overgrowth syndromes with advanced bone age. However, advanced skeletal maturation in MRSHSS is much more severe than that seen in other overgrowth syndromes. In addition, bullet-shaped phalanges in MRSHSS are so distinctive that it enables a firm diagnosis on radiological grounds.

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CASES 1–3: Three neonates. Case 1 shows typical craniofacial dysmorphism (prominent forehead, bushy eyebrows, shallow orbits with prominent eyes, depressed nasal bridge with upturned nose, low-set ears and micrognathia). Radiographs of Case 2 (a–e). This also shows multiple Wormian bones.

Marshall-Smith Syndrome, NFIX-Related

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CASE 3: (a–d) Show distinctive broadening of the proximal and middle phalanges and to a lesser extent of the metacarpals, profoundly advanced skeletal maturation, sclerosis of the orbital rim and skull base and downward protrusion of the supraoccipital bone behind the foramen magnum.

BIBLIOGRAPHY Klaassens M, Morrogh D, Rosser EM et al. Malan syndrome: Sotos-like overgrowth with de novo NFIX sequence variants and deletions in six new patients and a review of the literature. Eur J Hum Genet. 2015; 23: 610–5. Malan V, Rajan D, Thomas S et al. Distinct effects of allelic NFIX mutations on nonsense-mediated mRNA decay engender either a Sotos-like or a Marshall-Smith syndrome. Am J Hum Genet. 2010; 87: 189–98. Martinez F, Marín-Reina P, Sanchis-Calvo A et al. Novel mutations of NFIX gene causing Marshall-Smith syndrome or Sotos-like syndrome: One gene, two phenotypes. Pediatr Res. 2015; 78: 533–9.

Schanze D, Neubauer D, Cormier-Daire V et al. Deletions in the 3’ part of the NFIX gene including a recurrent Alu-mediated deletion of exon 6 and 7 account for previously unexplained cases of Marshall-Smith syndrome. Hum Mutat. 2014; 35: 1092–100. Shaw AC, van Balkom ID, Bauer M et al. Phenotype and natural history in Marshall-Smith syndrome. Am J Med Genet A. 2010; 152A: 2714–26.

97 Proteus Syndrome, AKT1-Related Synonyms: PS; gigantism, partial, of hands and feet, naevi, hemihypertrophy and macrocephaly Diagnostic confirmation: identification of a specific somatic variant (mutation) in the AKT1 gene Frequency: probably fewer than 1 in 1,000,000; commonly misdiagnosed Genetics: PS is a mosaic overgrowth disorder. A somatic activating mutation (c.49G>A, p.Glu17Lys) in an oncogene AKT1 has been found. AKT1 is mapped on 14q32.3 and encodes the protein kinase AKT or protein kinase B (PKB), which is a crucial mediator of cell proliferation and apoptosis. This finding would support the Happle somatic mosaic hypothesis, according to which autosomal lethal genes may survive only in a mosaic state and would explain the characteristics of this syndrome. Non-haematopoietic cell samples are usually required to reveal the AKT1 somatic mutation. Germline PTEN mutations were previously reported in a few cases with PS. However, it is currently thought that the PTEN mutations cause only superficially similar phenotypes (see the differential diagnosis). Age/Gestational week of manifestation: disproportionate overgrowth may be perinatally detected. In most patients, however, the clinical features develop after 6 months of age. Clinical features: affected individuals show protean presentations; hence, the disorder is named after the Greek god, Proteus, who could change shape to avoid capture. • Cerebriform connective tissue naevi most commonly affecting the plantar surface of the feet: the most specific, but not absolutely pathognomonic • Disproportionate or segmental overgrowth in any tissues: asymmetric, distorting and relentlessly progressive • Skeletal overgrowth: limb overgrowth particularly common in digits and juxta-articular region; hyperostosis of the skull and external auditory canal; megaspondyly • Extraskeletal overgrowth: lipomatous overgrowth (may be associated with regional lipoatrophy); vascular (capillary and venous) and lymphatic malformation; asymmetric muscle development; visceromegaly, particularly splenic enlargement, epibulbar dermoids

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• Linear verrucous epidermal naevi; maculae with hyperpigmentation and/or hypopigmentation • Rarely brain malformation (hemimegalencephaly, cortical dysgenesis) • Lung bullae; susceptibility to venous thrombosis • Increased tumorigenesis • Sometimes mild craniofacial dysmorphism (dolichocephaly, long face, depressed nasal bridge, downslanting palpebral fissures, anteverted nares) Prenatal ultrasound features: a specific antenatal diagnosis is difficult, and there are very few reports. One case reported showed an abdominal cystic lymphangioma at 17 weeks of gestation, but only diagnosed at 26 weeks, as it was then combined with enlargement of a limb and malposition of the fingers and toes. Autopsy at 28 weeks confirmed the diagnosis of Proteus syndrome with more typical features (including hemihypertrophy, macrodactyly of one toe and hemimegalencephaly). The mass was confirmed to be a cystic lymphangioma. The authors suggest that the antenatal identification of an unusually sited cystic mass should prompt careful examination for other features of Proteus syndrome. Another case was detected at 22+5 weeks, showing macrocephaly, bilateral choroid plexus cysts, frontal bossing, midfacial hypoplasia and hypertelorism. Additional anomalies included bell-shaped chest, caliectasis of the right kidney, cutaneous syndactyly and bilateral clubfeet. Autopsy at 23 weeks revealed megalencephaly, periventricular nodular heterotopia, enlarged germinal matrix, focal polymicrogyria and vascular malformations on the right flank and left leg. A third case was detected at 23 weeks. Ultrasound showed macrocrania with frontal bossing and an enlarged third ventricle without limb overgrowth. Chromosomal microarray results were normal. Fetal MRI at 27 weeks demonstrated megalencephaly, polymicrogyria, grey matter heterotopia, enlarged third ventricle, dilated lateral ventricles, bilateral eyeball enlargement and segmental dilation of the umbilical vein. Exome sequencing performed on cultured amniocytes identified a pathogenic variant in AKT1. Radiographic features: irregular hyperostosis distorting the shape of the bones and manifesting as macrodactyly, epiphyseal and juxtaepiphyseal hyperostosis and elongation/broadening of the long bones; megaspondylodysplasia; and hyperostosis of the calvarium and external auditory canal.

DOI: 10.1201/9781003166948-103

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Prognosis: affected neonates and young infants may be normal or show only very mild segmental overgrowth. However, they develop a progressive, severe and unremitting overgrowth that starts in late infancy and early childhood. The relentless overgrowth gives rise to protean cutaneous, visceral and musculoskeletal complications. Intellectual disability may be present but is not a constant feature. The incidence of tumours is increased, particularly of bilateral ovarian cystadenomas and parotid monomorphic adenoma. Lung bullae may cause severe lung dysfunction and even mortality. There is susceptibility to venous thrombosis that may cause fatal pulmonary emboli. Differential diagnosis: PS should be differentiated from other segmental overgrowth syndromes: PTEN-related overgrowth syndromes, e.g., type 2 segmental Cowden disease alternatively

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termed SOLAMEN syndrome (segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal naevi) and Bannayan-Riley-Ruvalcaba syndrome; PIK3CA-related overgrowth syndromes (PROS), e.g., CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi and skeletal/spinal abnormalities) and Klippel-Trenaunay-Weber syndrome; other overgrowth syndromes; i.e., encephalocraniocutaneous lipomatosis and linear sebaceous naevus syndrome. PROS is most frequently misdiagnosed with PS; however, it is postulated that ballooning overgrowth in PROS contrasts with distorting overgrowth in PS. In principle, overgrowth syndromes, except PS, show simple hypertrophy of bone. Epiphyseal and/or juxtaepiphyseal hyperostosis in PS resembles that of dysplasia epiphysealis hemimelica (Trevor disease). ‘Severe cases with dysplasia epiphysealis hemimelica’ may be bone-restricted PS.

 

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CASE 1: (a) 1 month and (b) 1 year: the left foot shows mild soft tissue overgrowth. (c) 1.5 years: lipomatous overgrowth of the back develops. (d–g) 9 years: there is megalospondylydysplasia (large pedicles and vertebral bodies of the left side of the lower thoracic spine), dorsal lipomatosis seen on MRI, malalignment of the left toes due to progressive soft tissue overgrowth and development of soft tissue overgrowth of the right foot; the overgrowth pattern is ballooning and is indistinguishable from that of PROS (PIK3CA-related overgrowth syndrome).

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CASE 2: (a, b) 2 years; (c) 2 years and 9 months: there is distorting macrodactyly affecting the left second and third fingers, right third finger and both great toes. CASE 3: (a–c) 1 year and 11 months: there is epiphyseal overgrowth of the left proximal femoral epiphysis and left talus and intraarticular ectopic ossifications in the right hip and both knees. The epiphyseal and intraarticular changes resemble that of dysplasia epiphysealis hemimelica (Trevor disease).

 

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BIBLIOGRAPHY Abell K, Tolusso L, Smith N et al. Prenatal diagnosis of proteus syndrome: Diagnosis of an AKT1 mutation from amniocytes. Birth Defects Res. 2020; 112: 1733–7. Biesecker LG, Sapp JC. Proteus Syndrome. 2012 [updated 2019 Jan 10]. In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2021. Bornstein E, Bacino CA, Maliszewski K, et al. Isolated fetal macrodactyly: Phenotypic and genetic disparities in mosaic overgrowth syndrome. J Ultrasound Med. 2014; 33: 1305–7. Fogarty L, Currie L, Skidmore D et al. Prenatal diagnosis of a fetus with proteus syndrome. Prenat Diagn. 2018; 38: 467–70. Happle R. Type 2 segmental Cowden disease vs. proteus syndrome. Br J Dermatol. 2007; 156: 1089–90. Keppler-Noreuil KM, Sapp JC, Lindhurst MJ et al. Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum. Am J Med Genet A. 2014; 164A: 1713–33.

481 Lindhurst MJ, Sapp JC, Teer JK et al. A mosaic activating mutation in AKT1 associated with the proteus syndrome. N Engl J Med. 2011; 365: 611–19. Martinez-Lopez A, Blasco-Morente G, Perez-Lopez I et al. CLOVES syndrome: Review of a PIK3CA-related overgrowth spectrum (PROS). Clin Genet. 2017; 91: 14–21. Pazzaglia UE, Beluffi G, Bonaspetti G et al. Bone malformations in proteus syndrome: An analysis of bone structural changes and their evolution during growth. Pediatr Radiol. 2007; 37: 829–35. Sapp JC, Buser A, Burton-Akright J et al. A dyadic genotypephenotype approach to diagnostic criteria for proteus syndrome. Am J Med Genet C Semin Med Genet. 2019; 181: 565–70. Sigaudy S, Fredouille C, Gambarelli D et al. Prenatal ultrasonographic findings in proteus syndrome. Prenat Diagn. 1998; 18: 1091–4. Turner JT, Cohen MM Jr, Biesecker LG. Reassessment of the proteus syndrome literature: Application of diagnostic criteria to published cases. Am J Med Genet A. 2004; 130A: 111–22.

98 Cleidocranial Dysplasia, RUNX2-Related

Synonyms: CCD Confirmation of diagnosis: mutations in RUNX2 or the typical clinical and radiographic features Frequency: 1 in 1,000,000 Genetics: autosomal dominant, caused by mutations in RUNX2, encoding transcription factor CBFA1; detection rate is 70–85%. RUNX2 is a transcription factor essential for the differentiation of osteoblasts during intramembranous ossification; it also regulates chondrocyte maturation in the endochondral ossification process. Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester (15 weeks) in high-risk pregnancies. Clinical features: • Abnormally large, wide-open fontanelles, which may remain open throughout life; delayed closure of the skull sutures; midface hypoplasia • Hypoplastic or absent clavicles resulting in narrow shoulders • Dental anomalies: delayed eruption of secondary dentition, permanence of primary teeth, supernumerary teeth, dental crowding, malocclusion • Brachydactyly, tapering fingers, short, broad thumbs • Mild short stature • Occasional fractures, pseudarthroses, kyphoscoliosis Prenatal ultrasound features: most fetuses have been detected because of a positive family history, based on identification of clavicular abnormalities. Prenatal diagnosis of nasal bone aplasia/hypoplasia is a potential marker for cleidocranial dysplasia, improving early detection of affected fetuses with a negative family history. Ultrasound examination shows hypomineralisation of the skull, demonstrated by the unusually clear view of the intracranial structures, wide sutures, frontoparietal bossing and relatively low nasal bridge. Later in the second trimester, a slight to moderate shortening of long bones may be seen. Partial to complete aplasia of the clavicle may be found. Fetal movements may cause bending and twisting of the clavicles; sometimes pseudarthrosis is identified. The forms with minor clavicular hypoplasia and moderately short limbs

482

are usually unrecognised. Maximum-mode three-dimensional ultrasound enables clear visualisation of the widened fontanelles, sutures, Wormian bones, calvarial hypomineralisation, brachycephaly, midfacial hypoplasia and micrognathia. A panoramic ultrasound image of the fetal tooth buds can be obtained between 14 and 28 weeks of gestation, but the optimal window for imaging and the stage of dental mineralisation is at 26–28 weeks of gestation. A dental panorama using 3D ultrasound can detect the number, location and shape of the 20 deciduous teeth and diagnose abnormal dentition, including variable numbers of supernumerary teeth along with dental crowding that are present in CCD. Radiographic features: bone density is normal or slightly reduced. In the skull there are multiple Wormian bones, wide sutures and fontanelles. The biparietal diameter is relatively wide. The clavicles are short or absent or may have unilateral or bilateral pseudarthroses. Absence of clavicles results in a narrow upper thorax and a low shoulder girdle. In the spine there is some underossification of the neural arches, and the bodies appear rounded. The ilia are narrow and vertical and the pubic rami short or even absent. There is often coxa valga, and the capital femoral epiphyses appear rounded. In the hands there are variable changes with pseudoepiphyses of all the metacarpals, short middle and distal phalanges (sometimes with cone-shaped epiphyses) and there may be acro-osteolysis. Rarely, long bone pseudarthroses occur. Cleidocranial dysplasia may be seen in association with hypophosphatasia with a combination of radiographic features and with the biochemical markers. These patients have the additional findings of decreased bone density, long bone bowing and fracturing or pseudarthroses and sometimes kyphoscoliosis. Prognosis: viable – intellect is usually normal; motor milestones are delayed due to orthopaedic problems (pes planus, genu valgum). Recurrent sinus infections and conductive hearing loss can occur. Other complications include fractures, scoliosis, joint dislocation (shoulders, elbows) and, rarely, long bone pseudarthrosis. Differential diagnosis: Cousin syndrome (p. 548); parietal foramina with cleidocranial dysplasia: similar to CCD, the clavicular involvement is milder, there are no dental abnormalities and parietal foramina are typically present. Caused by mutations in MSX2. Crane-Heise syndrome: severe rare lethal syndrome characterised by disproportionately large and scarcely

DOI: 10.1201/9781003166948-104

Cleidocranial Dysplasia, RUNX2-Related

483

mineralised cranium, cleft lip and palate, low-set dysplastic ears, hypoplastic clavicles and scapulae, agenesis of some cervical vertebrae and talipes. Mandibuloacral dysplasia: progressive ageing disorder caused by recessive mutations of the genes LMNA and ZMPSTE24. Main features include short stature, delayed closure of cranial sutures, mandibular hypoplasia and dysplastic clavicles. Over time the following features may develop: alopecia, stiff joints, acro-osteolysis, early tooth loss,

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atrophy of the skin and decreased subcutaneous fat. Pycnodysostosis (p. 394); Yunis-Varon syndrome (p. 488); CDAGS syndrome: craniosynostosis and paradoxically delayed closure of the fontanelles, clavicular hypoplasia, anal and genitourinary malformations and skin eruption (porokeratosis); hypophosphatasia (p. 452); congenital pseudarthrosis of the clavicle; cytogenetic abnormalities; 8p22 duplication; partial trisomy 11q; partial trisomy 11q/22q; trisomy 20p.

 

 

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CASE 1: A 23-week-old fetus: Wormian bones, bilateral clavicular pseudarthroses, deficient ossification pubic rami, oval vertebral bodies with coronal clefts, hypoplastic terminal phalanges. CASE 2: Prenatal US at 23 weeks’ gestation shows a wide-open anterior fontanelle and depressed nasal bridge.

484

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CASE 3: Multiple Wormian bones; wide fontanelles and sutures; absent ossification of pubic rami. CASE 4: Hypoplastic clavicles; absent ossification of pubic rami, coxa valga; short middle and terminal phalanges with tapering of the terminal phalanges. CASE 5: Wide sutures and multiple Wormian bones.

Cleidocranial Dysplasia, RUNX2-Related

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CASE 6: After the diagnosis of CCD in this fetus, genetic and radiological assessment identified that the father was affected by CCD. Molecular analysis revealed a new heterozygous pathogenic mutation in RUNX2: c.209dup p.(Gln71Alafs*90). (a) 2D US. Axial scan of the fetal head at 24+5 weeks of gestation showing unusually well-defined brain structures in the hemisphere proximal to the transducer, suggesting hypomineralisation of the skull bones and widening of the coronal sutures. Parietal bossing is evident. (b, c) 3D US maximum-mode rendering is the method of choice for evaluating the cranial sutures. This case highlights abnormally large metopic and coronal sutures. (d) 3D US maximum mode demonstrates widening of the coronal suture and absence of the squamous temporal bone. (e) 2D US. During fetal motion, a change and angulation of the clavicle axis are present, suggesting a pseudarthrosis (white arrows).

486

Fetal and Perinatal Skeletal Dysplasias

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CASE 6: (f) Pregnancy at 27 weeks of gestation; 3D US multiplanar display maximum mode and tomographic mode. Abnormal fetal dentition includes the number, location and shape of the deciduous teeth. CCD is characterised by a variable number of supernumerary teeth along with dental crowding detectable with US. (g) Transabdominal 2D US. Sagittal scan of the fetal head. Wide sutures and large anterior fontanelle permit optimal demonstration of the midline intracranial structures. (h) 3D US maximum mode. Frontal view showing a remarkably wide metopic suture (white arrows). 3D US HD live. (i) Fetal face in profile highlights a depressed nasal bridge and flat midface.

Cleidocranial Dysplasia, RUNX2-Related

BIBLIOGRAPHY Bufalino A, Paranaíba LM, Gouvêa AF et al. Cleidocranial dysplasia: Oral features and genetic analysis of 11 patients. Oral Dis. 2012 Mar; 18(2): 184–90. doi: 10.1111/j.16010825.2011.01862.x. Epub 2011 Oct 24. El-Gharbawy AH, Peeden JN, Lachman RS et al. Severe cleidocranial dysplasia and hypophosphatasia in a child with microdeletion of the C-terminal region of RUNX2. Am J Med Genet A. 2010; 152A: 169–74. Franceschi R, Stringari G, Soli F et al. Newborn with cleidocranial dysplasia. Skeletal Radiol. 2022; 51: 2351–2. Gao X, Li K, Fan Y et al. Identification of RunX2 variants associated with cleidocranial dysplasia. Hereditas. 2019; 156: 31. Garcia-Minaur S, Mavrogiannis LA, Rannan-Eliya SV et al. Parietal foramina with cleidocranial dysplasia is caused by mutation in MSX2. Europ J Hum Genet. 2003; 11: 892–905. Hermann NV, Hove HD, Jørgensen C et al. Prenatal 3D ultrasound diagnostics in cleidocranial dysplasia. Fetal Diagn Ther. 2009; 25: 36–9. Lou Y, Javed A, Hussain S et al. A Runx2 threshold for the cleidocranial dysplasia phenotype. Human Molecular Genetics. 2009; 18: 556–68.

487 Lu J, Sahota DS, Poon LC et al. Objective assessment of the fetal facial profile at second and third trimester of pregnancy. Prenat Diagn. 2019; 39: 107–15. Morava E, Kárteszi J, Weisenbach J et al. Cleidocranial dysplasia with decreased bone density and biochemical findings of hypophosphatasia. Eur J Pediatr. 2002; 161: 619–22. Paladini D, Lamberti A, Agangi A et al. Cleidocranial dysostosis: Prenatal ultrasound diagnosis of a late onset form. Ultrasound Obstet Gynecol. 2000; 16: 100–2. Soto E, Richani K, Gonçalves LF et al. Three-dimensional ultrasound in the prenatal diagnosis of cleidocranial dysplasia associated with B-cell immunodeficiency. Ultrasound Obstet Gynecol. 2006; 27: 574–9. Unger S, Mornet E, Mundlos S et al. Severe cleidocranial dysplasia can mimic hypophosphatasia. Eur J Pediatr. 2002; 161: 623–6. Xue R, Zhang G, Chen X, Ye X. Cleidocranial dysplasia causing respiratory distress in neonates: A case report and literature review. Front Genet. 2021; 12: 696685. doi: 10.3389/ fgene.2021.696685 Zhang J, Li YZ, Chen WQ et al. Genome sequencing identified a novel exonic microdeletion in the RUNX2 gene that causes cleidocranial dysplasia. Clin Chim Acta. 2022; 528: 6–12.

99 Yunis-Varon Dysplasia, FIG4- and VAC14-Related

Synonyms: YVS; cleidocranial dysplasia with micrognathia, absent thumbs and distal aphalangia Diagnostic confirmation: identification of biallelic pathogenic variants of the FIG4 gene Frequency: very rare – a few dozen cases reported Genetics: an autosomal recessive condition. Phosphatidylinositol 3,5-bisphosphate or PI(3,5)P2 in endosomal membranes plays an important role in formation and absorption of intracellular transport vesicles. FIG4 is mapped on 6q21 and encodes PI(3,5)P2 5-phosphatase, alternatively named SAC domaincontaining protein 3 (Sac3). Sac3, together with PI(3,5)P2synthesising enzyme (PIKFYVE), and its activator (VAC14), tightly regulates the level of PI(3,5)P2 in endosomal membranes. Dysregulation of PI(3,5)P2 gives rise to intracytoplasmic vacuoles in multiorgan cells, including the neuron, muscle, heart, cartilage and fibroblasts. Thus, YVS was once assumed to be a lysosome storage disease. Biallelic pathogenic variants in FIG4 are also responsible for neurological disorders, including Charcot-Marie-Tooth disease type-4J (CMT4J), polymicrogyria and striatonigral degeneration. Age/Gestational week of manifestation: YVS can be detected by ultrasound during the second or third trimester of pregnancy (16–30 weeks). Clinical features: • Fetal hydrops and polyhydramnios in a proportion of cases • Prenatal and postnatal growth deficiency • Hypoplastic or absent clavicles • Hypoplastic or absent thumbs and great toes • Hypoplastic distal phalanges with hypoplastic or aplastic nails of other digits • Craniofacial abnormalities: craniofacial disproportion with hypoplastic facial bones; microcephaly in a minority of cases; hypomineralisation of the skull with widely open fontanelles; small, proptotic eyes; dysplastic pinna; full cheeks; anteverted nostrils; short philtrum, thin lips, labiogingival retraction, narrow or cleft palate, micrognathia • Ectodermal abnormalities: sparse hair, eyebrows and eyelashes; broad alveolar ridge; hypodontia, delayed dental eruption and premature loss of deciduous teeth 488

• Brain anomalies: Dandy-Walker malformation, hydrocephalus, agenesis of corpus callosum, hypoplasia of the cerebellar vermis • Other possible malformations: sclerocornea and cataracts; genital abnormalities: congenital heart defect and cardiomegaly Prenatal ultrasound features: sonography in an at-risk fetus at 18 weeks showed four digits on each limb. The diagnosis was suggested by fetoscopy confirming the absence of thumbs and halluces. Another case was detected at 29 weeks’ gestation identifying absent thumbs and halluces. On ultrasound there is growth retardation before birth (approximately 50% of patients). The most frequent craniofacial abnormalities are wide sutures with large fontanelles (95%), detectable with three-dimensional ultrasound; prominent eyes (81%) due to midfacial hypoplasia; mild hypertelorism; cleft palate; and micrognathia (100%). Several structural central nervous system abnormalities can be detected including hydrocephalus with DandyWalker malformation, hypoplasia of the cerebellar vermis and agenesis or hypoplasia of the corpus callosum. An accurate and complete ultrasound examination includes assessment of the fetal hands and feet showing agenesis/hypoplasia of thumbs and halluces (91% and 95%, respectively) and distal/middle phalangeal hypoplasia or aplasia of hands and feet. Clavicular abnormalities (hypoplasia or agenesis) are present in 56–74% and reduced ossification of the sternum in 30–89%. Congenital heart malformations include ventricular septal defect and cardiac hypertrophy. Polyhydramnios and hydrops fetalis may be associated. Radiographic features: the hallmarks include an extremely poorly ossified skull vault with wide sutures, and large fontanelles, hypoplastic facial bones, clavicular hypoplasia, slender ribs, slender long bones with flared metaphyses occasionally associated with fractures, short or absent thumbs and halluces and absent or hypoplastic distal and middle phalanges. Prognosis: usually lethal in infancy. Neonates are short and show poor growth. There is usually severe developmental delay. Cardiac anomalies are not common, but when present they are severe, including biventricular hypertrophy and cardiomegaly. Severe hearing impairment and papillomacular atrophic chorioretinopathy with ‘salt-and-pepper’ appearance have been reported in individual cases. Differential diagnosis: the unique combination of defective calvarial ossification, clavicular hypoplasia and hypoplasia of

DOI: 10.1201/9781003166948-105

Yunis-Varon Dysplasia, FIG4- and VAC14-Related

489

the great toes and thumbs is sufficient to make the diagnosis. However, the combination of the former two findings may raise a suspicion of certain disorders, e.g., cleidocranial dysplasia (p. 482), Crane-Heise syndrome (a rare, occasionally lethal syndrome characterised by disproportionately large and barely mineralised cranium, cleft lip and palate, low-set dysplastic

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ears, hypoplastic clavicles and scapulae, agenesis of some cervical vertebrae and talipes) and mandibuloacral dysplasia (a progeroid syndrome with short stature, delayed closure of cranial sutures, mandibular hypoplasia, dysplastic clavicles, stiff joints, acro-osteolysis, alopecia, early loss of the teeth, atrophy of the skin and subcutaneous fat atrophy.

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CASES 1, 2: These female infant siblings died at 3 and 7 weeks. There were craniofacial abnormalities including relative macrocephaly, a wide anterior fontanelle, a flat face and small jaw. The thumbs and halluces were absent. They also had multiple skeletal abnormalities with slender long bones and ribs, flared metaphyses, short narrow fingers with absent distal phalanges, virtually absent ossification of the skull vault, tall vertebral bodies, supra-acetabular constrictions and several fractures.

490

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CASE 3: The first child of normal parents. A second affected sibling was identified on an 18-week US scan because of absent thumbs and halluces and underwent a termination of pregnancy. The face was dysmorphic with prominent eyes, indentation of the temples, opaque iris, low-set ears, absent earlobes, small nose and high arched palate. The nails were hypoplastic. Radiographs showed slender long bones and ribs, flared metaphyses, absent thumbs and halluces, and distal phalanges of the digits. The infant became oxygen dependent at 3 months and died at 4 months.

BIBLIOGRAPHY Basel-Vanagaite L, Kornreich L, Schiller O. Yunis-Varon syndrome: Further delineation of the phenotype. Am J Med Genet A. 2008; 146A: 532–7. Campeau PM, Lenk GM, Lu JT et al. Yunis-Varon syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase. Am J Hum Genet. 2013; 92: 781–91. Corona-Rivera JR, Romo-Huerta CO, Lopez-Marure E. New ocular findings in two sisters with Yunis-Varon syndrome and literature review. Eur J Med Genet. 2011; 54: 76–81. Lenk GM, Szymanska K, Debska-Vielhaber G et al. Biallelic mutations of VAC14 in pediatric-onset neurological disease. Am J Hum Genet. 2016; 99: 188–94.

Lines MA, Ito Y, Kernohan KD et al. Yunis-Varon syndrome caused by biallelic VAC14 mutations. Eur J Hum Genet. 2017; 25: 1049–54. Siddique AW, Ahmed Z, Haider A et al. Univ-Varon. J Ayub Med Coll Abbottabad. 2019; 31: 290–2. Umair M, Alkharfy TM, Sajjad S et al. FIG4-associated YunisVaron syndrome: Identification of a novel missense variant. Mol Syndromol. 2021; 12: 386–92. Wright GC, Brown R, Grayton H et al. Clinical and radiological characterization of novel FIG4-related combined system disease with neuropathy. Clin Genet. 2020; 98: 147–54.

100 Pfeiffer Syndrome, FGFR1- and FGFR2-Related

Synonyms: acrocephalosyndactyly, type V; ACS5; ACS V; Noack syndrome; craniofacial-skeletal-dermatologic dysplasia Confirmation of diagnosis: identification of pathogenic variants in FGFR1 or FGFR2 with appropriate clinical findings Frequency: 1 in 100,000 Genetics: autosomal dominant, may be caused by heterozygous pathogenic variants in the gene FGFR1 (8p12) or in FGFR2 (10q26). In a proportion of families molecular and linkage analyses exclude involvement of these loci; therefore, a broader genetic heterogeneity is likely. FGFR1 and FGFR2 are expressed during embryogenesis in cartilage and bone precursors that will form the craniofacial and apical skeleton. The promiscuous binding of various FGFs to both receptors induces their dimerisation and activation of intrinsic tyrosine kinase, which initiates intracellular cascade signalling. FGFR1 and FGFR2 variants are always missense, gainin-function. FGFR2 variants are usually of paternal origin; they are thought to convey an advantage in sperm production. Advanced paternal age is common in affected cases. Pathogenic variants in FGFR1 are usually associated with milder phenotypes. Age/Gestational week of manifestation: may be detected by ultrasound during the second trimester (20 weeks). Clinical features: Pfeiffer syndrome is subdivided into three clinical subtypes depending on severity. Common features are: • Coronal and lambdoid suture synostosis • Midface hypoplasia, ocular hypertelorism, proptosis, small nose • Cleft palate • Variable degree of brachydactyly, broad and medially deviated thumbs and great toes Pfeiffer syndrome type 1: • Brachycephaly, moderate to severe midface hypoplasia, occasionally hydrocephalus • Hearing loss may be a feature

DOI: 10.1201/9781003166948-106

Pfeiffer syndrome type 2: • Cloverleaf skull, extreme proptosis, hydrocephalus • Ankylosis of elbows and knees • Choanal stenosis or atresia, laryngo/tracheo/ bronchomalacia Pfeiffer syndrome type 3: • Turribrachycephalic skull, extreme proptosis, hydrocephalus • Ankylosis of elbows and knees Prenatal ultrasound features: the diagnosis can be made using two- and three-dimensional ultrasound, which identifies a combination of craniosynostosis (with or without cloverleaf skull), hypertelorism, proptosis and a broad thumb. Other antenatal findings include glossoptosis, clubfeet with broad great toes and frontal bossing (midface hypoplasia). Radiographic features: there are varying degrees of premature fusion of the sutures depending on the type (cloverleaf skull in type 2). The frontal bone is high and prominent, the facial bones small and there is relative prognathism. In the hands the thumbs are broad and the middle phalanges hypoplastic with wide distal phalanges. The feet have broad halluces in the valgus position due to a hypoplastic, triangular, medially placed proximal phalanx, or there may be preaxial polydactyly. The middle phalanges are absent or hypoplastic, and there is variable soft tissue syndactyly. In types 2 and 3 there is elbow synostosis with a right-angled flexion deformity (usually humeroradial, but occasionally humeroulnar). There may be knee ankylosis. Vertebral body and neural arch fusions may be present at any level but most commonly in the cervical region. Prognosis: usually viable – Pfeiffer syndrome type 1 is milder, with affected individuals usually having normal intelligence and a normal life span. Patients with types 2 and 3 are at increased risk of early death due to neurologic and respiratory problems – tracheal cartilaginous sleeve and laryngeal web have been reported; seizures and intellectual disability are common. Children affected by Pfeiffer syndrome may require numerous surgical procedures to improve cranial, orbital, dental and upper airway anomalies.

491

492

Fetal and Perinatal Skeletal Dysplasias

Differential diagnosis: other conditions that are FGFR2-­related (allelic): Crouzon syndrome – similar although milder craniofacial features, normal hands and feet; Apert syndrome (p. 496); Beare-Stevenson cutis gyrate – similar craniofacial features, normal hands and feet, natal teeth, cutis gyrata (may be present at birth), genital anomalies; Antley-Bixler syndrome (p. 500). Syndromes with craniosynostosis: thanatophoric dysplasia (p. 36); Carpenter syndrome (p. 507); Cole-Carpenter syndrome (p. 450); craniofrontonasal syndrome – coronal synostosis and frontonasal dysplasia (severe hypertelorism, broad bifid nose, asymmetric frontal bossing), occasionally cleft lip and palate, neck webbing, rounded shoulders, abnormal clavicles, cutaneous syndactyly and hypoplastic fingers and toes;

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more severe in females and X-linked dominant, caused by mutations in EFNB1. Saethre-Chotzen syndrome: coronal synostosis (unilateral or bilateral), facial asymmetry, ptosis, characteristic appearance of the ear (small pinna with a prominent crus), syndactyly of digits 2 and 3 of the hand. Short stature, parietal foramina, radioulnar synostosis, cleft palate and heart malformations may occasionally occur. Caused by mutations in TWIST1. Greig syndrome (p.); Baller-Gerold syndrome: usually involves the coronal sutures, but can affect multiple sutures, also shows radial aplasia, absent thumb, short and bowed ulna, absent carpal and metacarpal bones. Occasionally ocular hypertelorism, epicanthic folds, prominent nasal bridge, midline capillary haemangiomas, genitourinary malformations and mental retardation. Caused by mutations of the gene RECQL4.

 

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CASES 1–4: Four cases show phenotypic variations of craniosynostosis and broad halluces in Pfeiffer syndrome. Case 1 presents with brachycephaly, Case 2 with cloverleaf skull, Case 3 with turridolichocephaly and Case 4 with turribrachycephaly. Case 1 shows duplication of the metatarsal, proximal phalanx and distal phalanx of the great toe. Cases 2–4 show short, delta-shaped proximal phalanx of the hallux.

Pfeiffer Syndrome, FGFR1- and FGFR2-Related

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CASE 5: A neonate with broad thumbs and halluces. CASE 6: A neonate with cloverleaf skull and elbow dislocation.

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CASE 7: A stillbirth with cloverleaf skull and elbow ankylosis. CASES 8–11: Variations of craniosynostosis in Pfeiffer syndrome, ranging from cloverleaf skull through turridolichocephaly to turribrachycephaly. Note tonsillar herniation due to a small posterior cranial fossa in Case 11 (a).

Pfeiffer Syndrome, FGFR1- and FGFR2-Related

BIBLIOGRAPHY Blaumeiser B, Loquet P, Wuyts W et al. Prenatal diagnosis of Pfeiffer syndrome type II. Prenat Diagn. 2004; 24: 644–6. Gonzales M, Heuertz S, Martinovic J et al. Vertebral anomalies and cartilaginous tracheal sleeve in three patients with Pfeiffer syndrome carrying the S351C FGFR2 mutation. Clin Genet. 2005; 68: 179–81. Harada A, Miyashita S, Nagai R et al. Prenatal sonographic findings and prognosis of craniosynostosis diagnosed during the fetal and neonatal periods. Congenit Anom (Kyoto). 2019; 59: 132–41.

495 Katsuragi SY, Hirose E, Arai Y et al. Autopsy case of Pfeiffer syndrome type 2, a phenotype of fibroblast growth factor receptor-associated craniosynostosis syndromes, with tracheal cartilage sleeve and abnormal hyperplasia of bronchial cartilages. Am J Case Rep. 2021; 9: 22:e932450. Vimercati A, Olivieri C, Dellino M et al. Prenatal diagnosis of Pfeiffer syndrome and role of three-dimensional ultrasound: Case report and review of literature. J Matern Fetal Neonatal Med. 2022; 35: 7840–3.

101 Apert Syndrome, FGFR2-Related

Synonyms: acrocephalosyndactyly, type I; ACS1; ACSI Confirmation of diagnosis: identification of pathogenic variants in FGFR2 Frequency: 1/100,000 Genetics: autosomal dominant, due to gain-in-function mutations of the fibroblast growth factor receptor-2 gene (FGFR2). Detection rate is 100%; usually sporadic; paternal age effect has been demonstrated. Age/Gestational week of manifestation: can be detected by ultrasound after the 15th week of gestation. Clinical features: • Turribrachycephalic skull shape with a prominent forehead due to bicoronal synostosis, rarely hydrocephalus and brain anomalies • Moderate to severe midface hypoplasia, shallow orbits, hypertelorism, proptosis, downslanting palpebral fissures, depressed nasal bridge with a beaked nose, choanal stenosis or atresia, narrow palate, sometimes cleft palate, mandibular prognathism • Syndactyly of fingers and toes described as the ‘mitten’ or ‘sock’ appearance, involving a variable number of digits, sometimes with nail fusion • Internal organ anomalies in up to 10% of cases: cardiovascular, genitourinary (hydronephrosis, cryptorchidism), respiratory system, intracranial and gastrointestinal Prenatal ultrasound features: turribrachycephaly and premature fusion of the sutures are present. Other dysmorphic craniofacial findings include midface hypoplasia, proptosis, prominent metopic ridge and high forehead. Intracranial abnormalities may be identified. These include anomalies of limbic-septal-callosal structures, agenesis of the corpus callosum, ventriculomegaly, overconvolution of the medial temporal lobes and white matter hypoplasia. There is syndactyly of the second to fifth fingers with a relatively normal length of the appendicular skeleton; occasionally polyhydramnios develops. Radiographic features: brachycephaly and turricephaly are due to premature fusion of the coronal sutures. This also results in shallow orbits and midface hypoplasia with relative

496

prognathism. There is fusion in the cervical spine, usually at the C5–C6 levels. Large joints may also be abnormal with progressive synostosis particularly affecting the elbows. In the hands there is bony syndactyly, particularly of the distal phalanges, giving the ‘mitten’ deformity. The thumbs are short. There may be proximal synostosis of the fourth and fifth metacarpals. In older patients there is a progressive synostosis across the carpometacarpal joints. In the feet there is syndactyly – usually soft tissue – and there may be duplication of the short halluces. Prognosis: viable – developmental delay and intellectual impairment can occur in a significant proportion; timely craniofacial surgery can improve the outcome. Children affected by Apert syndrome can require numerous surgical procedures to improve skull growth; correct eye, dental and upper airway problems; and reconstruct the hands and feet. Differential diagnosis: other FGFR2-related syndromes: Crouzon syndrome – similar craniofacial features, normal hands and feet; Pfeiffer syndrome (p. 491); Beare-Stevenson cutis gyrata – similar craniofacial features, normal hands and feet, natal teeth, cutis gyrata (can be seen at birth), genital anomalies (bifid scrotum, anteriorly placed anus). Syndromes with craniosynostosis: Antley-Bixler syndrome (p. 500); Carpenter syndrome (p. 507); Cole-Carpenter syndrome (p. 450); thanatophoric dysplasia (p. 36); craniofrontonasal syndrome – coronal synostosis and frontonasal dysplasia (severe hypertelorism, broad bifid nose, asymmetric frontal bossing), occasionally cleft lip and palate, neck webbing, rounded shoulders, abnormal clavicles. Cutaneous syndactyly and hypoplastic fingers and toes can be present; more severe in females; X-linked dominant, caused by mutations in EFNB1. Saethre-Chotzen syndrome: coronal synostosis (unilateral or bilateral), facial asymmetry, ptosis, characteristic appearance of the ear (small pinna with a prominent crus), syndactyly of digits 2–3 of the hand. May also have short stature, parietal foramina, radioulnar synostosis, cleft palate, heart malformations. Dominant mutations in TWIST1 are causative. Greig syndrome (p. 583); Baller-Gerold syndrome: syndromic craniosynostosis involving the coronal sutures (but can affect multiple sutures), radial aplasia, absent thumb, short and bowed ulna, absent carpal and metacarpal bones. Occasional findings: ocular hypertelorism, epicanthic folds, prominent nasal bridge, midline capillary haemangiomas, genitourinary malformations, intellectual disability. Caused by mutations of the gene RECQL4.

DOI: 10.1201/9781003166948-107

Apert Syndrome, FGFR2-Related

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CASES 1, 2: Both neonates show turribrachycephaly, mitten hand, broad halluces and soft tissue syndactyly of the second to fifth toes.

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CASE 3: Prenatal US shows coronal synostosis with proptosis, mitten hands and soft tissue syndactyly of the feet. CASE 4: A stillbirth at 23 weeks of gestation. The skeletal changes are like those seen in Case 3.

Apert Syndrome, FGFR2-Related

BIBLIOGRAPHY Bulfamante G, Gana S, Avagliano L et al. Congenital diaphragmatic hernia as prenatal presentation of Apert syndrome. Prenat Diagn. 2011; 31: 910–11. Casteleyn T, Horn D, Henrich W, Verlohren S. Differential diagnosis of syndromic craniosynostosis: A case series. Arch Gynecol Obstet. 2022; 306: 49–57. De Jong T, Maliepaard M, Bannink N et al. Health-related problems and quality of life in patients with syndromic and complex craniosynostosis. Childs Nerv Syst. 2012; 28: 879–82. Goriely A, Wilkie AO. Paternal age effect mutations and selfish spermatogonial selection: Causes and consequences for human disease. Am J Hum Genet. 2012; 90: 175–200. Harada A, Miyashita S, Nagai R et al. Prenatal sonographic findings and prognosis of craniosynostosis diagnosed during the fetal and neonatal periods. Congenit Anom (Kyoto). 2019; 59: 132–41.

499 Kimonis V, Gold J-A, Hoffman TL et al. Genetics of craniosynostosis. Semin Pediatr Neurol. 2007; 14: 150–61. Quintas-Neves M, Soares-Fernandes JP. Fetal brain MRI in Apert syndrome: Early detection of temporal lobe malformation. Child Nerv Syst. 2018; 34: 1617–18. Tonni G, Grisolia G, Baldi M et al. Early prenatal ultrasound and molecular diagnosis of Apert syndrome: Case report with postmortem CT scan and chondral plate histology. Fetal Pediatr Pathol. 2022; 41: 281–92. Vieira C, Teixeira N, Cadilhe A, Reis I. Apert syndrome: Prenatal diagnosis challenge. BMJ Case Rep 2019; 12: e231982. doi: 10.1136/bcr-2019-231982

102 Antley-Bixler Syndrome, FGFR2- and POR-Related

Synonyms: ABS; trapezoidocephaly-synostosis syndrome; multisynostotic osteodysgenesis with long bone fractures; osteodysgenesis multisynostotic with fractures; Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis; ABS1 Confirmation of diagnosis: identification of pathogenic variants in POR or FGFR2 with appropriate clinical findings Frequency: very rare – fewer than 100 cases reported Genetics: can be caused by heterozygous, dominant pathogenic variants in the gene FGFR2 (10q26) (type 1) or by homozygous, recessive pathogenic variants in the gene POR (7q11.2) (type 2), encoding cytochrome P450 (lanosterol 14 alpha-demethylase) oxidoreductase (POR). The latter gene is involved in steroidogenesis, and consequently, patients with ABS type 2 can show sexual ambiguity. A phenocopy of ABS is observed in patients exposed in utero to fluconazole, an antifungal agent which inhibits lanosterol 14 alpha-demethylase. Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester (20 weeks). Clinical features: • Brachycephaly, hydrocephalus • Midfacial hypoplasia, ocular hypertelorism, proptosis, small nose, choanal stenosis, dysplastic prominent low-set ears, stenotic external auditory canals • Radiohumeral or radioulnar synostosis, medial bowing of ulnae, short, bowed femora, camptodactyly, rocker-bottom feet, multiple contractures • Fractures are common • In ABS type 2 genital anomalies and congenital adrenal hyperplasia are common • Cardiac (transposition of the great vessels, septal defects, hypoplastic right atrium) and renal malformations are common (hypoplasia, duplication or ectopia, horseshoe kidney, ureteral obstruction); occasionally gastrointestinal malformations can be found (imperforate anus, malrotation) Prenatal ultrasound features: immobility of the elbows with fixed flexion due to radiohumeral synostosis can be identified. There is bowing of the femora and ulnae, with long hands and

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fingers. These findings have been identified in an at-risk fetus, resulting in termination of pregnancy. Radiographic features: there is brachycephaly and a prominent frontal bone due to premature fusion of the coronal and lambdoid sutures and occasionally a cloverleaf skull deformity. The long bones and ribs are slender, and fractures may occur. There is a small, narrow thorax and hypoplastic scapulae. Radiohumeral or occasionally radioulnar synostoses and bowed ulnae are present. In the extremities the hands and feet are narrow with arachnodactyly, camptodactyly, carpal fusions, advanced skeletal maturation and vertical tali. The iliac bones are narrow. There are bowed femora, which may be short due to proximal deficiency. Vertebral body and neural arch fusions and other segmentation anomalies occur. Prognosis: early death due to respiratory complications is relatively common. In the patients who survive the first years of life, the prognosis may be reasonably good. Cognitive functioning ranges from moderate intellectual disability to normal intelligence. Differential diagnosis: other FGFR2-related conditions: Apert syndrome (p. 496); Crouzon syndrome – similar craniofacial features, normal hands and feet; Pfeiffer syndrome types 2 and 3 (p. 491); Beare-Stevenson cutis gyrata: similar craniofacial features to Pfeiffer syndrome, normal hands and feet, natal teeth, cutis gyrata (can be seen at birth), genital anomalies. Syndromes with craniosynostosis: Carpenter syndrome (p. 507); Cole-Carpenter syndrome (p. 450); thanatophoric dysplasia (p. 36); craniofrontonasal syndrome: coronal synostosis and frontonasal dysplasia (severe hypertelorism, broad bifid nose, asymmetric frontal bossing), occasionally cleft lip and palate, neck webbing, abnormal clavicles, cutaneous syndactyly and hypoplastic fingers and toes. More severe in females. X-linked dominant, caused by mutations in EFNB1. Saethre-Chotzen syndrome: coronal synostosis, facial asymmetry, ptosis, characteristic appearance of the ear (small pinna with a prominent crus), syndactyly of digits 2 and 3 of the hand. Occasionally: short stature, parietal foramina, radioulnar synostosis, cleft palate, heart malformations. Dominant mutations in TWIST1 are causative. Baller-Gerold syndrome: coronal or multiple sutures, synostosis, radial aplasia, absent thumb, short and bowed ulna, absent carpal and metacarpal bones. Occasionally ocular hypertelorism, epicanthic folds, prominent nasal bridge, midline capillary haemangiomas, genitourinary malformations, mental retardation. Caused

DOI: 10.1201/9781003166948-108

Antley-Bixler Syndrome, FGFR2- and POR-Related

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by mutations of the gene RECQL4. Fluconazole embryopathy: craniosynostosis due to coronal and lambdoid suture closures, shallow orbits, hypoplastic supraorbital ridges, hypertelorism, mild ptosis, radioulnar synostosis, metacarpophalangeal symphalangism. Bowed limbs: Campomelic dysplasia (p. 302);

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osteogenesis imperfecta (p. 429); hypophosphatasia (p. 452); congenital bowing; Stüve-Wiedeman syndrome (p. 311). Cousin syndrome (p. 548). CYP26B1-asssociated ABS-like disorder and fluconazole embryopathy may be indistinguishable from ABS on clinical grounds.

 

 

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CASE 1: A younger brother of Case 2. Images as a neonate and at 1 month (a–g) show mild craniosynostosis (shortening of the anterior cranial fossa), overtubulation of the ribs and tubular bones, bowing of the left femur, elbow ankylosis and arachnodactyly. These findings were also identified on fetal CT (h).

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Fetal and Perinatal Skeletal Dysplasias

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CASE 2: An older brother of Case 1. The image as a neonate and at age 1 month (a–f) show almost the same findings as those of Case 1, although femoral bowing is absent, while craniosynostosis with brachycephaly is more overt and capitate-hamate fusion is seen. The images at age 3 years (g, h) show more clearly elbow ankylosis and carpal fusion. The distal phalanges are hypoplastic. There is mild shortening of the anterior cranial fossa, overtubulation of the ribs and tubular bones, arachnodactyly, radioulnar synostosis and capitate-hamate fusion.

Antley-Bixler Syndrome, FGFR2- and POR-Related

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CASE 3: A neonate. The skeletal phenotype is much milder those of Cases 1 and 2. There is mild shortening of the anterior cranial fossa, overtubulation of the ribs and tubular bones, arachnodactyly, radioulnar synostosis, and capitate-hamate fusion.

BIBLIOGRAPHY Lopez-Rangel E, Van Allen MI. Prenatal exposure to fluconazole: An identifiable dysmorphic phenotype. Birth Defects Research (Part A). 2005; 73: 919–23. Oldani E, Garel C, Bucourt M, Carbillon L. Prenatal diagnosis of Antley-Bixler syndrome and POR deficiency. Am J Case Rep. 2015; 16: 882–5. Reardon W, Smith A, Honour JW et al. Evidence for digenic inheritance in some cases of Antley-Bixler syndrome? J Med Genet. 2000; 37: 26–32. Schinzel A, Savoldelli G, Briner J et al. Antley-Bixler syndrome in sisters: A term newborn and A prenatally diagnosed fetus. Am J Med Genet. 1983; 14: 139–47.

Sulaiman AR, Nawaz H, Munajat I et al. Proximal femoral focal deficiency as A manifestation of Antley-Bixler syndrome: A case report. J Orthop Surg. 2007; 15: 84–6. Tzetis M, Konstantinidou A, Sofocleous C et al. Compound heterozygosity of a paternal submicroscopic deletion and a maternal missense mutation in POR gene: Antley-Bixler syndrome phenotype in three sibling fetuses. Birth Defects Res A Clin Mol Teratol. 2016; 106: 536–41.

103 Shprintzen-Goldberg Syndrome, SKI-Related

Synonyms: SGS; craniosynostosis with arachnodactyly and abdominal hernias; marfanoid disorder with craniosynostosis, type I; marfanoid craniosynostosis syndrome Confirmation of diagnosis: identification of heterozygous pathogenic variants in SKI Frequency: rare – fewer than 100 cases reported Genetics: autosomal dominant, caused by heterozygous pathogenic variants in the gene SKI on chromosome 1p36. The variants are usually missense, and the majority are located in exon 1. SKI encodes a nuclear protooncogene which negatively regulates SMAD-dependent TGF-β signalling. TGF-β signalling is crucial for a normal development and preservation of vessels, as well as various organs. The pathogenic mechanism is an excessive activation of TGF-β signalling cascades. Age/Gestational week of manifestation: craniosynostosis and contractures can be detected by ultrasound during the second trimester (20 weeks). Clinical features: • Craniosynostosis involving coronal, sagittal or lambdoid sutures • Specific craniofacial features: high prominent forehead, exophthalmos, hypertelorism, downslanting palpebral fissures, maxillary hypoplasia, high palate, cleft palate, prominent palatine ridges, micrognathia, low-set and posteriorly rotated ears • Marfanoid habitus, pectus excavatum or carinatum, scoliosis • Respiratory distress • Joint hypermobility, contractures • Arachnodactyly, camptodactyly • Brain anomalies: hydrocephalus, Arnold-Chiari 1 malformation • Mitral valve prolapse, less frequently aortic dilatation • Minimal subcutaneous fat, hyperelastic skin, umbilical hernia, inguinal hernia • Cryptorchidism Prenatal ultrasound features: there are no reports of antenatal diagnosis; although two- and three-dimensional ultrasound may detect craniosynostosis, hypertelorism, contractures and hydrocephalus. 504

Radiographic features: in the skull there is craniosynostosis resulting in brachycephaly and turricephaly and pronounced convolutional markings. The occiput is small, and there is a steep skull base. The thorax is long and narrow, and there may be an additional pair of ribs. The ribs have an irregular contour (‘ribbon’ ribs). Pectus carinatum or excavatum develops. In the spine the interpedicular distances are wide and the pedicles long and slender. The vertebral bodies have concave anterior and posterior borders. Kyphoscoliosis develops during childhood. Defects of the first cervical vertebral body have been reported. There is a narrow pelvic inlet. The iliac bones are hypoplastic inferiorly, and there is a vertical groove of the lateral borders. The long bones are mildly bowed with wide metaphyses. There may be dislocation of the radial heads. In the hands there is arachnodactyly, and contractures result in camptodactyly. There is talipes equinovarus. Prognosis: viable – craniosynostosis may require neurosurgical intervention. Patients usually develop mild to moderate intellectual impairment. In some cases, conductive hearing loss has been reported. Dilatation of the aorta can develop in a proportion of individuals, as well as middle artery aneurysms and arterial tortuosity. Physiotherapy is frequently needed to improve mobility in patients with congenital contractures and severe skeletal anomalies. The combination of connective tissue and skeletal anomalies can affect pulmonary function and make intubation and ventilation more difficult. There is increased susceptibility to muscle relaxants. Scoliosis can be severe and require surgical treatment, which is, however, associated with a high incidence of peri- and postoperative complications. Differential diagnosis: Loeys-Dietz syndrome; probably the most similar condition, is characterised by generalised arterial tortuosity and aneurysms, cardiac defects and brain abnormalities; developmental delay can be present. Caused by mutations in the genes TGFBR1 and TGFBR2. Marfan syndrome (p. 471). Congenital contractural arachnodactyly, an autosomal dominant disorder caused by mutations in FBN2, does not show intellectual impairment or craniosynostosis. Homocystinuria caused by a deficiency of the enzyme cysthathionine synthetase; presents with a very similar phenotype and mental ­retardation but also subluxation of the lens and thrombophilia. Lujan-Fryns syndrome is an X-linked disorder also characterised by marfanoid habitus and mental delay but does not show craniosynostosis and joint contractures. Melnick-Needles syndrome (p. 141); frontometaphyseal dysplasia (p. 137). DOI: 10.1201/9781003166948-109

Shprintzen-Goldberg Syndrome, SKI-Related

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CASE 1: Mildly bowed long bones with wide, lucent metaphyses; dislocated radial heads; talipes equinovarus, arachnodactyly; long, narrow thorax; 13 pairs of ribs and six lumbar vertebrae; wide lumbar interpedicular distances.

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CASE 2: Turricephaly and small occiput with steep skull base; small mandible; dilated lateral ventricles; bowed long bones with wide, lucent metaphyses; narrow bases of ilia and narrow pelvic inlet; long pedicles in the lumbar region; arachnodactyly.

BIBLIOGRAPHY Carmignac V, Thevenon J, Adès L et al. In-frame mutations in exon 1 of SKI cause dominant Shprintzen-Goldberg syndrome. Am J Hum Genet. 2012; 91: 950–57. Doyle AJ, Doyle JJ, Bessling SL et al. Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. Nat Genet. 2012; 44: 1249–54. Robinson PN, Neumann LM, Demuth S et al. ShprintzenGoldberg syndrome: Fourteen new patients and a clinical analysis. Am J Med Genet A. 2005; 135A: 251–62.

Saito T, Nakane T, Yagasaki H et al. Shprintzen-Goldberg syndrome associated with first cervical vertebra defects. Pediatr Int. 2017; 59: 1098–100. Schepers D, Doyle AJ, Oswald G et al. The SMAD-binding domain of SK1: A hotspot for de novo mutations causing Shprintzen-Goldberg syndrome. Eur J Hum Genet. 2015; 23: 224–8. Watanabe K, Okada E, Kosaki K et al. Surgical treatment for scoliosis in patients with Shprintzen-Goldberg syndrome. J Pediatr Ortho. 2011; 31: 186–93.

104 Carpenter Syndrome, RAB23- and MEGF8-Related

Synonyms: ACPS2; acrocephalopolysyndactyly type 2 Confirmation of diagnosis: identification of biallelic pathogenic variants in RAB23 or MEGF8 Frequency: fewer than 100 cases have been reported in the literature Genetics: autosomal recessive condition, mainly caused by pathogenic variants of the gene RAB23; Rab proteins belong to the Ras superfamily and are small GTPases involved in the regulation of intracellular membrane trafficking. RAB23 has been demonstrated to negatively regulate the sonic hedgehog signalling pathway. A small proportion of cases are caused by pathogenic variants in the gene MEGF8, encoding a protein whose function is not yet understood but likely to be involved in intracellular trafficking. Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester (20 weeks).

brain, there was agenesis of the corpus callosum, dilated lateral ventricles and aqueduct of Sylvius with absent third ventricle, cerebellar hypoplasia and agyria. Bowed femora have been identified on antenatal ultrasound. Other findings described include a large ovarian cyst and heterotaxy. Radiographic features: craniosynostosis, which may range in severity from fusion of the metopic suture to a cloverleaf skull deformity. In the hands there is hypoplasia/agenesis of the middle phalanges resulting in brachydactyly and some camptodactyly. The proximal phalanges of the thumbs are duplicated, the thumbs are broad and there may be postaxial polydactyly of the hands. In the feet there is preaxial polydactyly or attempted duplication of the halluces. There is soft tissue syndactyly of the hands and feet. Occasional findings include hydrocephalus, genu valgum and kyphoscoliosis. Prognosis: viable – patients may develop neurodevelopmental delay, obesity and hypogonadism; timely craniofacial surgery can reduce the probability of developing intellectual impairment.

Clinical features: • Acrocephaly, synostosis of sagittal and lambdoid sutures; bicoronal synostosis • Specific facies: midface hypoplasia, epicanthic folds, microcornea, flat nasal bridge, arched palate, hypodontia, low-set malformed ears • Brachydactyly, syndactyly, postaxial polydactyly in the hands; preaxial or insertional polydactyly and syndactyly of the feet • Cryptorchidism, hypoplastic male genitalia • Possible associated anomalies include congenital heart disease, umbilical hernia or exomphalos, hydronephrosis, accessory spleen, hearing loss • Laterality defects, such as dextrocardia and situs inversus, are rarely present and are associated with MEGF8 variants Prenatal ultrasound features: the abnormal skull shape, brachydactyly and polydactyly may be identified on routine scanning. One case presented with polyhydramnios at 20 weeks’ gestation. There were dilated lateral ventricles, an exomphalos and talipes equinovarus. A stillborn fetus was delivered at 23 weeks’ gestation. There was craniosynostosis with a cloverleaf skull. At postmortem examination of the

DOI: 10.1201/9781003166948-110

Differential diagnosis: other acrocephalopolysyndactylies: Greig syndrome (p. 583). Syndromes with craniosynostosis: Pfeiffer syndrome (p. 491); Apert syndrome (p. 496); BeareStevenson cutis gyrata: shows normal hands and feet, natal teeth, cutis gyrata (can be seen at birth), genital anomalies. These syndromes are all due to pathogenic variants in the gene FGFR2. Cole-Carpenter syndrome (p. 507); thanatophoric dysplasia (p. 36); craniofrontonasal syndrome: coronal synostosis and frontonasal dysplasia (severe hypertelorism, broad bifid nose, asymmetric frontal bossing), occasionally cleft lip and palate, neck webbing, abnormal clavicles, cutaneous syndactyly and hypoplastic fingers and toes. X-linked dominant; more severe in females; caused by pathogenic variants in EFNB1. Saethre-Chotzen syndrome: coronal synostosis (unilateral or bilateral), facial asymmetry, ptosis, characteristic appearance of the ear (small pinna with a prominent crus), syndactyly of digits 2 and 3 of the hand. Occasionally: short stature, parietal foramina, radioulnar synostosis, cleft palate, heart malformations. Dominant pathogenic variants in TWIST1 are causative. Baller-Gerold syndrome: coronal or multiple suture synostosis, radial aplasia, absent thumb, short and bowed ulna, absent carpal and metacarpal bones. Occasionally hypertelorism, epicanthic folds, prominent nasal bridge, midline capillary haemangiomas, genitourinary malformations, mental retardation. Caused by pathogenic variants of the gene RECQL4.

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CASE 1: A stillbirth with facial dysmorphism, soft tissue syndactyly of the hands and polysyndactyly of the feet and multiple visceral anomalies (intestinal malrotation, pancreatic hypoplasia and multilobed spleen). Postmortem radiograph shows turricephaly and mild broadening of long bones.

