Atlas of Genetic Diagnosis and Counseling Chen [1 ed.] 9781588296818, 1-58829-681-4, 1-59259-956-7

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ATLAS OF GENETIC DIAGNOSIS AND COUNSELING

ATLAS

OF

GENETIC

DIAGNOSIS AND

COUNSELING

HAROLD CHEN,

MD, FAAP, FACMG

Professor of Pediatrics, Obstetrics and Gynecology, and Pathology, Louisiana State University Health Science Center, Shreveport, LA

© 2006 Humana Press Inc. 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512 humanapress.com For additional copies, pricing for bulk purchases, and/or information about other Humana titles, contact Humana at the above address or at any of the following numbers: Tel.: 973-256-1699; Fax: 973-256-8341; E-mail: [email protected]; Website: humanapress.com All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher. All articles, comments, opinions, conclusions, or recommendations are those of the author(s), and do not necessarily reflect the views of the publisher. Due diligence has been taken by the publishers, editors, and author of this book to ensure the accuracy of the information published and to describe generally accepted practices. The contributors herein have carefully checked to ensure that the drug selections and dosages set forth in this text are accurate in accord with the standards accepted at the time of publication. Notwithstanding, as new research, changes in government regulations, and knowledge from clinical experience relating to drug therapy and drug reactions constantly occurs, the reader is advised to check the product information provided by the manufacturer of each drug for any change in dosages or for additional warnings and contraindications. This is of utmost importance when the recommended drug herein is a new or infrequently used drug. It is the responsibility of the health care provider to ascertain the Food and Drug Administration status of each drug or device used in their clinical practice. The publisher, editors, and authors are not responsible for errors or omissions or for any consequences from the application of the information presented in this book and make no warranty, expressed or implied, with respect to the contents in this publication. Cover illustrations: To Come Production Editor: Nicole E. Furia Cover design by Patricia F. Cleary This publication is printed on acid-free paper. ∞ ANSI Z39.48-1984 (American National Standards Institute) Permanence of Paper for Printed Library Materials. Photocopy Authorization Policy: Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Humana Press Inc., provided that the base fee of US $30.00 per copy is paid directly to the Copyright Clearance Center at 222 Rosewood Drive, Danvers, MA 01923. For those organizations that have been granted a photocopy license from the CCC, a separate system of payment has been arranged and is acceptable to Humana Press Inc. The fee code for users of the Transactional Reporting Service is: [1-58829-681-4/06 $30.00]. e-ISBN 1-59259-956-7 Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1

Library of Congress Cataloging-in-Publication Data Atlas of genetic diagnosis and counseling / authored by Harold Chen. p. cm. Includes bibliographical references. ISBN 1-58829-681-4 (alk. paper) 1. Genetic disorders--Diagnosis--Atlases. 2. Genetic counseling--Atlases. [DNLM: 1. Genetic Diseases, Inborn--Atlases. 2. Genetic Counseling--Atlases. 3. Prenatal Diagnosis--Atlases. QZ 17 A880383 2006] I. Chen, Harold. RB155.6.A93 2006 616'.042--dc22 2005005388

Preface This book, Atlas of Genetic Diagnosis and Counseling, reflects my experience in 38 years of clinical genetics practice. During this time, I have cared for many patients and their families and taught innumerable medical students, residents, and practicing physicians. As an academic physician, I have found that a picture is truly “worth a thousand words,” especially in the field of dysmorphology. Over the years, I have compiled photographs of my patients, which are incorporated into this book to illustrate selected genetic disorders, malformations, and malformation syndromes. A detailed outline of each disorder is provided, describing the genetics, basic defects, clinical features, diagnostic investigations, and genetic counseling, including recurrence risk, prenatal diagnosis, and management. Color photographs are used to illustrate the clinical features of patients of different ages and ethnicities. Photographs of prenatal ultrasounds, imagings, cytogenetics, and postmortem findings are included to help illustrate diagnostic strategies. The cases are supplemented by case history and diagnostic confirmation by cytogenetics, biochemical, and molecular studies, if available. An extensive literature review was done to ensure up-to-date information and to provide a relevant bibliography for each disorder. This book was written in the hope that it will help physicians improve their recognition and

understanding of these conditions and their care of affected individuals and their families. It is also my intention to bring the basic science and clinical medicine together for the readers. Atlas of Genetic Diagnosis and Counseling is designed for physicians involved in the evaluation and counseling of patients with genetic diseases, malformations, and malformation syndromes, including medical geneticists, genetic counselors, pediatricians, neonatologists, developmental pediatricians, perinatologists, obstetricians, neurologists, pathologists, and any physicians and health care professionals caring for handicapped children such as craniofacial surgeons, plastic surgeons, otolaryngologists, and orthopedics. I am grateful to many individuals for their invaluable help in reading and providing cases for illustration. The acknowledgments are provided on a separate page. Without the patience and encouragement of my dear wife, Cheryl, this atlas would not have been possible. I would like to dedicate this book to Children’s Hospital, Louisiana State University Health Sciences Center in Shreveport, for its continued excellence in pediatric care and education. I would welcome comments, corrections, and criticism from readers. Harold Chen, MD, FAAP, FACMG

v

Contents Cleidocranial Dysplasia . . . . . . . . . . . . . . . . . . . . . . Cloacal Exstrophy . . . . . . . . . . . . . . . . . . . . . . . . . . Collodion Baby . . . . . . . . . . . . . . . . . . . . . . . . . . . . Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency) . . . . . . . . . . . . . . . . Congenital Cutis Laxa . . . . . . . . . . . . . . . . . . . . . . . Congenital Cytomegalovirus Infection . . . . . . . . . . Congenital Generalized Lipodystrophy . . . . . . . . . . Congenital Hydrocephalus . . . . . . . . . . . . . . . . . . . . Congenital Hypothyroidism . . . . . . . . . . . . . . . . . . . Congenital Muscular Dystrophy . . . . . . . . . . . . . . . Congenital Toxoplasmosis . . . . . . . . . . . . . . . . . . . . Conjoined Twins . . . . . . . . . . . . . . . . . . . . . . . . . . . . Corpus Callosum Agenesis/Dysgenesis . . . . . . . . . . Craniometaphyseal Dysplasia . . . . . . . . . . . . . . . . . Cri-Du-Chat Syndrome . . . . . . . . . . . . . . . . . . . . . . Crouzon Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi Acardia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Achondrogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Achondroplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Adams-Oliver Syndrome . . . . . . . . . . . . . . . . . . . . . . 23 Agnathia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Aicardi Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 Alagille Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Albinism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Amniotic Band Syndrome . . . . . . . . . . . . . . . . . . . . . 42 Androgen Insensitivity Syndrome . . . . . . . . . . . . . . . 50 Angelman Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . 56 Apert Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 Aplasia Cutis Congenita . . . . . . . . . . . . . . . . . . . . . . . 70 Arthrogryposis Multiplex Congenita . . . . . . . . . . . . . 74 Asphyxiating Thoracic Dystrophy . . . . . . . . . . . . . . . 84 Ataxia Telangiectasia . . . . . . . . . . . . . . . . . . . . . . . . . 92 Atelosteogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 Autism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 Beckwith-Wiedemann Syndrome . . . . . . . . . . . . . . . Behcet Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bladder Exstrophy . . . . . . . . . . . . . . . . . . . . . . . . . . Body Stalk Anomaly . . . . . . . . . . . . . . . . . . . . . . . . Branchial Cleft Anomalies . . . . . . . . . . . . . . . . . . . .

109 114 118 122 126

Campomelic Dysplasia . . . . . . . . . . . . . . . . . . . . . . . Cat Eye Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . Cerebro-Costo-Mandibular Syndrome . . . . . . . . . . . Charcot-Marie-Tooth Disease . . . . . . . . . . . . . . . . . CHARGE Association . . . . . . . . . . . . . . . . . . . . . . . Cherubism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chiari Malformation . . . . . . . . . . . . . . . . . . . . . . . . . Chondrodysplasia Punctata . . . . . . . . . . . . . . . . . . . Chromosome Abnormalities in Pediatric Solid Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cleft Lip and/or Cleft Palate . . . . . . . . . . . . . . . . . .

131 136 139 142 149 153 157 161

Dandy-Walker Malformation . . . . . . . . . . . . . . . . . . De Lange Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . Del(22q11.2) Syndromes . . . . . . . . . . . . . . . . . . . . . Diabetic Embryopathy . . . . . . . . . . . . . . . . . . . . . . . Down Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dyschondrosteosis (Leri-Weill Syndrome) and Langer Mesomelic Dysplasia . . . . . . . . . . . . . . . . Dysmelia (Limb Deficiency/Reduction) . . . . . . . . . Dysplasia Epiphysealis Hemimelica . . . . . . . . . . . . Dystonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dystrophinopathies . . . . . . . . . . . . . . . . . . . . . . . . . . Ectrodactyly-Ectodermal Dysplasia-Clefting (EEC) Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . Ehlers-Danlos Syndrome . . . . . . . . . . . . . . . . . . . . . Ellis-van Creveld Syndrome . . . . . . . . . . . . . . . . . . Enchondromatosis (Maffucci Syndrome; Ollier Syndrome) . . . . . . . . . . . . . . . . . . . . . . . . . Epidermolysis Bullosa . . . . . . . . . . . . . . . . . . . . . . . Epidermolytic Palmoplantar Keratoderma . . . . . . . .

169 180 vii

185 191 195 198 207 212 217 221 227 231 236 241 247 252 256 261 265 273 276 282 289 295 305 312 323 326 331

339 342 350 355 360 366

viii

CONTENTS

Faciogenital (Aarskog) Dysplasia . . . . . . . . . . . . . . Facioscapulohumeral Muscular Dystrophy . . . . . . . Familial Adenomatous Polyposis . . . . . . . . . . . . . . . Familial Hyperlysinemia . . . . . . . . . . . . . . . . . . . . . Fanconi Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . Femoral Hypoplasia-Unusual Facies Syndrome . . . Fetal Akinesia Syndrome . . . . . . . . . . . . . . . . . . . . . Fetal Alcohol Syndrome . . . . . . . . . . . . . . . . . . . . . . Fetal Hydantoin Syndrome . . . . . . . . . . . . . . . . . . . Fibrodysplasia Ossificans Progressiva . . . . . . . . . . . Finlay-Marks Syndrome . . . . . . . . . . . . . . . . . . . . . . Fragile X Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . Fraser Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . Freeman-Sheldon Syndrome . . . . . . . . . . . . . . . . . . Frontonasal Dysplasia . . . . . . . . . . . . . . . . . . . . . . .

371 375 380 386 389 395 398 403 407 410 415 417 423 427 431

Galactosemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gastroschisis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gaucher Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . Generalized Arterial Calcification of Infancy . . . . . Glucose-6-Phosphate Dehydrogenase Deficiency . . . Glycogen Storage Disease, Type II . . . . . . . . . . . . . Goldenhar Syndrome . . . . . . . . . . . . . . . . . . . . . . . .

437 442 446 452 457 461 465

Hallermann-Streiff Syndrome . . . . . . . . . . . . . . . . . Harlequin Ichthyosis (Harlequin Fetus) . . . . . . . . . . Hemophilia A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hereditary Hemochromatosis . . . . . . . . . . . . . . . . . . Hereditary Multiple Exostoses . . . . . . . . . . . . . . . . . Holoprosencephaly . . . . . . . . . . . . . . . . . . . . . . . . . . Holt-Oram Syndrome . . . . . . . . . . . . . . . . . . . . . . . . Hydrops Fetalis . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hyper-IgE Syndrome . . . . . . . . . . . . . . . . . . . . . . . . Hypochondroplasia . . . . . . . . . . . . . . . . . . . . . . . . . . Hypoglossia-Hypodactylia Syndrome . . . . . . . . . . . Hypohidrotic Ectodermal Dysplasia . . . . . . . . . . . . Hypomelanosis of Ito . . . . . . . . . . . . . . . . . . . . . . . . Hypophosphatasia . . . . . . . . . . . . . . . . . . . . . . . . . .

469 473 476 482 487 493 502 506 513 517 521 524 528 532

Incontinentia Pigmenti . . . . . . . . . . . . . . . . . . . . . . . 539 Infantile Myofibromatosis . . . . . . . . . . . . . . . . . . . . 545 Ivemark Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 549 Jarcho-Levin Syndrome . . . . . . . . . . . . . . . . . . . . . . 553 Kabuki Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . 559

Kasabach-Merritt Syndrome . . . . . . . . . . . . . . . . . . KID Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Klinefelter Syndrome . . . . . . . . . . . . . . . . . . . . . . . . Klippel-Feil Syndrome . . . . . . . . . . . . . . . . . . . . . . . Klippel-Trenaunay Syndrome . . . . . . . . . . . . . . . . . Kniest Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . .

563 567 570 575 580 585

Larsen Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . LEOPARD Syndrome . . . . . . . . . . . . . . . . . . . . . . . Lesch-Nyhan Syndrome . . . . . . . . . . . . . . . . . . . . . . Lethal Multiple Pterygium Syndrome . . . . . . . . . . . Lowe Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . .

589 597 600 604 613

Marfan Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . McCune-Albright Syndrome . . . . . . . . . . . . . . . . . . Meckel-Gruber Syndrome . . . . . . . . . . . . . . . . . . . . Menkes Disease (Kinky-Hair Syndrome) . . . . . . . . Metachromatic Leukodystrophy . . . . . . . . . . . . . . . Miller-Dieker Syndrome . . . . . . . . . . . . . . . . . . . . . Möbius Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . Mucolipidosis II (I-Cell Disease) . . . . . . . . . . . . . . . Mucolipidosis III (Pseudo-Hurler Polydystrophy) . Mucopolysaccharidosis I (MPS I) (α-L-Iduronidase Deficiency): Hurler (MPS I-H), Hurler-Scheie (MPS I-H/S), and Scheie (MPS I-S) Syndromes . . . . . . . . . . . . Mucopolysaccharidosis II (Hunter Syndrome) . . . . Mucopolysaccharidosis III (Sanfilippo Syndrome) . Mucopolysaccharidosis IV (Morquio Syndrome) . . Mucopolysaccharidosis VI (Maroteaux-Lamy Syndrome) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Multiple Epiphyseal Dysplasia . . . . . . . . . . . . . . . . Multiple Pterygium Syndrome . . . . . . . . . . . . . . . . . Myotonic Dystrophy Type 1 . . . . . . . . . . . . . . . . . .

619 630 636 639 646 650 655 660 664

Netherton Syndrome . . . . . . . . . . . . . . . . . . . . . . . . Neu-Laxova Syndrome . . . . . . . . . . . . . . . . . . . . . . . Neural Tube Defects . . . . . . . . . . . . . . . . . . . . . . . . . Neurofibromatosis I . . . . . . . . . . . . . . . . . . . . . . . . . Noonan Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . .

715 718 721 731 744

Oblique Facial Cleft Syndrome . . . . . . . . . . . . . . . . Oligohydramnios Sequence . . . . . . . . . . . . . . . . . . . Omphalocele . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Osteogenesis Imperfecta . . . . . . . . . . . . . . . . . . . . . Osteopetrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

751 755 758 762 773

669 678 682 687 692 697 702 708

CONTENTS

Pachyonychia Congenita . . . . . . . . . . . . . . . . . . . . . Pallister-Killian Syndrome . . . . . . . . . . . . . . . . . . . . Phenylketonuria (PKU) . . . . . . . . . . . . . . . . . . . . . . Pierre Robin Sequence . . . . . . . . . . . . . . . . . . . . . . . Polycystic Kidney Disease, Autosomal Dominant Type . . . . . . . . . . . . . . . . . . . . . . . . . . Polycystic Kidney Disease, Autosomal Recessive Type . . . . . . . . . . . . . . . . . . . . . . . . . . . Prader-Willi Syndrome . . . . . . . . . . . . . . . . . . . . . . . Progeria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prune Belly Syndrome . . . . . . . . . . . . . . . . . . . . . . . Pseudoachondroplasia . . . . . . . . . . . . . . . . . . . . . . .

781 784 788 793 797 803 809 815 821 826

R(18) Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . Retinoid Embryopathy . . . . . . . . . . . . . . . . . . . . . . . Rett Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rickets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Roberts Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . Robinow Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . Rubinstein-Taybi Syndrome . . . . . . . . . . . . . . . . . . .

831 835 839 844 852 856 860

Schizencephaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Schmid Metaphyseal Chondrodysplasia . . . . . . . . . Seckel Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . Severe Combined Immune Deficiency . . . . . . . . . . . Short Rib Polydactyly Syndromes . . . . . . . . . . . . . . Sickle Cell Disease . . . . . . . . . . . . . . . . . . . . . . . . . . Silver-Russell Syndrome . . . . . . . . . . . . . . . . . . . . . Sirenomelia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Smith-Lemli-Opitz Syndrome . . . . . . . . . . . . . . . . . Smith-Magenis Syndrome . . . . . . . . . . . . . . . . . . . . Sotos Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . Spinal Muscular Atrophy . . . . . . . . . . . . . . . . . . . . .

867 870 874 878 884 892 899 903 907 912 916 921

ix

Spondyloepiphyseal Dysplasia . . . . . . . . . . . . . . . . . 927 Stickler Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 934 Sturge-Weber Syndrome . . . . . . . . . . . . . . . . . . . . . 939 Tay-Sachs Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 943 Tetrasomy 9p Syndrome . . . . . . . . . . . . . . . . . . . . . 947 Thalassemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 950 Thanatophoric Dysplasia . . . . . . . . . . . . . . . . . . . . . 955 Thrombocytopenia-Absent Radius Syndrome . . . . . 962 Treacher-Collins Syndrome . . . . . . . . . . . . . . . . . . . 967 Trimethylaminuria . . . . . . . . . . . . . . . . . . . . . . . . . . 972 Triploidy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 976 Trismus Pseudocamptodactyly Syndrome . . . . . . . . 982 Trisomy 13 Syndrome . . . . . . . . . . . . . . . . . . . . . . . 985 Trisomy 18 Syndrome . . . . . . . . . . . . . . . . . . . . . . . 990 Tuberous Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . 997 Turner Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 1007 Twin–Twin Transfusion Syndrome . . . . . . . . . . . . 1015 Ulnar-Mammary Syndrome . . . . . . . . . . . . . . . . . . 1021 VATER (VACTERL) Association . . . . . . . . . . . . . 1025 Von Hippel-Lindau Disease . . . . . . . . . . . . . . . . . . 1029 Waardenburg Syndrome . . . . . . . . . . . . . . . . . . . . . 1035 Williams Syndrome . . . . . . . . . . . . . . . . . . . . . . . . 1040 Wolf-Hirschhorn Syndrome . . . . . . . . . . . . . . . . . . 1047 X-Linked Ichthyosis . . . . . . . . . . . . . . . . . . . . . . . . XXX Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . XXXXX Syndrome . . . . . . . . . . . . . . . . . . . . . . . . XXXXY Syndrome . . . . . . . . . . . . . . . . . . . . . . . . XY Female . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XYY Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . .

1057 1061 1064 1068 1071 1075

Acknowledgments HIROKO TANIAI, MD • A case of Finlay-Marks syndrome and help in searching of references for the Atlas. THEODORE THURMON, MD • Comments on the Atlas and cases on achondrogenesis, arthrogryposis, cleidocranial dysplasia, chondrodysplasia punctata, de Lange syndrome, Crouzon syndrome, cutis laxa, Freeman-Sheldon syndrome, hypophosphatasia, multiple epiphyseal dysplasia, omphalocele, prune belly syndrome, Sturge-Weber syndrome, and Treacher-Collins syndrome. CATHY TUCK-MULLER, PhD • A karyotype on Roberts syndrome. SUSONNE URSIN, MD • Cases of galactosemia and Gaucher disease and helps covering patient care for me during the last stage of preparing the Atlas. WLADIMIR WERTELECKI, MD • Enjoy working together on birth defects and congenital malformations and appreciate friendship and encouragement. SAMUEL YANG, MD • Meticulous reading and editing of the whole manuscript from the start to the end during his retirement and encouragement throughout the preparation of the Atlas. Special thanks to contribution of his life-time collection of cases on skeletal dysplasias and malformation syndromes (acardius, achondrogenesis, achondroplasia, amniotic band syndrome, anencephaly, asphyxiating thoracic dystrophy, body stalk anomaly, cebocephaly, campomelic dysplasia, Chiari malformation, colon polyposis, congenital cytomegalovirus infection, congenital toxoplasmosis, cyclopia, cystic fibrosis, Duchenne muscular dystrophy, Ellis van Creveld syndrome, gastroschisis, hypophosphatasia, I-cell disease, Kniest syndrome, polycystic kidney diseases, premaxillary agenesis, prune belly syndrome, SED congenita, sirenomelia, short rib polydactyly syndromes, Tay-Sachs disease, thanatophoric dysplasia, twin-twin transfusion placentas, VATER association, and Werdnig-Hoffman syndrome). CHENG W. YU, PhD • Karyotypes/FISH on pediatric tumors (meningioma, Wilms tumor), Cri-du-chat syndrome, and Wolf-Hirschhorn syndrome.

Individuals DIANA BIENVENU, MD • A case of Marfan syndrome with apical bleb rupture. SAMI BAHNA, MD • Comments on del(22q11.2), hyper IgE syndrome, Netherton syndrome, and severe combined immunodeficiency. JOSEPH BOCCHINI, JR. MD • Comments on congenital cytomegalovirus infection and congenital toxoplasmosis and encouragement and support throughout preparation of the Atlas. CHUNG-HO CHANG, MD • Cases on Duchenne muscular dystrophy and congenital toxoplasmosis. SAU CHEUNG, PhD • FISH on a case of STS deficiency. JAMES GANLEY, MD • Cases on ophthalmology (Behcet disease, Lisch nodule in NF1, cherry spot in Tay-Sachs disease, and retinal changes in congenital toxoplasmosis, von-Hippel Lindal disease, and Waardenburg syndrome). ENRIQUE GONZALEZ, MD • Valuable comments on pathological aspects of clinical entities and cases on acardius, agnathia, cloacal exstrophy, congenital cytomegalovirus infection, omphalocele, pediatric solid tumors (meningioma, neuroblastoma, retinoblastoma, and Wilms tumor), phocomelia, sickle cell anemia, thalassemia, and Gaucher disease. WILLIAM HOFFMAN, MD • Comments on topics of endocrinological interest and cases on androgen insensitivity and hypophosphatemic rickets. RACHEL FLAMHOLZ, MD • Peripheral blood smears on sickle cell anemia and thalassemia. MAJED JEROUDI, MD • A case of sickle cell anemia dactylitis. DANIEL LACEY, MD • Comments on dystrophinopathy, spinal muscular atrophy, neural tube defects, and holoprosencephaly. MARY LOWERY, MD • Comments on the Atlas and cases on molecular cytogenetics/pathology (FISH on trisomy 21, trisomy 13, trisomy 18, X/XXX, Williams syndrome, and neuroblastoma; mutation analysis on cystic fibrosis and hereditary hemochromatosis). LYNN MARTIN, LPN • Help in caring for the patients including obtaining the photographs of patients and searching for clinical information of the old files. LEONARD PROUTY, PhD • Reading of several topics in the Atlas. DAN SANUSI, MD • A case of X-linked ichthyosis. TOHRU SONODA, MD • Cases on chondrodysplasia punctata, del(22q11.2), Kabuki syndrome, KlippelTrenaunay syndrome, and tuberous sclerosis.

Institutions Louisiana State University Health Sciences Center in Shreveport, Louisiana (Drs. Joseph Bocchini, Jr., David Lewis, Rose Brouillette, Rodney Wise) Pinecrest Developmental Center in Pineville, Louisiana (Drs. Gaylon Bates, Tony Hanna, Renata Pilat) Shreveport Shriner’s Hospital for Children (Dr. Richard McCall) xi

Acardia Acardia is a bizarre fetal malformation occurring only in twins or triplets. It is also called acardius acephalus, acardiac twinning, or twin reversed arterial perfusion (TRAP) syndrome or sequence. This condition is very rare and occurs 1 in 35,000 deliveries, 1 in 100 monozygotic twins, rarely in triplet pregnancy, and even in quintuplet gestations.

b) Presence of rudimentary nerve tissue in addition to anatomical features in acardius amorphous iii. Acardius acephalus a) The most common type b) Missing head, part of the thorax, and upper extremities c) May have additional malformations in the remaining organs iv. Acardius anceps a) Presence of a partially developed fetal head, a thorax, abdominal organs, and extremities b) Lacks even a rudimentary heart v. Acardius acormus a) The rarest type b) Lacks thorax c) Presence of a rudimentary head only d) The umbilical cord inserts in the head and connects directly to the placenta 4. The acardia a. Characterized by the absence of a normally functioning heart b. Acardia as a recipient of twin transfusion sequence i. Reversal of blood flow in various types of acardia, hence the term “twin reversed arterial perfusion (TRAP) sequence” has been proposed ii. Receiving the deoxygenated blood from an umbilical artery of its co-twin through the single umbilical artery of the acardiac twin and returning to its umbilical vein. Therefore, the circulation is entirely opposite to the normal direction c. Usually the severe reduction anomalies occur in the upper part of the body d. May develop various structural malformations i. Growth retardation ii. Anencephaly iii. Holoprosencephaly iv. Facial defects v. Absent or malformed limbs vi. Gastrointestinal atresias vii. Other abnormalities of abdominal organs 5. The co-twin a. Also known as the “pump twin or donor twin” b. The donor “pump” twin perfuses itself and its recipient acardiac twin through abnormal arterial anastomosis in the fused placenta c. Increased cardiac workload often leads to cardiac failure and causes further poor perfusion and oxygenation of the acardiac co-twin d. May develop various malformations (about 10%)

GENETICS/BASIC DEFECTS 1. Etiology a. Rare complication of monochorionic twinning, presumably resulting from the fused placentation of monochorionic twins b. Represents manifestation of abnormal embryonic and fetal blood flow rather than a primary defect of cardiac formation c. Heterogeneous chromosomal abnormalities are present in nearly 50% of the cases, although chromosome errors are not underlying pathogenesis of the acardiac anomaly. i. 45,XX,t(4;21)del(4p) ii. 46,X,i(Xp) iii. 47,XX,+2 iv. 47,XX,+11 v. 47,XY,+G vi. 47,XXY vii. 69,XXX viii. 70,XXX,+15 ix. 94,XXXXYY 2. Pathogenesis: reversal of fetal arterial perfusion a. First hypothesis i. A primary defect in the development of the heart ii. Survival of the acardiac twin as a result of the compensatory anastomoses that develop b. Second hypothesis i. The acardiac twin beginning life as a normal fetus ii. The reversal of the arterial blood flow resulting in atrophy of the heart and the tributary organs 3. Classification of TRAP sequence (syndrome) a. Classification according to the status of the heart of the acardiac twin i. Hemiacardius (with incompletely formed heart) ii. Holoacardius (with completely absent heart) b. Morphologic classification of the acardiac twin i. Acardius amorphous a) The least differentiated form; no resemblance to classical human form b) Anatomical features: presence of only bones, cartilage, muscles, fat, blood vessels, and stroma ii. Acardius myelacephalus a) Resembles the amorphous type, except for the presence of rudimentary limb formation

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CLINICAL FEATURES 1. Perinatal problems associated with acardiac twinning a. Pump-twin congestive heart failure b. In utero fetal death of the pump fetus c. Maternal polyhydramnios d. Premature rupture of membrane e. Preterm delivery f. Spontaneous abortions g. Soft tissue dystocia h. Uterine rupture i. Postpartum hemorrhage j. Increased rate of cesarean section, up to 50% 2. Majority of acardiac twins and their normal twin counterparts are females 3. Nonviable 4. Gross features a. Severe reduction anomalies, particularly of the upper body b. Characteristic subcutaneous edema c. Internal organs: invariably missing d. Absent or rudimentary cardiac development: the key diagnostic feature i. Pseudoacardia (rudimentary heart tissue) ii. Holoacardia (completely lacking a heart) 5. Growth abnormality 6. Cranial vault a. Absent b. Partial c. Intact 7. Brain a. Absent b. Necrotic c. Open cranial vault d. Holoprosencephaly 8. Facial features a. Absent facial features b. Rudimentary facial features c. Present with defects d. Anophthalmia/microphthalmia e. Cleft lip/palate 9. Upper limbs a. Absent b. Rudimentary c. Radial aplasia d. Syndactyly/oligodactyly 10. Lower limbs a. Absent b. Rudimentary/reduced c. Syndactyly/oligodactyly d. Talipes equinovarus 11. Thorax a. Absent b. Reduced c. Diaphragmatic defect 12. Lungs a. Absent b. Necrotic or rudimentary c. Single midline lobe

13. Cardiac a. Absent heart tissue b. Unfolded heart tube c. Folded heart with common chamber 14. Gastrointestinal a. Esophageal atresia b. Short intestine c. Interrupted intestine d. Omphalocele e. Incomplete rotation of the gut f. Imperforated anus g. Ascites 15. Liver a. Absent b. Reduced 16. Kidney a. Absent (bilateral) b. Hypoplastic and/or lobulated 17. Other viscera a. Absent gallbladder b. Absent spleen c. Absent-to-reduced pancreas d. Absent adrenal e. Absent-to-hypoplastic gonads f. Exstrophy of the cloaca g. Skin with myxedematous thickening 18. Umbilical cord vessels a. Two vessels b. Three vessels 19. Severe obstetrical complications a. Maternal polyhydramnios b. Preterm labor c. Cord accidents d. Dystocia e. Uterine rupture 20. Severe neonatal complications a. Hydrops b. Intrauterine demise c. Prematurity d. Heart failure e. Anemia f. Twin-to-twin transfusion syndrome 21. Outcome for the normal sib in an acardiac twin pregnancy a. Unsatisfactory i. Adapting to the increasing circulatory load, resulting in the following situations: a) Intrauterine growth retardation b) Hydrops c) Ascites d) Pleural effusion e) Hypertrophy of the right ventricle f) Hepatosplenomegaly g) Severe heart failure resulting in pericardial effusion and/or tricuspid insufficiency ii. Stillbirth iii. Prematurity iv. Neonatal death b. Mortality for the normal twin reported as high as 50% without intervention

ACARDIA

DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Absent or rudimentary skull b. Absent or rudimentary thorax c. Absent or rudimentary heart d. Vertebral anomalies e. Rib anomalies f. Limb defects, especially upper limbs 2. Pathology a. Microcephaly b. Severely rudimentary brain c. Developmental arrest of brain at the prosencephalic stage (holoprosencephaly) d. Hypoxic damage to the holospheric brain mantle with cystic change (hydranencephaly)

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: overall recurrence risk of about 1 in 10,000 (The recurrence risk is for monoamniotic twinning [1% for couples who have had one set of monozygotic twins] times the frequency of the occurrence of TRAP sequence with near-term survival [about 1% of monozygotic twin sets]) b. Patient’s offspring: not applicable (a lethal condition) 2. Prenatal ultrasonography a. Monochorionic placenta with a single umbilical artery in 2/3 of cases b. Acardiac fetus i. Unrecognizable head or upper trunk ii. Without a recognizable heart or a partially formed heart iii. A variety of other malformations iv. Reversal of blood flow in the umbilical artery with flow going from the placenta toward the acardiac fetus (reversed arterial perfusion). Such a reversal of the blood flow in the recipient twin can be demonstrated in utero by transvaginal Doppler ultrasound as early as 12 weeks of gestation v. Early diagnosis by transvaginal sonography on the following signs: a) Monozygotic twin gestation (absence of the lambda sign) b) Biometric discordance between the twins c) Diffuse subcutaneous edema or morphologic anomalies of one of the twins, or both d) Detection of reversed umbilical cord flow; cardiac activity likely to disappear as the pregnancy progresses e) Absence of cardiac activity, although hemicardia or pseudocardia may be present c. The donor fetus i. Hydrops ii. Cardiac failure (cardiomegaly, pericardial effusion, and tricuspid regurgitation)

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2. Amniocentesis to diagnose associated chromosome abnormalities (about 10% of pump twins) 3. Management of pregnancies complicated by an acardiac fetus a. Conservative treatment i. Monitor pregnancy by serial ultrasonography ii. Conservative approach as long as there is no evidence of cardiac circulatory decompensation in the donor twin b. Termination of pregnancies c. Treatment and prevention of preterm labor by tocolytics i. Magnesium sulphate ii. Beta-Sympathomimetics iii. Indomethacin d. Treatment of pump fetus heart failure involving maternal digitalization e. Treatment of polyhydramnios by therapeutic repeated amniocentesis f. Selective termination of the acardiac twin i. To occlude the umbilical artery of the acardiac twin in order to stop umbilical flow through the anastomosis a) Intrafunicular injection and mechanical occlusion of the umbilical artery b) Embolization by steel or platinum coil, alcohol-soaked suture material, or ethanol c) Hysterotomy and delivery of acardiac twin d) Ligation of the umbilical cord e) Hysterotomy and umbilical cord ligation ii. Fetal surgery: best available treatment for acardiac twinning a) Endoscopic laser coagulation of the umbilical vessels at or before 24 weeks of gestation b) Endoscopic or sonographic guided umbilical cord ligation after 24 weeks of gestation iii. Summary of acardiac twins treated with invasive procedures reported in the literature a) Mortality of the pump twin (13.6%) b) Preterm delivery (50.3%) c) Delivery before 30-weeks gestation (27.2%) d) Perinatal mortality, if untreated, is at least 50%

REFERENCES Aggarwal N, Suri V, Saxena SV, et al.: Acardiac acephalus twins: a case report and review of literature. Acta Obstet Gynecol Scand 81:983–984, 2002. Alderman B: Foetus acardius amorphous. Postgrad Med J 49:102–105, 1973. Arias F, Sunderji S, Gimpelson R, et al.: Treatment of acardiac twinning. Obstet Gynecol 91:818–821, 1998. Benirschke K, des Roches Harper V: The acardiac anomaly. Teratology 15:311–316, 1977. Blaicher W, Repa C, Schaller A: Acardiac twin pregnancy: associated with trisomy 2. Hum Reprod 15:474–475, 2000. Blenc AM, Gömez JA, Collins D, et al.: Pathologic quiz case. Pathologic diagnosis: acardiac fetus, acardius acephalus type. Arch Pathol Lab Med 123:974–976, 1999. Bonilla-Musoles F, Machado LE, Raga F, et al.: Fetus acardius. Two- and threedimensional ultrasonographic diagnoses. J Ultrasound Med 20:1117–1127, 2001. Chen H, Gonzalez E, Hand AM, Cuestas R: The acardius acephalus and monozygotic twinning. Schumpert Med Quart 1:195–199, 1983.

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Donnenfeld AE, Van de Woestijne J, Craparo F, et al.: The normal fetus of an acardiac twin pregnancy: perinatal management based on echocardiographic and sonographic evaluation. Prenat Diagn 11:235–244, 1991. French CA, Bieber FR, Bing DH, et al.: Twins, placentas, and genetics: acardiac twinning in a dichorionic, diamniotic, monozygotic twin gestation. Hum Pathol 29:1028–1031, 1998. Hanafy A, Peterson CM: Twin-reversed arterial perfusion (TRAP) sequence: case reports and review of literature. Aust N Z J Obstet Gynaecol 37:187–191, 1997. Healey MG: Acardia: predictive risk factors for the co-twin’s survival. Teratology 50:205–213, 1994.

Sanjaghsaz H, Bayram MO, Qureshi F: Twin reversed arterial perfusion sequence in conjoined, acardiac, acephalic twins associated with a normal triplet. A case report. J Reprod Med 43:1046–1050, 1998. Søgaard K, Skibsted L, Brocks V: Acardiac twins: Pathophysiology, diagnosis, outcome and treatment. Six cases and review of the literature. Fetal Diagn Ther 14:53–59, 1999. Van Allen MI, Smith DW, Shepard TH: Twin reversed arterial perfusion (TRAP) sequence: a study of 14 twin pregnancies with acardius. Semin Perinatol 7:285–293, 1983.

ACARDIA

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Fig. 2. Radiographs of the above acardiac fetus showing a missing head, cervical vertebrae and part of upper thoracic vertebrae, rudimental lower ribs, malformed lower thoracic and lumbar vertebrae, and relatively well-formed lower limbs.

Fig. 1. Ventral view of an acardiac acephalus fetus (upper photo) shows a large abdominal defect, gastroschisis (arrow), through which small rudiments of gastrointestinal tract are seen. Dorsal view (lower photo) shows a very underdeveloped cephalic end and relatively welldeveloped lower limbs. The co-twin had major malformations consisting of a large omphalocele, ectopia cordis, and absent pericardium, incompatible with life. Fig. 3. The head and part of the thorax of this acardiac fetus are completely missing with relatively well-formed lower limbs.

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Fig. 4. Another acardiac fetus with a missing head and part of the upper thorax. Radiograph shows missing head, and cervical and part of thoracic vertebrae and ribs. Pelvis and lower limbs are well formed.

Fig. 5. Acardius (second twin, 36-weeks gestation) showing spherical body with a small amorphous mass of leptomeningeal and glial tissue at the cephalic end. There were one deformed lower extremity and a small arm appendage. Small intestinal loops, nodules of adrenal glands, and testicles were present in the body. There was no heart or lungs. The placenta was nonoamniotic monochorionic with velamentous insertion of the umbilical cord. The other identical twin was free of birth defects. Radiograph of acardius twin shows a short segment of the spine, a femur, a tibia, and a fibula.

Achondrogenesis Achondrogenesis is a heterogeneous group of lethal chondrodysplasias. Achondrogenesis type I (Fraccaro-Houston-Harris type) and type II (Langer-Saldino type) were distinguished on the basis of radiological and histological criteria. Achondrogenesis type I was further subdivided, on the basis of convincing histological criteria, into type IA, which has apparently normal cartilage matrix but inclusions in chondrocytes, and type IB, which has an abnormal cartilage matrix. Classification of type IB as a separate group has been confirmed recently by the discovery of its association with mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene, making it allelic with diastrophic dysplasia.

e. Heart i. Patent ductus arteriosus ii. Atrial septal defect iii. Ventricular septal defect f. Protuberant abdomen g. Limbs i. Extremely short (micromelia), shorter than type II ii. Flipper-like appendages 3. Achondrogenesis type II a. Growth i. Lethal neonatal dwarfism ii. Mean birth weight of 2100 g b. Craniofacial features i. Disproportionately large head ii. Large and prominent forehead iii. Midfacial hypoplasia a) Flat facial plane b) Flat nasal bridge c) Small nose with severely anteverted nostrils iv. Normal philtrum v. Micrognathia vi. Cleft palate c. Extremely short neck d. Thorax i. Short and flared thorax ii. Bell-shaped cage iii. Lung hypoplasia e. Protuberant abdomen f. Extremely short limbs (micromelia)

GENETICS/BASIC DEFECTS 1. Type IA: an autosomal recessive disorder with an unknown chromosomal locus 2. Type IB a. An autosomal recessive disorder b. Resulting from mutations of the DTDST gene, which is located at 5q32-q33 3. Type II a. Autosomal dominant type II collagenopathy b. Resulting from mutations in the COL2A1 gene, which is located at 12q13.1-q13.3

CLINICAL FEATURES 1. Prenatal/perinatal history a. Polyhydramnios b. Hydrops c. Breech presentation d. Perinatal death 2. Achondrogenesis type I a. Growth i. Lethal neonatal dwarfism ii. Mean birth weight of 1200 g b. Craniofacial features i. Disproportionately large head ii. Soft skull iii. Sloping forehead iv. Convex facial plane v. Flat nasal bridge, occasionally associated with a deep horizontal groove vi. Small nose, often with anteverted nostrils vii. Long philtrum viii. Retrognathia ix. Increased distance between lower lip and lower edge of chin x. Double chin appearance c. Extremely short neck d. Thorax i. Short and barrel-shaped thorax ii. Lung hypoplasia

DIAGNOSTIC INVESTIGATIONS 1. Radiological features a. Variable features b. No single obligatory feature c. Distinction between type IA and type IB on radiographs not always possible d. Degree of ossification: age dependent, and caution is needed when comparing radiographs at different gestational ages e. Achondrogenesis type I i. Skull: Varying degree of deficient cranial ossification consisting of small islands of bone in membranous calvaria ii. Thorax and ribs a) Short and barrel-shaped thorax b) Thin ribs with marked expansion at costochondral junction, frequently with multiple fractures iii. Spine and pelvis a) Poorly ossified spine, ischium, and pubis b) Poorly ossified iliac bones with short medial margins 7

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iv. Limbs and tubular bones a) Extreme micromelia, with limbs much shorter than in type II b) Prominent spike-like metaphyseal spurs c) Femur and tibia frequently presenting as short bone segments v. Subtype IA (Houston-Harris type) a) Poorly ossified skull b) Thin ribs with multiple fractures c) Unossified vertebral pedicles d) Arched ilium e) Hypoplastic but ossified ischium f) Wedged femur with metaphyseal spikes g) Short tibia and fibula with metaphyseal flare vi. Subtype IB (Fraccaro type) a) Adequately ossified skull b) Absence of rib fractures c) Total lack of ossification or only rudimentary calcification of the center of the vertebral bodies d) Ossified vertebral pedicles e) Iliac bones with ossification only in their upper part, giving a crescent-shaped, “paragliderlike” appearance on X-ray f) Unossified ischium g) Shortened tubular bones without recognized axis h) Metaphyseal spurring giving the appearance of a “thorn apple” or “acanthocyte” (a descriptive term in hematology) i) Trapezoid femur j) Stellate tibia k) Unossified fibula l) Poorly ossified phalanges f. Achondrogenesis type II i. Skull a) Normal cranial ossification b) Relatively large calvaria ii. Thorax and ribs a) Short and flared thorax b) Bell-shaped cage c) Shorter ribs without fractures iii. Spine and pelvis: relatively well-ossified iliac bones with long, crescent-shaped medial and inferior margins iv. Limbs and tubular bones a) Short, broad bones, usually with some diaphyseal constriction and flared, cupped metaphyseal ends b) Metaphyseal spurs, usually smaller than type I 2. Histologic features a. Achondrogenesis type IA i. Normal cartilage matrix ii. Absent collagen rings around the chondrocytes iii. Vacuolated chondrocytes iv. Presence of intrachondrocytic inclusion bodies (periodic acid-Schiff [PAS] stain positive, diastase resistant) v. Extraskeletal cartilage involvement

vi. Enlarged lacunas vii. Woven bone b. Achondrogenesis type IB i. Abnormal cartilage matrix: presence of “demasked” coarsened collagen fibers, particularly dense around the chondrocytes, forming collagen rings ii. Abnormal staining properties of cartilage a) Reduced staining with cationic dyes, such as toluidine blue or Alcian blue, probably because of a deficiency in sulfated proteoglycans b) This distinguishes type IB from type IA, in which the matrix is close to normal and inclusions can be seen in chondrocytes, and from achondrogenesis type II, in which cationic dyes give a normal staining pattern c. Achondrogenesis type II i. Cartilage a) Slightly larger than normal b) Grossly distorted (lobulated and mushroomed) ii. Markedly deficient cartilaginous matrix iii. Severe disturbance in endochondral ossification iv. Hypercellular and hypervascular reserve cartilage with large, primitive mesenchymal (ballooned) chondrocytes with abundant clear cytoplasm (vacuoles) (“Swiss cheese-like”) v. Overgrowth of membranous bones resulting in cupping of the epiphyseal cartilages vi. Decreased amount and altered structure of proteoglycans vii. Relatively lower content of chondroitin 4-sulfate viii. Lower molecular weight and decreased total chondroitin sulfation ix. Absence of type II collagen x. Increased amounts of type I and type III collagen 3. Biochemical testing a. Lack of sulfate incorporation: cumbersome and not used for diagnostic purposes b. Sulfate incorporation assay in cultured skin fibroblasts or chondrocytes: recommended in the rare instances in which the diagnosis of achondrogenesis type IB is strongly suspected but molecular genetic testing fails to detect SLC26A2 (DTDST) mutations 4. Molecular genetic studies a. Mutation analysis of the DTDST gene, reported in: i. Achondrogenesis type IB (the most severe form) ii. Atelosteogenesis type II (an intermediate form) iii. Diastophic dysplasia (the mildest form) iv. Recessive multiple epiphyseal dysplasia b. Achondrogenesis type IB i. Mutation analysis: testing of the following four most common SLC26A2 (DTDST) gene mutations (mutation detection rate about 60%) a) R279W b) IVS1+2T>C (“Finnish” mutation) c) delV340 d) R178X

ACHONDROGENESIS

ii. Sequence analysis of the SLC26A2 (DTDST) coding region (mutation detection rate over 90%) a) Private mutations b) Common mutations c. Achondrogenesis type II: mutation analysis of the COL2A1 gene

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Achondrogenesis type IA and type IB (autosomal recessive disorders) a) Recurrence risk: 25% b) Unaffected sibs of a proband: 2/3 chance of being heterozygotes ii. Achondrogenesis type II a) Usually caused by a new dominant mutation, in which case recurrence risk is not significantly increased b) Asymptomatic carrier parent (germline mutation for a dominant mutation) may be present in the families of affected patients, in which case recurrence risk is 50% b. Patient’s offspring: lethal entities not surviving to reproduction 2. Prenatal diagnosis a. Ultrasonography i. Polyhydramnios ii. Fetal hydrops iii. Disproportionally big head iv. Nuchal edema v. Cystic hygroma vi. A narrow thorax vii. Short limbs viii. Poor ossification of vertebral bodies and limb tubular bones (leading to difficulties in determining their length) ix. Suspect achondrogenesis type I a) An extremely echo-poor appearance of the skeleton b) A poorly mineralized skull c) Short limbs d) Rib fractures b. Molecular genetic studies i. Prenatal diagnosis of achondrogenesis type IB and type II by mutation analysis of chorionic villus DNA or amniocyte DNA in the first or second trimester ii. Achondrogenesis type IB a) Characterize both alleles of DTDST beforehand b) Identify the source parent of each allele c) Theoretically, analysis of sulfate incorporation in chorionic villi might be used for prenatal diagnosis, but experience is lacking iii. Achondrogenesis type II a) The affected fetus usually with a new dominant mutation of the COL2A1 gene

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b) Possible presence of asymptomatic carriers in families of an affected patient c) Prenatal diagnosis possible if the mutation has been characterized in the affected family 3. Management a. Supportive care b. No treatment available for the underlying lethal disorder

REFERENCES Balakumar K: Antenatal diagnosis of Parenti-Fraccaro type achondrogenesis. Indian Pediatr 27:496–499, 1990. Bonafé L, Ballhausen D, Superti-Furga A: Achondrogenesis type 1B. Gene reviews, 2004. http://www.genetests.org Borochowitz Z, Lachman R, Adomian GE, et al.: Achondrogenesis type I: delineation of further heterogeneity and identification of two distinct subgroups. J Pediatr 112:23–31, 1988. Borochowitz Z, Ornoy A, Lachman R, et al.: Achondrogenesis II-hypochondrogenesis: variability versus heterogeneity. Am J Med Genet 24:273–288, 1986. Benacerraf B, Osathanondh R, Bieber FR: Achondrogenesis type I: ultrasound diagnosis in utero. J Clin Ultrasound 12:357–359, 1984. Chen H: Achondrogenesis. Emedicine, 2001. http://www.emedicine.com Chen H: Skeletal dysplasia. Emedicine, 2002. http://www.emedicine.com Chen H, Liu CT, Yang SS: Achondrogenesis: a review with special consideration of achondrogenesis type II (Langer-Saldino). Am J Med Genet 10:379–394, 1981. Faivre L, Le Merrer M, Douvier S, et al.: Recurrence of achondrogenesis type II within the same family: Evidence for germline mosaicism. Am J Med Genet 126A:308–312, 2004. Godfrey M, Hollister DW: Type II achondrogenesis-hypochondrogenesis: identification of abnormal type II collagen. Am J Hum Genet 43:904–913, 1988. Horton WA, Machado MA, Chou JW, et al.: Achondrogenesis type II, abnormalities of extracellular matrix. Pediatr Res 22:324–329, 1987. Körkkö J, Cohn DH, Ala-Kokko L, et al.: Widely distributed mutations in the COL2A1 gene produce achondrogenesis type II/hypochondrogenesis. Am J Med Genet 92:95–100, 2000. Langer LO, Jr, Spranger JW, Greinacher I, et al.: Thanatophoric dwarfism. A condition confused with achondroplasia in the neonate, with brief comments on achondrogenesis and homozygous achondroplasia. Radiology 92:285–294 passim, 1969. Meizner I, Barnhard Y: Achondrogenesis type I diagnosed by transvaginal ultrasonography at 13 weeks’ gestation. Am J Obstet Gynecol 173:1620–1622, 1995. Molz G, Spycher MA: Achondrogenesis type I: light and electron-microscopic studies. Eur J Pediatr 134:69–74, 1980. Mortier GR, Wilkin DJ, Wilcox WR, et al.: A radiographic, morphologic, biochemical and molecular analysis of a case of achondrogenesis type II resulting from substitution for a glycine residue (Gly691>Arg) in the type II collagen trimer. Hum Mol Genet 4:285–288, 1995. Ornoy A, Sekeles E, Smith P, et al.: Achondrogenesis type I in three sibling fetuses. Scanning and transmission electron microscopic studies. Am J Pathol 82:71–84, 1976. Smith WL, Breitweiser TD, Dinno N: In utero diagnosis of achondrogenesis, type I. Clin Genet 19:51–54, 1981. Soothill PW, Vuthiwong C, Rees H: Achondrogenesis type 2 diagnosed by transvaginal ultrasound at 12 weeks’ gestation. Prenat Diagn 13:523–528, 1993. Spranger J: International classification of osteochondrodysplasias. Eur J Pediatr 151:407–415, 1992. Spranger J, Winterpacht A, Zabel B: The type II collagenopathies: a spectrum of chondrodysplasias. Eur J Pediatr 153:56–65, 1994. Superti-Furga A: Achondrogenesis type 1B. J Med Genet 33:957–961, 1996. 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 12:100–102, 1996. 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 63:144–147, 1996.