Carpenter Syndrome, RAB23- and MEGF8-Related

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CASE 2: A neonate. Radiographs show scaphocephaly with hypotelorism, broad long bones, preaxial polydactyly and hypoplastic middle phalanges of the hands and broad halluces with unossified proximal phalanges and postaxial polydactyly of the feet.

BIBLIOGRAPHY Alessandri JL, Dagoneau N, Laville JM et al. RAB23 pathogenic variant in a large family from Comoros Islands with Carpenter syndrome. Am J Med Genet A. 2010; 152A: 982–6. Haye D, Collett C, Sembely-Taveau C et al. Prenatal findings in Carpenter syndrome and a novel mutation in RAB23. Am J Med Genet A. 2014; 164A: 2926–3290. Jenkins D, Baynam G, De Catte L, et al. Carpenter syndrome: Extended RAB23 pathogenic variant spectrum and analysis of nonsense-mediated mRNA decay. Hum Mutat. 2011; 32: E2069–2078. doi: 10.1002/humu.21457

Rubio EI, Blask A, Bulas DI. Ultrasound and MR imaging findings in prenatal diagnosis of craniosynostosis syndromes. Pediatr Radiol. 2016; 46: 709–18. Twigg SR, Lloyd D, Jenkins D et al. Mutations in multidomain protein MEGF8 identify a Carpenter syndrome subtype associated with defective lateralization. Am J Hum Genet. 2012; 91: 897–905. Victorine AS, Weida J, Hines KA et al. Prenatal diagnosis of Carpenter syndrome: Looking beyond craniosynostosis and polysyndactyly. Am J Med Genet A. 2014; 164A: 820–3.

105 Acrofacial Dysostosis, Nager Type, SF384-Related

Synonyms: mandibulofacial dysostosis, Treacher Collins type, with limb anomalies; Nager acrofacial dysostosis; AFD, Nager type; preaxial acrofacial dysostosis Confirmation of diagnosis: clinical, typical combination of MFD and limb anomalies and identification of pathogenic variants in the SF3B4 gene. Frequency: rare, around 100 cases described in the literature Genetics: autosomal dominant, caused by heterozygous pathogenic loss-of-function variants (mutations) in the gene SF3B4, encoding a component of the U2 pre-mRNA spliceosomal complex. Age/Gestational age of manifestation: can be suspected by ultrasound at the end of the first trimester. Increased nuchal translucency may be present. Clinical features: • Mandibulofacial dysostosis (MFD): downslanting palpebral fissures, ptosis of upper lids, coloboma of lower lids, deficiency of eyelashes of the medial onethird to two-thirds of the lower eyelids, malar hypoplasia, cleft or high arched palate, microretrognathia • Hypoplasia of larynx and epiglottis • Ear abnormalities: low set, posteriorly rotated, dysplastic, preauricular tags, external auditory canal atresia • Radial ray anomalies: hypoplasia or absence of thumbs, triphalangeal thumbs, radial aplasia or hypoplasia, radioulnar synostosis • Short forearms, very rarely phocomelia • Lower limb can sometimes be involved, the more common anomalies are missing, hypoplastic, overlapping toes, syndactyly, broad hallux, clubfeet • Rarely other abnormalities have been reported involving the kidney (unilateral agenesis), heart (tetralogy of Fallot, septal defects) and abdomen (gastroschisis, Hirschsprung disease) Prenatal ultrasound features: the earliest signs can be detected at around 12 weeks as increased nuchal translucency, micrognathia, short long bones, malformed wrist and talipes equinovarus. After the 20th week of gestation, 2D and 3D

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ultrasound can show craniofacial and limb anomalies, with a wide variability in manifestations and severity; these include hypertelorism, flat facial profile, severe microretrognathia and small low-set ears up to microtia. Polyhydramnios due to microretrognathia-induced glossoptosis is often observed in the second and third trimester. Cleft palate is common. Limb malformations are often asymmetrical, but both upper limbs are usually involved, with thumb hypoplasia or aplasia and/ or hypoplasia/aplasia of the radius. A more pronounced mesomelic shortening may be associated with a short humerus. Bilateral talipes equinovarus is the most common deformity in the lower limbs; rarely fibular agenesis with bowed tibia and missing toes are detected. Heart defects (ventricular septal defects, tetralogy of Fallot), diaphragmatic hernia and kidney abnormalities have been reported. Radiographic features: the upper limbs are more commonly affected than the lower limbs, and in the upper limbs the mesomelic segment is more commonly affected than the rhizomelic. Findings include radial aplasia/hypoplasia (the humerus and ulna may also be involved), preaxial polydactyly/thumb duplication, triphalangeal thumb, and 2/3 syndactyly. Proximal radioulnar synostosis has been described. A broad hallux and clubfeet are recognised features. Limb changes may be bilateral, but not necessarily symmetrical. The malar and mandibular bones are hypoplastic. Prognosis: viable – respiratory distress and feeding difficulties may be severe, and around 20% of patients die in the neonatal period. The majority of affected individuals show normal intelligence and have an average life span. Mild intellectual impairment has been reported in some. Conductive hearing loss is present in 90% of cases. Differential diagnosis: mandibulofacial dysostosis: oculoauriculo-vertebral spectrum or hemifacial microsomia (Goldenhar syndrome) has facial asymmetry, epibulbar dermoids and vertebral/cervical spine anomalies Upper limb anomalies are not part of the spectrum; Miller syndrome: postaxial rather than preaxial limb defects. Mutations in the gene DHODH have been identified and are autosomal recessive. TreacherCollins-Franceschetti syndrome: limbs are normal, caused by dominant mutations in TCOF1. Acrofacial dysostosis syndrome type Rodriguez: preaxial and postaxial limb deficiencies, shoulder and pelvic girdle hypoplasia, cardiac and central nervous system malformations, early lethality. Patterson-Stevenson-Fontaine syndrome: MFD associated with

DOI: 10.1201/9781003166948-111

Acrofacial Dysostosis, Nager Type, SF384-Related e­ctrodactyly; no other anomalies are usually present. ­Richieri-Costa-Pereira syndrome: rare condition characterised by MFD and preaxial and postaxial limb defects; patients also have short stature, clubfeet, cleft mandible and of the lower alveolar margin with absent incisors. Limb anomalies: Roberts syndrome (p. 550); Holt-Oram syndrome (p. 536); Fanconi anaemia (p. 573); thrombocytopenia absent radius (TAR) syndrome – radial aplasia with preservation of the thumbs and early onset, usually transient, thrombocytopenia. Micrognathia may be present, but MFD is not a feature. Other anomalies, congenital heart defects, dislocations and lower limb malformations may also be present. The disorder is caused by a combination of a microdeletion of the proximal 1q21.1 region and of a low-frequency polymorphism in RBM8A, located in the same locus, which determines a minimal expression of the protein Y14. Tetra-amelia: rare disorder with severe malformations, including cleft palate; aplasia of the peripheral pulmonary vessels; anal atresia; diaphragmatic defect; hypoplasia or aplasia

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511 of lung, kidneys, spleen, adrenal gland, uterus and ovaries. Recessive mutations in the gene WNT3 in some cases. Splenogonadal fusion with limb defects and micrognathia: dominant disorder which shows a peculiar fusion between the spleen and the gonad or derivatives of the mesonephros, sometimes tetraamelia, micrognathia and cleft palate. DK phocomelia syndrome (p. 596); Cornelia de Lange syndrome (p. 540); thalidomide embryopathy – rare nowadays; thalidomide was used as a sedative/antiemetic but was withdrawn in the 1960s because of recognised teratogenicity. The most common defects involved the long bones and ranged from loss of digits to amelia or phocomelia. Interestingly, Roberts syndrome (p. 550) (pseudothalidomide syndrome) mimics the consequences of thalidomide ingestion during pregnancy. Al-Awadi Raas-Rothschild limbpelvis aplasia-hypoplasia syndrome (p. 546); Baller-Gerold syndrome – radial ray defects and growth retardation are associated with coronal craniosynostosis and poikiloderma; autosomal recessive, due to mutations in RECQL4.

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CASE 1: Prenatal US showed severe micrognathia, right thumb aplasia and proximally placed left thumb. Fetal CT demonstrated micrognathia and right elbow ankylosis. Postnatal radiographs confirmed the prenatal imaging findings.

 

 

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CASE 2: A terminated fetus. Postmortem radiographs show severe micrognathia and aplasia of the thumbs. Abnormal approximation between the radius and ulna implies radioulnar synostosis. CASE 3: Radiographs show wide distal humeri, dislocated elbows, mesomelic shortening of forearms and aplasia of the thumbs along with postaxial syndactyly. CT shows antimongoloid slant of eyes, malar hypoplasia and severe micrognathia along with mandibular hypoplasia. MRI shows strikingly small mandible.

Acrofacial Dysostosis, Nager Type, SF384-Related

BIBLIOGRAPHY Ansart-Franquet H, Houfflin-Debarge V, Ghoumid J et al. Prenatal diagnosis of Nager syndrome in a monochorionicdiamniotic twin pregnancy. Prenat Diagn. 2009; 29: 187–9. Bernier FP, Caluseriu O, Ng S et al. Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome. Am J Hum Gene. 2012; 90: 925–33. Cassina M, Cerqua C, Rossi S et al. A synonymous splicing mutation in the SF3B4 gene segregates in a family with highly variable Nager syndrome. Eur J Hum Genet. 2017; 25: 371–5. Castori M, Bottillo I, D’Angelantonio D et al. A 22-week-old fetus with Nager syndrome and congenital diaphragmatic hernia due to a novel SF3B4 mutation. Mol Syndromol. 2014; 5: 241–4. Couyoumjian CA, Treadwell MC, Barr M. Prenatal sonographic diagnosis of Nager acrofacial dysostosis with unilateral upper limb involvement. Prenat Diagn. 2008; 28: 964–6.

513 Dimitrov B, Balikova I, Bradinova I et al. The acrofacial dysostoses: A wide spectrum of overlapping phenotypes. Genet Couns. 2005; 16: 181–6. Drozniewska M, Kilby MD, Vogt J et al. Second-trimester prenatal diagnosis of Nager syndrome with a deletion including SF3B4 detected by chromosomal microarray. Clin Case Rep. 2020; 8: 508–11. Lund IC, Vestergaard EM, Christensen R et al. Prenatal diagnosis of Nager syndrome in a 12-week-old fetus with a whole gene deletion of SF3B4 by chromosomal microarray. Eur J Med Genet. 2016; 59: 48–51. Paladini D, Tartaglione A, Lamberti A et al. Prenatal diagnosis of Nager syndrome. Ultrasound Obstet Gynecol. 2003; 21: 195–7. Senggen E, Laswed T, Meuwly JY et al. First and second branchial arch syndromes: Multimodality approach. Pediatr Radiol. 2011; 41: 549–61.

106 Acromelic Frontonasal Dysostosis, ZSW1M6-Related

Synonyms: AFND Confirmation of diagnosis: typical clinical features associated with the detection of the recurrent pathogenic variant in ZSWIM6 Frequency: very rare, fewer than 30 cases reported in the literature Genetics: autosomal dominant, due to a recurrent, heterozygous, pathogenic variant (c.3487C>T) in the gene ZSWIM6, which might confer gain of function. There is variable expressivity and reduced penetrance, suggesting the possibility of mosaicism or genetic modifiers. Some authors suggest AFND might result from a perturbation of the hedgehog pathway. Age/Gestational week of manifestation: can be suspected by ultrasound during the first to second trimester (11–13+6 weeks). Clinical features: • Severe frontonasal dysostosis: frontal bossing, hypertelorism, epibulbar dermoid, broad nasal root, midline nasal cleft, complete separation of the nostrils, no cleft palate • Wide fontanelles and sutures • Upper limbs may have pre- and/or postaxial polydactyly • Short lower limbs, tibial aplasia or hypoplasia in 50% of cases; bilateral talipes equinovarus and preaxial polysyndactyly of the feet • Bilateral inguinal herniae, cryptorchidism • Brain malformations: agenesis of the corpus callosum, absent septum pellucidum, hydrocephalus, encephalocele, neuronal migration defects Prenatal ultrasound features: in the late first trimester, there might be an absent nasal bone, marked hypertelorism and occipital encephalocele. Mesomelic shortening of the lower limbs is often associated with bilateral talipes equinovarus. Early in

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the second trimester, 3D ultrasound can show a flat profile, median cleft face with distinctive nasal bifurcation, with separation of the nostrils and widely separated nasal alae. In the second trimester, wide sutures are visible on 3D ultrasound; there can be tibia hypoplasia/aplasia with clubfeet, preaxial polydactyly of the feet and/or pre- or postaxial polydactyly of the hands. Variable brain anomalies include dysgenesis of the corpus callosum, interhemispheric lipoma, absent septum pellucidum and ventriculomegaly. Radiographic features: in the skull the sutures are wide and the fontanelles large. A posterior encephalocele may be seen as a midline soft tissue mass associated with an underlying bony defect. Agenesis of the corpus callosum and interhemispheric lipoma are associated. The base of the skull is short. The hands may show postaxial polydactyly. In the feet there is talipes equinovarus and preaxial polydactyly. There are varying degrees of tibial hypoplasia associated with ankle and knee dislocations. Prognosis: viable. Although neonatal respiratory distress has only been reported in a few cases, 50% of patients die in the first years of life due to respiratory compromise or apnoea. Developmental delay has been reported in many cases. Lower limb anomalies might require orthopaedic surgery. Additional medical problems can include glaucoma and hypogonadotropic hypogonadism. Differential diagnosis: frontonasal dysplasia is also present in acro-fronto-facio-nasal dysostosis: recessive disorder with postaxial camptobrachypolysyndactyly. Craniofrontonasal dysplasia: X-linked dominant, combines frontonasal dysplasia with craniosynostosis, intelligence is usually normal. Brachycephalofrontonasal dysplasia: dominant disorder with normal intelligence and stature, short hands but no polydactyly. Syndromes with prominent broad forehead, hypertelorism and polydactyly include hydrolethalus syndrome: severe hydrocephalus or hydranencephaly, hydramnios, postaxial polydactyly. Acrocallosal syndrome: with severe mental retardation, agenesis of the corpus callosum and preaxial polydactyly of feet and postaxial polydactyly of hands. Greig syndrome: (p. 583).

DOI: 10.1201/9781003166948-112

Acromelic Frontonasal Dysostosis, ZSW1M6-Related

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CASE 1: (a–c) Dislocated knee and ankle with talipes; short tibia; preaxial polydactyly; small occiput and short skull base. Hypoplastic ilia and pubic rami; (d, e) MRI: thickened fornix with central high signal on the sagittal image consistent with fat – possibly within a lipoma or dermoid; large ventricles. (f–h) 3D CT reconstruction: Expanded anterior fontanelle with a bone island located centrally. Bony defect extends anteriorly to involve the metopic suture. A further bony defect is related to the posterior segment of the sagittal suture, and the posterior fontanelle underlies the posterior encephalocele. Hypertelorism and wide, poorly formed nasal bone.

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BIBLIOGRAPHY Hing AV, Syed N, Cunningham ML. Familial acromelic frontonasal dysostosis: Autosomal dominant inheritance with reduced penetrance. Am J Med Genet A. 2004; 128A: 374–82. Martinex-Payo C, Garciá-Santiago FA, Heath KE et al. Prenatal diagnosis of acromelic frontonasal dysostosis. Mol Syndromol. 2021; 12: 41–5. Slaney SF, Goodman FR, Eilers-Walsman BL et al. Acromelic frontonasal dysostosis. Am J Med Genet. 1999; 83: 109–16.

Fetal and Perinatal Skeletal Dysplasias Smith JD, Hing AC, Clarke CM et al. Exome sequencing identifies a recurrent de novo ZSWIM6 mutation associated with acromelic frontonasal dysostosis. Am J Hum Genet. 2014; 95: 235–40. Twigg SR, Ousager LB, Miller KA et al. Acromelic frontonasal dysostosis and ZSWIM6 mutation: Phenotypic spectrum and mosaicism. Clin Genet. 2016; 90: 270–5.

107 Spondylocostal Dysostosis, DLL3-, MESP2-, LFNG-, HES7-, TBX6- and RIPPLY2-Related

Synonyms: spondylocostal dysostosis, SCDO (1–6). Previously also described as Jarcho-Levin syndrome; JLS, spondylothoracic dysostosis Confirmation of diagnosis: typical clinical and radiological features, associated with pathogenic variants in the related genes Frequency: 1 in 40,000; pan-ethnic Genetics: SCD is an autosomal recessive disorder. Four genes define different subtypes (1–4): DLL3 (delta-like 3), MESP2 (mesoderm posterior 2), LFNG (lunatic fringe) and HES7 (hairy/enhancer of split, homolog of drosophila, 7). All encode proteins involved in the notch-signalling pathway, crucial to normal somitogenesis. DLL3 is a notch ligand, crucial in the cell-signalling processes which generate rostro-caudal somite boundary formation with a defined temporal periodicity driven by the molecular ‘segmentation clock’. MESP2 is a member of the basic helix-loop-helix (bHLH) family of transcriptional regulatory proteins. LFNG is a glycosyltransferase; it localises to the Golgi and post-translationally modifies the notch family receptors. Its expression is indirectly regulated by DLL3. HES7 encodes a bHLH-orange domain transcriptional repressor protein. In the mouse, HES genes are direct targets of notch and repress their own transcription through the interaction with their own promoters; due to their very short half-lives, cyclic waves of transcription are generated every 90–120 minutes. A rare form of SCD with autosomal dominant inheritance has been reported; the gene is still unknown. Age/Gestational week of manifestation: can be usually detected by ultrasound during the second trimester (14–18 weeks). Clinical features: • Scoliosis, usually mild and non-progressive, rarely severe • Symmetric thorax, mild respiratory insufficiency Prenatal ultrasound features: increased nuchal translucency thickness or cystic hygroma may present in the first trimester. At 12–13 weeks, 2D and 3D ultrasound can detect a totally disorganised fetal spine. Early in the second trimester (14–18 weeks), ultrasound can demonstrate a short spine with a short

DOI: 10.1201/9781003166948-113

and small trunk. The axial skeleton is characterised by multiple vertebral segmentation and formation defects, misaligned ribs with points of fusion and sometimes a reduction in number with left/right asymmetry. Intrinsic rib anomalies include broadening, bifurcation and fusion of the ribs. These anomalies are asymmetric and, in contrast to spondylothoracic dysostosis (STD), do not display a ‘crab-like’ configuration of the thorax. Vertebral bodies may appear randomly arranged, ovoid in shape (‘pebble beach sign’) or more angular. Associated features include equinovarus deformity, congenital heart disease, urogenital and anal anomalies, diaphragmatic and inguinal hernias and closed and open neural tube defects. Radiographic features: the subtypes of AR-SCD and ADSCD can be differentiated according to the radiographic features. Involvement of at least 10 contiguous vertebral bodies. SCDO1 due to DLL3 homozygous mutations: this is the most implicated gene in generalised multiple segmentation defects of the spine. The somewhat randomly arranged pattern of ovoid vertebral bodies gives rise to a ‘pebble beach’ appearance. In this form, the vertebral pedicles are not well ossified, in contrast to SCDO2. The spine is short and the chest small. The ribs are wavy with occasional points of fusion along their length; some ribs may be missing, with left/right asymmetry; however, overall, there is a general symmetry to the thoracic cage. Some spinal curvature is common, but overall, the spine is stable and major scoliosis is unusual at any stage of life. SCDO2 due to MESP2 mutations is the second most implicated gene in generalised multiple segmentation defects of the spine. The vertebral bodies (especially in the lumbar spine) are more angular and irregular than in SCDO1 and the entire spine may be involved, although with regional differences. SCDO3 due to LFNG mutations has more severe spinal involvement than either SCDO1 or SCDO2. SCDO4 due to HES7 mutations: the vertebral bodies are angular and there is disorganisation of the entire spine. There may be an absence of ribs and fusion of ribs with progressive scoliosis. SCDO5 due to TBX6 mutations: there is a mild scoliosis, which is usually non-progressive. The ribs are fused posteriorly (costovertebral), fanning out laterally to give a ‘crablike’ appearance of the chest. Unlike SCDO1, there is no left/right asymmetry of the ribs. Ossification of the vertebral pedicles leads to the so-called ‘tramline’ appearance. There may be block vertebrae and fusion of C1 to the occiput. SCDO6 due to RIPPLY2 mutations: the cervical spine is most

517

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Fetal and Perinatal Skeletal Dysplasias

affected with failure of formation of the posterior elements of the upper cervical spine. Hemivertebrae, butterfly vertebrae and cervical and thoracic scoliosis are associated. Prognosis: viable. Respiratory function can occasionally be compromised in neonates, owing to the small thorax. Inguinal herniae can be relatively frequent, especially in males. In the most severe cases, scoliosis may require surgical intervention. Management includes monitoring growth, respiratory function and spinal curvature. Differential diagnosis: generalised vertebral segmentation defects: Casamassima-Morton-Nance syndrome: rare; likely a recessive disease which also shows anal atresia and genitourinary abnormalities. Many different syndromes can present with multiple segmentation defects of the vertebrae, particularly Alagille

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syndrome: typically has butterfly vertebrae, cholestasis due to bile duct paucity, heart malformations, posterior embryotoxon, specific facial features. Hemifacial microsomia (Goldenhar): has facial asymmetry, epibulbar dermoids and vertebral/cervical spine anomalies, usually involving only a few segments. VATER association (p. 531). Klippel-Feil anomaly: refers to cervical vertebral segmentation anomalies and fusions. It is described in a wide spectrum of phenotypes, including Poland syndrome, MURCS and Muenke syndrome. Neural tube defects can present with segmentation anomalies of the spine, but these are not part of the spondylocostal dysostoses. Large group of undefined conditions with localised or generalised vertebral segmentation defects: fewer than 10 contiguous vertebral bodies involved, significant asymmetrical rib involvement and asymmetry of the chest wall, scoliosis of varying severity which may progress, none of the typical features of SCDO1.

 

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CASES 1–3: A neonate and stillbirths. There are multiple vertebral segmentation defects with a ‘pebble beach’ appearance and broad chest with short, fused and missing ribs.

 

Spondylocostal Dysostosis, DLL3-, MESP2-, LFNG-, HES7-, TBX6- and RIPPLY2-Related

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CASE 4: A stillbirth with a homozygous mutation in DLL3. The ‘pebble beach’ sign of randomly arranged ovoid vertebral bodies is evident. There is general symmetry of the thoracic cage, and the ribs are wavy with reduced numbers bilaterally. The spine is short in relation to the body with no other skeletal abnormalities. CASE 5: A neonate with a homozygous mutation in DLL3. The randomly arranged ovoid vertebral bodies are described as the ‘pebble beach’ sign. At this stage, the vertebral pedicles are not well ossified. There is general symmetry to the thoracic cage, and the ribs are wavy and partly fused. The spine is short and the thorax small. There is a reduced number of ribs and some asymmetry. CASE 6: A neonate with a homozygous mutation in MESP2. The vertebral bodies appear poorly ossified and only part of the pedicles are clearly visible (the ‘tramline’ sign). The chest is very small. The ribs tend to be straight rather than wavy and fused posteriorly at the costovertebral junctions. Death occurred from respiratory insufficiency at a few months of age.

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Fetal and Perinatal Skeletal Dysplasias

 

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CASE 7: A fetus with a homozygous mutation in MESP2. The ribs are relatively straight and fused posteriorly. There is prominent ossification of the vertebral pedicles compared to the vertebral bodies (tramline sign).

BIBLIOGRAPHY Dane C, Yayla M, Dane B. Prenatal diagnosis of Jarcho-Levin syndrome in the first trimester. Gynecol Obstet Invest. 2007; 63: 200–2. Grigorios P, George M, Ioannis S, Konstantinos P. Jarcho-Levin syndrome: Two consecutive cases in the same family. J Family Reprod Health. 2019; 13: 220–2. Gucev ZS, Tasic V, Pop-Jordanova N et al. Autosomal dominant spondylocostal dysostosis in three generations of a Macedonian family: Negative mutation analysis of DLL3, MESP2, HES7, and LFNG. Am J Med Genet A. 2010; 152A: 1378–82. Lemire GT, Beauregard-Lacroix É, Campeau PM et al. Retrospective analysis of fetal vertebral defects: Associated anomalies, etiologies, and outcome. Am J Med Genet A. 2020; 182: 664–72. McInerney-Leo AM, Sparrow DB, Harris JE et al. Compound heterozygous mutations in RIPPLY2 associated with vertebral segmentation defects. Hum Molec Genet. 2015; 24: 1234–42.

Offiah A, Alman B, Cornier AS et al. ICVAS (International Consortium for Vertebral Anomalies and Scoliosis). Pilot assessment of a radiologic classification system for segmentation defects of the vertebrae. Am J Med Genet A. 2010; 152A: 1357–1. Sparrow DB, Sillence D, Wouters M et al. Two novel missense mutations in HAIRY-AND-ENHANCER-OF-SPLIT-7 in a family with spondylocostal dysostosis. Eur J Hum Genet. 2010; 18: 674–9. Turnpenny PD, Alman B, Cornier AS et al. Abnormal vertebral segmentation and the notch signaling pathway in man. Dev Dynamics. 2007; 236: 1456–74. Wax JR, Watson WJ, Miller RC et al. Prenatal sonographic diagnosis of hemivertebrae: Associations and outcomes. J Ultrasound Med. 2008; 27: 1023–7.

108 Cerebro-Costo-Mandibular Syndrome (Rib Gap Syndrome), SNRPB-Related

Synonyms: CCM syndrome; CCMS; rib gap defects with micrognathia Confirmation of diagnosis: identification of pathogenic variants in SNRPB Frequency: rare – fewer than 100 cases reported Genetics: heterozygous mutations in SNRPB (small nuclear ribonucleoprotein polypeptides B and B1), which encode components of the major spliceosome, have been found to cause CCMS. These mutations cluster in an alternatively spliced regulatory exon and result in altered SNRPB expression. Likely heterogeneous, as both recessive and dominant pedigrees have been reported. Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester (12–18 weeks). Clinical features: • Pierre Robin sequence: severe micrognathia, U-shaped cleft palate, glossoptosis • Bell-shaped thorax, posterior rib gaps, sometimes with respiratory insufficiency • Intrauterine growth retardation • Polyhydramnios • Cerebral anomalies occur in about 50% of cases and include microcephaly, agenesis of the corpus callosum, cerebral heterotopias, absent olfactory bulbs, neural tube defects • Characteristic facial traits: epicanthus, ptosis, long philtrum, microstomia, low-set ears • Musculoskeletal defects include bilateral adducted thumbs; hyperlaxity of elbows; hypoplastic humerus, ulna, radius, clavicle and sternum; coxa valga; and clubfeet • Occasionally other anomalies may be present, including tracheal cartilage anomalies, redundant skin, pterygia, renal anomalies and cardiac septal defects Prenatal ultrasound features: early prenatal diagnosis is possible, especially in at-risk families. Increased nuchal translucency has been described at 11 weeks and micrognathia at

DOI: 10.1201/9781003166948-114

12 weeks, with failure to identify the ribs at 18 weeks. Cystic hygroma and redundant nuchal skin folds may be present in the first and second trimesters. The number of ribs involved varies from only a few to almost all, and both sides are usually involved, although not necessarily in a symmetrical fashion; rudimentary or absent ribs have also been described. Ultrasound may demonstrate micrognathia/microretrognathia late in the first trimester (12–13 weeks’ gestation), whereas in the second and third trimester, the facial maxillary angle (FMA) or the maxilla-nasion-mandible angle (MNMA) can objectively diagnose micrognathia. Cleft palate, glossoptosis, narrow thorax and rib gaps are better visualised with 3D ultrasound. Pre- and postnatal growth retardation is common in CCMS. Three-dimensional fetal CT can provide precise information on the extent of the rib gaps. Fetal MRI may be used to assess the degree of lung hypoplasia and cerebral anomaly (microcephaly, corpus callosum dysgenesis and heterotopias). Vertebral anomalies (severe posterior curvature of the sacrum) and neural tube defects are described. Early prenatal diagnosis is possible, especially in at-risk families. Radiographic features: the mandible is short; microcephaly may be present in about 20% of cases. There are gaps in one or more ribs, and these range from virtually complete absence of all ribs, with an associated small narrow thorax, to a small posterior defect of one rib only. In addition, hypoplastic and missing ribs have been described. CT and MRI may demonstrate hypoplasia or atresia of the external auditory meatus, inner ear abnormalities and choanal atresia, as well as cerebral anomalies. Prognosis: approximately 50% of cases die within the first year of life because of severe respiratory distress. Among survivors, many show normal intelligence, but almost a third will develop moderate to severe intellectual impairment, probably secondary to perinatal and postnatal hypoxia; in all cases there is short stature. The rib gaps might ‘heal’ partially and turn into pseudarthroses. Microcephaly, scoliosis, hearing loss and speech delay have been reported. Differential diagnosis: cerebro-costo-mandibular–like syndrome (congenital disorder of glycosylation type IIg, or CDG2G): recessive condition recently described caused by a mutation in the COG1 gene. Costovertebral anomalies included posterior rib gaps, but also rib fusions, sagittal cleft vertebrae, osteopenia and misaligned vertebrae. Other features include

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failure to thrive, generalised hypotonia, microcephaly, psychomotor retardation, bilateral maculopathy, rhizomelic short stature and clubfoot. Other syndromes with Pierre Robin sequence: 22q11.2 deletion syndrome: the phenotypic spectrum is wide and frequently presents with typical facial features, conotruncal cardiopathy, hypoplastic thymus and parathyroid glands, mild intellectual impairment, psychiatric disorders and short

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stature. Skeletal anomalies are uncommon, apart from scoliosis; the ribs are normal. Stickler syndrome (p. 89): dominantly inherited, genetically heterogeneous (associated genes are COL2A1, COL11A1 and COL11A2); Catel-Manzke syndrome (p. 293). Non-accidental injury: no dysmorphic features, fractures at other sites, other features of abuse, rib fractures heal (with callus) on follow-up radiographs at 14–21 days.

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CASE 1: Ossification of the ribs is totally missing. The mandible is rudimentary. CASE 2: Only the posterior segment of the ribs is ossified. Severe micrognathia is seen. CASE 3: Multiple rib gaps are seen. CASE 4: Rib gaps are confined to the middle ribs. Micrognathia is also mild.

Cerebro-Costo-Mandibular Syndrome (Rib Gap Syndrome), SNRPB-Related

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CASE 5: Multiple rib gaps are clearly delineated on CT.

BIBLIOGRAPHY Neuschulz J, Wilhelm L, Christ H, Braumann B. Prenatal indices for mandibular retrognathia/micrognathia. J Orafac Orthop. 2015; 76: 30–40. Ramaswamy P, Negus S, Homfray T, De Rooy L. Severe micrognathia with rib dysplasia: Cerebro-costo-mandibular syndrome. Arch Dis Child Fetal Neonatal Ed. 2016; 101: F85.

Tooley M, Lynch D, Bernier F et al. Cerebro-costo-mandibular syndrome: Clinical, radiological and genetic findings. Am J Med Genet A. 2016; 170A: 1115–26. Zeevaert R, Foulquier F, Dimitrov B et al. Cerebrocostomandibularlike syndrome and a mutation in the conserved oligomeric Golgi complex, subunit 1. Hum Molec Genet. 2009; 18: 517–24.

109 Diaphanospondylodysostosis, BMPER-Related

Synonyms: DSD; ischiospinal dysostosis (ISD) Diagnostic confirmation: identification of biallelic pathogenic variants in the BMPER gene Frequency: rare. About two dozen affected families, including those with milder phenotypes termed ISD, have been reported. Genetics: DSD is an autosomal recessive disorder due to biallelic pathogenic variants in BMPER mapped on chromosome 7q14.3 and encoding bone morphogenic protein (BMP)–binding endothelial regulator protein (a negative regulator for BMP signalling). Age/Gestational age of manifestation: can be detected as early as 12–14 weeks of pregnancy. Clinical features: the clinical features are caused by disturbance of early development of the paraxial mesoderm, interfering with spinal segmentation and renal organogenesis: • Short stature with short neck and trunk as a result of spinal maldevelopment • Thoracic hypoplasia due to costovertebral malformation, causing neonatal respiratory failure • Lumbosacral neurological deficits (weakness and contracture of the lower extremities, neurogenic bladder, faecal dysfunction) • Mild facial dysmorphism (hypertelorism, depressed nasal bridge, short nose, low-set ears) • Nephroblastomatosis presenting as multiple renal cysts Prenatal ultrasound features: increased nuchal translucency (NT) or cystic hygroma may be evident at 11–13 weeks. Substantial narrowness of the thorax, distension of the abdomen and hyperechogenic kidneys can be identified at 14 weeks’ gestation. Over the following weeks, the thorax is more clearly bell-shaped; the thoracic cage may appear short and increased in the anteroposterior diameter, with missing ribs, short ribs with abnormal shape (ribbon-like) and posterior gaps. The major skeletal features are absent or delayed ossification of the vertebral bodies, more prominent in the lumbosacral spine; therefore, unossified vertebral bodies below T12 is a characteristic feature. Translucent vertebrae are due to decreased ossification. Appendicular skeleton is normal. Elevated echogenicity of kidneys is due to the presence of multiple medullar,

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cortical and partially subcapsular small cysts. Dysplastic and/ or cystic kidneys and nephrogenic rests or nephroblastomatosis have often been observed at autopsy. In the second trimester dysmorphic features include enlarged fontanelles, short neck, hypertelorism, depressed nasal bridge and low-set ears more easily visualised by 3D ultrasound. Radiographic features: diaphano refers to the Greek word ‘transparent’. Diaphanospondylo means the transparent appearance of the spine due to severe ossification defects of the vertebral bodies. Defective ossification of the posterior arches is likened to a ‘zipper’. In early gestation, vertebral body ossification is completely missing throughout the spine, and ossification of the lumbosacral neural arches is absent as well. In the neonatal period, the cervical spine has malsegmentation or Klippel-Feil anomaly (fusion of the vertebral bodies and/or neural arches); the thoracic spine shows singly or in combination multiple sagittal clefts, hemivertebrae and block vertebrae, as well as a zipper-like appearance of the neural arches; ossification of the lower lumbar and sacral spine is still missing; the lumbosacral spine is severely hypoplastic along with the absence of disc formation, narrowing of the spinal canal and maldevelopment of the lower spinal cord and conus. In childhood, spinal ossification catches up, which facilitates identification of the malsegmentation pattern of the cervicothoracic spine and hypoplasia of the lumbosacral spine. The ribs are hypoplastic, partially missing, ribbon-like and commonly associated with posterior rib gaps. Hypoplasia or aplasia of the ischial rami is a radiological hallmark of DSD and IDS. The long bones are normal. Imaging findings of associated nephroblastomatosis are mostly likened to adult-type polycystic kidney disease but rarely akin to infantile polycystic kidney. Prognosis: often lethal because of respiratory failure despite medical intervention. Neonates with DSD inevitably manifest with short stature and respiratory distress and require intensive respiratory support. By contrast, individuals with ISD may escape medical attention in the neonatal period. Longer survivors with DSD and individuals with IDS show a progressive short trunk and short stature and commonly develop lumbosacral neurological symptoms, such as weakness of the leg, pes equinovarus, lack of urinary control and faecal incontinence and/or impaction. Scoliosis is not common because spinal malsegmentation tends to be symmetric. Differential diagnosis: the early gestational manifestation (total absence of vertebral ossification) may lead to a misdiagnosis

DOI: 10.1201/9781003166948-115

Diaphanospondylodysostosis, BMPER-Related

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of achondrogenesis (p. 58, 105, 256) and spondylo-megaepiphyseal-metaphyseal dysplasia. Severe shortening of the limbs in ACG allows the differential diagnosis. Prenatal differential diagnosis between SMMD and DSD/ISD may be difficult.

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Ischial hypoplasia is also associated with ischio-pubic-patellar dysplasia and ischiospinal dysplasia (a manifestation of surviving Campomelic dysplasia); however, these disorders do not show spinal malsegmentation.

 

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CASE 1: Radiographs as a neonate (a–e) show wavy ribs with rib gaps; broad, short ischia; missing vertebral bodies of the lower cervical and upper thoracic spine; multiple sagittal clefts of the thoracic vertebral bodies; defective ossification of the neural arches of the lower thoracic and lumbar spine; and absent ossification of the lower lumbar spine and scarum.

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Fetal and Perinatal Skeletal Dysplasias

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CASE 2: Radiographs as a neonate (a–d) show almost the same skeletal changes as those of Case 1. Ultrasonography shows renal cysts.

 

 

Diaphanospondylodysostosis, BMPER-Related

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CASE 3: A neonate. Wavy ribs with rib gaps and a small thorax. The spine shows absent pedicles, rounded hypoplastic vertebral bodies and absent ossification of the sacrum. In the pelvis the ischia are hypoplastic with absent inferior pubic rami. The iliac wings are flared with wide sacrosciatic notches.

BIBLIOGRAPHY Funari VA, Krakow D, Nevarez L et al. BMPER mutation in diaphanospondylodysostosis identified by ancestral autozygosity mapping and targeted high-throughput sequencing. Am J Hum Genet. 2010; 87: 532–7. Gonzales M, Verloes A, Saint Frison MH et al. Diaphanospondylodysostosis (DSD): Confirmation of a recessive disorder with abnormal vertebral ossification and nephroblastomatosis. Am J Med Genet A. 2005; 136A: 373–6. Greenbaum L, Gilboa Y, Raas-Rothschild A et al. Diaphanospondylodysostosis: Refining the prenatal diagnosis of a rare skeletal disorder. Eur J Med Genet. 2019; 62: 167–71.

Kuchinskaya E, Grigelioniene G, Hammarsjö A et al. Extending the phenotype of BMPER-related skeletal dysplasias to ischiospinal dysostosis. J Orphanet J Rare Dis. 2016; 11 (1) 1–5. Legare JM, Seaborg K, Laffin J et al. Diaphanospondylodysostosis and ischiospinal dysostosis, evidence for one disorder with variable expression in a patient who has survived to age 9 years. Am J Med Genet A. 2017; 173: 2808–13. Nishimura G, Kimizuka M, Shiro R et al. Ischio-spinal dysostosis: A previously unrecognised combination of malformations. Pediatr Radiol. 1999; 29: 212–7. Spranger J, Self S, Clarkson KB et al. Ischiospinal dysostosis with rib gaps and nephroblastomatosis. Clin Dysmorphol. 2001; 10: 19–23.

110 Uniparental Disomy, Paternal, for Chromosome 14 (UPD14; Kagami-Ogata Syndrome)

Synonyms: paternal UPD 14; UPD14(pat); patUPD 14 Confirmation of diagnosis: detection of UPD of chromosome 14 combined with typical clinical and radiological features Frequency: extremely rare – more so than maternal UPD 14 Genetics: the chromosomal region 14q32–14q32.33 is one of those that are subject to genomic imprinting, an epigenetic germline modification that determines differences in gene expression depending on parental origin. Uniparental disomy (UPD) describes the situation in which both homologs of a chromosome pair are inherited exclusively from one parent and results in overexpression of some genes and absence of expression of others. Consequently, paternal and maternal uniparental disomy for chromosome 14 (UPD(14)pat and UPD(14)mat) cause distinct phenotypes. Among the paternally expressed genes (PEGs) are DLK1 and RTL1, while among the maternally expressed genes (MEGs) are MEG3 (or GTL2), RTL1 (RTL1 antisense) and MEG8. Most cases of UPD14 are secondary to abnormal segregation at meiosis of a paternal Robertsonian translocation, resulting in a trisomic zygote with the subsequent loss of one of the three copies of the chromosome involved (trisomy rescue). Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester (around 20 weeks). Clinical features: • Polyhydramnios • Birth weight and length are generally normal • Axial skeletal abnormalities: short neck, small thorax, kyphoscoliosis • Joint contractures, particularly the wrists with bilateral ulnar deviation • Dysmorphic facial features: hirsute forehead, blepharophimosis, broad and depressed nasal bridge with

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anteverted nares, protruding philtrum, hypoplasia of the maxilla and mandible, small ears • Hypotonia • Redundant lax skin, inguinal herniae, anterior abdominal wall defects Prenatal ultrasound features: polyhydramnios is almost universal with a high rate of premature labour. A small thorax is probably present in all cases but not always recognised. The ribs are short with a characteristic angulation. Other features include hydrops, short limbs, abdominal wall defects and joint contractures. The trio of polyhydramnios, small thorax and characteristic angulation of the ribs may allow the specific diagnosis of patUPD 14 to be made. Radiographic features: the characteristic, if not pathognomonic, feature of this condition is the ‘coat-hanger’ appearance of the ribs, so called because of the sharply curved ribs with bulbous anterior ends. The thorax is narrow and bell-shaped. There is lax redundant abdominal skin, and inguinal herniae may be present. There may be mild spurring of the metaphyses. The distal phalanges may have a spatulate appearance with broad tufts. Mild mesomelic shortening of the lower limbs and absent glenoid fossae are additional findings that may be present. Prognosis: usually severe; there is often spontaneous miscarriage or perinatal death due to pulmonary compromise. Survivors show developmental delay and intellectual impairment. Differential diagnosis: syndromes with short ribs and also with polydactyly include asphyxiating thoracic dysplasia (Jeune) (p. 196) and chondroectodermal dysplasia (Ellis-van Creveld) (p. 203) and cranioectodermal dysplasia (p. 212). Other lethal disorders with narrow thorax: Campomelic dysplasia (p. 302), thanatophoric dysplasia (p. 36), achondrogenesis all types (p. 58, 105, 256).

DOI: 10.1201/9781003166948-116

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CASES 1–3: All cases show a narrow, bell-shaped thorax with ‘coat-hanger’ deformity of the ribs and abdominal protuberance. The ilia are wide. The long bones are not remarkable. Metaphyseal radiolucency results from trophic changes due to postnatal general illness.

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CASE 4: Prenatal US at 33 weeks of gestation revealed polyhydramnios and joint contractures. Prenatal MRI showed a narrow, bell-shaped thorax, protuberant abdomen and retrognathia.

BIBLIOGRAPHY Irving MD, Buiting K, Kanber D et al. Segmental paternal uniparental disomy (patUPD) of 14q32 with abnormal methylation elicits the characteristic features of complete patUPD14. Am J Med Genet A. 2010; 152A: 1942–50. Kagami M, Sekita Y, Nishimura G et al. Deletions and epimutations affecting the human 14q32.2 imprinted region in individuals with paternal and maternal upd(14)-like phenotypes. Nat Genet. 2008; 40: 237–42. Kagami M, Matsubara K, Nakabayashi K et al. Genome-wide multilocus imprinting disturbance analysis in temple syndrome and Kagami-Ogata syndrome. Genet Med. 2017; 19: 476–82. Kuriki A, Hosoya S, Ozawa K et al. Quantitative assessment of coat-hanger ribs detected on three-dimensional ultrasound for prenatal diagnosis of Kagami-Ogata syndrome. J Obstet Gyneclol Res. 2022; 48: 3314–8.

Kurosawa K, Sasaki H, Sato Y et al. Paternal UPD14 is responsible for a distinctive malformation complex. Am J Med Genet. 2002; 110: 268–72. Miyazaki O, Nishimura G, Kagami M et al. Radiological evaluation of dysmorphic thorax of paternal uniparental disomy 14. Pediatr Radiol. 2011; 41: 1013–9. Offiah AC, Cornette L, Hall CM. Paternal uniparental disomy 14: Introducing the “coat-hanger” sign. Pediatr Radiol. 2003; 33: 509–12. Watanabe T, Go H, Kagami M et al. Prenatal findings and epimutations for paternal uniparental disomy for chromosome 14 syndrome. J Obstet Gyneclol Res. 2015; 41: 1133–6.

111 VATER/VACTERL Association

Synonyms: VATER association; VACTERL association Confirmation of diagnosis: identification of at least three of the associated congenital abnormalities Frequency: 1.6 in 10,000 Genetics: VATER is an acronym for the non-random association of vertebral defects, anal atresia, tracheo-oesophageal fistula/oesophageal atresia and radial or renal dysplasia. At least three of these abnormalities are necessary to establish the diagnosis. VACTERL is an expanded acronym of the same association, but also includes cardiac malformations and limb anomalies. The VACTERL association is probably a heterogeneous condition, and the cause is still unknown. Nearly all cases have been sporadic. It is more frequent in infants of diabetic mothers than in the general population. Recurrence risk is low, around 1%. In a few cases with an overlapping phenotype, variants in the genes HOXD13, PTEN, TRAP1, HSPA6 and 16q24 microdeletions have been reported. Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester (20 weeks). Clinical features: • Congenital vertebral anomalies, scoliosis, spinal dysraphism • Anorectal atresia • Tracheo-oesophageal fistula with oesophageal atresia • Radial dysplasia: aplasia, hypoplasia, radioulnar synostosis • Congenital cardiac defects: ventricular septal defects, tetralogy of Fallot, transposition of the great arteries • Congenital renal anomalies: aplasia, duplication, dysplasia, hydronephrosis, ectopia • Limb anomalies: thumb hypoplasia, triphalangeal thumb, preaxial polydactyly, syndactyly • Agenesis of a lung is occasionally associated Prenatal ultrasound features: severe scoliosis and anomalies of the vertebral bodies can now be identified in early pregnancy. The spine may appear disorganised due to hemivertebrae, which may or may not be associated with rib anomalies. In the first trimester, new sonographic markers of open spina bifida – the ‘crash sign’ and the ‘dry brain’ – when present, should prompt assessment of the posterior fossa and spine, which should be

DOI: 10.1201/9781003166948-117

examined in all three planes. Limb defects, particularly radial ray defects, may be detected in the first trimester. Radial ray abnormalities include aplasia, hypoplasia and/or an abnormal thumb. Charts of normal skeletal size, including length of long bones, chest size and renal size, are available from gestations as early as 12 weeks. However, hemivertebra, wedge vertebra, butterfly vertebra and segmentation failure with ribs and sternal abnormalities are better detected in the second trimester. Limb anomalies and prenatal growth deficiency may be present. In the second and third trimester, long bones may be at or below the fifth centile. Cardiac anomalies, if diagnosed in the first trimester, must be confirmed in the second trimester. Heart defects include ventricular septal defects, tetralogy of Fallot and transposition of the great vessels. Renal abnormalities include renal dysplasia, aplasia and hydronephrosis. Oesophageal atresia (OA) with or without trachea-oesophageal fistula is difficult to diagnose. OA without fistula is diagnosed in the presence of a dilated oesophageal pouch but may be suspected in the case of absent or small stomach with increased amniotic fluid. OA with fistula is difficult to diagnose. Prenatal ultrasound correctly identifies 77.9% of cases with oesophageal atresia and 21.9% of cases of oesophageal atresia with an associated tracheo-oesophageal fistula. Fetal MRI and amniotic fluid analysis have a high diagnostic accuracy for oesophageal atresia. The DATE association (duodenal obstruction, anorectal malformation [ARM], tracheo-oesophageal fistula with oesophageal atresia type C] is a low-frequency entity, often occurring among the wider spectrum of VACTERL association. Anal atresia and imperforate anus are commonly associated with VATER/VACTERL, with genital, urinary and lumbosacral spine abnormalities. The normal anus appears as an external hypoechoic ring with an echogenic centre, which represents the anal sphincter muscles and the anal mucosa, respectively. Ultrasound findings of suspected anorectal malformation may include failure to display an ‘anal dimple’ and dilatation of the distal colon/rectum. Anal atresia may be diagnosed early in the second trimester, but it is often not recognised prenatally, especially in cases of anal atresia with fistula. During the second trimester polyhydramnios is commonly present. Radiographic features: the skeletal findings relate to vertebral and radial ray abnormalities. In the spine there are usually segmentation defects – mainly hemivertebrae and increased segmentation. In the presence of oesophageal atresia with or without a fistula, there is commonly increased thoracic

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532 segmentation with 13 pairs of ribs. If anorectal atresia is present, there may be six lumbar vertebrae. With a high rectal atresia, the sacrum is short. The radial ray defect is usually unilateral and ranges from complete absence of the radius and thumb to duplication of the distal phalanx of the thumb only. Contrast imaging or MRI may be required to demonstrate the extent of the cardiac abnormalities, the oesophageal or rectal atresia and the renal anomalies. Prognosis: viable – prognosis and treatment are strictly related to the severity and to the combination of the malformations in each case. Intelligence is within the normal range. Pre- and postnatal growth impairment has been reported. Differential diagnosis: the main differential diagnosis is with VACTERL-H (with hydrocephalus), a distinct, more severe heterogeneous entity with both X-linked recessive and autosomal recessive inheritance: at least a proportion of these cases will have Fanconi anaemia (p. 573). Tracheo-oesophageal fistula with oesophageal atresia: CHARGE syndrome also has coloboma of the eye, choanal atresia or cleft palate, hearing loss, frequently hypogonadism; prenatal exposure to methimazole; some chromosomal abnormalities can present with some of the typical VACTERL association features, including trisomy of chro-

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Fetal and Perinatal Skeletal Dysplasias mosomes 18 and 21, 22q11 deletion syndrome and deletions at chromosomes 17q22q23.3 and 13q32. Feingold syndrome is a dominantly inherited disorder that presents with a significant phenotypical overlap with VACTERL association, but also shows microcephaly, facial dysmorphism, mental retardation, brachymesophalangy in the hands and syndactyly of the toes. Anophthalmia-oesophageal-genital (AEG) syndrome also shows brain and genital anomalies; caused by pathogenic variants in the gene SOX2. More rarely: Opitz B/GGG syndrome, KaufmanMcKusick syndrome (p. 599) and hemifacial microsomia: facial asymmetry, epibulbar dermoids and vertebral/cervical spine anomalies. Upper limb anomalies are not part of the spectrum. Anal atresia: Pallister-Hall syndrome (p. 587); Townes-Brocks syndrome: autosomal dominant disorder; combines external ear anomalies, preaxial polydactyly, imperforate anus and renal malformations, oesophageal atresia is not present. Radial ray defects: Holt-Oram syndrome (p. 536); prenatal exposure to teratogens (vitamin A, valproate, cocaine, thalidomide). Thrombocytopenia-absent radius (TAR) syndrome: bilateral radial aplasia, malformed but not absent thumbs, thrombocytopenia. Duane-radial ray syndrome (DRRS) is characterised by Duane anomaly, ocular coloboma and renal abnormalities.

 

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CASE 1: A fetus at 27 weeks of gestation. US shows tetralogy of Fallot. (a) The arrow points to the aorta (red) overriding the pulmonary artery (blue) and hemivertebrae. (b) The arrow points to a misshapen vertebral body. Postnatal radiograph shows sagittal cleft thoracic vertebrae, hemivertebrae and rib fusions.

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CASE 2: A fetus at 22 weeks of gestation. 3D US shows thoracic scoliosis due to an asymmetrical butterfly vertebra (a). Axial four-chamber view with colour Doppler shows an apical ventricular septal defect (VSD) (b) and a small muscular VSD (c). Abdominal US shows that both kidneys are located as if they were embraced by the iliac vessels (d): this type of anomaly is called ‘cake kidney’, in which the median surface of the two organs is partially fused along their border (p: renal pelvis; B: bladder). Colour Doppler with 3D rendering shows the renal arteries originate from the common iliac arteries, and they are connected in ‘Y’ shape and direct to the fused kidneys (e). CASES 3–5: 3D and 2D US can clearly show spinal malsegmentation.

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(6f ) CASE 6: A fetus (male) at 21 weeks of gestation. 3D US shows radial agenesis and radial clubhand (a). Postmortem 3D CT shows a rudimentary right thumb (a curved arrow) (b) and unilateral radial ray defect (c). 2D US (coronal view) shows moderate ventriculomegaly with absence of the septum pellucidum, dangling of choroid plexuses and normal posterior fossa (d). 2D and 3D US show a duplicated renal collecting system with mild dilatation (e). Pathologic findings confirmed hydrocephalus, with aqueduct stenosis (red arrow) confirmed at the microscopic level.

VATER/VACTERL Association

BIBLIOGRAPHY Holden ST, Cox JJ, Kesterton I et al. Fanconi anaemia complementation group B presenting as X linked VACTERL with hydrocephalus syndrome. J Med Genet. 2006; 43: 750–4. Kause F, Zhang R, Ludwig M et al. HSPA6: A new autosomal recessive candidate gene for the VATER/VACTERL malformation spectrum. Birth Defects Res. 2019; 111: 591–7. Pariza PC, Stavarache I, Dumitru VA et al. VACTERL association in a fetus with multiple congenital malformations – Case report. J Med Life. 2021; 14: 862–7. Saisawat P, Kohl S, Hilger AC et al. Whole exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association. Kidney Int. 2014; 85: 1310–7.

535 Sepulveda W, Wong AE, Fauchon DE. Fetal spinal anomalies in a first-trimester sonographic screening program for aneuploidy. Prenat Diagn. 2011; 31: 107–14. Shaw-Smith C. Genetic factors in esophageal atresia, tracheoesophageal fistula and the VACTERL association: Roles for FOXF1 and the 16q24.1 FOX transcription factor gene cluster, and review of the literature. Eur J Med Genet. 2010; 53: 6–13. Solomon BD, Pineda-Alvarez DE, Raam MS et al. Analysis of component findings in 79 patients diagnosed with VACTERL association. Am J Med Genet A. 2010; 152A: 2236–44. Solomon BD. The etiology of VACTERL association: Current knowledge and hypotheses. Am J Med Genet C Semin Med Genet. 2018; 178: 440–6.

112 Holt-Oram Syndrome, TBX5- and SALL4-Related

Synonyms: HOS; heart-hand syndrome; atriodigital dysplasia Confirmation of diagnosis: identification of pathogenic variants in TBX5 or SALL4 with appropriate clinical findings Frequency: 1 in 100,000 Genetics: autosomal dominant, almost complete penetrance. Mutations in the gene TBX5 can be found in roughly 70% of patients; in a few cases mutations in the gene SALL4 have been identified. TBX5 is a member of the T-box family of transcription factors and is involved in specification of cardiac and forelimb structures during embryogenesis. TBX5 interacts with NKX2.5 and GATA4 in regulating cardiogenesis, particularly in cardiac septation, and is involved in the development of the cardiac conduction system. SALL4 encodes the sal-like protein 4, which contains three C2H2 double zinc finger domains of the SAL type. Sal-like protein 4 is essential for the development of the epiblast and primitive endoderm from the inner embryonic cell mass. It interacts with SALL1 in anorectal, heart, brain and renal development and with TBX5 in patterning and morphogenesis of the first digit of the upper limbs. Other conditions caused by mutations in SALL4 are Duane radial ray (Okihiro) syndrome and acro-renal-ocular syndrome (AROS). Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester (13 weeks). Clinical features: • Thumb anomalies: absent, triphalangeal, non-opposable, finger-like, rarely bifid • Other fingers might be absent or have clinodactyly or syndactyly • Upper extremity malformations involving radial, thenar or carpal bones, occasionally phocomelia • Ostium secundum atrial septal defect, ventricular septal defect, cardiac conduction defect (85–95% of cases) • Rarely renal or urogenital malformation

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Prenatal ultrasound features: increased nuchal translucency thickness may be seen at 13 weeks’ gestation. The upper limb malformations and cardiac defects (on the four-chamber view) have been identified from about 16 weeks of gestation. In atrisk pregnancies, severe upper limb and cardiac anomalies may be identified as early as 14 weeks. There is considerable variability in the severity within families. 3D sonography is of value in a detailed description of the upper limb abnormalities. Antenatal ultrasound may not demonstrate mild deformities. The radio-ulnar complex is the most difficult to visualise and measure during the second trimester because of supination/ pronation. The best time to visualise the forearm is between 13 and 16 weeks when the extremities are moving freely in relatively higher volumes of amniotic fluid. Specific findings include short radius and ulna, inability to supinate the hands, absent thumbs and ventricular septal defect. It has been suggested that right atrial enlargement may be a feature of HoltOram syndrome in the fetus. Radiographic features: there are asymmetric upper limb abnormalities, the left usually being more severely affected. There are various radial ray abnormalities, aplasia/hypoplasia of the radius and radio-ulnar synostosis. Thumb abnormalities include absence, proximal placement due to a hypoplastic first metacarpal, non-opposition with thenar hypoplasia, triphalangeal and occasionally bifid. Other digits may be abnormal, and there may be syndactyly. The carpals are often abnormal with carpal fusions, hypoplasia of the scaphoid and the presence of an os centrale representing a third row of carpal bones as found in amphibians. There is usually some mild hypoplasia of the humeri, and the shoulder joints and shoulder girdle (scapula and clavicle) may be abnormal. The sternum may also be deformed. Prognosis: viable. Severe malformation may require surgery early in life to repair septal defects and for pollicisation in the case of thumb aplasia/hypoplasia. Children with severe limb involvement may benefit from prostheses. The prognosis is largely dependent on the severity of the heart anomalies. Potential life-threatening complications include congestive heart failure, pulmonary hypertension, arrhythmias, progressive cardiac conduction disease, heart block and atrial fibrillation. In cases of severe heart block, pacemaker implantation might be

DOI: 10.1201/9781003166948-118

Holt-Oram Syndrome, TBX5- and SALL4-Related

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needed. Rarely, respiratory insufficiency is present in infancy. Mental development is normal.

and palate, mental retardation, hypocalcaemia and immune deficiency. VATER, VACTERL (p. 531).

Differential diagnosis: triphalangeal thumbs and/or radial ray anomalies: Townes-Brocks syndrome: triad of imperforate anus, overfolded helices and sensorineural deafness and triphalangeal thumbs; caused by mutations of SALL1. Fanconi anaemia (FA) (p. 573); thrombocytopenia-absent radius (TAR) syndrome: bilateral radial aplasia, thumbs can be malformed but never absent. Thrombocytopenia is a specific feature. Thalidomide embryopathy: includes amelia, phocomelia, radial hypoplasia, external ear abnormalities, facial palsy, eye abnormalities and heart defects. 22q11.2 deletion syndrome: characterised by a wide range of anomalies including congenital heart disease (typically conotruncal malformations), cleft lip

SALL4-related disorders: Duane-radial ray syndrome (DRRS) and acro-renal-ocular syndrome (AROS), characterised by unilateral or bilateral Duane anomaly, ocular coloboma, renal abnormalities (malrotation, ectopia, hypoplasia, horseshoe kidney, vesicoureteral reflux, bladder diverticula).

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‘Heart-hand’ syndromes: heart-hand syndrome II (Tabatznik syndrome): dominant disorder characterised by type D brachydactyly and intraventricular conduction defect. Heart-hand syndrome III (Spanish type): combination of type C brachydactyly and intraventricular conduction defects. Sick sinus syndrome may also occur.

 

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CASE 1: Large heart, lateral clavicular hooks, absent glenoid fossae, delayed ossification of the proximal humeri. Absent radius and thumb on the left. Short humerus and hypoplastic thumb on the right.

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CASE 2: Fetal US at 21 weeks’ gestation. 2D US shows the short ulna with unilateral, left radial ray aplasia. The thumb is absent and in its place is a rounded skin appendage (white arrow) with only four digits. Other anomalies detected in utero: left diaphragmatic hernia with polyhydramnios; atrial septal defect not diagnosed on prenatal imaging. CASE 3: Neonate with Holt-Oram syndrome. (a) 2D US showing severe cardiomegaly with a right mega-auricle and large septum secundum defect (SASD). (b) 2D US shows dilatation of the right side of the heart. (c) A long triphalangeal thumb of the left hand.

Holt-Oram Syndrome, TBX5- and SALL4-Related

BIBLIOGRAPHY He G-N, Wang X-Y, Kang M et al. Prenatal diagnosis of HoltOram syndrome with a novel mutation of TBX5 gene: A case report. Front Pediatr. 2021; 9: 737633. doi: https://doi. org/10.3389/fped.2021.737633 Law KM, Tse KT. Prenatal sonographic diagnosis of familial Holt-Oram syndrome associated with type B interrupted aortic arch. Hong Kong Med J. 2008; 14: 317–20. McDermott DA, Bressan MC, He J et al. TBX5 genetic testing validates strict clinical criteria for Holt-Oram syndrome. Pediatr Res. 2005; 58: 981–6. Epub 2005 Sep 23.

539 Paladini D, Tiesi M, Buffi D et al. Unexplained right atrial enlargement may be a sign of Holt-Oram syndrome in the fetus. Ultrasound Obstet Gynecol. 2014; 43: 475–6. Sepulveda W, Enriquez G, Martinez JL, Mejia R. Holt-Oram syndrome: Contribution of prenatal 3-dimensional sonography in an index case. J Ultrasound Me. 2004; 23: 983–7. Sunagawa S, Kikuchi A, Sano Y et al. Prenatal diagnosis of HoltOram syndrome: Role of 3-D ultrasonography. Congenit Anom (Kyoto). 2009; 49: 38–41.

113 Cornelia De Lange Syndrome, NIPBL-, SMC1A-, SMC3-, RAD21- and HDAC8-Related

Synonyms: CDL; CDLS; CdLS; Cornelia de Lange syndrome; Brachmann-de Lange syndrome; BDLS Confirmation of diagnosis: identification of monoallelic pathogenic variants in NIPBL, SMC1A, SMC3, RAD21 and HDAC8 Frequency: variably reported: 1 in 10,000 to 1 in 100,000; 1 in 50,000; 1 in 87,000 (severe phenotypes); 1 in 37,000 (severe and mild phenotypes) Genetics: CDLS is a genetically heterogeneous disease; six different genes have been found to be associated with the disorder, all encoding proteins which are components of the cohesion complex. About 70% of cases of CDLS (CDLS1) are due to dominant pathogenic variants in the NIPBL gene and are usually the most severe. The possibility of mosaicism (15–20% of individuals with classic CDLS) requires the analysis of other tissues than blood in the case of negative molecular screening. Germline mosaicism has been reported. A second gene, SMC1A, Xlinked, accounts for about 5% of cases (CDLS2), usually with a milder phenotype. The other genes are SMC3, RAD21 and BRD4, transmitted with an autosomal dominant mode of inheritance, and HDAC8 with an X-linked mode of inheritance. De novo heterozygous variants in ANKRD11 have been reported in individuals with overlapping features with CDLS. Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester (16–20 weeks); increased nuchal translucency thickness has been reported in the first trimester. Clinical features: marked clinical variability: • Prenatal and postnatal growth retardation, developmental delay • Typical craniofacial features: microbrachycephaly; low anterior hairline; arched eyebrows; synophrys; long, thick, curved eyelashes; depressed nasal bridge with anteverted nares; maxillary prognathism; long philtrum; thin lips; ‘carp’ mouth; cleft palate • Upper limb anomalies (73.1%): symmetric or asymmetric reduction defects, from complete absence of the forearms to postaxial oligodactyly; contractures secondary to radioulnar synostosis, small hands with short fifth finger and proximally small thumbs

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• Lower limbs rarely involved: small feet, 2–3 syndactyly of the toes • Hirsutism • Hypoplastic nipples and umbilicus, cutis marmorata • Other frequent findings: cardiac malformations (45.6%) (septal defects, pulmonary stenosis, tetralogy of Fallot, hypoplastic left heart); central nervous system malformations (40.2%); congenital gastrointestinal anomalies including intestinal malrotation, hiatus hernia, congenital diaphragmatic hernia; feeding difficulties; myopia; cryptorchidism and hypoplastic genitalia • Intellectual disability of variable degrees Prenatal ultrasound features: increased nuchal translucency thickness and/or cystic hygroma in the first trimester. There is prenatal growth deficiency in the second trimester. The identification of asymmetrical forearm anomalies with oligodactyly and increased first-trimester nuchal translucency, associated with micro/brachycephaly and/or intrauterine growth retardation, suggests the diagnosis. The facial gestalt is characteristic, and associated upper limb malformations are confirmatory. The characteristic craniofacial features include an abnormal fetal profile: increased skin thickness over the forehead (prenasal and prefrontal oedema), depressed nasal bridge, small nose, anteverted nostrils, a long philtrum, overhanging upper lip, micrognathia and low-set ears. Long eyelashes (a characteristic feature present in 99% of affected infants) have been detected on ultrasound. The upper limbs may reveal unilateral digital anomalies (oligodactyly, monodactyly, adactyly) and radial ray defects (hypoplasia of the thumb and first metacarpal); however, severe reduction defects are more frequent and range from hypoplasia/aplasia of the ulna to an absent forearm with digits present just distal to the elbow. Lower limb anomalies are rare. Other findings include congenital heart defects, diaphragmatic hernia and structural anomalies of the genitourinary tract, including hydronephrosis and hypoplastic male genitalia. Radiographic features: microcephaly, brachycephaly and a small mandible/retrognathia may be present. Upper limb abnormalities are variable and usually asymmetric. They range from a short hypoplastic first metacarpal, oligodactyly, monodactyly and ectrodactyly to transverse limb defects. Absent digits are commonly on the ulnar side. There may be radioulnar synostosis and a hypoplastic ulna.

DOI: 10.1201/9781003166948-119

Cornelia De Lange Syndrome, NIPBL-, SMC1A-, SMC3-, RAD21- and HDAC8-Related Prognosis: viable – life expectancy is not significantly reduced in individuals who do not have severe malformations or gastrointestinal disorders. Affected individuals show prenatal-onset proportionate short stature, mental retardation (IQ 30–102, average of 53) and often show behavioural problems, autism and self-aggression. Seizures and decreased pain sensation have also been reported. Hearing loss is common as well as ocular anomalies, especially myopia, strabismus, glaucoma, nasolacrimal duct stenosis, microcornea, optic atrophy or coloboma. One main complication is gastro-oesophageal reflux, which affects most individuals. In a few affected children, thrombocytopenia and pancytopenia have also been reported. Differential diagnosis: other disorders with limb reduction defects: Roberts syndrome (p. 550) and Fryns syndrome. Other conditions include TAR syndrome; radial aplasia, with preservation of the thumbs, is combined with thrombocytopenia of early onset. There are also lower limb malformations, congenital heart defects and abnormalities of the ribs and cervical spine. Holt-Oram syndrome (p. 536), Fanconi anaemia (p. 573) and Baller-Gerold syndrome: coronal or multiple suture synostosis, radial aplasia, absent thumb, short and bowed ulna, absent carpal and metacarpal bones. Occasionally hypertelorism, epicanthic folds, prominent nasal bridge, midline capillary haemangiomas, genitourinary malformations, mental retardation. Caused by mutations of the gene RECQL4. Other disorders with similar facial features: fetal alcohol syndrome (FAS): features common to CDLS include prenatal

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growth retardation, microcephaly, facial hirsutism in the newborn, short palpebral fissures, short, upturned nose, smooth underdeveloped philtrum, thin upper lip, cardiac defects. There are no skeletal anomalies. Developmental anomalies are present but less severe. Coffin-Siris syndrome (ARID1B and genes encoding subunits of the SWI/SNF complex): recessive disorder characterised by microcephaly, coarse facial features, sparse scalp hair, hirsutism, microstomia, growth impairment and early feeding problems. Skeletal anomalies are not usually associated, except for fifth finger anomalies in the hands and feet (from absent nails to absent digits). KBG syndrome (ANKRD11): dominant disorder, with macrodontia of the upper central incisors, skeletal anomalies, namely block vertebrae, abnormal ribs, short femoral necks, broad and small hands. Wiedemann-Steiner (KMT2A): hirsutism. Partial duplication 3q: postnatal growth retardation, hirsutism, synophrys, low frontal hairline, microcephaly, cryptorchidism. Major malformations are very rare. Diagnosis is made through standard karyotyping. Variants in several additional genes have been identified by exome sequencing in individuals exhibiting some CDLS clinical features: EP300 associated with Rubinstein-Taybi syndrome, AFF4 in CHOPS syndrome, NAA10 in Ogden syndrome, TAF6 in Alazami-Yuan syndrome.

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(2b)

CASE 1: A neonate (a, b). Short first metacarpal and middle phalanges and dislocated elbow. CASE 2: A neonate. (a, b) The iliac wings are long. The proximal radius is hypoplastic and subluxed. The first metacarpal is extremely short.

 

542

Fetal and Perinatal Skeletal Dysplasias

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CASE 3: A stillbirth. (a–c) Postmortem photograph and radiographs show depressed nasal bridge, anteverted nares, long philtrum, overhanging upper lip and severe micrognathia, micromelia and longitudinal hemimelia of the forearms (ulnar agenesis) with oligodactyly. (d–f) Fetal US at 21 weeks of gestation confirms the postmortem findings. CASE 4: A fetus at 24 weeks of gestation. (a, b) 3D US images of the facial profile show a depressed nasal bridge, upturned nares (arrow), overhanging lip and synophrys along the supraorbital ridge (arrow). (c, d) 2D US and postmortem radiograph of the hand show ectrodactyly and missing second and third digits

Cornelia De Lange Syndrome, NIPBL-, SMC1A-, SMC3-, RAD21- and HDAC8-Related

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(5b)

543

 

 

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CASE 5: A fetus at 20 weeks of gestation. (a) 3D US demonstrates typical facial features and hypoplasia of the upper limbs. (b, c) Fetal CT shows bilateral ulnar dimelia and oligodactyly.

544

Fetal and Perinatal Skeletal Dysplasias

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(6c) CASE 6: Termination of pregnancy at 21 weeks of gestation. (a–c) There is bilateral absence of the ulnae, and the radii are short. On the right there is monodactyly. On the left, there is oligodactyly with three digits on the ulnar side missing.

Cornelia De Lange Syndrome, NIPBL-, SMC1A-, SMC3-, RAD21- and HDAC8-Related

BIBLIOGRAPHY Avagliano L, Bulfamante GP, Massa V. Cornelia de Lange syndrome: To diagnose or not to diagnose in utero? Birth Defects Res. 2017; 109: 771–7. Kennelly MM, Moran P. A clinical algorithm of prenatal diagnosis of radial ray defects with two- and three-dimensional ultrasound. Prenat Diagn. 2007; 27: 730–7. Kline AD, Moss JF, Selicorni A et al. Diagnosis and management of Cornelia de Lange syndrome: First international consensus statement. Nat Rev Genet. 2018; 19: 649–66. Lalatta F, Russo S, Gentilin B et al. Prenatal/neonatal pathology in two cases of Cornelia de Lange syndrome harboring novel mutations of NIPBL. Genet Med. 2007; 9: 188–94. Liu J, Krantz ID. Cornelia de Lange syndrome, cohesin, and beyond. Clin Genet. 2009; 76: 303–14. Pajkrt E, Griffin DR, Chitty LS. Brachmann-de Lange syndrome: Definition of prenatal sonographic features to facilitate definitive prenatal diagnosis. Prenat Diagn. 2010; 30: 865–72.

545

Panaitescu AM, Duta S, Gica N et al. A broader perspective on the prenatal diagnosis of Cornelia de Lange syndrome: Review of the literature and case presentation. Diagnostics (Basel) 2021; 11: 142. doi: 10.3390/diagnostics11010142 Schrier SA, Sherer I, Deardorff MA et al. Causes of death and autopsy findings in a large study cohort of individuals with Cornelia de Lange syndrome and review of the literature. Am J Med Genet A. 2011; 155A: 3007–24. Sepulveda W, Wong AE, Dezerega V. Brachmann-de Lange syndrome. Prenatal diagnosis with 2- and 3-dimensional sonography. J Ultrasound Med. 2009; 28: 401–4. Wu T, Chen J. Prenatal diagnosis of Cornelia de Lange syndrome from 12 to 17 weeks’ gestation. Prenat Diagn. 2022; 42: 1511–3.

114 Limb Reduction Syndrome (Al-Awadi Raas-Rothschild Limb-Pelvis Hypoplasia-Aplasia), WNT7A-Related

Synonyms: Al-Awadi/Raas-Rothschild syndrome; AARRS; limb-pelvis-hypoplasia-aplasia syndrome; LPHAS; ulna and fibula, absence of, with severe limb deficiency; Schinzel phocomelia syndrome Confirmation of diagnosis: identification of biallelic pathogenic variants in the WNT7A gene Frequency: very rare – a few dozen cases reported Genetics: autosomal recessive, caused by pathogenic variants in the gene WNT7A (wingless-type MMTV integration site family, member 7A), a crucial element in dorso-ventral and proximal-distal limb growth and development. Pathogenic variants in the same gene have also been found in Fuhrmann syndrome. Age/Gestational week of manifestation: can be detected by ultrasound between the first and the second trimester (12–18 weeks). Clinical features: • Disproportionate short stature • Severe limb defects, lower limbs more affected than upper limbs, phocomelia is common • Polydactyly, oligodactyly, ectrodactyly • Occipital bone defects, with or without meningocele • Thoracic anomalies: barrel-shaped chest, prominent sternum, pseudarthrosis of clavicle • Absent or hypoplastic pelvic bones, genital malformations (anteriorly displaced genitalia, Mullerian aplasia, agenesis of uterus and vagina, micropenis, cryptorchidism) • Typical facial features: long face, broad nasal bridge, high and narrow palate, cleft lip and palate, macrostomia, large ears

546

• Hip dislocation, elbow flexion contracture • Other possibly associated anomalies: genitourinary abnormalities including renal agenesis, oesophageal atresia with tracheo-oesophageal fistula and imperforate anus Prenatal ultrasound features: bilateral absence of the lower limbs has been identified at 15 weeks’ gestation. Hypoplasia of the pelvis may also be seen at this stage. Radiographic features: there are severe limb abnormalities, with the lower limbs more severely affected. There are varying degrees of proximal shortening, bowing, angulation and even absence of the femora resulting in hip dislocation and failure of development of the acetabula with hypoplastic ilia. The fibulae are absent, the tibiae may be hypoplastic and the feet severely hypoplastic or show oligodactyly, monodactyly or ectrodactyly with absence of various short tubular bones. Similar changes are present in the hands, and in addition there may be carpal synostosis or aplasia. The radii and/or ulnae may be hypoplastic or absent, resulting in elbow joint contractures. In the skull there may be an occipital defect with a meningocele. The thorax is short and broad and the ribs and clavicles wide. Differential diagnosis: Roberts syndrome (p. 550); acheiropody: absence of hands and feet; can show more extensive reduction defects involving the forearm, elbow joint, fibula and distal third of the tibia; due to a deletion in the gene C7ORF2. Grebe dysplasia (p. 283); DK phocomelia syndrome (p. 596); femurfibula-ulna syndrome (p. 556). Tetra-amelia: also shows multiple malformations, including cleft palate, aplasia of the peripheral pulmonary vessels, anal atresia, diaphragmatic defect, hypoplasia or aplasia of lung, kidneys, spleen, adrenal gland, uterus and ovaries. Recessive pathogenic variants in the WNT3 gene have been found. Fuhrmann syndrome: milder disorder which shows bowed femora, aplastic or hypoplastic fibulae, poly/oligo/syndactyly, dystrophic nails. Autosomal recessive pathogenic variants in WNT7A have been found.

DOI: 10.1201/9781003166948-120

Limb Reduction Syndrome (Al-Awadi Raas-Rothschild Limb-Pelvis Hypoplasia-Aplasia), WNT7A-Related

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547

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CASE 1: A neonate. Radiographs show hypoplastic iliac wings, absent pubic rami, dislocated hips, lower limb peromelia and aplasia of the ulnae.

BIBLIOGRAPHY Alp E, Alp H, Emre Atabek M et al. Al-Awadi/Raas-Rothschild syndrome in a newborn with additional anomalies. J Clin Res Ped Endo. 2010; 2: 49–51. Garavelli L, Wischmeijer A, Rosato S et al. Al-Awadi-RaasRothschild (limb/pelvis/uterus- hypoplasia/aplasia) syndrome and WNT7A mutations: Genetic homogeneity and nosological delineation. Am J Med Genet A. 2011; 155A: 332–6.

Raas-Rothschild A, Goodman RM, Meyer S et al. Pathological features and prenatal diagnosis in the newly recognised limb/pelvis-hypoplasia/aplasia syndrome. J Med Genet. 1988; 25: 687–97. Woods CG, Stricker S, Seemann P et al. Mutations in WNT7A cause a range of limb malformations, including Fuhrmann syndrome and Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome. Am J Hum Genet. 2006; 79: 402–8.

115 Cousin Syndrome, TBX15-Related

Synonyms: craniofacial dysmorphism, hypoplasia of scapula and pelvis and short stature; pelviscapular dysplasia Diagnostic confirmation: identification of biallelic pathogenic variants of the TBX15 gene Frequency: very rare; only four affected families (two affected siblings and three sporadic patients) have been reported Genetics: Cousin syndrome is an autosomal recessive disorder due to homozygous or compound heterozygous pathogenic variants in TBX15 mapped on 1p12 and encoding Tbx15, a member of the T-box family of caudal transcription factors. Age/Gestational age of manifestation: the diagnosis is confirmed on radiological grounds at birth. The major features (scapular hypoplasia and elbow ankylosis) can be prenatally identified. Clinical features: • Short stature • Macrocephaly • Facial dysmorphism (frontal bossing, tented eyebrows, sparse hair of the temporal region, hypertelorism, narrow palpebral fissures with deep-set eyes, strabismus, low-set and posteriorly rotated ears) • Short neck with a low hairline and redundant posterior skin folds • Elbow ankylosis and hip dislocation

(1a)

• Mild brachydactyly • Narrow auditory canals; hearing impairment Prenatal ultrasound features: prenatal manifestations have not been reported. However, the major skeletal changes (elbow ankylosis, hypoplasia of the scapulae and ilia and hip dislocation) could be detectable in the second trimester. Radiographic features: the radiological hallmarks include platybasia with basilar invagination and caudal displacement of the occipital bone, hypoplasia of the scapular wings, humeroradial synostosis, hypoplasia of the iliac wings, hip dislocation and mild femoral bowing. Prognosis: short stature is severe. The final height of two adult patients was about –8 standard deviations (SD). However, general health is not affected, and mental development is normal. The medical problems are only physical complications of the elbow and hip. Affected individuals show a distinctive ear morphology composed of a laterally orientated drooping helix, narrow cochlear opening and increased posterior angulation. The ear deformity recapitulates droopy ears seen in a spontaneous mouse mutant of Tbx15. Differential diagnosis: similar scapula hypoplasia is present in Campomelic dysplasia (p. 302). Elbow (humeroradial) ankylosis may be seen in Antley-Bixler syndrome (p. 500). Pelvis-shoulder dysplasia (scapuloiliac dysostosis; Kosenow syndrome) has scapuloiliac hypoplasia but not humeroradial synostosis or facial dysmorphism.

 

(1b)

 

CASE 1: Neonate. (a–d) Radiographs show absence of the scapular wings, mild retardation of vertebral ossification, hypoplasia of the ilia, wide ischiopubic junction, vertical ischia, femoral bowing and humeroradial synostosis.

548

DOI: 10.1201/9781003166948-121

Cousin Syndrome, TBX15-Related

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BIBLIOGRAPHY Cousin J, Walbaum R, Cegarra P et al. Dysplasie pelvis-scapulaire familiale avec anomalies epiphysaires, nanisme et dysmorphies: Un nouveau syndrome? Arch Fr Pediatr. 1982; 39: 173–5. Dikoglu E, Simsek-Kiper PO, Utine GE et al. Homozygosity for a novel truncating mutation confirms TBX15 deficiency as the cause of Cousin syndrome. Am J Med Genet A. 2013; 161A: 3161–5.

549

 

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King M, Arnold JS, Shanske A et al. T-genes and limb bud development. Am J Med Genet A. 2006; 140: 1407–13. Lausch E, Hermanns P, Farin HF et al. TBX15 mutations cause craniofacial dysmorphism, hypoplasia of scapula and pelvis, and short stature in Cousin syndrome. Am J Hum Genet. 2008; 83: 649–55. Sheeba CJ, Logan MP. The roles of T-box genes in vertebrate limb development. Curr Top Dev Biol. 2017; 122: 355–81.

116 Roberts Syndrome, ESCO2-Related

Synonyms: RBS; Roberts-SC phocomelia syndrome; long bone deficiencies associated with cleft lip/palate; SC pseudo thalidomide syndrome; SC phocomelia Diagnostic confirmation: identification of pathogenic variants in the ESCO2 gene Frequency: rare – about 150 cases described in the literature Genetics: autosomal recessive disorder caused by pathogenic variants in the gene ESCO2 (establishment of cohesion 1 homolog 2), encoding an acetyltransferase required for the establishment of sister chromatid cohesion during the S phase of the cell cycle. Cohesion of sister chromatids is essential for correct chromosome segregation and genomic stability. Cells of patients affected by RBS show a phenomenon known as premature centromere separation (PCS) or heterochromatin repulsion (HR), which manifests itself as an absence of the centromeric constriction and ‘puffing’ at the heterochromatic regions. This phenomenon can cause random chromosome loss and micronuclei and/or nuclear lobulation in the interphase cells. RBS cells also exhibit hypersensitivity to clastogens such as mitomycin C (MMC), cisplatin and gamma and UV radiation. Because of the cohesion defect, there is an increase in cell death and a decreased proliferation capacity, which is at the root of the reduced growth and developmental phenotype in RBS. Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester (16–18 weeks), occasionally at the end of the first trimester. Clinical features: • Prenatal and postnatal growth retardation • Symmetric mesomelic limb reduction, upper limbs more commonly and severely affected than lower limbs, severity ranges from phocomelia to mild reduction defects • Skeletal anomalies follow a cephalocaudal, distal to proximal and anterior to posterior pattern • Hands: the thumb is usually affected, less commonly the fingers, which may show brachydactyly or syndactyly

550

• Upper limbs: radius is always affected, followed in frequency by ulna and humerus • Lower limbs: fibula is most commonly and severely affected, followed by tibia and femur • Microcephaly, brachycephaly • Facial abnormalities: exophthalmos, hypertelorism, downslanting palpebral fissures, hypoplastic nasal alae, malar hypoplasia but prominent premaxilla, midfacial haemangioma, cleft lip and palate, micrognathia, ear anomalies • Eye anomalies (corneal opacity, microphthalmia, glaucoma) • Other possible associated anomalies include cardiac defects, abnormal kidneys, cryptorchidism and genital anomalies Prenatal ultrasound features: symmetrical micromelia/aplasia/hypoplasia/phocomelia may be detected at around 17–20 weeks’ gestation. Arthrogryposis has been reported. There is intrauterine growth retardation. The thumbs may be abnormally positioned. Three-dimensional ultrasound improves the detection of facial abnormalities such as cleft lip and exophthalmos. Hydrocephalus and umbilical cord cyst have also been reported. Radiographic features: in the skull there may be microcephaly or macrocephaly due to hydrocephalus. Anterior meningoceles/encephaloceles may occur, and rarely there may be craniosynostosis causing confusion with Baller-Gerold syndrome. There is micrognathia. There is severe limb shortening, more severe in the upper limbs and predominantly affecting the radial ray. There may be phocomelia, radiohumeral synostosis, radial aplasia, oligodactyly with absence of the thumb and syndactyly. In the lower limbs there may be shortening or absence of the long bones, predominantly affecting the fibula. Prognosis: lethal at birth in a proportion of cases; early death is common due to cardiac or renal malformations. Survivors frequently show severe intellectual disability, microcephaly, hearing loss and short stature. Facial malformations and limb defects may require surgical correction. Neoplasias have been reported in four cases, including melanoma, rhabdomyosarcoma and oculomotor nerve cavernous angiomas. Life expectancy is reduced.

DOI: 10.1201/9781003166948-122

Roberts Syndrome, ESCO2-Related Differential diagnosis: syndromes with severe preaxial reduction defects or phocomelia/amelia: thrombocytopenia-absent radius (TAR) syndrome: bilateral absence of the radii and thrombocytopenia are the hallmarks of this syndrome. Typically, the thumbs are present. Occasionally presents with involvement of other systems (lower limbs, gastrointestinal, cardiovascular). Cleft lip and palate are not features. The disorder is caused by a combination of a microdeletion of the proximal 1q21.1 region and of a low-frequency polymorphism in RBM8A, located in the same locus, which determines a minimal expression of the protein Y14. Tetra-amelia: rare disorder with multiple severe malformations, including cleft palate; aplasia of the peripheral pulmonary vessels; anal atresia; diaphragmatic defect; hypoplasia or aplasia of lung, kidneys, spleen, adrenal gland, uterus and ovaries. Recessive pathogenic variants in the gene WNT3 have been found in some cases. Spleno-gonadal fusion with limb defects and micrognathia: dominant disorder which shows a peculiar fusion between the spleen and the gonad or derivatives of the mesonephros. Some-

(1a)

551 times tetra-amelia, micrognathia and cleft palate are associated. DK phocomelia syndrome (p. 596); Cornelia de Lange syndrome (p. 540); Holt-Oram syndrome (p. 536). Thalidomide embryopathy: rare nowadays; thalidomide was used as a sedative/antiemetic but was withdrawn from the market in the 1960s because of recognised teratogenicity. The most common defects involved the long bones and ranged from loss of digits to amelia or phocomelia. Interestingly, Roberts syndrome has also been referred to as ‘pseudothalidomide’ syndrome, in that it is deemed to mimic the consequences of thalidomide ingestion during pregnancy. Al-Awadi Raas-Rothschild limb/pelvisaplasia/hypoplasia syndrome (p. 546). Syndromes with preaxial reduction defects but with milder skeletal phenotype include Baller-Gerold syndrome: radial ray defects and growth retardation are associated with coronal craniosynostosis and poikiloderma; autosomal recessive, due to pathogenic variants in RECQL4. Nager acrofacial dysostosis (p. 510); Fanconi anaemia (FA) (p. 573).

 

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CASE 1: A stillbirth with hypoplastic nasal alae, cleft lip and nose, oligosyndactyly and flexion contractures of the elbow and knee. Postmortem radiographs show reduction deformity of the limbs, including malformed humeri with tapered proximal ends and broad distal ends, missing radii and ulnae, relatively normal femora, a globular bone of the right shank, missing tibiae and fibulae of the left limb and oligodactyly of the hands and feet.

552

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Fetal and Perinatal Skeletal Dysplasias

 

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CASE 2: A stillbirth with bilateral cleft lip and palate, low-set ears and syndactyly in the hands and feet, whose short limbs were identified on US at 18 weeks and who died in utero at 21 weeks of gestation. Cytogenetic analyses of amniotic fluid cells showed premature centromere division and puffing of chromosomes. The skeletal changes are like those of Case 1. The tibiae are formed, but short and broad.

BIBLIOGRAPHY Ayaz R, Göktas E, Balasar M. A case of Roberts syndrome: Its ultrasonographic characteristics and genetic diagnosis. Perinatal J. 2020; 28: 212–6. Dulman DJ, Matsuoka M, Uketa E et al. Antenatal three-dimensional sonographic features of Roberts syndrome. Arch Gynecol Obstet. 2011; 284: 241–4. Gordillo M, Vega H, Trainer AH et al. The molecular mechanism underlying Roberts syndrome involves loss of ESCO2 acetyltransferase activity. Hum Mol Genet. 2008; 17: 2172–80. Okpala BC, Echendu ST, Ikechebelu JI et al. Roberts syndrome with tetraphocomelia: A case report and literature review. SAGE Open Med Case Rep. 2022; 10: 2050313X221094077. doi: 10.1177/2050313X221094077.

Sanchez AC, Thren ED, Iovine MK, Skibbens RV. Esco2 and cohesin regulate CRL4 ubiquitin ligase ddb1 expression and thalidomide teratogenicity. Cell Cycle. 2022; 21: 501–13. Vega H, Trainer AH, Gordillo M et al. Phenotypic variability in 49 cases of ESCO2 mutations including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome. J Med Genet. 2010; 47: 30–7. Zhu L, Cao D, Chen M, et al. Prenatal diagnosis of Roberts syndrome in a Chinese family based on ultrasound findings and whole exome sequencing: A case report. BMC Med Genomics. 2022; 15: 16. doi: 10.1186/s12920-022-01161-8.

117 Tibial Hemimelia-Polysyndactyly-Triphalangeal Thumb (Werner Syndrome), ZRS-Related

Synonyms: tibial hypoplasia-polydactyly-triphalangeal thumb; THPTTS; mesomelic dysplasia Werner type; tibial hemimeliapolydactyly-triphalangeal thumbs with fibular dimelia; tibia, hypoplasia of, with polydactyly; tibial hypoplasia-polydactylysyndactyly. It is probably the severe end of a spectrum of disorders that includes triphalangeal thumb-polysyndactyly syndrome, preaxial polydactyly type 2 and/or 3 and Haas-type polysyndactyly. Confirmation of diagnosis: identification of a mutation in the SHH regulatory element (ZRS) in intron 5 of the LMBR1 gene. Frequency: rare – fewer than 300 cases reported in the literature Genetics: inheritance is autosomal dominant with variable expressivity and due to a heterozygous mutation in an SHH regulatory element (ZRS) that resides in intron 5 of the LMBR1 gene. Point mutations within the SHH regulatory region (ZRS) cause tibial aplasia-five-fingered hand-polydactyly syndrome, while complete duplications of the ZRS region lead to Haas type polysyndactyly or triphalangeal thumb-polysyndactyly syndrome but do not affect the lower limbs. Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester (16–20 weeks). Clinical features: • Limbs bilateral, occasionally asymmetric shortening due to agenesis or hypoplasia of tibiae • Absent patellae, dislocated fibulae • Preaxial polysyndactyly of hands and feet • Five fingers (the most lateral digit is often incorrectly described as a triphalangeal thumb)

DOI: 10.1201/9781003166948-123

• Occasionally limitation of elbow movement due to radioulnar synostosis • Hirschsprung disease. Prenatal ultrasound features: absent or hypoplastic tibiae and polydactyly are the key findings. Even in the absence of polydactyly, careful examination may reveal an absent thumb or a ‘triphalangeal thumb’. Prenatal diagnosis has been made at 20.5 weeks. Radiographic features: there is usually symmetric hypoplasia or aplasia of the tibiae with dislocation of the knees and preaxial polysyndactyly of the feet. In the upper limbs there is a varying degree of syndactyly, absence of the thumbs and five fingers. The most radial digit has a long metacarpal, has no accompanying thenar muscles and is not opposable; it is therefore a finger but has often been incorrectly referred to as a triphalangeal thumb. There may be preaxial polydactyly – this extra digit is often hypoplastic. Proximal radioulnar synostosis has been reported. Prognosis: viable – mental development is normal. Differential diagnosis: the association of mesomelic dysplasia and polydactyly is also present in acromelic-frontonasal dysostosis (p. 514); oral-facial-digital syndromes, particularly types 8 and 10, which are also characterised by telecanthus, cleft lip and palate and anomalies in the oral cavity. Triphalangeal thumbs and preaxial polydactyly are present in Townes-Brocks syndrome, with no mesomelic dysplasia; there is also fusion of metatarsals, imperforate anus, sensorineural deafness, preauricular pits or tags and malformations of the kidneys, heart and gastrointestinal tract. Caused by dominant mutations in SALL1.

553

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Fetal and Perinatal Skeletal Dysplasias

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CASE 1: Absent left tibia; hypoplastic right tibia; dislocated knees; syndactyly, preaxial polydactyly of hands and feet with triphalangeal sixth digit. CASE 2: Bilateral tibial aplasia, triphalangeal thumb and cutaneous syndactyly of the right hand and incomplete mirror-imaged polydactyly of the right foot.

Tibial Hemimelia-Polysyndactyly-Triphalangeal Thumb (Werner Syndrome), ZRS-Related

BIBLIOGRAPHY Canún S, Lomelí RM, Martínez R et al. Absent tibiae, triphalangeal thumbs and polydactyly: Description of a family and prenatal diagnosis. Clin Genet. 1984; 25: 182–6. Goldenberg A, Milh M, de Lagausie P et al. Werner mesomelic dysplasia with Hirschsprung disease. Am J Med Genet A. 2003; 123A: 186–9. Hall CM. Werner’s mesomelic dysplasia with ventricular septal defect and Hirschprung’s disease. Pediatr Radiol. 1981; 10: 247–9. Kantaputra PN, Chalidapong P. Are triphalangeal thumb-polysyndactyly syndrome (TPTPS) and tibial hemimeliapolysyndactyly-triphalangeal thumb syndrome (THPTTS) identical? A father with TPTPS and his daughter with THPTTS in a Thai family. Am J Med Genet. 2000; 93: 126–31. Klopocki E, Ott CE, Benatar N, Ullmann R et al. A microduplication of the long range SHH limb regulator (ZRS) is associated with triphalangeal thumb-polysyndactyly syndrome. J Med Genet. 2008; 45: 370–5.

555

Lamb DW, Wynne-Davies R, Whitmore JM. Five-fingered hand associated with partial or complete tibial absence and preaxial polydactyly: A kindred of 15 affected individuals in five generations. J Bone Joint Surg Br. 1983; 65: 60–3. Norbnop P, Srichomthong C, Suphapeetiporn K et al. ZRS 406A>G mutation in patients with tibial hypoplasia, polydactyly and triphalangeal first fingers. J Hum Genet. 2014; 59: 467–70. VanderMeer JE, Lozano R, Sun M et al. A novel ZRS mutation leads to preaxial polydactyly type 2 in a heterozygous form and Werner mesomelic syndrome in a homozygous form. Hum Mutat. 2014; 35: 945–8. Wieczorek D, Pawlik B, Li Y et al. A specific mutation in the distant sonic hedgehog (SHH) cis-regulator (ZRS) causes Werner mesomelic syndrome (WMS) while complete ZRS duplications underlie Haas type polysyndactyly and preaxial polydactyly (PPD) with or without triphalangeal thumb. Hum Mutat. 2010; 31: 81–9.

118 Gollop-Wolfgang Complex

Synonyms: GWC; femur, unilateral, bifid, with monodactylous ectrodactyly

skeletal limb malformations, namely bifid femur, contracture of the knee, tibial agenesis, ectrodactyly and/or oligodactyly. Ultrasound examination reveals distal femoral bifurcation and tibial agenesis, with or without ectrodactyly. Additional anomalies which can be detected with ultrasound include ulna hypoplasia, heart defects, segmentation defects of the spine, cleft lip and palate, oesophageal atresia, tracheo-oesophageal fistula and proximal focal femoral deficiency.

Confirmation of diagnosis: typical radiological and clinical findings Frequency: very rare – around 50 cases reported Genetics: unknown – usually sporadic; two familial cases reported. A homozygous duplication and a heterozygous triplication of a 210-Kb chromosomal segment in 17p13.3, including the gene BHLHA9, has been detected in two Japanese patients and considered a susceptibility factor for the limb malformation.

Radiographic features: although involvement may be bilateral, it is not always symmetrical. The distal femora and humeri may be bifid. The long tubular bones (femora, tibiae, fibulae, radii, ulnae) may be hypoplastic or absent. Proximal radiohumeral and/or elbow joint synostosis has been described. Other features in the hand include soft tissue syndactyly, oligodactyly and monodactylous ectrodactyly. In the foot the hallux may be hypoplastic or absent, or there may be an absence of other toes (oligodactyly or monodactyly).

Age/Gestational week of manifestation: usually detectable by ultrasound during the second trimester (16 weeks). Clinical features: • Bifid femur, absent or hypoplastic tibia and ulna with limb shortening • Oligodactyly, ectrodactyly • Frequently asymmetric • May be associated with other abnormalities, namely congenital heart defects, cleft lip and palate and tracheo-oesophageal fistula

Prognosis: viable – intellectual impairment and early death due to organ malformation–related complications have been reported. Differential diagnosis: tibial aplasia with split-hand/split-foot deformity is now considered to fall into the same spectrum as GWC and also defined as SHFM with or without long bone deficiency (SHFLD). Autosomal dominant; atelosteogenesis type 2 (p. 108).

Prenatal ultrasound features: all cases of GWC reported so far have had a striking phenotype and share a common core of

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556

 

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DOI: 10.1201/9781003166948-124

557

Gollop-Wolfgang Complex

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CASE 1: A stillbirth. Postmortem radiographs show bifurcation of the right distal femur, right tibial aplasia and oligodactyly of the right hand and both feet (a–d). Prenatal US at 20 weeks’ gestation initially showed false bending and ultimately distal bifurcation of the right femur on longitudinal scans (e, f); 3D US showed only two ulnar fingers of the right hand (g, h); 2D US demonstrated only two digits on the right foot and four digits on the left foot (i, j).

558

Fetal and Perinatal Skeletal Dysplasias

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CASE 2: A neonate. Radiographs show widening of the left distal femur reflecting incomplete bifurcation, bilateral tibial aplasia and oligodactyly of the right hand. Clinical photos show oligodactyly of the right hand and both feet. CASE 3: (a) An infant. Antenatal US at 23 weeks’ gestation (2D longitudinal scan) for the right thigh shows a curved femur with lateral concavity (red curved dashed line), and the next scan demonstrates an unusually triangular appearance of the distal femur (the red dashed line refers to the first femoral appearance); these findings indicate that the femur divides into two separate distal ends (red arrows). (b) The distal part of the thigh is abnormally wide (double-headed arrow) due to femoral bifurcation; the most lateral distal end is articulated with the fibula (red arrow), associated with homolateral tibial hemimelia and clubfoot (curved arrow). (c–e) 3D US at 23 weeks and postnatal radiograph show bifurcation of the right distal femur (yellow arrows), right tibial aplasia and hypoplasia of the right great toe.

Gollop-Wolfgang Complex

BIBLIOGRAPHY Bergère A, Amzallag-Bellenger E, Lefebvre G et al. Imaging features of lower limb malformations above the foot. Diagn Interv Imaging. 2015; 96: 901–14. Caforio L, Pagnotta G, Romiti A et al. Prenatal diagnosis of Gollop-Wolfgang complex. Ultrasound Obstet Gynecol. 2015; 45: 4888–90. Erickson RP. Agenesis of tibia with bifid femur, congenital heart disease and cleft lip with cleft palate or tracheoesophageal fistula: Possible variants of Gollop-Wolfgang complex. Am J Med Genet A. 2005; 134A: 315–7. Forzano F, Viassolo V, Castagnetta M et al. Prenatal diagnosis of Gollop-Wolfgang complex. Prenat Diagn. 2009; 29: 724–6.

559 Hapani R, Shastri M. A rare case of limb deficiency syndrome: Gollop Wolfgang syndrome. Radiol Case Rep. 2021; 16: 2053–5. Mendilcioglu I, Mihci E, Pestereli E, Simsek M. Prenatal diagnosis of Gollop-Wolfgang complex (tibial agenesis and femoral bifurcation). Prenat Diagn. 2009; 29: 182–6. Nagata E, Kano H, Kato F, et al. Japanese founder duplications/ triplications involving BHLHA9 are associated with splithand/foot malformation with or without long bone deficiency and Gollop-Wolfgang complex. Orphanet J Rare Dis. 2014; 9: 125. doi: 10.1186/s13023-014-0125-5.

119 Femoral Facial Syndrome

Synonyms: femoral-facial syndrome; femoral hypoplasia-unusual facies syndrome Confirmation of diagnosis: clinical. The combination of femoral hypoplasia with typical facial features and absence of other anomalies. Frequency: very rare – fewer than 100 cases reported Genetics: most cases are sporadic; associated with maternal diabetes in half of cases; autosomal dominant inheritance has been reported. Age/Gestational week of manifestation: usually detectable by ultrasound during the second trimester. Clinical features: • Usually asymmetrical • Short, laterally bowed femora, bilaterally affected • Typical facial features: short, upturned nose, long philtrum, thin upper lip, micrognathia, cleft palate, upslanting palpebral fissures • Possible associated skeletal anomalies: vertebral segmentation defects, preaxial polydactyly of the feet, talipes equinovarus • Other possible associated anomalies: ear defects, genitourinary tract abnormalities, lung hypoplasia, dysplastic kidneys, patent ductus arteriosus • Very rarely: central nervous system anomalies, namely cortical/subcortical atrophy, colpocephaly, partial agenesis of corpus callosum, hypoplasia of the falx cerebri and absent septum pellucidum

560

Prenatal ultrasound features: there is asymmetric shortening and bowing of the femora associated with micrognathia and usually unilateral cleft lip and palate. Other reported findings include talipes equinovarus, other malformations involving the lower limbs (fibular hypoplasia or agenesis), mildly short humerus and genitourinary tract abnormalities. The earliest reported case diagnosed on two- and three-dimensional ultrasound was at 12 weeks’ gestation and showed short limbs and micrognathia, which were best seen by transvaginal ultrasound. More usually, it is detected in the mid-trimester. Minor facial anomalies such as a short nose with broad tip, long philtrum and ear anomalies may be identified on three-dimensional ultrasound. Radiographic features: micrognathia – the key features are the proximally short, bowed femora with some asymmetry. Possible additional findings are congenital anomalies of the spine including spinal dysraphism and a short sacrum, acetabular hypoplasia, shoulder girdle abnormalities (scapula and proximal humerus), elbow and radioulnar synostosis, asymmetric leg shortening, talipes equinovarus and preaxial polydactyly of the feet. Prognosis: viable – normal intelligence; usually good prognosis, except for the rare cases with major malformations. Differential diagnosis: proximal focal femoral deficiency (PFFD); femur-fibula-ulna complex (p. 566); kyphomelic dysplasia (p. 313); limb-pelvis hypoplasia-aplasia (p. 546); Campomelic dysplasia (p. 302); Antley-Bixler syndrome (p. 500); caudal regression sequence is characterised by agenesis or dysgenesis of the sacrum, abnormal vertebral bodies of the lumbar spine and pelvic deformities. Femoral hypoplasia, talipes and urogenital anomalies can be associated. Facial anomalies are absent.

DOI: 10.1201/9781003166948-125

561

Femoral Facial Syndrome

(1)

 

(2c)

 

(3a)

(2a)

 

(2d)

 

 

(2b)

(2e)

(3b)

CASE 1: A fetus. Postmortem radiographs show short, bowed femora; bilateral hip dislocation; and left radiohumeral synostosis. CASE 2: A fetus terminated at 27 weeks of gestation who had microretrognathia with cleft palate, right talipes, left rocker-bottom foot and syndactyly of the toes. (a, b) Postmortem radiographs show short humeri with radiohumeral synostosis and proximal focal femoral deficiency. (c) Prenatal US shows micrognathia, (d) short femora and (e) a normal tibia with foot deformity. CASE 3: Skeletal changes are similar to, but much more severe than, those of Case 2.

562

Fetal and Perinatal Skeletal Dysplasias

(4a)

 

 

(4c)

 

(4e)

 

(4b)

(4d)

(4f )

CASE 4: (a–e) Prenatal US at 14 weeks of gestation shows micrognathia, short femora, oligodactyly of the feet and multicystic dysplastic kidney. (f–i) Postmortem CT and radiographs show proximal focal femoral deficiency of the right femur and sharp angulation of the left femur. Other long bones are normal.

563

Femoral Facial Syndrome

(4g)

 

(5a)

 

(6a)

(4h)

 

(5b)

 

 

(5c)

(4i)

 

(5d)

(6b)

CASE 5: A stillbirth. Postmortem radiographs show shortening and sharp angulation of the right femur, mild bowing of the left femur and severe micrognathia. Other long bones, spine, shoulder girdle and pelvis are normal. CASE 6: A stillbirth at 16 weeks of gestation. Postmortem radiographs show short, angulated femora, dislocation of the left radial heads, lateral clavicular hook and micrognathia.

564

(7a)

Fetal and Perinatal Skeletal Dysplasias

 

(7b)

 

(7e)

(7g)

(7c)

 

 

 

(7h)

(7d)

(7f )

 

(7i)

CASE 7: A terminated fetus at 23 weeks of gestation. On postmortem 3D CT, volume-rendering imaging shows sharp angulation of the right femur, mild bowing of the left femur and clubfeet (a–c); surface-rendering imaging demonstrates severe micrognathia (d). On prenatal US, the facial profile shows micrognathia and a long philtrum; Maxilla-Nasion-Mandible (MNM) angle measurement (MNMA: 25° > 95° centile) indicates the presence of severe micrognathia; femoral length measurement is more severe on the right than that of the left femur; 3D US clearly shows sharp angulation of the right femur and mild bowing of the left femur.

Femoral Facial Syndrome

BIBLIOGRAPHY Campbell F, Vujanic GM. Bilateral femoral agenesis in femoral facial syndrome in a 19-week-old fetus. Am J Med Genet. 1997; 72: 315–8. Figueroa C, Plasencia W, Eguiluz I et al. Prenatal diagnosis and tridimensional ultrasound features of bilateral femoral hypoplasia: Unusual facies syndrome. J Matern Fetal Neonatal Med. 2009; 22: 936–9. Filly AL, Robnett-Filly B, Filly RA. Syndromes with focal femoral deficiency strengths and weaknesses of prenatal sonography. J Ultrasound Med. 2004; 23: 1511–6. Gillerot Y, Fourneau C, Willems T et al. Lethal femoral-facial syndrome: A case with unusual manifestations. J Med Genet. 1997; 34: 518–9. Lacarrubba-Flores MDJ, Carvalho DR, Ribeiro EM et al. Femoral-facial syndrome: A review of the literature and 14 additional patients including a monozygotic discordant twin pair. Am J Med Genet A. 2018; 176: 1917–28.

565 Leal E, Macías-Gómez N, Rodríguez L et al. Femoral-facial syndrome with malformations in the central nervous system. Clin Imaging. 2003; 27: 23–6. Nowaczyk MJ, Huggins MJ, Fleming A et al. Femoral-facial syndrome: Prenatal diagnosis and clinical features; Report of three cases. Am J Med Genet A. 2010; 152A: 2029–33. Paladini D, Maruotti GM, Sglavo G et al. Diagnosis of femoral hypoplasia—Unusual facies syndrome in the fetus. Ultrasound Obstet Gynecol. 2007; 30: 354–8. Robinow M, Sonek K, Buttino L et al. Femoral-facial syndrome— Prenatal diagnosis-autosomal dominant inheritance. Am J Med Genet. 1995; 57: 397–9. Tadmor OP, Hammerman C, Rabinowitz R et al. Femoral hypoplasia—Unusual facies syndrome: Prenatal ultrasonographic observations. Fetal Diagn Ther. 1993; 8: 279–84. Urban JE, Ramus RM, Stannard MW et al. Autopsy, radiographic, and prenatal ultrasonographic examination of a stillborn fetus with femoral facial syndrome. Am J Med Genet. 1997; 71: 76–9.

120 Femur-Fibula-Ulna Syndrome

Synonyms: FFU syndrome Confirmation of diagnosis: clinical diagnosis, typical association of asymmetric anomalies Frequency: rare Genetics: the cause is unknown; cases are usually sporadic in a family; low recurrence risk. Males are preferentially affected. Age/Gestational week of manifestation: usually detectable by ultrasound during the late first to second trimester (13–18 weeks). Clinical features: • Males slightly more often affected than females • Upper limbs more often affected than lower limbs • In the upper limbs the right side is preferentially involved • Lower limb deficiency is asymmetrical and may be more severe on the contralateral side to the upper limb defect • Proximal focal femoral deficiency • Upper limb defects include amelia (absence) of one arm, peromelia (Greek for mutilation) of the humerus, radiohumeral synostosis and defect of the ulna or ulnar rays

(1)

 

(2a)

Prenatal ultrasound features: major limb malformations can be identified in the first trimester. There may be a combination of asymmetrically short, bowed femora; short, bowed tibiae; and absent fibulae with oligosyndactyly of the feet, usually on the fibular (postaxial) side. In the upper limbs, which may be more severely affected, there is also asymmetry with ulnar ray deficiency and oligodactyly. The skull and thorax are normal, and there is no growth restriction. Radiographic features: there is absence of the proximal part of the femur with fibular or fibular ray defects and ulnar or ulnar ray abnormalities. The fibula deficiency is often on the opposite side to that of the femur. Asymmetry is common, and the findings may be unilateral. Upper limbs are more often affected than lower, and the right side more commonly affected than the left. Abnormalities of the arms include amelia, peromelia of the humerus, radiohumeral synostosis, bifurcation of the distal humerus and ulnar ray defects and oligodactyly. In the feet talocalcaneal coalition occurs. Prognosis: viable – prognosis improved with corrective orthopaedic management. Differential diagnosis: proximal focal femoral deficiency: exclusive involvement of the femora. Femoral hypoplasia-­ unusual facies syndrome (p. 560); limb-pelvis hypoplasiaaplasia (p. 546).

 

(2b)

CASE 1: A stillbirth with bilateral ulnar ray deficiency and a malformed single bone in the leg, probably representing a hypoplastic femur fused with a relatively normal tibia and fibular aplasia. CASE 2: A stillbirth with micrognathia with U-shaped cleft palate, absent left ulna with oligodactyly and elbow pterygium, absent right fibula and hypoplastic right tibia.

566

DOI: 10.1201/9781003166948-126

567

Femur-Fibula-Ulna Syndrome

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(3c)

(3b)

 

(3d)

CASE 3: A stillbirth at 20 weeks of gestation with hypoplasia of the right femur and fibular ray deficiency. Prenatal ultrasonography revealed a short femur, mildly bowed tibia, and absent fibula (c) compared with the normal leg (d). The foot showed distal anomalies of digits with syndactyly.

BIBLIOGRAPHY Capece G, Fasolino A, Della Monica M et al. Prenatal diagnosis of femur-fibula-ulna complex by ultrasonography in a male fetus at 24 weeks of gestation. Prenat Diagn. 1994; 14: 502–5. Florio I, Wisser J, Huch R et al. Prenatal diagnosis of a femurfibula-ulna complex during the first half of pregnancy. Fetal Diagn Ther. 1999; 14: 310–12. Geipel A, Berg C, Gerner U et al. Prenatal diagnosis of femurfibula-ulna complex by ultrasound examination at 20 weeks of gestation. Ultrasound Obstet Gynecol. 2003; 22: 79–81.

Lenz W, Zygulska M, Horst J. FFU complex: An analysis of 491 cases. Hum Genet. 1993; 91: 347–56. Richieri-Costa A, Opitz JM. Ulnar ray a/hypoplasia: Evidence for a developmental field defect on the basis of genetic heterogeneity: Report of three Brazilian families. Am J Med Genet. 1986; 2(Suppl.): 195–206. Sorge G, Ardito S, Genuardi M et al. Proximal femoral focal deficiency (PFFD) and fibular a/hypoplasia (FA/H): A model of a developmental field defect. Am J Med Genet. 1995; 55: 427–32.

121 Sirenomelia

Synonyms: Duhamel anomaly; sacrococcygeal dysgenesis association; mermaid syndrome Confirmation of diagnosis: clinical and radiographic appearances Frequency: 1.5–4.2 in 100,000 Genetics: sirenomelia is usually a sporadic condition, but rare familial recurrences have been described. The pathogenesis is complex and not yet completely understood; maternal diabetes can have a role, but genetic or epigenetic factors probably also contribute. Some authors hypothesise that an early developmental disruption of the caudal mesoderm is responsible for a malformation spectrum, including sirenomelia and caudal regression syndrome. Age/Gestational week of manifestation: it is usually detected by ultrasound late in the first trimester or early during the second trimester, but occasionally it can be detected as early as 9 gestational weeks. Clinical features: • Single lower limb, various degrees of involvement ranging from single to separate femurs in the same shaft (Stocker and Heifetz classification) • Classification system

• Limbs

• Fused bones • Type I

• Paired femora, tibiae and fibulae

• Type II

• Single fused fibula

• Type III

• Fibula absent

• Type IV

• Femora partly fused, single fibula

• Type V

• Femora partly fused, fibula absent

• Type Vi

• Single femur and tibia

• Type Vii

• Single femur, absent tibia and fibula

• Presence of two feet (sympode mermaid) or one foot (monopode mermaid); occasional absence of both feet (ectromelic mermaid) (Förster classification) • Urogenital anomalies include bilateral renal agenesis, absence of outflow tract and absence of external genitalia, imperforate anus and sacrococcygeal agenesis • Other possible malformations include severe pulmonary hypoplasia and atrial septal defect 568

• Single umbilical artery originating from the abdominal aorta • Oligohydramnios in the second trimester Prenatal ultrasound features: an indirect sign in the first trimester is increased nuchal translucency. Prenatal diagnosis may be made in the first trimester using combined transvaginal and transabdominal two- and three-dimensional sonography, colour and Doppler imaging. Early direct prenatal diagnosis is made when the lower limbs appear fused with one or two feet shown at the end of the single and abnormally positioned ­extremity. Colour and power Doppler may demonstrate a single large intra-abdominal vessel (the vitelline artery, not branching) within the fetal pelvis not feeding into the iliac vessels but coursing ventrally into the umbilical cord, which has a single umbilical artery. In sirenomelic fetuses, during the second and third trimesters, the presence of bilateral renal agenesis causes oligo-/anhydramnios that limits reliable sonographic evaluation of the lower extremity. Sirenomelia sequence and bilateral renal agenesis are characterised by an absence of renal vessels. Severe oligohydramnios, anhydramnios and maternal obesity are limiting factors in diagnosis due to poor resolution of fetal anatomy. Additional diagnostic tools have been used to better visualise the lower fetal extremity, such as infusion of normal saline into the amniotic cavity, fetal MRI and 3D CT. Radiographic features: there is most frequently (but not ­always) only a single lower limb with variable absence of the long tubular bones, with or without fusions of those that are present. The limb is usually in a flexed position. There is variable absence of tarsal bones with talipes deformity and oligodactyly. In the spine, sacral agenesis may be partial or complete, and there may be segmentation defects at more proximal levels. Thirteen pairs of ribs have been described; the upper limbs are normal. Prognosis: perinatally lethal. Differential diagnosis: caudal regression syndrome (CRS) – some authors consider sirenomelia to be an extreme form of CRS, while others argue that they are two distinct entities. CRS is characterised by a hypoplastic or aplastic lumbar vertebrae and sacrum and consequent neural tube defects; genitourinary, gastrointestinal and respiratory anomalies may coexist with lower extremity defects. VATER association (p. 531); Al-Awadi Raas-Rothschild limb-pelvis aplasia-hypoplasia syndrome (p. 546).

DOI: 10.1201/9781003166948-127

569

Sirenomelia

(1)

(3)

 

(2a)

 

 

(2b)

(4a)

CASE 1: A stillbirth with sirenomelia type VI (single femur and tibia). The sacrum is missing. CASE 2: A fetus terminated at 23 weeks of gestation with complex congenital heart defects. The skeletal changes belong to sirenomelia type II (single fused fibula) together with spinal malsegmentation, absent sacrum and coccyx, absent pubic ossification, a single ischium and fused feet. CASE 3: A fetus terminated at 30 weeks of gestation with bilateral renal agenesis and imperforate anus. The skeletal changes are classified into sirenomelia type I. The femora and tibiae are paired, and the fibulae are partially paired. The upper segments of the ilia are fused, and the proximal segment of the ischia are close together.

570

Fetal and Perinatal Skeletal Dysplasias

(4b)

(5a)

 

 

(4c)

(5b)

CASE 4: A stillbirth with sirenomelia type III (absent fibula). The lumbosacral spine is missing. Prenatal US clearly reveals fusion of the lower legs and feet and paired tibiae. CASE 5: 3D US at 12 weeks of gestation shows soft tissue caudal appendage (a, white arrow). Transvaginal 3D and 2D US at 14 weeks of gestation show sirenomelia with a single femur and two tibiae. (b–e) There is a single retroverted foot with oligodactyly.

571

Sirenomelia

(5d)

(5e)

(5c)

(6a)

 

(6d)

(6b)

 

 

(6c)

(6e)

CASE 6: (a–e) 3D and 2D US demonstrate a caudal appendage and sirenomelia with a single femur and absent tibia and fibula. (f) Transvaginal US more clearly shows the single femur.

572

Fetal and Perinatal Skeletal Dysplasias

(6f )

BIBLIOGRAPHY Akbayir O, Gungorduk K, Sudolmus S et al. First trimester diagnosis of sirenomelia: A case report and review of the literature. Arch Gynecol Obstet. 2008; 278: 589–92. Clemente CM, Farina M, Cianci A et al. Sirenomelia with oligodactylia: Early ultrasonographic and hysteroscopic embryoscopic diagnosis during the first trimester of gestation. Fetal Diagn Ther. 2010; 28: 43–5. Contu R, Zoppi MA, Axiana C et al. First trimester diagnosis of sirenomelia by 2D and 3D ultrasound. Fetal Diagn Ther. 2009; 26: 41–4. Dosedla E, Kalafusovai M, Calda P. Sirenomelia apus after trimethoprim exposure: First-trimester ultrasound diagnosis-a case report. J Clin Ultrasound. 2012 Mar 29. doi: 10.1002/ jcu.21915. [Epub ahead of print] Guven MA, Uzel M, Ceylaner S et al. A prenatally diagnosed case of sirenomelia with polydactyly and vestigial tail. Genet Couns. 2008; 19: 419–24. Kitova TT, Uchikova EH, Uchikov PA, Kitov BD. Mermaid syndrome associated with VACTERL-H syndrome. Folia Med (Plovdiv). 2021; 63: 272–6. Ladure H, D’Hervé D, Loget P et al. Diagnostic antenatal d’une sirénomélie. J Gynecol Obstet Biol Reprod. 2006; 35: 181–5. Lee KA, Park CW, Park JS et al. Prenatal diagnosis of syrenomelia with a single umbilical artery: A case report. J Women’s Med. 2008; 1: 51–4. Nisenblat V, Leibovitz Z, Paz B et al. Dizygotic twin pregnancy discordant for sirenomelia. J Ultrasound Med. 2007; 26: 97–103.

Orioli IM, Amar E, Arteaga-Vazquez J et al. Sirenomelia: An epidemiologic study in a large dataset from the International Clearinghouse of Birth Defects Surveillance and Research, and literature review. Am J Med Genet C Semin Med Genet. 2011; 157C: 358–73. Rougemont AL, Bouron-Dal Soglio D, Désilets V et al. Caudal dysgenesis, sirenomelia and situs inversus totalis: A primitive defect in blastogenesis. Am J Med Genet A. 2008; 146A: 1470–6. Stevens SJC, Stumpel CTRM, Diderich KEM et al. The broader phenotypic spectrum of congenital caudal abnormalities associated with mutations in the caudal type homeobox 2 gene. Clin Genet. 2022; 101: 183–9. Stevenson RE. Common pathogenesis for sirenomelia, OEIS complex, limb-body wall defect, and other malformations of caudal structures. Am J Med Genet. 2021; 185A: 1379–87. Thottungal AD, Charles AK, Dickinson JE et al. Caudal dysgenesis and sirenomelia-single centre experience suggests a common pathogenic basis. Am J Med Genet A. 2010; 152A: 2578–87. Van Keirsbilck J, Cannie M, Robrechts C et al. First trimester diagnosis of sirenomelia. Prenat Diagn. 2006; 26: 684–8. Vijayaraghavan SB, Amudha AP. High resolution sonographic diagnosis of sirenomelia. J Ultrasound Med. 2006; 25: 555–7. Zanforlin Filho SM, Guimarães Filho HA, Araujo E Jr et al. Sirenomelia sequence: Early prenatal diagnosis of one rare case associated with a cardiac malformation. Arch Gynecol Obstet. 2007; 275: 315–6.