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Tongsong T, Srisomboon J, Sudasna J: Prenatal diagnosis of Langer-Saldino achondrogenesis. J Clin Ultrasound 23:56–58, 1995. van der Harten HJ, Brons JT, Dijkstra PF, et al.: Achondrogenesis-hypochondrogenesis: the spectrum of chondrogenesis imperfecta. A radiological, ultrasonographic, and histopathologic study of 23 cases. Pediatr Pathol 8:571–597, 1988. Yang SS, Bernstein J: Letter: Proposed readjustment of eponyms for achondrogenesis. J Pediatr 87:333–334, 1975. Yang S-S, Heidelberger KP, Brough AJ, et al.: Lethal short-limbed chondrodysplasia in early infancy. Persp Pediatr Pathol 3:1–40, 1976.

Yang SS, Bernstein J: Achondrogenesis type I. Arch Dis Child 52:253–254, 1977. Yang SS, Gilbert-Barnes E: Skeletal system. In: Gilbert-Barness E (ed): Potter’s Pathology of the Fetus and Infant. St Louis: Mosby, 1997, pp 1423–1478. Yang SS, Brough AJ, Garewal GS, et al.: Two types of heritable lethal achondrogenesis. J Pediatr 85:796–801, 1974. Yang SS, Heidelberger KP, Bernstein J: Intracytoplasmic inclusion bodies in the chondrocytes of type I lethal achondrogenesis. Hum Pathol 7:667–673, 1976.

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Fig. 1. A neonate with achondrogenesis type I showing large head, short trunk, and extreme micromelia. Radiograph shows unossified calvarium, vertebral bodies and some pelvic bones. The remaining bones are extremely small. There are multiple rib fractures. The sagittal section of the femora and the humeri are similar. An extremely small ossified shaft is capped by a relatively large epiphyseal cartilage at both ends. Photomicrographs of resting cartilage with high magnification show many chondrocytes that contain large cytoplasmic inclusions which are within clear vacuoles (Diastase PAS stain). Electron micrograph shows inclusion as a globular mass of electron dense material. It is within a distended cistern of rough endoplasmic reticulum.

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ACHONDROGENESIS

Fig. 2. Achondrogenesis type II. As in type I, this neonate shows large head, short trunk, and micromelia. Sagittal section of the femur shows much better ossification of the shaft than type I. The cartilage lacks glistering appearance due to cartilage matrix deficiency. Photomicrograph of the entire cartilage shows severe deficiency of cartilage matrix. The cartilage canals are large, fibrotic, and stellate in shape. Physeal growth zone is severely retarded.

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Fig. 3. Two infants with achondrogenesis type II showing milder spectrum of manifestations, bordering the type II and spondyloepiphyseal congenita.

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Fig. 4. A newborn girl with achondrogenesis type II showing large head, midfacial hypoplasia, short neck, small chest, and short limbs. The radiographs shows generalized shortening of the long bones of the upper and lower extremities with marked cupping (metaphyseal spurs) at the metaphyseal ends of the bones. This is most evident at the distal ends of the tibia, fibular, radius and ulna, and distal ends of the digits. Radiographs also shows short ribs without fractures and hemivertebrae involving thoracic vertebrae as well as the sacrum. Conformation-sensitive gel electrophoresis analysis indicated a sequence variation in the fragment containing exon 19 and the flanking sequences of the COL2A1 gene (Gly244Asp). Similar mutations in this area have been seen in patients diagnosed with hypochondroplasia and achondrogenesis type II.

Achondroplasia Achondroplasia is the most common form of short-limbed dwarfism. Gene frequency is estimated to be 1/16,000 and 1/35,000. There are about 5000 achondroplasts in the USA and 65,000 on Earth. The incidence for achondroplasia is between 0.5 and 1.5 in 10,000 births. The mutation rate is high and is estimated to be between 1.72×10–5 and 5.57×10–5 per gamete per generation. Most infants with achondroplasia are born unexpectedly to parents of average stature.

CLINICAL FEATURES 1. Major clinical symptoms a. Delayed motor milestones during infancy and early childhood b. Sleep disturbances secondary to both neurological and respiratory complications c. Breathing disorders i. A high prevalence (75%) of breathing disorders during sleep ii. Obstructive apnea caused by upper airway obstruction iii. The majority of respiratory complaints due to restrictive lung disease secondary to diminished chest size or upper airway obstruction and rarely due to spinal cord compression d. Symptomatic spinal stenosis in more than 50% of patients as a consequence of a congenitally small spinal canal i. Back pain ii. Lower extremity sensory changes iii. Incontinence iv. Paraplegia v. Onset of symptoms: usually after 20 seconds or 30 seconds e. Neurologic symptoms classified based on neurologic severity and presentation of spinal stenosis (Lutter and Langer, 1977) i. Type I (back pain with sensory and motor change of an insidious nature) ii. Type II (intermittent claudication limiting ambulation) iii. Type III (nerve root compression) iv. Type IV (acute onset paraplegia) f. Symptoms secondary to foramen magnum stenosis i. Respiratory difficulty ii. Feeding problems iii. Cyanosis, quadriparesis iv. Poor head control g. Symptoms secondary to cervicomedullary compression i. Pain ii. Ataxia iii. Incontinence iv. Apnea v. Progressive quadriparesis vi. Respiratory arrest 2. Major clinical signs a. Disproportionate short stature (dwarfism) b. Hypotonia during infancy and early childhood c. Relative stenosis of the foramen magnum in all patients, documented by CT d. Foramen magnum stenosis considered as the cause of increased incidence of:

GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal dominant disorder with complete penetrance b. Sporadic in about 80% of the cases, the result of a de novo mutation c. Presence of paternal age effect (advanced paternal age in sporadic cases) d. Gonadal mosaicism (two or more children with classic achondroplasia born to normal parents) 2. Caused by mutations in the gene of the fibroblast growth factor receptor 3 (FGFR3) on chromosome 4p16.3 a. About 98% of achondroplasia with G-to-A transition and about 1% G-to-C transversion at nucleotide 1138. Both mutations resulted in the substitution of an arginine residue for a glycine at position 380 (G380A) of the mature protein in the transmembrane domain of FGFR3 b. A rare mutation causing substitution of a nearby glycine 375 with a cysteine (G375C) c. Another rare mutation causing substitution of glycine346 with glutamic acid (G346E) d. The specific mechanisms by which FGFR3 mutations disrupt skeletal development in achondroplasia remain elusive 3. Basic defect: zone of chondroblast proliferation in the physeal growth plates a. Abnormally retarded endochondral ossification with resultant shortening of tubular bones and flat vertebral bodies, while membranous ossification (skull, facial bones) is not affected b. Physeal growth zones show normal columnization, hypertrophy, degeneration, calcification, and ossification. However, the growth is quantitatively reduced significantly c. Achondroplasia as the result of a quantitative loss of endochondral ossification rather than the formation of abnormal tissue d. Normal diameter of the bones secondary to normal subperiosteal membranous ossification of tubular bones; the results being production of short, thick tubular bones, leading to short stature with disproportionately shortened limbs 15

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i. Hypotonia ii. Sleep apnea iii. Sudden infant death syndrome e. Symptomatic hydrocephalus in infancy and early childhood rarely due to narrowing of the foramen magnum f. Characteristic craniofacial appearance i. Disproportionately large head ii. Frontal bossing iii. Depressed nasal bridge iv. Midfacial hypoplasia v. Narrow nasal passages vi. Prognathism vii. Dental malocclusion g. A normal trunk length h. A thoracolumbar kyphosis or gibbus usually present at birth or early infancy i. Exaggerated lumbar lordosis when the child begins to ambulate j. Prominent buttocks and protuberant abdomen secondary to increased pelvic tilt in children and adults k. Generalized joint hypermobility, especially the knees l. Rhizomelic micromelia (relatively shorter proximal segment of the limbs compared to the middle and the distal segments) m. Limited elbow and hip extension n. Trident hands (inability to approximate the third and fourth fingers in extension produces a “trident” configuration of the hand) o. Short fingers (brachydactyly) p. Bowing of the legs (genu varum) due to lax knee ligaments q. Excess skin folds around thighs 3. Complications/risks a. Recurrent otitis media during infancy and childhood i. Conductive hearing loss ii. Delayed language development b. Thoraco-lumbar gibbus c. Osteoarthropathy of the knee joints d. Neurological complications i. Small foramen magnum ii. Cervicomedullary junction compression causing sudden unexpected death in infants with achondroplasia iii. Apnea iv. Communicating hydrocephalus v. Spinal stenosis vi. Paraparesis vii. Quadriparesis viii. Infantile hypotonia e. Obesity i. Aggravating the morbidity associated with lumbar stenosis ii. Contributing to the nonspecific joint problems and to the possible early cardiovascular mortality in this condition f. Obstetric complications i. Large head of the affected infant ii. An increased risk of intracranial bleeding during delivery iii. Marked obstetrical difficulties secondary to very narrow pelvis of achondroplastic women

4. Prognosis a. Normal intelligence and healthy, independent, and productive lives in vast majority of patients. Rarely, intelligence may be affected because of hydrocephalus or other CNS complications b. Mean adult height i. Approximately 131 ± 5.6 cm for males ii. Approximately 124 ± 5.9 cm for females c. Psychosocial problems related to body image because of severe disproportionate short stature d. Life- span for heterozygous achondroplasia i. Usually normal unless there are serious complications ii. Mean life expectancy approximately 10 years less than the general population e. Homozygous achondroplasia i. A lethal condition with severe respiratory distress caused by rib-cage deformity and upper cervical cord damage caused by small foramen magnum. The patients die soon after birth ii. Radiographic changes much more severe than the heterozygous achondroplasia f. Normal fertility in achondroplasia i. Pregnancy at high risk for achondroplastic women ii. Respiratory compromise common during the third trimester iii. Advise baseline pulmonary function studies before pregnancy to aid in evaluation and management iv. A small pelvic outlet usually requiring cesarean section under general anesthesia since the spinal or epidural approach is contraindicated because of spinal stenosis g. Anticipatory guidance: patients and their families can benefit greatly from anticipatory guidance published by American Academy of Pediatrics Committee on Genetics (1995) h. Adaptations of patients to the environment to foster independence i. Lowering faucets and light switches ii. Using a step stool to keep feet from dangling when sitting iii. An extended wand for toileting iv. Adaptations of toys for short limbs i. Support groups: Many families find it beneficial to interact with other families and children with achondroplasia through local and national support groups

DIAGNOSTIC INVESTIGATIONS 1. Diagnosis of achondroplasia made by clinical findings, radiographic features, and/or FGFR3 mutation analysis 2. Radiologic features a. Skull i. Relatively large calvarium ii. Prominent forehead iii. Depressed nasal bridge iv. Small skull base v. Small foramen magnum vi. Dental malocclusion

ACHONDROPLASIA

b. Spine i. Caudal narrowing of interpedicular distances in the lower lumbar spine ii. Short vertebral pedicles iii. Wide disc spaces iv. Dorsal scalloping of the vertebral bodies in the newborn v. Concave posterior aspect of the vertebral bodies in childhood and adulthood vi. Different degree of anterior wedging of the vertebral bodies causing gibbus c. Pelvis i. Lack of iliac flaring ii. Narrow sacroiliac notch iii. Horizontal acetabular portions of the iliac bones d. Limbs i. Rhizomelic micromelia ii. Square or oval radiolucent areas in the proximal humerus and femur during infancy iii. Tubular bones with widened diaphyses and flared metaphyses during childhood and adulthood iv. Markedly shortened humeri v. Short femoral neck vi. Disproportionately long fibulae in relation to tibiae 3. Craniocervical MRI a. Narrowing of the foramen magnum b. Effacement of the subarachnoid spaces at the cervicomedullary junction c. Abnormal intrinsic cord signal intensity d. Mild-to-moderate ventriculomegaly 4. Histology a. Normal histologic appearance of epiphyseal and growth plate cartilages b. Shorter than normal growth plate: the shortening is greater in homozygous than in heterozygous achondroplasia, suggesting a gene dosage effect 5. Mutation analysis a. G1138A substitution in FGFR3 (about 98% of cases) b. G1138C substitution in FGFR3 (about 1% of cases)

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Recurrence risk of achondroplasia in the sibs of achondroplastic children with unaffected parents: presumably higher than twice the mutation rate because of gonadal mosaicism. Currently, the risk is estimated as 1 in 443 (0.2%) ii. 50% affected if one of the parents is affected iii. 25% affected with homozygous achondroplasia (resulting in a much more severe phenotype that is usually lethal early in infancy) and 50% affected with heterozygous achondroplasia if both parents are affected with achondroplasia b. Patient’s offspring i. 50% affected (with heterozygous achondroplasia) if the spouse is normal ii. 25% affected with homozygous achondroplasia and 50% affected with heterozygous achondropla-

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sia if the spouse is also affected with achondroplasia. There is still a 25% chance that the offspring will be normal 2. Prenatal diagnosis a. Prenatal ultrasonography i. Suspect achondroplasia on routine ultrasound findings of a fall-off in limb growth, usually during the third trimester of pregnancy, in case of parents with normal heights. About one-third of cases are suspected this way. However, one must be cautious because disproportionately short limbs are observed in a variety of conditions ii. Inability to make specific diagnosis of achondroplasia with certainty by ultrasonography unless by radiography late in gestation or after birth iii. Request of prenatal ultrasonography by an affected parent, having 50% risk of having a similarly affected child, to optimize obstetric management iv. Follow pregnancy by a femoral growth curve in the second trimester by serial ultrasound scans to enable prenatal distinction between homozygous, heterozygous, and unaffected fetuses, in case of both affected parents b. Prenatal molecular testing i. Molecular technology applied to prenatal diagnosis of a fetus suspected of or at risk for having achondroplasia ii. Simple methodology requiring only one PCR and one restriction digest to detect a very limited number of mutations causing achondroplasia iii. Preimplantation genetic diagnosis a) Available at present (Montou et al., 2003) b) The initial practice raising questions on the feasibility of such a test, especially with affected female patients 3. Management a. Adaptive environmental modifications i. Appropriately placed stools ii. Seating modification iii. Other adaptive devices b. Obesity control c. Obstructive apnea i. Adenoidectomy and tonsillectomy ii. Continuous positive airway pressure (CPAP) and bilevel positive airway pressure (BiPAP) for clinically significant persistent obstruction iii. Extremely rare for requiring temporary tracheostomy d. Experimental growth hormone therapy resulting in transient increases in growth velocity e. Hydrocephalus i. Observation for benign ventriculomegaly ii. May need surgical intervention for clinically significant hydrocephalus f. Kyphosis i. Adequate support for sitting in early infancy ii. Bracing using a thoracolumbosacral orthosis for severe kyphosis in young children iii. Surgical intervention for medically unresponsive cases

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g. Surgical decompression for unequivocal evidence for cervical cord compression h. Decompression laminectomy for severe and progressive lumbosacral spinal stenosis i. Limb lengthening through osteotomy and stretching of the long bones i. Controversial ii. Difficult to achieve the benefits of surgery a) Need strong commitment on the part of the patients and their families for the time in the hospital and the number of operations b) Occurrence of possible severe permanent sequelae j. Potential anesthetic risks related to: i. Obstructive apnea ii. Cervical compression k. Risks associated with pregnancy in women with achondroplasia: relatively infrequent i. Worsening neurologic symptoms related to increasing hyperlordosis and maternal respiratory failure ii. Anticipate a scheduled cesarean delivery due to cephalopelvic disproportion iii. Preeclampsia iv. Polyhydramnios

REFERENCES Allanson JE, Hall JG: Obstetrics and gynecologic problems in women with chondrodystrophies. Obstet Gynecol 67:74–78, 1986. American Academy of Pediatrics Committee on Genetics: Health supervision for children with achondroplasia. Pediatrics 95:443–451, 1995. Bellus GA, Hefferon TW, Ortiz de Luna RI, et al.: Achondroplasia is defined by recurrent G380R mutations of FGFR3. Am J Hum Genet 56:368–373, 1995. Chen H, Mu X, Sonoda T, et al.: FGFR3 gene mutation (Gly380Arg) with achondroplasia and i(21q) Down syndrome: phenotype-genotype correlation. South Med J 93:622–624, 2000. Francomano CA: Achondroplasia. Gene Reviews, 2003. http:// www.genetests.org Fryns JP, Kleczkowska A, Verresen H, et al.: Germinal mosaicism in achondroplasia: a family with 3 affected siblings of normal parents. Clin Genet 24:156–158, 1983. Hall JG: The natural history of achondroplasia. In: Nicoletti B, Kopits SE, Ascani E, et al. (eds): Human Achondroplasia: A Multidisciplinary Approach. New York: Plenum Press, 1988 pp 3–10. Hall JG, Dorst J, Taybi H, et al.: Two probable cases of homozygosity for the achondroplasia gene. Birth Defects Orig Art Ser V(4):24–34, 1969. Hecht JT, Butler IJ: Neurologic morbidity associated with achondroplasia. J Child Neurol 5:84–97, 1990. Hecht JT, Francomano CA, Horton WA et al.: Mortality in achondroplasia. Am J Hum Genet 41:454–464, 1987. Henderson S, Sillence D, Loughlin J, et al.: Germline and somatic mosaicism in achondroplasia. J Med Genet 37:956–958, 2000. Horton WA: Molecular genetic basis of the human chondrodysplasias. Endocr Metabol Clin 25:683–697, 1996. Horton WA: Fibroblast growth factor receptor 3 and the human chondrodysplasias. Curr Opin Pediatr 9:437–442, 1997. Horton WA, Rotter JI, Rimoin DL, et al.: Standard growth curves for achondroplasia. J Pediatr 93:435–438, 1978. Horton WA, Hood OJ, Machado MA, et al.: Growth plate cartilage studies in achondroplasia. In: Nicoletti B, Kopits SE, Ascani E, et al. (eds): Human Achondroplasia: A Multidisciplinary Approach. New York: Plenum Press 1988, pp 81–89.

Horton WA, Hecht JT, Hood OJ, et al.: Growth hormone therapy in achondroplasia. Am J Med Genet 42: 667–670, 1992. Hunter AGW, Hecht JT, Scott CI: Standard weight for height curves in achondroplasia. Am J Med Genet 62:255–261, 1996. Hunter AGW, Bankier A, Rogers JG, et al.: Medical complications of achondroplasia: a multicenter patient review. J Med Genet 35:705–712, 1998. Kornblum M, Stanitski DF: Spinal manifestations of skeletal dysplasias. Orthop Clin N Amer 30:501–520, 1999. Langer LO Jr, Baumann PA, Gorlin RJ: Achondroplasia. Am J Roentgen 100:12–26, 1967. Lattanzi DR, Harger JH: Achondroplasia and pregnancy. J Reprod Med 27:363–366, 1982. Mettler G, Fraser FC: Recurrence risk for sibs of children with “sporadic” achondroplasia. Am J Med Genet 90:250, 251, 2000. Mogayzel PJ Jr, Carroll JL, Loughlin GM, et al.: Sleep-disordered breathing in children with achondroplasia. J Pediatr 132:667–671, 1998. Moutou C, Rongieres C, Bettahar-Lebugle K, et al.: Preimplantation genetic diagnosis for achondroplasia: genetics and gynaecological limits and difficulties. Hum Reprod 18:509–514, 2003. Overlaid F, Danks DM, Jensen F, et al.: Achondroplasia and hypochondroplasia. Comments on frequency, mutation rate, and radiological features in skull and spine. J Med Genet 16:140–146, 1979. Patel MD, Filly RA: Homozygous achondroplasia: US distinction between homozygous, heterozygous, and unaffected fetuses in the second trimester. Radiology 196:541–545, 1995. Pauli RM: Achondroplasia. In: Cassidy SB, Allanson JE (eds): Management of Genetic Syndromes. New York: Wiley-Liss, 2001. Philip N, Auger M, Mattei JF, et al.: Achondroplasia in sibs of normal parents. J Med Genet 25:857–859, 1988. Pierre-Kahn A, Hirsch JF, Renier D, et al.: Hydrocephalus and achondroplasia. A study of 25 observations. Child’s Brain 7:205–219, 1980. Prinos P, Kilpatrick MW, Tsipouras P, et al.: A novel G346E mutation in achondroplasia. Pediatr Res 37:151, 1994. Rimoin DL: Limb lengthening: past, present, and future. Growth Genet Hormones 7:4–6, 1991. Rousseau F, Bonaventure J, Legeal-Mallet L, et al.: Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371:252–254, 1994. Shiang R, Thompson LM, Zhu Y-Z, et al.: Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78:335–342, 1994. Shohat M, Tick D, Barakat S, et al.: Short-term recombinant human growth hormone treatment increases growth rate in achondroplasia. J Clin Endocr Metab 81:4033–4037, 1996. Spranger JW, Langer LO Jr, Wiedemann HR: Bone dysplasias.An atlas of constitutional disorders of skeletal development. Philadelphia: WB Saunders Co., 1974. Todorov AB, Scott CI, Warren AE, et al.: Developmental screening tests in achondroplastic children. Am J Med Genet. 9:19–23, 1981. Vajo Z, Francomano CA, Wilkin DJ: The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: The achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans. Endocr Rev 21:23–39, 2000. Velinov M, Slaugenhaupt SA, Stoilov I, et al.: The gene for achondroplasia maps to the telomeric region of chromosome 4p. Nature Genet 6:318–321, 1994. Yang SS, Corbett DP, Brough AJ, et al.: Upper cervical myelopathy in achondroplasia. Am J Clin Path 68:68–72, 1977. Yang SS, Gilbert-Barnes E: Skeletal system. In: Gilbert-Barness E (ed): Potter’s Pathology of the Fetus and Infant. St Louis: Mosby, 1997, pp 1423–1478. Yasui N, Kawahata H, Kojimoto H, et al.: Lengthening of the lower limbs in patients with achondroplasia and hypochondroplasia. Clin Orthop 344:298–306, 1997. Zucconi M, Weber G, Castronova V, et al.: Sleep and upper airway obstruction in children with achondroplasia. J Pediatr 129:743–749, 1996.

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Fig. 2. A 4-month-old boy with achondroplasia showing typical craniofacial features and rhizomelic shortening of limbs (confirmed by radiograms). Molecular study revealed 1138 G-to-A transition mutation.

Fig. 1. A newborn with achondroplasia showing large head, depressed nasal bridge, short neck, normal length of the trunk, narrow chest, rhizomelic micromelia, and trident hands. The radiographs showed narrow chest, characteristic pelvis, micromelia, and oval radiolucent proximal portion of the femurs. Molecular analysis showed 1138G→C mutation.

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Fig. 3. Another achondroplastic neonate with typical clinical features and radiographic findings. Note the abnormal vertebral column with wide intervertebral spaces and abnormal vertebral bodies.

Fig. 5. Two older children with achondroplasia showing rhizomelic micromelia, typical craniofacial features, exaggerated lumbar lordosis, and trident hands.

Fig. 4. A boy (7 month and 2 year 7 month old) with achondroplasia showing a large head, small chest, normal size of the trunk, rhizomelic micromelia, and exaggerated lumbar lordosis.

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Fig. 6. A boy with achondroplasia and i(21q) Down syndrome presented with diagnostic dilemma. Besides craniofacial features typical for Down syndrome, the skeletal findings of achondroplasia dominate the clinical picture. The diagnosis of Down syndrome was based on the clinical features and the cytogenetic finding of i(21q) trisomy 21. The diagnosis of achondroplasia was based on the presence of clinical and radiographic findings, and confirmed by the presence of a common FGFR3 gene mutation (Gly380Arg) detected by restriction enzyme analysis and sequencing of the PCR products.

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Fig. 7. Schematic of the FGFR3 gene and DNA sequence of normal allele and mutant FGFR3 achondroplasia allele (modified from Shiang et al., 1994). Fig. 9. Homozygous achondroplasia. Both parents are achondroplastic. The large head, narrow chest, and severe rhizomelic shortening of the limbs are similar to those of thanatophoric dysplasia. Radiograph shows severe platyspondyly, small ilia, and short limb bones. Photomicrograph of the physeal growth zone shows severe retardation and disorganization, similar to that of thanatophoric dysplasia.

Fig. 8. Nucleotide change in the 1138C allele creates a Msp1 site and nucleotide change in the 1138A allele creates a Sfc1. The base in the coding sequence that differs in the three alleles is boxed (modified from Shiang et al., 1994).

Adams-Oliver Syndrome In 1945, Adams and Oliver described congenital transverse limb defects associated with aplasia cutis congenita in a threegeneration kindred with typical autosomal dominant inheritance and intrafamilial variable expressivity.

d. May involve other areas of the body e. Severe end of the spectrum of scalp defects i. Encephalocele ii. Acrania 4. Congenital cardiovascular malformations (13.4–20%) a. Mechanisms proposed to explain the pathogenesis of congenital cardiovascular malformations i. Alteration of mesenchymal cell migration resulting in conotruncal malformations; e.g., tetralogy of Fallot, double outlet right ventricle, and truncus arteriosus ii. Alteration of fetal cardiac hemodynamics resulting in different malformations such as coarctation of the aorta, aortic stenosis, perimembranous VSD, and hypoplastic left heart iii. Persistence of normal fetal vascular channels resulting in postnatal vascular abnormalities b. Diverse vascular and valvular abnormalities i. Bicuspid aortic valve ii. Pulmonary atresia iii. Parachute mitral valve iv. Pulmonary hypertension 5. Other associated anomalies a. Cutis marmorata telangiectasia congenita (12%) b. Dilated and tortuous scalp veins (11%) c. Poland anomaly d. Encephalocele e. Facial features i. Hemihypoplasia ii. Hypertelorism iii. Epicanthal folds iv. Microphthalmia v. Esotropia vi. High arch palate vii. Cleft palate f. Cryptorchidism g. Lymphatic abnormalities i. Lymphedema of the leg ii. Chylothorax iii. Dilated pulmonary lymphatics iv. Intestinal lymphangiectasia v. Marmorata telangiectasia congenita (a cutaneous vascular abnormality) h. CNS abnormalities: unusual manifestation i. Mental retardation ii. Learning disability iii. Epilepsy i. Short stature j. Renal malformations k. Spina bifida occulta l. Accessory nipples

GENETICS/BASIC DEFECTS 1. Genetic heterogeneity a. Autosomal dominant in most cases b. Autosomal recessive in some cases 2. Pathogenesis a. Trauma b. Uterine compression c. Amniotic band sequelae d. Vascular disruption sequence i. Concomitant occurrence of Poland sequence ii. Both Poland sequence and Adams-Oliver syndrome: secondary to vascular disruption due to thrombosis of subclavian and vertebral arteries e. Massive thrombus from the placenta occluding the brachial artery f. Abnormalities in small vessel structures manifesting during embryogenesis g. A developmental disorder of morphogenesis

CLINICAL FEATURES 1. Marked intrafamilial and interfamilial variability 2. Terminal transverse limb defects a. Most common manifestation (84%) b. Usually asymmetrical c. Tendency toward bilateral lower limb rather than upper limb involvement d. Mild spectrum of defects i. Nail hypoplasia ii. Cutaneous syndactyly iii. Bony syndactyly iv. Ectrodactyly v. Brachydactyly e. Severe spectrum of transverse defects i. Absence of the hand ii. Absence of the foot iii. Absence of the limb 3. Aplasia cutis congenita a. Second most common defect (almost 75%) b. Associated with skull defect (64%) i. Small lesion: 0.5 cm in diameter ii. Intermediate lesion: 8–10 cm involving the vertex iii. Severe lesion: involves most of the scalp with acrania c. Skull defect without scalp defect, often mistaken for an enlarged fontanelle

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DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Transverse limb defects b. Ectrodactyly c. Brachydactyly d. Syndactyly e. Nail hypoplasia f. Skull defect 2. CT scan or MRI of the brain a. Polymicrogyria b. Ventriculomegaly c. Irregular cortical thickening d. Cerebral cortex dysplasia e. Microcephaly f. Arhinencephaly g. Periventricular and parenchymal calcium deposits

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Autosomal dominant: not increased unless a parent is affected in which case the risk is 50% ii. Autosomal recessive: 25% b. Patient’s offspring i. Autosomal dominant: 50% ii. Autosomal recessive: not increased unless the spouse carries the gene or is affected 2. Prenatal diagnosis by ultrasonography a. Transverse limb defects b. Concomitant skull defect 3. Management a. Treat minor scalp lesions with daily cleansing of the involved areas with applications of antibiotic ointment b. Surgically close larger lesions and exposed dura with minor or major skin grafting procedure (split-thickness or full-thickness) c. Prevent sepsis and/or meningitis from an open scalp lesion which is highly vascular and rarely involves the sagittal sinus predisposing to episodes of spontaneous hemorrhage d. Orthopedic care for various degrees of limb defects

REFERENCES Adams FH, Oliver CP: Hereditary deformities in man due to arrested development. J Hered 36:3–7, 1945. Arand AG, et al.: Congenital scalp defects: Adams-Oliver syndrome. A case report and review of the literature. Pediatr Neurosurg 17:203–207, 1991. Bamforth JS, Kaurah P, Byrne J, et al.: Adams Oliver syndrome: a family with extreme variability in clinical expression. Am J Med Genet 49: 393–396, 1994.

Becker R, Kunze J, Horn D, et al.: Autosomal recessive type of Adams-Oliver syndrome: prenatal diagnosis. Ultrasound Obstet Gynecol 20:506–-510, 2002. Bonafede RP, Beighton P: Autosomal dominant inheritance of scalp defects with ectrodactyly. Am J Med Genet 3:35–41, 1979. Bork K, Pfeifle J: Multifocal aplasia cutis congenita, distal limb hemimelia, and cutis marmorata telangiectatica in a patient with Adams-Oliver syndrome. Br J Dermatol 127:160–163, 1992. Burton BK, Hauser H, Nadler HL: Congenital scalp defects with distal limb anomalies: report of a family. J Med Genet 13:466–468, 1976. Frieden I: Aplasia cutis congenita: a clinical review and proposal for classification. J Am Acad Dermatol 14:646–660, 1986. Fryns JP: Congenital scalp defects with distal limb reduction anomalies. J Med Genet 24:493–496, 1987. Fryns JP, Leigius E, Demaere P, et al.: Congenital scalp defects, distal limb reduction anomalies, right spastic hemiplegia and hypoplasia of the left arterial cerebri media. Clin Genet 50:505–509, 1996. Hoyme HE, Der Kaloustian VM, Entin M, et al.: Possible common pathogenetic mechanisms for Poland sequence and Adams-Oliver syndrome: an additional clinical observation. Am J Med Genet 42:398–399, 1992. Klinger G, Merlob P: Adams-Oliver syndrome: autosomal recessive inheritance and new phenotypic-anthropometric findings. Am J Med Genet 79:197–199, 1998. Koiffmann CP, Wajntal A, Huyke BJ, et al.: Congenital scalp skull defects with distal limb anomalies (Adams-Oliver syndrome—McKusick 10030): further suggestion of autosomal recessive inheritance. Am J Med Genet 29:263–268, 1988. Küster W, Lenz W, Kaariainen H, et al.: Congenital scalp defects with distal limb anomalies (Adams-Oliver syndrome): report of ten cases and review of the literature. Am J Med Genet 31:99–115, 1988. Lin AE, Wesgate MN, van der Velde ME, et al.: Adams-Oliver syndrome associated with cardiovascular malformation. Clin Dysmorphol 7:235–241, 1998. Mempel M, Abeck D, Lange I, et al.: The wide spectrum of clinical expression in Adams-Oliver syndrome: a report of two cases. Br J Dermatol 140:1157– 1160, 1999. Pauli RM, et al.: Familial recurrence of terminal transverse defects of the arm. Clin Genet 27:555–563, 1985. Pereira-da-Silva L, Leal F, Cassiano Santos G, et al.: Clinical evidence of vascular abnormalities at birth in Adams-Oliver syndrome: report of two further cases. (Letter) Am J Med Genet 94:75–76, 2000. Pousti TJ, Bartlett RA: Adams-Oliver syndrome: genetics and associated anomalies of cutis aplasia. Plast Reconstr Surg 100:1491–1496, 1997. Shapiro SD, Escobedo MK: Terminal transverse defects with aplasia cutis congenita (Adams-Oliver syndrome). Birth Defects Orig Artic Ser 21(2):135–142, 1985. Stevenson RE, Deloache WR: Aplasia cutis congenita of the scalp. Proc Greenwood Genet Center 7:14–18, 1988. Sybert VP: Congenital scalp defects with distal limb anomalies (Adams-Oliver Syndrome—McKusick 10030): further suggestion of autosomal recessive inheritance. Am J Med Genet 32:266–-267, 1989. Tekin M, Bodurtha J, Çiftçi E, et al.: Further family with possible autosomal recessive inheritance of Adams-Oliver syndrome. (Letter) Am J Med Genet 86:90–91, 1999. Toriello HV, Graff RG, Florentine MF, et al.: Scalp and limb defects with cutis marmorata telangiectatica congenita: Adams-Oliver syndrome?. Am J Med Genet 29:269–276, 1988. Verdyck P, Holder-Espinasse M, Hul WV, et al.: Clinical and molecular analysis of nine families with Adams-Oliver syndrome. Eur J Hum Genet 11:457–463, 2003. Whitley CB, Gorlin RJ: Adams-Oliver syndrome revisited. Am J Med Genet 40:319–326, 1991. Zapata HH, Sletten LJ, Pierpont MEM: Congenital cardiac malformations in Adams-Oliver syndrome. Clin Genet 47:80–84, 1995.

ADAMS-OLIVER SYNDROME

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Fig. 1. A 9-month-old boy with Adams-Oliver syndrome showing alopecia, absent eyebrows and eyelashes, scalp defect, tortuous scalp veins, and limb defects (brachydactyly, syndactyly, broad great toes, and nail hypoplasia). Radiography showed absent middle and distal phalanges of 2nd–5th toes and absent distal phalanges of the great toes.

Agnathia Agnathia is an extremely rare lethal neurocristopathy. The disorder has also been termed agnathia-holoprosencephaly, agnathia-astomia-synotia, or cyclopia-otocephaly association. The incidence is estimated to be 1/132,000 births in Spain.

11. Cleft lip/palate 12. Occular malformations a. Microphthalmos/anophthalmia b. Proptosis (protruding eyes) c. Absence of the eyelids d. Epibulbar dermoid e. Aphakia f. Retinal dysplasia g. Microcornea h. Anterior segment dysgenesis i. Uveal colobomas 13. Nasal anomalies a. Absence of the nasal cavity b. Cleft nose c. Blind nasal pharynx 14. Various visceral malformations a. Choanal atresia b. Tracheoesophageal fistula c. Absence of the thyroid gland d. Absence of the submandibular and parotid salivary glands e. Abnormal glottis and epiglottis f. Thyroglossal duct cyst g. Carotid artery anomalies h. Situs inversus i. Cardiac anomalies j. Unlobulated lungs k. Renogenital anomalies i. Unilateral renal agenesis ii. Renal Ectopia iii. Cystic kidneys iv. Horseshoe kidneys v. Solitary kidney vi. Mullerian duct agenesis vii. Cryptorchidism 15. Skeletal anomalies a. Vertebral anomalies b. Rib anomalies c. Tetramelia 16. Anatomical variations a. Ears i. Absence of the tragus ii. Synotia b. Mandible i. Rudimentary ii. Absent iii. Two small separate masses c. Mouth: microstomia with vertical orientation d. Buccopharyngeal membrane: absent to present e. Tongue i. Small to absent body ii. Present in (hypo)pharynx f. Absent submandibular glands

GENETICS/BASIC DEFECTS 1. Sporadic occurrence in majority of cases 2. Rare autosomal recessive inheritance 3. Possible autosomal dominant inheritance a. Supported by an observation of dysgnathia in mother and daughter b. Possibility of a defect in the OTX2 gene as the basis of the disorder 4. A prechordal mesoderm inductive defect affecting neural crest cells a. A developmental field defect b. Different etiologic agents (etiological heterogeneity) acting on the same developmental field producing a highly similar complex of malformations 5. Possible existence of a mild form of agnathia without brain malformation (holoprosencephaly) a. Situs inversus-congenital hypoglossia b. Severe micrognathia, aglossia, and choanal atresia 6. A well-recognized malformation complex in the mouse, guinea pig, rabbit, sheep, and pig

CLINICAL FEATURES 1. Polyhydramnios due to persistence of oropharyngeal membrane or blind-ending mouth 2. Agnathia (absence of the mandible) 3. Microstomia or astomia (absence of the mouth) 4. Aglossia (absence of the tongue) 5. Blind mouth 6. Ear anomalies a. Otocephaly (variable ear positions) b. Synotia (external ears approaching one another in the midline) c. Dysplastic inner ear d. Atretic ear canal 7. Down-slanting palpebral fissures 8. Variable degree of holoprosencephaly a. Cyclopia b. Synophthalmia c. Arrhinencephaly 9. Other brain malformations a. Cerebellar hypoplasia b. Septum pellucidum Cavum c. Absence of cranial nerves (I-IV) d. Absence of the corpus callosum e. Meningocele 10. Intrauterine growth retardation 26

AGNATHIA

g. Other skull bones: approximated maxillae, palatine, zygomatic, and temporal

DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Reduced maxilla b. Absence of the zygomatic process c. Absence of the hyoid bone d. Vertebral anomalies e. Absence of the ribs f. Sprengel deformity 2. Cranial ultrasonography to define holoprosencephaly 3. Chromosome analysis a. Normal in majority of cases b. Unbalanced der(18),t(6;18)(pter→p24.1;p11.21→qter) in two female sibs with agnathia-holoprosencephaly 4. Autopsy to define postmortem findings

GENETIC COUNSELING 1. Recurrence risks a. Risk to patient’s sib: not increased unless in a rare autosomal recessive inheritance b. Risk to patient’s offspring: not applicable since affected patients do not survive to reproduce 2. Prenatal diagnosis by ultrasonography or three-dimensional imaging by helical computed tomography (CT) a. Polyhydramnios b. Intrauterine growth retardation c. Mandibular absence (agnathia) or major hypoplasia d. Holoprosencephaly e. Cyclopia, marked hypotelorism or frontal proboscis 3. Management: a lethal entity

REFERENCES Bixler D, Ward R, Gale DD: Agnathia-holoprosencephaly: a developmental field complex involving face and brain. Report of 3 cases. J Craniofac Genet Dev Biol (Suppl) 1:241–249, 1985. Blaas HG, Eriksson AG, Salvesen KA, et al.: Brains and faces in holoprosencephaly: pre- and postnatal description of 30 cases. Ultrasound Obstet Gynecol 19:24–38, 2002.

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Carles D, Serville F, Mainguene M, et al.: Cyclopia-otocephaly association: a new case of the most severe variant of Agnathia-holoprosencephaly complex. J Craniofac Genet Dev Biol 7:107–113, 1987. Cohen MM: Perspectives on holoprosencephaly: Par III. Spectra, distinctions, continuities and discontinuities. Am J Med Genet 34:271–288, 1989. Ebina Y, Yamada H, Kato EH, et al.: Prenatal diagnosis of agnathia-holoprosencephaly: three-dimensional imaging by helical computed tomography. Prenat Diagn 21:68–71, 2001. Erlich MS, Cunningham ML, Hudgins L: Transmission of the dysgnathia complex from mother to daughter. Am J Med Genet 95: 269–274, 2000. Gaba AR, et al.: Alobar holoprosencephaly and otocephaly in a female infant with a normal karyotype and placental villitis. J Med Genet 19:78, 1982. Henekam RC: Agnathia-holoprosencephaly: a midline malformation association. Am J Med Genet 36:525, 1990. Hersh JH, McChane RH, Rosenberg EM, et al.: Otocephaly-midline malformation association. Am J Med Genet 34:246–249, 1989. Hinojosa R, Green JD, Brecht K, et al.: Otocephalus: histopathology and threedimensional reconstruction. Otloaryngol Head neck Surg 114:44–53, 1996. Johnson WW, Cook JB: Agnathia associated with pharyngeal isthmus atresia and hydramnios. Arch Pediatr 78:211–217, 1961. Kamiji T, Takagi T, Akizuki T, et al.: A long surviving case of holoprosencephaly agnathia series. Br J Plast Surg 44:386–389, 1991. Krassikoff N, Sekhon GS: Familial agnathia-holoprosencephaly caused by an inherited unbalanced translocation and not autosomal recessive inheritance. Am J Med Genet 34:255–257, 1989. Lawrence D, Bersu ET: An anatomical study of human otocephaly. Teratology 30:155–165, 1985. Leech RW, Bowlby LS, Brumback RA, et al.: Agnathia, holoprosencephaly, and situs inversus: report of a case. Am J Med Genet 29:483–490, 1988. Meinecke P, Padberg B, Laas R: Agnathia, holoprosencephaly, and situs inversus: a third report. Am J Med Genet 37:286–287, 1990. Özden S, Fiçiciog˘lu C, Kara M, et al.: Agnathia-holoprosencephaly-situs inversus. Am J Med Genet 91:235–236, 2000. Pauli RM, Graham JM Jr, Barr M Jr: Agnathia, situs inversus, and associated malformations. Teratology 23:85–93, 1981. Pauli RM, Pettersen JC, Arya S, et al.: Familial agnathia-holoprosencephaly. Am J Med Genet 14:677–698, 1983. Rolland M, Sarramon MF, Bloom MC: Astomia-agnathia-holoprosencephaly association. Prenatal diagnosis of a new case. Prenat Diagn 11:199–203, 1991. Santana SM et al.: Agnathia and associated malformations. Dysmorph Clin Genet 1:58–63, 1987. Scholl HW Jr: In utero diagnosis of agnathia, microstomia, and synotia. Obstet Gynecol 49(1 Suppl):81–83, 1977. Suda Y, Nakabayashi J, Matsuo I, Aizawa S: Functional equivalency between Otx2 and Otx1 in development of the rostral head. Development 126: 743–757, 1999.

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Fig. 1. A neonate (28 week gestation) with agnathia-holoprosencephaly complex showing a large defect involving entire midface area with almost total absence of jaw, absence of eyes and nose, and severe microtia. Absence of olfactory bulbs and grooves (arrhinencephaly) were demonstrated by necropsy. Additional anomalies included 13 pairs of ribs, atresia of left ureter with resultant hydronephrosis, and left renal cortical cysts. Maternal hydramnios was present.

Aicardi Syndrome In 1965, Aicardi et al. reported a new syndrome consisting of spasms in flexion, callosal agenesis, and ocular abnormalities. Actual frequency of the condition is not known, but about 1–4% of cases of infantile spasms from tertiary referral centers may be due to Aicardi syndrome.

5. Extra-CNS tumors a. Soft palatal benign teratoma b. Hepatoblastoma c. Parapharyngeal embryonal cell carcinoma d. Limb angiosarcoma e. Scalp lipoma f. Multiple gastrointestinal polyps 6. Scoliosis or costovertebral anomalies 7. Severe cognitive and physical handicaps a. Global developmental delay b. Moderate to severe mental retardation in most patients c. Unable to ambulate in most children d. Limited visual ability 8. New diagnostic criteria (Aicardi, 1999) a. Classic triad i. Infantile spasms ii. Chorioretinal lacunae iii. Agenesis/dysgenesis of the corpus callosum b. New major features (present in most patients studied by MRI) i. Cortical malformations, mostly microgyria (probably constant but may not be possible to evidence) ii. Periventricular and subcortical heterotopia iii. Cysts around the third ventricle and/or choroid plexuses iv. Papillomas of choroid plexuses v. Optic disc/nerve coloboma c. Supporting features (present in some cases) i. Vertebral and costal abnormalities ii. Microphthalmia and/or other eye abnormalities iii. “Split-brain” EEG (associated suppression-burst tracing) iv. Gross hemispheric asymmetry 9. Estimated survival rate a. 76% at 6 years of age b. 40% at 15 years of age

GENETICS/BASIC DEFECTS 1. Inheritance a. X-linked dominant, lethal in males b. Almost exclusively affects females (heterozygous for a particular mutant X-chromosome gene to manifest) c. Exception: boys with XXY chromosome constitution allowing heterozygous expression of the gene as in the female d. Not known to be a familial condition, except an isolated familial instance involving two sisters 2. Gene map postulated on chromosome Xp22 from an observation in an affected girl with t(X;3)(p22;q12)

CLINICAL FEATURES 1. Classic triad a. Pathognomonic chorioretinal lacunae i. Multiple, rounded, unpigmented, and yellowwhite lesions ii. Occasionally unilateral iii. May be absent in rare cases b. Infantile spasms/seizures i. Frequently asymmetric ii. Often preceded or precipitated by a focal clonic or tonic seizure limited to the side in which the spasms predominate c. Agenesis of the corpus callosum 2. Other CNS abnormalities a. Ependymal cysts b. Choroid plexus papillomas c. Cortical migration abnormalities d. Optic disk coloboma e. Hydrocephaly f. Porencephaly g. Cerebellar agenesis h. Heterotopias 3. Variable neurologic abnormalities a. Hemiparesis or hemiplegia i. The most frequent abnormality ii. Often on the side where the spasms predominate b. Quadriplegia c. Hypotonia d. Hypertonia e. Development of microcephaly, though head circumference is normal at birth 4. Microphthalmia

DIAGNOSTIC INVESTIGATIONS 1. Ophthalmological examination a. Choroid retinal lacunae b. Optic disc coloboma 2. Electroencephalograms a. Asymmetry or asynchrony b. Quasiperiodicity c. Hypsarrhythmia 3. CT or MRI of the brain a. Agenesis or partial agenesis of the corpus callosum b. Choroid plexus papillomas c. Cerebellar dysgenesis d. Cortical heterotopias e. Porencephaly f. Agenesis or hypoplasias of the cerebellar vermis 29

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4. Radiography for skeletal malformations 5. Chromosome analysis in case of Klinefelter syndrome 6. Histopathology a. Multiple brain malformations i. Complete or partial agenesis of the corpus callosum ii. Cortical heterotopias iii. Gyral malformation iv. Intraventricular cysts v. Microscopic evaluation of the parenchyma a) Disordered cellular organization b) Disruption of the normal layered appearance of the cortex b. Chorioretinal lacunae i. Well-circumscribed, punched-out lesions in the retinal pigment epithelium and choroid ii. Severely disrupted retinal architecture a) All layers are thinned b) Choroidal vessel number and caliber are decreased c) Presence of pigmentary ectopia and pigmentary epithelial hyperplasia

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sibs: recurrence not likely (exception with one report of two affected sibs, likely due to gonadal mosaicism in one of the parent) b. Patient’s offspring: 50% of offspring of affected females are expected to carry the abnormal X chromosome but affected individuals are not expected to survive to reproduce 2. Prenatal diagnosis: not available currently. The prenatal ultrasonographic findings include: a. Arachnoid cysts b. Agenesis of the corpus callosum (development of the corpus callosum may not be complete until 22 weeks of gestation) c. Ventriculomegaly 3. Management a. Anticonvulsants for control of seizures b. Specific therapy for infantile spasm i. Adrenocorticotropic hormone (ACTH): effective for some patients ii. Vigabatrin, a more recently introduced therapy for infantile spasm a) An enzyme that breaks down GABA, the major inhibitory neurotransmitter in the brain b) Effective for infantile spasm without the serious life-threatening adverse effects of ACTH c) Possible ophthalmologic sequelae of constriction of the visual fields d) Not currently approved for use in the US c. A multidisciplinary team approach to developmental handicaps

REFERENCES Aicardi J: Aicardi syndrome: old and new findings. Int Pediatr 14:5–8, 1999. Aicardi J, Lefèbvre J, Lerique-Koechlin A: A new syndrome: spasms in flexion, callosal agenesis, ocular abnormalities. Electroenceph Clin Neurophysiol 19:609–610, 1965. Bertoni JM, von Loh S, Allen RJ: The Aicardi syndrome: report of 4 cases and review of the literature. Ann Neurol 5:475–482, 1979. Bromley B, Krishnamoorthy KS, Benacerraf BR: Aicardi syndrome: prenatal sonographic findings. A report of two cases. Prenat Diagn 20:344–346, 2000. Costa T, Greer W, Rysiecki M, et al.: Monozygotic twins discordant for Aicardi syndrome. J Med Genet 34:688–691, 1997. De Jong JGY, Delleman JW, Houben M, et al.: Agenesis of the corpus callosum, infantile spasms, ocular anomalies (Aicardi’s syndrome). Clinical and pathological findings. Neurology 26:1152–1158, 1976. Dennis J, Bower BD: The Aicardi syndrome. Dev Med Child Neurol 14:382–390, 1972. Difazio MP, Davis RG: Aicardi syndrome. Emedicine, 2003. http://www. emedicine.com. Donnenfeld AE, Packer RJ, Zackai EH, et al.: Clinical, cytogenetic, and pedigree findings in 18 cases of Aicardi syndrome. Am J Med Genet 32:461–467, 1989. Donnenfield AE, Graham JM, Packer RJ, et al.: Microphthalmia and chorioretinal lesions in a girl with Adv Neurol Xp22-pter deletion and partial 3p trisomy: clinical observation relevant to Aicardi syndrome gene location. Am J Med Genet 37:182–186, 1990. Font RL, Marines HM, Cartwright J, et al.: Aicardi syndrome. A clinicopathological case report including electron microscopic observations. Ophthalmology 98:1727–1731, 1991. Gorrono-Echebarria MB: Genetics of Aicardi syndrome. Surv Ophthalmol 38:321, 1993. Hoag HM, Taylor SAM, Duncan AMV, et al.: Evidence that skewed X inactivation is not needed for the phenotypic expression of Aicardi syndrome. Hum Genet 100:459–464, 1997. Hopkins IJ, Humphrey J, Keith CG, et al.: The Aicardi syndrome in a 47,XXY male. Aust Pediatr J 15:278–280, 1979. McMahon RG, Bell RA, Moore GRW, et al.: Aicardi syndrome. A clinicopathologic study. Arch Ophthalmol 102:250–253, 1984. Menezes AV, McGregor DL, Buncic JR: Aicardi syndrome: Natural history and possible predictors of severity. Pediatr Neurol 11:313–318, 1994. Menezes AV, Enzenauer RW, Buncic JR: Aicardi syndrome: the elusive mild case. Br J Ophthalm 78:494–496, 1994. Molina JA, Mateos F, Merino M, et al.: Aicardi syndrome in two sisters. J Pediatr 115:282–283, 1989. Neidich JA, Nussbaum RL, Packer RJ, et al.: Heterogeneity of clinical severity and molecular lesions in Aicardi syndrome. J Pediatr 116:911–917, 1990. Ohtsuka Y, Oka E, Terasaki T: Aicardi syndrome: a longitudinal clinical and electroencephalographic study. Epilepsia 1993 Jul-Aug; 34(4): 627–634. Robinow M, Johnson GJ, Minella PA: Aicardi syndrome: papilloma of the choroid plexus, cleft lip and cleft of the posterior palate. J Pediatr 104:404, 405, 1984. Ropers HH, Zuffardi O, Blanchi E, et al.: Agenesis of corpus callosum, ocular, and skeletal anomalies (X-linked dominant Aicardi’s syndrome) in a girl with balanced X/3 translocation. Hum Genet 61:364–368, 1982. Rosser T: Aicardi syndrome. Arch Neurol 60:1471-1473, 2003. Rosser TL, Acosta MT, Packer RJ: Aicardi syndrome: spectrum of disease and long-term prognosis in 77 females. Pediatr Neurol 27:343–346, 2002. Tachibana H, Matsui A, Takeshita K, et al.: Aicardi syndrome with multiple papilloma of the choroids plexus. Arch Neurol 39:194, 1982. Trifiletti RR, Incorpora G, Polizzi A, et al.: Aicardi syndrome with multiple tumors: a case report with literature review. Brain Dev 17:283–285, 1995.

AICARDI SYNDROME

Fig. 1. A 8 month old girl with Aicardi syndrome characterized by infantile spasms, chrioretinopathy, brain malformation, and costovertebral anomalies.

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Alagille Syndrome In 1969, Alagille et al. described a syndrome characterized by chronic cholestasis resulting from paucity of interlobular bile ducts, peripheral pulmonary stenosis, butterfly-like vertebral arch defect, posterior embryotoxon, and peculiar facies. The syndrome is also known as arteriohepatic dysplasia. Alagille syndrome occurs in approximately 1 in 100,000 live births.

vi. Tricuspid regurgitation vii. Right ventricular hypertrophy d. Vertebral arch anomalies (butterfly-like vertebrae) e. Posterior embryotoxon (prominent Schwalbe’s ring) 3. Less frequently associated features a. Growth retardation b. Neurologic complications from vitamin E deficiency c. Mental retardation (2–30%) d. Systemic vascular malformations i. Coarctation of the aorta ii. Middle aortic syndrome iii. Arterial hypoplasia (hepatic, renal, carotid, celiac) iv. Artery stenosis (renal, subclavian) v. Moyamoya disease vi. Carotid artery aneurysm vii. Intracranial hemorrhage viii. Hypoplastic portal vein branch e. Renal abnormalities i. Interstitial nephritis ii. Glomerular intramembranous and mesangial lipidosis iii. Tubular dysfunction iv. Renal hypoplasia v. Renal agenesis vi. Horseshoe kidney vii. Cystic disease f. Small bowel atresia or stenosis g. Pancreas i. Diabetes ii. Exocrine pancreatic insufficiency h. Lung: tracheal and bronchial stenosis i. Larynx: high-pitched voice j. Eye abnormalities i. Retinal pigmentation ii. Iris strands iii. Cataract iv. Myopia v. Strabismus vi. Glaucoma vii. Optic disk drusen viii. Fundus hypopigmentation k. Skeletal abnormalities i. Lack of normal progression of interpedicular distance in the lumbar spine ii. Spina bifida iii. Shortening of distal phalanges and metacarpal bones iv. Clinodactyly 4. Prognosis a. Characterized by recurrent episodes of cholestasis b. Often associated with common respiratory tract infections, especially during the first year of life c. Good long survival but mortality rate may be up to 25%

GENETICS/BASIC DEFECTS 1. Inheritance: a. Sporadic in 45–50% of cases b. Autosomal dominant i. Reduced penetrance ii. Variable expressivity c. Alagille syndrome gene mapped to 20p12 2. Molecular defect a. Caused by mutations or deletions of Jagged-1 gene (JAG1), encoding a ligand for the Notch transmembrane receptor, implicated in cell differentiation b. More than 120 described intragenic mutations of the JAG1 gene c. No clear genotype-phenotype correlation in Alagille syndrome

CLINICAL FEATURES 1. High variability of phenotypic findings 2. Major features a. Neonatal chronic cholestasis i. Episodes of jaundice separated by periods of remission ii. Pruritus iii. Hepatomegaly iv. Splenomegaly: may be associated with portal hypertension v. Xanthoma: progressive and observed in: a) Extensor surface of the fingers b) Palmar creases c) Nape of the neck d) Anal folds e) Popliteal fossa f) Inguinal areas b. Facial features i. Broad prominent forehead ii. Deep-set, widely spaced eyes iii. Long, straight nose iv. Underdeveloped mandible c. Complex congenital cardiovascular anomalies i. Pulmonary artery stenosis (67%) ii. Ventricular septal defects iii. Patent ductus arteriosus iv. Pulmonary valve atresia v. Tetralogy of Fallot (7–16%) 32

ALAGILLE SYNDROME

DIAGNOSTIC INVESTIGATIONS 1. Biochemical studies a. Hypercholesterolemia b. Hyperphospholipidemia c. Hypertriglyceridemia d. Prominent increase in the pre-β-lipoprotein and apolipoprotein B levels e. Very high total bile acids, gammaglutamyl transferase, and alkaline phosphatase blood levels 2. Ophthalmologic assessment for posterior embryotoxon and other ocular anomalies 3. Abdominal ultrasonography a. Evaluation of the hepatobiliary tree and hepatic parenchyma b. Evaluation of renal anomalies 4. Radiography for vertebral anomalies 5. Other imagings a. Dimethyl iminodiacetic acid scanning b. Magnetic resonance cholangiopancreatography c. Endoscopic retrograde cholangiopancreatography d. Intraoperative cholangiography 6. Echocardiography for cardiovascular malformations 7. Histology (liver biopsy) a. Paucity of interlobular bile ducts b. Cholestasis in hepatocytes and canaliculi 8. Molecular genetic analysis a. Sequence analysis of the JAG1 gene detects mutations in approximately 70% of individuals who meet clinical diagnostic criteria b. FISH detects a microdeletion of 20p12, including the entire JAG1 gene, in approximately 5–7% of cases

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. A low but slightly increased risk due to parental germline mosaicism in clinically normal appearing parents ii. A 50% risk if a parent is affected b. Patient’s offspring: a 50% risk of having an offspring with Alagille syndrome 2. Prenatal diagnosis a. Prenatal ultrasonography i. Severe pulmonary artery stenosis ii. Progressive severe intrauterine growth retardation b. Prenatal molecular diagnosis on fetal DNA obtained from amniocentesis or CVS is available if a diseasecausing mutation (demonstrated by molecular genetic testing) or a deletion (detected by FISH) is identified in an affected family member 3. Management a. Medical care i. Low-fat diets with medium-chain triglyceride supplementation ii. Hypercaloric diets to severely malnourished patients iii. Vitamin supplements

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iv. Pruritus a) Antihistamine agents b) Cholestyramine or rifampin in management of bile acid-induced pruritus b. Surgical care for patients with refractory disease i. Biliary diversion ii. Eventual orthotopic liver transplantation with following indications: a) Progressive hepatic dysfunction b) Severe portal hypertension c) Failure to thrive d) Intractable pruritus and osteodystrophy iii. Cardiac surgery for complex congenital heart defects

REFERENCES Alagille D: Alagille syndrome today. Clin Invest Med 19:325–330, 1996. Alagille D, Estrada A, Hadchouel M, et al.: Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J Pediatr 110:195–200, 1987. Albayram F, Stone K, Nagey D, et al.: Alagille syndrome: prenatal diagnosis and pregnancy outcome. Fetal Diagn Ther 17:182–184, 2002. Anad F, Burn J, Matthews D, et al.: Alagille syndrome and deletion of 20p. J Med Genet 27:729–737, 1990. Berrocal T, Gamo E, Navalon J, et al.: Syndrome of Alagille: radiological and sonographic findings. A review of 37 cases. Eur Radiol 7:115–118, 1997. Brodsky MC, Cunniff C: Ocular anomalies in the Alagille syndrome (arteriohepatic dysplasia). Ophthalmology 100:1767–1774, 1993. Cardona J, Houssin D, Gauthier F, et al.: Liver transplantation in children with Alagille syndrome—a study of twelve cases. Transplantation 60:339–342, 1995. Colliton RP, Bason L, Lu FM, et al.: Mutation analysis of Jagged1 (JAG1) in Alagille syndrome patients. Hum Mutat 17:151–152, 2001. Connor SE, Hewes D, Ball C, et al.: Alagille syndrome associated with angiographic moyamoya. Childs Nerv Syst 18:186–190, 2002. Crosnier C, Attie-Bitach T, Encha-Razavi F, et al.: JAGGED1 gene expression during human embryogenesis elucidates the wide phenotypic spectrum of Alagille syndrome. Hepatology 32:574–581, 2000. Crosnier C, Driancourt C, Raynaud N, et al.: Mutations in JAGGED1 gene are predominantly sporadic in Alagille syndrome. Gastroenterology 116:1141–1148, 1999. Crosnier C, Driancourt C, Raynaud N, et al.: Fifteen novel mutations in the JAGGED1 gene of patients with Alagille syndrome. Hum Mutat 17:72– 73, 2001. Crosnier C, Lykavieris P, Meunier-Rotival M, et al.: Alagille syndrome. The widening spectrum of arteriohepatic dysplasia. Clin Liver Dis 4:765–778, 2000. Deleuze F, Hadchouel M: Submicroscopic deletions are rare in Alagille syndrome. Am J Hum Genet 59:477, 478, 1996. Desmaze C, Deleuze JF, Dutrillaux AM, et al.: Screening of microdeletions of chromosome 20 in patients with Alagille syndrome. J Med Genet 29:233–235, 1992. Emerick KM, Rand EB, Goldmuntz E, et al.: Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology 29:822–829, 1999. Giannakudis J, Ropke A, Kujat A, et al.: Parental mosaicism of JAG1 mutations in families with Alagille syndrome. Eur J Hum Genet 9:209–216, 2001. Hingorani M, Nischal KK, Davies A, et al.: Ocular abnormalities in Alagille syndrome. Ophthalmology 106:330–337, 1999. Jones EA, Clement-Jones M, Wilson DI: JAGGED1 expression in human embryos: correlation with the Alagille syndrome phenotype. J Med Genet 37:663–668, 2000. Kamath BM, Loomes KM, Oakey RJ, et al.: Facial features in Alagille syndrome: specific or cholestasis facies? Am J Med Genet 112:163–170, 2002. Kamath BM, Bason L, Piccoli DA, et al.: Consequences of JAG1 mutations. J Med Genet 40:891–895, 2003.

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Kasahara M, Kiuchi T, Inomata Y, et al.: Living-related liver transplantation for Alagille syndrome. Transplantation 75:2147–2150, 2003. Krantz ID, Colliton RP, Genin A, et al.: Spectrum and frequency of jagged1 (JAG1) mutations in Alagille syndrome patients and their families. Am J Hum Genet 62:1361–1369, 1998. Krantz ID, Piccoli DA, Spinner NB: Alagille syndrome. J Med Genet 34:152–157, 1997. Krantz ID, Piccoli DA, Spinner NB: Clinical and molecular genetics of Alagille syndrome. Curr Opin Pediatr 11:558–564, 1999. Krantz ID, Rand EB, Genin A, et al.: Deletions of 20p12 in Alagille syndrome: frequency and molecular characterization. Am J Med Genet 70:80–86, 1997. Laufer-Cahana A, Krantz ID, Bason LD, et al.: Alagille syndrome inherited from a phenotypically normal mother with a mosaic 20p microdeletion. Am J Med Genet 112:190–193, 2002. Li L, Krantz ID, Deng Y, et al.: Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 16:243–251, 1997. Piccoli DA, Spinner NB: Alagille syndrome and the Jagged1 gene. Semin Liver Dis 21:525–534, 2001. Ropke A, Kujat A, Graber M, et al.: Identification of 36 novel Jagged1 (JAG1) mutations in patients with Alagille syndrome. Hum Mutat 21:100, 2003.

Raas-Rothschild A, Shteyer E, Lerer I, et al.: Jagged1 gene mutation for abdominal coarctation of the aorta in Alagille syndrome. Am J Med Genet 112:75–78, 2002. Ropke A, Kujat A, Graber M, et al.: Identification of 36 novel Jagged1 (JAG1) mutations in patients with Alagille syndrome. Hum Mutat 21:100,2003. Scheimann A: Alagille syndrome. Emedicine, 2003. http://www.emedicine.com. Shulman SA, Hyams JS, Gunta R, et al.: Arteriohepatic dysplasia (Alagille syndrome): extreme variability among affected family members. Am J Med Genet 19:325–332, 1984. Spinner NB, Colliton RP, Crosnier C, et al.: Jagged1 mutations in Alagille syndrome. Hum Mutat 17:18–33, 2001. Spinner NB: Alagille syndrome and the notch signaling pathway: new insights into human development. Gastroenterology 116:1257–1260, 1999. Spinner NB, Krantz ID: Alagille syndrome. Gene Reviews, 2004. http://www. genetests.org. Spinner NB, Rand EB, Fortina P, et al.: Cytologically balanced t(2;20) in a twogeneration family with Alagille syndrome: cytogenetic and molecular studies. Am J Hum Genet 55:238–243, 1994. Witt H, Neumann LM, Grollmuss O, et al.: Prenatal diagnosis of Alagille syndrome. J Pediatr Gastroenterol Nutr 38:105, 106, 2004.

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Fig. 1. An infant with Alagille syndrome showing neonatal jaundice, broad forehead, and underdeveloped mandible. This infant had peripheral pulmonary artery stenosis and paucity of interlobular bile ducts.

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Albinism v. OCA1ts (tyrosinase related albinism with thermolabile enzyme) a) A temperature sensitive tyrosinase is only partly functional b) The first reported cases had a missense substitution within the tyrosinase gene b. OCA2 (tyrosinase positive albinism) i. OCA2 gene: the pink-eye dilution gene (p) located at 15q11-13 ii. Caused by mutations of the P gene on the chromosome 15, homologous to the mouse pinkedeye dilution, or P gene iii. The mutated region is also deleted in PraderWilli syndrome (PWS) and Angelman syndrome (AS), accounting for close linkage of OCA2 to PWS and AS c. OCA3 (Brown albinism) i. OCA3 gene: tyrosinase-related protein-1 gene (TRP1) located at 9p23 ii. The gene homologous to the mouse “brown” gene iii. Mutation of the gene possibly synergistic with a polymorphism or partially active mutation in OCA1 or OCA2 d. OA1 (X-linked ocular albinism) i. OA1 gene located at Xp22.3-22.2 ii. Intragenic deletions, frameshift mutations, and point mutations identified e. OAR (autosomal recessive ocular albinism) i. Gene mapping: 6q13-q15 ii. May not be a clinical entity iii. Tyrosinase in some cases iv. P protein in some cases f. Hermansky-Pudlak syndromes (HPS): a group of related disorders i. Hermansky-Pudlak syndrome 1 is caused by mutations of the HPS1 gene which is localized to 10q23 ii. HPS2 gene was localized to 5q13. HermanskyPudlak syndrome 2 is caused by mutation of the APB1 gene, which is localized to 5q13, resulting in a defect in adapter complex 3 AP-3, β3A subunit g. Chediak-Higashi syndrome: defect in CHS1 gene (lysosomal trafficking regular gene LYST) located at 1q42.1-q42.2 3. Pathophysiology a. Melanin in the skin i. Melanin, a photoprotective pigment in the skin, absorbs UV light from the sun, thus preventing skin damage ii. Normal skin tans upon sun exposure due to increased melanin pigment in the skin iii. Patient with albinism developing sunburn because of the lack of melanin

Albinism refers to a group of inherited abnormalities of melanin synthesis resulting in congenital hypopigmentation. It involves the skin, hair, and eyes (oculocutaneous albinism) or may be limited primarily to the eyes (ocular albinism). The estimated frequency of affected individuals in the USA is approximately 1/17,000.

GENETICS/BASIC DEFECTS 1. Classification of albinism (genetic heterogeneity) a. Oculocutaneous albinism (OCA): a common phenotype for a group of recessive genetic disorders of melanin synthesis. Mutations in at least 12 genes are responsible for this phenotype. Mutations in OCArelated genes result in reduction of melanin synthesis by the melanocytes i. Common types of OCA with cutaneous and ocular hypopigmentation without significant involvement of other tissue a) Oculocutaneous albinism 1 (OCA1): subdivided into OCA1A, OCA1B, OCA1ts b) Oculocutaneous albinism 2 (OCA2) c) Oculocutaneous albinism 3 (OCA3) ii. Less common types of OCA with more complex manifestations a) Hermansky-Pudlak syndromes b) Chediak-Higashi syndrome b. Ocular albinism i. Ocular albinism 1 (OA1): X-linked recessive ii. Autosomal recessive ocular albinism (AROA) 2. Molecular defects causing albinism a. OCA1 (tyrosinase related albinism) i. Caused by mutations of tyrosinase gene (TYR) located at 11q14-21 ii. Several different types of mutations to the tyrosinase gene (missense, nonsense, and frameshift) are responsible for producing OCA1A and OCA1B iii. OCA1A (tyrosinase negative albinism with inactive enzyme) produced by null mutations of the Tyr gene a) 0% tyrosinase enzyme activity b) Over 100 mutations spanning all parts of the gene reported c) Compound heterozygotes with different maternal and paternal alleles in majority of patients iv. OCA1B (tyrosinase related albinism with partially active enzyme) produced by leaky mutations of the Tyr gene a) “Yellow” form of albinism with 5–10% activity of tyrosinase b) A base substitution within the gene may result in reduced rather than completely abolished enzyme activity 36

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b. Consequence of the absence of melanin during the development of the eye i. Hypoplasia of fovea ii. Alteration of neural connections between the retina and the brain c. Melanin pathway i. Consisting of a series of reactions that converts tyrosine into 2 types of melanin, black-brown eumelanin and red-blond pheomelanin ii. Tyrosinase: a major enzyme in a series of conversions to melanin from tyrosine and it is also responsible for converting tyrosine to DOPA and then to dopaquinone, which subsequently converts to either eumelanin or pheomelanin iii. Two other enzymes involved in the formation of eumelanin: tyrosinase-related protein 1 (TRP1, DHICA oxidase) and tyrosinase-related protein 2 (TRP2, dopachrome tautomerase). Mutation of the TRP1 results in OCA3; mutation of the TRP2 does not cause albinism iv. P protein, a melanosomal membrane protein, believed to be involved in the transport of tyrosine prior to melanin synthesis. Mutation of this P gene causes OCA2 4. Pathogenesis of the ocular features a. Development of the optic system highly dependent on the presence of melanin b. Ocular features appear if melanin is reduced or absent c. Mechanisms i. Misrouting of the retinogeniculate projections resulting in abnormal decussation of optic nerve fibers ii. Sensation of photophobia and decreased visual acuity caused by light scattering within the eye iii. Light-induced retinal damage postulated as a contributing mechanism to decreased visual acuity iv. Foveal hypoplasia: the most significant factor causing decreased visual acuity

CLINICAL FEATURES 1. General clinical features of albinism a. Skin, hair, and eye discoloration caused by abnormalities of melanin metabolism (might not be obvious in ocular albinism) b. Reduced visual acuity due to foveal hypoplasia c. Translucent iris due to reduction in iris pigment d. Visible choroid vessels due to reduction in retinal pigment e. Photophobia due to iris pigmentary abnormalities f. Anomalous visual pathway projections due to misrouting of the optic nerves at the chiasm g. Nystagmus due to abnormal decussation of optic nerve fibers h. Alternating strabismus i. Hyperopia, myopia, and astigmatism 2. Oculocutaneous albinism 1 (OCA1) a. Incidence: approximately 1 in 40,000 individuals b. Oculocutaneous albinism 1A (OCA1A)

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i. ii. iii. iv.

Classic tyrosinase-negative OCA phenotype Most severe form of OCA White hair and white skin that does not tan Blue and translucent irides that do not darken with age v. Foveal hypoplasia vi. No tanning potential vii. At risk for sun burning and skin cancer viii. Diminished visual acuity as low as 20/400 ix. Photophobia and nystagmus worst in this subtype c. Oculocutaneous albinism 1B (OCA1B) i. Yellow mutant type OCA, referred to as Amish albinism, or xanthous albinism ii. Variable pigmentation ranging from very little cutaneous pigmentation to nearly normal skin pigmentation iii. Increased skin, hair, and eye pigment with age and tan with sun exposure iv. Yellow hair pigment develops in the first few years of life and continuously accumulates pigment, principally yellow-red pheomelanin, in the hair, eyes, and skin in the later life v. Decreased visual acuity improving with age d. Temperature-sensitive albinism (OVA1ts) i. A subtype of OCA1B ii. Mutation of the tyrosinase gene that produces a temperature-sensitive tyrosinase enzyme iii. The heat-sensitive tyrosinase enzyme activity is approximately 25% of the normal tyrosinase activity at 37°C. The activity improves at lower temperatures iv. Dark hair pigment in the arms and legs (cooler areas of the body) while axillary and scalp hair remains white v. Pigment is absent in the fetus because of high fetal temperature 3. Oculocutaneous albinism 2 (OCA2) a. Tyrosinase positive OCA b. Incidence: approximately 1 in 15,000 individuals c. Most prevalent type of albinism in all races and especially frequent among African-American population (1 in 10,000) d. Phenotypic variability i. Ranging from absence of pigmentation to almost normal pigmentation ii. Absence of black pigment (eumelanin) in the skin, hair, or eyes at birth iii. Gradual development of pigmentation with age iv. Increased pigmentation resulting in improved vision 4. Oculocutaneous albinism 3 (OCA3) a. Previously known as red/rufous OCA b. Incidence of the disease unknown c. Phenotype in African patients i. Light brown skin and hair ii. Blue-brown irides iii. Ocular features not fully consistent with diagnosis of OCA (no iris translucency, nystagmus, strabismus, or foveal hypoplasia) d. Phenotype in Caucasians and Asians: not known

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5. Ocular albinism 1 (OA1) a. X-linked recessive OA (XLOA) b. Incidence of the disease approximately 1 in 50,000 individuals c. Extreme variability in clinical expression d. Involving eyes only i. Decreased visual acuity ii. Refractive errors: typical findings a) Hypermetropia b) Astigmatism iii. Hypopigmentation of the fundus and the iris iv. Absent foveal reflex (foveal hypoplasia) v. Congenital nystagmus vi. Photophobia vii. Strabismus viii. Iris translucency ix. Posterior embryotoxon x. Loss of stereoscopic vision due to misrouting of the optic tracts e. Normal skin f. Male manifesting complete phenotype g. Carrier females i. Normal vision ii. Hypopigmented streaks (characteristic patchy hypopigmentation as a result of mosaic inactivation of the affected X chromosomes) in the periphery iii. Marked iris translucency h. Severity depending on ethnic background: less severe in races exhibiting very dark constitutive skin pigmentation than those more lightly pigmented 6. Autosomal recessive ocular albinism (OAR) a. Children with ocular features of albinism and normal cutaneous pigmentation born to normally pigmented parents b. Classified as autosomal recessive because both males and females are affected c. Not considered a clinical entity 7. Hermansky-Pudlak syndrome a. A group of related disorders i. Common oculocutaneous albinism ii. A platelet storage disorder iii. Ceroid-lipofuscin lysosomal storage disease b. An autosomal recessive disorder with very variable expression c. Incidence of the disease rare, except in Puerto Rico where its frequency is 1 in 1800 individuals d. Bleeding diathesis resulting from a platelet storage pool deficiency e. Ceroid storage disease i. Accumulation of a Ceroid-lipofuscin material in various organ systems ii. Pulmonary fibrosis iii. Granulomatous colitis and gingivitis iv. Kidney failure v. Cardiomyopathy 8. Chediak-Higashi syndrome a. An autosomal recessive disorder with variable expression b. Consisting of a very rare group of conditions c. Severe immune disorder

d. e.

f.

g.

h.

i. Abnormal intracellular granules in most cells, especially white cells ii. Susceptible to bacterial infections iii. Defective neutrophils function iv. Episodes of macrophage activation known as accelerated phases: a) Fever b) Anemia c) Neutropenia d) Occasionally thrombocytopenia e) Hepatosplenomegaly f) Lymphadenopathy g) Jaundice Hypopigmentation of skin, hair, irides, and ocular fundi Bleeding diathesis i. Easy bruising ii. Mucosal bleeding iii. Epistaxis iv. Petechiae Eye symptoms i. Photophobia ii. Nystagmus iii. Reduced stereoacuity iv. Strabismus Often succumb during childhood to severe viral and bacterial infections, bleeding or development of the accelerated phase May develop a peripheral and cranial neuropathy in survivors i. Autonomic dysfunction ii. Weakness and sensory deficits iii. Loss of deep tendon reflexes iv. Clumsiness with a wide-based gait v. Seizures vi. Abnormal EEG vii. Abnormal EMG with decreased motor nerve conduction velocities

DIAGNOSTIC INVESTIGATIONS 1. Ophthalmologic examination for detection of reduced retinal pigment with visualization of the choroidal blood vessels (OCA1) and foveal hypoplasia 2. Visual acuity reduction 3. Hair bulb incubation assay for tyrosinase activity a. OCA1A: no tyrosinase activity b. OCA1B: greatly reduced activity of tyrosinase but still present 4. Visual-evoked potential (VEP): an accurate diagnostic test for albinism by demonstrating an asymmetry of VEP between the two eyes secondary to misrouting of optic pathways 5. Electron microscopy of skin and hair bulb: not routinely performed but probably the best diagnostic method for albinism 6. Ultrastructural examination of skin: The presence of macromelanosomes in the skin is considered specific for OA1 7. Molecular genetic analysis

ALBINISM

a. Genetic sequence analysis of the tyrosinase (TYR) gene to differentiate between various forms of albinism i. Rarely used for confirmatory diagnostic testing ii. Most commonly used for carrier detection iii. Prenatal diagnosis b. Molecular genetic testing is available clinically by sequencing of the entire coding region of mutation scanning of OCA1 gene c. Testing for the 2.7-kb deletion found in individuals of African heritage: available clinically. Sequence analysis of the OCA2 gene is available on a research basis d. Molecular genetic testing of the gene OA1 is available clinically and detects mutations in >90% of affected males 8. Hermansky-Pudlak syndrome a. Simple blood clotting tests b. Electron microscopic examination of platelets for identification of the absence of dense bodies (delta granules) 9. Chediak-Higashi syndrome a. Blood smear: identification of neutrophils containing giant cytoplasmic granules b. Defective neutrophils chemotaxis or killing c. Prolonged bleeding time caused by impaired platelet function

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Autosomal recessive oculocutaneous albinism: 25% recurrence risk of being affected ii. X-linked recessive ocular albinism: a) If the mother is a carrier: 50% of brothers affected and 50% of sisters carriers b) If the mother is not a carrier: The recurrence risk is low but still exists since the risk of germline mosaicism in mothers is not known but is likely rare b. Patient’s offspring i. Autosomal recessive oculocutaneous albinism: recurrence risk not increased unless the spouse is also a carrier in which case, there is a 50% recurrence risk (as in the pseudodominance) ii. X-linked recessive ocular albinism: none of the sons will be affected; all daughters will be carriers 2. Prenatal diagnosis a. Genetic sequence diagnosis possible on fetal DNA obtained from amniocentesis or CVS for pregnancies at 25% risk when the disease-causing mutations of the TYR gene in an affected family member is known i. OCA1: available clinically in families with an identified OCA1 mutation ii. OCA2: possible in families with an identified OCA2 mutation iii. XLOA: available clinically in families with an identified OA1 mutation b. Fetoscopy (a high risk procedure) to obtain fetal skin biopsy to demonstrate the lack of melanin in skin melanocytes: an invasive procedure not recommended clinically

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3. Management a. Albinism i. Skin care: avoid prolonged sun exposure to protect skin from ultraviolet radiation and minimize the risk of malignancy a) Protective clothing b) Sun screens ii. Ophthalmologic care a) Use of sunglasses for photophobia b) Correction of refractory errors secondary to hyperopia, myopia, or astigmatism to improve visual acuity c) Considering strabismus surgery for better ocular alignment iii. Ensure full benefits of a good education a) Provide large print textbooks b) Seating at the front of classroom b. Hermansky-Pudlak syndrome i. Treat extreme bleeding diathesis with platelet and blood transfusions ii. High dose of steroids for Granulomatous colitis or pulmonary fibrosis c. Chediak-Higashi syndrome i. Treat infections ii. Bone marrow transplantation: improves immunological status but no effect on ocular and cutaneous albinism

REFERENCES Abadi R, Pascal E: The recognition and management of albinism. Ophthalmic Physiol Opt 9:3–15, 1989. Biswas S, Lloyd IC: Oculocutaneous albinism. Arch Dis Child 80:565–569, 1999. Boissy RE, Nordlund JJ: Albinism. Emedicine, 2001. http://www.emedicine.com Carden SM, Boissy RE, Schoettker PJ, et al.: Albinism: modern molecular diagnosis. Br J Ophthalmol 82:189–195, 1998. Creel DJ, Summers CG, King RA: Visual anomalies associated with albinism. Ophthalmic Paediatr Genet 11:193–200, 1990. Hasanee K, Ahmed IIK: Albinism. Emedicine, 2001. http://www.emedicine.com Hsieh YY, Wu JY, Chang CC, et al.: Prenatal diagnosis of oculocutaneous albinism two mutations located at the same allele. Prenat Diagn 21:200–201, 2001. King RA: Oculocutaneous albinism type 1. Gene Reviews, 2002. http://www. genetests.org King RA: Oculocutaneous albinism type 2. Gene Reviews, 2003. http://www. genetests.org King RA, Summers GC, Haefemeyer JW, et al.: Facts about albinism. Available at: www.cbc.umn.edu/iac/facts.htm King RA, Summers CG: Albinism. Dermatol Clin 6:217–228, 1988. King RA, Hearing VJ, Creed DJ, et al.: Albinism. In Scriver CR, Beaudet al., Sly WS, Valle D (eds): The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001, Chapter 220, pp 5587–5627. King RA, Pietsch J, Fryer JP, et al.: Tyrosinase gene mutations in oculocutaneous albinism 1 (OCA1): definition of the phenotype. Hum Genet 113:502–513, 2003. Lang GE, Rott HD, Pfeiffer RA: X-linked ocular albinism. Characteristic pattern of affection in female carriers. Ophthalmic Paediatr Genet 11:265–271, 1990. Nagle DL, Karim MA, Woolf EA, et al.: Identification and mutation analysis of the complete gene for Chediak-Higashi syndrome. Nat Genet 14:307–311, 1996. Oetting WS: Albinism. Curr Opin Pediatr 11:565–571, 1999. Oetting WS: New insights into ocular albinism type 1 (OA1): Mutations and polymorphisms of the OA1 gene. Hum Mutat 19:85–92, 2002. Oetting WS, King RA: Molecular basis of albinism: mutations and polymorphisms of pigmentation genes associated with albinism. Hum Mutat 13:99–115, 1999.