122 Fanconi Anaemia

Synonyms: FA Confirmation of diagnosis: typical clinical features associated with pathogenic variants in one of the genes associated Incidence: 1 in 100,000 worldwide, higher incidence in some populations, such as Ashkenazi Jews, Spanish Gypsies and black South Africans Genetics: Fanconi anaemia is a genetically heterogeneous disorder; 13 genes have been identified to date, which define the respective FA complementation groups: FANCA (includes the previously designated FANCH), FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG (XRCC9), FANCI (KIAA1794), FANCJ (BRIP1), FANCL (PHF9), FANCM, FANCN (PALB2) and FANCO (RAD51C). All the FA subtypes are autosomal recessive disorders, except for FANCB, which is X-linked. The products of the genes FANC A, C, E, F, G and L are part of a nuclear complex which regulates the monoubiquitination of FANCD2 during the S phase of the cell cycle or after DNA damage by crosslinking agents (e.g., mitomycin C, diepoxybutane [DEB], cisplatin), which targets FANCD2 to BRCA1 nuclear foci containing BRCA2 (FANCD1) and RAD51. The FA/BRCA pathway (FANCD1-BRCA2, FANCJ-BRIP1, FANCN-PALB2) is implicated in the repair of DNA damage. Age/Gestational week of manifestation: can be detected by ultrasound during the second trimester (19 weeks). Radial ray defects and hand anomalies can be detected in the first trimester (12–14 weeks) if they are present. Clinical features: • A proportion (25%–40%) of cases have no physical anomalies • Short stature • Malformation of the thumbs (absent, hypoplastic, supernumerary), absent first metacarpal, polydactyly • Absent or hypoplastic radii and ulnae (correlates with abnormal thumbs) • Eye anomalies: microphthalmia, strabismus, epicanthal folds, ptosis, cataracts, nystagmus • Genitourinary anomalies • Abnormal skin pigmentation: hyperpigmentation, café au lait spots, hypopigmentation

DOI: 10.1201/9781003166948-128

• Occasionally cardiac malformations • Pancytopenia from about 8 years, sometimes leukaemia Prenatal ultrasound features: in the second trimester radial ray defects (partial or complete absence of the radius and/or radial ray structures, absent/hypoplastic or supernumerary thumbs) may be identified. There is also intrauterine growth retardation, microcephaly, hypoplastic kidneys, double collecting system and ear and cardiac anomalies. Radial clubhand is a deformity resulting from defects of the radial ray and shows increasing degrees of severity. 3D US multiplanar and maximum-mode rendering allow to evaluate the forearm and the hand in three orthogonal planes from a single acquisition of volume data and assure assessment of completeness of structure, including metacarpals, fingers and thumb, and assess the posture and configuration of the hand. Radiographic features: there are radial ray abnormalities ranging from complete radial and thumb agenesis, to varying degrees of radial ray hypoplasia, to duplication of the thumb or a triphalangeal thumb. There may be microcephaly and significant short stature. Sometimes congenital vertebral anomalies may occur. Other imaging modalities will demonstrate associated renal or cardiac malformations. Oesophageal atresia is frequently described. Prognosis: viable. Developmental delay is common, and conductive hearing loss secondary to middle ear abnormalities can sometimes be present. The hematologic complications are variable, can present as early as the newborn period and generally occur within the first decade of life. There is a significantly higher incidence of hematologic malignancies, especially AML, and solid tumours, which are generally squamous cell carcinomas of the head and neck, skin, and gastrointestinal and genital tracts. By the age of 50 years, the prevalence of bone marrow failure is 90%, of hematologic malignancies 10–33%, and of non-hematologic malignancies 28–29%. Treatment is difficult due to cell sensitivity to DNA damage (including chemotherapy and radiotherapy). Differential diagnosis: other disorders with radial ray defects: VATER/VACTERL association (p. 531). A phenotype including hydrocephalus, VACTERL-H, represents severe Fanconi anaemia (FANCB).

573

574 Thrombocytopenia-absent radius (TAR) syndrome: hallmarks are bilateral absence of the radii but not of the thumbs and thrombocytopenia; occasionally presents with involvement of other systems (lower limbs, gastrointestinal, cardiovascular). Autosomal recessive. Baller-Gerold syndrome: also shows growth retardation, coronal craniosynostosis and poikiloderma. Due to recessive mutations in RECQL4. Nager acrofacial dysostosis (p. 510); Holt-Oram syndrome (p. 536); Okihiro syndrome: association with radial ray defects, eye anomalies, namely Duane anomaly, and renal anomalies. Occasionally vertebral anomalies can be present, very rarely cardiac septal defects. Autosomal dominant, due to mutation in the gene SALL4. Other ‘chromosomal breakage’ syndromes: Bloom syndrome: pre- and postnatal growth retardation, microcephaly, dolichocephaly, sun-sensitive telangiectatic erythema, patchy areas of hyper- and hypopigmentation of the skin, occasionally syndactyly or polydactyly, no further skeletal anomalies. Specific features are immunodeficiency and significant cancer predisposition due to marked genetic instability. Caused by recessive mutations in the gene RECQL3. Nijmegen breakage syndrome (NBS): short stature, microcephaly, neurodegeneration in infancy, café au lait spots, immunodeficiency, increased risk of cancer. Skeletal anomalies are not present. Caused by recessive mutations in the gene NBS1. NBS cells can manifest chromosomal instability in PHA-­stimulated lymphocytes and hypersensitivity to ionising radiation. Aase syndrome: developmental delay, triphalangeal thumbs, radial hypoplasia, hypoplastic anaemia, hypertelorism, retinopathy, cleft palate, short, webbed neck, parietal foramina and scoliosis. Blackfan-Diamond syndrome: may be the same as Aase syndrome. Acrofacial dysostosis type Rodriguez: preaxial and postaxial limb deficiencies, shoulder and pelvic girdle hypoplasia, cardiac and CNS malformations, early lethality. Amniotic bands/disruption sequence: congenital ring constrictions or amputation of digits and limbs, talipes, multiple craniofacial, visceral and body wall defects, which include facial clefts, hydrocephalus, exencephaly, acrania and encephalocele. Limb-body-wall complex: comprises a vari-

Fetal and Perinatal Skeletal Dysplasias able combination of lateral body-wall defects, limb reduction defects, craniofacial defects, abnormal genitalia, anal atresia and renal defects. Constrictive amniotic bands, adhesions and umbilical cord abnormalities are almost always present. Pathogenesis should include early amnion rupture, vascular disruption and early embryonic maldevelopment. Cornelia de Lange syndrome (p. 540); DK phocomelia (p. 596); Trisomy 18; Chr13q syndrome: radial ray anomalies with midline CNS and cardiac abnormalities. Dysmorphic features include trigonocephaly, micrognathia, broad nasal bridge, coloboma. Duane anomaly-radial defects: limitation of abduction and retraction and narrowing of the palpebral fissure on adduction; often presents as strabismus; coloboma; renal malformations; can occur within families combined with radial defects of variable severity. Fetal valproate syndrome: a distinctive dysmorphic syndrome with brachycephaly, a high forehead, shallow orbits, prominent eyes, thin eyebrows and an unusual fold of skin below the lower eyelid. The mouth is small, the upper lip long and thin and the lower lip prominent. Limb abnormalities can include preaxial or postaxial polydactyly and radial defects. Fryns syndrome-acral defects: polyhydramnios with normal fetal growth; coarse face, a broad flat nasal bridge; a large nose anteriorly; short upper lip; small jaw; cleft lip and palate and poorly shaped auricles with attached earlobes. The distal phalanges are hypoplastic and the nails rudimentary and dysplastic. Internally, diaphragmatic defects and secondary lung hypoplasia may be present. Hemifacial microsomia. MURCS association: uterine aplasia/hypoplasia, renal agenesis/ectopia, abnormal cervical or upper thoracic vertebrae, abnormal ribs, Sprengel shoulder, upper limb abnormalities and deafness. Poland syndrome: there is usually unilateral shortening, predominantly of middle phalanges of the digits, with cutaneous syndactyly and sometimes distal symphalangism. The thumb is least severely affected. There is ipsilateral absence of one or more portions of the pectoralis major (usually the sternal head). Ipsilateral rib defects and absence of the breast or nipple may also occur. Roberts syndrome (p. 550). XK-aprosencephaly: absence of telencephalic or diencephalic structures, radial defects, congenital heart defect and occasionally anal atresia. Facial abnormalities range from hypotelorism to complete absence of all ocular and nasal structures.

575

Fanconi Anaemia

(1) CASE 1: Stillbirths (twins). Postmortem radiographs show bilateral radial clubhands in one and unilateral radial clubhand in the other.

BIBLIOGRAPHY García-de-Teresa B, Rodríguez A, Frias S. Chromosome instability in Fanconi anemia: From breaks to phenotypic consequences. Genes (Basel). 2020; 11: 1528. Kennelly MM, Moran P. A clinical algorithm of prenatal diagnosis of Radial Ray Defects with two and three dimensional ultrasound. Prenat Diagn. 2007; 27: 730–7. Lecourt S, Vanneaux V, Leblanc T et al. Bone marrow microenvironment in Fanconi anemia: A prospective functional study in a cohort of Fanconi anemia patients. Stem Cells Dev. 2010; 19: 203–8.

Peake JD, Noguchi E. Fanconi anemia: Current insights regarding epidemiology, cancer, and DNA repair. Hum Genet. 2022; 141: 1811–36. Savage SA, Walsh MF. Myelodysplastic syndrome, acute myeloid leukemia, and cancer surveillance in Fanconi anemia. Hematol Oncol Clin North Am. 2018; 32: 657–68. Thakur S, Chaddha V, Gupta R et al. Spectrum of fetal limb anomalies. J Clin Ultrasound. 2023; 51: 96–106. Vilcheck SK, Ceryak S, O’Brien TJ, Patierno SR. FANCD2 monoubiquitination and activation by hexavalent chromium [Cr(VI)] exposure: Activation is not required for repair of Cr(VI)-induced DSBs. Mutat Res. 2006; 610: 21–30.

123 Split Hand-Foot Malformation (Isolated Form, Types 1–6)

Synonyms: SHFM; split-hand/foot deformity; SHFD; SHSF; split-hand deformity; ectrodactyly; ECD; includes the subtypes SHFM1, SHFM2, SHFM3 (limb deficiencies, distal, with micrognathia; chromosome 10q24 duplication syndrome), SHFM4, SHFM5, SHFM6, SHFM7 and SHFM8 Diagnostic confirmation: clinical. Identification of pathogenic variants in the associated genes can refine the diagnosis and subtype. Frequency: 1 in 18,000 Genetics: heterogeneous disorder, six subtypes known: SHFM1 maps to chromosome 7q21, and recently variants in the genes DLX5 and DLX6 have been identified; SHFM2 maps to chromosome Xq26; SHFM3 is caused by duplication of chromosome 10q24; SHFM4 is caused by pathogenic variants in the TP63 gene (chromosome 3); SHFM5 maps to chromosome 2q31; SHFM7 has been associated with pathogenic variants in the ZAK gene on chromosome 2q31; and SHFM8 has been reported in one consanguineous family with a homozygous variant in EPS15L1. Inheritance is autosomal dominant in SHFM 1, 3 and 4; X-linked recessive in SHFM2; unknown in SHFM5; and autosomal recessive in SHFM6 and SHFM7 and likely in SHFM8. Penetrance is incomplete. Age/Gestational week of manifestation: can be detected by ultrasound as early as the first trimester (12 weeks). Clinical features: central ray malformation that randomly affects from one to all four limbs. The feet are usually more severely involved. There are median clefts of hands and feet; aplasia or hypoplasia of phalanges, metacarpals and metatarsals; and syndactyly (‘lobster claw’ appearance or ‘ectrodactyly’). The etymology of the term ‘ectrodactyly’ comes from the Greek ‘ektroma’, or ‘aborted’, and ‘dactylos’ or ‘finger’. SHFM Type

Inheritance

Gene/Locus

Type 1

AD

DLX5, DLX6 (7q21.3)

Type 2

XLR

Xq26

Type 3

AD

10q24dup

576

Possible Associated Features Orofacial clefting, deafness, occasionally cardiac malformations Frequent preaxial involvement of upper limbs, microretrognathia, oligomeganephronia

Type 4

AD

TP63 (3q27)

Type 5

Unknown

2q31, suspected Orofacial clefting, dysregulation of cardiac malformations HOXD cluster

Type 6

AR

WNT10B (12q13) Rarely fused radius and ulna

Type 7 or SFMMP

AR

ZAK (2q31)

EPS15LUnclear, related or possibly type 8 AR

Similar involvement of hands and feet, orofacial clefting, lacrimal duct anomalies

Mesoaxial polydactyly

Homozygous Preaxial and postaxial variant in syndactyly EPS15L1 (19p13.11) in one consanguineous family

Prenatal ultrasound features: many types of hand and foot malformations, isolated or associated with other abnormalities, can be detected early in pregnancy during evaluation of the fetus between 11 and 14 weeks’ gestation. Reported cases of SHFM diagnosed in the first trimester may or may not be associated with an increased nuchal translucency. High-frequency transvaginal ultrasonography may visualise the hands and feet in the late first trimester because of a relatively larger volume of amniotic fluid, greater fetal movements and extension of the fingers. However, the mildest form represented by a simple cleft with no missing tissue may be difficult to diagnose in utero. As the malformation increases in severity with absence of the central rays, the most severe forms up to monodactyly can be detected by ultrasound at the end of the first trimester. If the fetal fingers cannot be seen to align normally in an early second-trimester scan, follow-up is indicated. Prenatal diagnosis is easier and earlier in at-risk families. Three-dimensional ultrasound maximum-mode rendering provides additional information in the assessment of fetal hands and feet. In ectrodactyly, bony structures can be evaluated by two-dimensional ultrasound, while 3D ultrasound HD-live with silhouette effect emphasises the spatial relations of the skeleton with the body contours. 3D ultrasound HD-live surface rendering is superior to 2D ultrasound for demonstrating cutaneous syndactyly and for further evaluation of the fetal phenotype. Radiographic features: ectrodactyly is the absence of the phalanges and usually the associated metacarpals or metatarsals of the central rays of the hands or feet. Occasionally there may be

DOI: 10.1201/9781003166948-129

577

Split Hand-Foot Malformation (Isolated Form, Types 1–6) monodactyly, syndactyly of the short tubular bones, carpal and tarsal fusions, radioulnar synostosis or preaxial polydactyly of the hands or feet. Prognosis: viable – management includes surgical repair of malformation and orthesis. Some patients may have intellectual impairment. Differential diagnosis: other similar disorders caused by pathogenic variants in TP63: EEC3: ectrodactyly, ectodermal dysplasia and cleft lip/palate; AEC: ankyloblepharon-­ectodermal dysplasia-clefting; ADULT: acro-dermato-ungual-lacrimaltooth; limb-mammary syndrome: cleft palate, absent or aplastic mammary glands and nipples but normal hair, skin and teeth. Many syndromes can have SHFM within their spectrum, including a number of chromosomal anomalies, such as trisomies 13 and 18, and partial trisomies or monosomies scattered through many chromosomal loci. Patterson-­Stevenson-Fontaine syndrome also shows mandibulofacial dysostosis. Ulnar-­mammary syndrome shows posterior limb defects, hypoplasia of the mammary gland, abnormal dentition and genital anomalies; caused by dominant pathogenic variants in TBX3. Adams-Oliver syndrome: transverse limb defects associated with aplasia cutis, usually limited to the scalp vertex, occasionally presents with vascular defects and cardiac malformations. Cenani-Lenz syndactyly syndrome: also called ‘total syndactyly’, shows a total fusion of fingers and toes, extensive fusion of carpals and metacarpals with single, partial or complete radioulnar synostosis and brachymesomelia; due to recessive pathogenic variants in LRP4. SHFM with or without long bone deficiency (SHFLD): also shows bilateral aplasia of the tibiae, distal hypoplasia or

(1a) CASE 1: Sibling stillbirths. This has four-limb ectrodactyly.

 

b­ ifurcation of the femora, aplasia or hypoplasia of ulnae, aplasia of patellae; maps to chromosomes 1q42.2-q43, 6q14.1 and 17p13.3. A predisposing, dominant microduplication encompassing BHLHA9 on 17p13.3 has been described. This phenotype also includes Gollop-Wolfgang complex (p. 556); Cornelia de Lange syndrome (p. 540); CCGE (cleft palate, cardiac defect, genital anomalies, ectrodactyly): a very rare and severe disorder, brain anomalies can be present and early lethality has been reported in the few described cases. Goltz syndrome: the hallmark is focal dermal hypoplasia, which can be extensive and may spread to involve the entire body surface; associated features include ocular anomalies (coloboma of iris and choroid, microphthalmia), hypoplastic teeth, striated bones, cardiac malformations and intellectual impairment. X-linked dominant, caused by pathogenic variants in PORCN, lethal in utero in males. SHFM has also been reported in severe cases of Smith-Lemli-Opitz syndrome and VACTERL association (p. 531); in these cases the multiple malformation pattern is striking and usually allows the correct diagnosis to be made. Hartsfield syndrome is a dominant condition associated with variants in FGFR1, also showing microcephaly, lobar holoprosencephaly, agenesis of the corpus callosum, cleft lip and palate and severe developmental delay. A syndromic form of SHFM associated with ectodermal dysplasia, ectrodactyly and macular dystrophy (EEMS) is caused by dominant pathogenic variants in CHD3. Aplasia cutis congenita with ectrodactyly skeletal syndrome (ACCES) is caused by heterozygous pathogenic variants in the UBA2 gene and has a complex phenotype also including microcephaly; cleft chin and facial asymmetry; and ocular, teeth, cardiac and kidney anomalies.

(1b)

578

Fetal and Perinatal Skeletal Dysplasias

(2a)

 

(4)

(6b)

 

 

(7a)

(2b)

(5)

 

 

(6a)

(7b)

CASE 2: Sibling stillbirths. This has normal lower limbs and right upper limb and hypoplasia of the left upper limb with three digits. CASES 4–7: Prenatal US shows variable patterns of ectrodactyly.

579

Split Hand-Foot Malformation (Isolated Form, Types 1–6)

(8a)

 

(8b)

CASE 8: Prenatal 3D US clearly shows bilateral ectrodactyly of the upper limbs.

BIBLIOGRAPHY Allen LM, Maestri MJ. Three-dimensional sonographic findings associated with ectrodactyly-ectodermal dysplasia-clefting syndrome. J Ultrasound Med. 2008; 27: 149–54. Chen CP, Chen YJ, Chern SR et al. Prenatal diagnosis of concomitant Wolf-Hirschhorn syndrome and split hand-foot malformation associated with partial monosomy 4p (4p16.1→pter) and partial trisomy 10q (10q25.1→qter). Prenat Diagn. 2008; 5: 450–3. Elliott AM, Evans JA. The association of split hand foot malformation (SHFM) and congenital heart defects. Birth Defects Res A Clin Mol Teratol. 2008; 82: 425–34. Holder-Espinasse M, Jamsheer A, Escande F et al. Duplication of 10q24 locus: Broadening the clinical and radiological spectrum. Eur J Hum Genet. 2019; 27: 525–34. Kang A, Visca E, Bruder E et al. Prenatal diagnosis of a case of ectrodactyly in 2D and 3D ultrasound. Ultraschall Med. 2009; 30: 121–3. Klopocki E, Lohan S, Doelken SC et al. Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion. J Med Genet. 2012; 49: 119–25.

Koo BS, Baek SJ, Kim MR et al. Prenatally diagnosed ectrodactyly at 16 weeks’ gestation by 2- and 3-dimensional ultrasonography: A case report. Fetal Diagn Ther. 2008; 24: 161–4. Pinette M, Garcia L, Wax JR et al. Familial ectrodactyly. J Ultrasound Med. 2006; 25: 1465–7. Ram KT, Goffman D, Ilagan J et al. First-trimester diagnosis of familial split-hand/split-foot malformation. J Ultrasound Med. 2009; 28: 1397–400. Rypens F, Dubois J, Garel L et al. Obstetric US: Watch the fetal hands. Radiographics. 2006; 26: 811–29. Shamseldin HE, Faden MA, Alashram W et al. Identification of a novel DLX5 mutation in a family with autosomal recessive split hand and foot malformation. J Med Genet. 2012; 49: 16–20. Stoll C, Alembik Y, Dott B et al. Associated malformations in patients with limb reduction deficiencies. Eur J Med Genet. 2010; 53: 286–90.

124 Mirror-Image Polydactyly of Hands and Feet (Laurin-Sandrow), SHH-Related

Synonyms: LSS; Sandrow syndrome; mirror hands and feet with nasal defects; tetramelic mirror-image polydactyly; TMIP; mirror-image polydactyly; MIP; fibula and ulna, duplication of, with absence of tibia and radius Confirmation of diagnosis: identification of small duplications of the SHH regulatory region (ZRS), located in intron 5 of LMBR1 Frequency: very few cases reported Genetics: autosomal dominant inheritance, caused by heterozygous small ( A, p.(Gly870Ser) variant in A patient with Schinzel-Giedion syndrome: An illustrative case of the utility of whole exome sequencing in A critically ill neonate. Ital J Pediatr. 2020; 46: 74. doi: 10.1186/s13052-020-00839-y Lestner JM, Chong WK, Offiah A et al. Unusual neuroradiological features in Schinzel-Giedion syndrome: A novel case. Clin Dysmorphol. 2012; 21: 152–4.

Appendix 1: Fetal Growth Charts and Biometric Measurements for Different Countries Growth and measurement charts are used to establish the biometric ultrasound parameters of an individual fetus. The normal measurements for individual bones and other parts of the body are given. The normal range is usually interpreted as including a range of plus or minus two standard deviations from the mean. It should be remembered that normal measurements follow a Gaussian distribution, with the apex of the curve representing the median. Some normal individuals may fall outside two standard deviations from the median at the upper and lower tails of the Gaussian curve. Therefore, for any individual fetus, it is important to assess sequential measurements to differentiate between a small (but normal) fetus and a progressive falling-off of growth parameters. This may be seen in some non-lethal skeletal dysplasias (achondroplasia) or with intrauterine growth failure, which may occur either with placental insufficiency in an otherwise normal fetus or in some malformation syndromes. When assessing fetal size and growth, charts appropriate for relevant parts of the world and parental ethnicity should be used. For example, there are areas where constitutional short stature is more prevalent (parts of Southeast Asia, southern Europe and southern America, for example). In these areas the normal Gaussian distribution will be shifted to the left. Conversely, a shift to the right as a result of relatively larger measurements may be expected in some areas such as Scandinavia and North America. If maternal height is one standard deviation below the mean, that fetus has a higher risk of an abnormal biparietal diameter–to–femur length ratio at the time of screening ultrasound (18–19 weeks’ gestation) than the risk shown for tall

women. In addition, femur lengths in second-trimester fetuses are shorter in Asians and Hispanics than in blacks and whites. In a given population, the relative position of the normal Gaussian curve may also change over time. For example, during periods of prolonged and severe deprivation (periods of war or recurrent famine), the curve may gradually move to the left. In a similar way, some ethnic groups moving into relatively more affluent parts of the world may expect the Gaussian distribution for their ethnic population in the new area to move to the right. The shape of the normal Gaussian curve may vary. For example, in diverse multiethnic, densely populated areas that include a wide range of statures, the normal Gaussian distribution will be wider and with a lower median apex. Rather than provide a single sample chart of different measurements, standard deviations and gestational ages, we have provided the following links to growth charts in use in different parts of the world. • Australia (Aborigines): http://onlinelibrary.wiley.com/ doi/10.1111/j.1479-828X.2000.tb01166.x/abstract • United States: http://pediatrics.aappublications.org/ content/125/2/e214.full.pdf±html • South Africa: www.ncbi.nlm.nih.gov/pubmed/ 10468335 • United Kingdom: www.bmus.org/policies-guides/ 23-17-3-161_ultBMUS.pdf

615

Appendix 2: Gamuts

Disorders in italics do not have dedicated chapters within the Atlas but are discussed within the relevant differential diagnoses sections. For these conditions, we have cited the title of the chapter within which they are mentioned as well as the page number for that chapter.

1

2

3

List of Signs Skeletal Dysplasias Acromelic/acromesomelic limb Acromelic dysplasia shortening Acromelic frontonasal dysostosis Acromesomelic dysplasia Acromicric dysplasia Cerebro-osseous-digital syndrome Cranioectodermal dysplasia Grebe dysplasia Robinow Angulated/bent/bowed bones

Advanced skeletal maturation

Achondrogenesis (all types) Asphyxiating thoracic dystrophy (Jeune ) Antley-Bixler syndrome Astley-Kendall dysplasia Baller-Gerold syndrome Bent bone dysplasia Blomstrand dysplasia Bruck syndrome Caffey disease (severe lethal variant) Campomelic dysplasia Cousin syndrome Cumming syndrome CYP26B1-asssociated ABS-like disorder Dysosteosclerosis Dyssegmental dysplasia Fluconazole embryopathy Hajdu-Cheyney syndrome Hypophosphatasia Kyphomelic dysplasia Mucolipidosis 2 (I-cell disease) Neonatal hyperparathyroidism – severe form Otopalatodigital syndrome type 2 Osteogenesis imperfecta Osteogenesis imperfecta with craniosynostosis (Cole-Carpenter syndrome) Parvovirus infection Schwartz-Jampel syndrome type 2 Stuve-Wiedemann syndrome Scapulo-iliac dysostosis Thanatophoric dysplasia Trisomy 21

Page (p. 266 in Opsismodysplasia)

(p. 283 in Grebe dysplasia) (p. 266 in Opsismodysplasia)

(p. 491 in Pfeiffer syndrome)

(p. 311 in Stuve-Wiedemann syndrome) (p. 500 in Antley-Bixler syndrome)

(p. 500 in Antley-Bixler syndrome)

(p. 429 in Osteogenesis imperfecta) (p. 311 in Stuve-Wiedemann syndrome) (p. 302 in Campomelic dysplasia)

Antley-Bixler syndrome Asphyxiating thoracic dystrophy (Jeune) Blomstrand dysplasia Chondroectodermal dysplasia Desbuquois dysplasia (Continued)

616

617

Appendix 2: Gamuts List of Signs

4

5

Asymmetry

Brachydactyly

Skeletal Dysplasias Frontometaphyseal dysplasia Grieg cephalopolysyndactyly Marshall-Smith syndrome Overgrowth syndromes Schneckenbecken dysplasia Spondyloepimetaphyseal dysplasia (NANS related) Spondyloepimetaphyseal dysplasia (short limb-abnormal calcification type) Spondyloepimetaphyseal dysplasia with joint laxity (Beighton type) Acrofacial dysostosis (Nager type) Aplasia cutis congenita with ectrodactyly skeletal syndrome Brachydactyly type B Branchio-oto-renal syndrome (BOR) Caffey disease (including infantile and attenuated forms) CHARGE syndrome Chondrodysplasia punctata (CDPX2) CLOVE syndrome Cornelia de Lange syndrome Craniofrontonasal syndrome Femoral facial syndrome Femur-fibula-ulna syndrome Gollop-Wolfgang complex Hemifacial microsomia Holt-Oram syndrome Klippel-Trenaunay-Weber syndrome Isolated hemihypertrophy Larsen syndrome Oculo-auriculo-vertebral spectrum Osteodysplasty, Melnick-Needles Osteogenesis imperfecta Proteus syndrome Proteus-like syndrome Proximal focal femoral deficiency Saethre-Chotzen syndrome Silver-Russell syndrome Spondylocostal dysostosis Spondylothoracic dysostosis Thoracolaryngopelvic dysplasia (Barnes) Tibial agenesis-polydactyly syndrome Tibial aplasia five-fingered hand – polydactyly syndrome Tibial hemimelia-polysyndactyly-triphalangeal thumb Achondroplasia Asphyxiating thoracic dysplasia (Jeune) Atelosteogenesis type 1 and 3 Bent bone dysplasia Brachydactyly type A, C, E Brachydactyly type B Brachydactyly type C Brachydactyly type D Brachydactyly, Temtamy type Brachyphalangy, polydactyly and tibial aplasia syndrome Cardioacrofacial dysplasia Carpenter syndrome Cartilage-hair hypoplasia Catel-Manzke syndrome

Page

(p. 475 in Marshall-Smith syndrome)

(p. 576 in Split hand-foot malformation)

(p. 478 in Proteus syndrome) (p. 491 in Pfeiffer syndrome)

(p. 478 in Proteus syndrome) (p. 478 in Proteus syndrome) (p. 510 in Acrofacial dysostosis – Nager type)

(p. 478 in Proteus syndrome) (p. 556 in femur-fibula-ulna syndrome) (p. 491 in Pfeiffer syndrome) (p. 342 in Saul-Wilson syndrome)

(p. 286 in Brachydactyly type B)

(p. 288 in Brachydactyly type C) (p. 553 in Tibial agenesis-polydactyly syndrome) (p. 203 in chondroectodermal dysplasia)

(Continued)

618

Appendix 2: Gamuts List of Signs

6

Brain anomalies Corpus callosum anomalies

Skeletal Dysplasias Chondrodysplasia punctata tibia-metacarpal type Chondroectodermal dysplasia Cleidocranial dysplasia Cook syndrome Cranioectodermal dysplasia (Sensenbrenner syndrome) Diastrophic dysplasia Dysplastic cortical hyperostosis (Al Gazali type) Familial digital arthropathy-brachydactyly (FDAB) Fibular hypoplasia and complex brachydactyly (Du Pan syndrome) Grebe dysplasia Greenberg dysplasia Hajdu-Cheyney syndrome Heart-hand syndromes Homozygous achondroplasia Hypochondroplasia Keipert syndrome Lenz-Majewski hyperostotic dysplasia Lethal neonatal short limb dysplasia (AL Gazali 1996) Odontochondrodysplasia Oral-facial-digital syndrome type 1 Osteocraniostenosis Pfeiffer syndrome Richieri-Costa brachydactyly Roberts syndrome Robinow dysplasia/syndrome Schneckenbecken dysplasia Short rib-polydactyly syndrome type 1/3 Short rib-polydactyly syndrome type 2 Sorsby syndrome Spondyloepimetaphyseal dysplasia (with immune deficiency and intellectual disability) Spondylometaphyseal dysplasia, Sedaghatian type Spondyloepimetaphyseal dysplasia (short limb-abnormal calcification type) Spondyloperipheral dysplasia Thanatophoric dysplasia Warfarin embryopathy

Page

Acrocallosal syndrome

(p. 583 in Greig cephalopolysyndactyly syndrome)

Acromelic frontonasal dysostosis Apert syndrome Carpenter syndrome Cephalopolysyndctyly syndrome (Greig) Cerebro-costo-mandibular syndrome Cerebro-hepato-renal syndrome DK phocomelia Femoral facial syndrome Fetal alcohol syndrome Hartsfield syndrome Greig cephalopolysyndactyly syndrome Hemifacial microsomia Lenz-Majewski hyperostotic dysplasia Marshall-Smith syndrome Microcephalic osteodysplastic primordial dwarfism type 1/3

(p. 286 in Brachydactyly type B)

(p. 111 in Diastrophic dysplasia) (p. 283 in Grebe dysplasia)

(p. 536 in Holt-Oram syndrome)

(p. 587 in Pallister-Hall syndrome)

(p. 298 in Brachydactyly, Temtamy type)

(p. 286 in Brachydactyly type B)

(p. 89 in Stickler syndrome)

(p. 338 in Microcephalic osteodysplastic primordial dwarfism type 1/3) (p. 576 in Split hand-foot malformation)

(Continued)

619

Appendix 2: Gamuts List of Signs

Dandy-Walker malformation

Encephalocele

Skeletal Dysplasias Osteopathia striata with cranial sclerosis Osteopetrosis Raine dysplasia Rubinstein-Taybi syndrome Schinzel-Giedion syndrome Short rib-polydactyly syndrome type 4 Smith-Lemli-Opitz syndrome Spondylometaphyseal dysplasia, Sedaghatian type Warfarin embryopathy Yunis-Varon dysplasia Acromelic frontonasal dysostosis Cumming syndrome Meckel syndrome Oral-facial-digital syndrome type 1 Orofaciodigital syndrome type 4 Otopalatodigital syndrome type 2 Short rib-polydactyly syndrome type 4 Trisomy 18 Warfarin embryopathy Yunis-Varon dysplasia Acromelic frontonasal dysostosis Amniotic bands/disruption sequence Boomerang dysplasia DK phocomelia Dyssegmental dysplasia Encephalocraniocutaneous lipomatosis Hemifacial microsomia Meckel syndrome OEIS complex Oral-facial-digital syndrome type 4 Otopalatodigital syndrome type 2 Raine dysplasia Roberts syndrome Short rib-polydactyly syndrome type 4 Thanatophoric dysplasia

Hydrocephalus/Ventriculomegaly Achondroplasia Acrodysostosis Acromelic frontonasal dysostosis Amniotic bands/disruption sequence Antley-Bixler syndrome Apert syndrome Carpenter syndrome Cephalopolysyndactyly syndrome (Greig) Cerebroarthrodigital syndrome Cerebro-hepato-renal syndrome CHARGE syndrome DK phocomelia Fetal alcohol syndrome Fibrochondrogenesis Greig cephalopolysyndactyly syndrome Hemifacial microsomia Homozygous achondroplasia Hydrolethalus syndrome Linear sebaceous nevus syndrome Marshall-Smith syndrome

Page

(p. 375 in Warfarin embryopathy)

(p. 217 in Meckel syndrome) (p. 587 in Pallister-Hall syndrome)

(p. 573 in Fanconi anaemia)

(p. 478 in Proteus syndrome)

(p. 286 in Brachydactyly type B) (p. 573 in Fanconi anaemia)

(p. 338 in Microcephalic osteodysplastic primordial dwarfism type 1/3)

(p. 209 in Orofaciodigital syndrome type 4) (p. 478 in Proteus syndrome) (Continued)

620

Appendix 2: Gamuts List of Signs

7

Skeletal Dysplasias Maternal systemic lupus erythematosus Meckel syndrome Menkes disease OEIS complex Opsismodysplasia Osteogenesis imperfecta Osteogenesis imperfecta with craniosynostosis Osteopathia striata with cranial sclerosis Osteopetrosis Otopalatodigital syndrome type 2 Pfeiffer syndrome Raine dysplasia Roberts syndrome Schinzel-Giedion syndrome Shprintzen-Goldberg syndrome Short rib-polydactyly syndrome type 4 Spondyloepimetaphyseal dysplasia (NANS related) Spondyloepimetaphyseal dysplasia (short limb-abnormal calcification type) Spondylometaphyseal dysplasia (Sedaghatian type) Thanatophoric dysplasia VACTERL-H Warfarin embryopathy Yunis-Varon dysplasia

Polymicrogyria

Cerebro-hepato-renal syndrome Fibrochondrogenesis Orofaciodigital syndrome type 4 Proteus syndrome Spondyloepimetaphyseal dysplasia (NANS related) Yunis-Varon dysplasia

Cleft lip/palate

Aase syndrome Achondrogenesis type 2/hypochondrogenesis Acrofacial dysostosis, Nager type Acromelic frontonasal dysostosis AEC Amniotic band sequence Antley-Bixler syndrome Apert syndrome Atelosteogenesis type 1 Atelosteogenesis type 2 Atelosteogenesis type 3 Bartsocas-Papas syndrome Boomerang dysplasia Brachydactyly Temtamy type Campomelic dysplasia Catel-Mantzke syndrome CCGE Cerebro-costo-mandibular syndrome (rib gap syndrome) CHARGE syndrome Chondrodysplasia punctata group Chondroectodermal dysplasia (Ellis van Creveld) Crane-Heise syndrome Craniofrontonasal syndrome de Lange syndrome Desbuquois dysplasia Desmosterolosis

Page

(p. 531 in VATER association)

(p. 573 in Fanconi anaemia)

(p. 576 in Split hand-foot malformation) (p. 608 in OEIS complex)

(p. 605 in Multiple pterygium syndrome)

(p. 576 in Split hand-foot malformation)

(p. 482 in Cleidocranial dysplasia) (in Pfeiffer syndrome)

(p. 411 in Dysplastic cortical hyperostosis) (Continued)

621

Appendix 2: Gamuts List of Signs

Skeletal Dysplasias Diastrophic dysplasia DK phocomelia Dubowitz syndrome Dyssegmental dysplasia Ectrodactyly, ectodermal dysplasia and cleft lip/palate (EEC) syndrome type 3 Femoral facial syndrome Fibrochondrogenesis Frontometaphyseal dysplasia Fryns syndrome-acral defects Gollop-Wolfgang complex Hartsfield syndrome Hemifacial microsomia Hypophosphatasia perinatal lethal and infantile forms Kniest dysplasia Kyphomelic dysplasia Larsen syndrome Lenz-Majewski hyperostotic dysplasia Limb-mammary syndrome Limb reduction syndrome Meckel syndrome Mesomelic dysplasia, Kozlowski-Reardon type Microcephalic osteodysplastic primordial dwarfism type 1/3 Multiple pterygium syndrome Omodysplasia Orofaciodigital syndrome type 4 Orofaciodigital syndromes Osteopathia striata with cranial sclerosis Otopalatodigital syndrome type 1 Otopalatodigital syndrome type 2 Otospondylomegaepiphyseal dysplasia Pallister-Hall syndrome Pfeiffer syndrome Pseudodiastrophic dysplasia Raine dysplasia Roberts syndrome Robinow syndrome Saethre-Chotzen syndrome Schneckenbecken dysplasia Schwartz-Jampel syndrome type 2 Short rib-polydactyly syndrome type 2 Short rib-polydactyly syndrome type 4 Shprintzen-Goldberg syndrome Smith-Lemli-Opitz syndrome Spleno-gonadal fusion with limb defects and micrognathia Split hand-foot malformation Spondyloepimetaphyseal dysplasia Strudwick type Spondyloepimetaphyseal dysplasia with joint laxity Spondyloepiphyseal dysplasia congenita Stickler syndrome Tetra-amelia Trisomy 13 Trisomy 18 Warfarin embryopathy Yunis-Varon dysplasia 22q11.2 deletion syndrome

Page

(p. 338 in Microcephalic osteodysplastic primordial dwarfism type 1/3) (p. 576 in Split hand-foot malformation)

(p. 573 in Fanconi anaemia) (p. 576 in Split hand-foot malformation)

(p. 576 in Split hand-foot malformation)

(p. 209 in Orofaciodigital syndrome type 4)

(p. 151 in Larsen syndrome)

(p. 491 in Pfeiffer syndrome) (p. 166 in Dyssegmental dysplasia)

(pp. 352–375) in Chondrodysplasia punctata group) (p. 550 in Roberts syndrome)

(p. 550 in Roberts syndrome)

(p. 536 in Holt-Oram syndrome) (Continued)

622

Appendix 2: Gamuts List of Signs

Skeletal Dysplasias

8

Cloverleaf skull

Antley-Bixler syndrome Bent bone dysplasia Carpenter syndrome Osteocraniostenosis Pfeiffer syndrome type 2 Raine dysplasia Spondylo-epiphyseal-metaphyseal dysplasia with immune deficiency and intellectual disability Thanatophoric dysplasia type 2

9

Congenital heart malformation

Acrofacial dysostosis type Rodriguez Adams-Oliver syndrome Alagille syndrome Antley-Bixler syndrome Campomelic dysplasia Carpenter syndrome Catel-Manzke syndrome CCGE Cerebro-costo-mandibular syndrome (rib gap) CHARGE syndrome CHILD syndrome Chitayat 1993, hyperphalangism-hallux valgus-bronchomalacia Chondrodysplasia punctata group Chondroectodermal dysplasia (Ellis van Creveld) Congenital hypothalamic hamartoma syndrome Cornelia de Lange syndrome Desbuquois syndrome Diastrophic dysplasia Fanconi anaemia Fetal alcohol syndrome Frontometaphyseal dysplasia Gollop-Wolfgang complex Goltz syndrome Hajdu-Cheyney syndrome Hallerman-Streiff Heart-hand syndromes Hemifacial microsomia Holt-Oram syndrome Hydrolethalus syndrome Kabuki syndrome Kaufman-McKusick syndrome Larsen syndrome Loeys-Dietz syndrome Maternal systemic lupus erythematosus Meckel syndrome Menkes syndrome Microcephalic osteodysplastic primordial dwarfism type 1/3 Multiple joint dislocations, short stature, craniofacial dysmorphisms and skeletal dysplasia with or without heart defects Multiple pterygium syndrome Neu-Laxova syndrome Noonan syndrome OEIS complex Okihiro syndrome Omodysplsia, recessive and dominant types

Page

(p. 510 in Acrofacial dysostosis Nager type) (p. 576 in Split hand-foot malformation) (p. 517 in Spondylocostal dysostosis)

(p. 576 in Split hand-foot malformation)

(pp. 352–375 in Chondrodysplasia punctata group)

(p. 587 in Pallister-Hall syndrome)

(p. 338 in Microcephalic osteodysplastic primordial dwarfism type 1/3)

(p. 576 in Split hand-foot malformation)

(p. 536 in Holt-Oram syndrome)

(p. 587 in Pallister-Hall syndrome)

(p. 504 in Shprintzen-Goldberg syndrome)

(p. 591 in Cerebroarthrodigital syndrome) (p. 605 in Multiple pterygium syndrome) (p. 573 in Fanconi anaemia) (Continued)

623

Appendix 2: Gamuts List of Signs

Skeletal Dysplasias Oral-facial-digital syndrome type 4 Oral-facial-digital syndromes Osteodysplasty, Melnick-Needles Osteopathia striata with cranial sclerosis Otopalatodigital syndrome type 2 Pallister-Hall syndrome Pentalogy of Cantrell Roberts syndrome Rubinstein-Taybi syndrome Saethre-Chotzen syndrome Schinzel-Giedion syndrome Short rib-polydactyly syndrome type 1/3 Short rib-polydactyly syndrome type 4 Sirenomelia Split hand-foot malformation SPONASTRIME Spondylocostal dysostosis Spondylometaphyseal dysplasia, Sedaghatian type TAR syndrome Thalidomide embryopathy Thanatophoric dysplasia Tibial agenesis-polydactyly syndrome Townes-Brocks syndrome Trisomy 13 Trisomy 18 VATER/VACTERL association Warfarin embryopathy XK-aprosencephaly Yunis-Varon dysplasia Zellweger syndrome Zimmermann-Laband syndrome 22q11.2 deletion syndrome

Arrythmia, conduction defect

Heart-hand syndromes Holt-Oram syndrome Spondylometaphyseal dysplasia, Sedaghatian type

Cardiomyopathy

Maternal systemic lupus erythematosus Yunis-Varon dysplasia Zimmermann-Laband syndrome

Coarctation of aorta

Blomstrand dysplasia Desbuquois syndrome Hajdu-Cheyney syndrome Microcephalic osteodysplastic primordial dwarfism type 1/3

Septal defect

Acrofacial dysostosis Nager type Antley-Bixler syndrome Cardioacrofacial dysplasia Carpenter syndrome Cerebro-costo-mandibular syndrome (rib gap) Cerebro-hepato-renal (Zellweger) syndrome CHARGE syndrome Chitayat 1993, hyperphalangism-hallux valgus-bronchomalacia Chondrodysplasia punctata group Chondrodysplasia with congenital joint dislocations (Recessive Larsen syndrome)

Page (p. 587 in Pallister-Hall syndrome)

(p. 608 in OEIS)

(p. 491 in Pfeiffer syndrome)

(p. 127 in Spondyloepimetaphyseal dysplasia [SEMD])

(p. 540 in Cornelia de Lange syndrome) (p. 536 in Holt-Oram syndrome)

(p. 553 in Tibial aplasia-five fingered hand-polydactyly)

(p. 573 in Fanconi anaemia)

(p. 286 in Brachydactyly type B) (p. 536 in Holt-Oram syndrome) (p. 536 in Holt-Oram syndrome)

(p. 286 in Brachydactyly type B)

(p. 203 in Chondroectodermal dysplasia)

(Continued)

624

Appendix 2: Gamuts List of Signs

Skeletal Dysplasias Chondroectodermal dysplasia (Ellis van Creveld) Cornelia de Lange syndrome Desbuquois syndrome Fetal alcohol syndrome Frontometaphyseal dysplasia Hajdu-Cheyney syndrome Holt-Oram syndrome Microcephalic osteodysplastic primordial dwarfism types 1 and 3 Okihiro syndrome Oral-facial-digital syndrome type 4 Osteopathia striata with cranial sclerosis Otopalatodigital syndrome type 2 Pallister-Hall syndrome Schinzel-Giedion syndrome Sirenomelia Spondyloepimetaphyseal dysplasia with joint laxity Spondylometaphyseal dysplasia, Sedaghatian type VATER/VACTERL association Warfarin embryopathy Yunis-Varon dysplasia

Tetralogy of Fallot

Acrofacial dysostosis Nager type Cornelia de Lange syndrome Fetal alcohol syndrome

Page

(p. 338 in Microcephalic osteodysplastic primordial dwarfism types 1 and 3)

(p. 573 in Fanconi anaemia)

(p. 338 in Microcephalic osteodysplastic primordial dwarfism type 1 and 3)

Kaufman-McKusick syndrome Melnick-Needles syndrome Microcephalic osteodysplastic primordial dwarfism type 1 and 3 Orofaciodigital syndrome type 4 VATER/VACTERL association Transposition of the great vessels

Antley-Bixler syndrome VATER/VACTERL association

10

Contractures

Antley-Bixler syndrome Arthrogryposis multiplex congenita Bruck syndrome Cerebroarthrodigital syndrome Cerebro-osseous-digital syndrome CHILD syndrome Congenital contractural arachnodactyly Congenital myasthenic syndromes Cornelia de Lange syndrome Crisponi syndrome Diaphanospondylodysostosis Diastrophic dysplasia Distal arthrogryposis Fetal akinesia deformation sequence Fibrochondrogenesis Frontometaphyseal dysplasia Gollop-Wolfgang complex Limb reduction syndrome Loeys-Dietz syndrome Marfan syndrome Metaphyseal dysplasia Jansen type

(p. 447 in Bruck syndrome)

(p. 375 in Warfarin embryopathy) (p. 471 in Marfan syndrome) (p. 605 in Multiple pterygium syndrome) (p. 311 in Stuve-Wiedemann syndrome)

(p. 111 in Diastrophic dysplasia) (p. 151 in Larsen syndrome)

(p. 447 in Bruck syndrome)

(Continued)

625

Appendix 2: Gamuts List of Signs

11

12

Skeletal Dysplasias Metatropic dysplasia Microcephalic osteodysplastic primordial dwarfism type 1 and 3 Mucolipidosis 2 (I-cell disease) Multiple epiphyseal dysplasia, autosomal recessive Multiple joint dislocations, short stature, craniofacial dysmorphisms and skeletal dysplasia with or without heart defects Multiple pterygium syndrome Myotonic chondrodystrophy Otopalatodigital syndromes Pseudodiastrophic dysplasia Rhizomelic type chondrodysplasia punctata Shprintzen-Goldberg syndrome Spinal muscular atrophy Spondyloepimetaphyseal dysplasia with joint laxity, Beighton type Spondyloepimetaphyseal dysplasia with joint laxity, Hall type Stuve-Wiedemann syndrome Thanatophoric dysplasia Uniparental disomy, paternal, for chromosome 14

Cortical hyperostosis/Periosteal Caffey disease (including infantile and attenuated forms) new bone Caffey dysplasia (severe lethal variant) Dysplastic cortical hyperostosis (Al-Gazali type) Dysplastic cortical hyperostosis (Kozlowski-Tsuruta type) FGF23-related hyperphospatemic hyperostosis/tumoral calcinosis Mucolipidosis type 2 (I-cell disease) Raine syndrome Cystic hygroma/hydrops

Achondrogenesis, all types Bent bone dysplasia Blomstrand dysplasia Campomelic dysplasia Caffey disease (severe lethal variant) Cerebro-costo-mandibular syndrome Cerebro-osseous-digital syndrome Cornelia de Lange syndrome Desbuquois dysplasia Diaphanospondylodysostosis Dysplastic cortical hyperostosis (Kozlowski-Tsuruta) Dyssegmental dysplasia Fibrochondrogenesis Greenberg dysplasia Kaufman-McKusick syndrome Infantile galactosialidosis Infantile sialic acid storage disease Multiple pterygium syndrome Osteocraniostenosis Schneckenbecken dysplasia Short rib-polydactyly syndrome, all types Spondylocostal dysostosis Uniparental disomy, paternal, for chromosome 14 Warfarin embryopathy Yunis-Varon dysplasia

Page

(p. 111 in Diastrophic dysplasia)

(p. 111 in Diastrophic dysplasia)

(p. 382 in Cerebro-hepato-renal syndrome)

(p. 411 in Caffey disease)

(p. 348 in Mucolipidosis type 2) (p. 348 in Mucolipidosis type 2)

(Continued)

626

13

Appendix 2: Gamuts List of Signs

Skeletal Dysplasias

Craniosynostosis

Antley-Bixler syndrome Apert syndrome Bent bone dysplasia Baller-Gerold syndrome Beare-Stevenson cutis gyrata Carpenter syndrome Craniofrontonasal syndrome CDAGS syndrome Cranioectodermal dysplasia (Sensenbrenner syndrome) ERF syndromes Fluconazole embryopathy Frontometaphyseal dysplasia Gorlin-Chaudhry-Moss syndrome Greig cephalopolysyndactyly syndrome Hypophosphatasia Osteocraniostenosis Osteogenesis imperfecta with craniosynostosis Osteoglophonic dysplasia Osteopathia striata with cranial sclerosis Pfeiffer syndrome Piepkorn dysplasia (atelosteogenesis type 1) Pycnodysostosis Raine dysplasia Roberts syndrome Saethre-Chotzen syndrome Shprintzen-Goldberg syndrome Spondylo-epiphyseal-metaphyseal dysplasia with immune deficiency and intellectual disability

14

Dislocations

Acromelic frontonasal dysostosis Acromesomelic dysplasia Hunter-Thompson type Atelosteogenesis type 1 Atelosteogenesis type 2 Atelosteogenesis type 3 Campomelic dysplasia Catel-Manzke Cerebroarthrodigital syndrome Cerebro-osseous-digital syndrome Chondrodysplasia with congenital joint dislocations Cleidocranial dysplasia Cousin syndrome Desbuquois dysplasia Diastrophic dysplasia Ehlers-Danlos syndrome Frontometaphyseal dysplasia Hajdu-Cheyney Microcephalic osteodysplastic primordial dwarfism types 1 and 3 Mirror-image polydactyly of hands and feet Mucolipidosis 2 (I-cell disease) Multiple joint dislocations, short stature, craniofacial dysmorphisms and skeletal dysplasia, with or without heart defects Multiple pterygium syndrome Larsen syndrome Limb reduction syndrome OEIS complex

Page

(p. 491 in Pfeiffer syndrome) (in Carpenter syndrome) (p. 491 in Pfeiffer syndrome) (p. 482 in Cleidocranial dysplasia) (p. 298 in Hyperphalangism, characteristic facies, hallux valgus and bronchomalacia) (p. 500 in Antley-Bixler syndrome) (p. 342 in Saul-Wilson syndrome)

(p. 319 in Bent bone dysplasia)

(p. 491 in Pfeiffer syndrome)

(p. 283 in Grebe dysplasia)

(p. 151 in Larsen syndrome)

(Continued)

627

Appendix 2: Gamuts

15

List of Signs

Skeletal Dysplasias Page Omodysplasia, recessive type Osteogenesis imperfecta (type 5) Otopalatodigital syndrome type 1 Pseudodiastrophic dysplasia (p. 111 in Diastrophic dysplasia) Robinow syndrome Rubenstein-Taybi Shprintzen-Goldberg syndrome Spondyloepimetaphyseal dysplasia with joint laxity, Beighton type Spondyloepimetaphyseal dysplasia with joint laxity, Hall type Thrombocytopenia absent radius syndrome (p. 510 in Acrofacial dysostosis, Nager type) Tibial hemimelia-polysyndactyly-triphalangeal thumb

Dumbbell-shaped tubular bones

Dyssegmental dysplasia Fibrochondrogenesis Kniest dysplasia Metatropic dysplasia Myotonic chondrodystrophy Otospondylomegaepiphyseal dysplasia Schneckenbecken dysplasia Stickler syndrome type 1

16

Ear anomalies

Acrofacial dysostosis, Nager type Antley-Bixler syndrome Bent bone dysplasia Brachydactyly, Temtamy type Brachydactyly type B Carpenter syndrome Catel-Manzke syndrome Cerebro-costo-mandibular syndrome Cerebro-osseous-digital syndrome Chondrodysplasia with congenital joint dislocations Congenital contractual arachnodactyly Crane-Heise syndrome Cornelia de Lange Cranioectodermal dysplasia (Sensenbrenner syndrome) Cousin syndrome Diaphanospondylodysostosis DK phocomelia Dubowitz syndrome Dysplastic cortical hyperostosis Fanconi anaemia Femoral facial syndrome Fibrochondrogenesis Fryns syndrome-acral defects Hajdu-Cheyney Keutel syndrome Kyphomelic dysplasia with facial dysmorphism Larsen syndrome Lenz-Majewski hyperostotic dysplasia Limb reduction syndrome Marshall-Smith syndrome Metaphyseal dysplasia with pancreatic insufficiency and cyclical neutropenia Multiple pterygium syndrome Omodysplasia, recessive type

(p. 471 in Marfan syndrome) (p. 482 in Cleidocranial dysplasia)

(p. 338 in Microcephalic osteodysplastic primordial dwarfism types 1 and 3)

(p. 573 in Fanconi anaemia) (p. 375 in Warfarin embryopathy)

(Continued)

628

Appendix 2: Gamuts List of Signs

17

Eye anomalies Cataract

Coloboma

Skeletal Dysplasias Otopalatodigital syndrome type 1 Otopalatodigital syndrome type 2 Opsismodysplasia Osteocraniostenosis Pallister-Hall syndrome Raine dysplasia Roberts syndrome Robinow syndrome Rubinstein-Taybi syndrome Saethre-Chotzen syndrome Schinzel-Giedion syndrome Short rib-polydactyly syndrome type 4 Shprintzen-Goldberg syndrome Spondyloepimetaphyseal dysplasia, NANS-related Spondylometaphyseal dysplasia, Sedaghatian type Thalidomide embryopathy Townes-Brocks syndrome Uniparental disomy, paternal, for chromosome 14 Cerebro-osseous-digital syndrome Chondrodysplasia punctata group Congenital myotonic dystrophy Hajdu-Cheyney syndrome Hallermann-Streiff syndrome Fanconi anaemia Fibrochondrogenesis Kniest dysplasia Marfan syndrome Osteocraniostenosis Osteopathia striata with cranial sclerosis Otospondylomegaepiphyseal dysplasia Marfan syndrome Marshall-Smith syndrome Myotonic chondrodystrophy (Schwartz-Jampel syndrome Raine dysplasia Rubinstein-Taybi syndrome Saul-Wilson syndrome Spondyloepiphyseal dysplasia congenita Stickler syndrome type 1 Trisomy 13 Trisomy 18 Warfarin embryopathy Zellweger syndrome Acrofacial dysostosis, Nager type Acro-renal-ocular syndrome Cat-eye syndrome Catel-Manzke syndrome CHARGE syndrome Cornelia de Lange syndrome Duane anomaly-radial defects Goltz syndrome Kabuki syndrome Okihiro syndrome Osteopetrosis Proteus syndrome Renal coloboma syndrome (papillorenal)

Page

(p. 491 in Pfeiffer syndrome)

(p. 536 in Holt-Oram) (p. 531 in VATER/VACTERL association)

(p. 382 in Zellweger syndrome)

(p. 536 in Holt-Oram syndrome)

(p. 573, 531, 536 in Fanconi anaemia, VACTERL association and Holt-Oram syndrome) (p. 576 in Split hand-foot malformation)

(Continued)

629

Appendix 2: Gamuts List of Signs

Glaucoma

Hypertelorism

Skeletal Dysplasias Rubinstein-Taybi syndrome Sorsby syndrome Treacher-Collins syndrome Trisomy 13 Trisomy 18 Acromelic frontonasal dysostosis Cornelia de Lange syndrome Desbuquois dysplasia Frank ter Haar syndrome Marfan syndrome Oculo-dento-digital dysplasia Spondyloepiphyseal dysplasia congenita Roberts syndrome Rubinstein-Taybi syndrome Aase syndrome Acrocallosal syndrome Acromelic frontonasal dysostosis Antley-Bixler syndrome Apert syndrome Atelosteogenesis type 1 and 3 ATRX Baller-Gerold syndrome

Bent bone dysplasia Hydrolethalus syndrome Hyperphalangism characteristic facies hallux valgus and bronchomalacia (Chitayat) Boomerang dysplasia Brachydactyly type B Brachydactyly, Temtamy type Caffey disease (including infantile and attenuated forms) Caffey disease (severe and lethal variant) Carpenter syndrome Catel-Manzke syndrome Cephalopolysyndactyly syndrome (Greig) Chitayat 1993, hyperphalangism-hallux valgus-bronchomalacia Chondroectodermal dysplasia Cole-Carpenter syndrome Cousin syndrome Craniofrontonasal syndrome DK phocomelia Diaphanospondylodysostosis Fluconazole embryopathy Frontometaphyseal dysplasia Gorlin syndrome Greig syndrome Hajdu-Cheyney syndrome Hydrolethalus syndrome Keipert syndrome Kniest dysplasia Larsen syndrome Lenz-Majewski hyperostotic dysplasia Loeys-Dietz syndrome Marshall-Smith syndrome

Page (p. 286 in Brachydactyly type B) (p. 510 in Acrofacial dysostosis, Nager type)

(p. 141 in Osteodysplasty, Melnick-Needles) (p. 333 in Hallermann-Streiff syndrome)

(p. 573 in Fanconi anaemia) (p. 514 in Acromelic frontonasal dysostosis)

(p. 540 in de Lange syndrome) (p. 496, 500, 507, 540 in Apert syndrome, Antley-Bixler syndrome and Carpenter syndrome, Cornelia de Lange syndrome) (p. 514 in Acromelic frontonasal dysostosis)

(p. 496, 507 in Apert syndrome and Carpenter syndrome)

(p. 500 in Antley-Bixler syndrome) (p. 583 in Greig syndrome)

(p. 515 in Acromelic frontonasal dysostosis)

(p. 447 in Bruck syndrome) (Continued)

630

Appendix 2: Gamuts List of Signs

Skeletal Dysplasias Meckel syndrome Mesomelic dysplasia, Langer type Metatropic dysplasia Multiple joint dislocations, short stature, craniofacial dysmorphisms and skeletal dysplasia, with or without heart defects, B3GAT3-related Multiple pterygium syndrome Nager acrofacial dysostosis Neu-Laxova syndrome Opsismodysplasia Oral-facial-digital syndrome type 4 Oral-facial-digital syndromes Osteopathia striata with cranial sclerosis Osteocraniosclerosis Osteopetrosis Otopalatodigital syndrome type 1 Otopalatodigital syndrome type 2 Otospondylomegaepiphyseal dysplasia Pfeiffer syndrome Proteus syndrome Raine dysplasia Roberts syndrome Robinow dysplasia/syndrome Schinzel-Giedion syndrome Short rib-polydactyly syndrome type 4 Shprintzen-Goldberg syndrome Spondyloepimetaphyseal dysplasia, Strudwick type Spondyloepimetaphyseal dysplasia short limbs abnormal calcification type Spondyloepiphyseal dysplasia congenita Spondylometaphyseal dysplasia, Sedaghatian type Temtamy preaxial brachydactyly syndrome Tetrasomy 12p Trisomy 13 Trisomy 18 Yunis-Varon dysplasia Zellweger syndrome

Hypotelorism

Page

(p. 591 in Cerebroarthrodigital syndrome)

(p. 587 in Pallister-Hall syndrome)

(p. 270 in Langer type homozygous dyschondrosteosis)

(p. 540 in de Lange syndrome)

Osteocraniostenosis

Microphthalmia/Anophthalmia Anophthalmia-oesophageal-genital syndrome Fanconi anaemia Goltz syndrome Hallermann-Streiff syndrome Hemifacial microsomia Meckel syndrome Oculo-dento-digital dysplasia Osteocraniostenosis Osteopetrosis Roberts syndrome Short rib polydactyly syndrome type 4 (Beemer) Trisomy 13 Trisomy 18 Warfarin embryopathy Proptosis

(p. 531 in VATER/VACTERL) (p. 576 in Split hand-foot malformation)

(p. 333 in Hallermann-Streiff syndrome)

Antley-Bixler syndrome Apert syndrome (Continued)