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Oetting WS, Brilliant MH, King RA: The clinical spectrum of albinism in humans. Mol Med Today 2:330–335, 1996. Oetting WS, Gardner JM, Fryer JP, et al.: Mutations of the human P gene associated with Type II oculocutaneous albinism (OCA2). Hum Mutat 12:434, 1998. Oetting WS, Fryer JP, Shriram S, et al.: Oculocutaneous albinism type 1: the last 100 years. Pigment Cell Res 16:307–311, 2003. Okulicz JF, Shah RS, Schwartz RA, et al.: Oculocutaneous albinism. J Eur Acad Dermatol Venereol 17:251–256, 2003. Peracha MO, Eliott D, Garcia-Valenzuela E: Ocular manifestations of albinism. eMedicine J, 2001. Emedicine, 2001. http://www.emedicine.com

Rosenberg T, Schwartz M: Ocular albinism, X-linked. Gene Reviews, 2004. http://genetests.org Rosenberg T, Schwartz M: X-linked ocular albinism: prevalence and mutations-a national study. Eur J Hum Genet 6:570–577, 1998. Russell-Eggitt I: Albinism. Ophthalmol Clin North Am 14:533–546, 2001. Sarangarajan R, Boissy RE: Tyrp1 and oculocutaneous albinism type 3. Pigment Cell Res 14:437–444, 2001. Shen B, Samaraweera P, Rosenberg B, et al.: Ocular albinism type 1: more than meets the eye. Pigment Cell Res 14:243–248, 2001. Spritz RA: Molecular genetics of oculocutaneous albinism. Semin Dermatol 12:167–172, 1993.

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Fig. 1. Oculocutaneous albinism in different age groups including one set of identical twins.

Amniotic Band Syndrome Amniotic band syndrome occurs in one of every 5000 to 15,000 births and had been demonstrated in 1–2% of malformed infants.

h. Incompetent cervix i. Amniocentesis implicated. An increased incidence of anomalies related to amniotic band syndrome in association with prenatal amniocentesis in animal models j. Familial occurrences reported despite no evidence for a genetic predisposition to amniotic band syndrome 5. Synonyms and acronyms a. Congenital band syndrome b. Streeter’s dysplasia c. Simonart’s bands d. Amniotic band disruption complex e. Congenital annular defects f. Congenital ring constrictions g. Constriction ring syndrome h. ADAM (Amniotic Deformity, Adhesion, Mutilations) complex i. TEARS (The Early Amnion Rupture Spectrum)

GENETICS/BASIC DEFECTS 1. Streeter intrinsic theory a. An intrinsic defect of the subcutaneous germ plasm causes soft tissue to slough. The resulting external healing leads to the constriction ring b. Significant rate of associated anomalies as indirect proof of existence of some genetic force at work to cause the syndrome 2. Torpin extrinsic theory (currently most popular theory) a. Early amniotic rupture leading to the formation of mesodermal fibrous strands that entangle limbs and appendages b. Amnion rupture without injury to the chorion resulting in amniotic bands c. Oligohydramnios playing a major role in the development of the constricting bands d. Higher incidence of club feet possibly resulting from continuous pressure on the feet from the undersized uterus e. Amniotic bands essentially encircling the affected part resulting in constricting rings f. Supporting evidence i. Constriction rings often occurring in a straight line across multiple digits as if one external band affects multiple adjacent digits ii. Frequent involvement of the central digits iii. Occasional attachment of amnion in the constricting ring iv. Facial clef ting which does not follow developmental planes 3. Other theory: simultaneous occurrence of both extrinsic and intrinsic factors in the development of constriction band syndrome 4. Other factors/mechanisms implicated in the etiology of amniotic band syndrome: The cause of amniotic band syndrome remains elusive and controversial a. Simple oligohydramnios b. Fetal hypertension c. Venous stasis d. Localized fetal ischemia caused by uterine contractions e. Intrauterine hemorrhage as the precipitating event f. Vascular compromise (lack of distal blood flow demonstrated in association with forearm amputation defects) g. Cocaine drug abuse: cocaine acting as a teratogen by inducing fetal hypoxemia through impaired uteroplacental fetal blood flow and directly through its vasoconstrictive properties on the fetal vasculature

CLINICAL FEATURES 1. The nature and severity of deformities: related to the timing and initiating event of amniotic rupture 2. Triad of amniotic band syndrome a. Amnion-denuded placenta b. Fetal attachment or entanglement by amniotic remnants c. Fetal deformation, malformation, and/or disruption i. Fetal deformation (fetal compression secondary to oligohydramnios; fetal entanglement by amniotic bands) ii. Fetal malformation resulting from amniotic band interfering with the normal sequence of embryologic development iii. Fetal disruption secondary to cleavage of structures that have already developed normally 3. Craniofacial disruptions (up to one third of cases) a. Facial clefting i. Most likely associated with swallowing of band at about 5 months of gestation ii. Unusual extensions with asymmetric locations, such as oblique facial clefting b. Orbital defects i. Anophthalmos ii. Microphthalmos iii. Enophthalmos iv. Hypertelorism c. Corneal abnormalities i. Anomalous eyelid configuration ii. Ineffective eye closure d. Other ocular abnormalities i. Strabismus due to defects in extraocular muscles ii. Epiphora related to either lacrimal system involvement or eyelid abnormalities 42

AMNIOTIC BAND SYNDROME

4.

5.

6.

7.

8.

9.

e. CNS involvement: usually associated with amniotic band rupture before 45 days of gestation i. Neural tube defects (cranioschisis, atypical or asymmetrical meningocele, myelomeningocele, encephalocele, or anencephaly) ii. Ventriculomegaly iii. Pressure defects of the parenchyma f. Calvarial defects g. Cleft lip/palate Limb abnormalities a. Limb reduction defects b. Intrauterine amputations c. Ring constrictions with or without distal lymphedema, clubbing, or syndactyly i. Deeper rings ii. Circumferential rings d. Club feet e. Digital anomalies: frequently involved i. Syndactyly ii. Acrosyndactyly iii. Digital hypoplasia iv. Symphalangism v. Symbrachydactyly vi. Camptodactyly f. Significant neurovascular impairment distal to the constricting band Umbilical cord strangulation by amniotic bands a. Common occurrence (10%) b. Cord strangulation c. Severe strangulation of the umbilical cord may result in fetal death d. Stillbirths observed in about 97% of umbilical cord strangulation by amniotic bands Associated anomalies a. Hemangiomas b. Cardiac defect c. Limb/body wall defects d. Thoracoabdominal wall defects i. Thoracoschisis ii. Extrathoracic heart iii. Omphalocele iv. Gastroschisis e. Aplasia cutis f. Short umbilical cord g. Oligohydramnios sequence Patterson’s classification system of congenital ring constriction based on the severity of the syndrome a. Simple constriction rings b. Constriction rings associated with deformity of the distal part, with or without lymphedema c. Constriction rings associated with soft tissue fusions of distal parts (acrosyndactyly) d. Intrauterine amputation Hall’s classification system for amniotic band syndrome a. Mild constriction without lymphedema b. Moderate constriction with lymphedema c. Severe constriction with amputation Weinzweig’s classification system for amniotic band syndrome

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a. Mild constriction without lymphedema b. Moderate constriction with distal deformity, syndactyly, or discontinuous neurovascular or musculotendinous structures without vascular compromise i. Without lymphedema ii. With lymphedema c. Severe constriction with progressive lymphaticovenous or arterial compromise i. Without soft-tissue loss ii. With soft-tissue loss d. Intrauterine amputation 10. Lockwood’s classification of fetal anomalies in amniotic band syndrome according to their presumed mechanism a. Anomalies caused by interruption of embryonic morphogenesis i. Cleft lip and palate ii. Omphalocele iii. Cardiac anomalies iv. Renal agenesis or dysplasia v. Bladder exstrophy vi. Imperforate anus b. Anomalies caused by fetal vascular compromise i. Gastroschisis ii. Gallbladder agenesis iii. Single umbilical artery c. Anomalies caused by intrauterine constraint i. Club foot ii. Clubbed hands iii. Abnormal facies iv. Valgus-varus deformities v. Kyphoscoliosis d. Anomalies caused by disruption of normally developed structures i. Severe central nervous system or calvarial defect ii. Acrosyndacytly iii. Amputations iv. Constriction bands v. Facial clefts (anatomically inappropriate) vi. Aplasia cutis 11. Prognosis a. Prenatally diagnosed amniotic adhesion with a grim prognosis b. Most cases of cranial and body wall defects incompatible with extrauterine life c. Infants born with limited limb abnormalities: better prognosis with good results after surgical repair of the constrictions or syndactyly

DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Syndactyly with amputation of distal parts b. Intrauterine amputation of limbs and digits 2. MRI imagings a. Delineate the depth of the constriction band b. Delineate the extent of the resultant lymphedema c. Delineate the integrity of the musculature d. Define the vascular anatomy, which may be anomalous; may help to prevent injury to the vessels during surgery

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AMNIOTIC BAND SYNDROME

3. Histology a. Absence of amniotic membrane on the fetal surface of the chorionic sac, including the placental sac b. Presence of amnion remnant as a cuff of thick membrane at the base of the umbilical cord at its insertion site c. Amniotic squames and cellular debris are frequently embedded in the superficial soft tissue of the chorion indicating chronic amniotic rupture d. Constricting bands encircling digits

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased b. Patient’s offspring: not increased 2. Prenatal diagnosis possible by ultrasonography during second and third trimester a. Visualization of amniotic sheets or bands attached to the fetus. The diagnosis of amniotic band syndrome should not be made solely on the basis of a membrane observed in the uterine cavity b. Restricted fetal movement c. Characteristic asymmetric fetal anomalies d. Constriction bands around the limbs 3. Management a. Surgery not needed for shallow constriction bands that are not circumferential and without distal swelling b. Distal edema or impairment of neurovascular function requiring staged constriction band excision, Zplasty, or W-plasty c. Digital amputation may be required for a ring so constrictive that distal edema is massive d. Multiple plastic surgical procedures required for corrections of the complex craniofacial abnormalities e. Procedures for the upper-extremity deformities i. Band release, Z- or W-plasty ii. Syndactyly/web space release iii. Skin graft iv. Stump revision v. Osteotomy/osteoclasis vi. Hardware removal vii. Ray resection/transposition viii. Distraction osteogenesis ix. Pollicization/osteocutaneous transfer x. Tendon transfer xi. Excision supernumerary digit xii. Amputation f. Procedures for the lower-extremity deformities i. Band release, Z- or W-plasty ii. Syndactyly release iii. Simple revision iv. Amputation/excision toe v. Clubfoot procedure vi. Hip procedure vii. Tibial derotation viii. Removal of skin tag g. Careful follow-up on congenital constriction band of the trunk because the evolution of this condition is benign

h. In utero surgical intervention proposed to avoid amputation or permanent damage to the extremity of the fetus, provided the maternal and fetal risks of surgery are small

REFERENCES Al-Qattan MM: Classification of the pattern of intrauterine amputations of the upper limb in constriction ring syndrome. Ann Plast Surg 44:626–632, 2000. Askin G, Ger E: Congenital constriction band syndrome. J Pediatr Orthop 8:461–466, 1988. Bagatin M, Der Sarkissian R, Larrabee WF Jr: Craniofacial manifestations of the amniotic band syndrome. Otolaryngol Head Neck Surg 116:525–528, 1997. Bahadoran P, Lacour JP, Terrisse A, et al.: Congenital constriction band of the trunk. Pediatr Dermatol 14:470–472, 1997. Baker CJ, Rudolph AJ: Congenital ring constrictions and intrauterine amputations. Am J Dis Child 121:393–400, 1971. Bourne MH, Klassen RA: Congenital annular constricting bands: Review of the literature and a case report. J Pediatr Orthop 7:218–221, 1987. Burton DJ, Filly RA: Sonographic diagnosis of the amniotic band syndrome. Am J Roentgenol 156:555–558, 1991. Chen H, Gonzalez E: Amniotic band sequence and its neurocutaneous manifestations. Am J Med Genet 28:661–673, 1987. Day-Salvatore DL, Guzman E, Weinberger B, et al.: Genetics casebook. Amniotic band disruption sequence. J Perinatol 15:74–77, 1995. De Pablo A, Calb I, Jaimovich L: Congenital constriction bands: Amniotic band syndrome J Am Acad Dermatol 32:528–529, 1995. Eppley BL, David L, Li M, et al.: Amniotic band facies. J Craniofac Surg 9:360–365, 1998. Foulkes GD, Reinker K: Congenital constriction band syndrome: a seventyyear experience. J Pediatr Orthop 14:242–248, 1994. Garza A, Cordero JF, Mulinare J: Epidemiology of the early amnion rupture spectrum (TEARS) of defects. Am J Dis Child 142:541–544, 1988. Hall EJ, Johnson-Giebina R, Vascones LO: Management of the ring constriction syndrome: a reappraisal. Plast Reconst Surg 69:532–536, 1982. Higginbottom MC, Jones KL, Hall BD, et al.: The amniotic band disruption complex: timing of amniotic rupture and variable spectra of consequent defects. J Pediatr 95:544–549, 1979. Heifitz SA: Strangulation of the umbilical cord by amniotic bands: Report of 6 cases and literature review. Pediatr Pathol 2:285–304, 1984. Hollsten DA, Katowitz JA: The ophthalmic manifestations and treatment of the amniotic band syndrome. Ophthal Plast Reconstr Surg 6:1–15, 1990. Keller H, Neuhauser G, Durkin-Stamm MV, et al.: “ADAM complex” (amniotic deformity, adhesions, mutilations)-a pattern of craniofacial and limb defects. Am J Med Genet 2:81–98, 1978. Kino Y: Clinical and experimental studies of the congenital constriction band syndrome, with an emphasis on its etiology. J Bone Joint Surg Am 57:636, 1975. Laberge LC, Rszkowski A, Morin F: Amniotic band attachment to a fetal limb: demonstration with real-time sonography. Ann Plast Surg 35:316–319, 1995. Laor T, Jaramillo D, Hoffer FA, et al.: MR imaging in congenital lower limb deficiencies. Pediatr Radiol 26:381–387, 1996. Levy PA: Amniotic bands. Pediatr Rev 19:249, 1998. Light TR, Ogden JA: Congenital constriction band syndrome. Pathophysiology and treatment. Yale J Biol Med 66:143–155, 1993. Lockwood C, Ghidini A, Romero R, et al.: Amniotic band syndrome: Reevaluation of its pathogenesis. Am J Obstet Gynecol 160:1030–1033, 1989. Lubinsky M, Sujansky E, Sanders W, et al.: Familial amniotic bands. Am J Med Genet 14:81–87, 1983. Mahony BS, Filly RA, Callen PW, et al.: The amniotic band syndrome: antenatal sonographic diagnosis and potential pitfalls. Am J Obstet Gynecol 152:63–68, 1985. Mishima K, Sugahara T, Mori Y, et al.: Three cases of oblique facial cleft. J Cranio-Maxillofac Surg 24:372–377, 1996. Moerman P, Fryns JP, Vandenberghe L, et al.: Constrictive amniotic bands, amniotic adhesions, and limb body wall complex, discrete disruption sequence with pathogenic overlap. Am J Med Genet 42:470–479, 1992.

AMNIOTIC BAND SYNDROME Nishi T, Nakano R: Amniotic band syndrome: Serial ultrasonographic observations in the first trimester. J Clin Ultrasound 22:275–278, 1994. Ossipoff V, Hall BD: Etiologic factors in the amniotic band syndrome: a study of 24 patients. Birth Defects Orig Artic Ser 13:117–132, 1977. Patterson TJS: Congenital ring constrictions. Br J Plast Surg 14:1–31, 1961. Quintero RA, Morales WJ, Phillips J, et al.: In utero lysis of amniotic bands. Ultrasound Obstet Gynecol 10:316–320, 1997. Seidman JD, Abbondanzo SL, Watkins WG, et al.: Amniotic band syndrome. Arch Pathol Lab Med 113:891–897, 1989. Streeter GL: Focal deficiencies in fetal tissues and their relationship to intrauterine amputation. Contributions to Embryology of the Carnegie Institute 22:1–44, 1930. Takayuki M: Congenital constriction band syndrome. J Hand Surg Am 9:82, 1984. Temtamy SA, McKusick VA: Digital and other malformations associated with congenital ring constrictions. Birth Defects 14:547, 1978.

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Torpin R: Amniochorionic mesoblastic fibrous strings and amniotic bands; associated constricting fetal malformations or fetal death. Am J Obstet Gynecol 91:65–75, 1965. Torpin R: Intrauterine amputation with the missing member found in the fetal membranes. JAMA 198:205–207, 1966. Trasler DG: Congenital malformations produced by amniotic sac puncture. Science 124:439, 1988. Walter JH Jr, Goss LR, Lazzara AT: Amniotic band syndrome. J Foot Ankle Surg 37:325–333, 1998. Weinzweig N: Constriction band-induced vascular compromise of the foot: classification and management of the “intermediate” stage of constriction-ring syndrome. Plast Reconstr Surg 96:972–977, 1995. Yamaguchi M, Yasuda H, Kuroki T, et al.: Early prenatal diagnosis of amniotic band syndrome. Am J Perinatol 5:5–7, 1988. Yang SS: ADAM sequence and innocent amniotic band: Manifestations of early amnion rupture. Am J Med Genet 37:562–568, 1990.

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Fig. 1. A small stillborn fetus (110 gm) showing amniotic constriction band at left ankle. Amputation and pseudosyndactyly of fingers and toes are present.

Fig. 2. A small stillborn fetus (60gm) with a fibrous amniotic band constricting a portion of the head and facial cleft.

Fig. 3. A small fetus with a large amniotic band which caused anencephaly.

AMNIOTIC BAND SYNDROME

47

Fig. 4. The left hand of a 1–100 gm fetus showing in utero amputation of the 3rd and 4th fingers.

Fig. 7. A fetus with a large meningoencephalocele and an amniotic band attaching to its base. Facial defects, a large gastroschisis, and talipes equinovarus were also present. Histology of the scalp shows an amniotic band fused with the soft tissue of the upper dermis. The amniotic epithelium of the band is visible as a darker line on the surface. The epidermis of the scalp is denuded at the site of band attachment.

Fig. 5. A placenta with a long strand of amniotic band which was pulled out of the mouth of the premature neonate at birth. The baby did not have amniotic band syndrome.

Fig. 6. Cord strangulation by amniotic band.

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Fig. 8. A fetus with marked craniofacial defects and the site of amniotic band attachment at the base of the skull. The fetus also had amputation of the distal left great toe (not shown). Prenatal ultrasonography showed a complex structures arising from the top and front of the craniofacial region. Fig. 10. An infant with club left hand with a missing finger, constricting rings with marked distal lymphedema of the right index finger, and pseudosyndactyly of the right foot.

Fig. 9. An infant with marked craniofacial anomalies, a constricting ring of a finger with distal lymphedema, and an amputation of the 5th finger.

AMNIOTIC BAND SYNDROME

Fig. 11. An infant with deep constricting groove around the lower onethird of both legs. The patient also had terminal amputation and constriction rings of fingers with a small amniotic band still attached to the constricting ring of the second finger (not shown).

Fig. 12. A hand of an infant with constriction bands of the fingers with amputations, shown by the radiograph.

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Androgen Insensitivity Syndrome Androgen insensitivity syndrome (AIS) is a disorder of male sexual differentiation caused by a defective, deficient, or absent androgen receptor. The syndrome was first described by Morris in 1953 who coined the term testicular feminization syndrome, based on the observation of the complete absence of signs of virilization in phenotypic females with testes and a 46,XY karyotype. AIS probably represents the most common cause of male pseudohermaphroditism. It is an X-linked recessive disorder in 46,XY individuals with normal androgen production and metabolism. The AIS is estimated to be present in 1 in 20,000 to 1 in 64,000 male births.

c. Incomplete androgen insensitivity syndrome (IAIS): partial resistance to the action of testosterone and dihydrotestosterone d. Reifenstein syndrome: Variable resistance to the action of testosterone and dihydrotestosterone e. Mild androgen insensitivity syndrome (MAIS): Resistance to the action of androgen varies in different tissues

CLINICAL FEATURES 1. Variable phenotypic expression allowing the classification of AIS into complete and partial forms, and a rare group of phenotypically normal men with azoospermia 2. Complete androgen insensitivity syndrome a. Presumptive diagnosis of CAIS i. Absence of extragenital abnormalities ii. Two nondysplastic testes iii. Absent or rudimentary müllerian structures (absence of fallopian tubes, uterus, or cervix) iv. A short vagina v. Undermusculinization of the external genitalia at birth vi. Impaired spermatogenesis (sterility) and/or somatic virilization at puberty b. External phenotype i. Invariably presenting as a normal female external appearance (female habitus) ii. Female external genitalia (“testicular feminization;” Tfm) iii. Underdeveloped, short blind-ending vagina iv. Normal breast and female adiposity development v. Unaffected sexual identity and orientation vi. Scant or absent pubic and/or axillary hair c. Urogenital tract i. Absent or rudimentary Wolffian duct derivatives (epididymides and/or vas deferens) ii. Inguinal or labial masses subsequently identified as testes d. Other features i. Primary amenorrhea at puberty ii. Complete androgen insensitivity syndrome almost always runs true in families (i.e., affected XY relatives usually have normal female external genitalia and seldom have any sign of external genital masculinization, such as clitoromegaly or posterior labial fusion) 3. Partial androgen insensitivity syndrome (PAIS) a. Predominantly female external genitalia (incomplete androgen insensitivity syndrome) i. Signs of external genital masculinization a) Clitoromegaly b) Partial fusion of the labioscrotal folds

GENETICS/BASIC DEFECTS 1. Inheritance a. X-linked recessive inheritance i. Affected XY individuals ii. Carrier XX females b. Manifesting carrier females (about 10% of carrier females) 2. Caused by mutations of androgen receptor (AR) gene (mapped to chromosomal locus Xq11-q12) a. Mutations of androgen receptor: responsible for a variable degree of impaired androgen action b. De novo mutations i. De novo mutation rate close to 30% ii. Somatic or germ-line mosaicism observed for “de novo” mutations in which the mutation is present in some of the cells in one of the clinically unaffected parents c. Type of mutations i. Point mutations ii. Complete and partial gene deletions iii. Small insertions/deletions d. Variable expressivity of a particular point mutation attributable to somatic mosaicism for the mutation 3. Pathogenesis a. Androgen insensitivity syndrome i. The result of an end-organ resistance to androgens caused by an abnormality of the androgen receptor ii. Normal production of testosterone and normal conversion to dihydrotestosterone (DHT) by the normal testes in affected individuals, differentiating this condition from 5α reductase deficiency iii. Absence of fallopian tubes, uterus or proximal (upper) vagina in affected individuals because testes produce normal amounts of müllerianinhibiting factor (MIF) b. Complete androgen insensitivity syndrome (CAIS) i. Most severe form ii. Complete resistance to all actions of testosterone and dihydrotestosterone 50

ANDROGEN INSENSITIVITY SYNDROME

ii. iii. iv. v.

Female habitus and breast development Normal axillary and pubic hair Inguinal or labial testes as in CAIS Wolffian duct derivatives emptying into the vagina vi. Distinct urethral and vaginal openings or a urogenital sinus vii. No Müllerian duct derivatives b. Ambiguous external genitalia (Reifenstein syndrome) i. Microphallus (95% of patients b. PAIS: detected in T mutation i. Milder phenotype ii. Longer lifespan

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4. Malignancy a. The second most frequent cause of death b. Eventual malignancy during lifetime in 38% of patients c. Malignancy of hematologic origin most common (85% of patients) i. Predominance of malignant lymphomas, usually of B-cell type ii. Acute lymphocytic leukemia of T-cell origin in younger patients iii. T-cell prolymphocytic leukemia in older patients d. Other neoplasms i. Breast cancer, even in female relatives who do not have ataxia telangiectasia ii. Gastric cancer iii. Melanoma iv. Leiomyoma v. Sarcoma 5. Ectodermal changes a. Appearance of premature aging i. Diffuse graying of the hair ii. Atrophic and hidebound facial skin iii. Inelastic ears iv. Facial wasting b. Frequent pigmentary changes: hyperpigmentation/ hypopigmentation with cutaneous atrophy and telangiectasia c. Partial albinism d. Vitiligo e. Café-au-lait spots f. Seborrheic dermatitis 6. Endocrine manifestations a. Occasional female hypogonadism associated with ovarian hypoplasia or dysplasia b. Male hypogonadism with delayed puberty and characteristic high-pitched voice 7. Clubbing: observed in 40% of Costa Rican patients not correlated with chronic lung disease, humoral immunodeficiency, or with a particular mutation 8. Other features a. Mild postnatal growth retardation b. Hypersensitivity to ionizing radiation c. Wheelchair-bound by 10 years of age

DIAGNOSTIC INVESTIGATIONS 1. Significant humoral and cellular immune defects in most patients a. Thymic hypoplasia b. Low numbers of circulating T-cells c. Functional impairment of T-cell-mediated immunity d. Selective deficiencies of IgA, IgE, IgG2, and IgG4 e. Low or absent serum levels of IgA in 60% of patients f. Low or absent serum levels of IgG2 in 80% of patients g. Hyper-IgM in approximately 1% of patients, sometimes associated with myeloma-like gammopathy, lymphadenopathy, hepatosplenomegaly, and lymphocytic interstitial pneumonitis 2. Increased serum levels of alpha-fetoprotein (AFP) levels in over 90% of older children with A-T 3. Increased plasma levels of carcinoembryonic antigen

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4. Colony survival assay by in vitro testing for radiosensitivity on lymphoblastoid cell line to measure the colony survival fraction after 1 Gy of in vitro radiation: sensitivity and specificity exceeding 95% but takes 2–3 months to complete 5. Western blot analysis to detect ATM protein in lysates of a lymphoblastoid cell line 6. DNA-based mutation analysis of the ATM gene available clinically a. Sequence analysis of the ATM coding region b. Linkage analysis to identify carriers among family members at risk if direct DNA testing fails to identify two disease-causing mutations in the index case 7. Chromosome analysis to identify genetic instability, a hallmark of the A-T phenotype a. Types of spontaneous in vitro chromosome aberrations, frequent in both lymphoid and nonlymphoid cells i. Chromosome breaks ii. Acentric fragments iii. Dicentric chromosomes iv. Structural arrangements v. Aneuploidy b. A-T lymphocytes i. Increased chromosome breaks. Common breakage points include 7p14, 7q35, 14q12, 14qter, 2p11, 2p12, and 22q11-q12 ii. Clonal rearrangements involving abnormalities of chromosome 14, especially tandem duplication of 14q at 14q11-q12 and t(7;14) c. Nonlymphoid cells: break points randomly distributed 8. Radiography a. Decreased or absent adenoidal tissue in the nasopharynx b. Small or absent thymic shadow c. Decreased mediastinal lymphoid tissue d. Pulmonary changes similar to those seen in cystic fibrosis 9. EMG and nerve conduction velocities a. Frequently normal in children b. Showing denervation on EEG and reduced nerve conduction in the late stage of the disease, especially in sensory fibers 10. Electrooculography a. Shows characteristic oculomotor abnormality of A-T b. Differentiates A-T from Friedreich ataxia 11. MRI of the brain a. A small cerebellum b. Widened sulci c. Enlargement of the fourth ventricle 12. Histology a. Degeneration of Purkinje and granule cells in the cerebellum: the major pathological marker of A-T in the CNS b. Late degenerative gliovascular nodules in the white matter c. Lesions of the basal ganglia observed only occasionally d. Degeneration of spinal tracts and anterior horn cells often present in late stages e. Nucleocytomegaly, a feature of several cell types throughout the body

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GENETIC COUNSELING 1. Recurrence risk: counseling according to autosomal recessive inheritance a. Patient’s sib i. A 25% recurrence risk ii. Two-thirds of unaffected sibs are carriers b. Patient’s offspring: most patients with A-T do not reproduce 2. Prenatal diagnosis a. Elevated maternal serum AFP levels b. Demonstration of chromosome breaks in amniocytes c. Molecular genetic analysis i. Direct DNA mutation analysis on fetal DNA obtained from amniocentesis or CVS for pregnancies at-risk with previously identified specific disease-causing mutation ii. DNA-based testing with linkage analysis for atrisk family members if no specific disease-causing mutation identified 3. Management a. No specific treatment available b. Early physical therapy, occupational therapy, and speech therapy c. Antibiotics for infections d. Prevention of infection by regular injection of immunoglobulins in patients with antibody deficiency e. Beta-Adrenergic blockers may improve fine motor coordination in some cases f. Controversial use and doses of radiation therapy and chemotherapy g. Avoid bleomycin, actinomycin D, and cyclophosphamide h. Regular cancer surveillance of heterozygotes essential. ATM heterozygosity is a risk factor for breast and lung cancers i. Desferroxamine: recently shown to increase genomic stability of A-T cells and may present a promising tool in A-T treatment j. Usually requires wheelchair by ten years of age

REFERENCES Anmann AJ, Cain WA, Ishizaka K, et al.: Immunoglobulin deficiency in ataxiatelangiectasia. N Engl J Med 281:469–472, 1969. Calonje D, El-Harazi SM: Ataxia-telangiectasia. Emedicine, 2001. http://www. emedicine.com Chessa L, Piane M, Prudente S, et al.: Molecular prenatal diagnosis of ataxia telangiectasia heterozygosity by direct mutational assays. Prenat Diagn 19:542–545, 1999. Concannon P, Gatti RA: Diversity of ATM gene mutations detected in patients with ataxia-telangiectasia. Hum Mutat 10:100–107, 1997. Gatti RA: Diversity of ATM gene mutations detected in patients with ataxiatelangiectasia. Hum Mutat 10:100–107, 1997. Gatti RA: Ataxia-telangiectasia. Gene Reviews, 2003. http://genetests.org Gatti RA, Boder E, Vinters H, et al.: Ataxia-telangiectasia: an interdisciplinary approach to pathogenesis. Medicine 70:99–117, 1991. Huo YK, Wang Z, Hong JH, et al.: Radiosensitivity of ataxia-telangiectasia, Xlinked agammaglobulinemia, and related syndromes using a modified colony survival assay. Cancer Res 54:2544–2547, 1994. Jozwiak S, Janniger CK: Ataxia-telangiectasia. Emedicine, 2004. http://www. emedicine.com Meyn MS: Ataxia-telangiectasia, cancer and the pathobiology of the ATM gene. Clin Genet 55:289–304, 1999. Petersen RD, Kelly WD, Good RA: Ataxia-telangiectasia: its association with a defective thymus, immunological-deficiency disease and malignancy. Lancet 1:1189–1193, 1964. Regueiro JR, Porras O, Lavin M, et al.: Ataxia-telangiectasia. A primary immunodeficiency revisited. Immunol Allergy Clin N Am 20(1):177–206, 2000. Spacey SD, Gatti RA, Bebb G: The molecular basis and clinical management of ataxia telangiectasia. Can J Neurol Sci 27:184–191, 2000. Sparkes RS, Como R, Golde DW: Cytogenetic abnormalities in ataxia telangiectasia with T-cell chronic lymphocytic leukemia. Cancer Genet Cytogenet 1:329–336, 1980. Sun X, Becker-Catania SG, Chun HH, et al.: Early diagnosis of ataxia-telangiectasia using radiosensitivity testing. J Pediatr 140:724–731, 2002. Swift M, Morrell D, Cromartie E, et al.: The incidence and gene frequency of ataxia-telangiectasia in the United States. Am J Hum Genet 39:573–583, 1986. Swift M, Reitnauer PJ, Morrell D, et al.: Breast and other cancers in families with ataxia-telangiectasia. N Engl J Med 316:1289–1294, 1987. Swift M, Morrell D, Massey RB, et al.: Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med 325:1831–1836, 1991. Taylor AM, Metcalfe AJA, Thick J, et al.: Leukemia and lymphoma in ataxia telangiectasia. Blood 87:423–438, 1996. Taylor M, Teraoka S, Wang Z, et al.: Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations. Am J Hum Genet 62:86–97, 1998. Woods CG, Taylor AMR: Ataxia-telangiectasia in the British Isles: the clinical and laboratory features of 70 affected individuals. Quart J Med 82:169–179, 1992.

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Fig. 1. A boy with ataxia-telangiectasia showing conjunctival telangiectasis and chronic lung disease requiring oxygen support.

Fig. 2. A girl with ataxia-telangiectasia showing conjunctival telangiectasis and anemia.

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Atelosteogenesis ii. Reduced sulfate transport in chondrocytes of individuals with DTDST mutations resulting in the undersulfation of proteoglycans, which in turn leads to abnormal cartilage formation g. Factors in addition to the intrinsic sulfate transport properties of the DTDST protein may influence the phenotype in individuals with DTDST mutations 3. Atelosteogenesis III (AOIII) a. Inheritance: autosomal dominant b. Features overlapping with AOI and AOII but most similar to those of AOI c. Caused by mutations in FLNB gene 4. Genotype–phenotype correlation in a compound heterozygote (atelosteogenesis type-II diastrophic dysplasia) a. Atelosteogenesis type II i. R178X mutations of the SLC26A2 gene ii. Features typical of AOII a) Severe and progressive cervical kyphosis b) V-shaped distal humerus c) Bowed radii d) Horizontal sacrum e) Gap between the first and second toes b. Diastrophic dysplasia i. R279W mutations of the SLC26A2 gene ii. Features suggestive of diastrophic dysplasia a) Cystic swelling of the external ears b) Cervical kyphosis c) Rhizomelia d) “Hitchhiker” thumbs e) Bilateral talipes equinovarus f) Short toes c. Combination of a severe and a mild mutation leads to an intermediate clinical picture, representing an apparent genotype-phenotype correlation

In 1982, Maroteaux et al. proposed the term “atelosteogenesis” for a newborn skeletal dysplasia characterized by specific patterns of aplasia/hypoplasia of humeri, femora, spine, and other skeletal elements. Atelosteogenesis encompasses a heterogeneous group of disorders with overlapping phenotypic features.

GENETICS/BASIC DEFECTS 1. Atelosteogenesis I (AOI)/boomerang dysplasia (BD) a. Inheritance: de novo autosomal dominant mutation, suggested by: i. Sporadic in all observed cases ii. No familial cases reported b. Previously known as spondylohumerofemoral dysplasia and giant cell chondrodysplasia c. Caused by mutations in filamin B (FLNB) gene, which also causes the following disorders: i. Atelosteogenesis type III ii. Autosomal recessive spondylocarpotarsal syndrome iii. Autosomal dominant Larsen syndrome d. A common pathogenesis suggested for atelosteogenesis type I and BD i. Forming a spectrum of findings within the same nosologic entity with BD ii. Similar histopathology in BD iii. Overlapping radiologic features with BD 2. Atelosteogenesis II (AOII) a. Inheritance: autosomal recessive suggested by: i. Recurrence in the subsequent pregnancy ii. Parental consanguinity b. Synonymous with De la Chapelle dysplasia c. Phenotypic and radiographic overlap with AOI but with distinctive matrix histopathology with a major disturbance in cartilage matrix macromolecules d. Common pathogenetic features with disorders of sulfation of connective tissue matrix macromolecules. An overlap of phenotypic, radiographic, morphological, and cartilage histochemical features with the following conditions: i. Diastophic dysplasia ii. Achondrogenesis type IB e. Caused by mutated diastrophic dysplasia sulfate transporter (DTDST; SLC26A2) gene which also causes the following recessively inherited chondrodysplasias: i. Diastrophic dysplasia ii. Multiple epiphyseal dysplasia iii. Achondrogenesis IB f. The DTDST gene i. Encodes a sulfate transporter that also accepts chloride and possibly bicarbonate as substrates

CLINICAL FEATURES 1. AOI a. Stillborn or neonatal death due to respiratory distress b. Polyhydramnios c. Facial dysmorphism i. Depressed nasal bridge ii. Eyelid edema iii. Micrognathia iv. Cleft soft palate d. Small chest e. Protuberant abdomen f. Deficient ossification of various bones i. Humerus ii. Femur iii. Thoracic spine iv. Hand bones 96

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g. Rhizomelic micromelic dwarfism i. Short and broad hands ii. Incurved legs iii. Club feet iv. Often dislocation of the elbows h. Laryngeal hypoplasia: an important role in the respiratory failure and death 2. BD a. Distinct facial features i. Horizontal palpebral fissures ii. Broad nasal root iii. Hypoplastic nasal septum iv. Prominent philtrum v. Cleft palate b. Small chest c. Protuberant abdomen d. Marked rhizo/mesomelic shortening of limbs e. Well-developed hands (broad, paddle-shaped) and feet f. Bowed lower limbs g. Calcaneovalgus deformities 3. AOII a. Lethal in neonatal period i. Pulmonary hypoplasia ii. Tracheobronchomalacia iii. Laryngeal stenosis b. Deficient ossification of parts of the skeleton c. Facial dysmorphism i. Midface hypoplasia ii. Depressed nasal bridge iii. Epicanthal folds iv. Micrognathia v. Cleft palate d. Small chest e. Protuberant abdomen f. Extremities i. Severe rhizomelic limb shortening ii. Talipes iii. Abducted (hitch-hiked) thumbs and toes iv. Ulnar deviation of the fingers v. Gap between the first and second toes 4. AOIII a. Milder, usually nonlethal b. Limb anomalies i. Rhizomelic shortening ii. Clubfeet iii. Short broad thumbs and great toes c. Craniofacial abnormalities i. Ocular hypertelorism ii. A flat nasal bridge iii. Micrognathia iv. Cleft palate d. Small chest e. Protuberant abdomen f. Multiple dislocations of elbows, hips, and knees g. Respiratory and feeding difficulties secondary to laryngomalacia h. Apparent cause of death i. Respiratory complications ii. Cervical spine instability i. Long survival possible

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DIAGNOSTIC INVESTIGATIONS 1. AOI a. Radiography: overlapping radiological features with BD i. Humeri: absent/geometric (AOI), absent (AOI/BD), absent (BD) ii. Hand phalanges: presence of distal and absent middle (AOI), hypoplastic middle (AOI/BD), presence of distal and absent proximal/middle (BD) iii. Femora: pointed distally (AOI), geometric (AOI/BD), absent (BD) iv. Tibia: bowed (AOI), hypoplastic (AOI/BD), bowed/boomerang (BD) v. Fibula: absent (AOI), absent (AOI/BD), absent (BD) vi. Spine: coronal clefts in the lumbar vertebrae (AOI) and vertebrae, and uniform lack of ossification of the centra of the vertebral bodies (BD) vii. Pelvis: hypoplasia of the ischiopubis (AOI), lack of ossification of ischiopubis (BD), flared ilia with hypoplasia of the inferior one-third (AOI, BD), producing a key-hole shape viii. Foot: lack of ossification of the calcaneal centers (AOI, BD) ix. Ribs: 10–13 pairs (BD) b. Histopathology i. Uniformly abnormal ii. Lack of ossification iii. Nonhomogeneous cell distribution with hypocellular and acellular areas iv. Occasional multinucleated giant chondrocytes in the relatively acellular areas of resting cartilage (alternatively named “giant cell chondrodysplasia”) v. Disorganized growth plate in some cases vi. Similar histopathology in BD 2. BD a. Radiography i. Triangular, boomerang-shaped long bones, diagnostic of the syndrome ii. Missing some tubular bone ossification centers iii. Ossified fingers and toes from the periphery iv. Characteristic shaped pelvis v. Retarded ossification of the spine, especially cervical and thoracic spine vi. Coronal clefts in the lower thoracic and lumbar spine b. Histopathology i. Chondrocytes in the resting cartilage are irregularly reduced in number with focal acellularity. Multinucleated giant chondrocytes have been noted ii. The physeal growth zones are markedly retarded and disorganized 3. AOII a. Radiography i. Humeri: pointed distally and bifurcated ii. Hand phalanges: irregular size and shape, hitchhiker thumbs

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iii. iv. v. vi.

Femora: clubbed distally Tibia: bowed/hypoplastic Fibula: hypoplastic Spine: more completely formed vertebral centra but coronal clefts present in some cases, a Sshaped cervical spine with a kyphosis in lateral profile vii. Pelvis: flared ilia with horizontal acetabula and a spicule at the medial border of the acetabula b. Histopathology i. Irregularly distributed resting cartilage chondrocytes ii. Attenuation of cartilage matrix with concentric matrix condensation rings around degenerating chondrocytes iii. Shortened proliferative and hypertrophic zones iv. Histopathology of cartilage essentially similar to that of diastrophic dysplasia and achondrogenesis IB reflecting the paucity of sulfated proteoglycans in cartilage matrix c. Mutation analysis (mutation detection rate about 60%) and sequence analysis (mutation detection rate >90%) of DTDST gene: Mutations in the DTDST gene can be found in more than 90% of patients with radiologic and histologic features compatible with the diagnosis of AOII d. Carrier testing for AOII i. Carrier testing available to at-risk family members once the mutation of the DTDST gene has been identified in the proband ii. For the partner of a heterozygous individual. The partners can be screened for the four most common pathogenic alleles, R279W, IVS1+2T>C, delV340, and R178X. When these four alleles are excluded, the risk of carrying DTDST mutation is reduced from the general risk of 1 : 100 to about 1 : 300 4. AOIII a. Radiography i. Humeri: pointed distally ii. Hand phalanges: tombstone-shaped proximal phalanges, widened distal phalanges iii. Femora: pointed distally iv. Tibia: short v. Fibula: absent vi. Spine: coronal clefts in the lumbar vertebrae, severe thoracolumbar kyphosis with an S-shaped cervical spine in lateral profile vii. Pelvis: hypoplastic ischiopubis, banana-shaped pubic rami b. Histopathology: hypocellularity without clustering, acellular areas, or “giant cells”

GENETIC COUNSELING 1. Recurrence risk a. AOI i. Patient’s sib: low ii. Patient’s offspring: a lethal entity not surviving to reproduce

b. AOII i. Patient’s sib: 25% ii. Patient’s offspring: a lethal entity not surviving to reproduce c. AOIII i. Patient’s sib: low ii. Patient’s offspring: 50% 2. Prenatal diagnosis a. Fetal ultrasonography i. Short limbs (micromelia) ii. Abnormal facial profile (depressed nasal base, micrognathia, apparent hypertelorism) iii. Absence of ossification in the humerus, radius, ulna, and cervical and upper thoracic vertebral bodies iv. Coronal clefts in the ossified vertebral bodies v. Talipes equinovarus b. Fetal MRI using an ultrafast sequence i. Dysmorphic features ii. Pulmonary hypoplasia iii. A large cysterna magna c. Mutation analysis of DTDST gene for pregnancy at risk: possible for AOII 3. Management a. AOI and AOII: supportive measures for these two lethal conditions b. AOIII i. Ventilatory support and tracheostomy often necessary for respiratory distress due to laryngotracheomalacia ii. Treat recurrent respiratory tract infections iii. Cleft palate repair iv. Conductive hearing loss evaluation and management v. Orthopedic care for club feet and joint dislocations

REFERENCES Bejjani BA, Oberg KC, Wilkins I, et al.: Prenatal Ultrasonographic description and postnatal pathological findings in atelosteogenesis type 1. Am J Med Genet 79:392–395, 1998. Bonafe L, Ballhausen D, Superti-Furga A: Atelosteogenesis type 2. Gene Reviews, 2002. http://www.genetests.org Cai G, Nakayama M, Hiraki Y, et al.: Mutational analysis of the DTDST gene in a fetus with Atelosteogenesis type 1B. Am J Med Genet 78:58–60, 1998. Chervenak FA, Isaacson G, Rosenberg JC, et al.: Antenatal diagnosis of frontal cephalocele in a fetus with atelosteogenesis. J Ultrasound Med 5:111–113, 1986. Den Hollander NS, Stewart PA, Brandenburg H, et al.: Atelosteogenesis, type I. The Fetus 3:23–26, 1993. Fallon MJ, Hockey A, Hallam LA: Atelosteogenesis type III: A case report. Pediatr Radiol 24:47–49, 1994. Fryer AE, Carty H: A new lethal skeletal dysplasia or the severe end of the atelosteogenesis spectrum? Pediatr Radiol 26:678–679, 1996. Greally MT, Jewett T, Smith WL Jr, et al.: Lethal bone dysplasia in a fetus with manifestations of atelosteogenesis I and boomerang dysplasia. Am J Med Genet 47:1086–1091, 1993. Hastbacka J, Superti-Furga A, Wilcox WR, et al.: Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): Evidence for a phenotypic series involving three chondrodysplasias. Am J Med Genet 58:255–262, 1996. Herzberg AJ, Effmann EL, Bradford WD: Variant of atelosteogenesis? Report of a 20-week fetus. Am J Med Genet 29:883–890, 1988. Hunter AGW, Carpenter BF: Atelosteogenesis I and boomerang dysplasia: A question of nosology. Clin Genet 39:471–480, 1991.

ATELOSTEOGENESIS International Working Group on Constitutional Diseases of Bone: International nomenclature and classification of the osteochondrodysplasias. Am J Med Genet 79:376–382, 1998. Kozlowski K, Sillence D, Cortis-Jones R, Osborn R: Boomerang dysplasia. Br J Radiol 58:369–371, 1985. Krakow D, Robertson SP, King LM, et al.: Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formations and skeletogenesis. Nat Genet 36:405–410, 2004. Krakow D, Robertson SP, Sebald ET, et al.: Clustering of mutations in the actin-binding domain of filamin B leads to atelosteogenesis types I and III. American Society of Human Genetics Annual meeting. Abstract No.2416, 2004. Kuwashima S, Nishimura G, Kikushima H, et al.: Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year. Acta Paediatr Jpn 34:543–546, 1992. Macias-Gomez NM, Megarbane A, Leal-Ugarte E, et al.: Diastrophic dysplasia and atelosteogenesis type II as expression of compound heterozygosis: first report of a Mexican patient and genotype-phenotype correlation. Am J Med Genet 129A:190–192, 2004. Mansberg VJ, Mansberg G: Atelosteogenesis type 1. Australas Radiol 37:283–285, 1993. Maroteaux P, Spranger J, Stanescu V, et al.: Atelosteogenesis. Am J Med Genet 13:15–25, 1982. Newbury-Ecob R: Atelosteogenesis type 2. J Med Genet 35:49–53, 1998. Nishimura G, Horiuchi T, Kim OH, et al.: Atypical skeletal changes in otopalatodigital syndrome type II: phenotypic overlap among otopalatodigital syndrome type II, Boomerang dysplasia, atelosteogenesis type I and type III, and lethal male phenotype of Melnick-needles syndrome. Am J Med Genet 73:132–138, 1997. Nores JA, Rotmensch S, Romero R, et al.: Atelosteogenesis type II: sonographic and radiological correlation. Prenat Diagn 12:741–753, 1992. 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 36:330–332, 1999. Rimoin DL, Sillence DO, Lachman R, et al.: Giant cell chondrodysplasia: second case of a rare lethal newborn skeletal dysplasia. Am J Hum Genet 32:125A, 1980. Rossi A, Superti-Furga A: Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 novel mutations, mutations review, associated skeletal phenotypes, and diagnostic relevance. Hum Mutat 17(3):159–171, 2001. [Erratum in Hum Mutat 18:82, 2001.]

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Rossi A, van der Harten HJ, Beemer FA, et al.: Phenotypic and genotypic overlap between atelosteogenesis type 2 and diastrophic dysplasia. Hum Genet 98:657–661, 1996. Schrander-Stumpel C, Havenith M, Linden EV, et al.: De la Chapelle dysplasia (atelosteogenesis type II): case report and review of the literature [corrected]. Clin Dysmorphol 3:318–327, 1994. Schultz C, Langer LO, Laxova R, et al.: Atelosteogenesis type III: Long term survival, prenatal diagnosis, and evidence for dominant transmission. Am J Med Genet 83:28–42, 1999. Sillence DO, Rimoin DL, Lachman R, et al.: Giant cell chondrodysplasia. A new lethal newborn skeletal dysplasia. Proceedings of the 1978 Birth Defects Conference, 193A, 1978. Sillence DO, Lachman RS, Jenkins T, et al.: Spondylohumerofemoral hypoplasia (giant cell chondrodysplasia): a neonatally lethal short-limb skeletal dysplasia. Am J Med Genet 13:7–14, 1982. Sillence D, Kozlowski K, Rogers J, et al.: Atelosteogenesis: Evidence for heterogeneity. Pediatr Radiol 17:112–118, 1987. Sillence D, Worthington S, Dixon J, et al.: Atelosteogenesis syndromes: A review, with comments on their pathogenesis. Pediatr Radiol 27:388–396, 1997. Spranger JW, Brill PW, Poznanski A: Bone Dysplasias. An Atlas of Genetic Disorders of Skeletal Development. 2nd ed. Oxford: Oxford Univ Press, 2002. 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 36:183–195, 1990. Superti-Furga A, Bonafe L, Rimoin DL: Molecular-pathogenetic classification of genetic disorders of the skeleton. Am J Med Genet (Semin Med Genet) 106:282–293, 2001. Temple K, Hall CA, Chitty L, et al.: A case of atelosteogenesis. J Med Genet 27:194–197, 1990. Tenconi R, Kozlowski K, Largaiolli G: Boomerang dysplasia. Fortschr Röntgenstr 138:378–380, 1983. Ueno K, Tanaka M, Miyakishi K, et al.: Prenatal diagnosis of atelosteogenesis type I at 21 weeks’ gestation. Prenat Diagn 22:1071–1075, 2002. Whitley C, Burke B, Gnaroth G, et al.: De la Chapelle dysplasia. Am J Med Genet 25:29–39, 1986. Winship I, Cremin B, Beighton P: Boomerang dysplasia. Am J Med Genet 36:440–443, 1990. Yang SS, Roskamp J, Liu CT, et al.: Two lethal chondrodysplasias with giant chondrocytes. Am J Med Genet 15:615–625, 1983.

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Fig 1. A male infant with AOI/BD. Prenatal ultrasound showed polyhydramnios and a short limb dwarf. The infant died at 57 days. He showed relatively large head, hypertelorism, depressed nasal bridge, midfacial hypoplasia, micrognathia, cleft palate, short neck, relatively narrow chest, protuberant abdomen, severe “rhizomelic” micromelia, absent elbow joints, genu varus, and talipes equinovarus. Radiographic features included unossified vertebrae (T6–T9), single boomeranglike long bone (between acromion and wrist), short tapered femora, short bowed tibias, absent fibulas, calcified distal phalanges, nonossified carpals, metacarpals and proximal phalanges, and irregularly ossified tarsals and metatarsals. Histopathology of the cartilage showed disorganized physeal growth zones and irregular areas of hypocellularity in the resting cartilage. Multinucleated giant chondrocytes were not observed.

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Autism Autism is a pervasive developmental disorder, defined by impairments in social and communication function, and repetitive and stereotyped behavioral patterns. It occurs in approximately 7–40 out of 10,000 persons.

GENETICS/BASIC DEFECTS 1. Secondary autism (nongenetic and genetic conditions associated with autism): accounts for a small minority of individuals with autism (6 of the following areas: i. Qualitative impairment in social interaction, in at least two of the following areas: a) Marked impairment in the use of multiple nonverbal behaviors, such as eye-to-eye gaze, facial expression, body postures, and gestures, to regulate social interaction b) Failure to develop peer relationships appropriate to developmental level c) Lack of spontaneous seeking to share enjoyment, interests, or achievements with other people (e.g., by lack of showing, bringing, or pointing out objects of interest) d) Lack of social or emotional reciprocity ii. Qualitative impairment in communication, in at least one of the following areas: a) Delay in, or total lack of, the development of spoken language (not accompanied by an attempt to compensate through alternative modes of communication, such as gesture or mime) b) Marked impairment in the ability to initiate or sustain a conversation with others in individuals with adequate speech c) Stereotyped and repetitive use of language, or idiosyncratic language d) Lack of varied, spontaneous make-believe, or social imitative play appropriate to developmental level iii. Restrictive repetitive and stereotypic patterns of behavior, interests, and activities, in at least one of the following areas: a) Encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal either in intensity or focus b) Apparently inflexible adherence to specific nonfunctional routines or rituals c) Stereotyped and repetitive motor mannerisms (e.g., hand or finger flapping or twisting, or complex whole-body movements) d) Persistent preoccupation with parts of objects b. Delays or abnormal functioning with onset prior to 3 years of age, in at least one of the following areas: i. Social interaction ii. Language as used in social communication iii. Symbolic or imaginative play c. The disturbance is not better accounted for by Rett syndrome or childhood disintegrative disorder 8. Differential diagnosis with other pervasive developmental disorders a. Asperger disorder i. A variant of autism typically occurring in highfunctioning individuals without mental retardation, not considered as a separate disorder

AUTISM

ii. Language develops better than classic autism iii. Problems with the semantic and pragmatic use of language iv. Many individuals are misdiagnosed early on and in adulthood as odd or eccentric b. Rett syndrome i. A specific genetic disorder of postnatal brain development, caused by a single-gene defect predominantly affecting girls ii. Cause: de novo mutations or microdeletions of the methyl-CpG-binding protein 2 (MeCP2) gene on Xq28 in the majority of cases c. Childhood disintegrative disorder i. Behavioral, cognitive, and language regression between 2 and 10 years of age after entirely normal early development ii. Experience in at least two of the following areas: language, social skills, bowel or bladder control, and play or motor skills iii. Cognitive skills usually impaired significantly d. Pervasive developmental disorder, not otherwise specified i. Onset after 3 years of age ii. Individuals who have autistic features but do not fit any of the other subtypes iii. Presence of a wide range of cognitive and behavioral problems iv. In general, less severe social, communicative, and behavioral deficits

DIAGNOSTIC INVESTIGATIONS 1. Cytogenetic studies and molecular genetic analyses a. High-resolution or multi-FISH telomere chromosome studies i. Chromosomal abnormality involving the proximal long arm of chromosome 15 (15q11-q13) observed in more than 1% of autistic individuals. Duplication is usually maternally derived, with one or two extra copies of the area roughly corresponding to the typical Angelman syndrome/Prader Willi syndrome deletion region: a) Pseudodicentric 15 (inverted duplication 15) b) Atypical marker chromosomes ii. Other chromosome abnormality: cytogenetic abnormalities have been found on virtually every chromosome in individuals with autism b. Molecular genetic testing for fragile X syndrome: unlikely positive in the presence of high-functioning autism 2. Metabolic studies: positive in probably 40% of familial cases b) Mutations infrequent (q24.3). Am J Med Genet 57:610–614, 1995. Pagon RA, Graham JM Jr, Zonana J, et al.: Coloboma, congenital heart disease, and Choanal atresia with multiple anomalies: CHARGE association. J Pediatr 99:223–227, 1981.

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Russell-Eggitt JM, Blake KD, Taylor DSL, et al.: The eye in CHARGE association. Br J Ophthalmol 74:421–426, 1990. Sanlaville D, Romana SP, Lapierre JM, et al.: A CGH study of 27 patients with CHARGE association. Clin Genet 62:135–138, 2002. Siebert JR, Graham JM, MacDonald C: pathological features of the CHARGE association: support for involvement of the neural crest. Teratology 31:331–336, 1985. Tellier AL, Lyonnet S, Cormier-Daire V, et al.: Increased paternal age in CHARGE association. Clin Genet 50:548–550, 1996. Tellier AL, Theopile D, Bonner D, et al.: CHARGE association: report of 47 cases with genotypic analysis of chromosomes 7q36 and 22q11. Am J Hum Genet 59 (suppl):100A, 1996. Telllier AL, Cormier-Daire V, Abadie V, et al.: CHARGE association: report of 47 cases and review. Am J Med Genet 76:402–409, 1998. Tellier AL, Amiel J, Delezoide AL, et al.: Expression of the PAX2 gene in human embryos and exclusion in the CHARGE syndrome. Am J Med Genet 93:85–88, 2000. Thelin JW, Mitchell JA, Hefner MA: CHARGE syndrome: part II. Hearing loss. Int J Pediatr Otorhinolaryngol 12:145–163, 1986. Vissers LELM, van Ravenswaaij CMA, Admiraal R, et al.: Mutations in a novel member of the chromodomain gene family cause CHARGE syndrome. American Society of Human Genetics 54th Annual Meeting, Abstract #1, 2004. Warburg M: Ocular colobomata and multiple congenital anomalies: the CHARGE association. Ophthalmol Paediatr Genet 6:31–36, 1983. Wiener-Vacher SR, Amanou L, Denixe P, et al.: Vestibular function in children with the CHARGE association. Arch Otolaryngol Head Neck Surg 125:342–347, 1999.

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CHARGE ASSOCIATION

Fig. 1. A boy with typical CHARGE association at ages 11 (front view) and 15 (lateral view). The patient had bilateral colobomas, choanal atresias, growth and mental retardation, hypogonadism, and ear anomalies with hearing loss.

Cherubism In 1933, Jones first described familial occurrence of painless enlargement of the jaws in three siblings. Jones later in 1938 reported observations on the same family under the title “familial multilocular cystic disease of the jaws” and coined the term “cherubism” after the cherubs of Renaissance art for the full round cheeks and the upward cast of the eyes giving the children a peculiarly grotesque, cherubic appearance.

GENETICS/BASIC DEFECTS

6. 7.

1. Inheritance a. Autosomal dominant b. Familial in 80% of cases c. Males affected twice as often as females d. 80% overall penetrance i. 100% in males ii. 50–70% in females e. Variable expressivity 2. Cause a. Caused by mutations in the gene encoding c-Ablbinding protein SH3BP2 b. Gene for cherubism mapped to chromosome region 4p16.3

8.

9.

CLINICAL FEATURES 1. Variable size of the jaw lesions in cherubism a. Minor lesions of both jaws b. Massive involvement of both jaws 2. Natural history: a. Classically normal at birth b. Onset usually between 14 months and 5 years. However, the severe cases are evident at birth c. Progresses until puberty d. Usually progression stops after puberty e. Regression of the bone lesions (involution of the disease) without treatment in some cases f. Rapidly growing and extensively deforming lesions of the maxilla and the mandible including the coronoids and condyles in severely affected individuals 3. Characteristic ‘eyes raised to heaven’ cherubic appearance: an appearance of the cherubs portrayed in Renaissance art a. Fullness of the lower half of the face (cheeks and jaw) b. Retraction of the lower lids by the stretched skin over the cheeks pulling down the lower eyelids. Consequently, a thin line of sclera is exposed beneath the iris and the eyes appear to be raised heavenward in a manner reminiscent of a “the cherubs in Renaissance paintings” 4. Painless hard enlargement of the jaws 5. Exclusively affecting maxilla and mandible a. Mandible usually involved b. Involvement of the maxilla in 60% of cases

10.

11.

12. 13.

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c. Painless lesions d. Bilateral enlargement with loss of bone in the jaws and its replacement with large amount of fibrous tissue e. Dental effect by bone lesion i. Premature loss of deciduous teeth ii. Displacement of permanent dentition f. Swelling usually abates by the third decade, whereas radiographic changes commonly persist into the fourth decade Submandibular lymph node enlargement in 45% of cases Ocular manifestations a. Lower lid retraction b. Proptosis c. Diplopia d. Globe displacement e. Visual loss due to optic nerve atrophy f. Rare extension of lesion into the orbits Rare upper airway involvement a. Displaced tongue affecting speech, mastication, swallowing, and respiration b. Obstructive apnea Extremely rare extrafacial skeletal involvement a. Upper humerus b. Bilateral triquetral bones c. Anterior ribs d. Upper femoral necks Rare associated syndromes a. Noonan syndrome (Addante, 1996) b. Ramon syndrome i. Cherubism ii. Short stature iii. Mental retardation iv. Gingival fibromatosis v. Epilepsy c. Fragile X syndrome d. Craniosynostosis Functional impairment a. Mastication problems b. Speech difficulty c. Tooth alteration d. Loss of normal vision Psychological consequences Differential diagnosis a. Four main types of fibrous dysplasia i. Monostotic fibrous dysplasia: only one bone is affected ii. Polyostotic: multiple bones are affected iii. McCune-Albright syndrome a) Polyostotic form b) Accompanied by pigmentary lesions c) Endocrine dysfunction presenting as precocious puberty in females iv. Craniofacial form of fibrous dysplasia

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a) Only bones of the craniofacial complex are affected b) Onset in the second decade in majority of patients c) Generally unilateral lesions, tend to become static once skeletal maturity is reached d) Clinically difficult to differentiate from cherubism if the skeletal abnormalities are localized to the jaws e) Molecularly different from cherubism b. Infantile cortical hyperostosis i. Diagnosed in the first 6 months of life ii. Radiographically does not produce cystic areas iii. Characterized by thickening of the mandibular lower border iv. Does not have bilateral expression c. Osteitis fibrosa cystica secondary to hyperparathyroidism i. Increased serum alkaline phosphatase ii. Increased serum calcium iii. Decreased serum phosphorus iv. Increased urinary phosphorus d. Various tumors of the jaws

DIAGNOSTIC INVESTIGATIONS 1. Serum alkaline phosphatase levels may be elevated 2. Radiography a. Extensive involvement of the mandible and the maxilla b. Multilocular radiolucent areas in the mandible and maxilla with expansion of the bony cortex i. Often very extensive ii. With a few irregular bony septa iii. Multilocular rarefactions replaced by sclerosis with progressive calcification in the adult c. Absent and displaced teeth in the involved areas 3. CT scan a. Superior in making the diagnosis b. Determining the degree of severity 4. Histological changes in cherubism a. Replacement of the normal bony architecture with proliferating fibrous tissue containing numerous giant cells b. Mononuclear fibroblastic stroma i. Nonneoplastic fibrous lesions rich in multinucleated giant cells identified as osteoclasts ii. Irregular bone formation c. A peculiar perivascular cuffing of collagen: considered by some to be pathognomonic for the condition d. Histological resemblance to the following disorders: i. Giant cell tumor ii. Giant cell granulomas iii. Ossifying fibroma iv. Fibrous dysplasia of the jaw v. Paget disease of bone 5. Molecular genetic analysis: detection of a SH3BP2 gene mutation by sequencing of select exons or entire coding region is available clinically

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased unless a parent is affected b. Patient’s offspring: 50% 2. Prenatal diagnosis a. Ultrasonography: not possible since the lesion is postnatal in nature b. Molecular analysis possible on fetal DNA obtained by amniocentesis or CVS if the disease-causing mutation is identified in an affected family member 3. Management a. Observation i. Generally self-limiting lesions and subside with age ii. Surgical intervention required only in cases with esthetic or functional problems b. Tracheostomy to secure the airway for upper airway obstruction c. Teeth extraction from the sites of fibrous changes d. Curettage alone or in combination with surgical contouring: considered the treatment of choice e. Resection of the orbital lesions may be required to improve visual impairment f. Prompt recurrence likely if surgery is performed at an early age g. Radiation therapy ineffective and contraindicated in view of the following risks: i. Osteoradionecrosis ii. Interference with dentofacial growth and development iii. Affect on future surgical procedures h. Experimental use of calcitonin to treat cherubism described recently

REFERENCES Ayoub AF, El-Mofty SS: Cherubism: report of an aggressive case and review of the literature. J Oral Maxillofac Surg 51:702–705, 1993. Battaglia A, Merati A, Magit A: Cherubism and upper airway obstruction. Otolaryngol Head Neck Surg 122:573–574, 2000. Bianchi SD, Boccardi A, Mela F, et al.: The computed tomographic appearances of cherubism. Skeletal Radiol 16:6–10, 1987. Caballero Herrera R, Vinals Iglesias H: Cherubism: a study of three generations. Medicina Oral 3:163–171, 1998. Caffey J, Williams JL: Familial fibrous swelling of the jaws. Radiology 56: 1–5, 1951. Carroll AL, Sullivan TJ: Orbital involvement in cherubism. Clin Experiment Ophthalmol 29:38–40, 2001. Colombo F, Cursiefen C, Neukam FW, et al.: Orbital involvement in cherubism. Ophthalmology 108:1884–1888, 2001. Dunlap C, Neville B, Vickers RA, et al.: The Noonan syndrome/cherubism association. Oral Surg Oral Med Oral Pathol 67:698–705, 1989. Faircloth WJ, Edwards RC, Farhood VW: Cherubism involving a mother and daughter: case reports and review of the literature. J Oral Maxillofac Surg 49:535–542, 1991. Hart W, Schweitzer DH, Slootweg PJ, et al.: Een man met cherubisme. Ned Tijdschr Geneeskd 144:34–38, 2000. Hitomi G, Nishide N, Mitsui K: Cherubism: diagnostic imaging and review of the literature in Japan. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81:623–628, 1996.

CHERUBISM Imai Y, Kanno K, Moriya T, et al.: A missense mutation in the SH3BP2 gene on chromosome 4p16.3 found in a case of nonfamilial cherubism. Cleft Palate Craniofac J 40:632–638, 2003. Jones WA: Familial multilocular cystic disease of the jaws. Am J Cancer 17:946–950, 1933. Jones WA: Cherubism. Oral Surg 20:648–653, 1965. Jones WA: Further observations regarding familial multilocular cystic disease of the jaws. Br J Radiol 11:227–240, 1938. Jones WA, Gerrie J, Pritchard J (1950). Cherubism-familial fibrous displasia of the jaws. J Bone Joint Surg Br 32b:334–347, 1950. Katz JO, Dunlap CL, Ennis RLJ (1992). Cherubism: report of a case showing regression without treatment. J Oral Maxillofac Surg 50:301–303, 1992. Kaugars GE, Niamtu III J, Svirsky JA: Cherubism: diagnosis, treatment, and comparison with central giant cell granulomas and giant cell tumors. Oral Surg Oral Med Oral Pathol 73:369–374, 1992. Khosla VM, Korobkin M: Cherubism. Am J Dis Child 120:458–461, 1970. Kozakiewicz M, Perczynska-Partyka W, Kobos J: Cherubism-clinical picture and treatment. Oral Dis 7:123–130, 2001. Lo B, Faiyaz-Ul-Haque M, Kennedy S, et al.: Novel mutation in the gene encoding c-Abl-binding protein SH3BP2 causes cherubism. Am J Med Genet 121A:37–40, 2003. Mangion J, Rahman N, Edkins S, et al.: The gene for cherubism maps to chromosome 4p16.3. Am J Hum Genet 65:151–157, 1999.

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Mangion J, Edkins S, Goss AN, et al.: Familial craniofacial fibrous dysplasia: absence of linkage to GNAS1 and the gene for cherubism. J Med Genet 37:E37, 2000. Peters WJN: Cherubism: a study of twenty cases from one family. Oral Surg 47:307–311, 1979. Ramon Y, Engelberg IS: An unusually extensive case of cherubism. J Oral Maxillofac Surg 44:325–328, 1986. Silver EC, de Souza PEA, Barreto DC, et al.: An extreme case of cherubism. Br J Oral Maxillofac Surg 40:45–48, 2002. Southgate J, Sarma U, Townend JV, et al.: Study of the cell biology and biochemistry of cherubism. J Clin Pathol 51:831–837, 1998. Tiziani V, Reichenberger E, Buzzo CL, et al.: The gene for cherubism maps to chromosome 4p16. Am J Hum Genet 65:158–166, 1999. Ueki Y, Tiziani V, Santanna C, et al.: Mutations in the gene encoding c-Abl-binding protein SH3BP2 cause cherubism. Nature Genet 28:125–126, 2001. Wada S, Udagawa N, Nagata N, et al.: Calcitonin receptor down-regulation relates to calcitonin resistance in mature mouse osteoclast. Endocrinology 137:1042–1048, 1996. Zachariades N, Papanicolaou S, Xypolyta A, et al.: Cherubism. Int J Oral Surg 14:138–145, 1985. Zohar Y, Grausbord R, Shabtai F, et al.: Fibrous dysplasia and cherubism as an hereditary familial disease: follow-up of four generations. J Craniomaxillofac Surg 17:340–344, 1989.

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Fig. 1. A boy with cherubism showing full cheeks and jaw and the retraction of the lower eyelids with symmetrical augmentation on both mandibular angles.

Chiari Malformation In 1891, Chiari first described a dysplasia of the nervous system consisting of herniation of the cerebellar tonsils into foramen magnum. There are three types of Chiari malformation. The commonest ones are type I and type II, the latter has been named the Arnold-Chiari malformation. (De Reuck, 1976)

GENETICS/BASIC DEFECTS

c.

d.

1. Classification of Chiari malformations according to the severity a. Type I (the milder malformation) i. Ectopia of the cerebellar tonsils (caudal herniation of the cerebellar tonsils and inferior cerebellum through the foramen magnum) ii. Usually an isolated feature encountered in adults b. Type II (the more severe malformation) i. Downward displacement of the cerebellar medulla and fourth ventricle into the spinal canal ii. Almost always associated with meningomyelocele iii. May be associated with polygyria, cortical heterotopia, and dysgenesis of the corpus callosum c. Type III (the most severe malformation) i. Downward displacement of most of the cerebellum into a high cervical/low occipital encephalocele ii. Malformation consisting of anatomical anomalies typical of Chiari type II malformation with those of a high cervical/occipital encephalocele 2. Acquired Chiari I malformation caused by conditions leading to increased intracranial pressure a. Head injury b. Hydrocephalus c. Craniosynostosis 3. Brainstem dysfunction, sensory disturbance, and motor loss caused by impaction of the tonsils against the cervicomedullary structures

e.

f.

CLINICAL FEATURES 1. Patients with Chiari I malformation a. Asymptomatic in majority of patients b. General symptoms i. Headache ii. Fatigue iii. Memory loss iv. Pressure on the neck v. Back pain vi. Insomnia vii. Poor circulation viii. Nausea ix. Menstrual problems x. Sexual alterations xi. Hypothermia xii. Bronchial aspirations

g.

157

xiii. Respiratory alterations xiv. Drop attacks xv. Rare reports of sudden death Ocular symptoms i. Loss of vision ii. Intolerance of bright light iii. Diplopia Otolaryngologic symptoms i. Vestibular manifestations a) Imbalance b) Swaying c) Dizziness d) Positional vertigo e) Spontaneous vertigo f) Nystagmus g) Hearing loss h) Tinnitus ii. Alterations of cranial pairs a) Dysphagia b) Dysphonia c) Alterations in tongue mobility d) Loss of smell e) Facial hyposthesia iii. Sleep apnea Cerebellum compression symptoms i. Ataxia ii. Nystagmus iii. Gait difficulties iv. Opisthotonos v. Horner’s syndrome vi. Paralysis of the last cranial nerves vii. Hypotonia viii. Trembling ix. Dysarthria x. Dysmetria Associated CNS anomalies i. Stenosis of the aqueduct of Silvia ii. Meningomyelocele iii. Syringomyelia (cystic dilation of the spinal cord) Symptoms associated with syringomeyelia i. Known to accompany 50% to 70% of patients with Chiari I malformations ii. Obstructed cerebrospinal fluid at the site of cerebellar tonsillar herniation shows perivascular movement of CSF from the spinal subarachnoid space into the spinal cord with each Valsalva maneuver and cause syringomyelia iii. Tingling, hyposthesia, and burning sensation in the extremities iv. Thermalgesic anesthesia v. Alteration in muscular reflexes vi. Areflexia vii. Alteration of kinesthesia

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viii. Motor skill dysfunction ix. Headache or nonradicular pain in the shoulder, back, and limbs x. Headache usually suboccipital and upper cervical in location and is exacerbated by Valsalva maneuvers xi. Associated with the development of a painful, rapidly progressive, or left-curving scoliosis xii. Recent reports of spontaneous radiographic improvement of childhood Chiari malformations and syringomyelia 2. Chiari I malformation in children and adolescents a. Natural history of an asymptomatic Chiari I malformation in children i. Not well understood ii. Rarely reported to resolve spontaneously iii. Asymptomatic at the time of diagnosis in many children iv. Degree of tonsillar ectopia correlating well with the presence of neurologic signs and symptoms v. Rare reports of sudden death b. Group I (asymptomatic) i. Age at diagnosis: 3 months to 17 years ii. Associated conditions a) Hydrocephalus b) Craniofacial syndromes c) Epilepsy d) Occult spinal dysraphism c. Group II (brain stem compression) i. Age at diagnosis: 7 months to 26 years ii. Associated conditions a) Craniofacial syndromes b) Hydrocephalus c) Precocious puberty iii. Symptoms a) Neck pain b) Vertigo c) Headache d) Numbness e) Swallowing difficulties f) Apnea g) Opisthotonos h) Brachialgia i) Hyposthenia j) Spasticity k) Hemifacial pain d. Group III (presence of syringomyelia). Symptoms are: i. Numbness ii. Sensory loss iii. Neck pain iv. Vertigo v. Scoliosis vi. Hyposthenia vii. Headache viii. Muscle hypotrophy ix. Swallowing difficulties x. Limb pain 3. Patients with Chiari II malformation

a. Almost invariably associated with myelomeningocele (90%) b. Brain stem signs in 20% of patients with Chiari II malformation in children and adolescence i. Vertigo ii. Bioccipital headache iii. Cerebellar dysfunction iv. Progressive paresis of the arms 4. Patients with Chiari III malformation a. Rarest of the Chiari malformations b. Associated with a high cervical or occipital encephalocele c. Prognosis for nearly all reported patients i. Various degree of developmental delay ii. Epilepsy iii. Hypotonia iv. Spasticity v. Upper and/or lower motor neuron deficits vi. Lower cranial nerve dysfunction d. CNS anomalies usually observed in an occipital encephalocele i. A small cranial fossa ii. Caudal displacement of cerebellar tonsils and vermis iii. Medullary kinking iv. Tectal beaking v. Obvious hydrocephalus

DIAGNOSTIC INVESTIGATIONS 1. CT or MRI a. Chiari I malformation i. Incidental detection in asymptomatic individuals ii. Herniation of the tonsils >5 mm below the foramen magnum on MRI considered diagnostic b. Chiari II malformation i. Caudal cerebellum (100%) ii. Kinking of medulla on spinal cord (79%) iii. Elongation of brainstem and low medulla, stretched aqueduct and fourth ventricle (75%) iv. Beaking of quadrigeminal plate (60%) v. Large massa intermedia (55%) vi. Large fourth ventricle (25%) vii. Hydromyelia (15%) c. Chiari III malformation i. An occipitocervical meningoencephalo-cele protruding through a bony defect involving the lower occipital squama and/or the posterior arch of the first cervical vertebrae ii. A small posterior cranial fossa with low tentorial attachment iii. Scalloping of the clivus iv. Massive herniation of the hypoplastic cerebellar structures into the malformation v. Beaking of the tectal plate vi. Dysgenesis of the corpus callosum vii. Severe ventricular dilatation (hydrocephalus) 2. Brainstem auditory evoked potentials (BAEP)

CHIARI MALFORMATION

a. Consistently abnormal in symptomatic Chiari II malformation b. Showing a positive predictive value of 88% in predicting central neurologic sequelae in newborns and infants

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased b. Patient’s offspring: not increased 2. Prenatal diagnosis a. Prenatal ultrasonography i. Classic ‘lemon and banana’ signs, the gold standard in the early screening of Chiari II malformation ii. Clivus-supraocciput angle below 5th centile of nomogram in cases of Chiari II malformation b. Prenatal MRI: Chiari III malformation diagnosed during third trimester using single shot fast spin echo sequence to avoid motion artifact 3. Management a. Chiari I malformation i. Conservative treatment for asymptomatic patients ii. Main treatment consisting of decompressing the structures trapped in the foramen magnum a) Suboccipital craniectomy with or without dural patch grafting and cervical laminectomies: the most often used procedure b) Syringosubarachnoid shunt when indicated iii. Shunting of hydrocephalus iv. Major preexisting sensory or motor deficits: poor prognosticators for functional recovery b. Chiari II (Arnold-Chiari) malformation i. Seen most often in children with myelomeningocele ii. Shunting of hydrocephalus often resolves brainstem symptoms and surgical decompression may not be necessary iii. Surgical decompression of posterior fossa and upper cervical spine may be required if brainstem compression symptoms remain after shunting iv. Surgical intervention indicated to prevent further deterioration of the motor function and to diminish the progress of spasticity and scoliosis from tethered cord syndrome c. Chiari III malformation i. Primary closure of the malformation: usually the treatment of choice ii. CSF shunting of the associated hydrocephalus postponed to a later phase iii. Neonates often require intensive care treatment for the associated severe respiratory distress

159

REFERENCES Aribal ME, Gurcan F, Aslan B: Chiari III malformation: MRI. Neuroradiology 38:184–186, 1996. Bindal AK, Dunsker SB, Tew JM: Chiari I malformation: classification and management. Neurosurgery 37:1069–1074, 1995. Caldarelli M, Rea G, Cincu R, et al.: Chiari type III malformation. Childs Nerv Syst 18:207–210, 2002. Cama A, Tortori-Donati P, Piattelli GL, et al.: Chiari complex in children. Neuroradiological diagnosis, neurosurgical treatment and proposal of a new classification. Eur J Pediatr Surg 5 (Suppl):35–38, 1995. Castillo M, Quencer RM, Dominquez R: Chiari III malformation: imaging features. AJNR 13:107–113, 1992. D’Addario V, Pinto V, Del Bianco A, et al.: The clivus-supraocciput angle: a useful measurement to evaluate the shape and size of the fetal posterior fossa and to diagnose Chiari II malformation. Ultrasound Obstet Gynecol 18:146–149, 2001. Dauser RC, Dipietro MA, Venes JL: Symptomatic Chiari I malformation in childhood: a report of 7 cases. Pediatr Neurosci 14:184–190, 1988. De Barros MC, Farias W, Ataide L, et al.: Basilar impression and Arnold Chiari malformation. A study of 66 cases. J Neurol Neurosurg Psychiatry 31: 596–605, 1968. De Reuck J, Theinpont L: Fetal Chiari’s type III malformation. Child’s Brain 2:85–91, 1976. Dure LS, Percy AK, Cheek WR, et al.: Chiari type I malformation in children. J Pediatr 115:573–576, 1989. Dyste GN, Menezes AH, Van Gildrer JC: Symptomatic Chiari malformations. J Neurosurg 71:159–168, 1989. Elster AD, Chen MYM: Chiari I malformations: clinical and radiologic reappraisal. Radiology 183:347–353, 1992. Gálvez MJN, Rodrigo JJF, Liesa RF, et al.: Otorhinolaryngologic manifestations in Chiari malformation. Am J Otolaryngol 23:99–104, 2002. Gammal TE, Mark EK, Brooks BS: MR imaging of Chiari II malformation. AJNR Am J Neuroradiol 35:1037–1044, 1987. Genitori L, Peretta P, Nurisso C, et al.: Chiari type I anomalies in children and adolescents: minimally invasive management in a series of 53 cases. Childs Nerv Syst 16:707–718, 2000. Häberle J, H¸lskamp G, Harms E, et al.: Cervical encephalocele in a newborn—Chiari III malformation. Case report and review of the literature. Childs Nerv Syst 17:373–375, 2001. Koehler J, Schwarz M, Urban PP, et al.: Masseter reflex and blink reflex abnormalities in Chiari II malformation. Muscle Nerve 24:425–427, 2001. Lee R, Tai K, Cheng P, et al.: Chiari III Malformation: Antenatal MRI Diagnosis. Clin Radiol 57:759, 2002. Milhorat TH, Chou MW, Trinidad EM et al.: Chiari I malformation redefined: clinical and radiographic findings for 364 symptomatic patients. Neurosurgery 44:1005–1017, 1999. Mohr PD, Strang FA, Sambrook MA, et al.: The clinical and surgical features in 40 patients with primary cerebellar ectopia (adult Chiari malformation). Q J Med 46:85–96, 1977. Nagib MG: An approach to symptomatic children (ages 4–14 years) with Chiari type I malformation. Pediatr Neurosurg 21:31–35, 1994 Naidich TP: Cranial CT signs of the Chiari II malformation. J Neuroradiol 8:207–227, 1981. Naya Galvez MJ, Fraile Rodrigo JJ, Liesa RF, et al.: Otorhinolaryngologic manifestations in Chiari malformation. Am J Otolaryngol 23:99–104, 2002. Paul KS, Lye RH, Strang FA, et al.: Arnold-Chiari malformation. Review of 71 cases. J Neurosurg 58:183–187, 1983. Rauzzino M, Oakes WJ: Chiari II malformation and syringomyelia. Neurosurg Clin N Am 6:293–309, 1995. Ventureyra EC, Aziz HA, Vassilyadi M: The role of cine flow MRI in children with Chiari I malformation. Childs Nerv Syst 19:109–113, 2003. Weinberg JS, Freed DL, Sadock J, et al.: Headache and Chiari I malformation in the pediatric population. Pediatr Neurosurg 29:14–18, 1998.

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Fig. 1. Sagittal section of a neonate with a large ruptured lumbar meningomyelocele. Arnold-Chiari malformation is evident: the brain stem and lower portion of cerebellum herniate through the foramen magnum and overlap the cervical cord which is severely flattened. The brain shows hydrocephalus.

Fig. 3. A 28-year-old female with Chiari I malformation with normal phenotype but complaining headache, dizziness, and neck pain worsen by pregnancy.

Fig. 2. A patient with multiple congenital anomalies (mental retardation, flat facial plane, epicanthus inversus, blepharophimosis, cataracts, nystagmus, elbow flexion contractures, and vertical talus) with Chiari I malformation (MRI of the brain).

Chondrodysplasia Punctata Chondrodysplasia punctata refers to punctate calcifications, due to abnormal calcium deposition in the areas of enchondral bone formation, described in a variety of chondrodysplasias.