631

Appendix 2: Gamuts List of Signs

18

19

20

Exomphalos

Fibular hypoplasia/aplasia

Flat face

Skeletal Dysplasias Bent bone dysplasia Blomstrand dysplasia Caffey disease (including infantile and attenuated forms) Caffey disease (severe and lethal variant) Cerebroarthrodigital syndrome Cerebro-osseous-digital syndrome Cole-Carpenter syndrome Desbuquois dysplasia Frontometaphyseal dysplasia Marshall-Smith syndrome Metatropic dysplasia Neu-Laxova syndrome Osteodysplasty, Melnick-Needles Osteopetrosis Otospondylomegaepiphyseal dysplasia Pfeiffer syndrome Raine dysplasia Schinzel-Giedion syndrome SEMD with joint laxity Beighton type Shprintzen-Goldberg syndrome

Page

Beckwith-Wiedemann syndrome Boomerang dysplasia Carpenter syndrome Desbuquois dysplasia Fibrochondrogenesis Melnick-Needles syndrome OEIS complex Osteodysplasty, Melnick-Needles Osteopathis striata with cranial sclerosis Otopalatodigital syndrome type 2 Pentalogy of Cantrell Short rib-polydactyly syndrome type 4 Trisomy 13 Trisomy 18

(p. 608 in OEIS complex)

Acheiropody

(p. 546 in Al-Awadi/Raas-Rothschild syndrome)

Al-Awadi/Raas-Rothschild syndrome Atelosteogenesis types 1/3 Boomerang dysplasia Campomelic dysplasia DK phocomelia syndrome Femoral hypoplasia unusual facies syndrome Femur-fibula-ulna complex Fibular hypoplasia and complex brachydactyly (Du Pan syndrome) Fuhrmann syndrome Hypophosphatasia Grebe dysplasia Mesomelic dysplasia, Langer type Otopalatodigital syndrome type 2 Roberts syndrome Sirenomelia Short rib polydactyly syndrome type 4 (Beemer) Atelosteogenesis type 1 ATRX Boomerang dysplasia Campomelic dysplasia

(p. 500 in Antley-Bixler syndrome)

(p. 608 in OEIS complex)

(p. 283 in Grebe dysplasia) (p. 546 in Al-Awadi/Raas-Rothschild syndrome)

(p. 540 in de Lange syndrome)

(Continued)

632

Appendix 2: Gamuts List of Signs

21

22

Flat nasal bridge

Fontanelles and sutures large

Skeletal Dysplasias Chondrodysplasia punctata group Cranioectodermal dysplasia (Sensenbrenner syndrome) Dyssegmental dysplasia Fibrochondrogenesis Kniest dysplasia Kyphomelic dysplasia Larsen syndrome Metatropic dysplasia Osteocraniostenosis Osteopathia striata with cranial sclerosis Otospondylomegaepiphyseal dysplasia Potter syndrome Raine dysplasia SEMD short limb abnormal calcification type SEMD with joint laxity (Beighton type) Short rib-polydactyly syndrome type 4 (Beemer) Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type Spondyloepiphyseal dysplasia congenita Stickler syndrome type 1 Zellweger syndrome Achondrogenesis, all types Achondroplasia Atelosteogenesis type 1 and 3 Campomelic dysplasia Carpenter syndrome Cerebro-osseous-digital syndrome Chondrodysplasia punctata group Desbuquois dysplasia Fibrochondrogenesis Fryns syndrome Greig syndrome Kniest dysplasia Kyphomelic dysplasia Larsen syndrome Metatropic dysplasia Microcephalic osteodysplastic primordial dwarfism Neu-Laxova syndrome Omodysplasia Osteocraniostenosis Osteopathia striata with cranial sclerosis Otopalatodigital syndrome type 2 Otospondylomegaepiphyseal dysplasia Pallister-Hall syndrome Short rib-polydactyly syndrome, all types Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type Spondyloepiphyseal dysplasia congenita Stickler syndrome type 1 Thanatophoric dysplasia Acromelic frontonasal dysostosis Atelosteogenesis type 1 Bent bone dysplasia Boomerang dysplasia Caffey dysplasia (severe lethal variant) Cephalopolysyndactyly syndrome (Greig) Cleidocranial dysostosis Congenital hypothyroidism

Page

(p. 328 in Osteocraniostenosis)

(p. 573 in Fanconi anaemia)

(p. 591 in Cerebroarthodigital syndrome)

(p. 382 in Zellweger syndrome) (Continued)

633

Appendix 2: Gamuts List of Signs

23

Fractures

Skeletal Dysplasias CDAGS syndrome Crane-Heise syndrome Hallermann-Streiff syndrome Hypophosphatasia Lenz-Majewski hyperostotic dysplasia Lethal neonatal short limb dysplasia (Al-Gazali 1996) Mandibuloacral dysostosis Opsismodysplasia Osteocraniostenosis Osteodysplasty, Melnick-Needles Osteogenesis imperfecta Otopalatodigital syndrome type 2 Piepkorn dysplasia Pycnodysostosis Raine dysplasia Schinzel-Giedion syndrome Trisomy 18 Yunis-Varon dysplasia Zellweger syndrome Achondrogenesis type 1A Antley-Bixler syndrome Astley-Kendall dysplasia Bent bone dysplasia Bruck syndrome Cleidocranial dysplasia Cole-Carpenter syndrome Dysosteosclerosis Fetal infection with parvovirus Hajdu-Cheyney syndrome Hypophosphatasia Kyphomelic dysplasia Menkes disease Metaphyseal dysplasia, Jansen type Metaphyseal dysplasia, Shwachman-Bodian-Diamond type Mucolipidosis 2 (I-cell disease) Multiple pterygium syndrome Neonatal hyperparathyroidism Non-accidental injury

Page (p. 488 in Yunis-Varon) (p. 482 in Cleidocranial dysplasia)

(p. 482 in Cleidocranial dysplasia)

(p. 156 in Boomerang dysplasia)

(p. 429 in Osteogenesis imperfecta)

(p. 521 in Cerebro-costo-mandibular syndrome and osteogenesis imperfecta)

Osteocraniostenosis Osteogenesis imperfecta Osteopathis striata with cranial sclerosis Osteopetrosis Pycnodysostosis Raine dysplasia Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type Stuve-Wiedemann dysplasia Yunis-Varon dysplasia 24

Frontal bossing

Achondroplasia Acromelic frontonasal dysostosis Apert syndrome Cephalopolysyndactyly syndrome (Greig) Chitayat 1993, hyperphalangism-hallux valgus-bronchomalacia Cornelia de Lange syndrome Cousin syndrome (Continued)

634

Appendix 2: Gamuts List of Signs

Skeletal Dysplasias Craniofrontonasal syndrome Chondrodysplasia punctata group Desmosterolosis

Page (p. 491 in Pfeiffer syndrome) (p. 416 in Dysplastic cortical hyperostosis, Kozlowski-Tsuruta type)

Dysosteosclerosis Greig syndrome Hallermann-Streiff syndrome Homozygous achondroplasia Menkes disease Omodysplasia, recessive type Osteopathia striata with cranial sclerosis Otopalatodigital syndrome type 2 Pfeiffer syndrome Proteus syndrome Raine dysplasia Schinzel-Giedion syndrome 25

Genital abnormalities

Al Awadi/Raas Rothschild limb/pelvis-hypoplasia/aplasia Antley-Bixler syndrome Beare-Stevenson cutis gyrata Campomelic dysplasia Carpenter syndrome Cat-eye syndrome Caudal regression syndrome CCGE Cerebro-osseous-digital syndrome CHARGE syndrome Cornelia de Lange syndrome Desmosterolosis DK phocomelia Fanconi anaemia Holt-Oram syndrome Hydrolethalus syndrome Kaufman-McKusick syndrome Meckel syndrome Microcephalic osteodysplastic primordial dwarfism type 1/3 Multiple pterygium syndrome OEIS complex Oral-facial-digital syndrome type 4 Osteocraniostenosis Roberts syndrome Robinow dysplasia/syndrome Schinzel-Giedion syndrome Short rib-polydactyly syndrome all types Sirenomelia Smith-Lemli-Opitz syndrome Spondylothoracic dysostosis Ulnar-mammary syndrome Yunis-Varon dysplasia

26

Hearing loss

Achondroplasia Achondrogenesis type 2 Acrodysostosis Acrofacial dysostosis, Nager type Brachydactyly type B Brachydactyly, Temtamy type Brachyo-oto-renal syndrome Campomelic dysplasia

(p. 491 in Pfeiffer syndrome)

(p. 568 in Sirenomelia) (p. 576 in Split hand-foot malformation)

(p. 411 in Dysplastic cortical hyperostosis)

(p. 587 in Pallister-Hall syndrome)

(pp. 352–375 in Chondrodysplasia punctata group) (p. 576 in Split hand-foot malformation)

(p. 266 in Opsismodysplasia)

(Continued)

635

Appendix 2: Gamuts List of Signs

Skeletal Dysplasias Carpenter syndrome Cerebro-costo-mandibular syndrome CHARGE syndrome Chondrodysplasia punctata group Cleidocranial dysplasia Cornelia de Lange syndrome Dysosteosclerosis Fanconi anaemia Fibrochondrogenesis Frontometaphyseal dysplasia Hajdu-Cheyney syndrome Hemifacial microsomia Kniest dysplasia Larsen syndrome Laurin-Sandrow syndrome Lenz-Majewski Melnick-Needles syndrome Metaphyseal dysplasia, Jansen type Metaphyseal dysplasia, Shwachman-Bodian-Diamond type Mucolipidosis 2 (I-cell disease) MURCS Oral-facial-digital syndrome type 4 Osteogenesis imperfecta Osteopathia striata with cranial sclerosis Osteopetrosis Otopalatodigital syndrome types 1 and 2 Otospondylomegaepiphyseal dysplasia Pfeiffer syndrome Platyspondylic dysplasia, Torrance type Renal coloboma syndrome Roberts syndrome Robinow syndrome Rubinstein-Taybi syndrome Saul-Wilson syndrome SEMD NANS-related SEMD Strudwick type Shprintzen-Goldberg syndrome Split hand-foot malformation Spondyloepiphyseal dysplasia congenita Stickler syndrome type 1 Thanatophoric dysplasia Townes-Brocks syndrome

Page

(p. 573 in Fanconi anaemia)

(p. 536, 553 in Holt-Oram syndrome and Tibial hemimelia-polydactyly-triphalangeal thumb [Werner])

Yunis-Varon dysplasia 27

28

Hip dislocation

Hyperlaxity

Al Awadi/Raas Rothschild limb/pelvis-hypoplasia/aplasia Cousin syndrome Ehlers-Danlos syndrome Frontometaphyseal dysplasia Larsen syndrome Mucolipidosis 2 (I-cell disease) Multiple joint dislocations B3GAT3-related OEIS complex SEMD with joint laxity (Hall and Beighton types) Yunis-Varon dysplasia Acromesomelic dysplasia, Maroteaux type Anauxetic dysplasia

(p. 471 in Marfan syndrome)

(p. 283 in Grebe dysplasia) (p. 224 in Cartilage-hair-hypoplasia) (Continued)

636

Appendix 2: Gamuts List of Signs

29

Hypoplastic lungs See 57. Thorax: small (short trunk, hypoplasia of thorax/ lungs)

30

Hyperphalangism

Skeletal Dysplasias Cartilage-hair-hypoplasia Cerebro-costo-mandibular syndrome (rib gap syndrome) Cranioectodermal dysplasia (Sensenbrenner syndrome) Desbuquois dysplasia Ehlers-Danlos syndrome Loeys-Dietz syndrome Marfan syndrome Occipital horn syndrome Osteogenesis imperfecta Shprintzen-Goldberg syndrome

Brachydactyly type C Catel-Manzke syndrome Chitayat 1993 hyperphalangism-hallux valgus-bronchomalacia Desbuquois syndrome Diastrophic dysplasia Richieri-Costa brachydactyly

Page

(p. 471 in Marfan syndrome) (p. 471 in Marfan syndrome) (p. 602 in Menkes disease)

(p. 288 in Brachydactyly type C) (p. 298 in Temtamy preaxial brachydactyly syndrome)

Temtamy preaxial brachydactyly syndrome 31

Iliac wing anomalies

Achondrogenesis (all types) Achondroplasia Antley-Bixler syndrome Asphyxiating thoracic dysplasia (Jeune) Atelosteogenesis type 1 Boomerang dysplasia Campomelic dysplasia Cousin syndrome Fibrochondrogenesis Frontometaphyseal dysplasia Greenberg dysplasia Hypophosphatasia Microcephalic osteodysplastic dwarfism type 1/3 Mucolipidosis 2 (I-cell disease) Opsismodysplasia Osteodysplasty, Melnick-Needles Scapuloiliac dysostosis

(p. 311, 302 in Stuve-Wiedemann syndrome and Campomelic dysplasia)

Scheckenbecken dysplasia Shprintzen-Goldberg syndrome Spondylometaphyseal dysplasia, Sedaghatian type Thanatophoric dysplasia Thoracolaryngopelvic dysplasia (Barnes) 32

Increased nuchal translucency (NT)

Achondrogenesis, all types Achondroplasia Asphyxiating thoracic dysplasia (Jeune) Campomelic dysplasia Catel-Manzke syndrome Cerebro-costo-mandibular syndrome (rib gap syndrome) Chondrodysplasia punctata Chondroectodermal dysplasia (Ellis van Creveld) Cranioectodermal dysplasia (Sensenbrenner syndrome) Cornelia de Lange syndrome (Continued)

637

Appendix 2: Gamuts

33

List of Signs

Skeletal Dysplasias Diaphanospondylodysostosis Diastrophic dysplasia Holt-Oram syndrome Hypophosphatasia Meckel syndrome Multiple pterygium syndrome Nager acrofacial dysostosis OEIS complex Oral-facial-digital syndrome type 4 Osteogenesis imperfecta Robinow syndrome Schneckenbecken dysplasia Short rib-polydactyly syndrome, all types Sirenomelia Split hand-foot malformation Spondylocostal dysostosis Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type Spondyloepiphyseal dysplasia congenita Thanatophoric dysplasia Trisomy 13 Trisomy 18 Zellweger syndrome

Macrocephaly

Achondroplasia Acrocallosal syndrome Bannayan-Riley-Ruvalcaba syndrome Campomelic dysplasia Cephalopolysyndactyly syndrome (Greig) Cerebroarthrodigital syndrome Cerebro-osseous-digital syndrome Cousin syndrome Desmosterolosis Encephalocraniocutaneous lipomatosis Fibrochondrogenesis Gorlin syndrome Homozygous achondroplasia Hydrolethalus syndrome Hypochondroplasia Kniest dysplasia Kyphomelic dysplasia Isolated benign macrocephaly Lethal neonatal short limb dysplasia (Al Gazali) Meckel syndrome Opsismodysplasia Osteopathia striata with cranial sclerosis Osteopetrosis Platyspondylic dysplasia, Torrance type Proteus syndrome Richieri-Costa 1985 Rhizomelic SMD, LBR-related Roberts syndrome Robinow syndrome Silver-Russell syndrome Schneckenbecken dysplasia SEMD short limb abnormal calcification type Thanatophoric dysplasia Zellweger syndrome

Page

(p. 583 in Cephalopolysyndactyly syndrome [Greig]) (p. 478 in Proteus syndrome)

(p. 403 in Raine syndrome) (p. 478 in Proteus syndrome) (p.421 in Osteopathia striata with cranial sclerosis) (p. 421 in Osteopathia striata with cranial sclerosis)

(p. 421 in Osteopathia striata with cranial sclerosis)

(p. 591 in Cerebroarthrodigital syndrome)

(p. 342 in Saul-Wilson syndrome)

(Continued)

638

34

Appendix 2: Gamuts List of Signs

Skeletal Dysplasias

Mesomelic limb shortening

Acrofacial dysostosis, Nager type Acromesomelic dysplasia, Maroteaux type Acromesomelic dysplasia, Hunter-Thompson type Acromelic frontonasal dysostosis Al-Awadi/Raas-Rothschild Syndrome Asphyxiating thoracic dysplasia (Jeune) CDP tibia-metacarpal type Chondroectodermal dysplasia (Ellis van Creveld) Cranioectodermal dysplasia (Sensenbrenner syndrome) Desbuquois syndrome Du Pan syndrome Dyschondrosteosis (Leri-Weill) Femur-fibula-ulna (FFU) syndrome Ferraz dysplasia Grebe dysplasia Greenberg dysplasia Kyphomelic dysplasia Langer type (homozygous dyschondrosteosis) Mesomelic dysplasia, Kantaputra type Mesomelic dysplasia, Kozlowski-Reardon type Mesomelic dysplasia, Nievergelt type Odontochondrodysplasia Osebold-Remondini dysplasia Oral-facial-digital syndrome type 4 Pallister-Hall syndrome Paternal uniparental disomy 14 Reinhardt-Pfeiffer syndrome

Page (p. 266, 283 in Opsismodysplasia and Grebe) (p. 283 in Grebe) (p. 283 in Grebe)

(p. 283 in Grebe) (p. 54 in Hypochondroplasia) (p. 283 in Grebe) (p. 270 in Langer type homozygous) dyschondrosteosis)

(p. 281, 270 in Mesomelic dysplasia, Kozlowski-Reardon and Langer types) (p. 283 in Grebe) (p. 270 in Langer type homozygous) dyschondrosteosis)

(p. 270 in Langer type homozygous dyschondrosteosis)

Roberts syndrome Robinow dysplasia/syndrome Schinzel-Giedion syndrome Short rib-polydactyly syndrome type 2 Split hand-foot malformation Tibial agenesis-polydactyly syndrome Tibial aplasia-five fingered hand-polydactyly syndrome (Werner) 35

Metaphyses Cupped metaphyses

Flared metaphyses

Achondrogenesis 1A Opsismodysplasia Platyspondylic dysplasia, Torrance type Schneckenbecken dysplasia SMD type Sedaghatian 3M syndrome Achondrogenesis, all types Atelosteogenesis type 2 Blomstrand dysplasia Cartilage-hair-hypoplasia Chondrodysplasia punctata group Desbuquois dysplasia Diastrophic dysplasia Dysosteosclerosis Dyssegmental dysplasia Fibrochondrogenesis Frontometaphyseal dysplasia (Continued)

639

Appendix 2: Gamuts

36

List of Signs

Skeletal Dysplasias Hallermann-Streiff syndrome Hypophosphatasia Kniest dysplasia Kyphomelic dysplasia Metatropic dysplasia Microcephalic osteodysplastic primordial dwarfism type 1/3 Neonatal hyperparathyroidism, severe form Opsismodysplasia Osteocraniostenosis Otospondylomegaepiphyseal dysplasia Raine dysplasia Saul-Wilson syndrome Schinzel-Giedion syndrome Schneckenbecken dysplasia Shprintzen-Goldberg syndrome Spondyloepimetaphyseal dysplasia, Strudwick type Spondylometaphyseal dysplasia, Sedaghatian type Stickler syndrome type 1 Stuve-Wiedemann syndrome Yunis-Varon dysplasia

Page

Microcephaly

Aplasia cutis congenita with ectrodactyly skeletal syndrome

(p. 576 in Split hand-foot malformation [isolated form, types 1–6]) (p. 573 in Fanconi anaemia)

Bloom syndrome Cerebroarthrodigital syndrome Cerebro-costo-mandibular syndrome (rib gap syndrome), SNRPB-related Coffin-Siris syndrome Congenital disorder of glycosylation type IIg de Lange syndrome DK phocomelia Fanconi anaemia Feingold syndrome Fetal alcohol syndrome Hartsfield syndrome Meckel syndrome Microcephalic osteodysplastic primordial dwarfism type 1/3 Microcephalic osteodysplastic primordial dwarfism type 2 Neu Laxova syndrome Nijmegen breakage syndrome Partial duplication 3q Raine dysplasia Roberts syndrome, ESCO2-related Rubinstein-Taybi syndrome Saul-Wilson syndrome Seckel syndrome Smith-Lemli-Opitz syndrome Temtamy preaxial brachydactyly syndrome Trisomy 13 Trisomy 18 Yunis-Varon dysplasia Warfarin embryopathy

(p. 540 in de Lange syndrome) (p. 521 in Cerebro-costo-mandibular syndrome (rib gap syndrome), SNRPB-related)

(p. 531 in VATER/VACTERL association) (p. 338 in Microcephalic osteodysplastic primordial dwarfism type 1/3) (p. 576 in Split hand-foot malformation [isolated form, types 1–6])

(p. 338 in Microcephalic osteodysplastic primordial dwarfism type 1/3) (p. 593 in Cerebro-osseous-digital syndrome) (p. 573 in Fanconi anaemia) (p. 540 in de Lange syndrome)

(p. 338 in Microcephalic osteodysplastic primordial dwarfism type 1/3) (pp. 352–375 in Chondrodysplasia punctata group) (p. 217 in Meckel syndrome) (p. 217 in Meckel syndrome)

(Continued)

640

37

Appendix 2: Gamuts List of Signs

Skeletal Dysplasias

Micrognathia/retrognathia

Achondrogenesis type 1A Achondrogenesis type 2/hypochondrogenesis Acrofacial dysostosis, Nager type Atelosteogenesis, all types Brachydactyly, Temtamy type Blomstrand dysplasia Boomerang dysplasia Bruck syndrome Caffey disease (including infantile and attenuated forms) Caffey disease (severe lethal variant) Campomelic dysplasia Catel-Manzke syndrome Cerebro-costo-mandibular syndrome (rib gap syndrome) Cerebro-hepato-renal syndrome (Zellweger syndrome) Cerebro-osseous-digital syndrome Cleidocranial dysplasia Cornelia de Lange syndrome Desbuquois syndrome Diastrophic dysplasia Dubowitz syndrome Femoral hypoplasia unusual facies syndrome Fibrochondrogenesis Fryns syndrome-acral defects Hemifacial microsomia Hydrolethalus syndrome Kniest dysplasia Kyphomelic dysplasia Larsen syndrome Marfan syndrome Marshall-Smith syndrome Menkes disease Mesomelic dysplasia, Kozlowski-Reardon type Mesomelic dysplasia, Langer type Microcephalic osteodysplastic primordial dwarfism type 1/3 Myotonic chondrodystrophy (Schwartz-Jampel syndrome) Multiple joint dislocations short stature, craniofacial dysmorphisms and skeletal dysplasia, with or without heart defects, B3GAT3-related Multiple pterygium syndrome Omodysplasia, recessive type Oral-facial-digital syndromes Oral-facial-digital syndrome type 4 Osteodysplasty, Melnick-Needles Osteopathia striata with cranial sclerosis Otopalatodigital syndrome type 1 Otopalatodigital syndrome type 2 Otospondylomegaepiphyseal dysplasia Pallister-Hall syndrome Pycnodysostosis Raine syndrome Roberts syndrome Rubinstein-Taybi syndrome Short rib-polydactyly syndrome type 2 Short rib-polydactyly syndrome type 4 Shprintzen-Goldberg syndrome Smith-Lemli-Opitz syndrome

Page

(p. 338 in Microcephalic osteodysplastic primordial dwarfism type 1/3)

(p. 573 in Fanconi anaemia) (p. 510 in Acrofacial dysostosis, Nager type ) (p. 587 in Pallister-Hall syndrome)

(p. 587 in Pallister-Hall syndrome)

(pp. 352–375 in Chondrodysplasia punctata group) (Continued)

641

Appendix 2: Gamuts List of Signs

38

Micromelic limb shortening

Skeletal Dysplasias Splenogonadal fusion with limb defects and micrognathia Split hand-foot malformation Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type Spondyloepimetaphyseal dysplasia with joint laxity Beighton type Spondyloepiphyseal dysplasia congenita Spondylometaphyseal dysplasia, Sedaghatian type Stickler syndrome, COL2A1-related Stuve-Wiedemann syndrome Trisomy 13 Trisomy 18 Thrombocytopenia absent radius Yunis-Varon dysplasia 22q11.2 deletion syndrome Achondrogenesis, all types Acrodysostosis Acromesomelic dysplasia Acromicric dysplasia Atelosteogenesis type 2 Blomstrand dysplasia Boomerang dysplasia Campomelic dysplasia Cerebro-osseous-digital syndrome Congenital hypothalamic hamartoma syndrome Desbuquois dysplasia Dysplastic cortical hyperostosis, Al-Gazali type, ADAMTSL2-related Dyssegmental dysplasia Fibrochondrogenesis Geleophysic dysplasia Grebe dysplasia Greenberg dysplasia Homozygous achondroplasia Mucolipidosis 2 (I-cell disease) Omodysplasia Opsismodysplasia Pallister-Hall syndrome Piepkorn dysplasia Platyspondylic dysplasia, Torrance type Roberts syndrome Schneckenbecken dysplasia Short rib-polydactyly syndrome, all types Stuve-Wiedemann syndrome Thanatophoric dysplasia

39

Oligodactyly

Acrofacial dysostosis, Nager type Al Awadi/Raas Rothschild limb/pelvis-hypoplasia/aplasia CHILD syndrome Cornelia de Lange syndrome DK phocomelia Femur-fibula-ulna complex Fuhrmann syndrome

Page (p. 510 in Acrofacial dysostosis, Nager type)

(p. 217 in Meckel syndrome) (p. 217 in Meckel syndrome) (p. 510 in Acrofacial dysostosis, Nager type) (p. 89 in Stickler syndrome) (p. 266 in Opsismodysplasia) (p. 266 in Opsismodysplasia) (p. 266 in Opsismodysplasia)

(p. 587 in Pallister-Hall syndrome)

(p. 418 in Dysplastic cortical hyperostosis, Al-Gazali type, ADAMTSL2-related)

(p. 46 in Achondroplasia)

(p. 151 in Larsen syndrome)

(p. 357 in Chondrodysplasia punctata, X-linked, dominant type, Conradi- Hünermann type)

(p. 546 in Al Awadi/Raas Rothschild limb/ pelvis-hypoplasia/aplasia)

Gollop-Wolfgang complex Holt-Oram syndrome Roberts syndrome (Continued)

642

40

41

Appendix 2: Gamuts List of Signs

Skeletal Dysplasias Sirenomelia Split hand-foot malformation

Page

Oligohydramnios

Fetal akinesia sequence Meckel syndrome Microcephalic osteodysplastic dwarfism type 1/3 Mucolipidosis II Osteocraniostenosis Osteodysplasty, Melnick-Needles Osteopathia striata with cranial sclerosis Otopalatodigital syndrome type 2 Sirenomelia Stuve-Wiedemann syndrome Trisomy 13 Trisomy 18

(p.328 in Osteocraniostenosis)

Ossification/Mineralisation Poor/Decreased

Increased/Sclerotic

Achondrogenesis, all types Astley-Kendall dysplasia Atelosteogenesis, all types Bent bone dysplasia, FGFR2-related Boomerang dysplasia Bruck syndrome Campomelic dysplasia Cerebroarthrodigital syndrome Cerebro-osseous-digital syndrome Chondrodysplasia punctata group Cleidocranial dysplasia Congenital rickets Crane-Heise syndrome Diaphanospondylodysostosis Fetal infection with parvovirus Greenberg dysplasia Hajdu-Cheney syndrome Hutchinson-Gilford progeria syndrome Hypophosphatasia Metaphyseal anadysplasia Metaphyseal dysplasia, Jansen type Kniest dysplasia Maternal systemic lupus erythematosus Meckel syndrome Menkes disease Microcephalic osteodysplastic primordial dwarfism type 1/3 Mucolipidosis 2 (I-cell disease) Osteocraniostenosis Osteogenesis imperfecta Otopalatodigital syndrome type 2 Piepkorn dysplasia Neonatal hyperparathyroidism, severe form Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type Spondyloepiphyseal dysplasia congenita Yunis-Varon dysplasia Astley-Kendall dysplasia Blomstrand dysplasia Caffey disease (including infantile and attenuated forms) Caffey disease (severe lethal variant) Dysosteosclerosis Craniodiaphyseal dysplasia

(p. 217 in Meckel syndrome) (p. 217 in Meckel syndrome)

(p. 457 in Neonatal hyperparathyroidism) (p. 482 in Cleidocranial dysplasia) (p. 429 in Osteogenesis imperfecta)

(p. 328 in Osteocraniostenosis)

(p. 151 in Larsen syndrome)

(p. 426 in Lenz-Majewski hyperostotic dysplasia) (Continued)

643

Appendix 2: Gamuts

42

List of Signs

Skeletal Dysplasias Craniometaphyseal dysplasia Fetal infection with parvovirus Frontometaphyseal dysplasia Greenberg dysplasia Lenz-Majewski hyperostotic dysplasia Lethal neonatal short limb dysplasia (Al-Gazali 1996) Microcephalic osteodysplastic primordial dwarfism, type 1 and 3 Osteocraniostenosis Osteodysplasty, Melnick-Needles Osteopathia striata with cranial sclerosis Osteopetrosis Pycnodysostosis Raine dysplasia Schinzel-Giedion syndrome Spondylometaphyseal dysplasia, Sedaghatian type

Polydactyly

Achondrogenesis type 2 Acrocallosal syndrome Acrofacial dysostosis, Nager type Acromelic frontonasal dysostosis Al-Awadi/Raas-Rothschild limb/pelvis-hypoplasia/aplasia Asphyxiating thoracic dysplasia (Jeune) Atelosteogenesis type 1 Bardet-Biedl syndrome Bloom syndrome Cardioacrofacial dysplasia Carpenter syndrome Cephalopolysyndactyly syndrome (Greig) Chondroectodermal dysplasia (Ellis van Creveld) Cranioectodermal dysplasia (Sensenbrenner syndrome) Fanconi anaemia Femoral facial syndrome Fetal valproate syndrome Fuhrmann syndrome Gorlin syndrome Grebe dysplasia Greenberg dysplasia Hydrolethalus syndrome Joubert syndrome Kaufman-McKusick syndrome Meckel syndrome Osteopathia striata with cranial sclerosis Oral-facial-digital syndrome type 4 Oral-facial-digital syndromes Pallister-Hall syndrome Pfeiffer syndrome Piepkorn dysplasia Preaxial polydactyly type 4 Rubinstein-Taybi syndrome Schinzel-Giedion syndrome Short rib-polydactyly syndrome, all types Smith-Lemli-Opitz syndrome Split hand-foot malformation Synpolydactyly Tibial hemimelia polysyndactyly-triphalangeal thumb Mirror image polydactyly

Page (p. 426 in Lenz-Majewski hyperostotic dysplasia) (p. 429 in Osteogenesis imperfecta)

(p. 583 in Cephalopolysyndactyly syndrome)

(p. 599 in Kaufman-McKusick syndrome) (p. 573 in Fanconi anaemia) (p. 203 in Ellis-van Creveld syndrome)

(p. 573 in Fanconi anaemia) (p. 546 in Al-Awadi/Raas-Rothschild syndrome) (p. 582 in Cephalopolysyndactyly syndrome)

(p. 514 in Acromelic frontonasal) (p. 196 in Jeune)

(p. 209 in Oral-facial-digital syndrome type 4)

(p. 151 in Larsen syndrome) (p. 583 in Cephalopolysyndactyly syndrome)

(p. 375 in Warfarin embryopathy) (p. 583 in Cephalopolysyndactyly syndrome)

(Continued)

644

43

Appendix 2: Gamuts List of Signs

Skeletal Dysplasias Townes-Brocks syndrome Trisomy 13 VATER/VACTERL

Polyhydramnios

Achondrogenesis, all types Acrofacial dysostosis, Nager type Apert syndrome Asphyxiating thoracic dysplasia (Jeune) Astley-Kendall Atelosteogenesis, all types Bent bone dysplasia Blomstrand dysplasia Boomerang dysplasia Bruck syndrome Caffey disease (including infantile and attenuated forms) Caffey disease (severe lethal variant) Carpenter syndrome Cerebro-costo-mandibular syndrome (rib gap syndrome) Cerebroarthrodigital syndrome Cerebro-osseous-digital syndrome CHARGE syndrome Chondrodysplasia punctata group Chondrodysplasia with congenital joint dislocation (recessive Larsen syndrome) Hyperphalangism-hallux valgus-bronchomalacia Chitayat Congenital myasthenic syndromes Desbuquois dysplasia Dysplastic cortical hyperostosis (Kozlowski-Tsuruta) Dyssegmental dysplasia Fetal akinesia deformation sequence Fibrochondrogenesis Fryns syndrome -acral defects Greenberg dysplasia Hemifacial microsomia Homozygous achondroplasia Kaufman-McKusick syndrome Kniest dysplasia Larsen syndrome Marshall-Smith syndrome Maternal systemic lupus erythematosus Melnick-Needles syndrome Mucolipidosis 2 (I-cell disease) Multiple pterygium syndrome Opsismodysplasia Osteocraniostenosis Osteopathia striata with cranial sclerosis Osteopetrosis Otopalatodigital syndrome type 2 Paternal uniparental disomy 14 Platyspondylic dysplasia, Torrance type Raine dysplasia Rubinstein-Taybi syndrome Schinzel-Giedion syndrome Schneckenbecken dysplasia Spondyloepimetaphyseal dysplasia, short limb-abnormal calcification Spondyloepimetaphyseal dysplasia with immune deficiency

Page (p. 531 in VATER) (p. 217 in Meckel syndrome)

(p. 531 in VATER)

(p. 605 in Multiple pterygium syndrome)

(p. 151 in Larsen syndrome) (p. 573 in Fanconi) (p. 510 in Acrofacial dysostosis)

(Continued)

645

Appendix 2: Gamuts List of Signs

44

Preauricular tags

Skeletal Dysplasias Spondyloepimetaphyseal dysplasia (SEMD) with joint laxity Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type Spondyloepiphyseal dysplasia congenita Stickler syndrome type 1 Thanatophoric dysplasia Thoracolaryngopelvic dysplasia (Barnes) Trisomy 13 Trisomy 18 VATER/VACTERL association Warfarin embryopathy X-linked myotubular myopathy Yunis-Varon dysplasia Acrofacial dysostosis, Nager type DK phocomelia Hemifacial microsomia Townes-Brocks syndrome Trisomy 18

45

Protuberant abdomen

Achondrogenesis, all types Asphyxiating thoracic dysplasia (Jeune) Atelosteogenesis, all types Blomstrand dysplasia Caffey disease (including infantile and attenuated forms) Caffey disease (severe lethal variant) Cranioectodermal dysplasia (Sensenbrenner syndrome) Fibrochondrogenesis Meckel syndrome Opsismodysplasia Platyspondylic dysplasia, Torrance type Schneckenbecken dysplasia Short rib-polydactyly syndrome, all types Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type Spondyloepiphyseal dysplasia congenita Thoracolaryngopelvic dysplasia (Barnes)

46

Pubic rami short/Absent See also 55. Symphysis pubis, wide

Achondrogenesis type 1A

Page

(p. 217 in Meckel syndrome) (p. 217 in Meckel syndrome)

(p. 382 in Zellweger syndrome)

(p. 531 in VATER) (p. 531 in VATER) (p. 217 in Meckel syndrome)

Achondrogenesis type 2/hypochondrogenesis Boomerang dysplasia Cerebroarthrodigital syndrome Cerebro-osseous-digital syndrome Cleidocranial dysplasia Kniest dysplasia Larsen syndrome Dysplastic cortical hyperostosis, Al Gazali type OEIS complex Opsismodysplasia Otopalatodigital syndrome type 2 Platysplondylic dysplasia, Torrance type Schinzel-Giedion syndrome Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type Spondyloepiphyseal dysplasia congenita 47

Radial ray defects

Acrofacial dysostosis, Nager type Acro-renal-ocular syndrome Atelosteogenesis type 2 Baller-Gerold syndrome CHARGE syndrome

(p. 536 in Holt-Oram syndrome) (p. 491 in Pfeiffer syndrome) (p. 531 in VATER) (Continued)

646

Appendix 2: Gamuts List of Signs

48

Renal anomalies

Skeletal Dysplasias de Lange syndrome Diastrophic dysplasia DK phocomelia Duane-radial ray syndrome Fanconi anaemia Hemifacial microsomia Holt-Oram syndrome Okihiro syndrome Oral-facial-digital syndrome type 8 Otopalatodigital syndrome type 2 Roberts syndrome Thalidomide embryopathy Thrombocytopenia absent radius syndrome Townes-Brocks syndrome Trisomy 18 VATER/VACTERL association Yunis-Varon dysplasia Acrofacial dysostosis, Nager type Acro-reno-ocular syndrome ADPKD Antley-Bixler syndrome Apert syndrome Aplasia cutis congenita with ectrodactyly skeletal syndrome Asphyxiating thoracic dystrophy (Jeune) Bardet-Biedl syndrome Beckwith-Wiedemann syndrome Campomelic dysplasia Carpenter syndrome Cerebro-costo-mandibular syndrome (rib gap syndrome) Cerebro-hepato-renal syndrome, Zellweger syndrome CHARGE syndrome Cranioectodermal dysplasia (Sensenbrenner syndrome) Cumming syndrome de Lange syndrome Diaphanospondylodysostosis DK phocomelia Duane radial ray syndrome Dysplastic cortical hyperostosis (Kozlowski-Tsuruta) Fanconi anaemia Femoral facial syndrome Hajdu-Cheney syndrome/serpentine fibula polycystic kidney syndrome Hemifacial microsomia Holt-Oram syndrome Joubert syndrome Kaufman-McKusick syndrome Limb-body wall complex Limb reduction syndrome, Al-Awadi/Raas-Rothschild limb/ pelvis-hypoplasia/aplasia Meckel syndrome Microcephalic osteodysplastic primordial dwarfism type 1/3 Multiple pterygium syndrome MURCS association OEIS complex Okihiro syndrome Oral-facial-digital syndromes Oral-facial-digital syndrome type 4

Page

(p. 536 in Holt-Oram syndrome) (p. 531 in VATER) (p. 536 in Fanconi anaemia) (p. 209 in Oral-facial-digital syndrome type 4)

(p. 531 in Holt-Oram syndrome) (p. 491 in Acrofacial dysostosis, Nager type) (p. 531 in Holt-Oram syndrome) (p. 217 in Meckel syndrome)

(p. 536 in Holt-Oram syndrome) (p. 217 in Meckel syndrome)

(p. 576 in Split-hand-foot-malformation) (p. 599 in Kaufman-McKusick syndrome) (p. 608 in OEIS complex)

(p. 531 in VATER) (p. 217 in Meckel syndrome)

(p. 531 in VATER)

(p. 531 in VATER) (p. 196 in Jeune syndrome) (p. 573 in Fanconi anaemia)

(p. 573 in Fanconi anaemia) (p. 573 in Fanconi anaemia) (p. 209 in Oral-facial-digital syndrome type 4) (Continued)

647

Appendix 2: Gamuts List of Signs

49

Rhizomelic limb shortening

Skeletal Dysplasias Osteodysplasty, Melnick-Needles Osteopath striata with cranial sclerosis Otopalatodigital syndrome type 2 Pallister-Hall syndrome Proteus syndrome Prune-belly syndrome Rhizomelic spondylo-metaphyseal dysplasia with remission, LBR-related Roberts syndrome Robinow syndrome Rubinstein-Taybi syndrome Schinzel-Giedion syndrome Serpentine fibula-polycystic kidney disease Short rib-polydactyly syndrome, all types Sirenomelia Sorsby syndrome Spondyloepimetaphyseal dysplasia with immune deficiency and ID Spondyloepimetaphyseal dysplasia with joint laxity, Beighton type Spondylothoracic dysostosis Tetra-amelia Thanatophoric dysplasia Townes-Brocks syndrome Trisomy 13 Trisomy 18 VATER/VACTERL association Achondroplasia Asphyxiating thoracic dysplasia (Jeune) Atelosteogenesis, all types Chondrodysplasia punctata group Congenital disorder of glycosylation type IIg Desbuquois dysplasia Desmosterolosis Diastrophic dysplasia Dysplastic cortical hyperostosis (Kozlowski-Tsuruta) Femoral facial syndrome Femur-fibula-ulna complex Fibrochondrogenesis Greenberg dysplasia Homozygous achondroplasia Hypochondroplasia Kyphomelic dysplasia Mesomelic dysplasia, Langer type Larsen syndrome Mesomelic dysplasia, Kantaputra type Metaphyseal anadysplasia Multiple joint dislocations, short stature, craniofacial dysmorphisms and skeletal dysplasia, with or without heart defects, B3GAT3-related Opsismodysplasia Otospondylomegaepiphyseal dysplasia Proximal focal femoral deficiency Pseudodiastrophic dysplasia Reinhardt-Pfeiffer mesomelic dysplasia Rhizomelic spondylo-metaphyseal dysplasia with remission Smith-Lemli-Opitz syndrome

Page

(p. 608 in OEIS complex)

(p. 141 in Melnick-Needles)

(p. 286 in Brachydactyly type B)

(p. 510 in Acrofacial dysostosis, Nager type) (p. 536 in Holt-Oram syndrome) (p. 217 in Meckel syndrome) (p. 217 in Meckel syndrome)

(p. 521 in Cerebro-costo-mandibular syndrome) (p. 403 in Raine dysplasia)

(p. 270 in Langer type (homozygous) dyschondrosteosis)

(p. 560 in femoral Facial) (p. 111 in Diastrophic dysplasia) (p. 270 in Langer type) (pp. 352–375 in Chondrodysplasia punctata group) (Continued)

648

Appendix 2: Gamuts List of Signs

Skeletal Dysplasias SPONASTRIME Spondyloepiphyseal dysplasia, Omani type

Page (p. 80 in SEMD Strudwick) (p. 117 in Chondrodysplasia with congenital joint dislocations, recessive Larsen syndrome)

Spondylometaphyseal dysplasia, Sedaghatian type Spondyloepimetaphyseal dysplasia, short limb-abnormal calcification type Spondyloepiphyseal-metaphyseal dysplasia with immune deficiency and ID 50

Slender bones

51

Spine anomalies

3M syndrome Achondrogenesis, all types Antley-Bixler syndrome Bent bone dysplasia Bruck syndrome Hallermann-Streiff syndrome Menkes disease Mucolipidosis 2 (I-cell disease) Multiple pterygium syndrome Osteocraniostenosis Osteogenesis imperfecta Pycnodysostosis Shprintzen-Goldberg syndrome Spondylometaphyseal dysplasia, Sedaghatian type Spondylometaphyseal dysplasia with joint laxity, Hall type Stuve-Wiedemann syndrome Yunis-Varon dysplasia

Absent or minimal ossification

Achondrogenesis type 2/hypochondrogenesis Astley-Kendall dysplasia Atelosteogenesis type 1/3 Boomerang dysplasia Campomelic dysplasia Cerebroarthrodigital syndrome Greenberg dysplasia Hypophosphatasia Opsismodysplasia Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type Spondyloepiphyseal dysplasia congenita

Cervical kyphosis

Atelosteogenesis type 2 Campomelic dysplasia Diastrophic dysplasia Larsen syndrome Osteopathia striata with cranial sclerosis Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type Spondyloepiphyseal dysplasia congenita

Cleft

Alagille syndrome Atelosteogenesis, all types Cerebro-osseous-digital syndrome Chondrodysplasia punctata group Chondrodysplasia with congenital joint dislocations, recessive Larsen syndrome CODAS syndrome Congenital disorder of glycosylation type IIg Desbuquois dysplasia Dysplastic cortical hyperostosis (Kozlowski-Tsuruta) Dyssegmental dysplasia

(p. 517 in Spondylocostal dysostosis)

(p. 249 in Spondyloepimetaphyseal dysplasia, NANS-related) (p. 517 in Cerebro-costo-mandibular syndrome)

(Continued)

649

Appendix 2: Gamuts List of Signs

Skeletal Dysplasias EVEN-PLUS syndrome Fibrochondrogenesis Hemifacial microsomia Kniest dysplasia Larsen syndrome Maternal systemic lupus erythematosus Metaphyseal anadysplasia Metatropic dysplasia Microcephalic osteodysplastic primordial dwarfism type 1/3 Multiple pterygium syndrome Myotonic chondrodystrophy, Schwartz-Jampel syndrome Odontochondrodysplasia Otopalatodigital syndrome type 2 Otospondylomegaepiphyseal dysplasia Spondyloepimetaphyseal dysplasia, NANS-related Spondyloepiphyseal dysplasia congenita Warfarin embryopathy X-linked SEMD with leukodystrophy

Pedicle anomalies

Achondroplasia Achondrogenesis type 1 Campomelic dysplasia Cerebro-osseous-digital syndrome Hypochondroplasia Shprintzen-Goldberg syndrome Spondylocostal dysostosis Spondylothoracic dysostosis Stickler type 1

Platyspondyly

Achondrogenesis, all types Achondroplasia Astley-Kendall syndrome Atelosteogenesis, all types Blomstrand dysplasia Cartilage-hair hypoplasia Cerebroarthrodigital syndrome Chondrodysplasia with congenital joint dislocations, recessive Larsen syndrome Chondrodysplasia punctata group CODAS syndrome Diastrophic dysplasia Dysosteosclerosis Dysplastic cortical hyperostosis, Al-Gazali type Dyssegmental dysplasia EVEN-PLUS syndrome Fibrochondrogenesis Greenberg dysplasia Hallermann-Streiff syndrome Homocystinuria Homozygous achondroplasia Kniest dysplasia Kyphomelic dysplasia Maternal systemic lupus erythematosus Metatropic dysplasia

Page (p. 249 in Spondyloepimetaphyseal dysplasia, NANS-related) (p. 531 in VATER)

(p. 249 in Spondyloepimetaphyseal dysplasia, NANS-related)

(p. 249 in Spondyloepimetaphyseal dysplasia, NANS-related)

(p. 249 in Spondyloepimetaphyseal dysplasia, NANS-related)

(p. 447 in Bruck syndrome)

(Continued)

650

Appendix 2: Gamuts List of Signs

Scoliosis

Skeletal Dysplasias Microcephalic osteodysplastic primordial dwarfism type 1/3 Multiple joint dislocations, short stature, craniofacial dysmorphisms and skeletal dysplasia, with or without heart defects, B3GAT3-related Myotonic chondrodystrophy, Schwartz-Jampel syndrome Odoontochondrodysplasia Opsismodysplasia Osteocraniostenosis Osteoglophonic dysplasia Osteopathia striata with cranial sclerosis Otopalatodigital syndrome type 2 Otospondylomegaepiphyseal dysplasia Piepkorn dysplasia Pseudodiastrophic dysplasia Platyspondylic dysplasia, Torrance type Rhizomelic spondylometaphyseal dysplasia with remission, LBR-related Saul-Wilson syndrome Schneckenbecken dysplasia Short rib-polydactyly syndrome type 1/3 Spondyloepimetaphyseal dysplasia (SEMD) NANS-related Spondyloepimetaphyseal dysplasia (SEMD)-short limbabnormal calcification Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type Spondyloepimetaphyseal dysplasia (SEMD) with immune deficiency Spondyloepimetaphyseal dysplasia (SEMD) with joint laxity, Hall type Spondyloepiphyseal dysplasia congenita Spondyloepiphyseal dysplasia, Kozlowski type Spondylometaphyseal dysplasia, Sedaghatian type Stickler syndrome type 1 Thanatophoric dysplasia X-linked SEMD with leukodystrophy 3M 22q11.2 deletion syndrome Atelosteogenesis, all types Brachydactyly type B Bruck syndrome Caffey disease, COL1A1-related Campomelic dysplasia Carpenter syndrome Catel-Mantzke syndrome Cerebro-costo-mandibular syndrome Chondrodysplasia punctata, X-linked dominant Chondrodysplasia with congenital joint dislocations, recessive Larsen syndrome Cleidocranial dysplasia Congenital disorder of glycosylation type IIg Desbuquois dysplasia Diaphanospondylodysostosis Diastrophic dysplasia Dyssegmental dysplasia Ehlers-Danlos syndrome kyphoscoliotic type Fanconi anaemia Frontometaphyseal dysplasia

Page

(p. 319 in Bent bone dysplasia)

(p. 156 in Atelosteogenesis type 1) (p. 111 in Diastrophic dysplasia)

(p. 176 in Metatropic dysplasia)

(p. 249 in Spondyloepimetaphyseal dysplasia, NANS-related) (p. 89 in Stickler syndrome)

(p. 521 in Cerebro-costo-mandibular syndrome)

(p. 471 in Marfan syndrome)

(Continued)

651

Appendix 2: Gamuts

52

List of Signs

Skeletal Dysplasias Page Hypochondroplasia Kniest dysplasia Larsen syndrome Marfan syndrome Marshall-Smith syndrome Melnick-Needles syndrome Metatropic dysplasia Multiple pterygium syndrome Myotonic chondrodystrophy, Schwartz-Jampel syndrome OEIS complex Osteogenesis imperfecta Osteopathia striata with cranial sclerosis Otopalatodigital syndrome type 2 Paternal uniparental disomy 14 Pseudodiastrophic dysplasia (p. 111 in Diastrophic dysplasia) Pycnodysostosis Robinow syndrome Saul-Wilson syndrome Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type Spondylocostal dysostosis Spondyloepimetaphyseal dysplasia (SEMD) with immune deficiency Spondyloepimetaphyseal dysplasia (SEMD) with joint laxity, Beighton type Spondyloepimetaphyseal dysplasia (SEMD) with joint laxity, Hall type Stickler syndrome Stuve-Wiedemann dysplasia Spinal muscular atrophy (p. 382 in Zellweger syndrome ) Shprintzen-Goldberg syndrome VATER/VACTERL

Segmentation defects

Alagille syndrome Antley-Bixler syndrome Atelosteogenesis, all types Casamassima-Morton-Nance syndrome Chondrodysplasia punctata group Diaphanospondylodysostosis Femoral facial syndrome Gollop-Wolfgang complex Hemifacial microsomia Klippel-Feil anomaly Larsen syndrome Multiple pterygium syndrome Neural tube defects Sirenomelia Spondylocostal dysostosis Spondylothoracic dysostosis VATER/VACTERL association

(p. 517 in Spondylocostal dysostosis)

Acrodysostosis Astley-Kendall dysplasia CHILD syndrome

(p. 286 in Brachydactyly type B)

Stippling

Chondrodysplasia punctata group Chromosomal anomalies Congenital hypothyroidism Dappled diaphyseal dysplasia

(p. 517 in Spondylocostal dysostosis)

(p. 531 in VATER) (p. 517 in Spondylocostal dysostosis)

(p. 517 in Spondylocostal dysostosis)

(p. 357 in Chondrodysplasia punctata, Conradi-Hünermann type) (p. 386 in Astley-Kendall dysplasia) (p. 375 in Warfarin embryopathy) (p. 371 in Greenberg dysplasia) (Continued)

652

Appendix 2: Gamuts List of Signs

Skeletal Dysplasias de Lange syndrome Disruption of vitamin K metabolism Fetal alcohol syndrome Fetal exposure to hydantoin Fibrochondrogenesis GM1-gangliosidosis type 2 Greenberg dysplasia Keutel syndrome Maternal Sjögren syndrome Maternal systemic lupus erythematosus Mucolipidosis 2 (I-cell disease) Smith-Lemli-Opitz syndrome Trisomy 18 Trisomy 21 Warfarin embryopathy Zellweger syndrome

53

Syndactyly

Acrofacial dysostosis Nager type Acro-fronto-facio-nasal dysostosis Acromelic frontonasal dysostosis Apert syndrome Atelosteogenesis type 1 and 3 Bloom syndrome Brachydactyly type B Brachydactyly, Temtamy type Carpenter syndrome Cenani-Lenz syndactyly syndrome Cephalopolysyndactyly syndrome (Greig) Hyperphalangism characteristic facies-hallux valgusbronchomalacia, Chitayat syndrome Chondroectodermal dysplasia (Ellis van Creveld) Craniofrontonasal dysplasia Cranioectodermal dysplasia (Sensenbrenner syndrome) de Lange syndrome Feingold syndrome Femur-fibula-ulna complex Fuhrmann syndrome Gollop-Wolfgang complex Holt-Oram syndrome Kaufman-McKusick syndrome Lenz-Majewski hyperostotic dysplasia Neu Laxova syndrome Oculo-dento-digital dysplasia Oral-facial-digital syndrome type 1 Oral-facial-digital syndrome type 2 Oral-facial-digital syndrome type 4 Osteopathia striata with cranial sclerosis Otopalatodigital syndrome type 2 Pallister-Hall syndrome Pfeiffer syndrome Piepkorn dysplasia Poland syndrome Proteus syndrome Roberts syndrome Robinow syndrome Sclerosteosis Sethre-Chotzen syndrome

Page (p. 386 in Astley-Kendall dysplasia) (p. 338 in Microcephalic primordial dwarfism type 1/3) (p. 378 in Maternal systemic lupus erythematosus) (pp. 352–375 in Chondrodysplasia punctata group) (p. 286 in Brachydactyly type B) (p. 375 in Warfarin embryopathy)

(pp. 352–375 in Chondrodysplasia punctata group) (p. 141 in Meckel syndrome) (p. 141 in Meckel syndrome)

(p. 514 in Acromelic frontonasal dysostosis)

(p. 573 in Fanconi anaemia)

(p. 576 in Split hand-foot malformation)

(p. 491 in Pfeiffer syndrome)

(p. 531 in VATER/VACTERL association) (p. 546 in Al-Awadi Raas-Rothschild)

(p. 591 in Cerebroarthrodigital syndrome) (p. 333 in Hallermann-Streiff syndrome) (p. 583 in Cephalopolysyndactyly syndrome [Greig]) (p. 209 in Oral-facial-digital syndrome type 4)

(p. 156 in Atelosteogenesis type 1) (p. 573 in Fanconi anaemia)

(p. 421 in Osteopathia striata with cranial sclerosis) (p. 491 in Pfeiffer syndrome) (Continued)

653

Appendix 2: Gamuts List of Signs

54

Synostosis

Skeletal Dysplasias Short rib-polydactyly syndrome type 2 Smith-Lemli-Opitz syndrome Split hand-foot malformation Tibial hemimelia-polydactyly-triphalangeal thumb Mirror-image polydactyly of hands and feet Trisomy 18 VATER/VACTERL association Yunis-Varon dysplasia Achondroplasia Acrofacial dysostosis, Nager type Al-Awadi/Raas-Rothschild limb/pelvis-hypoplasia/aplasia Antley-Bixler syndrome Apert syndrome Atelosteogenesis type 1 and 3 Baller-Gerold syndrome Beare-Stevenson cutis gyrata syndrome Bent bone dysplasia Boomerang dysplasia Brachydactyly type B Carpenter syndrome CDAGS syndrome Cenani-Lenz syndrome Cephalopolysyndactyly syndrome (Greig) Cerebro-osseous-digital syndrome Chondroectodermal dysplasia (Ellis van Creveld) Cousin syndrome Craniofrontonasal dysplasia Cranioectodermal dysplasia (Sensenbrenner syndrome) de Lange syndrome Femoral facial syndrome Femur-fibula-ulna complex Fluconazole embryopathy Frontometaphyseal dysplasia Gollop-Wolfgang complex Gorlin-Chaudhry-Moss syndrome Holt-Oram syndrome Hyperphalangism-hallux valgus-bronchomalacia Chitayat Hypophosphatasia Larsen syndrome Mesomelic dysplasia, Kozlowski-Reardon type Mesomelic dysplasia, Kantaputra type Mirror-image polydactyly of hands and feet Muenke syndrome Multiple joint dislocations, short stature, craniofacial dysmorphisms and skeletal dysplasia, B3GAT3-related Multiple pterygium syndrome Nievergelt dysplasia Osteocraniostenosis Osteogenesis imperfecta with craniosynostosis, ColeCarpenter syndrome Osteopathia striata with cranial sclerosis Pfeiffer syndrome Proteus syndrome Pycnodysostosis Raine dysplasia Roberts syndrome Saethre-Chotzen syndrome

Page (p. 375 in Warfarin embryopathy)

(p. 217 in Meckel syndrome)

(p. 491 in Pfeiffer syndrome) (p. 507 in Carpenter syndrome)

(p. 482 in Cleidocranial dysplasia) (p. 576 in Split hand-foot malformation)

(p. 491 in Pfeiffer syndrome)

(p. 500 in Antley-Bixler syndrome)

(p. 342 in Saul-Wilson syndrome)

(p. 270 in Langer type [homozygous dyschondrosteosis]) (p. 517 in Spondylocostal dysostosis)

(p. 283 in Grebe dysplasia)

(p.491 in Pfeiffer syndrome) (Continued)

654

Appendix 2: Gamuts List of Signs

Skeletal Dysplasias Shprintzen-Goldberg syndrome Split hand-foot malformation Spondylocarpotarsal synostosis syndrome Spondylo-epiphyseal-metaphyseal dysplasia with immune deficiency and ID, EXTL3-related Thanatophoric dysplasia Tibial hemimelia-polydactyly-triphalangeal thumb Trisomy 13 VATER/VACTERL association

55

Symphysis pubis, wide

Larsen syndrome Schinzel-Giedion syndrome

56

Talipes

Achondrogenesis type 1A Acrofacial dysostosis, Nager type Acromelic frontonasal dysostosis Amniotic band sequence Atelosteogenesis, all types Boomerang dysplasia Brachydactyly type C Campomelic dysplasia Carpenter syndrome Catel-Manzke syndrome Caudal regression sequence Cerebro-costo-mandibular syndrome (rib gap syndrome) Chondroectodermal dysplasia (Ellis van Creveld) Congenital disorder of glycosylation type IIg Crane-Heise syndrome Desbuquois dysplasia Diastrophic dysplasia Dyssegmental dysplasia Femoral facial syndrome Fibrochondrogenesis Kniest dysplasia Larsen syndrome Lethal neonatal short limb dysplasia (Al Gazali, 1996) Meckel syndrome Mirror-image polydactyly of hands and feet Multiple epiphyseal dysplasia autosomal recessive Multiple pterygium syndrome Myotonic chondrodystrophy, Schwartz-Jampel syndrome Nievergelt dysplasia OEIS complex Oral-facial-digital syndrome type 4 Osteopathia striata with cranial sclerosis Osteopetrosis Otospondylomegaepiphyseal dysplasia Pfeiffer syndrome Pseudodiastrophic dysplasia Richieri-Costa-Pereira syndrome Saul-Wilson syndrome Schinzel-Giedion syndrome Shprintzen-Goldberg syndrome Sirenomelia Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type SEMD with joint laxity (SEMD-JL, Beighton type) Spondyloepiphyseal dysplasia congenita Stuve-Wiedemann syndrome

Page

(p. 151 in Larsen syndrome)

(p. 217 in Meckel syndrome)

(p. 573 in Fanconi anaemia)

(p. 560 in Femoral facial syndrome)

(p. 521 in Cerebro-costo-mandibular syndrome) (p. 482 in Cleidocranial dysplasia)

(p. 111 in Diastrophic dysplasia)

(p. 283 in Grebe dysplasia)

(p. 108 in Atelosteogenesis type 2) (p. 510 in Acrofacial dysostosis, Nager type)

(Continued)

655

Appendix 2: Gamuts List of Signs

57

Thorax Ribs, short

Scapular anomalies

Skeletal Dysplasias Tibial agenesis-polydactyly syndrome Trisomy 13 Trisomy 18 Zellweger syndrome Achondrogenesis all types Asphyxiating thoracic dysplasia (Jeune) Astley-Kendall dysplasia Blomstrand dysplasia Chondroectodermal dysplasia (Ellis van Creveld) Cranioectodermal dysplasia (Sensenbrenner syndrome) Congenital hypothalamic hamartoma syndrome Diaphanospondylodysostosis Dyssegmental dysplasia Fibrochondrogenesis Greenberg dysplasia Homozygous achondroplasia Hypochondrogenesis Hypophosphatasia Kyphomelic dysplasia Lethal neonatal short limb dysplasia (Al Gazali, 1996) Metaphyseal dysplasia with pancreatic insufficiency (Shwachman-Diamond syndrome) Metatropic dysplasia Opsismodysplasia Paternal uniparental disomy 14 Piepkorn dysplasia Platyspondylic dysplasia, Torrance type Short rib-polydactyly syndrome all types Spondyloepimetaphyseal dysplasia, short limb-abnormal calcification type Thanatophoric dysplasia Thoracolaryngopelvic dysplasia (Barnes) Pycnodysostosis Raine dysplasia Schneckenbecken dysplasia Yunis-Varon dysplasia Achondrogenesis, all types Antley-Bixler syndrome Astley-Kendall dysplasia Caffey disease, COL1A1-related Campomelic dysplasia Chondrodysplasia punctata, X-linked dominant Cousin syndrome Crane-Heise syndrome Dysplastic cortical hyperostosis, Kozlowski-Tsuruta type Femoral facial syndrome Greenberg dysplasia Holt-Oram syndrome Kyphomelic dysplasia Osteogenesis imperfecta Osteopathia striata with cranial sclerosis Scapulo-iliac-dysostosis Schneckenbecken dysplasia Spondylometaphyseal dysplasia, Sedaghatian type Thanatophoric dysplasia