GENETICS/BASIC DEFECTS 1. Genetic heterogeneity of chondrodysplasia punctata a. Rhizomelic chondrodysplasia punctata type I (RCDP1) i. Autosomal recessive disorder ii. Caused by mutations in PEX7, mapped at 6q22-q24, which encodes the cytosolic peroxisomal targeting signal type 2 (PTS2)-receptor protein peroxin 7 iii. Genotype–phenotype correlations a) Classic RCDP1: all patients with homozygous for the L292X mutation b) Phenotype determined by the other allele if the patients are compound heterozygotes for L292X and another mutation c) A milder phenotype associated with several PEX7 alleles b. Rhizomelic chondrodysplasia punctata type 2 (RCDP2) i. Autosomal recessive disorder ii. Caused by mutations in the gene that encodes peroxisomal dihydroxyacetone phosphate acyltransferase (DHAPAT) c. Rhizomelic chondrodysplasia punctata type 3 (RCDP3) i. Autosomal recessive disorder ii. Caused by mutations in the gene (mapped at 2q31) that encodes peroxisomal alkyl-dihdroxyacetone phosphate synthase (ADHAPS) d. Relatively mild autosomal dominant ConradiHünermann syndrome i. Chondrodysplasia punctata, tibia-metacarpal type ii. Chondrodysplasia punctata, humero-metacarpal type e. X-linked dominant type only in females (ConradiHünermann-Happle syndrome) (CDPX2) i. Lethal in males ii. Caused by mutations of the 3β-hydroxysteroidΔ8-Δ7-isomerase (also called emopamil-binding protein, EBP) iii. The gene encoding EBP mapped to Xp11.22p11.23 iv. EBP: catalyzes an intermediate step in the conversion of lanosterol to cholesterol v. Presence of gonadal and somatic mosaicism in CDPX2 f. X-linked recessive type with a deletion of the short arm of the X chromosome (CDPX1) i. Caused by defects in arysulfatase E, a vitamin K-dependent enzyme 161

ii. The locus of the disease identified through the characterization of patients with chromosomal abnormalities involving the Xp22.3 region iii. The gene of CDPX1, named ARSE, encoding a new sulfatase (arylsulfatase E), showing a high sequence homology to steroid sulfatase iv. Point mutations of the ARSE gene detected in the DNA of karyotypically normal patients with chondrodysplasia punctata 2. Causes of stippled cartilaginous calcifications a. Peroxisomal disorders i. Zellweger syndrome a) A peroxisomal disorder b) An autosomal recessive inheritance c) Associated stippled calcifications of the epiphyses, particularly common in the patella d) Severe hypotonia e) Characteristic facies with a high forehead, hypertelorism, epicanthal folds, Brushfield spots, and shallow supraorbital ridges f) Club foot deformity g) The affected infants usually die early in infancy h) Involvement of other organ systems, especially the brain (migrational disorders) and kidneys (cortical cystic disease of the kidneys) ii. Rhizomelic chondrodysplasia punctata b. Genetic disorders i. Conradi-Hunermann chondrodysplasia punctata ii. X-linked dominant chondrodysplasia punctata iii. Smith-Lemli-Opitz syndrome iv. Greenberg dysplasia (cholesterol biosynthesis disorder) a) An autosomal recessive disorder b) Appears to be caused by an error of sterol metabolism at the level of 3β-hydroxysteroidΔ14 reductase c) Nonimmune hydrops fetalis d) Mid-face hypoplasia e) Micrognathia f) Rhizo-mesomelic dwarfism with relatively long and broad hands and feet g) Narrow thorax h) Protuberant abdomen i) Radiographic findings of grossly irregular and deficient ossification of the short tubular bones, fragmented ossification at the ends of the long tubular bones, small pelvic bones with irregular “moth-eaten” contours, platyspondyly with multiple ossification centers of the ver-

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v.

vi.

vii. viii.

ix. x. xi. xii. xiii. xiv. xv.

xvi. xvii. xviii. xix. xx.

xxi.

tebral bodies, and deficient ossification of the calvaria CHILD syndrome a) Congenital hemidysplasia b) Ichthyosiform erythroderma c) Limb defects (unilateral hypomelia with ipsilateral epiphyseal stippling) Dappled diaphyseal dysplasia (lethal shortlimbed dysplasia, type Carty) a) An autosomal recessive disorder b) All cases were stillborn or died in utero c) Fetal hydrops d) Polyhydramnios e) Short limbs with relatively long hands and feet f) Small thorax g) Protuberant abdomen h) Radiographic findings of fragmented appearance of the ribs, small islands of ossification from disruption of the facial bones, axial and appendicular skeleton (multifocal or dappled ossification of long bones), and absent ossification of the calvaria Acrodysostosis De Barsy syndrome a) Cutis laxa b) Corneal clouding c) Mental retardation d) Stippled epiphysis GM1 gangliosidosis Galactosialidosis Fibrochondrogenesis Mucolipidosis II De Lange syndrome X-linked ichthyosis Keutel syndrome a) Stippled epiphysis (knees, elbows) b) Brachytelephalangism c) Pulmonary stenosis Hypothyroidism Chromosome translocation Trisomy 21 and 18 Turner syndrome Brachytelephalangic chondrodysplasia punctata a) An X-linked recessive disorder b) Male infants affected with a very small nose, anteverted and grooved nares c) Benign type of chondrodysplasia punctata d) Also observed in a patient with Xp terminal deletion with ichthyosis and mental retardation e) Distal phalangeal hypoplasia: the most characteristic radiological sign of this form Chondrodysplasia punctata, metacarpal type a) Including tibial-metacarpal type and humeralmetacarpal type b) An autosomal dominant disorder c) Named for a specific long bone but with overlap in the long bone involved d) All have short metacarpals.

e) Affected children with a hypoplastic midface, a depressed nasal bridge, small mouth, micrognathia, short neck, and short limbs f) Radiographically, with short metacarpals associated with short tibias in the tibiametacarpal type and short humeri in humerometacarpal type xxii. Sheffield-type chondrodysplasia punctata a) Heterogeneous group of patients with punctate epiphyses, particularly in the calcaneus and spine b) A benign course c) Distal phalangeal hypoplasia d) Probably not a specific entity but rather a heterogeneous group of disorders that can be included in other entities xxiii. Pacman dysplasia a) A single case report with peculiar bone dysplasia, stippling in many areas, short bowed bones, and periosteal cloaking b) Osteoclasts with an unusual appearance reminiscent of the Pacman figures in computer games on bone histology c) The entire coccygeal and sacral regions replaced by stippling d) Dense stippling also observed in the thoracic region e) Considerable stippling also observed in the epiphyses of the proximal femur, talus, calcaneus, cuboid, and the bones of the hand f) Wide periosteal cloaking of many bones and poor ossification g) Bowed femora h) Superior inferior sagittal clefting in the AP views in the upper spine c. Vitamin K disorders i. Warfarin embryopathy a) Associated with maternal use of warfarin sodium b) Consistent features: saddle nose deformity, hypertelorism, frontal bossing, high-arched palate, short neck, and short stature c) Other features: rhizomelia, micromelia, flexion contractures, optic atrophy, psychomotor retardation, cataracts, congenital heart disease, and renal anomalies ii. Vitamin K epoxide reductase deficiency d. Acquired in utero i. Fetal alcohol syndrome ii. Phenacetin intoxication iii. Fetal hydantoin syndrome iv. Femoral hypoplasia unusual facies syndrome v. Maternal diabetes vi. Maternal systemic lupus erythematosis vii. Febrile illness e. Other conditions involving unusual calcification that may be confused with puncta i. Amelia and other absence deficiency ii. Cerebrocostomandibular syndrome

CHONDRODYSPLASIA PUNCTATA

iii. Dysplasia epiphysealis hemimelica iv. Calcifying arthritis v. Metachondromatosis

CLINICAL FEATURES 1. Recessive rhizomelic form a. Classic RCDP1 i. Skeletal abnormalities a) Severe symmetric shortening of the proximal limb segments (more severe in humeri than femora) b) Stippled (punctate) epiphyses involving knees, hips, elbows, shoulders, hyoid bone, larynx, sternum, and ribs ii. Peripheral calcifications iii. Facial dysmorphism a) Frontal bossing b) A short, saddle nose iv. Ocular features a) Cataracts: the most common ocular defect developing in virtually all patients: usually present at birth or appear in the first few months of life and are progressive b) Optic atrophy c) Posterior embryotoxon d) Strabismus e) Adhesions between iris and cornea in the ring of Schwabe v. Severe failure to thrive with profound postnatal growth deficiency vi. Gross developmental retardation vii. Contractures and stiff, painful joints, causing irritability in infancy viii. Other complications a) Seizures b) Recurrent respiratory tract infections caused by neurological compromise, aspiration, immobility, and a small chest with restricted expansion c) Spastic quadriplegia d) Ichthyotic skin changes e) Cleft soft palate f) Cervical spine stenosis g) Congenital heart disease h) Ureteropelvic junction obstruction ix. A high mortality a) About 60% survive the first year b) About 39% survive the second year c) Only a few survive beyond age ten years b. Mild RCDP1 i. Only a few patients reported ii. Consistent features a) Chondrodysplasia b) Cataracts iii. Variable expression a) Punctate calcifications b) Rhizomelia c) Mental and growth deficiency 2. X-linked dominant form (CDPX2)

163

a. Phenotype i. Usually a mild form of the disease identified in adult females ii. May be a stillborn iii. Occurring almost only in females iv. Presumably lethal in males, although a few affected males have been reported b. Lyonization (skewed X-chromosome inactivation) in females resulting in phenotypic variability and asymmetric findings c. Showing increased disease expression in successive generations (anticipation): another striking clinical feature of CDPX2 that may be associated with skewed methylation d. Skin lesions i. The hallmark of the X-linked dominant form ii. Congenital ichthyosiform erythroderma, distributed in a linear or blotchy pattern iii. Systematized atrophoderma mainly involving the fair follicles iv. Circumscribed alopecia v. Sparse eyebrows and lashes vi. Nails: flattened and split into layers e. Epiphyseal calcification in the first year of life f. Limb shortening i. Rhizomesomelic ii. Usually asymmetric iii. Severely affected infants with bilateral findings resembling those of RDCP1 g. Other later signs i. Palmoplantar keratosis ii. Follicular atrophoderma iii. Segmental cataracts iv. Tooth and bone abnormalities 3. X-linked recessive chondrodysplasia punctata, brachytelephalangic type (CDPX1) a. Clinical reports available so far are mainly those of patients who are nullisomic for Xp22.3 in which chondrodysplasia punctata is part of a complex phenotype due to a “contiguous gene syndrome” b. Wide spectrum of manifestations, ranging from aborted fetus, neonatal death, midfacial hypoplasia, and brachytelephalangy c. Facial anomalies with severe nasal hypoplasia d. Short stature e. Cardinal manifestations i. Epiphyseal stippling ii. Hypoplasia of the distal phalanges f. Abnormalities of proximal and middle phalanges after healing of the punctate calcifications: typical diagnostic signs g. Without limb shortening or cataracts h. Presence of ichthyosis attributed to the involvement of the STS gene in the patients with Xp deletion i. Mild ichthyosis that improves with age: may be part of the CDPX phenotype 4. Chondrodysplasia punctata, tibia-metacarpal type a. Symmetrical rhizomelic shortness of the upper limbs b. Punctate epiphyseal calcifications noted at birth

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c. d. e. f.

Abnormal face (flattened mid-face and nose) Short hands Normal height Normal mentation

DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Classic RCDP1 i. Bilateral shortening of the humerus and to a lesser degree the femur ii. Punctate calcifications in the epiphyseal cartilage at the knee, hip, elbow, shoulder, hyoid bone, larynx, sternum, and ribs iii. Radiolucent coronal clefts of the vertebral bodies that represent unossified cartilage iv. Abnormal epiphyses and flared and irregular metaphyses secondary to resolved punctate calcification after age one to three years b. Tibia-metacarpal type i. Shortened and bowed tibia and radii ii. Overgrowth of the fibulae iii. Ulnar hypoplasia iv. Calcific stippling of the proximal bones v. Punctate calcifications of the trachea, thyroid cartilage, entire spine, and sacrum vi. Clefting (coronal and/or sagittal) of the vertebral bodies vii. Symmetrical brachymetacarpy: shortened 2nd, 3rd, and 4th metacarpals viii. Shortened radial head ix. Patella dislocation 2. Biochemical/molecular studies a. RCDP1 i. Deficiency of red blood cell plasmalogens ii. Increased plasma concentration of phytanic acid iii. Deficiencies in plasmalogen biosynthesis and phytanic acid hydroxylation in cultured skin fibroblasts iv. PEX7 receptor defect in RCDP1 predicted by the following: a) Deficiency of plasmalogens in red blood cells b) Increased plasma concentration of phytanic acid c) Normal plasma concentration of very long chain fatty acids v. Molecular genetic analysis: PEX7 gene mutation analysis and sequencing b. RCDP2 i. Deficiency of the peroxisomal enzyme dihydroxyacetone phosphate acyltransferase (DHAPRT) in cultured skin fibroblasts ii. DHAPRT gene mutation analysis by sequencing of coding regions c. RCDP3 i. Deficiency of the peroxisomal enzyme, akkyldihydroxyacetone phosphate synthase (ADHAPS) in cultured skin fibroblasts ii. ADHAPS gene mutation analysis d. X-linked dominant form (CDPX2)

i. Diagnosis confirmed by measuring the plasma concentration of sterols which show accumulation of precursors, 8(9)-cholesterol and 8-dehydrocholesterol ii. Identify molecular defect in human EBP in CDPX2 patients e. X-linked recessive form (CDPX1): ARSE gene mutation analysis

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Autosomal recessive RCDP1: 25% ii. Autosomal dominant form: not increased unless one of the parents is affected iii. X-linked recessive form: 50% of brothers affected when the mother is a carrier iv. X-linked dominant form a) 50% of sisters and brothers (lethal) affected when the mother is a carrier b) Possibility of an apparently normal mother being a carrier to be considered when examining seemingly sporadic cases b. Patient’s offspring i. Autosomal recessive RCDP1: do not reproduce ii. Autosomal dominant form: 50% iii. X-linked recessive form: 50% risk of daughters to be carriers; none of sons will be affected iv. X-linked dominant form: affected mother: 50% of sons affected (lethal in male); 50% of daughters affected 2. Prenatal diagnosis a. Radiography i. Stippling of the bones of the extremities and pelvis ii. Abnormalities of the vertebral bodies b. Ultrasonography i. Rhizomelic form a) Severe rhizomelic limb shortening b) Punctuate epiphyseal calcifications c) Associated sonographic findings: profound hypoplasia of the humeri, metaphyseal flaring, a flattened midface, joint contracture, clubfoot deformity, and hydramnios ii. Nonrhizomelic form a) Asymmetric, variable limb shortening without a clear pattern of rhizomelia or mesomelia b) Calcifications in the long bone epiphyses, which may be recognizable in the second trimester or may not be recognizable even in the third trimester c) Other sonographic findings: spinal deformities, frontal bossing, a depressed nasal bridge, ascites, and polyhydramnios iii. X-linked dominant form a) Growth retardation b) Skeletal asymmetry c) Polyhydramnios

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c. Assays of plasmalogen biosynthesis in cultured chorionic villi or amniocytes for pregnancies at 25% risk for RCDP1 d. Enzyme activity of alkyl-dihydroxyacetone phosphate synthase (ADHAPS) and subcellular localization of peroxisomal thiolase performed on uncultured chorionic villi e. Molecular prenatal diagnosis in X-linked dominant chondrodysplasia punctata to identify disease-causing EBP mutation in the fetus 3. Management a. Mainly supportive b. G-tube placement for poor feeding and recurrent aspiration c. Cataract extraction to preserve vision d. Orthopedic procedures to correct contractures to improve function e. X-linked dominant form i. Emollients for ichthyosis ii. Splinting for clubbed feet iii. Surgery for polydactyly iv. Ophthalmological care for cataracts

REFERENCES Argo KM, Toriello HV, Jelsema RD, et al.: Prenatal findings in chondrodysplasia punctata, tibia-metacarpal type. Ultrasound Obstet Gynecol 8:350–354, 1996. Aughton DJ, Kelley RI, Metzenberg A, et al.: X-linked dominant chondrodysplasia punctata (CDPX2) caused by single gene mosaicism in a male. Am J Med Genet 116A:255–260, 2003. Barr DG, Kirk JM, al Howasi M, et al.: Rhizomelic chondrodysplasia punctata with isolated DHAP-AT deficiency. Arch Dis Child 68:415–417, 1993. Becker K, Csikós M, Horv·th A, et al.: Identification of a novel mutation in 3βhydroxysteroid-Δ8-Δ7-isomerase in a case of Conradi-HünermannHapple syndrome. Exp Dermatol 10:286–289, 2001. Borochowitz Z: Generalized chondrodysplasia punctata with shortness of humeri and brachymetacarpy: humero-metacarpal (HM) type: variation or heterogeneity? Am J Med Genet 41:417–422, 1991. Braverman N, Steel G, Obie C, et al.: Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata. Nat Genet 15:369–376, 1997. Braverman N, Lin P, Moebius FF, et al.: Mutations in the gene encoding 3βhydroxysteroid-Δ8-Δ7-isomerase cause X-linked dominant ConradiHünermann syndrome. Nature Genet 22:291–294, 1999. Braverman NE, Moser AB, Steinberg SJ: Rhizomelic chondrodysplasia punctata type I. Gene Reviews. 2004. http://www.genetests.org 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 20:284–297, 2002. Brites P, Motley A, Hogenhout E, et al.: Molecular basis of rhizomelic chondrodysplasia punctata type I: high frequency of the Leu-292 stop mutation in 38 patients. J Inherit Metab Dis 21:306–308, 1998. Brookhyser KM, Lipson MH, Moser AB, et al.: Prenatal diagnosis of rhizomelic chondrodysplasia punctata due to isolated alkyldihydroacetonephosphate acyltransferase synthase deficiency. Prenat Diagn 19:383–385, 1999.

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Brunetti-Pierri N, Andreucci MV, Tuzzi R, et al.: X-linked recessive chondrodysplasia punctata: spectrum of arylsulfatase E gene mutations and expanded clinical variability. Am J Med Genet 117A:164–168, 2003. Carty H: Dappled diaphyseal dysplasias. Rofo 150:228–229, 1989. Collins P, Olufs R, Karvitz H, et al.: Relationship of maternal warfarin therapy in pregnancy to chondrodysplasia punctata: report of a case. Am J Obstet Gynecol 127:444–446, 1977. Derry JMJ, Gormally E, Means GD, et al.: Mutations in a Δ8-Δ7 sterol isomerase in the tattered mouse and X-linked dominant chondrodysplasia punctata. Nature Genet 22:286–290, 1999. DiPreta EA, Smith KJ, Skelton H: Cholesterol metabolism defect associated with Conradi-Hunerman-Happle syndrome. Int J Dermatol 39:846–858, 2000. Happle R: X-linked dominant chondrodysplasia punctata. Review of literature and report of a case. Hum Genet 53:65–73, 1979. Happle R: Cataracts as a marker of genetic heterogeneity in chondrodysplasia punctata. Clin Genet 19:64–66, 1981. Has C, Bruckner-Tuderman L, Müller D, et al.: The Conradi-H¸nermannHapple syndrome (CDPX2) and emopamil binding protein: novel mutations, and somatic and gonadal mosaicism. Hum Mol Genet 9:1951–1955, 2000. Herman GE, Kelley RI, Pureza V, et al.: Characterization of mutations in 22 females with X-linked dominant chondrodysplasia punctata (Happle syndrome). Genet Med 4:434–438, 2002. Ikegawa S, Ohashi H, Ogata T, et al.: Novel and recurrent EBP mutations in Xlinked dominant chondrodysplasia punctata. Am J Med Genet 94: 300–305, 2000. Kelley RI, Wilcox WG, Smith M, et al.: Abnormal sterol metabolism in patients with Conradi-Hunermann-Happle syndrome and sporadic lethal chondrodysplasia punctata. Am J Med Genet 83:213–219, 1999. Kozlowski K, Bates EH, Young LW, et al.: Radiological case of the month. Dominant X-linked chondrodysplasia punctata. Am J Dis Child 142: 1233, 1988. Motley AM, Brites P, Gerez L, et al.: Mutational spectrum in the PEX7 gene and functional analysis of mutant alleles in 78 patients with rhizomelic chondrodysplasia punctata type 1. Am J Hum Genet 70:612–624, 2002. Parenti G, Buttitta P, Meroni G, et al.: X-linked recessive chondrodysplasia punctata due to a new point mutation of the ARSE gene. Am J Med Genet 73:139–143, 1997. Pauli RM, Lian JB, Mosher DF, et al.: Association of congenital deficiency of multiple vitamin K-dependent coagulation factors and the phenotype of warfarin embryopathy: Clues to the mechanism of teratogenicity of Coumadin derivatives. Am J Hum Genet 41:566–583, 1987. Poznanski AK: Punctate epiphyses: a radiological sign not a disease. Pediatr Radiol 24:418–424, 1994. Pradhan GM, Chaubal NG, Chaubal JN, et al.: Second-trimester sonographic diagnosis of nonrhizomelic chondrodysplasia punctata. J Ultrasound Med 21:345–349, 2002. Shirahama S, Miyahara A, Kitoh H, et al.: Skewed X-chromosome inactivation) causes intra-familial phenotypic variation of an EBP mutation in a family with X-linked dominant chondrodysplasia punctata. Hum Genet 112:78–83, 2003. Spranger JW, Brill PW, Poznanski A: Bone Dysplasias. An Atlas of Genetic Disorders of Skeletal Development. 2nd ed. Oxford: Oxford University Press.2002. pp 57–79. White AL, Modaff P, Holland-Morris F, et al.: Natural history of rhizomelic chondrodysplasia punctata. Am J Med Genet 118A:332–342, 2003. Whittock NV, Izatt L, Simpson-Dent SL, et al.: Molecular prenatal diagnosis in a case of an X-linked dominant chondrodysplasia punctata. Prenat Diagn 23:701–704, 2003.

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Fig. 2. FISH (patient 1) with a SHOX (short stature homeobox containing gene) probe for Xp22.3 (a pink signal) and Yp11.3 (a pink signal) showing a deleted pink Xp22.3 signal. The pink signal in the X chromosome is an X peri-centromere probe (SXZ1) and the green signal is a Yq12 probe (DXZ1).

Fig. 1. Patient 1 (a Japanese newborn boy) with X-linked recessive form of chondrodysplasia punctata. Radiographs show paravertebral and calcaneus punctate calcification.

Fig 3. The mother of patient 1 is a carrier of del(X)(p22.3p22.3) (SHOX-). Her FISH showed that a red signal (a probe for Xp22.3; SHOX gene) is deleted in one of her X chromosome.

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Fig. 5. Radiograph of another neonate with rhizomelic form of chondrodysplasia punctata, showing similar radiographic features.

Fig. 4. A neonate with rhizomelic form of chondrodysplasia punctata, showing short humeri and punctate calcifications in the shoulder and/or elbow joints illustrated by radiograph. Fig. 6. Another neonate with chondrodysplasia punctata showing depressed nasal bridge and under-developed nasal cartilage. The infant has punctate calcifications in the proximal femoral heads.

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Fig. 7. Radiographs of a child with an autosomal dominant chondrodysplasia punctata showing punctate calcifications in the knees.

Chromosome Abnormalities in Pediatric Solid Tumors Consistent chromosome abnormalities have been described in many pediatric solid tumors. These findings led to direct molecular investigation and a better understanding of tumor pathogenesis. Clinical correlation often produced useful prognostic information.

GENETICS/BASIC DEFECTS 1. Somatic mutation theory of cancer a. Resulting from the accumulation of specific genetic changes b. Several lines of evidence i. Monoclonal origin of most tumors, suggesting that they derive from a single progenitor cell ii. Several tumors occurring not only sporadically but also as familial hereditary traits iii. Mutagenic nature of most carcinogenic agents, at least in experimental systems iv. Acquired genetic changes in the tumor cells, many of which are detectable at the chromosome level and several of these mutations have been shown to be tumorigenic in experimental animals 2. Chromosome abnormalities in neoplastic cells a. Technical improvement in basic cytogenetic techniques i. Use of colchicine to arrest dividing cells in metaphase and hypotonic solutions to improve spreading of the chromosomes a) Description of the correct chromosome number in humans b) The first specifically neoplasia-associated chromosome aberration: the Ph1 chromosome in chronic myeloid leukemia ii. Introduction of chromosome banding techniques a) Possible to identify individual chromosome pairs b) To detect and characterize even subtle rearrangements b. Clonal chromosome aberrations in neoplasms i. Primary aberrations a) Nonrandomly associated with particular tumor types b) Sometimes observed as the sole karyotypic deviation c) Thought to constitute early and essential events in carcinogenesis d) Increased genomic instability thought to be one of the consequences of the acquisition of a primary cancer chromosome rearrangement e) Many primary aberrations affect cellular oncogenes, often fusing them with other genes to encode hybrid proteins or disrupting the normal control sequences of the oncogene, causing its inappropriate expression 169

ii. Secondary aberrations a) Occurrence of new abnormalities facilitated by primary aberrations b) Nonrandom c) Distribution of the secondary aberrations dependent on both the primary abnormality and the tumor type in which they occur iii. Cytogenetic noise a) Resulting from acquired instability b) Random changes with little or no selective value 3. Mechanisms by which chromosomal aberrations arise a. Aberrations that lead to aneuploidy i. Polyploidy ii. Aneuploidy iii. Reciprocal translocation iv. Nonreciprocal translocation v. Amplification (double minutes) vi. Amplification (HSR) vii. Amplification (distributed insertions) b. Aberrations that leave the chromosome apparently intact i. Loss of heterozygosity (LOH) (somatic recombination) ii. Loss of heterozygosity (duplication/loss) 4. Identification of specific chromosome rearrangements in neoplasms a. Leukemia and lymphoma i. Crucial for more detailed studies utilizing molecular genetic techniques ii. Possible to compare cytogenetic findings with morphologic, immunologic, and clinical parameters such as the response to therapy and survival iii. Diagnostic and prognostic implications of karyotyping b. Solid tumors i. In general, more complex karyotypes observed in solid tumors ii. Have distinct patterns of primary and secondary aberrations closely associated with histopathologic entities iii. Identification of only a few genes as a consequence of recurrent structural rearrangements iv. Fusion of transcription factor gene with other loci, a common feature v. Tumor suppressor genes a) Important in solid tumors b) Thought to encode inhibitors of unrestrained growth c) Behave in a recessive manner at the cellular level (i.e., loss or structural disruption of both wild-type alleles is required to unleash a neoplastic phenotype)

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5. Retinoblastoma (RB) a. A prototype tumor for understanding basic concepts in cancer genetics b. Genetics of retinoblastoma i. Thought to be a single gene disorder caused by mutation of the RB1 gene ii. Sporadic, nonhereditary form in most cases a) Unilateral or unifocal retinoblastoma b) A mutation in the RB1 locus occurred later in embryogenesis iii. Hereditary form (1/3rd of tumors) a) Bilateral or multifocal retinoblastoma b) Predisposition inherited as an autosomal dominant trait c) Mutations inherited from a carrier parent in 25% of the cases d) A new mutation occurring very early in embryogenesis in 75% of cases e) Overall estimates of the penetrance of the trait: 85–95% c. Retinoblastoma gene, RB1 i. The first cancer-predisposition gene to be cloned ii. Chromosome map: 13q14 iii. More than 100 different mutations reported to date a) Missense mutations b) Nonsense mutations c) Splice-site mutations d) Small and large deletions d. Knudson’s “two-hit hypothesis” of tumorigenesis i. In the unaffected individual, both RB1 genes are intact and serve as guardians of the retina ii. Retinoblastoma develops as a result of two separate mutations iii. Sporadic tumors: two separate mutations occurring somatically in the same retinal cell iv. Heritable retinoblastoma: The first mutation is germinal and the second somatic e. Inherited form of retinoblastoma i. Critical gene for retinoblastoma located in band 13q14, suggested by cytogenetic analyses of tumor cells and lymphocytes ii. Homozygous loss of DNA markers from 13q14 in tumor cells from individuals with familial retinoblastoma vs heterozygous loss of these DNA markers in normal cells, suggested by molecular genetic investigations 6. Neuroblastoma (NB) a. A malignant tumor derived from undifferentiated neural crest cells that are committed to differentiate into the sympathetic nervous system b. Inheritance i. Sporadic in most cases ii. A few clustered familial cases reported indicating an autosomal dominant inheritance with incomplete penetrance c. Molecular biology i. The amplification (i.e., increased number of DNA copies) of the oncogene MYCN (N-myc) and changes in the normal diploid chromosomal content

a) Both are correlated with disease prognosis and disease recurrence b) The amplification can be in the form of the double minute chromosomes, which are extragenomic segments of DNA, or in homogeneously staining chromosomal regions ii. Variable DNA content of neuroblastoma a) Near-triploid DNA index regardless of any clinical or biologic features predicts a smaller risk of progression to higher-stage diseases b) Diploid/tetraploid index tends to predict higher risk of progression or multiple relapses iii. Other molecular markers (receptors for nerve growth factors) associated with neuroblastoma a) Trk A: associated with favorable neuroblastomas b) Trk B: expressed in unfavorable neuroblastomas 7. Wilms tumor (WT) a. Biological pathways leading to the development of Wilms tumor i. Complex ii. Involvement of several genetic loci a) Two genes on chromosome 11p; one on chromosome 11p13 (the Wilms tumor suppressor gene, WT1) and the other on chromosome 11p15 (the putative Wilms tumor suppressor gene, WT2) b) Loci at 1p, 7p, 16q, 17p (the p53 tumor suppressor gene), and 19q (the putative familial Wilms tumor gene, FWT2) b. Inheritance i. Sporadic in majority of cases (>95%) ii. Familial predisposition to Wilms tumor is rare, affecting only1.5% of patients with Wilms tumor c. Association with specific genetic disorders or recognizable syndromes i. WAGR syndrome a) Large constitutional deletions of chromosome 11p13 b) Tumor suppressor gene: WT1 c) Mechanism of gene inactivation: hemizygous deletion d) Wilms tumor incidence: >30% e) Associated features: aniridia, genitourinary abnormalities f) Mental retardation g) Associated aniridia: caused by deletion of the PAX6 gene in the 11p13 region in close proximity to WT1 gene ii. Denys-Drash syndrome a) Chromosomal loss: 11p13 b) Tumor suppressor gene: WT1 c) Mechanism of gene inactivation: mutation (DNA binding domain) d) Wilms tumor incidence: >90% e) Associated features: pseudohermaphroditism, mesangeal sclerosis, renal failure

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iii. Beckwith-Weidemann syndrome a) Chromosomal loss: 11p15 b) Tumor suppressor gene: (WT2/BWS?) c) Mechanism of gene inactivation: unknown d) Wilms tumor incidence: 5% e) Associated features: organomegaly, hemihypertrophy, umbilical hernia, neonatal hypoglycemia, other tumors such as hepatoblastoma iv. Perlman syndrome a) Renal dysplasia b) Multiple congenital anomalies c) Gigantism d) Wilms’ tumor v. X-linked Simpson-Golabi-Behmel syndrome a) Overgrowth disorder b) Caused by mutations in the GPC3 gene located on Xq26 c) Overlapping physical features with BeckwithWiedemann syndrome d) Wilms’ tumor and other embryonal tumors 8. Primary tumors of the central nervous system a. Primitive neuroectodermal tumors (PNETs) i. Homozygous inactivation of the TP53 gene, a tumor-suppressor gene located in 17p, secondary to i(17p): implicated in the development of several tumor types ii. Molecular analyses indicating the existence of a second tumor-suppressor gene, distinct from and distal to the TP53 locus that might be pathogenetically involved in a subset of primitive neuroectodermal tumors b. Gliomas i. A tumor-suppressor gene in 22q implicated as an essential event in the genesis of a number of neurogenic neoplasms ii. A candidate for such a role: is NF2, thought to be mutated in neurofibromatosis type 2, a dominantly inherited disorder predisposing for gliomas, neurinomas, and meningiomas

CLINICAL FEATURES 1. Only retinoblastoma, neuroblastoma, and Wilms tumor will be discussed here 2. Retinoblastoma a. A rare malignant tumor arising from cells of the embryonal neural retina b. Develops only in infants and young children c. Unifocal retinoblastoma: presence of a single retinoblastoma d. Multifocal retinoblastoma: presence of more than one tumor i. Unilateral: occurrence of multiple RB tumors in one eye ii. Bilateral: occurrence of RB tumors in both eyes iii. “Trilateral” retinoblastoma: occurrence of bilateral retinoblastoma plus a pinealoma e. Presenting signs

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i. White papillary reflex (leukocoria): the most common presenting sign ii. Strabismus: the second most common presenting sign iii. Less common signs a) Poor vision b) Orbital swelling c) Unilateral mydriasis d) Heterochromia iridis e) Glaucoma f) Orbital cellulitis g) Uveitis h) Hyphema or vitreous hemorrhage i) Nystagmus f. Retinoma-associated eye lesions ranging from retinal scars to calcified phthisical eyes resulting from spontaneous regression of retinoblastoma (include benign retinal tumors called retinocytoma or retinoma) g. Patients with germline RB1 mutations: at an increased risk of developing tumors outside the eye i. Pinealomas ii. Osteosarcomas iii. Soft tissue sarcomas iv. Melanomas 3. Neuroblastoma a. The most frequently occurring solid tumor in children b. Responsible for 8–10% of all cancers in children and approximately 15% of all pediatric cancer deaths c. 40% of cases diagnosed in children under 1 year of age who have a very good prognosis d. 60% in older children and young adult who have a poor prognosis despite advanced medical and surgical management e. Amplification of MYCN gene found in neuroblastomas: i. A powerful prognostic indicator ii. Associated with: a) Advanced stages of disease b) Rapid tumor progression c) Poor outcome f. Clinical presentation i. Variable presentation a) Localized disease (1/3rd to 1/4th of cases) b) Metastatic disease (2/3rd to 3/4th of cases) c) Asymptomatic in small number of patients ii. Retroperitoneal and abdominal tumors (62–65%) a) A palpable mass b) Abdominal pain (34%) c) Weight loss (21%) d) Anorexia e) Vomiting f) Symptoms related to mass effect iii. Thoracic tumors (14%) a) Dysphagia b) Cough c) Respiratory distress iv. Pelvis (5%) and paraspinal tumors that compress the spinal cord

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a) Urinary dysfunction b) Constipation c) Fetal incontinence d) Lower extremity weakness v. Neck tumors a) Horner syndrome: present in patients with lesions in the cervical or upper thoracic sympathetic ganglia (1.7%) b) Airway distress vi. Liver metastasis a) Hepatomegaly b) Jaundice c) Abnormal liver function tests d) Abdominal pain vii. Bone metastases and bone marrow involvement a) Bone pain b) Palpable bony nodules c) Anemia d) Purpura viii. Fever (28%) ix. Lymph node metastases: palpable lymphadenopathy x. Retrobulbar and orbital metastases: periorbital ecchymoses xi. Severe diarrhea refractory to standard treatment due to production of vasoactive intestinal peptide by tumor cells (4%) xii. Acute cerebellar encephalopathy (2%) a) Cerebellar ataxia b) “Dancing eyes and dancing feet syndrome” (involuntary eye fluttering and muscle jerking) xiii. Symptoms related to high catecholamine levels (0.2%) a) Hypertension b) Palpitations c) Flushing d) Sweating e) Malaise f) Headache 4. Wilms’ tumor a. The most common kidney cancer in childhood b. Represents about 6% of all childhood cancers in the United States c. Clinical presentation i. Presence of an asymptomatic abdominal mass: the most common presentation a) Usually affects one kidney with multiple tumor foci in 8% of cases b) Bilateral in 6% of cases ii. Hypertension, gross hematuria, and fever observed in 5–30% of patients iii. Hypotension, anemia, and fever in a small number of patients who have hemorrhaged into their tumor iv. Rare respiratory symptoms related to the presence of lung metastases in patients with advancedstage disease d. Association with congenital malformations i. Found in 60% of the bilateral cases and 4% of the unilateral cases

ii. WAGR iii. Denys-Drash syndrome iv. Beckwith-Wiedemann syndrome v. Perlman syndrome vi. Beckwith-Wiedemann syndrome vii. X-linked Simpson-Golabi Behmel syndrome e. Likelihood of developing Wilms’ tumor in aniridia patients i. Aniridia patients without other anomalies: 1–2% ii. Aniridia patients with WAGR syndrome: 25–40%

DIAGNOSTIC INVESTIGATIONS 1. Cytogenetic and molecular genetic techniques used in analyzing tumor materials from patients a. Conventional and molecular cytogenetic techniques most commonly used i. Metaphase cytogenetics or karyotyping (G-, Q-, and R-bandings): a) Protein digestion and/or special dye generating banding pattern specific for each chromosome b) Identification of numerical and structural chromosomal anomalies ii. Fluorescence in situ hybridization (FISH) a) A small, labeled DNA fragment used as a probe to search for homologous target sequences in chromosome or chromatin DNA b) Identification of the presence, number of copies per cell, and localization of probe DNA c) Applicable to interphase cells iii. Comparative genomic hybridization (CGH) a) Comparative hybridization of differentially labeled total genomic tumor DNA and normal reference DNA to normal human metaphases used as templates b) Detection of variant DNA copy numbers at the chromosome level c) Applicable to fresh or preserved specimens iv. Multicolor karyotyping (M-FISH, SKY) a) Hybridization with 24 differentially labeled, chromosome-specific probes allowing the painting of every human chromosome in a distinct color b) Detection of rearrangements involving one or more chromosomes within individual metaphase spreads c) Accurate origin identification of all segments in complex rearrangements d) Clarification of marker chromosomes b. Other techniques i. Flow cytometry ii. Reverse transcriptase-polymerase chain reaction (RT-PCR) iii. Quantitative PCR iv. Southern blot analysis of gene rearrangements v. Loss of heterozygosity analysis (LOH) vi. Restriction landmark genome scanning vii. Representational difference analysis viii. cDNA gene expression microarrays

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ix. Proteomic methods a) Matrix Assisted Laser Desorption ionization Time of Flight (MALDI-TOF) b) Surface Enhanced Laser Desorption Ionization Time of Flight (SELDI-TOF) 2. Cytogenetic studies in retinoblastoma a. Cytogenetically visible changes of 13q14: infrequent in retinoblastoma b. Deletions or unbalanced translocations leading to loss of 13q14 band (10%) c. Monosomy 13 (10%) d. i(6p), mostly detected as a supernumerary isochromosome (1/3rd of cases) e. Gain of 1q material (1/3rd of cases) f. Cytogenetic aberrations in retinoblastoma i. Secondary to RB1 mutations ii. More related to tumor progression than to tumor establishment 3. Other studies for retinoblastoma a. Indirect ophthalmoscopy to examine the fundus of the eye to detect retinomas, preferably by a retinal specialist b. Imaging studies (CT, MRI, ultrasonography) to support the diagnosis and stage the tumor c. Histopathological examination to confirm the diagnosis d. Direct DNA testing of the RB1 gene in WBC DNA i. Identify a germline mutation in about 80% of individuals with a hereditary predisposition to retinoblastoma ii. Probability of detection of the RB1 gene mutation in an index case dependent on the following: a) Whether the tumor is unifocal or multifocal b) Whether the family history is positive or negative c) The sensitivity of the testing methodology 4. Cytogenetic studies in neuroblastoma a. Identification of multiple cytogenetic abnormalities in neuroblastoma i. Allelic losses on chromosomes 1p (particularly 1p36), 11q, 14q, 7q, 2q, 3p, and 19q ii. Allelic gains on chromosomes 17q, 18q, 1q, 7q, and 5q b. Hyodiploid, triploid or “near triploid”, or “neartetraploid” in modal chromosome number i. Majority (55%) with triploid or “near-triploid” (a chromosome number between 58–80) ii. Remainder with “near-diploid” (35 to 57 chromosomes) or “near-tetraploid” (81–103 chromosomes) c. Frequent partial 1p monosomy (70–80% of cases) with most commonly deleted region being between 1p32 and 1p36 d. Gain on the long arm of chromosome 17 (17q) i. Probably the most common genetic abnormality in neuroblastomas ii. Occurring in approximately 75% of primary tumors iii. Most often resulting from an unbalanced translocation of this region to other chromosomal sites, most frequently 1p or 11q iv. A powerful independent finding of adverse outcome

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e. Deletions of the long arms of chromosomes 11 (11q) and 14 (14q) i. Appears to be common in neuroblastomas ii. Both inversely related to MYCN amplification f. Frequent presence of extrachromosomal double minute chromatin bodies (DMs) or homogneously staining regions (HSRs) i. Cytogenetic evidence of gene amplification ii. Amplified region derived from the distal short arm of chromosome 2 (2p24) that contains the MYCN proto-oncogene 5. Other studies for neuroblastoma a. Imaging studies i. Chest radiography ii. Ultrasound iii. CT iv. MRI v. Radionucleotide bone scan b. Blood tests i. Elevated urinary and serum catecholamine metabolites a) Homovanillic acid (HVA) b) Vanillylmandelic acid (VMA) ii. Abnormal liver function tests 6. Cytogenetic studies in Wilms’ tumor a. A near-diploid chromosome count b. Triploid-tetraploid karyotypes in a few cases with tendency to have an anaplastic morphology c. Numerical aberrations i. Mainly involving gains of chromosomes a) Trisomy 12: particularly frequent b) Followed by trisomies 8, 6, 7, 13, 20, and 17 d. Structural rearrangements i. Involve all chromosomes except the Y chromosome ii. Recombinations of 11p (>20%) a) Vast majority of the breakpoints assigned to 11p13 and 11p15, indicating these loci are important in sporadic Wilms tumor b) Loss of heterozygosity studies indicating that alleles from 11p13 and 11p15 are often lost in Wilms’ tumor iii. Loss of the long arm of chromosome 16 occurring in about 20% of Wilms’ tumors: associated with poor prognosis independent of stage or tumor histology 7. Other studies in Wilms’ tumor a. Renal ultrasound to monitor Wilms’ tumor b. Abdominal CT scanning to determine the tumor’s origin, lymph node involvement, bilateral kidney involvement, and invasion into major vessels (e.g., inferior vena cava or liver metastases) c. Chest radiography to detect lung metastases d. Histopathological examination to confirm the diagnosis e. Further studies of certain patients with either Wilms tumor or associated anomalies i. Hemihypertrophy/Beckwith-Wiedemann syndrome: uniparental disomy studies to evaluate constitutional or somatic alterations of 11p15 ii. WAGR syndrome: molecular evaluation of the 11p13 region if chromosomal studies do not reveal a deletion

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a) Fluorescence in-situ hybridization (FISH) b) Pulsed-field electrophoresis iii. Denys-Drash syndrome: molecular evaluation of WT1 to determine whether the patient indeed carries a constitutional mutation. If the mutation is present, family members need to be screened iv. Aniridia a) Cytogenetic analysis and molecular evaluation of the WAGR region by FISH or pulsed field to rule out contiguous deletion of Pax6 and WT1 b) No further screening for Wilms tumor if Pax6 mutation is identified in isolated cases of aniridia 8. Cytogenetic studies of primary tumors of the central nervous system a. Primitive neuroectodermal tumors i. Near-diploid in most tumors ii. I(17q): the most consistent rearrangement b. Gliomas i. Mostly astrocytomas and ependymomas ii. No specific structural rearrangement found iii. Loss of 1p and gain of 1q found in a subset of tumors iv. Loss of chromosome 22 common in childhood gliomas v. Loss of material from chromosome 22, either numeric or structural aberrations, found recurrently in rhabdoid tumors, meningiomas, and neurinomas 9. Cytogenetic studies in hepatoblastoma a. Trisomy 2 or duplications of part of 2q: detected in half of the cases b. Trisomy 20 c. Duplication of 8q through either i(8q) formation or trisomy 8 10. Cytogenetic studies in sarcomas a. Ewing sarcoma/primitive neuroectodermal tumor i. Reciprocal translocation t(11;22)(q24;q12) a) Characteristic primary rearrangement b) Found in nearly 90% of the tumors c) Causing a fusion of the transcription factor gene FLI1 on chromosome 11 with EWS on chromosome 22 (FLI1-EWS, a fusion transcript). Only the chimeric gene expresses on the derivative chromosome 22 which contains a sequence encoding a DNA-binding domain from FLI1 ii. t(21;22)(q22;q12), ERG-EWS iii. t(7;22)(p22;q12), ETV1-EWS iv. t(17;22)(q12;q12), E1AF-EWS v. t(2;22)(q33;q12), FEV-EWS b. Additional chromosome changes i. Trisomy 8 ii. Der(16)t(1;16)(a10-q21;q10-13), leading to gain of 1q and loss of 16q c. Congenital or infantile fibrosarcoma i. t(12;15)(p13;q25), ETV6-NTRK3 ii. Hyperdiploid with few or no structural rearrangements

iii. Nonrandom numerical changes a) Trisomies 11 and 20, the most frequent changes, followed by: b) Trisomies 17 and 8 d. Osteosarcomas i. Highly complex karyotypes in the majority of cases ii. Chromosome number in the triploid-tetraploid range iii. Most common numeric aberrations involving −3, −10, −13, and −15 iv. Structural rearrangements involving chromosome arms 1p, 1q, 3p, 3q, 7q, 11p, 17p, and 22q v. Presence of many undefined chromosome markers e. Rhabdomyosarcoma i. The most common soft tissue sarcoma in childhood ii. Alveolar subtype a) t(2;13)(q35-37;q14), shown to juxtapose the PAX3 gene on chromosome 2 with the FKHR gene on chromosome 13, leading to the formation of a hybrid transcription factor (PAX3-FKHR) b) Found in about 70% of the alveolar tumors c) Only occasionally described in other subtypes iii. Embryonal subtype: numerical changes with +2, +8, +11, and +20, found in 35–50% of cases 11. Other common, recurrent translocation in solid and soft tissue tumors of childhood a. Alveolar soft part sarcoma: t(X;17)((p11;q25), ASPLTFE3 b. Inflammatory myofibroblastic tumor: 2p23 translocations, ALK-TPM3 c. Desmoplastic small round cell tumor i. t(11;22)(p13;q12), WT1-EWS ii. t(11;22)(q24;q12), FLI1-EWS, ERG-EWS d. Synovial sarcoma i. t(X;18)(p11.23;q11.2), SSX1-SSXT ii. t(X;18)(p11.21;q11), SSX2-SSXT e. Malignant melanoma of soft part (clear cell sarcoma): t(12;22)(q13;q12), ATF1-EWS f. Myxoid liposarcoma i. t(12;16)(q13;p11), CHOP-TLS(FUS) ii. t(12;22)(q13;q12), CHOP-EWS g. Extraskeletal myxoid chondrosarcoma: t(9;22)(q22;q12), CSMF-EWS h. Dermatofibrosarcoma protuberans and giant cell fibroblastoma: t(17;22)(q22;q13), COL1A1-PDGFB i. Lipomas: t(var;12)(var;q13-15), var, HMGI-C j. Leiomyomas: t(12;14)(q13;15), HMGI-C,? 12. Other primary chromosome changes in solid tumors a. Benign tumors i. Meningioma and acoustic neuroma a) −22 b) 22q− ii. Mixed tumors of salivary glands a) t(3;8)(p21;q12) b) t(9;12)(p13-22;q13–15) iii. Colonic adenomas

CHROMOSOME ABNORMALITIES IN PEDIATRIC SOLID TUMORS

a) 12q− and/or +7 b) 12q− and/or +8 iv. Cortical adenoma of the kidney (+7, +7, +17, −Y) b. Adenocarcinomas i. Bladder a) i(5p) b) +7 c) −9/9q− d) 11p− ii. Prostate: del(10)(q24) iii. Lungs (small cell carcinoma): del(3)(p14p23) iv. Colon a) 12q− b) +7 c) +8 d) +12 e) 17(q11) f) 17p− v. Kidney: del(3)(p11p21) vi. Uterus: 1q− vii. Ovary a) 6q− b) t(6;14)(q21;q24) viii. Endometrium a) Trisomy 1q b) +10 c. Embryonal and other tumors i. Testicular (germ cell tumors): i(12p) ii. Malignant melanoma a) Del(6)(q11q27) b) i(6p) c) Del(1)(p11p22) d) t(1;19)(q12;q13) iii. Mesothelioma: del(3)(p13p23) iv. Glioma: −22 13. Potential prognostic markers of neoplastic disease a. Breast cancer: allelic loss at 1p22–p31 (lymph node metastasis and tumor size >2 cm) b. Bladder cancer i. LOH RB (high grade/muscle invasion) ii. Genomic alterations (2q−, 5p+, 5q−, 6q−, 8p−, 10q−, 18q−, 20q+) (higher grade) c. Cervical carcinoma: LOH on chromosome (advanced stage) d. Colorectal cancer i. LOH at 18q21 or p53 expression (recurrence/ poor survival) ii. MSI (microsatellite instability) and K-ras mutations in normal appearing colonic mucosa (predictive of colorectal cancer) iii. P16-hypermethylation (shorter survival in Stage T3N0M0 tumors) e. Gastric cancer i. LOH p53 (invasive disease) ii. LOH of 7q (D7S95) (poor prognosis (in Stage III/IV)) f. Glioma: chromosome 22q loss (astrocytomas progression) g. Head and neck squamous cell carcinoma

h. i.

j. k.

l.

m. n.

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i. LOH of 14q (poor outcome) ii. LOH on 2q (poor prognosis) iii. LOH on 17p (chemoresistance) Melanoma: LOH in plasma (advanced stage/tumor progression) Neuroblastoma i. N-myc amplification (poor prognosis) ii. TrkA expression (good prognosis) iii. High telomerase expression (aggressive behavior) Neuroblastomas, 4s-: N-myc amplification, 1p deletion, 17q gains, elevated telomerase activity (poor prognosis) Non-small cell lung cancer i. Allelic imbalances on 9p (poor prognosis) ii. LOH 11p (poor prognosis) PNET i. LOH of 17p (metastatic disease) ii. C-myc amplification (poor prognosis) Prostate cancer: LOH on 13q (advanced stage) Retinoblastoma: LOH at RB1 locus (tumoral differentiation, absence of choroidal invasion)

GENETIC COUNSELING 1. Recurrence risk a. Retinoblastoma i. Predisposition to retinoblastoma which is caused by germline mutations in the RB1 gene: transmitted in an autosomal dominant fashion ii. Use RB1 mutation analysis to clarify the genetic status of at-risk sibs and offspring when a previously characterized germline cancer-predisposing mutation is available iii. Use indirect testing using polymorphic loci linked to the RB1 gene in some families to clarify genetic status of at-risk family members if RB1 direct DNA testing is not available or is uninformative iv. Use empiric recurrence risk estimates in all families in which direct DNA testing of RB1 and linkage analysis are unavailable or uninformative v. Risk to patient’s siblings a) When there is an existing family history: a 45% chance for siblings of bilaterally affected cases and a 30% chance for siblings of unilaterally affected cases to develop disease b) When there is absence of any family history: 2% risk for siblings of bilaterally affected cases and 1% for siblings of unilaterally affected cases to develop disease c) There is an additional risk to siblings in the absence of any family history or documented mutation in parental leukocyte DNA because of germline mosaicism. If neither parent has the cancer-predisposing RB1 germline†mutation that was identified in the index case, germline mosaicism in one parent is possible and the risk to each sib of having retinoblastoma is 3–5%

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d) If the index case has mosaicism for an RB1 cancer-predisposing mutation (the mutation arose as a post-zygotic event) and that neither parent has an RB1 germline mutation, the risk to the sibs is not increased and thus it is not warranted to test the sibs for the RB1 mutation identified in the index case vi. Risk for patient’s offspring a) About 45% by the age 6 years (consistent with an autosomal dominant inheritance with 90% penetrance) for the offsprings of survivors of hereditary (multifocal, bilateral) retinoblastoma b) About 2.5% for the offsprings of survivors of unilateral retinoblastoma c) The low (~1%), but not negligible, risk to the offspring of index cases with unifocal disease and a negative family history reflects the possibility of a germline RB1 mutation with low penetrance or mutational mosaicism b. Neuroblastoma i. Risk for patient’s sibling: low unless a parent has hereditary form of neuroblastoma ii. Risk for patient’s offspring: 50% c. Wilms’ tumor i. Risk for patient’s sibling: low unless a parent has hereditary form of Wilms tumor ii. Risk for patient’s offspring: 50% 2. Prenatal diagnosis a. Retinoblastoma i. Prenatal testing possible if the germline RB1 mutation in the parent is known or if RB1 linkage analysis is informative in the family ii. Mutation analysis on fetal DNA obtained from amniocentesis or CVS iii. Use prenatal ultrasonography to detect intraocular tumors if the disease-causing RB1 mutation is identified in the fetus b. Adrenal neuroblastoma i. Prenatal diagnosis adrenal neuroblastoma by ultrasonography usually made in the 3rd trimester ii. Sonographic appearance of the adrenal neuroblastoma varies a) Solid b) Purely cystic (50%) c) Mixed echo pattern (related to necrosis, hemorrhage or spontaneous tumoral involution) d) Fetal hydrops e) Hydropic placenta with metastases in the placenta iii. Frequently producing catecholamines and hence maternal symptoms could aid the diagnosis iv. Elevated catecholamines in the amniotic fluid c. Wilms tumor by prenatal ultrasonography i. A solid echogenic mass with a clearly defined capsule ii. Areas of hemorrhage and necrosis may be seen within the mass

3. Management a. Surgeries for most solid tumors b. Determining the genetic changes present in the tumor of an individual patient: becoming increasingly important for managing the oncology patient c. Retinoblastoma i. Goals of treatment: preservation of sight and life ii. Treatment options a) Enucleation b) Cryotherapy c) Photocoagulation d) Photochemistry e) External-beam radiation f) Radiation therapy using episcleral plaques iii. Novel treatment options: systemic chemotherapy combined with local therapy iv. Frequent postoperative follow-up examinations for early detection of new intraocular tumors v. Detection of second nonocular tumors vi. Individuals warrant surveillance for early manifestations of retinoblastoma a) Individuals with retinomas b) Asymptomatic at-risk children d. Neuroblastoma i. Localized, low-risk disease: a) Primary curative surgery b) Minimal therapy: low-dose radiation or chemotherapy c) Supportive care with surveillance ii. Intermediate-risk patients: combination therapy with radiation, chemotherapy, and surgery iii. High-risk patients a) Combination of radiation, myeloablative chemotherapy, and surgery (delayed) b) Autologous bone marrow transplant c) Research protocols e. Wilms tumor: the usual approach in most patients is nephrectomy followed by chemotherapy with or without postoperative radiotherapy

REFERENCES Albertson DG, Collins C, McCormick F, et al.: Chromosome aberrations in solid tumors. Nature Genet 34:369–376, 2003. Barcus ME, Ferreira-Gonzalez A, Buller AM, et al.: Genetic changes in solid tumors. Semin Surg Oncol 18:358–370, 2000. Bennicelli JL, Barr FG: Genetics and the biologic basis of sarcomas. Curr Opin Oncol 11:267–274, 1999. Brodeur GM, Maris JM, Yamashiro DJ, et al.: Biology and genetics of human neuroblastomas. J Pediatr Hematol Oncol 19:93–101, 1997. Carlson EA, Desnick RJ: Mutational mosaicism and genetic counseling in retinoblastoma. Am J Med Genet 4:365–381, 1979. Cavenee WK, Dryja TP, Phillips RA, et al.: Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 305:779–784, 1983. Clericuzio CL, Johnson C: Screening for Wilms tumor in high-risk individuals. Hematol Oncol Clin North Am 9:1253–1265, 1995. Cooper CS: Translocations in solid tumours. Curr Opin Genet Dev 6:71–75, 1996. Coppes MJ, Egeler RM: Genetics of Wilms tumor. Semin Urol Oncol 17:2–10, 1999. Draper GJ, Sanders BM, Brownbill PA, et al.: Patterns of risk of hereditary retinoblastoma and applications to genetic counseling. Br J Cancer 66:211–219, 1992. Davidoff AM, Hill DA: Molecular genetic aspects of solid tumors in childhood. Semin Pediatr Surg 10:106–118, 2001.

CHROMOSOME ABNORMALITIES IN PEDIATRIC SOLID TUMORS Heim S, Mitelman R: Primary chromosome abnormalities in human neoplasia. Adv Cancer Res 52:1–43, 1989. Heim S, Mitelman F: Cytogenetics of solid tumours. Recent Adv Histopathol 15:37–66, 1992. Horsthemke B: Genetics and cytogenetics of retinoblastoma. Cancer Genet Cytogenet 63:1–7, 1992. Karnes PS, Tran TN, Cui MY, et al.: Cytogenetic analysis of 39 pediatric central nervous system tumors. Cancer Genet Cytogenet 59:12–19, 1992. Kesrouani A, Duchatel F, Seilanian M, et al.: Prenatal diagnosis of adrenal neuroblastoma by ultrasound: a report of two cases and review of the literature. Ultrasound Obstet Gynecol 13:446–449, 1999. Knudson AG: Mutation and cancer: Statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:82–823, 1971. Lee KL, Ma JF, Shortliffe LD: Neuroblastoma: Management, recurrence, and follow-up. Urol Clin N Amer 30:881, 2003. Lohmann DR, Horsthemke B, Bornheld N, et al.: Retinoblastoma. Gene Reviews. 2003. http://www.genetests.org Maris JM, Matthay KK: Molecular biology of neuroblastoma. J Clin Oncol 17:2264–2279, 1999. Mertens F, Mandahl N, Mitelman F, et al.: Cytogenetic analysis in the examination of solid tumors in children. Pediatr Hematol Oncol 11:361–377, 1994. Mitelman Database of Chromosome Aberrations in Cancer: http:// cgap.nci,nih.gov/Chromosomes/Mitelman Pakakasama S, Tomlinson GE: Genetic predisposition and screening in pediatric cancer. Pediatr Clin N Amer 49:1393–1413, 2002.

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Pappo AS, Rodriguez-Galindo C, Dome JS, et al.: Pediatric tumors. In Abeloff: Clinical Oncology, 2nd ed, 2000. Chapter 80, 2346–2401. Paulino AC, Coppes MJ: Wilms tumor. eMedicine. 2003. http://www. emedicien.com Quesnel S, Malkin D: Genetic predisposition to cancer and familial cancer syndromes. Pediatr Clin N Amer 47:791–808, 1997. Rowland JM: Molecular genetic diagnosis of pediatric cancer: current and emerging methods. Pediatr Clin N Amer 49:1415–1435, 2002. Sandberg AA: Chromosomal lesions and solid tumors. Hosp Pract October 15:93–106, 1988. Sandberg AA, Turc-Carel C: The cytogenetics of solid tumors. Relation to diagnosis, classification and pathology. Cancer 59:387–395, 1987. Schwab M, Westermann F, Hero B, et al.: Neuroblastoma: biology and molecular and chromosomal pathology. Lancet Oncol 4:472–480, 2003. Sippel KC, Faioli RE, Smith GD, et al.: Frequency of somatic and germ-line mosaicism in retinoblastoma: implications for genetic counseling. Am J Hum Genet 62:610–619, 1998. Stanbridge EJ: Functional evidence for human tumour suppressor genes: Chromosome and molecular genetic studies. Cancer Surv 12:5–24, 1992. Vadeyar S, Ramsay M, James D, et al.: Prenatal diagnosis of congenital Wilms’ tumor (nephroblastoma) presenting as fetal hydrops. Ultrasound Obstet Gynecol 16:80–83, 2000. Varella-Garcia M: Molecular cytogenetics in solid tumors: laboratorial tool for diagnosis, prognosis, and therapy. The Oncologist 8:45–58, 2003.

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Fig. 1. Notice white firm neoplasm (retinoblastoma) filling the vitreous space of the eye.

Fig. 3. Karyotype of a patient with Wilms tumor showing 46,XY, der(11)(p11.2q13.5)del(11)(p13p15.1).

Fig. 4. Note a lobulated meningioma encroaching the brain at the inferior surface of left frontal lobe.

Fig. 2. Large well circumscribed ovoid Wilms tumor in the upper pole of the kidney. Barely identifiable small areas of hemorrhage and necrosis are present.

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Fig. 7. N-MYC amplification in a patient with neuroblastoma. Gross copy number of the orange signal is noted (LSIÆ N-MYC (2p24.1) SpectrumOrange TM probe).

Fig. 5. Karyotypes of two patients with meningioma showing 46,XX,del(22)(q12) (the first picture) and 44,XX,del(7)(q32q36), −11,der(14)t(11;14)(q12;p11),−22 (the second picture) respectively.

Fig. 6. Neuroblastoma smear. Note the anaplastic neuroblastic cells mixed with blood.

Cleft Lip and/or Cleft Palate Cleft lip and/or palate (CL/CP) is the most common craniofacial malformation with an estimated incidence of approximately 1 in 700 to 1 in 1000 live births among Caucasians. CL/CP may occur as an isolated finding or may be found in association with other congenital malformations.

patients in different populations has a positive family history of CL/CP iii. Isolated CL/CP is considered multifactorial in origin and demonstrates strong familial aggregation with a significant genetic component iv. No evidence of classic Mendelian inheritance attributable to any single gene, although a number of genes or loci have been implicated, including transforming growth factor-alpha, retinoic acid receptor alpha, BCL3, MSX-1 and several regions on chromosome 6p23-24 (OFC1), 2q13 (OFC2), 19q13.2 (OFC3), and other loci such as 4q25-4q31.3 and 17q21

GENETICS/BASIC DEFECTS 1. Environmental agents a. Cleft lip and cleft palate i. Alcohol ii. Anticonvulsants (phenytoin, sodium valproate) iii. Isotretinoin iv. Steroids v. Methotrexate vi. Maternal infections in the first trimester a) Rubella b) Toxoplasmosis vii. Maternal smoking b. Isolated clefts i. Little evidence linking to any single teratogenic agent, except anticonvulsant phenytoin ii. Use of phenytoin during pregnancy is associated with a tenfold increase in the incidence of cleft lip c. Cleft lip: incidence of cleft lip in infants in mothers who smoke during pregnancy is twice that of those born to nonsmoking mothers 2. Genetic factors a. Syndromic clefts associated with malformations involving other developmental regions i. About 25% of neonates with CL/CP show associated malformations, syndromes or aneuploidy ii. Van der Woude syndrome: the most commonly recognized syndrome associated with CL/CP, an autosomal dominant disorder characterized by CL/CP and blind sinuses or pits of the lower lip iii. Microdeletion of chromosome 22q11.2 (velocardiofacial syndrome, DiGeorge syndrome, and conotruncal anomaly face syndrome): currently the most common syndromic diagnoses among patients with clefts of the secondary palate alone iv. Other syndromes associated with clefts of the secondary palate alone: a) Stickler syndrome b) Ectrodactyly-ectodermal clefting (EEC) syndrome c) Popliteal pterygium syndrome b. Nonsyndromic cleft of the lip and/or palate i. An embryopathy derived from failure in fusion of the nasal process and/or palatal shelves ii. Genetic factors play an important role in the etiology of cleft lip and/or palate since one in five

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1. Classification of different types of orofacial clefting a. Cleft lip with or without cleft palate (CL/CP) i. Unilateral cleft lip ii. Unilateral cleft lip and cleft palate iii. Bilateral cleft lip iv. Bilateral cleft lip and cleft palate b. Cleft palate only i. Cleft palate ii. Submucous cleft palate iii. Velopharyngeal insufficiency iv. Robin sequence and robin complexes c. Median clefts i. Median cleft lip ii. Persistent infranasal furrow iii. Median frenular cleft iv. Median mandibular cleft d. Alveolar clefts (oral-facial-digital syndromes) e. Tessier type clefts including lateral and oblique facial clefts 2. Racial difference in CL/CP a. Whites: approximately 1 in 1000 births b. African Americans: 0.41 per 1000 births c. Asians: approximately twice of whites 3. Sex difference in CL/CP and isolated clefts of the secondary palate a. Children born with CL/CP: 60–80% are males b. Isolated clefts of the secondary palate: more frequently in females 4. Sites of clefts a. Isolated cleft lip: 21% b. CL/CP: 46% c. Clefts of the secondary palate alone: 33% d. Unilateral clefts i. More common in the left than the right (2:1) ii. Much more common than bilateral (9:1) iii. Associated with palatal clefts in 68% of cases

CLEFT LIP AND/OR CLEFT PALATE

e. Bilateral clefts of the lip: associated with palatal clefts in 86% of cases 5. Types of cleft lip a. Microform i. Presence of a vertical groove and vermilion notching ii. Associated with varying degrees of lip shortening b. Unilateral incomplete cleft lip i. Present with varying degrees of lip disruption ii. Associated with an intact nasal sill or Simonart band (a band of fibrous tissue from the edge of the red lip to the nostril floor) c. Complete cleft lip: characterized by disruption of the lip, alveolus, and nasal sill 6. Secondary medical problems with the presence of cleft plate a. Difficulty in sucking b. Inadequate intake of formula c. Aspiration d. Deviated nasal septum (airway obstruction) e. Hearing impairment f. Recurrent ear infections g. Malocclusion h. Abnormal craniofacial growth i. Inability to generate a pressure gradient between the oral and nasal chambers (hinders sucking in most infants) j. Speech dysfunction i. The most serious untoward consequence associated with cleft palate ii. Hypernasality or escape of sound into the nasal cavity associated with the production of many consonant phonemes and vowels in the English language except m, n, and ng k. Cosmetic disfigurement associated with orofacial clefting

DIAGNOSTIC INVESTIGATIONS 1. Speech and hearing evaluation 2. Echocardiography for associated cardiac anomalies 3. Karyotyping if indicated, especially to detect del(22)(q11.2) 4. Molecular genetic analysis for a known mutation in a syndromic CL/CP

GENETIC COUNSELING 1. Recurrence risk a. Recurrence risk for nonsyndromic CL ± CP i. Unaffected parent a) No previously affected child: about 0.1% (general population risk) b) With one previously affected child: about 4% c) With two previously affected children: about 14% ii. One affected parent a) No previously affected child: about 4% b) With one previously affected child: about 12% c) With two previously affected children: about 25%

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iii. Two affected parents a) No previously affected child: about 35% b) With one previously affected child: about 45% c) With two previously affected children: about 50% b. Recurrence risk for nonsyndromic CP i. Unaffected parent a) No previously affected child: about 0.04% (general population risk) b) With one previously affected child: about 3.5% c) With two previously affected children: about 13% ii. One affected parent a) No previously affected child: about 3.5% b) With one previously affected child: about 10% c) With two previously affected children: about 24% iii. Two affected parents a) No previously affected child: about 2.5% b) With one previously affected child: about 40% c) With two previously affected children: about 45% c. Presence of a microform such as a form fruste cleft lip, submucous cleft palate, or bifid uvula suggest genetic factors within the family, which would alter the inheritance risks (e.g., striking association with lower-lip pits in the van der Woude syndrome) d. Recurrence risk for CL/CP with associated anomalies i. Mendelian diseases and syndromes a) Autosomal dominant inheritance (e.g., Apert syndrome) b) Autosomal recessive inheritance (e.g., Smith-Lemli-Opitz syndrome) c) X-linked inheritance (e.g., oto-palato-digital syndrome) ii. Chromosome disorders (e.g., trisomy 13) 2. Prenatal diagnosis a. Prenatal ultrasonography i. CL/CP not reliably diagnosed until the soft tissues of the fetal face become distinct by 13–14 weeks by transabdominal (TA) sonography and by transvaginal (TV) sonography slightly earlier ii. Fetal palate best seen in the axial plane iii. Fetal lips optimally visualized in the coronal view iv. To demonstrate isolated CL/CP v. To demonstrate associated anomalies (limb and spine anomalies, most common with 33%; cardiovascular anomalies, 24%) b. Fetal echocardiography in case of fetal cardiac anomalies c. Fetal karyotyping in case of associated fetal anomalies 3. Management a. Medical i. A highly specialized multidisciplinary approach from birth to adulthood ii. Airway management iii. Establishment of feeding iv. Speech, hearing, and language therapies b. Surgical

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i. Primary surgery on the lip: usually carried out around the age of 3 months followed by palatal repair at around 6 months ii. Preventative and restorative dental care iii. Orthodontics iv. Secondary surgery in the form of alveolar bone grafting v. Pharyngeal flap or sphincter pharyngoplasty for velopharyngeal incompetence c. Psychological issues i. Parental stress ii. Parent-child relationship iii. Behavioral and emotional adjustment iv. Self-concept and personality v. Cosmetic disfigurement vi. Social functioning vii. Congnitive development and adjustment viii. Cleft Lip and Palate Association (CLAPA), a helpful source of support and information for both families and professionals d. Recent observation suggests beneficial effects of folic acid supplementation during pregnancy in the prevention of facial clefting

REFERENCES Bergé SJ, Plath H, Van de Vondel PT, et al.: Fetal cleft lip and palate: sonographic diagnosis, chromosomal abnormalities, associated anomalies and postnatal outcome in 70 fetuses. Ultrasound Obstet Gynecol 18:422–431, 2001. Bonaiti-Pellié C, Briand ML, Feingold J, et al.: An epidemiological and genetic study of facial clefting in France. I. Epidemiological and frequency in relatives. J Med Genet 11:374–377, 1982. Burdi AR: Epidemiology, etiology, and pathogenesis of cleft lip and palate. Cleft Palate J 14:14:262–269, 1977. Carinci F, Pezzetti F, Scapoli L, et al.: Genetics of nonsyndromic cleft lip and palate: a review of international studies and data regarding the Italian population. Cleft Palate Craniofac J 37:33–40, 2000. Chen H: Medical Genetics Handbook. St Louis: Warren H Green, 1988, pp 320–321. Cockell A, Lees M: Prenatal diagnosis and management of orofacial clefts. Prenat Diagn 20:149–151, 2000. Cohen MM Jr: Craniofacial disorders. In Rimoin DL, Connor JM, Pyeritz RE, Korf BR (eds): Emery and Rimoin’s Principles and Practice of Medical Genetics. 4th ed, London, Churchill Livingstone, 2002, Chapter 142, pp3689–3727. Curtis E, Fraser F, Warburton D: Congenital cleft lip and palate: risk figures for counselling. Am J Dis Child 102:853–857, 1961. De La Pedraja J, Erbella J, McDonald WS, et al.: Approaches to cleft lip and palate repair. J Craniofac Surg 11:562–571, 2000. Endrica MC, Kapp-Simon KA: Psychological issues in craniofacial care: state of the art. Cleft Palate-Craniofac J 36:3–11, 1999.

Farrall M, Holder S: Familial recurrence-pattern analysis of cleft lip with or without cleft palate. Am J Hum Genetics 50:270–277, 1992. Fraser FC: The genetics of cleft lip and palate. Am J Hum Genet 22:336–352, 1970. Fraser GR, Calnan GS: Cleft lip and palate: Seasonal incidence, birth weight, birth rank, sex, site, etc. Arch Dis Child 36:420, 1961. Habib Z: Factors determining occurrence of cleft lip and cleft palate. Surg Gynecol Obstet 146:105–110, 1978. Habib Z: Genetic counseling and genetics of cleft lip and palate. Obstet Gynecol Surv 33:441–447, 1978. Hartridge T: The role of folic acid in oral clefting. Br J Orthodontics 26:115–120, 1999. Hibbert SA, Field JK: Molecular basis of familial cleft lip and palate. Oral Dis 2:238–241, 1996. Kirschner RE, LaRossa D: Cleft lip and palate. Otolaryngol Clin N Amer 33:1191–1215, 2000. Lee W, Kirk JS, Shaheen KW, et al.: Fetal cleft lip and palate detection by three-dimensional ultrasonography. Ultrasound Obstet Gynecol 16: 314–320, 2000. Lynch HAT, Kimberling WJ: Genetic counseling in cleft lip and cleft palate. Plast Reconstr Surg 68:800–815, 1981. Matthews MS, Cohen M, Viglione M, et al.: Prenatal counseling for cleft lip and palate. Plast Reconstr Surg 101:1–5, 1998. Melnick M, Bixler D, Fogh-Anderson P, et al.: Cleft ± cleft palate: an overview of the literature and an analysis of Danish cases born between 1941 and 1968. Am J Med Genet 6:83–97, 1980. Milerad J, Larson O, Hagberg C, et al.: Associated malformations in infants with cleft lip and palate: a prospective, population-based study. Pediatrics 100:180–186, 1997. Mitchell LE, Risch N: Mode of inheritance of nonsyndromic cleft lip with or without cleft palate: a reanalysis. Am J Hum Genetics 51:323–332, 1992. Mulliken JB, Benacerraf BR: Prenatal diagnosis of cleft lip. What the sinologist needs to tell the surgeon. J Ultrasound Med 20:1159–1164, 2001. Murray JC: Gene/environment causes of cleft lip and/or palate. Clin Genet 61:248–256, 2002. Nyberg D, Sickler G, Hegge F, et al.: Fetal cleft lip with and without cleft palate: US classification and correlation with outcome. Radiology 195: 677–684, 1995. Prescott NJ, Winter RM, Malcolm S: Nonsyndromic cleft lip and palate: complex genetics and environmental effects. Ann Hum Genet 65:505–515, 2001. Stark RB: The pathogenesis of harelip and cleft palate. Plast Reconstr Surg 13:20–39, 1954. Stein J, Mullikan JB, Stal S, et al.: Nonsyndromic cleft lip with or without cleft palate: Evidence of linkage to BCL3 in 17 mutigenerational families. Am J Hum Genet 57:257–272, 1995. Tolarova M, Harris J: Reduced occurrence of orofacial clefts after periconceptional supplementation with high-dose folic acid and multivitamins. Teratology 51:71–78, 1995. Tolarova M, Cervenka J: Classification and birth prevalence of orofacial clefts. Am J Med Genet 75:126–137, 1998. Wyszynski DF, Beaty TH: Review of the role of potential teratogens in the origin of human non-syndromic oral clefts. Teratology 53:309–317, 1996. Wyszynski DF, Beaty TH, Maestri N: Genetics of nonsyndromic oral clefts revisited. Cleft Palate Craniofac J 33:406–417, 1996.

CLEFT LIP AND/OR CLEFT PALATE

Fig. 3. An infant and a boy with cleft palate. Fig. 1. Two infants with bilateral cleft lips and cleft palate.

Fig. 4. A boy with high-arched palate. Fig. 2. An infant with unilateral cleft lip and cleft palate.

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Fig. 5. An infant with bilateral CL/CP associated with trisomy 13.

Fig. 6. A stillborn with CL/CP and other multiple congenital anomalies including massive cystic hygroma.

Cleidocranial Dysplasia Cleidocranial dysplasia is a generalized skeletal dysplasia affecting not only the clavicles but almost the entire skeletal system. It is characterized by aplasia or hypoplasia of the clavicles, enlarged calvaria with frontal bossing, multiple Wormian bones, delayed tooth eruption, supernumerary unerupted teeth, distal phalanges with abnormally pointed tufts, hypoplasia of the pelvis, and numerous other abnormalities.

3.

GENETICS/BIRTH DEFECTS 1. Inheritance: autosomal dominant 2. Cause a. Caused by mutations in CBFA1 (RUNX2) gene resulting in haploinsufficiency. Types of mutations identified are: i. Deletion ii. Insertion iii. Missense iv. Nonsense b. The gene for cleidocranial dysplasia: called corebinding factor A1 (CBFA1) (a member of the runt family of transcription factors), mapped to 6p21. The alternative gene name is called RUNX2 c. CBFA1 encodes a transcription factor that activates osteoblast differentiation and plays a role in differentiation of chondrocytes 3. No significant genotype/phenotype correlations observed

4.

5.

6.

7.

CLINICAL FEATURES 1. Significant intra- and inter-familial variability of phenotypic expression 2. Abnormal craniofacial growth a. Head i. A large brachycephalic head ii. A broad forehead with frontal bossing iii. Delayed closure of the fontanelles and sutures iv. Poorly developed midfrontal area showing a frontal groove owing to incomplete ossification of the metopic suture v. Soft skull in infancy b. Face i. Frontal and parietal bossings, separated by a metopic groove ii. A depressed nasal bridge iii. Hypertelorism with possible exophthalmos iv. A small, flattened facial appearance (midface hypoplasia) with mandibular prognathism v. An anatomic pattern of dentofacial deformity consistent with the diagnosis of vertical maxillary deficiency (short face syndrome, type 2) c. Oral/dental i. High arched palate ii. Clefts involving soft and hard palates

8.

iii. Persistence of the deciduous dentition with delayed eruption of the permanent teeth: a relatively constant finding iv. Impaction of supernumerary permanent teeth v. Crowding/malocclusion vi. Dentigerous cysts Shoulders and thorax a. Ability to bring shoulders together b. Dimplings in the skin secondary to mild hypoplasia of the clavicles c. Sloping, almost absent shoulders secondary to severe hypoplasia or absence of the clavicles d. Narrow thorax: may lead to respiratory distress during early infancy Mildly disproportionate short stature with short limbs comparing to the trunk and more apparent in the upper limbs than the lower Spine a. Scoliosis b. Kyphosis Hands a. Brachydactyly b. Short distal phalanges c. Tapering fingers d. Nail dysplasia/hypoplasia e. Short, broad thumbs f. Clinodactyly of the 5th fingers Other abnormalities a. Hearing loss b. Abnormal gait c. Joint hypermobility d. Muscular hypotonia Cesarean section often required in the pregnant female due to dysplastic pelvis

DIAGNOSTIC INVESTIGATIONS

185

1. Molecular genetic studies of mutations involving PEBP2αA/CBFA1 2. Radiographic findings: generalized failure of midline ossification a. Skull i. Delayed closure of the anterior fontanelle (open fontanelle) and sagittal and metopic sutures, often for life ii. Unossified areas of the skull becoming smaller with increasing age iii. Multiple Wormian bones formation, particularly around the lambdoid suture iv. Small or absent nasal bones v. Segmental calvarial thickening vi. Underdeveloped maxilla vii. Delayed union of the mandibular symphysis viii. Platybasia

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b.

c.

d.

e.

f.

g.

ix. Small cranial base x. A large foramen magnum xi. Hypoplastic sinuses (paranasal, frontal, mastoid) Clavicles i. Absent clavicles: rare ii. Pseudarthrosis of one or both clavicles iii. Hypoplasia of the acromial end: common iv. Two separate fragments v. Absent sternal end with presence of the acromial end vi. Bilaterality is the rule but not always the case Chest i. Small bell-shaped thoracic cage ii. Short, oblique ribs iii. Presence of cervical ribs iv. Scapula often hypoplastic with deficient supraspinatus fossae and acromial facets v. Associated deficiency in musculature Pelvis i. Widened pubis symphysis resulting from delay in ossification during adulthood ii. Hypoplasia and anterior rotation of the iliac wings iii. Wide sacroiliac joints iv. Delayed ossification of the pubic bone v. Large femoral epiphyses vi. Unusual shape of femoral head reminiscent of a ‘chef’s hat’ vii. Broad femoral necks viii. Frequent coxa vara Spine i. Hemivertebrae ii. Posterior wedging iii. Spondylolysis and spondylolisthesis iv. Syringomyelia v. Spina bifida occulta of the cervical, thoracic, or lumbar region Tubular bones i. Presence of both proximal and distal epiphyses in the second metacarpals and metatarsals leading to excessive growth and length ii. Frequent cone-shaped epiphyses and premature closure of epiphyseal growth plates leading to shortening of bones iii. Wide epiphyses iv. Unusually short distal phalanges and the middle phalanges of the second and fifth fingers v. Poorly developed terminal phalanges giving a tapered appearance to the digit vi. Occasional hypoplasia, dysplasia, and aplasia of nails Dentition: impacted, supernumerary teeth

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased unless a parent is affected with the disorder or has germ line mosaicism b. Patient’s offspring: 50%

2. Prenatal diagnosis a. Ultrasonography i. Hypoplastic clavicles ii. Less calcified cranium than expected for gestational age iii. Other skeletal anomalies b. Direct DNA testing possible for those families with a known mutation in the CBFA1 3. Management a. Hearing evaluation b. Evaluate the presence of submucous cleft palate c. Evaluation of obstructive sleep apnea d. Medical and surgical therapy for upper airway obstruction, recurrent and chronic sinusitis and otitis e. Monitor skeletal and orthopedic complications f. Early surgical and orthodontic intervention of unerupted permanent teeth to induce eruption g. Orthognathic surgery to correct mid-face hypoplasia to reduce or correct significant upper respiratory complications and malocclusions h. Surgical and orthodontic management of vertical maxillary deficiency i. Women with cleidocranial dysplasia at risk for a Cesarean section delivery

REFERENCES Aktas S, Wheeler D, Sussman MD: The ‘chef’s hat’ appearance of the femoral head in cleidocranial dysplasia. J Bone Joint Surg Br 82:404–408, 2000. Chitayat D, Hodgkinson KA, Azouz EM: Intrafamilial variability in cleidocranial dysplasia: a three generation family. Am J Med Genet 42:298–303, 1992. Cohen MM Jr: RUNX genes, neoplasia, and cleidocranial dysplasia. Am J Med Genet 104:185–188, 2001. Cole WR, Levine S: Cleidocranial dysplasia. Br J Radiol 24:549–555, 1951. Cooper SC, Flaitz CM, Johnston DA, et al.: A natural history of cleidocranial dysplasia. Am J Med Genet 104:1–6, 2001. Dann JJ III, Crump P, Ringenberg QM: Vertical maxillary deficiency with cleidocranial dysplasia. Diagnostic findings and surgical-orthodontic correction. Am J Orthod 78:564–574, 1980. Dhooge I, Lantsoght B, Lemmerling M, et al.: Hearing loss as a presenting symptom of cleidocranial dysplasia. Otol Neurotol 22:855–857, 2001. Ducy P: Cbfa1: a molecular switch in osteoblast biology. Dev Dynamics 219:461–471, 2000. Farrar EL, Van Sickels JE: Early surgical management of cleidocranial dysplasia: a preliminary report. J Oral Maxillofac Surg 41:527–529, 1983. Feldman GJ, Robin NH, Brueton LA, et al.: A gene for cleidocranial dysplasia maps to the short arm of chromosome 6. Am J Hum Genet 56:938–943, 1995. Gelb BD, Cooper E, Shevell M, et al.: Genetic mapping of the cleidocranial dysplasia (CCD) locus on chromosome band 6p21 to include a microdeletion. Am J Med Genet 58:200–205, 1995. Golan I, Baumert U, Held P, et al.: Radiological findings and molecular genetic confirmation of cleidocranial dysplasia. Clin Radiol 57:525–529, 2002. Golan I, Preising M, Wagener H, et al.: A novel missense mutation of the CBFA1 gene in a family with cleidocranial dysplasia (CCD) and variable expressivity. J Craniofac Genet Dev Biol 20:113–120, 2000. Hamner LH III, Fabbri EL, Browne PC: Prenatal diagnosis of cleidocranial dysostosis. Obstet Gynecol 83:856–857, 1994. Hassan J, Sepulveda W, Teixeira J, et al.: Prenatal sonographic diagnosis of cleidocranial dysostosis. Prenat Diagn 17:770–772, 1997. International Working Group on Constitutional Diseases of Bone: International nomenclature and classification of the osteochondrodysplasias (1997). Am J Med Genet 79:376–382, 1998. Jarvis JL, Keats TE: Cleidocranial dysplasia. A review of 40 new cases. AJR 121:5–16, 1974.

CLEIDOCRANIAL DYSPLASIA Jensen BL: Somatic development in cleidocranial dysplasia. Am J Med Genet 35:69–74, 1990. Jensen BL, Kreiborg S: Development of the dentition in cleidocranial dysplasia. J Oral Pathol Med 19:89–93, 1990. Jensen BL, Kreiborg S: Development of the skull in infants with cleidocranial dysplasia. J Craniofac Genet Dev Biol 13:89–97, 1993. Jensen BL, Kreiborg S: Craniofacial abnormalities in 52 school-age and adult patients with cleidocranial dysplasia. J Craniofac Genet Dev Biol 13:98–108, 1993. Jensen BL, Kreiborg S: Craniofacial growth in cleidocranial dysplasia. A roentgenocephalometric study. J Craniofac Genet Dev Biol 15:35–43, 1995. Komori T, Yagi H, Nomura S, et al.: Targeted disruption of CBFA1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89:755–764, 1997. Kreiborg S, Jenson BL, Larsen P, et al.: Anomalies of craniofacial skeleton and teeth in cleidocranial dysplasia. J Craniofac Genet Dev Biol 19:75–79, 1999. Lee B, Thirunsvukkarasu K, Zhou I, et al.: Missense mutations abolishing DNA binding of the osteoblast-specific transcription factor OSF2/ CBFA1. Nat Genet 16:307–310, 1997. Mundlos S: Cleidocranial dysplasia: clinical and molecular genetics. J Med Genet 36:177–182, 1999. Mundlos S, Otto F, Mundlos C, et al.: Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89:773–779, 1997.

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Narahara K, Tsuji K, Yokoyama Y, et al.: Cleidocranial dysplasia associated with a t(6;18)(p12;q24) translocation. Am J Med Genet 56:119–120, 1995. Nienhaus H, Mau U, Zang KD, et al.: Pericentric inversion of chromosome 6 in a patient with cleidocranial dysplasia. Am J Med Genet 46:630–631, 1993. Otto F, Thornell AP, Crompton T, et al.: CBFA1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89:765–771, 1997. Quack I, Vonderstrass B, Stock M, et al.: Mutation analysis of core binding factor A1 in patients with cleidocranial dysplasia. Am J Hum Genet 65: 1268–1278, 1999. Stewart PA, Wallerstein R, Moran E, et al.: Early prenatal ultrasound diagnosis of cleidocranial dysplasia. Ultrasound Obstet Gynecol 15:154–156, 2000. Tesa A, Salvi S, Casali C, et al.: Six novel mutations of the RUNX2 gene in Italian patients with cleidocranial dysplasia. Hum Mutat mutation in Brief #626, 2003 online. Zackai EH, Robin NH, McDonald-McGinn DM: Sibs with cleidocranial dysplasia born to normal parents: germ line mosaicism? Am J Med Genet 69:348–351, 1997. Zhang YW, Yasui N, Kakazu N, et al.: PEBP2alphaA/CBFA1 mutations in Japanese cleidocranial dysplasia patients. Gene 244:21–28, 2000. Zhou G, Chen Y, Zhou L, et al.: CBFA1 mutation analysis and functional correlation with phenotypic variability in cleidocranial dysplasia. Hum Mol Genet 8:2311–2316, 1999.

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Fig. 2. A child with cleidocranial dysplasia showing prominent forehead, wide anterior fontanel and cranial sutures, wide eyes, depressed nasal bridge, and easily proximated shoulders. Radiographs show poorly ossified skull, wide fontanels, cone-shaped thorax, and absence of clavicles. Fig. 1. An infant and a child with cleidocranial dysplasia showing a large brachycephalic skull, frontal bossing, a large anterior fontanel, widely spaced eyes, flat nasal bridge, and easily proximated shoulders.

CLEIDOCRANIAL DYSPLASIA

Fig. 3. A girl with cleidocranial dysplasia at different ages showing short stature, frontal bossing, wide cranial sutures, wide set eyes, depressed nasal bridge, and sloping and easily proximated shoulders.

189

Fig. 4. An adult with cleidocranial dysplasia showing widened cranial sutures, a characteristic face, and sloping and easily proximated shoulders. Radiograph showed a cone-shaped thorax with absent clavicles.

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Fig. 5. A father and a son with cleidocranial dysplasia showing characteristic clinical findings and a dysplastic left clavicle presenting as two separate fragments, illustrated by radiograph.

Cloacal Exstrophy Cloacal exstrophy is a rare congenital malformation resulting in exstrophy of the urinary, intestinal and genital systems and is associated with anomalies of other organ systems. The term OEIS complex (omphalocele, exstrophy of the bladder, imperforate anus, and spinal defects) are used to describe the spectrum of malformations in cloacal exstrophy. The incidence of cloacal exstrophy is estimated to be 1/200,000–1/400,000 live births.

CLINICAL FEATURES

GENETICS/BASIC DEFECTS 1. Genetics a. Recurrence of OEIS complex in siblings can be explained by the following mechanisms: i. Autosomal recessive inheritance ii. Multifactorial determination iii. Gonadal mosaicism for a dominant mutation iv. Environmental factors v. Subclinical maternal disorder b. Higher incidence of OEIS complex in monozygotic twins than in dizygotic twins suggests a possible genetic contribution to the occurrence of these defects 2. Basic defects of OEIS complex a. Resulting from a single localized defect in the early caudal mesoderm at approximately 29 days of development b. Resulting in the following sequence of events: i. Failure of cloacal septation leading to a persistence of the cloaca with a rudimentary mid-gut and imperforate anus ii. Failure of break down of the cloacal membrane leading to exstrophy of the cloaca, omphalocele, and lack of fusion of the pubic rami iii. The lumbosacral somites giving rise to abnormal vertebrae in which there is protrusion of the dilated spinal cord (hydromyelia) and a cystic, skin-covered mass in the lumbosacral region 3. Cloaca and cloacal exstrophy a. Cloaca i. A transient embryological structures ii. The term ‘cloaca’ literally means ‘sewer’ in Latin iii. The term used to represent the emptying of the gastrointestinal and urogenital tracts into a common sinus iv. Defined as a common chamber (orifice) in the perineum into which the urinary, genital and intestinal tract drain b. Cloacal exstrophy: the common orifice empties onto the anterior abdominal wall

191

1. Classic exstrophy of the cloaca a. Lower abdominal defect b. Exposure of intestinal and bladder mucosa c. Accompanied by the following anomalies i. Omphalocele ii. Imperforate anus iii. Urogenital anomalies 2. Gastrointestinal malformations a. Omphalocele b. Imperforate anus c. Rectovestibular/rectovesical fistula d. Small bowel anomalies i. Foreshortened small bowel ii. Rotational anomalies e. Meckel diverticulum f. Inguinal hernias 3. CNS malformations a. Spina bifida: the most common CNS malformation i. Leptomeningocele ii. Myelomeningocele iii. Meningocele iv. Spina bifida occulta v. Cord tethering b. Craniosynostosis 4. Skeletal malformations a. Vertebral anomalies i. Presence of extra vertebrae ii. Hemivertebrae and associated scoliosis iii. Absent vertebrae b. Pubic diastasis c. Lower extremity anomalies i. Clubfoot deformities ii. Limb deficiencies 5. Genitourinary malformations a. Bladder anomaly i. Open ii. Separated into 2 halves iii. Flanking the exposed interior of the cecum iv. Openings to the remainder of the hindgut v. Prolapse of the terminal ileum as a “trunk” of bowel onto the cecal plate b. Renal anomalies i. A single kidney ii. Rudimentary kidney iii. Pelvic ectopic kidney iv. Ureteropelvic junction obstruction v. Malrotation vi. Crossed renal ectopia

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c. Ureteral anomalies i. Duplication ii. Ectopic insertion iii. Distal stricture and megaureter d. Male genitalia anomalies i. Small and bifid penis ii. Hemiglans located caudal to each hemibladder e. Female genitalia anomalies i. Bifid clitoris ii. Uterine duplication iii. Vaginal duplication iv. Vaginal agenesis 6. Prognosis a. Used to be uniformly fatal malformation in its worst form b. Currently with an 80–100% survival rate due to early surgical repair but accompanied by lifelong severe morbidity

DIAGNOSTIC INVESTIGATIONS 1. Evaluation of associated malformations 2. Karyotyping for genetic sex 3. Renal ultrasonography for renal and upper urinary tract anomalies 4. Voiding cystourethrography to assess bladder capacity in early childhood in preparation for continence reconstruction 5. Radiographic studies to demonstrate spinal dysraphism a. Plain spinal radiographs b. Myelography c. CT d. CT myelography e. Spinal MRI to identify occult abnormalities that predispose to symptomatic spinal cord tethering

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: recurrence in subsequent pregnancies noted in one report b. Patient’s offspring: Lack of offspring from patients with cloacal exstrophy making the determination of inheritance difficult 2. Prenatal diagnosis by ultrasonography a. Elevated maternal serum α-fetoprotein (AFP) in OEIS complex. The open ventral wall defect likely results in AFP leakage b. Ultrasonography i. Major ultrasound criteria a) Nonvisualization of the bladder (91%) b) A large midline infraumbilical anterior wall defect or cystic anterior wall structure (persistent cloacal membrane) (82%) c) Omphalocele (77%) d) Lumbosacral myelomeningocele (68%) ii. Minor (less frequent) ultrasound criteria a) Lower limb defects (23%) b) Renal anomalies (23%) c) Ascites (14%) d) Widened pubic arches (18%) e) A narrow thorax (9%)

f) Hydrocephalus (9%) g) A single umbilical artery (9%) 3. Management a. Appropriate parental counseling and referral to a center with significant expertise in the management of cloacal exstrophy when prenatal diagnosis is made b. Medical stabilization of the infant i. Fluid and electrolyte replacement ii. Parenteral nutrition iii. Moisten the exstrophied bladder and bowel with saline and cover them with a protective plastic dressing iv. Daily prophylactic antibiotics c. Gender assignment i. Evaluation of the genitalia ii. Decision limited to the genetic male patients with cloacal exstrophy a) Male gender assignment appropriate for male patients with adequate bilateral or unilateral phallic structures b) Male neonates with minimal phallic structures: appropriate to raise as female subjects with early excision of the gonads c) Appropriate hormonal manipulation to improve psychosexual dysfunction d) Improvements in phallic reconstruction eventually allow most genetic male patients to be assigned male gender iii. Initial sexual reassignment to be done in conjunction with extensive family counseling as well as continued counseling for the parents and children d. Management of gastrointestinal malformations i. Closure of omphalocele ii. Combined with gastrointestinal diversion or reconstruction a) Ileostomy with resection of the hindgut remnant b) Colostomy e. Management of genitourinary malformations i. Bladder closure ii. Initial bladder excision and urinary diversion iii. Further augmentation or urinary diversions to achieve continence f. Management of CNS malformations i. Closure of myelomeningocele ii. Cord untethering iii. Spinal fusion iv. Cranial expansion for craniosynostosis g. Management of orthopedic malformations i. Manage myelodysplasia ii. Pelvic osteotomies iii. Various orthopedic devices to assist with ambulation

REFERENCES Austin PF, Homsy YL, Gearhart JP, et al.: The prenatal diagnosis of cloacal exstrophy. J Urol 160:1179–1181, 1998. Baker Towell DM, Towell AD: A preliminary investigation into quality of life, psychological distress and social competence in children with cloacal exstrophy. J Urol 169:1850–1853, 2003.