Page (p. 217 in Meckel syndrome) (p. 217 in Meckel syndrome)

(p. 587 in Pallister-Hall syndrome)

(p. 156 in Atelosteogenesis type 1)

(p. 482 in Cleidocranial dysplasia)

(p. 302 in Campomelic dysplasia)

(Continued)

656

Appendix 2: Gamuts List of Signs

Skeletal Dysplasias Raine dysplasia Short rib-polydactyly syndrome type 4 Stuve-Wiedemann syndrome

Small (short trunk, hypoplasia of thorax/lungs)

Achondrogenesis, all types Achondroplasia Antley-Bixler syndrome Asphyxiating thoracic dystrophy (Jeune) Astley-Kendall dysplasia Atelosteogenesis, all types Blomstrand dysplasia Boomerang dysplasia Caffey disease (including infantile and attenuated forms) Caffey disease (severe lethal variant) Campomelic dysplasia with congenital joint dislocations, recessive Larsen syndrome Cerebroarthrodigital syndrome Cerebro-costo-mandibular syndrome (rib gap syndrome) Cerebro-osseous-digital syndrome Chondrodysplasia punctata group Chondrodysplasia Chondroectodermal dysplasia (Ellis van Creveld) Cranioectodermal dysplasia (Sensenbrenner syndrome) Cumming syndrome Desbuquois dysplasia Diaphanospondylodysostosis Diastrophic dysplasia Dysplastic cortical hyperostosis (Kozlowski-Tsuruta) Dyssegmental dysplasia Greenberg dysplasia Femoral hypoplasia unusual facies syndrome Fetal akinesia sequence Fibrochondrogenesis Frontometaphyseal dysplasia Fryns syndrome Homozygous achondroplasia Hypophosphatasia Kniest dysplasia Kyphomelic dysplasia Larsen syndrome Lethal neonatal short limb dysplasia (Al Gazali, 1996) Limb reduction syndrome, Al-Awadi/Raas-Rothschild limb/ pelvis-hypoplasia/aplasia Maternal systemic lupus erythematosus Mesomelic dysplasia, Kozlowski-Reardon type Metatropic dysplasia Mucolipidosis 2 (I-cell disease) Multiple pterygium syndrome Omodysplasia, recessive type Opsismodysplasia Oral-facial-digital syndrome type 4 Osteodysplasty, Melnick-Needles Osteogenesis imperfecta Otopalatodigital syndrome type 2 Paternal uniparental disomy 14 Platyspondylic dysplasia, Torrance type

Page

(p. 217 in Meckel syndrome)

(p. 605 in Multiple pterygium syndrome)

(p. 504 in Shprintzen-Goldberg syndrome)

(Continued)

657

Appendix 2: Gamuts List of Signs

Skeletal Dysplasias Raine dysplasia Schneckenbecken dysplasia Shprintzen-Goldberg syndrome Short rib-polydactyly syndrome, all types Metaphyseal dysplasia with pancreatic insufficiency (Shwachman-Diamond syndrome) Spondylocostal dysostosis Spondyloepimetaphyseal dysplasia (SEMD), Strudwick type Spondyloepiphyseal dysplasia congenita Spondyloepiphyseal metaphyseal dysplasia with immune deficiency Spondylothoracic dysostosis Tetra-amelia Thanatophoric dysplasia Thoracolaryngopelvic dysplasia (Barnes) VATER/VACTERL association

58

Trident acetabula

Achondroplasia Asphyxiating thoracic dysplasia (Jeune) Chondroectodermal dysplasia (Ellis van Creveld) Homozygous achondroplasia Short rib-polydactyly syndrome type 1/3 Thanatophoric dysplasia

59

Trident hand

Achondroplasia and homozygous achondroplasia Acrodysostosis Asphyxiating thoracic dystrophy (Jeune) Chondroectodermal dysplasia Odontochondrodysplasia Short rib-polydactyly syndromes Thanatophoric dysplasia Aase syndrome Acrofacial dysostosis, Nager type Cook syndrome Fanconi anaemia Holt-Oram syndrome Mirror-image polydactyly of hands and feet (LaurinSandrow), SHH-related Tibial hemimelia-polysyndactyly-triphalangeal thumb (Werner syndrome), ZRS-related Townes-Brocks syndrome VATER/VACTERL association

60

61

Triphalangeal thumb

Wormian bones

Astley-Kendall dysplasia Cerebro-hepato-renal (Zellweger) syndrome Cleidocranial dysplasia Dysplastic cortical hyperostosis, Al-Gazali type Hajdu-Cheney syndrome Hallermann-Streiff syndrome Menkes disease Neonatal hypothyroidism Osteogenesis imperfecta Osteogenesis imperfecta with craniosynostosis (Cole-Carpenter syndrome) Pycnodysostosis Saul-Wilson syndrome

Page

(p. 510 in Acrofacial dysostosis, Nager type)

(p. 266 in Opsismodysplasia)

(p. 573 in Fanconi anaemia) (p. 286 in Brachydactyly type B)

(p. 531 in VATER)

(p. 375 in Warfarin embryopathy)

Index Note: Locators in italics represent figures and bold indicate tables in the text. 3D VR, 17 3M syndrome, 325, 326, 638, 648, 650 22q11.2 deletion syndrome, 89, 522, 532, 537 Aarskog syndrome, 277 Aase syndrome, 14, 574, 620, 629, 657 Abdomen, large, 220; see also Prominent abdomen Abdominal distension, 529, 599 Abdominal wall defects, 609 Aberrant sulci, 39 Absent/deficient fibula, 157, 159 Absent thumbs and Roberts syndrome, 550 and Yunis-Varon dysplasia, 488, 489 Acanthosis nigricans, 54 Acetabula, 76; see also Trident acetabula failure of development, 546 horizontal, 67, 148, 176, 260, 591 shallow, 302 in skeletal survey, 19 sloping, 82, 83–86, 110, 315 spurs on, 50, 166, 206, 262, 266 Acetabular constrictions, 489 Acetabular hypoplasia, 560 Acetabular roofs crescent-shaped, 59 horizontal, 54, 59, 68, 338 Acetylcholine receptor (AChR), 605 Acheiropody, 546, 631 Achondrogenesis, 70 all types, 616, 625, 632, 636, 638, 641, 642, 644, 645, 648, 649, 655, 656 identifying, 14 and narrow thorax, 182, 186 and small thorax, 14 type 1, 649 type 1A, 256, 257–259, 633, 638, 640, 645, 654 type 1B, 105, 105–106 type 2, 58–65, 59–65, 82, 89, 620, 634, 640, 643, 645, 648 Achondroplasia, 14, 15, 32, 46–47, 47–52, 617, 619, 632, 633, 634, 636, 637, 641, 647, 649, 653, 656, 657 homozygous, 37, 46, 54 Achondroplasia and homozygous achondroplasia, 657 Acrocallosal syndrome, 514, 583, 588, 618, 629, 637, 643 Acrocephalosyndactylies, 14, 507 Acrodysostosis, 266, 619, 634, 641, 651, 657 Acrofacial dysostosis, 644 Nager type, 510–511, 617, 620, 622, 623, 624, 627, 628, 629, 634, 638, 640, 641, 643, 644, 645, 646, 647, 652, 653, 654, 657 Rodriguez type, 510, 574, 622

Acro-fronto-facio-nasal dysostosis, 652 Acromelic/acromesomelic limb shortening, 616 Acromelic dysplasia, 616 Acromelic frontonasal dysostosis, 514, 515, 616, 618, 619, 620, 626, 629, 632, 633, 638, 643, 652, 654 Acromesomelic dysplasia, 266, 283, 616, 641 Hunter-Thompson type, 626, 638 Maroteaux type, 635, 638 Acromesomelic shortening, 212 Acromicric dysplasia, 616, 641 Acro-osteolysis, 395, 482 Acro-renal-ocular syndrome, 628, 645 Adams-Oliver syndrome, 577, 622 ADPKD, 646 Adrenoleukodystrophy, neonatal, 382 Advanced skeletal maturation, 616 AEC, 620 AEG syndrome, 532 AER (apical ectodermal ridge), 4 AKT1, 478 Alagille syndrome, 518, 622, 648, 651 type 2, 468 Al-Awadi Raas-Rothschild Limb-Pelvis Hypoplasia-Aplasia, 546, 634, 635, 641, 643, 653 Al-Awadi Raas-Rothschild syndrome, 283, 511, 546, 547, 551, 631, 638, 643, 652 Alcohol, fetal exposure to, 376, 383; see also Fetal alcohol syndrome ALPL, 452 Ambiguous genitalia and Meckel syndrome, 217 and OEIS complex, 608 and SRPS, 182, 186 Amelia, 511, 537, 551, 596 Amniocentesis, 32 Amniotic bands/disruption sequence, 574, 619, 620, 654 Amniotic band syndrome, 218 Amniotic fluid, high volume of, 17, 576 Amyoplasia, 605 Anaemia aplastic, 224 Anal atresia differential diagnosis of, 531 and DK phocomelia, 596 and OEIS complex, 608 and SRPS, 182 Anal malformations, and osteopathia striata, 421; see also Imperforate anus Anauxetic dysplasia, 224, 635 Anencephaly, 191, 217 Aneuploidy, 14 Aneurysms, 137, 504 Angulated/bent/bowed bones, 616

Angulated femora and campomelic dysplasia, 303 dislocated, 306 Angulated tibiae and Astley-Kendall dysplasia, 387 and campomelic dysplasia, 303 and osteogenesis imperfecta, 431, 432, 437 Anhydramnios, 568 Anisospondyly, 19, 64, 73, 74, 78, 166, 167 and dyssegmental dysplasia, 167, 170 Ankles, joint limitation at, 137 Anophthalmia, 191, 217 Anophthalmia-oesophageal-genital syndrome, 630 Anorectal atresia, 531 Anterior cranial fossa, 101, 501, 502, 503 Anterior cupping, 67, 95, 179 Anterior fontanelle, 395 in kyphomelic dysplasia, 338 large, 148, 266, 382, 452, 583, 611 open, 156, 333 wide, 403, 489 Anterior ribs prominent, 229 wide, 121 Anteverted nares, 542 Anteverted nostrils and achondrogenesis, 58, 256 and CED, 212 and de Lange syndrome, 540 and fibrochondrogenesis, 95 and Kniest dysplasia, 82 and omodysplasia, 273 and opsismodysplasia, 266 and OSMED, 98 and SLE, 378 and SRPS, 187 and Stickler syndrome, 89 Antley-Bixler syndrome, 311, 492, 496, 500–501, 501–503, 548, 560, 616, 619, 620, 622, 623, 624, 626, 627, 629, 631, 633, 634, 636, 646, 648, 651, 653, 655, 656 Aorta, coarctation of, 338, 464 Aortic dilatation, 471 Aortic valve prolapse, 471 Apert syndrome, 14, 492, 496–498, 497–498, 618, 619, 620, 626, 629, 630, 633, 644, 646, 652, 653 Aplasia cutis, 577 Apnoea obstructive, 121 and Schinzel-Giedion syndrome, 611 Aqueduct of Sylvius, 507 Arachnodactyly, 471, 500, 501, 502, 503, 505–506 Arachnoid cysts, 611 Arnold-Chiari malformations, 218, 504, 608

659

660 AROS (acro-renal-ocular syndrome), 536–537 Array comparative genomic hybridisation (aCGH), 31 Arrhythmias, 262, 536 Arrythmia, conduction defect, 623 Arteries spontaneous rupture of, 152 Arthritis early-onset, 89 and SEDC, 73 Arthrogryposis and cerebroarthrodigital syndrome, 591 and DTD, 111 multiplex congenital, 21, 624 Arthropathy, 89 Ascertain craniosynostosis, 323 Ascites and Blomstrand dysplasia, 464 and dyssegmental dysplasia, 166 and Greenberg dysplasia, 371 and SRPS, 187 Asphyxiating thoracic dysplasia (Jeune), 616, 617, 636, 638, 643, 644, 645, 646, 647, 655, 656, 657 Asplenia, see Spleen, absent Asthenic build, 222 Astley-Kendall dysplasia, 386, 387, 616, 633, 642, 644, 648, 649, 651, 652, 655, 656, 657 Asymmetry, 617 Atelosteogenesis all types, 640, 642, 644, 645, 647, 648, 649, 650, 651, 654, 656 other types of, 108 type 1, 162, 620, 626, 631, 632, 636, 643, 650, 652, 655 type 1 and 3, 617, 629, 631, 632, 648, 652, 653 type 2, 108–110, 109–110, 620, 626, 638, 641, 645, 648, 654 type 3, 162, 163–165, 620, 626 Atlanto-occipital fusion, 163 ATP7A, 602–603 Atrial fibrillation, 536 Atrial septal defect, 203, 262, 338, 536, 568 Atrioventricular canal defects, 141 Atrioventricular septal defect (AVSD), 207, 209 ATRX, 629, 631 Auditory canals atretic, 191 stenotic, 500 Auricular cartilage, hypertrophic, 111 Autism, 295, 541 Babygram, 18 Baller-Gerold syndrome, 492, 496, 500, 507, 511, 541, 550, 574, 616, 626, 629, 645, 653 Bannayan-Riley-Ruvalcaba syndrome, 479, 637 Bardet-Biedl syndrome, 14, 588, 599–560, 643, 646 Bartsocas-Papas syndrome, 606, 620 Basilar invagination, 430 Beare-Stevenson cutis gyrata, 398, 496, 500, 626, 634, 653

Index Beckwith-Wiedemann syndrome, 609, 631, 646 Bent bone dysplasia, 319, 320–323, 616, 617, 622, 625, 626, 627, 629, 631, 632, 633, 642, 644, 648, 650, 653 BHLHA9, 577 Biconvex, 243 Bicoronal synostosis, 496, 507 Bilateral calcaneovalgus in atelosteogenesis, 163 Bilateral equinovarus, 21 and atelosteogenesis, 110 Bilateral fixed flexion deformities, 315 Bilateral hip dislocation, 561 Bilateral knee dislocated, 122 Bilateral pleural effusion, 187 Bilateral postaxial polydactyly, 197 Bilateral short femora, 122 Bilateral talipes, 74, 204 Bilateral talipes equinovarus, 308 and campomelic dysplasia, 308 and chondroectodermal dysplasia, 206 and dyssegmental dysplasia, 167 and femoral facial syndrome, 561 and kyphomelic dysplasia, 315 and multiple pterygium syndrome, 606 and Schinzel-Giedion syndrome, 613 Bile duct proliferation, 196 Biliary dysgenesis, 217 Biometric measurements, 615 Biparietal diameter (BPD) and hypochondroplasia, 54 measuring, 14 Bitemporal narrowing, 376, 611 Bladder diverticula, 537, 602–603 exstrophy, 608 neuropathic, 602 non-visualised, 608 Blepharophimosis, 339 Blindness, 389, 399, 602; see also Visual impairment Blomstrand dysplasia, 464, 465, 616, 623, 625, 631, 638, 640, 641, 642, 644, 645, 649, 655, 656 Bloom syndrome, 574, 639, 643, 652 Blue sclerae and ostogenesis imperfecta, 429 BMP (bone morphogenetic protein), 4, 5, 298 BMP1, 430 BMPER, 524–525 BMPR1A, 5 Bone cell differentiation, 1 Bone density, 331 in cleidocranial dysplasia, 482–483 decreased, 212, 431 increased, 330–331, 404, 416, 426, 464 Bone disease, diagnosing, 13 Bone dysplasia, 1 Bone fragility, 430 Bone growth, 1 Bone marrow failure, 388, 573 Bone softening, 440 Bony defect, 515

Boomerang dysplasia, 156–157, 161, 162, 619, 620, 629, 631, 632, 633, 636, 640, 641, 642, 644, 645, 648, 653, 654, 656 Bowed bones, differential diagnosis of, 232 Bowed femora, 561 and achondroplasia, 46 and Antley-Bixler syndrome, 500 and campomelic dysplasia, 302, 309 and cartilage-hair hypoplasia, 224 and dyssegmental dysplasia, 166 and femoral facial syndrome, 560 and Jeune syndrome, 198 and kyphomelic dysplasia, 313 and Marfan syndrome, 471 and mucolipidosis, 350 and OFDS, 209 and osteogenesis imperfecta, 429, 431, 441 and Schinzel-Giedion syndrome, 612 short, 36, 436, 455, 561–564, 566 Stuve-Wiedemann syndrome, 312 and TD, 36, 39, 200 Bowed humeri and CED, 213 and chondroectodermal dysplasia, 203, 204 and mesomelic dysplasia, 282 Bowed long bones and atelosteogenesis, 149 and boomerang dysplasia, 156 and Caffey disease, 408 and CED, 212 and chondroectodermal dysplasia, 203 differential diagnosis of, 37, 411, 500 and dysosteosclerosis, 398 and dyssegmental dysplasia, 166 and FMD, 139 and frontometaphyseal dysplasia, 137 and hypophosphatasia, 452, 455 and Kniest dysplasia, 82 and kyphomelic dysplasia, 313, 318 and Marfan syndrome, 471 and Meckel syndrome, 217 and Melnick-Needles syndrome, 144 and mesomelic dysplasia, 281 and neonatal hyperparathyroidism, 458 and OPD1, 145 and OPD2, 148 and osteogenesis imperfecta, 429, 438 and Schinzel-Giedion syndrome, 611 and Schneckenbecken dysplasia, 260 and Shprintzen-Goldberg syndrome, 504 and SRPS, 193 and Stuve-Wiedemann dysplasia, 311 Bowed radii, 214 Bowed tibiae, 37, 139 in boomerang dysplasia, 156 and Caffey disease, 408 and FFU syndrome, 566 and FMD, 139 and kyphomelic dysplasia, 313 and osteogenesis imperfecta, 431, 440, 441 and osteopathia striata, 422 short, 566 and sirenomelia, 568 Stuve-Wiedemann syndrome, 311 Bowed ulnae and Antley-Bixler syndrome, 500–501 and Apert syndrome, 496

661

Index and Blomstrand dysplasia, 464 and boomerang dysplasia, 156 and Hallerman-Streiff syndrome, 333 and Pfeiffer syndrome, 492 and SRDS, 191 Bowel malrotation, and OFDS, 209 Brachycephaly, 502 and Antley-Bixler syndrome, 500 and Caffey disease, 411 and de Lange syndrome, 540 detection of, 14, 17, 19 and mucolipidosis, 348 and Pfeiffer syndrome, 491, 492–494 and Raine dysplasia, 404 and Roberts syndrome, 550 and Schinzel-Giedion syndrome, 611, 612–613 and Shprintzen-Goldberg syndrome, 504 Brachydactyly, 247, 617 and achondroplasia, 46, 48, 49, 52 and Carpenter syndrome, 507 and cartilage-hair hypoplasia, 224 and Catel-Manzke syndrome, 293 and CED, 212 and DTD, 111 dysplasia, 426 and hypochondroplasia, 54 and Jeune syndrome, 196 and opsismodysplasia, 212 and osteocraniostenosis, 328 and spondylometaphyseal dysplasia, 262 and spondyloperipheral dysplasia, 89 and SRPS, 182, 186 and TD, 36, 37 Temtamy type, 298, 617, 618, 620, 627, 629, 634, 640, 652 and trident hand, 37 type A, C, E, 617 type B, 286, 617, 618, 619, 623, 627, 629, 634, 647, 650, 651, 652, 653, 657 type C, 288, 617, 636, 654 type D, 617 and warfarin embryopathy, 375 Brachyo-oto-renal syndrome, 634 Brachyphalangy, polydactyly and tibial aplasia syndrome, 617 Brachytelephalangy, 286, 380 Brain, postmortem examination of, 19 Brain anomalies, 209 corpus callosum anomalies, 618 differential diagnosis of, 209 and DK phocomelia, 596 and OFDS, 209 and OPD2, 148 and Shprintzen-Goldberg syndrome, 504 and spondyloepimetaphyseal dysplasia, 81 and SRPS, 186, 191 and TD, 36 Brain atrophy, 602 Brain stem abnormalities, 388 compression, 430 hypoplasia, 36 Branchial arches, 4 Branchio-oto-renal syndrome (BOR), 617 Breasts, absent, 464 Broad-based nose, 187

Broad ilia, 99 and dyssegmental dysplasia, 168 Broad thorax, 100 Broad thumbs associated syndromes, 14 and brachydactyly type B, 286 and Carpenter syndrome, 507 and cleidocranial dysplasia, 482 and Greig syndrome, 583 and Pfeiffer syndrome, 491 Bronchomalacia, 300 Bruck syndrome, 430, 447, 448, 616, 624, 629, 633, 640, 642, 644, 648, 649, 650 Brushfield spots, 382 C7ORF2, 546 Café au lait spots, 573 Caffey disease (severe lethal variant), 19, 408, 409, 616, 617, 625, 629, 631, 632, 640, 642, 644, 645, 650, 655, 656 Calcanei, 101, 102 Calcaneovalgus, bilateral, 163 Calcaneum, 79 Callus, hyperplastic, 429 Callus formation, 386, 429 Calvarial mineralisation, 19, 453 Calvarium absent, 436 hyperostosis of, 478 hypomineralization of, 436 premature ossification of, 496 Campomelic dysplasia, 302, 303–310, 616, 620, 622, 625, 626, 631, 632, 634, 636, 637, 640, 641, 642, 646, 648, 649, 650, 654, 655, 656 and long bones, 37 and narrow thorax, 182, 186 prognosis for, 16 Camptodactyly and Antley-Bixler syndrome, 500 and atelosteogenesis, 162 and brachydactyly Temtamy type, 298 and Carpenter syndrome, 507 differential diagnosis of, 13 and mesomelic dysplasia, 281 and multiple pterygium syndrome, 605 and OFDS, 210 and OPD2, 148 and Shprintzen-Goldberg syndrome, 504 in skeletal survey, 19 and Stuve-Wiedemann dysplasia, 311 and Zellweger syndrome, 382 CANT1, 121 Capital femoral epiphyses advanced ossification of, 197, 205 avascular necrosis of, 288, 311 rounded, 482 Capitate-hamate fusion, 502, 503 Caput membranaceum, 452 Cardiac anomalies, 148 Cardiac conduction defect, 536–537 Cardiac defects, see Heart defects Cardiac valve defects and Pallister-Hall syndrome, 587 Cardiac valves, insufficiency of, 348, 471 Cardiac valvular dystrophy, myxomatous, 145 Cardioacrofacial dysplasia, 617, 623, 643

Cardiomegaly, 471, 538 Cardiomyopathy, 286, 623 Cardiothoracic ratio, 14 Carpal bone maturation, 200, 201 Carpal bones advanced ossification of, 464 in chondroectodermal dysplasia, 203 delayed ossification, 176 erosion of, 137 in OPD1, 145 stippling of, 378 third row of, 536 Carpal fusions, 502 and Antley-Bixler syndrome, 500 and brachydactyly Temtamy type, 298 and Holt-Oram syndrome, 536 and OPD1, 145 and Osebold-Remondini dysplasia, 270 and split hand-foot malformation, 577 Carpal synostosis, 546 Carpenter syndrome, 14, 507, 508–509, 583, 617, 618, 619, 622, 623, 626, 627, 629, 631, 632, 634, 635, 643, 644, 646, 650, 652, 653, 654 Carpometacarpal joints, 496 Cartilage, triradiate, 382 Cartilage-hair hypoplasia (CHH), 224, 225– 228, 464, 617, 635, 636, 638, 649 Casamassima-Morton-Nance syndrome, 518, 651 CASR, 457 Cataracts and cerebro-osseous-digital syndrome, 593 congenital, 73, 333 and Fanconi anaemia, 573 and fibrochondrogenesis, 95 and Kniest dysplasia, 82 and Marfan syndrome, 471 and osteocraniostenosis, 328 and Raine dysplasia, 403 and Rubinstein-Taybi syndrome, 295–296 and Stickler syndrome, 89 and warfarin embryopathy, 375 Catel-Manzke syndrome, 293, 294, 617, 620, 622, 626, 627, 628, 629, 636, 640, 650, 654 Cat-eye syndrome, 628, 634 Caudal regression sequence, 654 Caudal regression syndrome, 634 CCDC9, 325 CCGE, 620, 622, 634 CDAGS syndrome, 483, 626, 633, 653 CDP tibia-metacarpal type, 638 Cellular proliferation, 1 Cenani-Lenz syndactyly syndrome, 577, 652, 653 Central ray defects, 576 Cephalohaematomas, 602 Cephalopolysyndactyly syndrome (Greig), 618, 619, 629, 632, 633, 637, 643, 652, 653 Cerebellar atrophy, 375, 602 Cerebellar dysgenesis, 217 Cerebellar hypoplasia and Carpenter syndrome, 507 and OPD2, 148 and Rubinstein-Taybi syndrome, 295 Cerebellar vermis, see

662 Cerebellum, small, 403 Cerebral anomalies and CCM syndrome, 521 and Greig syndrome, 583 and Schinzel-Giedion syndrome, 611 Cerebral atrophy, 95, 209, 611 Cerebral heterotopias, 521 Cerebral mantle, 42, 388 Cerebral vessels, corkscrew appearance, 602 Cerebroarthrodigital syndrome, 591, 591–592, 619, 622, 624, 626, 630, 631, 632, 637, 639, 642, 644, 645, 648, 649, 652, 656 Cerebro-costo-mandibular (CCM) syndrome, 16, 521–522, 522–523, 618, 625, 627, 635, 647, 648, 650, 654 Cerebro-hepato-renal syndrome (Zellweger syndrome), 618, 619, 620, 623, 625, 640, 646, 657 Cerebro-osseous-digital syndrome, 593–594, 593–594, 616, 624, 625, 626, 627, 628, 631, 632, 634, 637, 639, 640, 641, 642, 644, 645, 648, 649, 653, 656 Cervical kyphosis, 648 and atelosteogenesis, 108, 109 and campomelic dysplasia, 302 and DTD, 111, 112–114 and Larsen syndrome, 151–152 and osteopathia striata, 421 and SEDC, 73 and spondyloepimetaphyseal dysplasia, 81 and warfarin embryopathy, 375 Cervical lymphocoele, 218, 311 Cervical spine, 71 absent ossification of, 58 fusion in, 496 instability, 157, 162, 266, 302 lateral, 18 Cervical vertebrae costal processes of, 4 CHARGE syndrome, 532, 617, 619, 620, 622, 623, 628, 634, 635, 644, 645, 646 Cheeks full, 137, 139, 348 sagging, 602 Chest; see also Thorax barrel-shaped, 60, 429, 546, 592, 593 bell-shaped, 192 broad, 518 circumference of, 14, 433, 441 lateral, 52 narrow, 74, see Narrow chest small, 192, see Small chest Chevron deformity, 111 Chiari malformation, 597, 608 Chicken drumstick appearance, 196, 200, 206, 212, 213 CHILD syndrome, 376, 622, 624, 641, 651 Chitayat (1993) hyperphalangism, 298, 300, 622, 623, 629, 633, 636 Choanal atresia and CCM syndrome, 521 and Kaufman-McKusick syndrome, 599 and Lenz-Majewski hyperostotic dysplasia, 426 and Pallister-Hall syndrome, 587 and Raine dysplasia, 403

Index and Schinzel-Giedion syndrome, 612–613 and warfarin embryopathy, 375 Choanal stenosis, 491, 496, 500, 611 Chondrocyte columns formation of, 270 Chondrocytes in DTD, 111 in fibrochondrogenesis, 95 in Kniest dysplasia, 82 large, 82 proliferation of, 166, 270 Chondrodysplasia, 117, 656 myotonic, 82 and osteoarthritis, 58, 67 Chondrodysplasia punctata (CDP), 51, 241, 636 Conradi-Hünermann type, 651 and CT, 18 due to warfarin, see Warfarin embryopathy group, 620, 621, 622, 623, 628, 632, 634, 635, 638, 639, 640, 642, 644, 647, 648, 649, 651, 652, 656 rhizomelic, 382 tibia-metacarpal type, 618 X1, 378, 650, 655 X2, 617 Chondrodysplasia with congenital joint dislocations, 623, 626, 627, 644, 648–650 Chondroectodermal dysplasia, 203, 204–208, 616, 617, 618, 620, 622, 623, 624, 629, 636, 638, 643, 652, 653, 654, 655, 656, 657 and narrow thorax, 37, 47, 176 and polydactyly, 14 and small thorax, 16 Choreoathetosis, 333 Choroid plexus cysts, 611 CHRNG, 605 Chromosomal anomalies, 651 Chromosomal breakage syndromes, 574 Chromosomal deletions, 574, 583 Chromosomes, puffing of, 552 CHST3, 117, 151 CHSY1, 298 Cisterna magna, 212, 403 Clavicles, 416, 417 absent, 482, 488 absent ossification of, 483 in Blomstrand dysplasia, 464 in Caffey disease, 314 curved, 260, 261 in dysplastic cortical hyperostosis, 416 formation of, 2 long, 317, 593, 606 normal, 24 osteolysis of, 333 pseudarthrosis of, 546 sclerotic, 426, 427 in skeletal survey, 19 slender, 328, 465 in thoracolaryngopelvic dysplasia, 222 wide, 546 Clavicular hooks, lateral, 112–114, 537, 563, 605 Clavicular hypoplasia, 482–483, 488 CLCN7, 388 Cleft lip, 620

and Al-Awadi Raas-Rothschild syndrome, 546 bilateral, 422 and Gollop-Wolfgang complex, 556 and kyphomelic dysplasia, 313, 315 and Meckel syndrome, 217 midline, 186, 187, 191, 203, 209 and Pallister-Hall syndrome, 587 and Roberts syndrome, 550, 552 and warfarin embryopathy, 375 Cleft palate, 74, 164, 189, 620 and achondrogenesis, 58, 105 and Al-Awadi Raas-Rothschild syndrome, 546 and Apert syndrome, 496 and atelosteogenesis, 108, 162, 164 and boomerang dysplasia, 156 and campomelic dysplasia, 302, 308 and Catel-Manzke syndrome, 293 and CCM syndrome, 521 and de Lange syndrome, 540 and Desbuquois dysplasia, 121, 123 and DTD, 111 and dyssegmental dysplasia, 166 and femoral facial syndrome, 560 and fibrochondrogenesis, 95 and FMD, 137 and Gollop-Wolfgang complex, 556 and Kniest dysplasia, 82 and kyphomelic dysplasia, 313, 315 and Larsen syndrome, 156 and Lenz-Majewski hyperostotic dysplasia, 426 and Meckel syndrome, 217 and mesomelic dysplasia, 281 and multiple pterygium syndrome, 605 and OPD1, 145 and OPD2, 148 and OSMED, 98 and osteopathia striata, 421 and Pallister-Hall syndrome, 587 and Raine dysplasia, 403 and Roberts syndrome, 550 and Schneckenbecken dysplasia, 260 and SEDC, 73, 74 and Shprintzen-Goldberg syndrome, 504 and Smith-Lemli-Opitz syndrome, 376 and spondyloepimetaphyseal dysplasia, 81 and SRPS, 186, 189, 191 and Stickler syndrome, 89, 90, 92 U-shaped, 566 and warfarin embryopathy, 375 and Yunis-Varon dysplasia, 488 Cleidocranial dysostosis, 632 Cleidocranial dysplasia, 2, 483–486, 618, 620, 626, 627, 633, 635, 640, 642, 645, 650, 653, 654, 655, 657 Clinodactyly and brachydactyly type C, 288 and Catel-Manzke syndrome, 293 and Holt-Oram syndrome, 536 and OFD4, 209 Clitoris, prominent, 382 Clivus steep, 146, 307 Cloacal exstrophy, 608 Cloverleaf skull, 622

663

Index Cloverleaf skull deformity, 330 and Antley-Bixler syndrome, 500 and Carpenter syndrome, 507 identifying, 14 and osteocraniostenosis, 328 and Pfeiffer syndrome, 491, 492–494 and Raine dysplasia, 403 in skeletal survey, 19 and TD, 36, 42 CLOVE syndrome, 479, 617 Clubfoot, 21, 29, 130, 134 and achondrogenesis, 106 and atelosteogenesis, 108, 162 bilateral, 110, 158 and campomelic dysplasia, 302 and CCM syndrome, 521–522 and Kniest dysplasia, 82 and mucolipidosis, 348 and OEIS complex, 608 and osteopathia striata, 421 and SEDC, 73 and spondyloepimetaphyseal dysplasia, 81 Stuve-Wiedemann syndrome, 311 Clubhands, 14, 575 Coarctation of aorta, 623 Cobra-head appearance, 105, 105, 108 Cocaine, 532 Coccyx long, 176 CODAS syndrome, 249, 648, 649 Coffin-Siris syndrome, 541, 639 COG1 gene, 521 COG4, 342 Cognitive delay, and omodysplasia, 273 Cognitive impairment, 197, 583 COL1A1, 408, 409, 430 COL1A2, 430 COL2A1 and achondrogenesis, 58–65 and Kniest dysplasia, 82 and OSMED, 58–65, 73, 74–79, 81, 82, 89 and platyspondylic dysplasia, 67, 68–71 and SEDC, 73 and spondyloepimetaphyseal dysplasia, 81 and Stickler syndrome, 58, 67, 73, 81, 82, 89, 90–93, 522 COL10A1, 55 COL11A1, 89, 95, 522 COL11A2, 98, 99–103, 522 Cole-Carpenter syndrome, 319, 450, 507, 629, 631, 633 Collar hoop sign, 46, 49 Coloboma, 295–296, 541, 628 Colon, duplicated, 608 Color Doppler, 207 Colpocephaly, 560 Columella prominent, 295 Conductive hearing loss and achondrogenesis, 58 and acrofacial dysostosis, 510 and cleidocranial dysplasia, 482 and Fanconi anaemia, 573 and Kniest dysplasia, 82 and mucolipidosis, 348 and OFDS, 209 and OPD1, 146 and OPD2, 149

and osteodysplasty, 141 and platyspondylic dysplasia, 67 and SEDC, 73 and Shprintzen-Goldberg syndrome, 504 and spondyloepimetaphyseal dysplasia, 81 and Stickler syndrome, 89 Congenital adrenal hyperplasia, 500 Congenital contractual arachnodactyly, 624, 627 Congenital disorder of glycosylation type IIg, 639, 647, 648, 650, 654 Congenital heart disease, 507, 537 Congenital heart malformation, 622 Congenital hypothalamic hamartoma syndrome, 622, 641, 655 Congenital hypothyroidism, 632, 651 Congenital limb deficiencies (CLDs), 17 diagnosis of, 17 Congenital myasthenic syndromes, 605, 624, 644 Congenital myotonic dystrophy, 383, 628 Congenital rickets, 642 Congestive heart failure, 536 Connective tissue disorders, 152, 427, 471 Connective tissue naevi, 478–479 Conotruncal cardiopathy, 89, 293, 522 Constipation, 295, 457 Contractures, 624 diagnosis of, 13 multiple, 500, 605 Stuve-Wiedemann syndrome, 311 Convolutional markings, pronounced, 137, 141, 504 Cook syndrome, 618, 657 Copy number variant (CNV) analysis, 31 Corneal opacities, 348, 375, 550 Corneal reflex, absent, 311 Cornelia de Lange syndrome, 540–541, 541–544, 617, 622, 623, 624, 625, 627, 628, 629, 633, 634, 635, 636, 640, 641 Corner spurs, 602 Coronal clefts and atelosteogenesis, 162 and Desbuquois dysplasia, 124 and dysplastic cortical hyperostosis, 416 and dyssegmental dysplasia, 166 and Kniest dysplasia, 83–87 and Larsen syndrome, 153, 156 and OPD2, 148 Coronal sutures, fusion of, 30, 49, 403, 496, 500 Coronal synostosis, 492, 496, 498, 500, 507 Corpus callosum dysgenesis of, 426 and SRPS, 191, 192 thin, 611 Corpus callosum agenesis and Apert syndrome, 496 and CCM syndrome, 521 and DK phocomelia, 596 and Greig syndrome, 583 and MOPD, 339 and osteopetrosis, 388 partial, 560 and Rubinstein-Taybi syndrome, 295 and Smith-Lemli-Opitz syndrome, 376 and spondylometaphyseal dysplasia, 262

and warfarin embryopathy, 375 and Yunis-Varon dysplasia, 488 Cortex, hyperechoic, 217 Cortical atrophy, 602 Cortical hyperostosis, 408, 411, 625 Cortical irregularity, 141, 416 Cortical thickening, 416, 427 Cortico-medullary differentiation, 217 Costal processes, 4 Costochondral junctions, 180, 204, 222 Costovertebral anomalies, 521 Cousin syndrome, 302, 311, 501, 548, 549, 616, 626, 627, 629, 633, 635, 636, 637, 653, 655 Coxa valga and CCM syndrome, 521 in cleidocranial dysplasia, 482 in Desbuquois dysplasia, 121 in FMD, 137, 138 in OPD1, 146 Coxa vara and hypochondroplasia, 55 and SEDC, 73 and spondyloepimetaphyseal dysplasia, 81 and Stuve-Wiedemann dysplasia, 311 Crane-Heise syndrome, 482, 498, 620, 627, 633, 642, 654, 655 Cranial abnormalities, 14 Cranial nerve compression, 388, 421 palsies, 398 Cranial osteosclerosis, 421 Cranial sclerosis; see also Osteopathia striata and Shprintzen-Goldberg syndrome, 142 Cranial sutures evaluation of, 13 large, 426 premature fusion of, 491, 496 wide, see Wide sutures Cranioectodermal dysplasia (CED), 197, 203, 212, 213–216, 616, 618, 626, 627, 632, 636, 638, 642, 643, 645, 646, 652, 653, 655, 656 Craniofacial anomalies and Yunis-Varon dysplasia, 488, 489 Craniofacial disproportion, 344 Craniofacial dysmorphism, 476, 500 Craniofrontonasal dysplasia, 652, 653 Craniofrontonasal syndrome, 492, 496, 500, 617, 620, 626, 629, 634 Craniometaphyseal dysplasia, 426, 643 Craniosynostosis, 30, 330, 451, 502, 626 and achondroplasia, 47 and boomerang dysplasia, 156 and Carpenter syndrome, 507 and CED, 212 differential diagnosis of, 492, 496, 500, 507 and FMD, 137 and hypophosphatasia, 452 and osteocraniostenosis, 328 and Pfeiffer syndrome, 491, 492 in postnatal imaging, 18 and Roberts syndrome, 550 sagittal, 212 and Shprintzen-Goldberg syndrome, 504 syndromic, 14, 496 and ultrasound, 17

664 Craniotubular disorders, 426 Cranium; see also Skull large, 191 soft, 440, 452 ultrasound assessment of, 17 CREBBP, 295 Crisponi syndrome, 624 Crouzon syndrome, 492, 496, 500 CRS (caudal regression syndrome), 568 CRTAP, 429, 430, 440 Cryptorchidism, 189 and Al-Awadi Raas-Rothschild syndrome, 546 and Apert syndrome, 496 and Carpenter syndrome, 507 and chondroectodermal dysplasia, 203 and de Lange syndrome, 540 and DK phocomelia, 596 and kyphomelic dysplasia, 338 and Lenz-Majewski hyperostotic dysplasia, 426 and OEIS complex, 608 and omodysplasia, 273 and Roberts syndrome, 550 and Rubinstein-Taybi syndrome, 295 and Shprintzen-Goldberg syndrome, 504 and SRPS, 189 and Zellweger syndrome, 382 CT (computerised tomography) and Kniest dysplasia, 82 and postnatal examination, 19 and TD, 37, 38, 39, 40, 41, 42, 43 use of, 17–18 CTSK, 394 CUL7, 325 Cumming syndrome, 218, 311, 616, 619, 646, 656 Cupped metaphyses, 68, 70, 179, 638 and achondrogenesis, 59, 60, 62, 256 and metatropic dysplasia, 179 and opsismodysplasia, 266, 267, 268 and platyspondylic dysplasia, 67 and Schneckenbecken dysplasia, 260 in spondylometaphyseal dysplasia, 262 Curry-Hall syndrome, 203 Curved femora, 312 Curved femur, 49 Cutis gyrata, 492, 500, 507 Cutis laxa, 602–603 Cutis marmorata, 540 CVS (chorionic villus sampling), 32, 429 CYP26B1-asssociated ABS-like disorder, 616 Cystic dysplasia, 191 Cystic-dysplastic kidneys, 187 Cystic hygroma, 625 and achondrogenesis, 58, 61, 105, 256 and de Lange syndrome, 540 and dyssegmental dysplasia, 166 and Greenberg dysplasia, 371 and multiple pterygium syndrome, 605 and SRPS, 182 Dandy-Walker malformation, 192, 619 and Meckel syndrome, 218 and OFDS, 209 and SRPS, 191, 192 and warfarin embryopathy, 375 and Yunis-Varon dysplasia, 488

Index Dappled diaphyseal dysplasia, 651 DDR2, 241 Deafness; see also Hearing loss and achondroplasia, 47 and brachydactyly Temtamy type, 298 conductive, see Conductive hearing loss and Lenz-Majewski hyperostotic dysplasia, 426 mixed, 141, 145, 149 progressive, 389 sensorineural, 82, 98, 298, 537 and split hand-foot malformation, 576 Deficiency and ID, EXTL3-related, 654 Dehydration, 457 De Lange syndrome, 540–541, 541–544, 620, 629, 630, 631, 639, 646, 652, 653 De novo mutations, 429 Dental abnormalities and brachydactyly Temtamy type, 298 and cleidocranial dysplasia, 482 and dysosteosclerosis, 398 and osteopetrosis, 389 Dental caries, 296 Dentinogenesis imperfecta, 240, 429, 430 Depressed nasal bridge and achondrogenesis, 105 and achondroplasia, 46, 47, 49 and Apert syndrome, 496 and atelosteogenesis, 108, 162, 164 and Blomstrand dysplasia, 464 and de Lange syndrome, 540, 542 and Greenberg dysplasia, 371 and Kniest dysplasia, 82 and mucolipidosis, 348 and omodysplasia, 273 and opsismodysplasia, 266 and OSMED, 98 and osteocraniostenosis, 328 and osteogenesis imperfecta, 437 and paternal uniparental disomy 14, 528 and platyspondylic dysplasia, 67 and Raine dysplasia, 403 and spondylometaphyseal dysplasia, 262 and SRPS, 182, 186 and Stickler syndrome, 89, 90 and TD, 36, 39, 41 Dermal ridges, hypoplastic, 611 Dermomyotome, 3 Desbuquois dysplasia, 121, 122–125, 616, 620, 625, 626, 629, 631, 632, 636, 638, 641, 644, 647, 648, 650, 654, 656 Desbuquois syndrome, 622, 623, 624, 636, 638, 640 Desmosterolosis, 404, 416, 620, 634, 637, 647 Developmental delay and Apert syndrome, 496 and atelosteogenesis, 162 and de Lange syndrome, 540 and dysosteosclerosis, 398 and Fanconi anaemia, 573 global, 95 and Greig syndrome, 583 and OFDS, 209 and omodysplasia, 273 and osteocraniostenosis, 328 and Pallister-Hall syndrome, 587 and paternal uniparental disomy 14, 528 DHAND, 5

DHCR7, 383, 587 DHODH, 510 Diabetes, maternal, 560, 568 Diaphanospondylodysostosis, 524–525, 526–527, 624, 625, 627, 629, 637, 642, 646, 650, 651, 655, 656 Diaphragm, compression of, 599 Diaphragmatic herniae, 540–541, 583 Diaphyseal spurs, 452 Diaphysis hyperostosis of, 408 wide, 593 Diarrhoea, 602 Diastrophic dysplasia (DTD), 14, 111, 112–115, 618, 621, 622, 624, 626, 637, 638, 640, 646, 647, 648, 649, 650, 654, 656 Digital anomalies, 145, 540 Digits; see also Fingers; Toes abnormal numbers of, 14 absent, 541, 567, 596, 597 and achondroplasia, 49 globular, 283 hypoplastic, 591, 593 long, 141, 176 postural deformities of, 13 ultrasound assessment of, 17 Dislocations, 626 Disruption of vitamin K metabolism, 652 Distal appendages, dysmorphic, 283 Distal arthrogryposis, 111, 624 Distal femora bifid, 556 Erlenmeyer flask appearance, 137 Distal femoral epiphyses, 224 and cartilage-hair hypoplasia, 227 Distal femoral metaphyses, 54 Distal humeri tapered, 163 Distal phalanges absent, 148, 286, 489 absent ossification of, 204, 287, 371, 588 and atelosteogenesis, 162 bifid, 121, 295 broad, 162, 295, 584 in CED, 212 in chondroectodermal dysplasia, 203 duplicated, 531, 532 in FMD, 137 hypoplastic, 145, 216, 328, 488, 611, 612–613 lateral angulation of, 300 in Melnick-Needles syndrome, 141, 143 osteolysis of, 333 short, 121, 143, 146, 339, 378, 482 in SLE, 378 spatulate, 156 syndactyly of, 496, 497 in warfarin embryopathy, 375 wide, 496 Distal radii, 212 Distal tibiae, 79, 270 Distal ulnae, 54, 212, 278 DK phocomelia, 511, 574, 596, 597, 618, 619, 621, 627, 629, 631, 634, 639, 641, 645, 646 DLK1, 528 DLL3, 3, 519

665

Index DNAJC21, 229 Dolichocephaly, 215 and campomelic dysplasia, 302, 307 and cranioectodermal dysplasia, 212 and Desbuquois dysplasia, 125 and Zellweger syndrome, 382 Dolichostenomelia, 471 Downslanting palpebral fissures and acrofacial dystosis, 510 and Apert syndrome, 496 and brachydactyly type B, 286 and OPD1, 145 and OPD2, 148 and Roberts syndrome, 550 and Rubinstein-Taybi syndrome, 295 and Shprintzen-Goldberg syndrome, 504 Down syndrome (trisomy 21), 13 DRRS (Duane-radial ray syndrome), 532, 537 DTDST, 105, 106, 108, 111 Duane anomaly, 532, 574 radial defects, 628 Duane radial ray syndrome, 646 Dubowitz syndrome, 621, 627, 640 Ductus arteriosus, 560 Dumbbell deformity, 99, 100, 101, 102 and dyssegmental dysplasia, 168, 170 Dumbbell femora, 181 Dumbbell-shaped tubular bones, 178, 179, 627 and metatropic dysplasia, 177, 179 Du Pan syndrome, 638 Dural ectasia, 471 DVL1, 276 DVL3, 276 DYNC2H1 mutations, 182, 186 Dysautonomia, 311 Dyschondrosteosis, 55, 270, 638 Dysmorphic facial features, 315 Dysmorphic scapulae, 239 Dysmorphisms and skeletal dysplasia B3GAT3-related, 653 with or without heart defects, 622 Dysosteosclerosis, 389, 398, 399–402, 616, 633, 634, 635, 638, 642, 649 Dysostosis, 1 Dysostosis multiplex, 348 Dysplastic cortical hyperostosis, 348, 404, 416, 416–417, 620, 627, 634 Al-Gazali type, 618, 625, 641, 645, 649, 657 Kozlowski-Tsuruta, 625, 644, 646, 647, 648, 655, 656 Dysplastic fetal kidneys, 189 Dysplastic nails, 206 Dyssegmental dysplasia, 166, 616, 619, 621, 625, 627, 632, 638, 641, 644, 648, 649, 650, 654, 655, 656 and dyssegmental dysplasia, 167 Rolland-Desbuquois type, 73, 82 Silverman-Handmaker type, 167 Ear abnormalities external, 532, 537 and femoral facial syndrome, 560 inner, 521 and Roberts syndrome, 550 Ear lobes absent, 490 protruding, 611

Ears; see also Low-set ears abnormal, 14, 191 anomalies, 627 crumpled, 471 floppy, 426 hypoplastic, 593 large, 546 posteriorly rotated, 148, 262, 293, 504, 587 small, 528 tags, 596 Echocardiography, 17 Ectoderm, dorsal, 5 Ectodermal anomalies, 212 Ectodermal dysplasia, 203, 577, 591 Ectopia lentis, 471 Ectrodactyly, 14, 19, 542, 546, 556, 576–577, 577–579 EEC (ectrodactylyectodermal dysplasia-cleft lip) syndrome, 14, 621 EFL1, 229 EFNB1, 492, 496, 500, 507, 583 Ehlers-Danlos syndrome, 152, 471, 626, 635, 636, 650 Elbow dislocation and acrofacial dysostosis, 511–512 and ateleosteogenesis, 109, 165 and cerebro-osseous-digital syndrome, 593 and de Lange syndrome, 540 and DTD, 114 and Larsen syndrome, 152 and Melnick-Needles syndrome, 143 and MOPD, 338 and omodysplasia, 273, 274 and OPDS2, 149 and opsismodysplasia, 267, 268 and osteogenesis imperfecta, 430 and Pfeiffer syndrome, 493 Elbows ankylosis, 491, 501, 502 contractures of, 311, 546 dislocated, 153, 160, 165, 271 extension, limited, 54, 145 hyperlaxity of, 521 immobile, 500 limited movement of, 137 pterygium, 566 synostosis, 491, 556, 560 Elephant trunk sign, 608 Ellis-van Creveld syndrome, 197, 643 Enamel dysplasia, 426 Encephalocele, 218, 220, 515, 619 and OFDS, 209 and OPD2, 148 and TD, 36 Encephalocraniocutaneous lipomatosis, 479, 619, 637 Endochondral bone formation, 1 Engrailed (EN1), 5 Eosinophilia, 224 EP300, 295 Epibulbar dermoids, 478 Epicanthic folds and Carpenter syndrome, 507 and cranioectodermal dysplasia, 212 and Fanconi anaemia, 573 and multiple pterygium syndrome, 605 and Rubinstein-Taybi syndrome, 295 and Zellweger syndrome, 382

Epicanthus, 521 Epidermal naevi, 478 Epiglottis bifid, 587 hypoplastic, 186, 209, 510 Epilepsy photosensitive, 422 and Schinzel-Giedion syndrome, 611 Epiphyseal calcification, 13 Epiphyseal cartilage, narrow, 464 Epiphyseal dysplasia, 82, 151 Epiphyseal stippling differential diagnosis of, 382–383 and Greenberg dysplasia, 373 and warfarin embryopathy, 375 and Zellweger syndrome, 383 Epiphyses, 230, 236, 243, 244, 251 absent officiation of, 81 cartilaginous, 62, 86 cone-shaped, 196, 224, 482 delayed ossification of, 47, 86, 121, 266, 338 delta, 298 flattened, 281 large, 471 premature fusion of, 121 rounded, 224 in skeletal survey, 19 Epispadias, 608 Epithelio-mesenchymal transition, 3 ERF syndromes, 626 Erythropoiesis deficient, 224 ESCO2, 550, 551 Escobar syndrome, 605–606 EVC2, 203 EVEN-PLUS syndrome, 649 Exomphalos, 631 and Carpenter syndrome, 507 and Desbuquois dysplasia, 121 differential diagnosis of, 609 and Melnick-Needles syndrome, 141, 143 and OEIS complex, 608 and OPD2, 148 and osteopathia striata, 421, 422 and SRPS, 187, 191 Exophthalmos and cerebro-osseous-digital syndrome, 593 and opsismodysplasia, 266 and Roberts syndrome, 550 and Schinzel-Giedion syndrome, 611 and Shprintzen-Goldberg syndrome, 504 EXTL3, 246 Extracellular matrix, abnormal, 108 Eye anomalies and de Lange syndrome, 540 and Fanconi anaemia, 573 and Hallerman-Streiff syndrome, 333 and Proteus syndrome, 478 and Stickler syndrome, 89 and warfarin embryopathy, 375 Eyebrows arched, 293, 298, 540 sparse, 333, 338 tangled, 602 Eyelashes curved, 540 long, 540 sparse, 333, 510

666 Eyelids coloboma of, 510 everted, 406 ptosis of, 510 Eyes anomalies cataract, 628 antimongoloid slant, 512 movements, abnormal, 197 prominent, 121, 137, 260, 403, 429, 488, 490 protruberant, 95 wide set, 187, 593 Face; see also Flat face development of, 4 examining, 14 long, 546 round, 123, 298 triangular, 429 Facial anomalies and fetal akinesia deformation sequence, 152 in Roberts syndrome, 550 Facial asymmetry, 141, 492 Facial bones absent ossification of, 452 hypoplastic, 488 overgrowth of, 426, 478 sclerosis of, 411, 414, 427 small, 491 Facial dysmorphism and atelosteogenesis, 162 and DTD, 111 and metatropic dysplasia, 178 and paternal uniparental disomy 14, 528 and Raine dysplasia, 403, 404 and SEDC, 73 and ultrasound, 14 Facial features, coarse, 67, 348, 541, 611 Facial haemangioma, 611 Facial hypoplasia, 464 Facial myotonia, and Stuve-Wiedemann syndrome, 311 Facial paralysis, 421 Faint vertebral bodies, 79 Falx cerebri, 560 FAM20C, 403 Familial digital arthropathy-brachydactyly (FDAB), 618 Fanconi anaemia, 14, 573–574, 575, 619, 620, 621, 622, 623, 624, 627, 628, 629, 630, 632, 634, 635, 639, 640, 643, 644, 646, 650, 652, 654, 657 FBLN1, 583 FBN1, 471 Feet abducted, 23 aphalangia of, 488 deformity, 314 long, 177 measuring length of, 13 medial deviation of, 121 retroverted, 569 rocker-bottom, 500, 606 small, 266, 283 Feingold syndrome, 532, 639, 652

Index Femora, 198; see also Bowed femora; Distal femora; Proximal femora; Short femur abduction, 315 absent, 546 angulated, 26, 302, 303, 306, 313, 314, 562–564 bifid, 556 bowed, see Bowed femora crumpled, 432, 440 curved, 26 diaphyseal sclerosis of, 386 and dyssegmental dysplasia, 167 growth rate of, 54 in hypophosphatasia, 455 in metatropic dysplasia, 178 in osteogenesis imperfecta, 436 in platyspondylic dysplasia, 67 posterior dislocation of, 591, 593 in sirenomelia, 568, 568, 569 in TD, 36 telephone receiver shape, 36, 37 Femoral bowing, 255 Femoral facial syndrome, 560, 561–564, 617, 618, 621, 627, 643, 646, 647, 651, 653, 654, 655 Femoral fractures, 445 Femoral heads, dislocated, 110, 593 Femoral hypoplasia focal, 26 unusual facies syndrome, 631, 640, 656 Femoral metaphyses, 48, 49, 50, 81 Femoral neck, 55 broad, 89, 90 short, 55, 311, 541 Femur, 239 ossification of cervicalangulation of, 309 Femur-fibula-ulna complex, 560, 631, 641, 647, 652, 653 Femur-fibula-ulna (FFU) syndrome, 283, 566, 566–567, 617, 638 Femur/foot length ratio normogram, 14 Ferraz dysplasia, 270, 638 Fetal akinesia deformation sequence (FADS), 13, 23, 152, 605, 624, 644 Fetal akinesia sequence, 642, 656 Fetal alcohol syndrome (FAS), 338, 541, 618, 624, 652 Fetal death, 18 Fetal exposure to hydantoin, 652 Fetal face, 279 Fetal growth, 54, 615 Fetal infection with parvovirus, 633, 642, 643 Fetal limbs and spondylometaphyseal dysplasia, 263 Fetal movements assessing, 17 lack of, 382, 605–606 Fetal oedema, 182, 186, 256 Fetal phenotype, 32, 576 Fetal skeletal dysplasias diagnosis of, 17 Fetal valproate syndrome, 574, 643 FGF2, 4, 166 FGFR1, 491 FGFR2, 319, 491–492, 496–498, 500–501, 507

FGFR3, 31 and achondroplasia, 46–7, 47–52 differential diagnosis of mutations, 37, 47, 54–55 and hypochondroplasia, 54–55, 55–7 mutations, 226 and TD, 31, 36 FGFs (fibroblast growth factors), 3, 5, 491 Fibrochondrogenesis, 95, 96, 176, 260, 619, 620, 621, 624, 625, 627, 628, 631, 632, 635, 636, 637, 638, 640, 641, 644, 645, 647, 649, 652, 654, 655, 656 Fibulae, 194; see also Short fibulae absent, 148, 149, 546, 566–567 in Caffey disease, 408 in FFU, 566 hypoplastic, 270, 283, 302, 560, 566 in Roberts syndrome, 550–551 in sirenomelia, 568 spurred, 455 unossified, 455 Fibular agenesis, 566–567 Fibular aplasia, 421, 566 Fibular hypoplasia, 631 and complex brachydactyly, 618, 631 Fibular ray defects, 566 Filamin B, 156 Fingers; see also Digits; Index fingers hyperphalangy of, 125 long, 500 radial deviation of, 298 tapering, 482 ulnar deviation of, 111, 311 First digits, broad, 492–494 Fixed hyperextension, 122 FKBP10, 429, 430, 447 Flared metaphyses, 71, 312, 336, 638 and achondrogenesis type 2, 58 and CHH, 224 and Hallerman-Streiff syndrome, 333 and hypochondroplasia, 54 and hypophosphatasia, 452 and osteocraniostenosis, 328 and platyspondylic dysplasia, 67 and Schneckenbecken dysplasia, 260 and Stickler syndrome, 90 and Yunis-Varon dysplasia, 488 Flared narrow ilia, 139 Flat acetabula and MOPD, 339, 339 Flat face, 631 and campomelic dysplasia, 302, 309 and dyssegmental dysplasia, 176 and kyphomelic dysplasia, 313 and metatropic dysplasia, 176 and OSMED, 98 and osteocraniostenosis, 328 and spondyloepimetaphyseal dysplasia, 81 and SRPS, 191 and Yunis-Varon dysplasia, 489 Flat nasal bridge, 192, 632 and achondrogenesis, 256 and atelosteogenesis, 162 and campomelic dysplasia, 302 and Carpenter syndrome, 507 and Chitayat (1993) hyperphalangism, 300 and Desbuquois dysplasia, 121

667

Index and kyphomelic dysplasia, 313, 315 and Larsen syndrome, 151 and MOPD, 338 and OPD2, 148 and Pallister-Hall syndrome, 587 and SEDC, 79 and SRPS, 191, 192 Flat nose and cerebro-osseous-digital syndrome, 593 and osteocraniostenosis, 328 and SRPS, 186 Flat profile, 151, 403, 421 Flattened nasal bridge, 79 FLNA mutations, 137, 141, 145, 148, 151 FLNB mutations, 151, 156, 162 Floating-Harbor syndrome, 342 Fluconazole embryopathy, 501, 616, 626, 629, 653 Focal occipital dysraphism, 192 Fontanelles, 320, 417, 468, 469 large, 156, 266, 328, 426, 488, 611 in skeletal survey, 19 and sutures large, 632 ultrasound assessment of, 17 wide, see Wide fontanelles wide-open, 482, 488 Foot deformity, 561 Foot-to-femur ratio, 56 Foramen magnum, 477 Forearms, 542 absent, 540–541 bowed, 283 and de Lange syndrome, 542 short, 510 Forehead broad, 164 high, 212, 313, 496 hirsute, 528 increased skin thickness over, 540 prominent, see Prominent forehead sloping, 338 tall, 382 Fornix, 515 Forster classification, 568 Four-limb postaxial polydactyly, 199 Fractures, 633 Frank-ter-Haar syndrome, 142, 629 Frenula, multiple, 203, 209, 583, 587 Frontal bone narrowing of, 403 prominent, 500 sloping, 338 Frontal bossing, 633 and achondroplasia, 46, 47, 48, 49, 52 and Chitayat (1993) hyperphalangism, 300 and Greig syndrome, 583 and Hallermann-Streiff syndrome, 333, 334 and omodysplasia, 273 and OPD2, 148 and osteogenesis imperfecta, 437 and osteopathia striata, 421 and Pfeiffer syndrome, 491 and Proteus syndrome, 478 and Raine dysplasia, 403 and Schinzel-Giedion syndrome, 611 in TD, 43 ultrasound assessment of, 14, 17

Frontal lobes, hypoplastic, 338 Frontal sinuses, 137, 141, 145 Frontometaphyseal dysplasia (FMD), 137–140, 138–140, 617, 621, 622, 624, 626, 629, 631, 635, 636, 638, 643, 650, 653, 656 Frontonasal dysplasia, 492, 496, 500 Fronto-oto-palato-digital osteodysplasia, 111 Fryns syndrome, 541, 574, 632, 656 Fryns syndrome-acral defects, 621, 627, 640, 644 Fuhrmann syndrome, 546, 631, 641, 643, 652 Funny fingers and toes, 139 FZD2, 276 Galactosialidosis, 348 GAPO syndrome, 212 Gastric polyps, 602 Gastro-oesophageal reflux, 602 Gastroschisis, 375, 510 GDF5, 283, 288 Geleophysic dysplasia, 641 Genetic tests, 31 Genital abnormalities, 634 Genital anomalies and Antley-Bixler syndrome, 500 and Roberts syndrome, 550 and warfarin embryopathy, 376 and Yunis-Varon dysplasia, 488 Genitalia absent, 191, 568, 608 and campomelic dysplasia, 308 in campomelic dysplasia, 302, 308 hypoplastic, 507, 540–541, 605 Genitourinary anomalies and Al-Awadi Raas-Rothschild syndrome, 546 and de Lange syndrome, 541 and Fanconi anaemia, 573 and femoral facial syndrome, 560 and Hallerman-Streiff syndrome, 333 and Pallister-Hall syndrome, 587 and sirenomelia, 568 and SRPS, 182 Genu recurvatum, 122 Genu valgum, 206, 482, 507 Genu varum, 47, 54 Ghent criteria, 471 GJA1, 333 Glaucoma, 629 and de Lange syndrome, 541 and Desbuquois dysplasia, 122 and Marfan syndrome, 471 and otopalatodigital syndrome, 142 and Roberts syndrome, 550 and Rubinstein-Taybi syndrome, 296 and SEDC, 73 GLB1, 348, 416 Glenoid fossae, 273 absent, 528, 537 GLI3, 5, 583, 587–588 Glossoptosis, 293, 491, 521 GM1 gangliosidosis, 348, 376, 383, 408, 416, 652 Gollop-Wolfgang complex, 556, 556–558, 617, 621, 622, 624, 641, 651, 652, 653 Goltz syndrome, 622, 628, 630

Gorlin-Chaudhry-Moss syndrome, 342, 626, 653 Gorlin syndrome, 583, 629, 637, 643 GPC6, 273 Gracile bones, 328, 597 Great toes absent, 488 bifid, 295 deviated, 491 Great vessels, transposition of, 500, 531 Grebe dysplasia, 283, 284, 616, 618, 626, 631, 635, 638, 641, 643, 653, 654 Greenberg dysplasia, 371, 372–373, 618, 625, 636, 638, 641, 642, 643, 644, 647, 648, 649, 651, 652, 655, 656 Greig cephalopolysyndactyly syndrome, 618, 619, 626 Greig syndrome, 492, 496, 507, 583, 584–586, 629, 632, 634, 637 Grieg cephalopolysyndactyly, 617 Grimacing smile, 295 Gross hyperostosis, 179 Growth deficiency and Catel-Manzke syndrome, 293 and de Lange syndrome, 540 Growth plates in cerebro-osseous-digital syndrome, 593 physeal, 47, 54 Growth retardation and acrofacial dysostosis, 511 and brachydactyly Temtamy type, 298 and de Lange syndrome, 540 differential diagnosis of, 550 intra-uterine, see IUGR and Lenz-Majewski dysplasia, 426 postnatal, 378 and Roberts syndrome, 550 and Yunis-Varon dysplasia, 488 Gums hypertrophy, 403 tethered, 206 thickened, 596 Gut malrotation, 141 Haematopoietic stem cell transplantation (HSCT), 389 Hair blond, 224 in Menkes disease, 602–603 sparse, 212, 338, 488, 541 in warfarin embryopathy, 375 Hairline, low anterior, 295, 540 Hajdu-Cheyney syndrome, 467–468, 468–469, 616, 618, 622, 623, 624, 626, 627, 628, 629, 633, 635, 642, 646, 657 Hallermann-Streiff syndrome, 333, 334–336, 622, 628, 629, 630, 633, 634, 639, 648, 649, 652, 657 Halluces abduction of, 111, 114, 295 absent, 148, 488, 489, 490 angulated, 295 attempted duplication of, 507 broad, 286, 491, 492, 497, 583, 589 hypoplastic, 145 polysyndactyly of, 492 short, 288, 300, 489, 496 Hallux valgus, 300

668 Hamartoblastoma, 191 hypothalamic, see Pallister-Hall syndrome Hands; see also Trident hand aphalangia of, 488 broad, 371, 508 examining, 13 long, 500 mitten-shaped, see Mitten deformity short, 224, 348 small, 266, 283 ulnar deviation of, 209, 566 Hartsfield syndrome, 618, 621, 639 HASTE imaging, 192 HDAC8, 540–541 Head, large, 186, 192, 256, 426, 440 Head circumference (HC) in campomelic dysplasia, 308 in hypochondroplasia, 56 measuring, 14 in Schneckenbecken dysplasia, 260 in spondylometaphyseal dysplasia, 263 in SRPS, 191 Hearing loss, 634; see also Deafness and Carpenter syndrome, 507 and CCM syndrome, 521 conductive, see Conductive hearing loss and de Lange syndrome, 541 and Larsen syndrome, 151 mixed, 90, 137 and osteogenesis imperfecta, 430 and osteopathia striata, 421 and Pfeiffer syndrome, 491 and Roberts syndrome, 550 sensorineural, 89, 98 and Yunis-Varon dysplasia, 488 Heart block, 536 hypoplastic, 605 large, see Cardiomegaly Heart defects and Antley-Bixler syndrome, 500 and Catel-Manzke syndrome, 293 and chondroectodermal dysplasia, 203 and de Lange syndrome, 540 and DTD, 111 and Fanconi anaemia, 573 and Gollop-Wolfgang complex, 556 and Hallerman-Streiff syndrome, 333 and Holt-Oram syndrome, 537 and Kaufman-McKusick syndrome, 599–560 and Larsen syndrome, 151 and Meckel syndrome, 217 and Menkes disease, 602 and nuchal translucency, 16 and OEIS complex, 608 and omodysplasia, 273 and osteopathia striata, 421 and Pallister-Hall syndrome, 587 and Roberts syndrome, 550–551 and Rubinstein-Taybi syndrome, 295 and SRPS, 182 and TD, 36 and VATER/VACTERL association, 531 and Yunis-Varon dysplasia, 488 Heart-hand syndromes, 537, 618, 622, 623 Hematopoiesis, extramedullary, 389

Index Hemifacial microsomia, 617, 618, 619, 621, 622, 630, 634, 635, 640, 644, 645, 646, 649, 651 Hemimegalencephaly, 478 Hemimelia longitudinal, 542 Hemivertebrae identifying, 14 incarcerated, 25 and Kaufman-McKusick syndrome, 599 and OEIS complex, 608 and spondylocostal dysostosis, 518 and VATER/VACTERL association, 531, 532 Hepatic enzymes, increased, 411 Hepatic fibrosis, 217 Hepatoblastoma, 611 Hepatomegaly, 200 Hepatosplenomegaly, 224, 382, 388, 411 Herniae; see also Diaphragmatic herniae; Inguinal hernia; Umbilical herniae and omodysplasia, 273 HES7, 3, 517 Heterozygosity, compound, 471 Hexadactyly, and Jeune syndrome, 196 Hiatus herniae, 540 High arched palate, 65, 212, 490, 510, 602 Hip dislocation, 76, 315, 635 and Al-Awadi Raas-Rothschild syndrome, 546, 547 and atelosteogenesis, 162 and campomelic dysplasia, 306 and FMD, 137, 139 and MOPD, 338 and mucolipidosis, 348 and multiple pterygium syndrome, 606 and OEIS complex, 608 Hippocampus, 36 Hips, 547 contractures of, 338 dislocated, 160, 306 limited mobility, 273 multiple dislocations, 124 Hirschsprung disease and acrofacial dysostosis, 510 and cartilage-hair hypoplasia, 224 and Jeune syndrome, 196 and Kaufman-McKusick syndrome, 599 and osteopathia striata, 421 Hirsutism, 166, 286, 540, 541 Hitchhiker thumbs, 14, 106, 111, 114 Holoprosencephaly and DK phocomelia, 596 and Pallister-Hall syndrome, 587 and SRPS, 191 and warfarin embryopathy, 376 Holt-Oram syndrome, 14, 532, 536–537, 537–538, 541, 574, 617, 618, 622, 623, 624, 628, 634, 637, 641, 645, 646, 647, 652, 653, 655, 657 tibial hemimeliapolydactyly-triphalangeal thumb, 635 Homocystinuria, 447, 471, 504, 649 Homozygous achondroplasia, 52, 618, 619, 634, 637, 641, 644, 647, 649, 655, 656, 657 Horizontal acetabula, 70

Horseshoe kidney, 500, 537, 596 HOXD13, 531, 583 HOX genes, 3, 4 HSPG2, 166, 172–173 Humeri, 119; see also Bowed humeri; Short humeri absent ossification of, 158 in atelosteogenesis, 162 bifid, 110 distal tapering of, 157 in hypophosphatasia, 455 hypoplastic, 536 peromelia of, 566 short, see Short humeri tapered, 114, 151, 153 Humeroradial synostosis, 548 Humerospinal dysostosis, 151 Hurler disease, 348 Hutchinson-Gilford progeria syndrome, 333, 642 Hydrocephalus and achondroplasia, 46 and Antley-Bixler syndrome, 500 and Apert syndrome, 496 and Carpenter syndrome, 507 and cerebroarthrodigital syndrome, 591 and Greig syndrome, 583 and Meckel syndrome, 218 and OPD2, 148 and opsismodysplasia, 266 and osteocraniostenosis, 329 and osteogenesis imperfecta, 430 and osteopathia striata, 421 and osteopetrosis, 388 and Pfeiffer syndrome, 491 and Roberts syndrome, 550–551 and Shprintzen-Goldberg syndrome, 504 and SRPS, 191 and TD, 36, 42, 43 and warfarin embryopathy, 375 and Yunis-Varon dysplasia, 488 Hydrocephalus, 329, 619 Hydrocolpos, 599 Hydrolethalus syndrome, 209, 514, 588, 619, 622, 629, 634, 637, 640, 643 Hydrometrocolpos, 599 Hydronephrosis and Apert syndrome, 496 and campomelic dysplasia, 302 and Carpenter syndrome, 507 and de Lange syndrome, 540 and Kaufman-McKusick syndrome, 599 and Melnick-Needles syndrome, 141 and Menkes disease, 602 and OEIS complex, 608 and OFDS, 209 and OPD2, 148 and Schinzel-Giedion syndrome, 611 and VATER/VACTERL association, 531 Hydrops (fetalis), 416 and achondrogenesis, 58, 61, 105, 256 and Blomstrand dysplasia, 464 and Caffey disease, 411, 413 and Desbuquois dysplasia, 121 differential diagnosis of, 371 and dysplastic cortical hyperostosis, 416, 416–417

669

Index and fibrochondrogenesis, 95 and Greenberg dysplasia, 371 and Kaufman-McKusick syndrome, 599 and paternal uniparental disomy 14, 528 and Schneckenbecken dysplasia, 260 and SRPS, 182, 186, 187, 191 and warfarin embryopathy, 375 and Yunis-Varon dysplasia, 488 Hydroureter, 599, 608 Hyoid bones, 464, 465 Hyoid cartilage, 464 Hypercalciuria, 452 Hyperdontia, 296 Hyperlaxity, 224, 429, 635 Hyperlordosis, 47 Hyperostosis, gross, 179 Hyperparathyroidism differential diagnosis of, 348 neonatal, 32, 457, 458–459 primary, 348 secondary, 348, 457 Hyperphalangism, 636 Hyperphalangism characteristic facies-hallux valgusbronchomalacia, Chitayat syndrome, 626, 629, 644, 652, 653 Hyperphalangy, 125 and brachydactyly Temtamy type, 298 and brachydactyly type C, 288 and Catel-Manzke syndrome, 293, 294 and Desbuquois dysplasia, 125 differential diagnosis of, 288, 293, 298 Hyperpigmentation, 573 Hypertelorism, 515, 629 and Apert syndrome, 496 and atelosteogenesis, 162 and boomerang dysplasia, 156 and brachydactyly Temtamy type, 298 and brachydactyly type B, 286 and Catel-Manzke syndrome, 293 and Chitayat (1993) hyperphalangism, 300, 300 and FMD, 137 and Greig syndrome, 583 and Larsen syndrome, 151 and Lenz-Majewski hyperostotic dysplasia, 426 and metatropic dysplasia, 176 ocular, 491, 496, 500–501 and OFDS, 209 and OPD1, 145 and OPD2, 148 and opsismodysplasia, 266 and OSMED, 98 and osteopathia striata, 421 and Raine dysplasia, 403 and Roberts syndrome, 550 and Schinzel-Giedion syndrome, 611 and SEDC, 73 and Shprintzen-Goldberg syndrome, 504 and SRPS, 191 ultrasound assessment of, 14, 17 and Yunis-Varon dysplasia, 488 and Zellweger syndrome, 382 Hyperthermia episodic, 311 malignant, 606 Hypertrichosis, 611

Hypertrophic zones Hypocalcaemia, 388, 457, 537 Hypocalciuria, 457 Hypochondrogenesis, 58–65, 59–65, 73, 82, 655 Hypochondroplasia, 54–55, 55–57, 618, 637, 638, 647, 649, 651 Hypodontia and Carpenter syndrome, 507 and Hallerman-Streiff syndrome, 333 and Larsen syndrome, 151 and OPD1, 145 and Rubinstein-Taybi syndrome, 296 and Yunis-Varon dysplasia, 488 Hypogammaglobulinaemia, 81 Hypoglycaemia, 602 Hypogonadism, 328, 507 Hypokinesia, fetal, 382 Hypomineralisation and achondrogenesis, 256 and spondoepimetaphyseal dysplasia, 81 Hypoparathyroidism, neonatal, 457 Hypophosphatasia, 452, 453–455, 616, 626, 631, 633, 636, 637, 639, 642, 648, 653, 655, 656 identifying, 14 perinatal lethal and infantile forms, 621 Hypopigmentation, 573–574 Hypopituitarism, 587 Hypoplasia, 543 Hypoplastic clavicles, 2 Hypoplastic distal, 216 Hypoplastic ilia, 279 Hypoplastic iliac wings, 547 Hypoplastic lungs, 204, 636 Hypoplastic penis, 189 Hypoplastic right tibia, 554 Hypoplastic scapulae, 309 Hypospadias and Chitayat (1993) hyperphalangism, 300 and chondroectodermal dysplasia, 203 glandular, 599 and kyphomelic dysplasia, 338 and Lenz-Majewski hyperostotic dysplasia, 426 and OPD2, 148 and Schinzel-Giedion syndrome, 611, 612–613 and Zellweger syndrome, 382 Hypotelorism, 14, 17, 574, 630 Hypothalamic hamartoma, 192 differential diagnosis of, 587–588 and Pallister-Hall syndrome, 587, 589 and SRPS, 191, 192 Hypothyroidism congenital, 383 neonatal, 376 Hypotonia and achondroplasia, 46 differential diagnosis of, 382–383 and Ehlers-Danlos syndrome, 152 generalised, 522 in Menkes disease, 602 and neonatal hyperparathyroidism, 457 and opsismodysplasia, 266 and paternal uniparental disomy 14, 528 and spondylometaphyseal dysplasia, 262

and TD, 36 and Zellweger syndrome, 382 Hypotrichosis, 224, 333 Hypoxia, perinatal, 521 Ilia, 131, 548 in achondrogenesis, 105 in Astley-Kendall dysplasia, 386 in cleidocranial dysplasia, 482 flared, 137, 145 fused, 569 in hypophosphatasia, 453 hypoplastic, 546, 611 narrow, 302, 303 in OSMED, 98 in osteogenesis imperfecta, 431 in platyspondylic dysplasia, 67 rounded, 96, 166, 167, 411, 414 sclerotic, 427 short, see Short ilia small, 83, 84, 87, 191, 273, 311 snail-like, 260 squared, 36 striated, 421 Iliac bases, narrow, 348, 504 Iliac bones in fibrochondrogenesis, 95 in Greenberg dysplasia, 371 hypoplastic, 504 inferior, 148 and Kniest dysplasia, 87 lytic defects of, 452 narrow, 612–613 square, 266 and thoracolaryngopelvic dysplasia, 222 Iliac crests, 19, 179–180, 262, 263–264, 453 Iliac hypoplasia, 55, 56 Iliac wings anomalies, 636 and boomerang dysplasia, 157 flared, 138, 141, 143, 149, 315, 348 hypoplastic, 547 rounded, 260, 261 short, 371 squared, 48, 65 Imaging strategies postnatal, 18–19 prenatal, 13 Immunodeficiency, 224 Imperforate anus and Al-Awadi Raas-Rothschild syndrome, 546 and Antley-Bixler syndrome, 500 and Kaufman-McKusick syndrome, 599 and OEIS complex, 608 and Pallister-Hall syndrome, 587 and sirenomelia, 568, 569 and SRPS, 182 Impulsivity, 295 Increased nuchal translucency (NT), 636 Incus, malleus and stapes, 4 Index fingers hyperphalangy of, 125, 294, 300 short, 288, 293 Infantile and attenuated forms, 617, 625, 629, 631, 640, 642, 644, 645, 656

670 Infantile galactosialidosis, 625 Infantile Refsum disease (IRD), 382 Infantile sialic acid storage disease, 625 Inguinal herniae and achondrogenesis, 105 bilateral, 212 and Menkes disease, 602 and paternal uniparental disomy 14, 528 and Shprintzen-Goldberg syndrome, 504 and spondylocostal dysostosis, 518 Intellectual disability and Proteus syndrome, 479 and Roberts syndrome, 550 Intellectual impairment and acrofacial dysostosis, 510 and anauxetic dysplasia, 224 and Apert syndrome, 496 and brachydactyly Temtamy type, 298 and campomelic dysplasia, 302 and Carpenter syndrome, 507 and Catel-Manzke syndrome, 293 and CCM syndrome, 521 and Gollop-Wolfgang complex, 556 and paternal uniparental disomy 14, 528 and Rubinstein-Taybi syndrome, 295 and Shprintzen-Goldberg syndrome, 504 and split hand-foot malformation, 577 Interosseous membrane, ossified, 430, 431, 445 Interpedicular distances narrow, 46, 176, 179–181, 591 wide, 138, 148, 504 Interpedicular spaces, 138 Interphalangeal subluxation, 134 Intervertebral spaces and SRPS, 182 wide, 36, 37, 39, 176 Intestinal malrotation and Blomstrand dysplasia, 464 and Carpenter syndrome, 508 and de Lange syndrome, 540 and Greenberg dysplasia, 371 and OEIS complex, 608 Intestinal obstruction, 599 Intracerebral arteries, tortuous, 602 Intracerebral calcifications, 403–404 Intracerebral haemorrhages, 430 Intracranial pressure, increased, 583 Intracranial structures, 14, 429, 452, 482 Intrauterine growth retardation, 326 Iris coloboma of, 293, 333, 577 opaque, 490 Irregular metaphyses, 68 and dysplastic cortical hyperostosis, 416, 416 in fibrochondrogenesis, 95 in hypophosphatasia, 453 and opsismodysplasia, 266 in Schneckenbecken dysplasia, 260 in spondylometaphyseal dysplasia, 262, 263 Ischia, 237, 527 absent, 593 absent ossification of, 593 in achondrogenesis, 105, 256 in boomerang dysplasia, 157 broad, 311

Index delayed ossification of, 266 in dyssegmental dysplasia, 167 in fibrochondrogenesis, 95, 96 sclerotic, 427 in sirenomelia, 569 in skeletal survey, 19 spurred, 338 stippling of, 386 vertical, 139, 148 Ischial bones, 15, 60, 82 Ischiopubic junction, 548 Isolated benign macrocephaly, 637 Isolated hemihypertrophy, 617 ISSD (infantile sialic acid storage disease), 348 IUGR (intrauterine growth retardation) and CCM syndrome, 521 and CED, 212 and cerebroarthrodigital syndrome, 591, 593 and cerebro-osseous-digital syndrome, 593 and de Lange syndrome, 540 and DK phocomelia, 596 and dysplastic limb reduction, 14, 17 and Fanconi anaemia, 573 and Lenz-Majewski hyperostotic dysplasia, 426 and MOPD, 338 and multiple pterygium syndrome, 605 and Roberts syndrome, 550 and SLE, 378 Stuve-Wiedemann syndrome, 311 and warfarin embryopathy, 375 Jansen syndrome, 3, 224 Jaundice, and Zellweger syndrome, 382 Jaw index, 313 large, 263 small, 308, 333, 489 squared-off, 176 Jeune syndrome, 16, 196–197, 197–202, 646 Johanson-Blizzard syndrome (JBS), 229 Joint contractures and cerebroarthrodigital syndrome, 591 and DTD, 111 and Marfan syndrome, 471 multiple, 151, 471, 606 and multiple pterygium syndrome, 605, 606 and paternal uniparental disomy 14, 528, 530 Joint deformity, 13, 209 Joint dislocations and Catel-Manzke syndrome, 293 and cleidocranial dysplasia, 482 and Desbuquois dysplasia, 121 diagnosis of, 13 multiple, 151 Joint hypermobility, 36, 89, 151, 295, 504 Joint laxity and CED, 212 and Desbuquois dysplasia, 121 and hypochondroplasia, 54 and Marfan syndrome, 471 Joint limitation and dyssegmental dysplasia, 266 in FMD, 137 in multiple pterygium syndrome, 605

Joints large, 95, 98, 111, 151, 496 mobility, 73 pain, 98 prominent, 176 in skeletal survey, 19 subluxations, 13, 141, 151 Joubert syndrome, 196, 218, 643, 646 Kabuki syndrome, 622, 628 Karyotyping, 32 Kaufman-McKusick syndrome, 203, 588, 599–600, 600, 622, 624, 625, 634, 643, 644, 646, 652 KBG syndrome, 541 Keipert syndrome, 618, 629 Keutel syndrome, 286, 376, 378, 383, 627, 652 Kidneys; see also Horseshoe kidney; Polycystic kidneys abnormal, 550 absent, 596 cysts, 209 dysplastic, 187, 189, 196, 560, 562 echogenic, 217, 220 enlarged, 204, 220 hyperechogenic, 220 multicystic, 562 small, 422 unilateral agenesis, 510 KIF22, 127 Kleeblattschädel, 36 Klippel-Feil syndrome, 10, 518, 651 Klippel-Trenaunay-Weber syndrome, 479, 617 Knee epiphyses, 127–128, 344 absent, 266, 338 flat, 121 Knees, 230 ankylosis of, 491 contractures of, 311, 338, 556 dislocated, 163, 210 flexion, 145 hyperextension of, 151 joint limitation at, 137 limited mobility, 273 multiple dislocations, 124 prominent, 82 Kniest dysplasia, 82, 83–88, 83–88, 172, 621, 627, 628, 629, 632, 635, 637, 639, 640, 642, 644, 645, 649, 651, 654, 656 Kozlowski-Tsuruta type, 416, 416–417 Kyphomelic dysplasia, 313, 314–318, 616, 621, 632, 633, 637, 638, 639, 640, 647, 649, 655, 656 with facial dysmorphism, 627 Kyphoscoliosis, 26 and atelosteogenesis, 108 and Blomstrand dysplasia, 421 and Carpenter syndrome, 507 and cleidocranial dysplasia, 482–483 and Desbuquois dysplasia, 121 and DTD, 111 and multiple pterygium syndrome, 606 and OEIS complex, 608 and osteogenesis imperfecta, 431 and paternal uniparental disomy 14, 528 progressive, 176, 302 and Shprintzen-Goldberg syndrome, 504

671

Index Kyphosis, 118, 242 and atelosteogenesis, 162 and campomelic dysplasia, 303 dorsal, 95 investigation of, 17 and Kniest dysplasia, 86 and multiple pterygium syndrome, 605 Labia, hypoplastic, 611 Labiogingival retraction, 488 Lacrimal duct anomalies, 576 Lacy ilia and spondylometaphyseal dysplasia, 264 Lambdoid sutures, 491, 500, 504, 507, 603 Lamellar bone, 1 Langer type (homozygous dyschondrosteosis), 630, 638, 647, 653 Large head, 192 Large skull vaults, 59 Large tali, 101, 102 Larsen dysplasia, 127 Larsen syndrome, 117, 151–152, 617, 621, 622, 624, 626, 627, 629, 632, 635, 640, 641, 642, 643, 644, 645, 647, 648, 649, 651, 653, 654, 656 Laryngeal cartilage, abnormal, 222 Laryngeal stenosis, 137, 222 Laryngotracheal stenosis, 111 Laryngotracheomalacia, 151, 162, 421 Larynx cleft, 587 hypoplastic, 209, 510 malformed, 186 Lateral ventricles, 95, 504, 507 Laurin-Sandrow syndrome, 580, 581, 635 LBR (lamin B receptor), 253, 371 Left femur, 431, 562, 563 Left heart, 205, 209, 540 Left humerus, 454 Left radial heads, 563 Left tibia, 444 Left ulna, 444, 566 Legs; see also Lower limbs asymmetric shortening, 560 soft tissue fusion of, 570 Leiomyosarcoma, 296 Lens dislocation of, 471 Lenz-Majewski hyperostotic dysplasia, 426, 427, 618, 621, 627, 629, 633, 642, 643, 652 LEPRE, 429 Lethal neonatal short limb dysplasia, 408, 411, 618, 633, 637, 643, 654, 655, 656 Leukaemia, 224, 296, 573 LFNG, 3, 517–518 Life expectancy, 270, 295, 471, 541, 550 LIFR, 311 Ligamentous laxity, 266 Limb anomalies and Al-Awadi Raas-Rothschild syndrome, 546 differential diagnosis of, 510 transverse, 540, 577 and VATER/VACTERL association, 531 Limb-body wall complex, 574, 608, 646

Limb defects and Al-Awadi Raas-Rothschild syndrome, 546 and de Lange syndrome, 540 and FFU syndrome, 566 and gracile bones, 328 and mesomelic dysplasia, 270 and osteogenesis imperfecta, 430, 439 and Roberts syndrome, 550 Limb-mammary syndrome, 621 Limb-pelvis hypoplasia-aplasia, 560 Limbs; see also Upper limbs asymmetry, 222 in boomerang dysplasia, 156 bowing, 137, 141, 411 contractures, 593 formation of, 4–5 reduction syndrome, 546, 547, 621, 624, 626, 627, 646, 656 short, see Short limbs Limb shortening; see also Mesomelic limb shortening; Rhizomelic limb shortening moderate, 98 Linear sebaceous naevus syndrome, 479, 619 Lipoma, 515 Lipomyelocystocoele, 608 Lips; see also Cleft lip; Upper lip everted, 212 full, 300 pursed, 311 thick, 273 thin, 488, 540 Lissencephaly, 262, 338 Liver anomalies, and Meckel syndrome, 218 cirrhosis, 196 enlarged; see also Hepatomegaly; Hepatosplenomegaly function, abnormal, 382 palpable, 222 LMX1B, 5 Lobster claw appearance, 576 Loeys-Dietz syndrome, 471, 504, 622, 624, 629, 636 Long bones, 56, 68, 75, 99, 102; see also Bowed long bones; Short long bones absent, 162, 546 angulated, 414, 433, 440, 453 in Astley-Kendall dysplasia, 386, 387 asymmetrical, 222 bone-in-bone appearance, 389 in boomerang dysplasia, 156 in Caffey disease, 411 and cartilage-hair hypoplasia, 227 in cerebroarthrodigital syndrome, 591, 592 in cerebro-osseous-digital syndrome, 593 cotton flakes of, 403 dumbbell appearance, 82, 83–84, 89, 95, 96, 98, 176, 179, 181, 260 in dysplastic cortical hyperostosis, 416 and dyssegmental dysplasia, 167 epiphyses of, 378 fractures of, 387, 431, 489, 500 in Greenberg dysplasia, 371 and hypochondroplasia, 54 and hypophosphatasia, 453

in kyphomelic dysplasia, 313, 338 and Marfan syndrome, 471 and mesomelic dysplasia, 271 in mucolipidosis, 348 in omodysplasia, 273 in osteogenesis imperfecta, 430, 432, 433 overmodelled, 330–331, 397 periosteal cloaking of, 349–351, 412 in Roberts syndrome, 551 in skeletal survey, 19 slender, 328, 330–331, 333, 336, 431, 488, 500, 602, 605–606, 606 spurred, 452 in SRPS, 193 striated, 421 in TD, 36, 37 ultrasound assessment of, 13, 17 and VATER/VACTERL association, 531 Long philtrum and CCM syndrome, 521 and Chitayat (1993) hyperphalangism, 300 and de Lange syndrome, 540, 542 and femoral facial syndrome, 560, 564 and opsismodysplasia, 266 and OSMED, 98 Long tubular bones, 65 absent, 568 in Gollop-Wolfgang complex, 556 in hypochondrogenesis, 65 in hypophosphatasia, 452 Lordosis, and atelosteogenesis, 162 Lower legs and campomelic dysplasia, 308 in campomelic dysplasia, 302, 308 in osteogenesis imperfecta, 440 Lower-limb long bone absent ossification of, 307 Lower limbs, 37 in acrofacial dysostosis, 510 bilateral absent, 546 bowed, 439 and campomelic dysplasia, 308 in campomelic dysplasia, 302, 308 in FFU, 566 and Jeune syndrome, 202 and Kniest dysplasia, 86 peromelia, 547 single, 568 Low-set ears, 189 and acrofacial dysostosis, 510 and Antley-Bixler syndrome, 500 and brachydactyly Temtamy type, 298 and Carpenter syndrome, 507 and Catel-Manzke syndrome, 293 and CCM syndrome, 521 and cleidocranial dysplasia, 483 and cranioectodermal dysplasia, 212 and fibrochondrogenesis, 95 and kyphomelic dysplasia, 313 and Larsen syndrome, 151 and multiple pterygium syndrome, 605 and OFDS4, 210 and omodysplasia, 273 and OPD2, 148 and osteocraniostenosis, 328 and Raine dysplasia, 403 and Roberts syndrome, 552 and Rubinstein-Taybi syndrome, 295

672 and Shprintzen-Goldberg syndrome, 504 and SRPS, 189 and Yunis-Varon dysplasia, 490 Lujan-Fryns syndrome, 504 Lumbar kyphoscoliosis, 110 Lumbar lordosis and hypochondroplasia, 54 and mesomelic dysplasia, 270 and Schneckenbecken dysplasia, 260 Lumbar scarum, 525 Lumbar scoliosis, 106, 110 Lumbar spinal stenosis, 47, 421 Lumbar spine, 525 and dyssegmental dysplasia, 167 and Kniest dysplasia, 87 Lumbar vertebrae aplastic, 568 costal processes of, 4 six, 505, 532 Lumbosacral lordosis, 108 Lungs abnormal lobulation of, 209, 371, 587 agenesis of, 531 biometry, 17 hypoplastic, see Pulmonary hypoplasia small, 187, 200 LWD (Leri-Weill dyschondrosteosis), 270 Lymphoma, and cartilage-hair hypoplasia, 224 Macrocephaly, 637 and achondroplasia, 46 and cerebroarthrodigital syndrome, 591, 593 and cerebro-osseous-digital syndrome, 593 differential diagnosis of, 421 and Greig syndrome, 583 and hypochondroplasia, 54 measuring, 14 and opsismodysplasia, 266 and osteopathia striata, 421 and osteopetrosis, 388–389 and platyspondylic dysplasia, 67 relative, 302 and Roberts syndrome, 550 and Schneckenbecken dysplasia, 260 and TD, 36, 39 and Yunis-Varon dysplasia, 489 and Zellweger syndrome, 382 Macrocornea, 142 Macrocrania, 36 Macrodactyly, 478–479 Macroglossia, 348, 464, 465 Macrostomia, 426, 546 Maculopathy, bilateral, 522 Madelung deformity, 55, 270, 288 Majewski syndrome, 186, 209 Malar hypoplasia, 73, 81, 333, 510, 550 Malar region, flat, 315 Malocclusion, 89, 151, 296, 482 Mandible antegonial notching of, 307 large, 262 overgrowth of, 403, 426 prominent, 408 sclerotic, 411, 414 short, 139, 464, 512, 521 small, 137, 293, 302, 506, 512, 540

Index Mandibular angle obtuse, 333, 334, 403 Mandibular hypoplasia and acrofacial dysostosis, 510, 512 and Hallermann-Streiff syndrome, 333, 334 and mesomelic dysplasia, 281 Mandibular osteomyelitis, 389 Mandibuloacral dysostosis, 633 Mandibuloacral dysplasia, 483, 489 Mandibulofacial dysostosis (MFD), 510–511, 577 Marfanoid habitus, 504 Marfan syndrome, 471, 624, 627, 628, 629, 635, 636, 640, 650, 651 Marked platyspondyly, 68, 71 Marshall-Smith syndrome, 475, 476–477, 617, 618, 619, 627, 628, 629, 631, 640, 644, 651 Marshall syndrome, 103 Mastoid air cells, 137, 141, 145 Maternal abdomen, 78 Maternal Sjögren syndrome, 652 Maternal systemic lupus erythematosus, 378, 379–380, 620, 622, 623, 642, 644, 649, 652, 656 Maxilla formation of, 4 Maxilla-nasion-mandible (MNM), 564 Maxillary hypoplasia, 504, 528 Meckel syndrome, 217–218, 218–220, 619, 620, 621, 622, 630, 634, 637, 639, 641, 642, 643, 644, 645, 646, 647, 652, 653, 654, 655, 656 Medial lobes, 42 Medullary cystic disease, 200, 217 Medulloblastoma, 296 MEG3, 528 MEG8, 528 Megacystis, 141 Megaepiphyses, 3, 99, 345 Megaspondyly, and Proteus syndrome, 478 Melanoma, 550 Melnick-Needles syndrome, 141–142, 142–144, 624, 631, 635, 644, 647, 651 Membranous vitreous anomaly, 89 Meningioma, 296 Meningocoele, 546, 550, 608 Meningoencephalocoele, 596 Meningomyelocoele, 608 Menkes disease, 602–603, 603–604, 620, 633, 634, 636, 640, 642, 648, 657 Mental retardation and acrodysotosis, 266 and Antley-Bixler syndrome, 500 and de Lange syndrome, 541 and Pfeiffer syndrome, 492 and Pierre Robin sequence, 89 Mesenchymal cells, 2, 4 Mesenchyme, 2, 4, 5 Mesoderm, lateral plate, 3, 4 Mesomelia, 55, 110, 196, 283 Mesomelic dysplasia Kantaputra type, 270, 638, 647, 653 Kozlowski-Reardon type, 281, 282, 468, 621, 638, 640, 653, 656 Langer type, 270, 271, 630, 631, 640, 647

Nievergelt type, 283, 638 Reardon-Kozlowski type, 468 Reinhardt-Pfeiffer type, 270 Robinow type, 270 Mesomelic limb shortening, 638 and acrofacial dysostosis, 512 and Desbuquois dysplasia, 121 and mesomelic dysplasia, 270, 281 and OFDS, 210 and Pallister-Hall syndrome, 587 and paternal uniparental disomy 14, 528 and Roberts syndrome, 550 and Schinzel-Giedion syndrome, 611, 612–613 MESP2, 3, 517–518, 519 Metabolic acidosis, 200 Metabolic syndromes, 31 Metacarpals, 244, 247, 320 absent, 573, 597 absent ossification of, 284, 592 and atelosteogenesis, 163–165 bases, 379 and boomerang dysplasia, 156 formation of, 4 hypoplastic, 536, 576 in osteocraniostenosis, 328, 330 proximal pointing of, 416 pseudoepiphyses of, 482 short, see Short metacarpals stippling of, 378 synostosis of, 496, 589 Metadiaphyses, 421 Metaphyseal anadysplasia (MANDP), 232, 233–234, 253, 642, 647, 649 Metaphyseal chondrodysplasia, see Cartilagehair hypoplasia Metaphyseal cupping, 3, 174, 197 Metaphyseal dysplasia (MD), 232, 233, 234, 254, 461, 462 Jansen type, 624, 633, 635, 642 with pancreatic insufficiency and cyclical neutropenia, 627 Shwachman-Bodian-Diamond type, 633, 635, 655, 657 Metaphyseal flaring, 174, 250 Metaphyseal fractures, 348, 457 Metaphyseal radiolucency, 312 Metaphyseal triangle, 453 Metaphyses, 230, 638 broad, 464 cupped, see Cupped metaphyses dense, 179, 445 domed, 151, 212, 273 expansion of, 176 flared, see Flared metaphyses frayed, 389–392, 399, 444 irregular, see Irregular metaphyses in kyphomelic dysplasia, 313 ossification defects of, 453 rounded, 151, 157, 162, 203 sclerotic, 398, 431 in skeletal survey, 19 sloping, 47, 206 smooth, 189, 191, 193, 206 spurred, 182, 196, 602 striated, 81, 388 wide, see Wide metaphyses

673

Index Metatarsals absent ossification of, 148, 592 attempted duplication of, 210 fused, 589 hypoplastic, 295, 298, 576 stippling of, 378 Metatarsus adductus, 142, 146 Metatropic dysplasia, 82, 95, 129, 176, 177–181, 260, 625, 627, 630, 631, 632, 639, 649, 650, 651, 655, 656 hyperplastic, 176, 180 Metopic ridge prominent, 496 Metopic suture, fusion of, 507 Metopic synostosis, 583 Microbrachycephaly, 540 Microcampomelia, 166 Microcephalic osteodysplastic primordial dwarfism, 632 type 2, 639 types 1 and 3, 618, 621, 624, 625, 626, 627, 639, 640 Microcephaly, 639 and CCM syndrome, 521–522 and cerebroarthrodigital syndrome, 591 and de Lange syndrome, 540 and DK phocomelia, 596 and Fanconi anaemia, 573 and Meckel syndrome, 217 and MOPD, 338 and Raine dysplasia, 403 and Roberts syndrome, 550–551 and Rubinstein-Taybi syndrome, 295 and Smith-Lemli-Opitz syndrome, 376 and Yunis-Varon dysplasia, 488 Microcornea, 333, 507, 541 Microcrania, 17, 597 Microglossia, 587 Micrognathia, 62, 79, 102, 189, 218, 562, 563, 640 and achondrogenesis, 58, 62, 65, 256 and acrofacial dysostosis, 510, 512 and atelosteogenesis, 108, 110 and Blomstrand dysplasia, 464 and boomerang dysplasia, 156 and brachydactyly Temtamy type, 298 and campomelic dysplasia, 302, 304, 306 and Catel-Manzke syndrome, 293 and CCM syndrome, 521, 522 and cerebro-osseous-digital syndrome, 593 and cleidocranial dysplasia, 482 and de Lange syndrome, 540, 542 and Desbuquois dysplasia, 121 and DTD, 111, 115 and femoral facial syndrome, 560, 561–564 and FFU syndrome, 566 and fibrochondrogenesis, 95 and hypochondrogenesis, 62, 65 and Kniest dysplasia, 82 and kyphomelic dysplasia, 313, 314, 315 and Larsen syndrome, 151 and Marfan syndrome, 218, 471 and Melnick-Needles syndrome, 141 and Menkes disease, 602 and mesomelic dysplasia, 270 and MOPD, 338

and multiple pterygium syndrome, 605, 606 and OFDS, 209, 210 and omodysplasia, 273 and OPD2, 148 and OSMED, 98 and Pallister-Hall syndrome, 587 and Roberts syndrome, 550–551 and Rubinstein-Taybi syndrome, 295 and SEDC, 73, 79 and Shprintzen-Goldberg syndrome, 504 and Smith-Lemli-Opitz syndrome, 376 and spondylometaphyseal dysplasia, 262 and SRPS, 186, 189, 191 and Stickler syndrome, 89, 90, 92, 93 Stuve-Wiedemann syndrome, 311 ultrasound assessment of, 14, 17 and Yunis-Varon dysplasia, 488 Micromelia, 39 and achondrogenesis, 58, 61, 105, 105, 256 and atelosteogenesis, 108, 162 and Blomstrand dysplasia, 464 and boomerang dysplasia, 156 and cerebro-osseous-digital syndrome, 593 and de Lange syndrome, 542 differential diagnosis of, 162 and dyssegmental dysplasia, 166 and Grebe dysplasia, 283 and Greenberg dysplasia, 371, 372 and lethal conditions, 16 and omodysplasia, 273 and osteogenesis imperfecta, 433 and platyspondylic dysplasia, 67 prenatal onset, 266 and SRPS, 182, 186 Stuve-Wiedemann syndrome, 311 and TD, 36, 39, 40, 43 Micromelic limb shortening, 641 Micropenis, 331, 338, 546, 596, 611 Microphthalmia, 630 and Fanconi anaemia, 573 and Hallerman-Streiff syndrome, 333 and Meckel syndrome, 217 and osteocraniostenosis, 328 and Roberts syndrome, 550 and warfarin embryopathy, 375 Microretrognathia, 421, 510, 521, 576 Microstomia, 333, 521, 541 Microtia, 596 Middle ear abnormalities, 573 Middle phalanges, 216, 477, 541 absent, 270, 286, 295, 426, 491 absent ossification of, 289 in atelosteogenesis, 162, 164 and cartilage-hair hypoplasia, 227 in FMD, 138 hypoplastic, 204, 295, 507, 613 short, 209, 210, 289, 298, 302, 309, 509, 541 Midface flattened, 48, 348 retraction, 611 Midface hypoplasia, 123 and achondroplasia, 46, 47 and Antley-Bixler syndrome, 500 and Apert syndrome, 496 and atelosteogenesis, 108 and boomerang dysplasia, 156

and brachydactyly Temtamy type, 298 and Carpenter syndrome, 507 and cleidocranial dysplasia, 482 and Greenberg dysplasia, 371 and OPD2, 148 and Pfeiffer syndrome, 491 and Raine dysplasia, 403 and Stickler syndrome, 89 Stuve-Wiedemann syndrome, 311 Midfacial haemangioma, 550 Midline dysplasias, 375 Mild craniosynostosis, 501 Mild dumbbell deformity, 173 and dyssegmental dysplasia, 168 Mild metaphyseal flaring, 56 Mild modification, 102 Mild platyspondyly, 100, 254 Mild-to-moderate micromelia, 312 MIP (maximum intensity projection), 17, 42 Mirror-image polydactyly of hands and feet, 580, 581, 626, 653, 654, 657 Missense, 73, 108, 151, 162, 491 Mitral valve prolapse, 89, 504 Mitten deformity, 14, 496, 497–498 MKKS, 599–600 MMC (mitomycin C), 550, 573 MMP9, 232 MMP13, 232 Molar tooth sign, 197, 218 Molecular diagnosis, 31–32 Monodactyly, 540, 546, 556, 577 Monosomies, 577 MOPD (microcephalic osteodysplastic primordial dwarfism), types 1 and 3, 338, 339–341 Morphogenesis, determinants of, 2 Morquio disease, 73 Mosaicism gonadal, 31, 36, 46, 145, 302 somatic, 58, 141, 151 Moustache-shaped clavicles, 321 Mouth carp, 540 downslanting corners, 605 inverted, 328 small, 260, 298 triangular, 405 MPR (multiplanar reformatted imaging), 17 MPS type 4, 73 MRI (magnetic resonance imaging) and achondrogenesis type 2, 62 and fetal lung volume, 16 and Kniest dysplasia, 82, 86 and postnatal examination, 19 and TD, 42 use of, 18 MRSHSS, 475 Mucolipidosis type 2 (I-cell disease), 348, 349–351, 616, 625, 626, 633, 635, 636, 641, 642, 644, 648, 652, 656 Muenke syndrome, 49, 518, 653 Multicystic dysplastic kidney, 562 Multiple coronal clefts, 100, 233 Multiple epiphyseal dysplasia autosomal recessive, 105, 111, 625, 654 and COL2A1, 58, 67, 73, 81, 82, 89

674 Multiple fractures, 328 and achondrogenesis, 256 and neonatal hyperparathyroidism, 457 and osteocraniostenosis, 328 Multiple healing fractures and achondrogenesis, 257 Multiple joint dislocations, 133, 157, 622, 625, 626, 630, 635, 640, 647, 650, 653 Multiple pterygium syndrome, 605–606, 606–607, 620, 621, 622, 624, 625, 626, 627, 630, 633, 634, 637, 640, 644, 646, 648, 649, 651, 653, 654, 656 Multiple sulphatase deficiency, 376 MURCS association, 518, 574, 635, 646 Muscle development, asymmetric, 478 Muscle weakness, 383, 591, 606 Muscular hypoplasia, 137, 591 Myelination, defective, 602 Myoclonic jerks, 209 Myopia and de Lange syndrome, 540–541 and fibrochondrogenesis, 95 and Kniest dysplasia, 82 and Marfan syndrome, 471 and multiple epiphyseal dysplasia, 58, 73, 81 and SEDC, 73 and spondyloepimetaphyseal dysplasia, 81 and Stickler syndrome, 89, 90 Myotome, 3, 3, 5, 5 Myotonia, 173 Myotonic chondrodystrophy, 172–173, 173–174, 625, 627, 628, 640, 649, 650, 651, 654 Nager acrofacial dysostosis, 630, 637 Nails aplastic, 488 dysplastic, 206 dystrophic, 212, 546 fusion, 496 hyperconvex, 611 hypoplastic, 330, 587 NANS, 249, 650 Nares, see Nostrils Narrow chest, 187, 189, 192, 206 differential diagnosis of, 176 and dyssegmental dysplasia, 166 and fibrochondrogenesis, 95 and Jeune syndrome, 200 and Kniest dysplasia, 82 and kyphomelic dysplasia, 313 and Schneckenbecken dysplasia, 260 and SRPS, 182, 188 and thoracolaryngopelvic dysplasia, 222, 223 Narrow fetal thorax, 37 Narrow interpedicular distances, 180 Narrow thorax, 19, 194, 197, 462 and achondrogenesis, 62, 105 and achondroplasia, 48 and Antley-Bixler syndrome, 500 and Astley-Kendall dysplasia, 386 and Blomstrand dysplasia, 465 and campomelic dysplasia, 309 and CCM syndrome, 521 and CED, 212

Index and chondroectodermal dysplasia, 203, 206–207 and Desbuquois dysplasia, 121 differential diagnosis of, 37, 47, 176, 186 and fibrochondrogenesis, 96 and Greenberg dysplasia, 371 and Jeune syndrome, 37, 176, 196, 200, 202 and kyphomelic dysplasia, 313, 315, 316 long, 200, 222, 464, 471 and Melnick-Needles syndrome, 141 and metatropic dysplasia, 176, 179 and omodysplasia, 273 and OPD2, 148 and opsismodysplasia, 266 and osteogenesis imperfecta, 433 and Shprintzen-Goldberg syndrome, 505 in spondylometaphyseal dysplasia, 262 and SRPS, 182, 184, 185, 186, 191, 194 and TD, 36, 37, 37, 39, 40 and warfarin embryopathy, 377 Nasal alae, hypoplastic, 551 Nasal bone, 515 aplasia, 482 Nasal bridge, 56, 542; see also Depressed nasal bridge; Flat nasal bridge broad, 148, 212, 376, 421, 546 high, 286 low, 49, 82, 256, 482, 611 Nasal hypoplasia, 286, 403 Nasal root, 156 short, 376, 587 Nasal tip, 56 bifid, 209 broad, 145, 560 bulbous, 286 Nasolacrimal duct duct stenosis, 541 obstruction, 426 Nasomaxillary hypoplasia, 375, 378 Natal teeth and chondroectodermal dysplasia, 206 and dysosteosclerosis, 398 and osteopathia striata, 421 and Pallister-Hall syndrome, 587 and Rubinstein-Taybi syndrome, 296 NBS1, 574 Neck pterygia, 606 short, see Short neck webbed, 574, 605 NEK1 mutations, 186 Neonatal hyperparathyroidism, 616, 633, 639, 642 Neonatal hypothyroidism, 657 Neonatal radiographs, 135 Neonates, 75 Neoplasias, 550 Nephronophthisis, 196 Neu-Laxova syndrome, 591, 593–594, 622, 630, 631, 632, 639, 652 Neural arches, 239 absent ossification of, 453 failure of fusion, 145 formation of, 3 underossification of, 482 Neural arch fusions, 491 Neural crest cells, 4 Neural tube defects, 518, 521, 608, 651

Neuroblastoma, 296 Neurodegeneration, 388, 398, 574, 602 Neurodevelopmental delay, 148, 151, 426, 507 Neurological abnormalities, 151, 382 Neuromuscular disorders, prenatal onset, 311 Neuronal degeneration, 602 Neuronal migration defects, 262 Neutrophilia, 411 Next-generation sequencing (NGS) technologies, 31 NFIX, 475 Nievergelt dysplasia, 653, 654 Nijmegen breakage syndrome (NBS), 574, 639 NIPBL, 540–541 Nipples absent, 464 hypoplastic, 540, 605 Nodular heterotopia, periventricular, 137, 141, 145 NOGGIN, 4 Non-accidental injury, 522, 633 Noonan syndrome, 622 Nose beaked, 295, 429, 496 flat, see Flat nose long, 286 pinched, 298 pointed, 333, 403 prominent, 338 saddle, see Saddle nose deformity short, see Short nose small, see Small nose Nostrils anteverted, see Anteverted nostrils hypoplastic, 156 upturned, 542 NOTCH2, 467–468 Notch pathway, 3 Nuchal oedema, 191 Nuchal thickening, 192, 293 Nuchal translucency (NT) and achondrogenesis, 256 and achondroplasia, 46 and CCM syndrome, 521 and CED, 212 and chondroectodermal dysplasia, 203 and de Lange syndrome, 540 and DTD, 111 and Holt-Oram syndrome, 536 and Jeune syndrome, 196 and OEIS complex, 608 and OFDS, 209 and osteogenesis imperfecta, 429 pathological, 20 in prognosis, 16 in Schneckenbecken dysplasia, 260 and sirenomelia, 568 and split hand-foot malformation, 576 and spondylocostal dysostosis, 517 and spondyloepimetaphyseal dysplasia, 81 and SRPS, 182 and TD, 36 and Zellweger syndrome, 382 Nucleus pulposus, 58 NXN, 276 Nystagmus, 73, 200, 573

675

Index Obesity, 295, 383, 507, 599 maternal, 568 OBSL1, 325 Occipital bone in Al-Awadi Raas-Rothschild syndrome, 546 flat, 382 midline defect, 187, 209 prominent, 307, 309, 338 spurred, 193 Occipital dysraphism, 192–193 Occipital encephalocoele, 166, 217, 218–220, 597 Occipital horn syndrome, 602, 636 Occipitoparietal synchondroses, 613 Occipitotemporal hyperplasia and TD, 39 Ocular coloboma, 532, 537 Oculo-auriculo-vertebral spectrum, 617 Oculo-dento-digital dysplasia, 333, 629, 630, 652 Oculomotor apraxia, 210 Oculomotor nerve cavernous angiomas, 550 ODCD, 236 Odontochondrodysplasia, 235, 236–240, 246, 618, 638, 649, 657 Odontoid hypoplasia, 73, 176, 266 Odontoid peg, 82 Odoontochondrodysplasia, 650 Oedema and cerebro-osseous-digital syndrome, 593 generalised, 182, 186, 191, 192 OEIS complex, 608–609, 609, 619, 620, 622, 623, 626, 631, 634, 635, 637, 645, 646, 647, 651, 654 Oesophageal atresia and Al-Awadi Raas-Rothschild syndrome, 546 and cartilage-hair hypoplasia, 224 and Gollop-Wolfgang complex, 556 and Kaufman-McKusick syndrome, 599 and VATER/VACTERL association, 531 Okihiro syndrome, 574, 622, 624, 628, 646 Olfactory bulbs absent, 209, 217, 521 Oligodactyly, 29, 544, 562, 641 and Al-Awadi Raas-Rothschild syndrome, 546 and de Lange syndrome, 540–541, 542–544 and femoral facial syndrome, 562 and FFU syndrome, 566–567 and Gollop-Wolfgang complex, 556 and Roberts syndrome, 550 and sirenomelia, 568, 570 in skeletal survey, 19 Oligodendroglioma, 296 Oligodontia, 145, 148 Oligohydramnios, 189, 642 and kyphomelic dysplasia, 338 and Meckel syndrome, 217, 220 and Melnick-Needles syndrome, 141 and OPD2, 148 and sirenomelia, 568 and SRPS, 189 Oligohypodontia, 137, 141 Oligomeganephronia, 576 Oligosyndactyly, 551, 566

Omenn syndrome, 224 Omodysplasia, 111, 151, 273, 274, 621, 632, 641 Omodysplasia, 277 Omodysplasia, recessive type, 622, 627, 634, 640, 656 OPD1, 137, 141, 145, 146, 148 OPD2, 137, 141, 145, 148, 149–150 Opitz B/GGG syndrome, 532 Opsismodysplasia, 235, 260, 266, 267–268, 616, 620, 628, 630, 633, 634, 636, 637, 638, 639, 641, 644, 645, 647, 648, 650, 655, 656, 657 Optic atrophy and brachydactyly Temtamy type, 298 and de Lange syndrome, 541 and dysosteosclerosis, 398 and osteopetrosis, 388 and warfarin embryopathy, 375 Oral-facial-digital syndromes (OFDS), 209, 211, 533, 553, 580, 623, 630, 640, 643, 646 shared features of, 209 type 1, 618, 619, 652 type 2, 652 type 4, 209, 210, 619, 623, 624, 630, 634, 635, 637, 638, 640, 643, 646, 652, 654, 656 type 8, 646 Orbital rim, 477 Orbits, shallow, 348, 496, 501, 574 Orofacial clefting, 576 Orofaciodigital syndrome type 4, 209, 210–211, 619, 620, 621, 624 Os centrale, 536 Osebold-Remondini dysplasia, 270, 638 Ossification absent, 156 centre distal, 122 deficient, 14 degree of, 14 and dyssegmental dysplasia, 170 ectopic, 109 endochondral, 95 endochondral ossification, 1–2 incomplete, 162 intramembranous ossification, 1 lateral mesoderm-derived bones, 1 mechanisms, 1 neural crest–derived bones, 1 periosteal, 148 subperiosteal, 166 Osteoarthritis and COL2A1, 58, 67, 73, 81, 82, 89 and OSMED, 98 premature, 89, 98 and spondyloepimetaphyseal dysplasia, 81 Osteoblasts, production of bone matrix, 2 Osteoclasts nonfunctional, 389 resorption lacuna, 388 resorption of bone matrix, 2 Osteocraniosclerosis, 630 Osteocraniostenosis, 328, 329–331, 618, 622, 625, 626, 628, 630, 632, 633, 634, 639, 642, 643, 644, 648, 650, 653

Osteodysplasty, 138, 141–142, 142–144, 623, 629, 631, 633, 636, 640, 642, 643, 647, 656; see also Melnick-Needles syndrome Osteogenesis imperfecta, 26, 429–431, 450, 616, 617, 620, 633, 635, 636, 637, 642, 643, 648, 651, 655, 656, 657 different types of, 430 identifying, 14–15 and long bones, 37 prognosis for, 15 radiographic features of, 431 recessive, 440–442 type 1, 431 type 2A, 432–434 type 2B, 432 type 2C, 435 type 3, 436–440 type 4, 442–443 type 5, 444–445 with craniosynostosis (Cole-Carpenter syndrome), 450, 616, 620, 626, 627, 653, 657 Osteoglophonic dysplasia, 626, 650 Osteomalacia, 430 Osteopaenia and Astley-Kendall dysplasia, 387 Osteopathia striata, 142, 421, 422–424 Osteopathia striata with cranial sclerosis, 619, 620, 621, 623, 624, 626, 628, 630, 631, 632, 633, 634, 635, 637, 640, 642, 643, 644, 647, 648, 650, 651, 652, 653, 654, 655 Osteopenia, 451 Osteoporosis, 333, 388–389, 389–392, 426, 429, 619, 620, 628, 630, 631, 633, 635, 637, 643, 644, 654 Osteosclerosis differential diagnosis of, 389, 398, 404 generalised, 388, 465 and Raine dysplasia, 403 OSTM1, 388 Otopalatodigital syndromes, 625 spectrum disorders, 111, 137, 141, 145, 148–149 type 1, 621, 627, 628, 630, 640 type 2, 616, 619, 620, 621, 623, 624, 628, 630, 631, 632, 633, 634, 640, 642, 644, 645, 646, 647, 649, 650, 651, 652, 656 Otospondylomegaepiphyseal dysplasia (OSMED), 98, 99–103, 621, 627, 628, 630, 631, 632, 635, 639, 640, 647, 649, 650, 654 Ovarian cystadenomas, 479 Overgrowth disproportionate, 478 syndromes, 617 Overmodelled long bones, 330, 331 Overtubulation, 469, 503 Ovoid radiolucency, 55, 56 P4HB, 450 Pachygyria, 249, 262 Pacman dysplasia, 348 Pain perception, decreased, 311, 541 Palate; see also Cleft palate arched, 440, 507

676 high, 295, 504 high arched, see High arched palate narrow, 488, 496, 546 Palatine ridges, prominent, 504 Pallister-Hall syndrome, 587–588, 588–589, 618, 619, 621, 622, 623, 624, 628, 630, 632, 634, 638, 640, 641, 643, 647, 652, 655 Palmar creases single, 382, 592, 611 Palpebral fissures downslanting, see Downslanting palpebral fissures small, 293 upward slanting, 382 Pancreas, malformed, 508 Pancreatic cysts, 196 Pancytopenia, 388, 541 Panhypopituitarism, 587 Parathormone levels, raised, 350 Parietal foramina, and cleidocranial dysplasia, 482 Partial duplication 3q, 639 Parvovirus infection, 430, 616 Patellae, dislocations of, 295 Paternal uniparental disomy 14, 528, 529–530, 638, 644, 651, 655, 656 Patterson-Stevenson-Fontaine syndrome, 510, 577 PCS (premature centromere separation), 550 Pebble beach appearance, 517, 519 Pectus carinatum and Desbuquois dysplasia, 121 and fibrochondrogenesis, 95 and Marfan syndrome, 471 and SEDC, 73 and Shprintzen-Goldberg syndrome, 504 and spondyloepimetaphyseal dysplasia, 81 Pectus excavatum and Catel-Manzke syndrome, 293 and CED, 212 and Marfan syndrome, 471 and Menkes disease, 602 and OPD1, 145 and Shprintzen-Goldberg syndrome, 504 Pedicle anomalies, 649 Pedicles, 59 absent, 593, 593 and achondrogenesis, 256 narrow, 138, 143, 149 ossification of, 59, 62, 257, 519 in Shprintzen-Goldberg syndrome, 504 in skeletal survey, 19 Pelger-Huet anomaly (PHA), 371, 372, 574 Pelvic angle, widened, 608–609 Pelvic bones in hypophosphatasia, 452 hypoplastic, 546 and mesomelic dysplasia, 271 Pelvic girdles, 448 Pelvic inlet, narrow, 222, 504, 506 Pelvic outlet, narrow, 143, 149 Pelvis, 527 examining, 14–15 radiograph, 37 in skeletal survey, 19 Pelviureteric junction obstruction, 375

Index Penis; see also Micropenis hypoplastic, 189 small, 589 Pentalogy of Cantrell, 609, 623, 631 Pericardial effusion, 433 Perinatal death, 18, 137, 430, 528 Periodontitis, 151 Periosteal cloaking, 348, 412 Periosteal hyperostosis, 408, 411 Periosteal new bone formation, 19, 403, 406, 408, 412 Periosteal thickening, 413 Perlecan, 166 Peromelia, 566 Peroxisome biogenesis disorders (PBDs), 382 Pfeiffer syndrome, 491–492, 492–494, 616, 617, 618, 620, 621, 623, 626, 628, 630, 631, 634, 635, 643, 645, 652, 653, 654 Pfeiffer syndrome type 2, 622 Phaeochromocytoma, 296 Phalanges; see also Distal phalanges; Middle phalanges; Proximal phalanges; Terminal phalanges absent, 576 absent ossification of, 59, 138 accessory, 300 angel-shaped, 320 and atelosteogenesis, 162, 164 and boomerang dysplasia, 156 broad, 151 and chondroectodermal dysplasia, 203 hypoplastic, 108, 148, 576 short, 111, 148, 287 tombstone, 163 Philtrum, 542 elongated, 302 long, see Long philtrum protruding, 528 short, 286, 328 Phocomelia; see also DK phocomelia and acrofacial dysostosis, 510 atypical, 29 differential diagnosis of, 551 and Holt-Oram syndrome, 536 and Roberts syndrome, 550–551 Phosphoethanolaminuria, 452 Piepkorn dysplasia, 156, 633, 641, 642, 643, 650, 652, 655 Piepkorn dysplasia (atelosteogenesis type 1), 626 Pierre Robin sequence and CCM syndrome, 521 differential diagnosis of, 293, 522 and Stickler syndrome, 89 Pilomatrixomas, 296 Pinnae, cystic lesions of, 111 Plantar oedema, 106 Platybasia, 431 Platyspondylic dysplasia, Torrance type, 37, 68–71, 73, 81, 635, 637, 638, 641, 644, 645, 650, 655, 656 Platyspondyly, 62, 79, 99, 127, 132, 242, 247, 250, 649 and achondroplasia, 48, 50, 52 and Astley-Kendall dysplasia, 386, 387 and atelosteogenesis, 108, 109, 162

and boomerang dysplasia, 156 and cerebroarthrodigital syndrome, 591 differential diagnosis of, 176 and DTD, 111 and dysosteosclerosis, 398, 399–402 and fibrochondrogenesis, 96 and Greenberg dysplasia, 371, 372 and Hallerman-Streiff syndrome, 333 and hypochondrogenesis, 62, 65 and Kniest dysplasia, 82 and kyphomelic dysplasia, 316 and metatropic dysplasia, 176, 177, 179, 180, 181 and OPD2, 148 and opsismodysplasia, 266, 268 and OSMED, 99 and osteocraniostenosis, 328, 330 and Schneckenbecken dysplasia, 260 and SEDC, 79 in skeletal survey, 14 and spondylometaphyseal dysplasia, 81, 262 and SRPS, 182 and Stickler syndrome, 89, 91 and TD, 36, 39, 40 thoracolumbar, 338 Pleural effusions, 187, 416 PLOD2, 447, 448 PNET (primitive neuroectodermal tumors), 611 Poikiloderma, 511, 574, 596 Poland sequence, 14 Poland syndrome, 518, 574, 652 Polycystic kidneys and Meckel syndrome, 217 and OFD1, 209 and SRPS, 182, 186 Polydactyly, 209, 554, 643; see also Postaxial polydactyly; Preaxial polydactyly and achondrogenesis type 2, 58 and Al-Awadi Raas-Rothschild syndrome, 546 and boomerang dysplasia, 156 and chondroectodermal dysplasia, 204–208 differential diagnosis of, 583 and Fanconi anaemia, 573 and Grebe dysplasia, 283 and Greenberg dysplasia, 371 and Jeune syndrome, 197, 199 and Kaufman-McKusick syndrome, 599 and Meckel syndrome, 217–218 mesoaxial, 587, 588, 599 and OFDS, 209 and Pallister-Hall syndrome, 588 in skeletal survey, 13–14, 19 and SRPS, 182, 184, 186, 187, 189, 191 Polyhydramnios, 23, 644 and achondrogenesis, 105, 256 and Apert syndrome, 496 and atelosteogenesis, 108, 162 and Blomstrand dysplasia, 464 and boomerang dysplasia, 156 and Caffey disease, 411 and Carpenter syndrome, 507 and CCM syndrome, 521 and cerebro-osseous-digital syndrome, 593

677

Index and Chitayat (1993) hyperphalangism, 300 and Desbuquois dysplasia, 121 and dysplastic cortical hyperostosis, 416 and dyssegmental dysplasia, 166 and fetal akinesia, 151 and Greenberg dysplasia, 371 and hypophosphatasia, 452 and Jeune syndrome, 196 and Kaufman-McKusick syndrome, 599 and Kniest dysplasia, 82 and multiple pterygium syndrome, 605 and OPD2, 148 and opsismodysplasia, 266 and paternal uniparental disomy 14, 528, 530 and platyspondylic dysplasia, 67 and Raine dysplasia, 403 and Rubinstein-Taybi syndrome, 295 and Schinzel-Giedion syndrome, 611 and Schneckenbecken dysplasia, 260 and SEDC, 73 and SLE, 378 and Stickler syndrome, 89 and thoracolaryngopelvic dysplasia, 222 and VATER/VACTERL association, 531 and warfarin embryopathy, 375 and Yunis-Varon dysplasia, 488 Polymicrogyria, 95, 209, 217, 488, 620 Polysyndactyly, 188 and Greig syndrome, 583 and OFD4, 209 and SRPS, 188 Polyuria, and neonatal hyperparathyroidism, 457 POR, 500 PORCN, 577 Porencephaly, 262, 596 Portal fibrosis, 372 Positional deformities, 14, 17, 311 Postaxial limb defects, 511, 574 Postaxial polydactyly, 204, 207, 208, 214, 219 and Carpenter syndrome, 507, 509 and CED, 212 and chondroectodermal dysplasia, 203, 204 differential diagnosis of, 14, 587–588 and Greenberg dysplasia, 372 and Jeune syndrome, 196 and Kaufman-McKusick syndrome, 599, 600 and Meckel syndrome, 217, 218–220 and OFDS, 210–211 and osteopathia striata, 421 and Pallister-Hall syndrome, 587 and Schinzel-Giedion syndrome, 611 and Smith-Lemli-Opitz syndrome, 376 and SRPS, 184 type A, 583 Posterior cleft palate, 193, 210, 308 Posterior encephalocoele, 596 Posterior fossa cysts, 192, 212 hypoplastic, 403 small, 149, 403 Posterior laryngeal cleft, 587 Posterior lobes, 42 Posterior vertebral arches, 137 Post-termination, 200, 202

Postural deformities, 17 diagnosis of, 17 fixed, 13 Potter face, 328 Potter syndrome, 632 PPIB, 429, 430 Prader-Willi syndrome, 383 Preauricular tags, 510, 645 Preaxial polydactyly, 29–30 and acrofacial dysostosis, 510 and femoral facial syndrome, 560 and Greig syndrome, 584 and Pfeiffer syndrome, 491 and split hand-foot malformation, 577 type 4, 583, 643 and VATER/VACTERL association, 531 Prefrontal oedema, 295, 540 Pregnancies examining, 17 history, 31 termination of, 32 Prenatal sonography, 61 Progeroid appearance, 426 Progeroid syndrome, 333 Prognathism, 491, 496, 540 Prominent abdomen, 68 in achondrogenesis, 105 in fibrochondrogenesis, 95 in opsismodysplasia, 266 in platyspondylic dysplasia, 67, 68 in Schneckenbecken dysplasia, 260 in SEDC, 74 Prominent forehead in achondroplasia, 46 in Larsen syndrome, 151 in metatropic dysplasia, 176 in OFDS, 209 in OPD2, 148 in opsismodysplasia, 266 in osteocraniostenosis, 328 in Schinzel-Giedion syndrome, 611 in Shprintzen-Goldberg syndrome, 504 in SRPS, 182, 186, 191 and TD, 36, 39 Proptosis and Antley-Bixler syndrome, 500 and Apert syndrome, 496, 498 and Blomstrand dysplasia, 464 and Caffey disease, 411, 412 and cerebro-osseous-digital syndrome, 593 and Desbuquois dysplasia, 121 and Melnick-Needles syndrome, 141 and OFDS, 210 and osteopetrosis, 388 and Pfeiffer syndrome, 491 and Raine dysplasia, 403, 405 relative, 98, 498 and Schinzel-Giedion syndrome, 611 and Stickler syndrome, 90 Proptosis Antley-Bixler syndrome, 630 Proteoglycans, 105, 108, 111 Proteus syndrome, 478–479, 479–480, 617, 619, 620, 628, 630, 634, 637, 647, 652, 653 Protuberant abdomen, 645 and achondrogenesis, 58, 105, 256 and atelosteogenesis, 108

and Blomstrand dysplasia, 464 and CED, 212 and Greenberg dysplasia, 372 and paternal uniparental disomy 14, 530 and platyspondylic dysplasia, 67 and SRPS, 182, 186 Proximal femora monkey wrench appearance, 121, 124 stippling of, 379, 386 ultrasound of, 46 Proximal fibullae, short, 281 Proximal focal femoral deficiency, 617, 647 Proximal humeral epiphyses, 189, 205 Proximal humeral metaphyses, 216 Proximal humeri delayed ossification of, 537 sloped, 203, 212 Proximal phalanges, 125 and atelosteogenesis, 108, 109, 162 duplicated, 295, 507, 509 hypoplastic, 295 and Kniest dysplasia, 82 medial displacement of, 295 radial angulation of, 298 triangular, 300, 492 Proximal radii, 278 short, 267 Proximal radioulnar synostosis and mesomelic dysplasia, 282 Proximal tibial epiphysis, 51, 90 Proximal ulnae bowed, 592 curved, 115, 266 Prune belly anomaly, 141, 609 Prune-belly syndrome, 647 Pseudarthrosis, 16, 482–483, 485, 546 Pseudodiastrophic dysplasia, 108, 111, 122, 133, 134–136, 152, 621, 625, 627, 647, 650, 651, 654 Pseudoepiphyses, 82, 108, 109, 145, 482 Pseudofracture, 412 Pseudoprogeria-Hallermann-Streiff syndrome (PHS), 333, 342 Psychomotor retardation, 522 PTCH1, 583 PTEN mutations, 478–479, 531 Pterygia and CCM syndrome, 521 and kyphomelic dysplasia, 313 multiple, 605; see also Multiple pterygium syndrome PTHLH, 2 PTHR (parathyroid hormone receptor), 464 PTHR1, 461 Ptosis and CCM syndrome, 521 and Fanconi anaemia, 573 and MOPD, 339 and multiple pterygium syndrome, 605 Pubic bones in achondrogensis, 256 delayed ossification of, 266 unossified, 148 Pubic rami, 160, 230, 331, 527, 547 absent, 547 absent ossification of, 307, 331, 484, 591, 593

678 broad, 311 hypoplastic, 608–609 in platyspondylic dysplasia, 67 in SEDC, 73, 74 short, 151, 482, 611, 612–613 in skeletal survey, 19 in spondyloepimetaphyseal dysplasia, 81 unossified, 157 Pubic rami short/absent, 645 and campomelic dysplasia, 303 Pubis, hypoplastic, 110 Pulmonary artery dilatation, 471, 532 Pulmonary embolism, 479 Pulmonary emphysema, 471 Pulmonary hypertension, 399, 536 Pulmonary hypoplasia, 187 and CCM syndrome, 521 and Desbuquois dysplasia, 121 and femoral facial syndrome, 560 and fetal akinesia, 152 and Greenberg dysplasia, 371 and multiple pterygium syndrome, 605 and OPD2, 148 and osteogenesis imperfecta, 433 prognosis for, 16 and Raine dysplasia, 403 and sirenomelia, 568 and small thorax, 14 and SRPS, 182, 186, 187, 191 Pulmonary insufficiency, 148 Pulmonary stenosis and de Lange syndrome, 540 and FMD, 137 Pulmonary valves, dysplastic, 399 Pulmonary venous drainage, anomalous, 209 Pulsed Doppler, 207 Pycnodysostosis, 394, 395–397, 626, 633, 640, 643, 648, 651, 653, 655, 657 Pyknoachondrogenesis, 404 RAD21, 540–541 Radial aplasia and acrofacial dysostosis, 510 and Baller-Gerold syndrome, 492, 496, 500 and Roberts syndrome, 550 Radial dysplasia, 531 Radial head dislocation and Blomstrand dysplasia, 464, 465 and campomelic dysplasia, 302, 304, 306 and DTD, 112–115 and FHUFS, 563 and mesomelic dysplasia, 281 and MOPD, 338 and omodysplasia, 273 and osteogenesis imperfecta, 431 and Shprintzen-Goldberg syndrome, 504, 505 Radial heads dislocated, 144 multiple dislocations, 124 subluxation, 611, 613 Radial hypoplasia, 14, 521, 537, 546, 573–574, 596 and Al-Awadi Raas-Rothschild syndrome, 546 and CCM syndrome, 521 and DK phocomelia, 596 and Fanconi anaemia, 573–574

Index and Holt-Oram syndrome, 536–537 sequence, 14 Radial ray defects, 645 and acrofacial dysostosis, 510 and de Lange syndrome, 540 differential diagnosis of, 532, 537, 551, 574 and DK phocomelia, 596 and Fanconi anaemia, 573 and Holt-Oram syndrome, 536 and postural deformities, 14 and VATER/VACTERL association, 531 Radii, 134, 544 bowed, 67, 191, 270, 271, 464 in hypophosphatasia, 452 in Roberts syndrome, 550 spurred, 454 Radiography, in diagnosis, 13 Radiohumeral synostosis, 500–501, 502, 503, 550, 556, 561, 566, 593 Radiological diagnosis, 345 Radioulnar synostosis, 502, 503 and acrofacial dysostosis, 510 and Antley-Bixler syndrome, 500 and de Lange syndrome, 540–541 and femoral facial syndrome, 560 and Holt-Oram syndrome, 536 proximal, 281, 510, 606 and split hand-foot malformation, 576–577 and talipes equinovarus, and multiple pterygium syndrome, 605–606 in TD, 36 and VATER/VACTERL association, 531 Raine dysplasia, 403–404, 404–406, 619, 620, 621, 622, 626, 628, 630, 631, 632, 633, 634, 639, 643, 644, 647, 653, 655, 656, 657 Raine syndrome, 416, 625, 637, 640 RANK, 388 RBM8A, 511, 551 Recessive Larsen syndrome, 117, 118–119, 650 RECQL3, 574 RECQL4, 492, 496, 501, 507, 511, 541, 574 Rectal atresia, 531, 608 Rectovaginal fistula, 608 Reduction defects, 540–541, 551, 551 Redundant skin and achondrogenesis, 62 and CCM syndrome, 521 and cerebroarthrodigital syndrome, 592 and osteocraniostenosis, 328 and paternal uniparental disomy 14, 528 and Schinzel-Giedion syndrome, 611 and spondylometaphyseal dysplasia, 262 Reinhardt-Pfeiffer mesomelic dysplasia, 647 Reinhardt-Pfeiffer syndrome, 638 Renal agenesis and Al-Awadi Raas-Rothschild syndrome, 546 and MURCS association, 574 and Pallister-Hall syndrome, 587 and sirenomelia, 568, 569 Renal anomalies, 646 and Antley-Bixler syndrome, 500 and CCM syndrome, 521 and Fanconi anaemia, 573 and Holt-Oram syndrome, 536 and OEIS complex, 608–609 and Roberts syndrome, 550

and Rubinstein-Taybi syndrome, 295 in SRPS, 182 in TD, 36 and VATER/VACTERL association, 531 Renal coloboma syndrome, 628, 635 Renal cysts, 526 and Jeune syndrome, 196 and Schinzel-Giedion syndrome, 611 and Zellweger syndrome, 382 Renal failure, chronic, 212 Renal insufficiency, 197, 218 Renal pelvis, dilated, 612–613 Respiratory difficulties, and Rubinstein-Taybi syndrome, 295 Respiratory distress, 308 and achondroplasia, 46 and acrofacial dysostosis, 510 and campomelic dysplasia, 302, 308 and Catel-Manzke syndrome, 293 and CCM syndrome, 521 and Desbuquois dysplasia, 121 and dysosteosclerosis, 399 and dyssegmental dysplasia, 166 and Jeune syndrome, 200 and Kaufman-McKusick syndrome, 599 and metatropic dysplasia, 176, 178 and neonatal hyperparathyroidism, 457 and opsismodysplasia, 266 and Pallister-Hall syndrome, 587 and Shprintzen-Goldberg syndrome, 504 and Stuve-Wiedemann dysplasia, 311 Respiratory failure and cerebroarthrodigital syndrome, 591 and Menkes disease, 602 Respiratory infection, 266, 399 Respiratory insufficiency and CCM syndrome, 521 and DTD, 111 and Holt-Oram syndrome, 537 and spondylocostal dysostosis, 517 Reticuloendotheliosis, 224 Retinal abnormalities, 209, 212, 599 Retinal atrophy, 388 Retinal detachment, 81, 82, 89 Retinal dysfunction, 295 Retinitis pigmentosa and CED, 212 and Jeune syndrome, 196 and Kaufman-McKusick syndrome, 599 and spondylometaphyseal dysplasia, 81 Retinoic acid, 587 Retrognathia, 281, 597 Rhabdomyosarcoma, 296, 550 Rhizomelia and Jeune syndrome, 196 Rhizomelic limb shortening, 647 and achondroplasia, 46, 49 and atelosteogenesis, 108, 162, 164 and DTD, 111 and dysplastic cortical hyperostosis, 416 and Greenberg dysplasia, 371 and hypochondroplasia, 56 and Larsen syndrome, 151 and mesomelic dysplasia, 270 and omodysplasia, 274 and OSMED, 98

679

Index and spondylometaphyseal dysplasia, 262, 263 and warfarin embryopathy, 377 Rhizomelic spondylo-metaphyseal dysplasia LBR-related, 637 with remission, 253, 254–255, 647 Rhizomelic type chondrodysplasia punctata, 625 Ribbon ribs, 148, 504 Rib cage deformities, 457 small, 111 Rib fractures in hypophosphatasia, 452 multiple, 257, 433, 445, 457 and osteogenesis imperfecta, 15, 431, 431, 437 Ribs, 230, 448, 462, 469, 502 abnormal numbers of, 505 absent ossification of, 521, 522 and Astley-Kendall dysplasia, 387 beaded, 429, 433–435, 437 bones, 501 broad, 432 coat-hanger deformity, 19, 213, 528 curved, 260, 260, 261, 528 in dysplastic cortical hyperostosis, 416 and fibrochondrogenesis, 96 formation of, 4 fusion, 16, 521, 532 gaps, 521–522, 525, 527 horizontal, 58, 186, 193, 222 irregular, 294, 453 missing, 519, 521, 606 ‘moth-eaten’ appearance, 371 periosteal cloaking of, 412 sclerotic, 426, 427 short, see Short ribs in skeletal survey, 19 slender, see Slender ribs thickened, 414 thin, 440, 441 ultrasound image of, 39 wavy, 138, 517, 519, 525, 527, 606 wide, 148, 411, 546, 593, 611, 612–613 Richieri-Costa 1985, 637 Richieri-Costa brachydactyly, 298, 618, 636 Richieri-Costa-Pereira syndrome, 654 Rickets, 266, 457 Right femur, 431, 557, 562 Right tibia, 448, 557, 566 Right ventricular outflow tract obstruction, 148 RMPR mutations, 225 Roberts syndrome, 511, 546, 551–552, 618, 619, 620, 621, 623, 626, 628, 629, 630, 631, 634, 635, 637–641, 646, 647, 652, 653 Robinow dysplasia/syndrome, 276–277, 277–279, 286, 616, 618, 621, 627, 628, 630, 634, 635, 637, 638, 647, 651, 652 ROR2, 276, 286 Rotated ears and OPD2, 148 and spondylometaphyseal dysplasia, 262 RTL1, 528

Rubinstein-Taybi syndrome, 295–296, 296, 619, 623, 627, 628, 629, 635, 639, 640, 643, 644, 647 RUNX2, 1, 482 Sacral agenesis, 14, 568, 591 Sacrococcygeal agenesis, 568 Sacrococcygeal teratomas, 611 Sacroiliac notches, 262 Sacrosciatic notches and achondroplasia, 47 in hypochondrogenesis, 65 narrow, 95, 96 in platyspondylic dysplasia, 67 wide, 176, 591, 593 Sacrum absent, 569, 608 hypoplastic, 569 long, 179, 180 short, 532, 560 unossified, 593 SADDAN (Severe Achondroplasia with Development Delay and Acanthosis Nigricans), 37, 47, 55 Saddle nose deformity, 46 Saethre-Chotzen syndrome, 492, 496, 500, 507, 617, 621, 623, 626, 628, 653 Sagittal clefts, 179 and atelosteogenesis, 162 and campomelic dysplasia, 306 and CCM syndrome, 521 and cerebro-osseous-digital syndrome, 593 and VATER/VACTERL association, 532 Sagittal craniosynostosis, 212, 213, 215 Sagittal notches, midline, 51 Sagittal sutures, 431 Sagittal synostosis, 507 SALL1, 537 SALL4, 537, 574 Sandal gap, 145, 146 Sanger sequencing, 31 Saul-Wilson syndrome, 342, 343–346, 617, 626, 628, 635, 637, 639, 650, 651, 653, 654, 657 SBDS, 229 Scalp oedema, 371 Scaphocephaly, 14, 17, 209 Scaphoid, hyoplastic, 536 Scapulae in Caffey disease, 411, 412, 414 in campomelic dysplasia, 302, 307 dysmorphic, 36 in Greenberg dysplasia, 371 hypoplastic, 302, 307, 500 sclerotic, 427, 431 short, 260 in skeletal survey, 19 small, 191 in spondylometaphyseal dysplasia, 262 stippling of, 386 striated, 421 Scapular anomalies, 655 Scapuloiliac dysostosis, 616, 636, 655 Scheckenbecken dysplasia, 636 Schinzel-Giedion syndrome, 611, 612–613, 619, 620, 623, 624, 628, 630, 631, 633, 634, 638, 639, 643, 644, 645, 647, 654

Schizencephaly, 209 Schneckenbecken dysplasia, 58, 67, 95, 260, 260–261, 617, 618, 621, 625, 627, 637, 638, 639, 641, 644, 645, 650, 655, 657 Schwartz-Jampel syndrome, 172–173 Schwartz-Jampel syndrome type 2, 616, 621 Sclerae blue, see Blue sclerae blue-grey, 300 white, 430 Sclerosis, generalised, 399, 464 Sclerosteosis, 421, 652 Sclerotic metaphyses, 180 Sclerotome, 3 Scoliosis, 650 and atelosteogenesis, 162 and Caffey disease, 408 and campomelic dysplasia, 306 and Catel-Manzke syndrome, 293, 294 and CCM syndrome, 521 and cleidocranial dysplasia, 482 and DK phocomelia, 596 and dyssegmental dysplasia, 166 and FMD, 137 and hypochondroplasia, 54 investigation of, 17 and Kniest dysplasia, 82 and Larsen syndrome, 151 and Marfan syndrome, 471 and Melnick-Needles syndrome, 141 and multiple pterygium syndrome, 605 and OPD2, 148 and Shprintzen-Goldberg syndrome, 504 and spondylocostal dysostosis, 517 and spondyloepimetaphyseal dysplasia, 81 and Stickler syndrome, 89 Stuve-Wiedemann syndrome, 311 and VATER/VACTERL association, 531 Scrotal raphe, 599 Scrotum, 189, 298, 496 Scurvy, 603 SEC24D, 450 Seckel syndrome, 639 Segmentation abnormalities, 500 Segmentation clock, 3, 517 Segmentation defects, 651 and atelosteogenesis, 162 differential diagnosis of, 518 and Gollop-Wolfgang complex, 556 and Larsen syndrome, 151 and OEIS complex, 609 and sirenomelia, 568, 569 and spondylocostal dysostosis, 517–518 and talipes equinovarus, and multiple pterygium syndrome, 605 and VATER/VACTERL association, 531 vertebral, see Vertebral segmentation defects Seizures and de Lange syndrome, 541 and Greig syndrome, 583 and Hallerman-Streiff syndrome, 333 and Menkes disease, 602 and Pallister-Hall syndrome, 587 and Pfeiffer syndrome, 491 and spondylometaphyseal dysplasia, 262, 263 and TD, 36

680 SEMD, 249, 250–252 SEMD NANS-related, 635 SEMD short limb abnormal calcification type, 241, 242–244, 632, 637 SEMD Strudwick type, 635, 648 SEMD with immune deficiency and intellectual disability, 246, 247 SEMD with Joint Laxity (SEMD-JL), 127, 127–128, 129, 130–132 Beighton type, 129, 631, 632, 654 Hall and Beighton types, 635 Hall type, 127 type 2, 129 Septal defects, 623; see also Ventricular septal defects and CCM syndrome, 521 and Desbuquois dysplasia, 121 and FMD, 137 and Holt-Oram syndrome, 536 and OPD2, 148 Septum pellucidum, 339, 560 Serpentine fibula-polycystic kidney disease, 142, 647 Serpentine fibula syndrome, 467–468 SERPINF1, 430 SERPINH1, 429 Sethre-Chotzen syndrome, 652 Sex reversal, 302 SHH, 580 Short bowel syndrome, 608 Shortening, 616 Short femora, 562 Short femoral necks, 76 Short femur and achondroplasia, 49 and Antley-Bixler syndrome, 501 and atelosteogenesis, 110 and femoral facial syndrome, 562 and hypophosphatasia, 453 Short fibulae, 270, 303, 431 dislocated, 306 Short fingers and achondroplasia, 48 and brachydactyly type B, 286 and brachydactyly type C, 288 and Lenz-Majewski dysplasia, 426 and mucolipidosis, 348 and Yunis-Varon dysplasia, 489 Short forearms, 284 Short humerus and femoral facial syndrome, 560 and Grebe dysplasia, 283 and Holt-Oram syndrome, 537 and metatropic dysplasia, 176 Short ilia, 236, 250 Short limbs, 30, 68, 187, 189, 192 and Astley-Kendall dysplasia, 386 and atelosteogenesis, 162 and campomelic dysplasia, 308, 309 and cartilage-hair hypoplasia, 224 and CED, 212 and cerebro-osseous-digital syndrome, 593 and chondroectodermal dysplasia, 203, 204 diagnosis of, 13, 17 and DTD, 111 and dysplastic cortical hyperostosis, 416, 416 and femoral facial syndrome, 560

Index and fibrochondrogenesis, 95 and hypochondroplasia, 55 and hypophosphatasia, 452 and Jeune syndrome, 196, 200 and Kniest dysplasia, 82 and kyphomelic dysplasia, 313 and metatropic dysplasia, 176 and MOPD, 338 and mucolipidosis, 348 and osteocraniostenosis, 328 and osteogenesis imperfecta, 429, 430, 433, 440 and paternal uniparental disomy 14, 528 and Roberts syndrome, 550 and SEDC, 74 and spondylometaphyseal dysplasia, 262 and SRPS, 182, 186, 187, 189, 191, 192 Short long bones, 68, 71 and achondrogenesis, 258 and achondrogenesis type 2, 58, 62 and atelosteogenesis, 108, 162 and cartilage-hair hypoplasia, 224 and cerebro-osseous-digital syndrome, 593 and chondroectodermal dysplasia, 203 and cleidocranial dysplasia, 482 and diastrophic dysplasia, 111 and DTD, 111, 112–114 and dyssegmental dysplasia, 166, 167 and fibrochondrogenesis, 95 and Grebe dysplasia, 283 and Jeune syndrome, 196 and Kniest dysplasia, 83, 87 and mesomelic dysplasia, 270, 281 and metatropic dysplasia, 180 and mucolipidosis, 350 and OPD2, 148 and opsismodysplasia, 266 and OSMED, 99 and osteocraniostenosis, 328 and platyspondylic dysplasia, 67 and Roberts syndrome, 551 and SRPS, 176, 184, 191 and Stickler syndrome, 89 Short metacarpals, 111 and brachydactyly Temtamy type, 298 and brachydactyly type C, 288, 289 and de Lange syndrome, 541 and Desbuquois dysplasia, 121 and diastrophic dysplasia, 111 and FMD, 138 and frontometaphyseal dysplasia, 138 and Larsen syndrome, 152 and mesomelic dysplasia, 270 and OPD1, 146 and OPD2, 148 and Schinzel-Giedion syndrome, 611 Short neck and achondrogenesis, 58, 105, 256 and cerebro-osseous-digital syndrome, 593 and Kniest dysplasia, 82 and MOPD, 338 and opsismodysplasia, 266 and paternal uniparental disomy 14, 528 and platyspondylic dysplasia, 67 and Schinzel-Giedion syndrome, 611 and spondylometaphyseal dysplasia, 262 and SRPS, 182, 191

Short nose and achondrogenesis, 58, 256 and Chitayat (1993) hyperphalangism, 300 and femoral facial syndrome, 560 and omodysplasia, 273 and opsismodysplasia, 266 and Pallister-Hall syndrome, 587 and Stuve-Wiedemann syndrome, 311 upturned, 541, 560, 611 Short rib-polydactyly group (SRP), 197 Short ribs, 194 and achondrogenesis, 58, 59, 257 and Astley-Kendall dysplasia, 386 and atelosteogenesis, 110 and Blomstrand dysplasia, 464, 465 and CED, 212 and chondroectodermal dysplasia, 203, 204, 206 and dysplastic cortical hyperostosis, 416 and dyssegmental dysplasia, 167 and fibrochondrogenesis, 95 and Greenberg dysplasia, 371 and hypophosphatasia, 452 and Jeune syndrome, 196, 197 and kyphomelic dysplasia, 313 and metatropic dysplasia, 176, 179–180 and opsismodysplasia, 266 and platyspondylic dysplasia, 67 and Schneckenbecken dysplasia, 260 and spondylometaphyseal dysplasia, 263 and SRPS, 183, 189, 191, 194 and TD, 36, 39, 40 and thoracolaryngopelvic dysplasia, 222 Short rib-thoracic dysplasia, 196–197, 197–202 Short sciatic notches and dyssegmental dysplasia, 167 Short stature and Al-Awadi Raas-Rothschild syndrome, 546 and atelosteogenesis, 162 and boomerang dysplasia, 156 and brachydactyly type C, 288 and campomelic dysplasia, 302 and cartilage-hair hypoplasia, 224 and CCM syndrome, 521 and chondroectodermal dysplasia, 203 and cleidocranial dysplasia, 482 and de Lange syndrome, 541 and Desbuquois dysplasia, 121–122 and dysosteosclerosis, 398 and Fanconi anaemia, 573 and Grebe dysplasia, 283 and Hallerman-Streiff syndrome, 333 and hypochondroplasia, 54 and Jeune syndrome, 196 and Kniest dysplasia, 82 and kyphomelic dysplasia, 313 and mesomelic dysplasia, 281 and OFDS, 209 and opsismodysplasia, 266 and osteogenesis imperfecta, 430 and Pierre Robin sequence, 89 progressive, 286, 295 and Roberts syndrome, 550 and SEDC, 73 and spondyloepimetaphyseal dysplasia, 81 and Stuve-Wiedemann dysplasia, 311

681

Index Short tibiae, 214 and campomelic dysplasia, 307 and chondroectodermal dysplasia, 206 and OFDS, 210, 211 in osteogenesis imperfecta, 431 Short trunk and achondrogenesis, 58, 105, 256 and cerebro-osseous-digital syndrome, 593 and dysplastic cortical hyperostosis, 416 and metatropic dysplasia, 176 Short tubular bones absent, 546 absent ossification of, 591 and atelosteogenesis, 162 and Blomstrand dysplasia, 465 and dyssegmental dysplasia, 166 and frontometaphyseal dysplasia, 138 and Melnick-Needles osteodysplasty, 142–143 and metatropic dysplasia, 176, 179 and opsismodysplasia, 266, 267, 268 and platyspondylic dysplasia, 67 syndactyly of, 577 Short ulnae and mesomelic dysplasia, 270 and OFDS, 209 Shoulders, 448 contractures of, 338 girdle, 482, 536, 560, 596 narrow, 482 SHOX, 55, 270 Shprintzen-Goldberg syndrome, 138, 142, 471, 504, 505–506, 620, 621, 622, 625, 626, 627, 628, 630, 631, 635, 636, 639, 640, 648, 649, 651, 654, 656, 657 Shwachman-Bodian-Diamond Syndrome (SBDS), 229 Shwachman-Diamond syndrome, 222, 224 Sick sinus syndrome, 537 Silver-Russell syndrome, 325, 342, 617, 637 Single umbilical artery (SUA), 238 Sinus infections, recurrent, 482 Sirenomelia, 568, 569–572, 623, 624, 631, 634, 637, 642, 647, 651, 654 Situs inversus, 187 Sjögren syndrome, 376, 383 Skeletal abnormalities axial, 528 diagnosis of, 17 multiple, 433, 484, 489 Skeletal dysplasias molecular diagnosis of, 31–32 postnatal diagnosis of, 18 prenatal diagnosis of, 13, 15 prognosis for, 15 Skeletal maturation, 477 Skeletal patterning, 1 Skeletal phenotype, 503 Skeletal survey and achondroplasia, 50 and campomelic dysplasia, 303, 304 and Desbuquois dysplasia, 123 radiographic, 18 Skeleton, development of, 2, 5 Skin atrophy, 333 dimpling, 281, 302

hirsute, 348 hyperelastic, 504 hyperkeratotic, 338 laxity, 212, 602 macular atrophy of, 398 oedema, 106, 411 tight, 593 wrinkled, 426 Skin anomalies and cerebro-osseous-digital syndrome, 593 Skin folds, redundant, 36, 46, 348 Skull, 448 and achondrogenesis type 2, 58 decreased diameter of, 494 decreased ossification of, 431, 433 examining, 14 formation of, 4 hypomineralisation of, 328, 482, 488 large, 82, 95, 593 overgrowth of, 426 in skeletal survey, 19 small, 416 soft, 429, 430 Skull base, 477 sclerotic, 139, 145, 148, 411, 414 steep, 504, 506, 611 thickened, 403 underdevelopment of, 464 Skull vault, 218 absent bones in, 433 absent ossification of, 431, 433, 452, 458, 489 and achondrogenesis, 258 decreased ossification of, 141, 156, 218, 331, 371, 431, 433, 488, 489 distortion of, 14 formation of, 4 hypomineralized, 148 large, 46, 256, 464, 591 in mucolipidosis, 348 in platyspondylic dysplasia, 67 sclerosis of, 421, 427 thickened, 148, 478 thin, 334, 452 SLC17A5, 348 SLC26A2 mutations, 106, 108, 109–110, 111 SLC35D1, 260 Sleep apnoea and Hallerman-Streiff syndrome, 333 obstructive, 47 and osteogenesis imperfecta, 430 and Rubinstein-Taybi syndrome, 295 Slender, 462, 469 Slender bones, 648 Slender ribs and achondrogenesis, 256 and Antley-Bixler syndrome, 500 and Hallermann-Streiff syndrome, 334 and Hallerman-Streiff syndrome, 333 and hypophosphatasia, 453 and Melnick-Needles syndrome, 142 and Menkes disease, 602 and neonatal hyperparathyroidism, 348 and osteocraniostenosis, 328 and osteogenesis imperfecta, 431 and spondylometaphyseal dysplasia, 262 and Stuve-Wiedemann dysplasia, 311 and Yunis-Varon dysplasia, 489

Sloping acetabula, 160 Small (short trunk, hypoplasiaof thorax/lungs), 656 Small bowel malrotation, 143, 186, 188, 599 Small chest and SRPS, 187 Small epiphyses, 3 Small jaw and campomelic dysplasia, 308 Small narrow thorax, 39 Small nose and Antley-Bixler syndrome, 500 and de Lange syndrome, 540 and DTD, 111 and Hallerman-Streiff syndrome, 333 and Kniest dysplasia, 82 and opsismodysplasia, 266 and Pfeiffer syndrome, 491 and platyspondylic dysplasia, 67 and Yunis-Varon dysplasia, 490 Small thorax, 68, 225, 226, 416 and achondrogenesis, 58, 105, 256, 258 and achondroplasia, 46, 50, 52 and atelosteogenesis, 108 bell-shaped, 62 and Blomstrand dysplasia, 464 and campomelic dysplasia, 306 and cerebroarthrodigital syndrome, 591 and cranioectodermal dysplasia, 215 and Desbuquois dysplasia, 121 in diagnosis, 14 and DTD, 111, 115 and dysplastic cortical hyperostosis, 416, 416 and dyssegmental dysplasia, 167 and fibrochondrogenesis, 95 and hypochondrogenesis, 65, 68, 69, 70, 71 and Kniest dysplasia, 86 and Larsen syndrome, 151 and multiple pterygium syndrome, 606 and OPD2, 148 and osteogenesis imperfecta, 431, 433–434 and osteopathia striata, 422 and paternal uniparental disomy 14, 528 in prognosis, 15–16 and Schneckenbecken dysplasia, 260 and spondylocostal dysostosis, 518 and TD, 39 and thoracolaryngopelvic dysplasia, 222 SMC1A, 540–541 SMC3, 540–541 SMD type Sedaghatian, 638 Smith-Lemli-Opitz syndrome, 619, 621, 634, 639, 640, 643, 647, 652, 653 and polydactyly, 14, 587 and SHFM, 577 and stippling, 376, 383 SNX10, 388 Soft tissue hyperplasia, 479 oedema, 60 webbing, 606 Somites, 3, 4 Sonic hedgehog (SHH) and Carpenter syndrome, 507 and Greig syndrome, 583 and limb morphogenesis, 5 Sorsby syndrome, 286, 618, 629, 647

682 SOX2, 532 Spatulate fingers, 156 Speech delay, 521 Spina bifida, 218, 608 Spinal cord compression and DTD, 112 Spinal dysplasia, 380 Spinal dysraphism, 14, 148, 531, 560, 608, 609 Spinal muscular atrophy, 383, 625, 651 Spinal stenosis, lumbar, 47 Spine, 448 curvature of, 19 decreased ossification of, 156 examining, 14 normal, 24 in skeletal survey, 19 Spine anomalies absent/minimal ossification, 648 Spleen absent, 328 accessory, 187, 507 multilobed, 508 palpable, 222 Spleno-gonadal fusion with limb defects and micrognathia, 621, 641 Split hand deformity, 14, 27 Split hand-foot malformation, 576–577, 577– 579, 617, 618, 620, 621, 622, 623, 628, 630, 634, 635, 637, 638, 639, 641, 642, 643, 646, 652, 653, 654 SPONASTRIME, 623, 648 Sponastrime dysplasia, 127, 249 Spondylocarpotarsal synostosis, 151, 162, 654 Spondylocostal dysostosis, 14, 16, 517–518, 518–520, 617, 622, 623, 625, 637, 648, 649, 651, 653, 657 Spondyloepimetaphyseal dysplasia (SEMD), 623 with immune deficiency, 644, 650, 651 with immune deficiency and intellectual disability, 618, 647 with joint laxity, 621, 624, 645 with joint laxity, Beighton type, 617, 625, 627, 641, 647, 651 with joint laxity, Hall type, 625, 627, 650, 651 NANS related, 617, 620, 628, 648, 649, 650 short limb-abnormal calcification type, 617, 618, 620, 630, 644, 648, 650, 655 specific features of, 81 Strudwick type, 80, 81, 621, 630, 632, 633, 637, 639, 641, 642, 645, 648, 650, 651, 654, 657 Spondyloepiphyseal dysplasia Namaqualand type, 58, 67, 73, 81, 82, 89 Kozlowski type, 650 Omani type, 151, 648 Strudwick type, 58, 67, 73 Spondyloepiphyseal dysplasia congenital (SEDC), 14, 73, 74–79, 621, 628, 629, 630, 632, 635, 637, 641, 642, 645, 648, 649, 650, 654, 657 COL2A1, 80 Strudwick, 80 Spondylo-epiphyseal-metaphyseal dysplasia with immune deficiency and intellectual disability, 622, 626, 648, 657 Spondylolysis, 163

Index Spondylo-megaepiphyseal-metaphyseal dysplasia, 525 Spondylometaphyseal dysplasia Hall type, 648 Kozlowski type, 176 Sedhagatian type, 262, 263–264, 266, 618, 619, 620, 623, 624, 628, 630, 636, 639, 641, 643, 648, 650, 655 Spondyloperipheral dysplasia, 58, 67, 73, 81, 82, 89–90, 618 Spondylothoracic dysostosis, 617, 634, 647, 649, 651, 657 Spontaneous fractures, 602 Sprengel shoulder, 574 Squamous cell carcinomas, 573 Squared-off metaphyses, 68 SRP54, 229 SRPS (short rib-polydactyly syndrome), 657 all types, 625, 632, 634, 637, 641, 643, 645, 647, 655, 657 and CT, 18 diagnosis of, 14 and narrow thorax, 37, 47, 176 prognosis for, 16 type 1/3, 182, 183–185, 618, 623, 650, 657 type 2, 186, 187–189, 618, 621, 638, 640, 653 type 4, 191, 192–194, 619, 620, 621, 623, 628, 630–632, 640, 656 Sternum angulation of, 224 formation of, 4 in Holt-Oram syndrome, 536 hypoplastic, 521 poor ossification of, 338, 488 prominent, 546 Stickler syndrome, 618, 621, 641, 651 other types of, 89 and platyspondyly, 176 type 1, 89, 90–93, 627, 628, 632, 635, 639, 645, 649, 650 type 2, 101, 102 Stillbirth, 32, 375 Stippling, 651 Stocker and Heifetz classification, 568 Strabismus, 295, 333, 541, 573 Stuve-Wiedemann dysplasia, 311, 312, 633, 651 Stuve-Wiedemann syndrome, 616, 624, 625, 639, 641, 642, 648, 654, 656 Subdural haemorrhages, 602 Subdural hematoma, 602 Sublingual hamartoma, 210 Sulphate transporters, 105, 108, 111 SUMF1, 376 Supraacetabular constriction, 396 Supracetabular notch, 138 Supraorbital ridges, 137, 139, 141, 382, 542 Suprasellar mass, 587 Symphalangism, 286, 298, 426 Symphysis pubis, 18, 151, 611, 654 Syndactyly, 27, 554, 652 and acrofacial dysostosis, 510 and Apert syndrome, 496, 497–498 and atelosteogenesis, 162 and boomerang dysplasia, 156 and brachydactyly Temtamy type, 298 and brachydactyly type B, 286 and Carpenter syndrome, 507, 508

and CED, 212 and Chitayat (1993) hyperphalangism, 300 and chondroectodermal dysplasia, 204 cutaneous, 583 and de Lange syndrome, 540 diagnosis of, 14 differential diagnosis of, 583 and FFU syndrome, 567 and Gollop-Wolfgang complex, 556 and Greig syndrome, 584 and Holt-Oram syndrome, 536 and Kaufman-McKusick syndrome, 599 and Lenz-Majewski hyperostotic dysplasia, 426, 427 and multiple pterygium syndrome, 606 and OPDS, 148 and Pallister-Hall syndrome, 587, 588 and Pfeiffer syndrome, 491 and Proteus syndrome, 478 and Roberts syndrome, 550, 552 in skeletal survey, 19 and Smith-Lemli-Opitz syndrome, 376 and split hand-foot malformation, 576–577 and VATER/VACTERL association, 531 Synophrys, 298, 300, 540, 541, 542 Synostosis, 653 progressive, 496 and skull shape deformities, 4 Synpolydactyly, 583, 643 Syphilis, congenital, 408 Syringomyelia, 430 Systemic lupus erythematosus (SLE), maternal, 376, 378, 379–380, 386 Talipes, 21, 654 and Catel-Manzke syndrome, 293 and chondroectodermal dysplasia, 203 and sirenomelia, 568 in skeletal survey, 19 Talipes equinovarus, 309 and achondrogenesis, 105 and atelosteogenesis, 108, 162 bilateral, see Bilateral talipes equinovarus and boomerang dysplasia, 156 and brachydactyly type C, 288 and campomelic dysplasia, 302, 308 and Carpenter syndrome, 507 and DTD, 111, 113–115 and dyssegmental dysplasia, 166 and femoral facial syndrome, 560 and fibrochondrogenesis, 95 and foot length, 14 and Kniest dysplasia, 82 and Larsen syndrome, 151 and Meckel syndrome, 217–218 and multiple pterygium syndrome, 606 and OEIS complex, 608 and OFDS, 209, 210 and Schinzel-Giedion syndrome, 611 and Shprintzen-Goldberg syndrome, 504, 505–506 and spondyloepimetaphyseal dysplasia, 81 and Zellweger syndrome, 382 Talipes equinus, 122 Talocalcaneal coalition, 566 Talon cusps, 296, 298 Talus, vertical, 23, 500 Talus valgus, 23

683

Index Tapered humeri, 165 TAR (thromobcytopaenia absent radius) and limb anomalies, 511, 537, 541, 551, 574 in skeletal survey, 14 Tarsal bones absent, 568 advanced maturation, 121 in fibrochondrogenesis, 95 fusion of, 298, 577 irregular ossifciation of, 262 in OPD1, 145 stippled, 348 Tarsal region, 379 TAR syndrome, 541, 623 TBX5, 536 TBX15, 548 TCIRG1, 388 TCOF1, 510 TCTN3, 209 Teeth abnormal, 212 crowded, 47 impacted, 464 malpositioned, 298 natal, see Natal teeth neonatal, 203, 333, 414 supernumerary, 482 Telecanthus, 212, 339 Temperature regulation, abnormal, 602 Temples, indented, 490 Temporal bone, 4 Temporal lobes hyperplastic, 36 medial, 42, 496 in TD, 36, 42 Temporal sutures, 602 Temporoparietal synchondroses, 611, 612–613 Temtamy preaxial brachydactyly syndrome, 630, 636, 639 Teratogens, 532, 591 Terminal ileum, prolapsed, 608 Terminal phalanges absent, 286 broad, 295 hypoplastic, 331, 383, 489 Tetra-amelia, 511, 546, 621, 647, 657 Tetralogy of Fallot, 624 and acrofacial dysostosis, 510 and de Lange syndrome, 540 and kyphomelic dysplasia, 338 and Melnick-Needles syndrome, 141 and OFDS, 209 and VATER/VACTERL association, 531, 532 Tetramelic campomelia, 218 Tetrasomy 12p, 630 TFLV (total fetal lung volume), 16 TGFBR1 and TGFBR2, 504 Thalidomide embryopathy, 511, 551, 623, 628, 646 Thanatophoric dysplasia (TD), 616, 618, 619, 620, 623, 625, 632, 635, 636, 637, 641, 645, 647, 650, 654, 655, 657 and FGFR, 47 and hypochondroplasia, 54 identification of, 14–15 molecular diagnosis of, 31 and narrow thorax, 176, 179, 186

prenatal diagnosis, 37 prognosis for, 15 type 1, 36–37, 37–44 type 2, 36–37, 37–44 Thanatophoric dysplasia type 2, 622 Thenar hypoplastia, 536 Thoracic anomalies, in Al-Awadi RaasRothschild syndrome, 546 Thoracic cage small, 452 Thoracic dysplasia, 19 asphyxiating, see Jeune syndrome Thoracic hypoplasia and atelosteogenesis, 162 and FMD, 137 and Melnick-Needles syndrome, 141 and OPD2, 148 and platyspondylic dysplasia, 67 Thoracic kyphosis, 82 Thoracic pedicles, 304 Thoracic scoliosis, 111 Thoracic segmentation, increased, 531–532 Thoracic spine, 593 Thoracic vertebrae, 4 Thoracolaryngopelvic dysplasia (Barnes), 197, 222, 222–223, 617, 636, 645, 655, 657 Thoracolumbar kyphosis, 47, 50, 50, 82 Thorax, 134 barrel-shaped, 36, 591, 593 bell-shaped, 201, 222, 429, 457, 521, 528, 529–530 collapsed, 437 deformed, 433 examining, 14, 17 hypoplastic, 82, 148 in Marfan syndrome, 471 narrow, see Narrow thorax short, 212, 260, 546 in Shprintzen-Goldberg syndrome, 504 in skeletal survey, 19 small, see Small thorax small (short trunk, hypoplasia of thorax/ lungs), 636 symmetric, 517–518, 519 ultrasound image of, 39 visualisation of, 25 Thorax ribs, short, 655 Thorax small and cartilage-hair hypoplasia, 227 Thrombocytopenia absent radius syndrome, 627, 641, 646 and de Lange syndrome, 541 and DK phocomelia, 596 Thumbs; see also Absent thumbs; Hitchhiker thumbs; Triphalangeal thumbs abducted, 112–114, 298 adducted, 521 agenesis, 573 angulated, 295–296 anomalies, 14 aplasia, 536 bifid, 295 deviated, 295, 491 duplicated, 125, 510, 573 in Fanconi anaemia, 573 in Holt-Oram syndrome, 536 hypoplastic, 14, 148, 510, 531, 537, 541

in Roberts syndrome, 550 short, 148, 489, 496 in VATER/VACTERL association, 534 Thymus, hypoplastic, 89, 293, 522 Tibiae, 194 angulated, see Angulated tibiae in Caffey disease, 409 curved, 270 fractured, 448 in hypophosphatasia, 452 hypoplastic, 210 in metatropic dysplasia, 178 punctiform, 302 short, 211, see Short tibiae in sirenomelia, 568, 569–570 spurred, 455 in SRPS, 186, 191 Tibial agenesis, 556 Tibial agenesis-polydactyly syndrome, 617, 623, 638, 655 Tibial aplasia, 554 and split hand-foot malformation, 577 Tibial aplasia-five fingered hand-polydactyly syndrome (Werner), 617, 623, 638 Tibial hemimelia-polydactyly-triphalangeal thumb, 653, 654 Tibial hemimelia-polysyndactyly-triphalangeal thumb, 533, 553, 554, 617, 627, 643, 657 Tibial hypoplasia and Al-Awadi Raas-Rothschild syndrome, 546 and Gollop-Wolfgang complex, 556 and split hand-foot malformation, 577 Tibial shortening, 380 Toes absent, 556 overlapping, 510 syndactyly of, 540 Tombstone phalanges, 163 Tongue abnormalities and phocomelia, 596 lobulated, 186, 209 prolongations, 209 ulceration, 311 Tonsillar herniation, 494 Townes-Brocks syndrome, 532, 537, 580, 623, 628, 635, 644, 645, 646, 647, 657 TP63, 576–577 Trabecular pattern, coarsening of, 348, 426 Tracheal cartilage, 464, 521 Tracheal malformations, 137 Tracheobronchomalacia, 111, 302, 308 Tracheomalacia, 333, 421 Tracheo-oesophageal fistula, 531–532, 546, 556, 599 Tracheostomy, 89l, 308 Transposition of the great vessels, 624 Transvaginal ultrasound and achondrogenesis, 105 and fetal diagnosis, 13 Treacher-Collins-Franceschetti syndrome, 510 Treacher-Collins syndrome, 629 Tricuspid regurgitation, 471 Tricuspid valve prolapse, 471 Trident acetabula, 198, 200, 204, 657 in achondroplasia, 47, 48, 52 in chondroectodermal dysplasia, 203

684 and Jeune syndrome, 196, 198 and SRPS, 183 in TD, 36, 38 Trident acetabulum, 37 Trident hand, 36, 37, 46, 48–49, 657 Trigonocephaly, 574 TRIP11, 235, 256 Triphalangeal thumbs, 657 and acrofacial dysostosis, 510 associated syndromes, 14 differential diagnosis of, 537 and Fanconi anaemia, 573 and VATER/VACTERL association, 531 Trisomy, partial, 483, 577 Trisomy 13, 621, 623, 628, 629, 630, 631, 637, 639, 641, 642, 644, 645, 647, 654, 655 Trisomy 18, 13, 376, 532, 619, 621, 623, 628, 629, 630, 631, 633, 637, 639, 641, 642, 645, 646, 647, 652, 653, 655 Trisomy 20p, 483 Trisomy 21, 616, 652, see Down syndrome Trochanters, 121, 124, 125 TRPV4, 81, 176 Trunk long, 36, 176 short, see Short trunk TTC21B, 196 Tubular bones, 138, 395, 468, 469, 501, 502; see also Long tubular bones; Short tubular bones and achondroplasia, 47 and atelosteogenesis, 162 in Lenz-Majewski hyperostotic dysplasia, 426 in osteogenesis imperfecta, 429 in skeletal survey, 19 and spondylometaphyseal dysplasia, 264 thick, 464 Tubulointerstitial nephropathy, 212 TUI (tomographic ultrasound imaging), 21 Turribrachycephaly, 491, 496 Turricephaly, 14, 19, 209, 262, 403, 504, 506 Twins discordant, 18 TWIST1, 492, 496, 500, 507 Ulnae, 544, 547 absent, 547 hypoplastic, 546, 556, 573 short, see Short ulnae Ulnar agenesis, 542 Ulnar deviation, 293, 300, 300 Ulnar-mammary syndrome, 634 Ulnar ray defects, 536, 566 Ultrasound checklist for, 17 in diagnosis, 13, 32 diagnostic accuracy of 10, 15 in prognosis, 15 Umbilical arteries, single, 568, 608 Umbilical cord cyst, 550 Umbilical herniae and achondrogenesis, 105 and Carpenter syndrome, 507 and Chitayat (1993) hyperphalangism, 300 and Greig syndrome, 583 and Menkes disease, 602 and Shprintzen-Goldberg syndrome, 504

Index Undermineralisation, 18, 429, 452 Uniparental disomy, paternal, for chromosome 14, 625, 628 Unusual dentition, 206 Upper limbs, 543 and de Lange syndrome, 540–541 and DK phocomelia, 596 in FFU, 566 and Holt-Oram syndrome, 536 hypoplastic, 510, 577 and Jeune syndrome, 202 and OFDS4, 209 and omodysplasia, 273 and Roberts syndrome, 550–551 in split hand-foot malformation, 576 Upper lip cupid’s bow, 602 long, 82, 95 midline cleft, 186, 206, 209 overhanging, 540, 542 prominent, 151 short, 574 thin, 560 Ureteric obstruction, 141, 148 Ureteric reflux, 602 Ureteric stenosis, 137 Urethral atresia, 141, 217 Urinary tract and FMD, 137 and Kaufman-McKusick syndrome, 599 and Menkes disease, 602 and osteodysplasty, 141 Uropathy, obstructive, 148 Uvula, bifid, 89 Vaginal atresia, 182, 599 Vaginal obstruction, 599 Varicella, 224 Vascular anomalies, and Proteus syndrome, 478 Vascular tortuosity, 602–603 VATER/VACTERL association, 14, 531–532, 532–534, 620, 623, 624, 628, 630, 639, 644, 645, 646, 647, 649, 651, 652, 653, 654, 657 Veins, prominent, 426 Ventricles, dilated, 95 Ventricular hypertrophy, 348 Ventricular septal defect (VSD), 209, 382 and Holt-Oram syndrome, 536 and VATER/VACTERL association, 531 and Yunis-Varon dysplasia, 488 Ventriculomegaly, 250 and Apert syndrome, 496 and dysosteosclerosis, 399 and Meckel syndrome, 217 and Menkes disease, 602 and osteogenesis imperfecta, 429 and osteopetrosis, 388 and Schinzel-Giedion syndrome, 611 and TD, 36 Vermis absent, 192 agenesis of, 338 hypoplasia of, 196, 488, 602 Vertebrae block, 541 misaligned, 521

Vertebral anomalies and Fanconi anaemia, 573 and Kaufman-McKusick syndrome, 599 and multiple pterygium syndrome, 605 and VATER/VACTERL association, 531 Vertebral bodies, 56, 102, 173 absent, 593 absent ossification of, 58, 59–62, 65, 71, 258, 266, 284, 306, 378, 386, 387, 452, 453–455, 591 and achondrogenesis, 257 in achondrogenesis, 256 bone-in-bone appearance, 389 collapsed, 431, 434, 602 coronal cleft, 51, 179, 416, 605 in Desbuquois dysplasia, 121 displaced, 532 faint, 79 in fibrochondrogenesis, 95 flattened, 78 fusion of, 137 hyperechogenic, 371 hypoplastic, 86, 111, 163, 164–165, 302, 593 increased diameter of, 611 increased height, 471 indistinct margins of, 398 lumbar, 82, 348 notched, 399 ossification of, 59, 341 ossification of cervical, 308 in osteocraniostenosis, 328 ovoid, 78, 483, 517, 519 posterior scalloping of, 47, 54, 471 reduced anteroposterior diameter of, 348 round, 37, 81 sagittal cleft, 96, 179, 593 in Shprintzen-Goldberg syndrome, 504 small, 453 squared, 421 thoracic, 143, 158, 162, 306 ultrasound image of, 39 Vertebral column, 2, 3, 25 Vertebral mineralization, 260 Vertebral ossification and MOPD, 339 Vertebral pedicles, 307, 518, 519 Vertebral segmentation defects, 518, 560, 568 Vertical ischia, 139, 548 Vesicoureteric reflux, 602 Visceral abnormalities, 15, 599 Viscerocranium, 2, 4 Visceromegaly, 478 Visual impairment, 404, 421 Vitamin K, 286, 375, 378, 383 Vitelline artery, 568 VLCFA (very-long-chain fatty acid), 32, 382 VOCAL (virtual organ computer-aided analysis), 16 Voice, hoarse, 141 Volume contrast imaging (VCI), 23, 37 Warfarin embryopathy, 375–376, 376–377, 378, 618, 619, 620, 621, 623, 624, 625, 627, 628, 630, 639, 643, 645, 649, 651, 652, 653, 657 Wavy long bones, 143 WDR19, 196, 212 WDR35, 212

685

Index Weissenbacher-Zweymuller dysplasia, 82, 89, 91, 98, 176 Werner syndrome, 533, 553, 554 White matter atrophy, 426 White matter hypoplasia, 496 Whole-genome sequencing (WGS), 31 Wide anterior ribs, 122 Wide fontanelles and cleidocranial dysplasia, 482 and osteogenesis imperfecta, 429 and Raine dysplasia, 404 Wide metaphyses and atelosteogenesis, 108 and Blomstrand dysplasia, 465 and Desbuquois dysplasia, 121 and fibrochondrogenesis, 95 in FMD, 139 and Kniest dysplasia, 82, 83 and kyphomelic dysplasia, 338 and OPD2, 148 and Raine dysplasia, 403 and Schinzel-Giedion syndrome, 611, 613 and Shprintzen-Goldberg syndrome, 504, 505–506

and Stickler syndrome, 89 and Stuve-Wiedemann dysplasia, 311 Wide sacrosciatic notches, 68 Wide sutures and cleidocranial dysplasia, 482, 484 and Hallerman-Streiff syndrome, 333 and hypophosphatasia, 452 and Raine dysplasia, 403, 404 and Schinzel-Giedion syndrome, 611 and Yunis-Varon dysplasia, 488 Wiedemann-Rautenstrauch syndrome, 342 Wilms tumour, 611 Winking, seesaw, 209 WNT3, 511, 551 WNT5A, 276 WNT7A, 5, 546 Wormian bones, 2, 257, 476, 657 in Astley-Kendall dysplasia, 386 in cleidocranial dysplasia, 482, 483 in Hallerman-Streiff syndrome, 333 and Menkes disease, 602, 603 and osteogenesis imperfecta, 431, 431, 444, 448 in skeletal survey, 19

Woven bone, 1 Wrists joint limitation at, 137 postural deformities of, 13 ulnar deviation of, 528 WTX, 421 XK-aprosencephaly, 623 X-linked myotubular myopathy, 645 X-linked SEMD with leukodystrophy, 649 Yunis-Varon dysplasia, 328, 483, 619, 620, 621, 623, 624, 625, 630, 633, 634, 635, 639, 641, 642, 645, 646, 648, 653, 655 Zellweger syndrome, 218, 382–383, 383–385, 623, 628, 630, 632, 633, 637, 645, 651, 652, 655 Zimmermann-Laband syndrome, 286, 623 ZPA (zone of polarising activity), 4, 5 ZRS, 533, 553 ZSW1M6, 514