CLOACAL EXSTROPHY Carey JC, Greenbaum B, Hall Arch Dermatol: The OEIS complex (omphalocele, exstrophy, imperforate anus, spinal defects). Birth Defects Orig Artic Ser XIV(6B):253–263, 1978. Chitrit Y, Zorn B, Filidori M, et al.: Cloacal exstrophy in monozygotic twins detected through antenatal ultrasound scanning. J Clin Ultrasound 21:339–342, 1993. Davidoff AM, Hebra A, Balmer D, et al.: Management of the gastrointestinal tract and nutrition in patients with cloacal exstrophy. J Pediatr Surg 31:771–773, 1996. Diamond DA, Jeffs RD: Cloacal exstrophy: a 22-year experience. J Urol 133:779–782, 1985. Dick EA, de Bruyn R, Patel K, et al.: Spinal ultrasound in cloacal exstrophy. Clin Radiol 56:289–294, 2001. Flanigan RC, Casale AJ, McRoberts JW: Cloacal exstrophy. Urology 23:227–233, 1984. Fujiyoshi Y, Nakamura Y, Cho T, et al.: Exstrophy of the cloacal membrane. A pathologic study of four cases. Arch Pathol Lab Med 111:157–160, 1987. Gosden C, Brock DJH: Prenatal diagnosis of exstrophy of the cloaca. JAMA8: 95, 1981. Hurwitz RS, Manzoni GA, Ransley PG, et al.: Cloacal exstrophy: a report of 34 cases. J Urol 138:1060–1064, 1987. Jeffs RD: Exstrophy and cloacal exstrophy. Urol Clin North Am 5:127–140, 1978. Kaya H, Oral B, Dittrich R, et al.: Prenatal diagnosis of cloacal exstrophy before rupture of the cloacal membrane. Arch Gynecol Obstet 263: 142–144, 2000. Kutzner DK, Wilson WG, Hogge WA: OEIS complex (cloacal exstrophy): prenatal diagnosis in the second trimester. Prenat Diagn 8:247–253, 1988.

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Lee DH, Cottrell JR, Sanders RC, et al.: OEIS complex (omphalocele-exstrophyimperforate anus-spinal defects) in monozygotic twins. Am J Med Genet 84:29–33, 1999. Loder RT, Dayioglu MM: Association of congenital vertebral malformations with bladder and cloacal exstrophy. J Pediatr Orthop 10:389–393, 1990. Lund DP, Hendren WH: Cloacal exstrophy: experience with 20 cases. J Pediatr Surg 28:1360–1368; discussion 1368–1369, 1993. Lund DP, Hendren WH: Cloacal exstrophy: a 25-year experience with 50 cases. J Pediatr Surg 36:68–75, 2001. Mathews R, Jeffs RD, Reiner WG, et al.: Cloacal exstrophy-improving the quality of life: the Johns Hopkins experience. J Urol 160:2452–2456, 1998. Meglin AJ, Balotin RJ, Jelinek JS, et al.: Cloacal exstrophy: radiologic findings in 13 patients. AJR Am J Roentgenol 155:1267–1272, 1990. Mitchell ME, Plaire C: Management of cloacal exstrophy. Adv Exp Med Biol 511:267–270; discussion 270–263, 2002. Molenaar JC: Cloacal exstrophy. Semin Pediatr Surg 5:133–135, 1996. Reddy RA, Bharti B, Singhi SC: Cloacal exstrophy. Arch Dis Child 88:277, 2003. Schober JM, Carmichael PA, Hines M, et al.: The ultimate challenge of cloacal exstrophy. J Urol 167:300–304, 2002. Smith NM, Chambers HM, Furness ME, et al.: The OEIS complex (omphaloceleexstrophy-imperforate anus-spinal defects): recurrence in sibs. J Med Genet 29:730–732, 1992. Smith EA, Woodard JR, Broecker BH, et al.: Current urologic management of cloacal exstrophy: experience with 11 patients. J Pediatr Surg 32: 256–261; discussion 261–252, 1997. Yerkes EB, Rink RC: Exstrophy and epispadias. 2002. www.emedicine.com

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Fig. 1. Two infants (A,B;C) with cloacal exstrophy. The schematic diagram (D) illustrates the anatomy of various defects in the second infant (C).

Collodion Baby b. The term “collodion baby” is considered a descriptive term for infants born encased in membrane-like thick scale and includes several heterogeneous conditions c. Several disorders of cornification showing this phenotype at birth d. A mutation of keratinocyte transglutaminase may play a role in lamellar ichthyosis, although lamellar ichthyosis is still considered genetically heterogeneous e. Keratinocytes lacking specific transglutaminase will not cause cross-linked envelopes

Collodion baby is a descriptive term for infants born encased in a membrane-like thick scale resembling oiled parchment or collodion. Neonates born with the features of collodion baby subsequently develop lamellar ichthyosis, ichthyosiform erythroderma, or other forms of ichthyosis. Collodion baby is a rare congenital condition accounting for 1 in 50,000 to 1 in 100,000 deliveries.

GENETICS/BASIC DEFECTS 1. Etiology a. Common severe phenotype (not associated with noncutaneous features) i. Autosomal recessive nonbullous congenital erythrodermic ichthyosis (50% of cases) including harlequin fetus. Harlequin ichthyosis represents the most severe end of the phenotypic spectrum ii. Autosomal recessive lamellar ichthyosis (10%) with mutations in the gene for keratinocyte transglutaminase (TGM1) on chromosome 14q11 in many patients iii. Two self-healing collodion baby siblings observed to have compound heterozygous transglutaminase 1 mutations G278R and D490G iv. Mapping of a second locus for lamellar ichthyosis to chromosome 2q33-q35 v. Rare reports of autosomal dominant lamellar ichthyosis vi. Other clinically indistinguishable cases linked to chromosomes 3 and 19 b. Common milder phenotypes i. Mild form of ichthyosis vulgaris (10%) ii. Recovery without sequaelae (10%) c. Associated congenital ichthyosis i. Trichothiodystrophy ii. Poorly documented true collodion membrane a) Sjogren-Larsson syndrome (ichthyosis, spastic paraplegia, mental retardation, and retinopathy with abnormal levels of fatty aldehyde dehydrogenase activity in cultured fibroblasts) b) Netherton syndrome c) Gaucher disease type II d) Congenital hypothyroidism e) Conradi syndrome f) Dorfman Chanarin syndrome g) Ketoadipiaciduria h) Koraxitrachitic syndrome i) Ichthyosis variegata j) Palmoplantar keratoderma with anogenital leukokeratosis 2. Pathogenesis a. Pathogenesis not yet clarified

CLINICAL FEATURES 1. Major clinical features a. Newborn covered with a taut, shiny membrane resembling plastic wrap b. The membrane often fissured and cracked at birth c. Lamellar exfoliation cracks and peels over the course of several weeks to reveal underlying normal skin or skin with mild scaling that goes on to resolve d. Red/ivory-colored (erythematous) underlying skin e. Persistence of mild ichthyosis in some patients f. Ectropion (eversion of the eyelids) g. Eclabium (eversion of the lips) h. Crumpled pinnae i. Resolved tapered fingertips and partially flexed hands with shedding of the encasing membrane 2. Minor clinical features a. Secondary skin infections in the cracks and fissures b. Scarring in the areas of deep fissuring 3. Complications a. Difficulties in temperature regulation b. Increased insensible water loss predisposing to hypernatremic dehydration c. Secondary infections from gram-positive organisms and Candida albicans d. Septicemia e. Pneumonia secondary to aspiration of squamous material in the amniotic fluid f. Respiratory difficulty due to restricted chest wall movement g. Possible loss of vision caused by corneal damage 4. Prognosis a. Long-term prognosis difficult to address at birth b. Infrequently, a collodion baby may have normal skin after exfoliation of the membranes

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1. Skin biopsy a. Transglutaminase assay b. Conventional and electron microscopy

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i. Hyperkeratosis with thick compact cornified layer (orthokeratoric stratum corneum) ii. Aberrant keratinized/cornified cells iii. Irregularly convoluted horny cells and numerous intercellular Odland bodies (lamellar granules) and nuclear debris in distal layer of the stratum corneum 2. Molecular genetic analysis a. TGM1 sequence analysis: identification of mutation of keratinocyte transglutaminase 1 gene for severe form of autosomal recessive lamellar ichthyosis and self-healing collodion baby b. TGM1 mutations include missense, nonsense, and splice site c. Carrier testing available to at-risk family members on a clinical basis once the mutation in TGM1 has been identified in the proband 3. Studies for other associated conditions a. Polarized light examination of hair and eye brows i. Trichothiodystrophy ii. Netherton syndrome b. Leukocyte lipid inclusions i. Dorfman Chanarin syndrome ii. Neonatal Gaucher disease c. Thyroid hormone level: congenital hypothyroidism d. Skeletal study: Conradi syndrome e. Neurosensory evaluation

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Autosomal recessive inheritance: 25% recurrence risk ii. Autosomal dominant inheritance: not increased unless a parent is affected b. Patient’s offspring i. Autosomal recessive inheritance: not increased unless the spouse is a carrier or affected ii. Autosomal dominant inheritance: 50% 2. Prenatal diagnosis: direct mutation analysis of the keratinocyte transglutaminase 1 gene on fetal DNA obtained from amniocentesis or CVS for severe form of autosomal recessive lamellar ichthyosis, provided the mutation in TGM1 has been identified in the proband 3. Management: requiring intensive care a. Maintain skin integrity i. Assess open skin lesions ii. Minimal handling with precaution iii. Prevent secondary infection and avoid prophylactic use of antibiotics b. Maintain body temperature i. Avoid radiant heat ii. Use humidified incubator for dehydration and hypothermia iii. Pre-warm all linen used to absorb weeping

c. Ophthalmological management of ectropion important for the prevention of conjunctivitis and keratitis d. Sedation with opioids indicated for severe pain e. Retinoids in case of delayed shedding of the collodion membrane beyond 3 weeks f. Use keratolytics agents (e.g., alpha-hydroxy acid preparations) to promote peeling and thinning of the stratum corneum as the child becomes older

REFERENCES Akcakus M, Gunes T, Kurtoglu S, et al.: Collodion baby associated with asymmetric crying facies: a case report. Pediatr Dermatol 20:134–136, 2003. Akiyama M: Severe congenital ichthyosis of the neonate. Int J Dermatol 37:722–728, 1998. Akiyama M, Shimizu H, Yoneda K, et al.: Collodion baby: ultrastructure and distribution of cornified cell envelope proteins and keratins. Dermatology 195:164–168, 1997. Akiyama M, Takizawa Y, Kokaji T, et al.: Novel mutations of TGM1 in a child with congenital ichthyosiform erythroderma. Brit J Derm 144: 401–407, 2001. Bale SJ: Autosomal recessive congenital ichthyosis. Gene Reviews, 2003. http://genetests.org Buyse L, Graves C, Marks R, et al.: Collodion baby dehydration: the danger of high transepidermal water loss. Br J Dermatol 129:86–88, 1993. Cserhalmi-Friedman PB, Milstone LM, Christiano AM: Diagnosis of autosomal recessive lamellar ichthyosis with mutations in the TMG1 gene. Br J Dermatol 144:726–730, 2001. Frenk E, de Techtermann F: Self-healing collodion: evidence for autosomal recessive inheritance. Pediatr Dermatol 9:95–97, 1992. Huber M, Rettler I, Bernasconi K, et al.: Mutations of keratinocyte transglutaminase in lamellar ichthyosis. Science 267:525–528, 1995. Jeon S, Djian P, Green H: Inability of keratinocytes lacking specific transglutaminase to form cross-linked envelopes: absence of envelopes as a simple diagnostic test for lamellar ichthyosis. Proc Natl Acad Sci USA 95: 687–690, 1998. Pigg M, Gedde-Dahl T Jr, Cox DW, et al.: Haplotype association and mutation analysis of the transglutaminase 1 gene for prenatal exclusion of lamellar ichthyosis. Prenat Diagn 20:132–137, 2000. Raghunath M, Hennies HC, Ahvazi B, et al.: Self-healing collodion baby: a dynamic phenotype explained by a particular transglutaminase-1 mutation. J Invest Dermatol 120:224–228, 2003. Russell LJ, DiGiovanna JJ, Rogers Genome Res, et al.: Mutations in the gene for transglutaminase 1 in autosomal recessive lamellar ichthyosis. Nat Genet 9:279–283, 1995. Sandler B, Hashimoto K: Collodion baby and lamellar ichthyosis. J Cutan Pathol 25:116–121, 1998. Schorderer DF, Huber M, Laurini RN, et al.: Prenatal diagnosis of lamellar ichthyosis by direct mutational analysis of the keratinocyte transglutaminase gene. Prenat Diagn 17:483–486, 1997. Shareef MJ, Lawlor-Klean P, Kelly KA, et al.: Collodion baby: a case report. J Perinatol 4:267–269, 2000. Stone DL, Carey WF, Christodoulou J, et al.: Type 2 Gaucher disease: the collodion baby phenotype revisited. Arch Dis Child Fetal Neonatal Ed 82:F163–166, 2000. Sybert VP: Disorders of the epidermis. In: Sybert VP (ed): Genetic Skin Disorders. New York, Oxford: Oxford University Press, 1997, pp 23–26. Taïeb A, Labrèze C: Collodion baby: What’s new. J Eur Acad Dermatol Venereol 16:436–437, 2002. Van Gysel D, Lijnen RLP, Moekti S, et al.: Collodion baby: a follow-up study of 17 cases. J Eur Acad Dermatol Venereol 16:472–475, 2002. Williams ML, Elias PM: Genetically transmitted, generalized disorders of cornification: The ichthyosis. Dermatol Clin 5:155–178, 1987.

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Fig 1. A collodion baby wrapped with a taut, shinny membrane over the whole body, red underlying skin, ectropion, crumpled pinnae, and partially flexed hands by encasing membrane.

Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency) 21-hydroxylase deficiency is the most common type of congenital adrenal hyperplasia (CAH). The incidence of classic 21hydroxylase deficiency is estimated to be 1/12,000–1/15,000 births. The nonclassical form of the disease, also called “lateonset” CAH, occurs in approximately 1 in 1000 of the general population depending on the ethnic group and in up to 6% of hirsute women.

GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. Biochemical and molecular basis a. Deficient 21-hydroxylase activity: the most common form (>90% of cases) of CAH b. Caused by mutations of CYP21 (CYP21A2) gene, mapped on the short arm of chromosome 6 (6p21.3): present in duplicate c. A highly homologous pseudogene (CYP21P) i. Located in the same chromosomal region as the active gene ii. Severe mutations of the pseudogene incompatible with coding for a functional enzyme d. About 95% of mutant alleles generated by recombination events between CYP21 and CYP21P e. Relatively common exchange of genetic material between these two homologous genes, the major reason for the high incidence of 21-hydroxylase deficiency compared to other forms of CAH 3. Pathophysiology a. Classic form of 21-hydroxylase deficiency i. Prenatal exposure to potent androgens (testosterone and delta4-androstenedione) at critical stages (8–12 weeks) of sexual differentiation resulting in virilization of the external genitalia in genetic females, resulting in varying degrees of genital ambiguity (female pseudohermaphroditism) at birth ii. Subdivision of classic form a) Simple virilizing form (about 25%) b) Salt-wasting form (>75%) in which aldosterone production is inadequate and at risk of life-threatening salt-wasting crises b. Nonclassic “late onset” form of 21-hydroxylase deficiency i. Has only moderate enzyme deficiency ii. Present postnatally with signs of hyperandrogenism iii. Females with the nonclassic form: not virilized at birth 4. CAH due to 21-hydroxylase deficiency a. 21-hydroxylase i. A microsomal cytochrome P450 enzyme ii. Required to convert: 198

a) 17-hydroxy-progesterone to 11-deoxycortisol b) Progesterone to deoxycorticosterone b. 21-hydroxylase deficiency i. Impairs the metabolism of cholesterol to cortisol, generating excessive level of 17-hydroxyprogesterone ii. Produces androstenedione and other androgens from the precursor (17-hydroxyprogesterone) via an alternative metabolic pathway iii. Aldosterone deficiency a) Inability to synthesize adequate amounts of aldosterone due to severely impaired 21hydroxylation of progesterone in about 75% of patients b) Resulting in sodium loss via the kidney, colon and sweat glands and excrete potassium from the renal tubules c. Cortisol deficiency i. Glucocorticoids a) Increase cardiac contractility b) Increase cardiac output c) Increase cardiac and vasculature sensitivity to the pressor effects of catecholamines and other pressor hormone ii. Absence of glucocorticoids a) Decrease in cardiac output b) Decrease in glomerular filtration leading to an inability to excrete free water and consequently to hyponatremia d. Shock and severe hyponatremia much more likely in 21-hydroxylase deficiency in which both cortisol and aldosterone biosynthesis are affected 5. Phenotype–genotype correlations a. Mutations in CYP21, such as deletions, frameshifts, or nonsense mutations i. Totally ablate enzyme activity ii. Most often associated with salt-wasting b. Mutations mainly consisting of the missense mutation Ile172Asn (Il72N) i. Yielding enzymes with 1–2% normal activity ii. Carried predominantly by patients with simple virilizing disease c. Mutations such as Val281Leu (V281L) and Pro30Leu (P30L) i. Producing enzymes with 20–60% of normal activity ii. Most often associated with the nonclassical disorder d. Two different CYP21 mutations i. Producing compound heterozygotes ii. Most often with a phenotype compatible with that of the less severe gene defects

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e. All patients homozygous or compound heterozygous for large deletions or gene conversions have a saltwasting classic form

CLINICAL FEATURES 1. Classic CAH phenotype a. Simple virilizing form (about 25% of patients) b. Salt wasting form (>75% of patients) i. Adrenal crises present at 1–4 weeks of age in severely affected patients a) Severe dehydration b) Hypotension c) Severe hyponatremia, hyperkalemia, and hyperreninemia d) Progressing to adrenal crisis (azotemia, vascular collapse, hypovolemic shock, and death) if adequate medical care is not provided e) Affected infant boys who are not detected in a newborn screening program are at high risk of a salt-wasting crisis since their normal genitalia fail to alert physicians to the diagnosis of congenital adrenal hyperplasia ii. Nonspecific symptoms a) Poor appetite/feeding b) Vomiting c) Hypotension d) Lethargy e) Failure to gain weight (weight loss) iii. Improved sodium balance and more efficient aldosterone synthesis with age in patients known to have severe slat-wasting episodes in infancy and early childhood iv. Siblings may be discordant for salt wasting v. The degree of salt wasting may vary in individuals carrying identical mutations vi. Patients with 3β-hydroxysteroid hydrogenase deficiency, aldosterone synthase deficiency, or lipoid hyperplasia a) Unable to synthesize aldosterone b) May present with salt-wasting crises c. Children with classic CAH i. Lack sufficient amounts of cortisol to mount a stress response and frequently succumb to minor illnesses ii. Premature closure of the epiphyses resulting in short stature even though these children grow at an accelerated rate when young d. Growth disturbances i. Accelerated skeletal maturation in untreated patients due to high levels of androgen ii. Growth retardation in patients treated with excessive doses of glucocorticoids iii. Final height, despite careful monitoring and good patient compliance, usually averaging one to two standard deviations below the population mean or the target height based on parental heights e. Reproductive problems in affected females

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i. Ambiguous genitalia typically present in the neonatal period a) Clitoromegaly (mild) b) With or without partial fusion of the labioscrotal folds (intermediate) c) Complete fusion of the labioscrotal folds with the appearance of a penile urethra (severe) ii. Internal genitalia a) Normal ovaries, fallopian tubes, and uteri b) Normal upper third of the vagina but urogenital sinus may be present distally with one opening on the perineum iii. Signs of androgen excess in affected females without glucocorticoid replacement therapy a) Clitoral enlargement b) Excessive linear growth c) Advanced bone age d) Acne e) Early onset of pubic and axillary hair f) Hirsutism g) Male pattern baldness h) Menstrual abnormalities i) Reduced fertility iv. Adolescence a) Late menarche in inadequately treated girls b) Sonographic finding of multiple ovarian cysts similar to patients with polycystic ovarian syndrome c) Anovulation d) Irregular bleeding e) Hyperandrogenic symptoms v. Pregnancy and live-birth rates a) Severely reduced in salt-wasting patients b) Mildly reduced in simple virilizing patients c) Normal in nonclassical patients vi. Factors suggested responsible for the impaired fertility a) Adrenal overproduction of androgens and progestins (17-hydroxyprogesterone, progesterone, and androstenedione) b) Ovarian hyperandrogenism c) Polycystic ovary syndrome d) Ovarian adrenal rest tumors e) Neuroendocrine factors f) Genital surgery g) Psychosocial factors (delayed psychosexual development, reduced sexual activity, low maternal feelings) vii. No evidence of an excess of congenital malformations in offspring of women with 21-hydroxylase deficiency viii. Other types of congenital adrenal hyperplasia a) 11β-hydroxylase deficiency: similar to 21hydroxylase deficiency b) 17α-hydroxylase deficiency: remains sexually infantile due to inability to synthesize sex hormones unless supplemented with estrogen c) 3β-hydroxysteroid hydrogenase deficiency: slightly virilized due to high levels of dehydroepiandrosterone

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f. Reproductive function and problems in affected males i. Signs of androgen excess in affected males without glucocorticoid replacement therapy a) Penile enlargement b) Small testes c) Excessive linear growth d) Advanced bone age e) Acne f) Early onset of pubic and axillary hair ii. Ability to father children iii. Testicular adrenal rests a) Most often benign b) Manifest as testicular enlargement c) Seen most often in inadequately treated patients, particularly those with the saltwasting form of 21-hydroxylase deficiency iv. Other types of congenital adrenal hyperplasia a) Men with 11β-hydroxylase deficiency: similar to those with 21-hydroxylase deficiency b) Genetic males with 3β-hydroxysteroid hydrogenase deficiency, 17α-hydroxylase deficiency, or lipoid hyperplasia: usually raised as females and castrated during or before adolescence to prevent malignant transformation of abdominal testes g. Effects on gender role, sexual orientation, and identity i. Gender role a) Referring to gender-stereotyped behaviors such as choice of play toys by young children b) Girls with 21-hydroxylase deficiency may show low interest in maternal behavior, extending from lack of doll play in early childhood to lack of interest in childrearing in women. ii. Sexual orientation a) Referring to homosexual versus heterosexual preferences b) Heterosexuality in most adult women with 21-hydroxylase deficiency c) Homosexuality or bisexuality or increased tendency to homo-erotic fantasies in a small but significant proportion in women with 21-hydroxylase deficiency iii. Gender identity a) Referring to self-identification as male or female b) Self-reassignment to the male sex is unusual in women with 21-hydroxylase deficiency c) Severely virilized females are more likely to be raised as males in cultures that value boys more highly and/or in third world countries in which the diagnosis is likely to be delayed 2. Nonclassic CAH phenotype a. Having only moderate enzyme deficiency b. Nonambiguous external genitalia, with normal or mild clitoromegaly, in females affected with mild, nonclassical form of 21-hydroxylase deficiency c. Signs of androgen excess i. Wide spectrum of symptoms and signs

ii. Asymptomatic in many affected individuals iii. Children: premature pubarche iv. Young women a) Severe cystic acne b) Hirsutism c) Oligomenorrhea d. Signs and symptoms suggesting mild CAH i. Children a) Moderate to severe recurrent sinus or pulmonary infections b) Severe acne c) Hyperpigmentation, especially of the genitalia d) Tall for age e) Early onset of puberty ii. Adults a) Childhood history as described above b) Syncope or near-syncope c) Shortened stature compared with either parent d) Hypotension (21-hydroxylase deficiency) e) Hypertension (11β-hydroxylase deficiency) iii. Women a) Clitoromegaly b) Poorly developed labia c) Premature adrenarche d) Hirsutism e) Menstrual disturbances f) Infertility g) Polycystic ovary syndrome

DIAGNOSTIC INVESTIGATIONS 1. Newborn screening a. Objectives i. Detect a common and potentially fatal childhood disease (classic form of CAH) ii. Prevent serious morbidity and mortality by early recognition and treatment iii. Prevent incorrect male sex assignment of affected female infants with ambiguous genitalia iv. Detect most, but not all, cases of the nonclassic form of 21-hydroxylase deficiency b. Filter-paper blood spot sample i. Markedly elevated 17-hydroxyprogesterone by radioimmunoassay ii. False positives a) Samples taken in the first 24 hours of life (elevated in all infants) b) Variation of weight adjusted cut-off values among newborn screening programs c) Infants with low birth weight or prematurity iii. Second level of screening based on detection of actual mutations on DNA extracted from the same dried blood spots c. Main benefits of newborn screening i. Reduced morbidity and mortality ii. Reduced time to diagnosis of infants with 21hydroxylase deficiency iii. Infants ascertained through screening a) Less severe hyponatremia b) Tend to be hospitalized for shorter periods of time

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2. Diagnosis of CAH a. Female neonates i. With genital ambiguity a) Genital ambiguity highly distressing to the family b) Require urgent expert medical attention c) Need immediate comprehensive evaluation by a multidisciplinary team including specialists from pediatric endocrinology, psychosocial services, pediatric surgery/ urology, and genetics ii. With or without salt loss iii. Presence of elevated concentration of serum 17hydroxyprogesterone a) Only diagnostic of CAH when measured after the 3rd day of life b) Presence of relatively high concentrations in the immediate neonatal period in normal infants iv. Normal internal female genitalia on pelvic ultrasonography v. Normal female karyotype (46,XX) b. Male neonates i. Salt-losing crises ii. Presence of elevated 17-hydroxyprogesterone concentration 3. Clinical chemistry a. Comparison of baseline and cortrosyn stimulated serum concentrations of the steroid precursor 17hydroxyprogesterone (nonclassical) b. Increased serum levels of progesterone, 17-hydroxyprogesterone, and androstenedione in affected males and females with classic 21-hydroxylase deficiency c. Elevated serum levels of testosterone and adrenal androgen precursors in affected girls d. Salt losers i. Low serum bicarbonates, sodium and chloride levels ii. Elevated levels of serum potassium and serum urea nitrogen iii. Hyponatremia and hyperkalemia usually not present before 7 days of age iv. Inappropriately increased urine sodium levels v. Elevated plasma rennin levels vi. Serum aldosterone level inappropriately low for the rennin level 4. Karyotyping or fluorescence in situ hybridization for sex chromosome material a. 46,XX in females with 21-hydroxylase deficiency b. 46,XY in males with 21-hydroxylase deficiency 5. Annual bone age radiography 6. Careful monitoring of linear growth 7. Transabdominal pelvic sonography a. Perform in patients with CAH undergoing vaginal reconstruction b. Provide adequate information about the anatomy of the vagina and urogenital sinus c. Demonstrate presence or absence of a uterus or associated renal anomalies 8. Urogenitogram helpful to define the anatomy of the internal genitalia

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9. Adrenal ultrasonography to detect enlarged, lobulated adrenals with stippled echogenicity invariably associated with CAH 10. Sonography or MRI for testicular adrenal rest tumors 11. Carrier detection a. Carriers: asymptomatic individuals who have one normal allele and one mutant allele b. ACTH stimulation test i. Resulting in slightly elevated serum concentrations of deoxycortisol and 17-hydroxyprogesterone ii. Overlap in serum concentration of 17-hydroxyprogesterone between carriers and noncarriers iii. No longer the preferred method of carrier detection c. Molecular genetic testing i. Molecular genetic testing of the CYP21A2 gene available to at-risk relatives, given that the diseasecausing mutation(s) have been identified in the proband ii. The preferred method of carrier detection 12. Molecular genetic testing a. Molecular genetic analysis for CYP21A2 gene for a panel of 9 common mutations and gene deletions detect about 90–95% of disease-causing alleles in affected individuals and carriers b. Complete gene sequencing detects more rare alleles in affected individuals in whom the panel of nine mutations and deletions reveals only one or neither disease-causing allele c. Applications i. Primarily used in genetic counseling for carrier detection of at-risk relatives and for prenatal diagnosis ii. Can be used for diagnosis in newborns with slight to moderate elevations of 17-hydroxyprogesterone

GENETIC COUNSELING 1. Recurrence risk a. Genetic counseling according to autosomal recessive inheritance i. Most parents: heterozygotes with one normal allele and one mutated allele ii. 1% of probands having only one parent who is heterozygous since 1% of mutations occur de novo iii. In some instances, a parent, who was previously not known to be affected, was found to have the nonclassic form of 21-hydroxylase deficiency b. Patient’s sib i. When the parents of a proband are both obligate heterozygotes a) 25% risk of inheriting both altered alleles and being affected b) 50% risk of inheriting one altered allele and being an unaffected carrier c) 25% risk of inheriting both normal allele and being unaffected d) 2/3rd chance of unaffected sibs of a proband being a carrier

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ii. When a parent of a proband has 21-hydroxylase deficiency and the other is heterozygous a) 50% risk of inheriting both mutant alleles and being affected b) 50% risk of inheriting one mutant allele and being a carrier c. Patient’s offspring for a woman with classic 21hydroxylase deficiency i. When the spouse status is unknown a) Risk of having an infant with the same disorder: approximately 1 in 120 births b) Risk of having an affected female infant: approximately 1 in 240 births c) Risk figures are based on an estimated 1 in 60 incidence of heterozygous individuals with a CYP21 mutation, derived from newborn screening data ii. When the spouse is not a carrier or not affected: risk is not increased iii. Appropriate to offer molecular genetic testing of the CYP21A2 gene to the spouse given the high carrier rate for 21-hydroxylase deficiency d. Patient’s offspring for a woman with nonclassic CAH and are compound heterozygotes with one severe CYP21A2 mutation: risk of having an affected infant with classic CAH is 1 in 4 pregnancies (or 1 in 8 pregnancies for an affected female infant) when the spouse is a known carrier of the severe form of CYP21A2 deficiency 2. Prenatal diagnosis a. Determination of amniotic fluid (AF) hormone levels i. Elevated 17α-hydroxyprogesterone ii. Elevated androstenedione b. Human leukocyte antigen (HLA) typing on cultured chorionic villus cells and cultured AF cells i. Basis for prenatal diagnosis: the gene for 21hydroxylase has been linked to the HLA system on chromosome 6 ii. HLA type a) Fetus with an HLA type identical to that of the proband with 21-hydroxylase deficiency predicted to be affected b) Fetus sharing 1 parental haplotype with the proband predicted to be a heterozygous carrier c) Fetus with both haplotypes different from the index case predicted to be homozygous normal c. Molecular DNA diagnosis i. Molecular genetic testing of the proband and both parents should be undertaken prior to conception: a) To identify the two disease-causing mutations b) To confirm both parents are carriers ii. Analysis of both parents a) To determine the phase of different mutations (whether they lie on the same or opposite alleles) b) To distinguish homozygotes and hemizygotes (individuals who have a mutation on one chromosome and a deletion on the other)

iii. De novo mutations, found in patients with CAH but not in parents, observed in 1% of diseasecausing CYP21B mutations iv. Before 10 weeks of gestation and prior to any prenatal testing, administer dexamethasone to the pregnant mother to suppress excess fetal adrenal androgen secretion and to prevent virilization of an affected female v. Obtain fetal cells to determine fetal sex by chromosome analysis or FISH using Y-chromosome specific probes a) CVS in the 10th–12th week of gestation (preferable because of early result) b) Amniocentesis at 16–18 weeks of gestation vi. If the fetus is a female and if the two CYP21A2 disease-causing mutations have been identified in the proband a) Perform molecular genetic testing to determine whether the fetus has inherited both disease-causing alleles b) Female fetus known to have 21-hydroxylase deficiency by DNA analysis or having an indeterminant status: continue dexamethasone treatment to term vii. If the fetus is a male or unaffected female by DNA analysis: discontinue dexamethasone treatment 3. Management a. Replacement with glucocorticoids (hydrocortisone, prednisone, dexamethasone) i. Indicated in all patients with classic and symptomatic non-classical patients with 21-hydroxylase deficiency ii. To suppress the excessive secretion of CRH and ACTH by the hypothalamus and pituitary iii. To reduce the abnormal blood levels of adrenal sex steroids iv. Situations in which increase hydrocortisone dose is needed in patients with classic 21-hydroxylase deficiency a) Febrile illness b) Surgery under general anesthesia v. Increase does of hydrocortisone or prednisone in pregnancy due to pregnancy-induced alterations in steroid metabolism and clearance vi. Glucocorticoid replacement also required in patients with CAH caused by other enzymatic deficiencies b. Mineralocorticoid replacement i. Mineralocorticoid (fludrohydrocortisone) and sodium chloride supplements required in infants with the salt-wasting form of 21-hydroxylase deficiency ii. Treat patients with simple virilizing form of the disease by fludrohydrocortisone to aid in adrenocortical suppression and reduce the dose of glucocorticoid required to maintain acceptable 17-hydroxyprogesterone levels iii. Signs of over treatment with mineralocorticoid and sodium replacement a) Hypertension b) Tachycardia

CONGENITAL ADRENAL HYPERPLASIA

c.

d.

e.

f.

g.

c) Suppressed plasma rennin activity iv. Other indications of fludrohydrocortisone replacement a) 3β-hydroxysteroid hydrogenase deficiency b) Aldosterone synthase deficiency c) Lipoid hyperplasia Other pharmacological approaches i. A novel 4-drug regimen for 21-hydroxylase deficiency a) Consisting of flutamide (an androgen receptor blocking drug), testolactone (an aromatase inhibitor), and low dose of hydrocortisone and fludrocortisone b) Benefit: produce less bone age advancement and attain more appropriate linear growth velocity than standard treatment c) Side effect: occurrence of central precocious puberty requiring treatment with gonadotrophin releasing hormone analog ii. Experimental treatment with carbenoxolone, an inhibitor of 11β-hydroxysteroid dehydrogenase Corrective surgery i. Decision about surgery a) Made by the parents, together with the clinical team b) After disclosure of all relevant clinical information and all available options c) Obtain informed consent ii. Objectives a) Genital appearance compatible with gender b) Unobstructed urinary emptying without incontinence or infections c) Good adult sexual and reproductive function iii. Clitoroplasty, rather than clitoridectomy, done in infancy iv. Vaginal reconstruction a) Often postponed until the age of expected sexual activity b) Single-stage corrective surgery in children Adrenalectomy i. Questionable therapeutic alternative ii. Likely to be used, if at all, in patients with severe 21-hydroxylase deficiency refractory to standard medical management Management of testicular adrenal rests i. Effective adrenal suppression with dexamethasone since many of these tumors are ACTHresponsive ii. Testis-sparing surgery for cases unresponsive to dexamethasone after imaging the tumor by sonography and/or MRI Management of adolescence with classical and nonclassical CAH i. Psychological assessment and support of the patient ii. Counseling a) Sexual function b) Future surgeries c) Gender role d) Issues related to living with a chronic disorder

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e) Low risk of women with CAH or nonclassic CAH having an affected fetus h. Management of pregnancy in women with classic 21hydroxylase deficiency i. Factors contributing to lower fertility rates a) Masculinization of the external genitalia b) An inadequate introitus c) Factors relating to genital reconstructive surgery (poor surgical repair, vaginal stenosis, and clitoral dysfunction) d) Hormonal factors (increased levels of adrenal androgens and progestational steroid, and ovarian hyperandrogenism) ii. Recent improvement of fertility prognosis a) Earlier detection and treatment of 21hydroxylase deficiency b) Surgical advances in genital reconstruction c) Higher patient compliance rates iii. Preconception issues for all women with classic 21-hydroxylase deficiency who desire pregnancy a) Need for glucocorticoid treatment b) Careful endocrine monitoring throughout gestation c) Ovulation induction with clomiphene citrate or gonadotropin therapy or in vitro fertilization for patients who do not achieve normal ovulatory cycles and fertility despite effective glucocorticoid therapy d) Most pregnancies are successful in carrying to term with a healthy outcome e) Preconceptional counseling about the risk of having a child affected with 21-hydroxylase deficiency iv. Gestational management a) Regular assessment of maternal clinical status, serum electrolytes, and circulating adrenal androgen levels during gestation to determine the need for increased glucocorticoid or mineralocorticoid therapy b) Signs of adrenal steroid insufficiency (excessive nausea, slat craving, and poor weight gain) c) Monitor hypertension and fluid retention in patients receiving mineralocorticoid therapy, particularly in the third trimester v. Labor and delivery a) Require stress doses of glucocorticoid therapy during labor and delivery b) Elective cesarean section considered for pregnant women with virilizing CAH, for cephalopelvic disproportion due to android pelvic characteristics and especially for those who have had reconstructive surgery of the external genitalia vi. Evaluation of the infant a) Clinical signs of adrenal suppression (hypotension, hypoglycemia), particularly in cases in which dexamethasone was administered during pregnancy b) Sign of ambiguous external genitalia

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c) Female pseudohermaphroditism secondary to either maternal hyperandrogenism or fetal 21hydroxylase deficiency (if the father is a carrier) i. Prenatal therapy i. Inclusion criteria a) A previously affected sibling or first-degree relative with known mutations causing classic CAH, proven by DNA analysis b) Reasonable expectation that the father is the same as the father of the proband c) Availability of rapid, high-quality genetic analysis d) Therapy started less than 9 weeks after the last menstrual period e) No plans for therapeutic abortion f) Reasonable expectation of patient compliance ii. Dexamethasone a) No salt-retaining activity b) Not significantly metabolized by placental 11β-hydroxysteroid dehydrogenase c) Able to cross the placenta iii. Administer dexamethasone to the mother in pregnancies at risk for a female child affected with virilizing adrenal hyperplasia a) To suppress fetal adrenal androgen production, beginning before the 7–8th week of gestation, to prevent ambiguity of the external genitalia in the female fetus with classic CAH b) To prevent progression of virilization on therapy after 7–8th week of gestation iv. Outcome of prenatally treated females a) Approximately 70% born with normal or only slightly virilized genitalia with clitoromegaly, partial labial fusion, or both b) Approximately 30% born with marked genital virilization v. Disadvantage: 7 out of 8 fetuses unnecessarily treated since CAH is inherited as an autosomal recessive disease and only affected girls benefit from the treatment vi. Prompt discontinuation of dexamethasone therapy to minimize potential risks of glucocorticoid toxicity if: a) Male sex determination by prenatal genetic diagnosis b) CYP21 genotype indicating that the fetus is unaffected vii. Refer patient to centers with expertise in the prenatal management of pregnancies at risk for CAH viii. Long-term follow-up studies still needed for prenatally treated children ix. Side effects of women treated to term (10%) a) Features of Cushing syndrome (excessive weight gain, severe striae, hypertension, hyperglycemia) b) Resolved when the treatment is discontinued x. Side effects of women treated for a shorter time (10–20%) a) Edema b) Gastrointestinal upset

c) Mood fluctuations d) Acne e) Hirsutism xi. Similar therapeutic approaches: effective in families at risk for 11β-hydroxylase deficiency, in which affected female fetuses may also suffer severe prenatal virilization xii. Prenatal therapy not appropriate for nonclassic CAH xiii. Parents of affected girls a) Many opting for prenatal medical treatment because of severe psychological impact of ambiguous genitalia on the child and on the family b) Obtain informed consent as to the potential fetal and maternal risks, some of which may yet to be recognized

REFERENCES Al-Alwan I, Navarro O, Daneman D, et al.: Clinical utility of adrenal ultrasonography in the diagnosis of congenital adrenal hyperplasia. J Pediatr 135:71–75, 1999. American Academy of Pediatrics Ad Hoc Writing Committee, 2000-2001: Technical Report: congenital adrenal hyperplasia. Pediatrics 106: 1511–1518, 2000. Bose HS, Sugawara T, Strauss JF III, et al.: The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. N Enl J Med 355:1970–1978, 1996. Chen H: Genetic disorders. In Paul I Liu (ed): Blue Book of Diagnostic Tests. Philadelphia, W. B. Saunders co., 1986, pp 421–462. Chertin B, Hadas-Halpern I, Fridmans A, et al.: Transabdominal pelvic sonography in the preoperative evaluation of patients with congenital adrenal hyperplasia. J Clin Ultrasound 28:122–124, 2000. Cutler GB Jr, Laue L: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N Engl J Med 323:1806–1813, 1990. David M, Forest MG: Prenatal treatment of congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency. J Pediatr 105:799–803, 1984. Deaton MA, Glorioso JE, Mclean DB: Congenital adrenal hyperplasia: not really a zebra. Am Fam Physician 59:1190–1196, 1999. Deneux C, Tardy V, Dib A, et al.: Phenotype-genotype correlation in 56 women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 86:207–213, 2001. Forest MG, Morel Y, David MP: Prenatal treatment of congenital adrenal hyperplasia. Trends Endocrinol Metab 9:284–289, 1998. Garner PR: Congenital adrenal hyperplasia in pregnancy. Semin Perinatol 22:446–456, 1998. Hall CM, Jones JA, Meyer-Bahlburg HF, et al.: Behavioral and physical masculinization are related to genotype in girls with congenital adrenal hyperplasia. J Clin Endocrinol Metab 89:419–424, 2004. Hoffman WH, Shin MY, Donohoue PA, et al.: Phenotypic evolution of classic 21-hydroxylase deficiency. Clin Endocrinol 45:103–109, 1996, Hughes IA: Clinical aspects of congenital adrenal hyperplasia: early diagnosis and prognosis. J Inher Metab Dis 9 (Suppl 1):115–123, 1986. Hughes IA: Management of congenital adrenal hyperplasia. Arch Dis Child 63:1399–1404, 1988. Hughes IA: Congenital adrenal hyperplasia: 21-hydroxylase deficiency in the newborn and during infancy. Semin Reprod Med 20:229–242, 2002. Hughes IA: Congenital adrenal hyperplasia: phenotype and genotype. J Pediatr Endocrinol Metab 15 (Suppl 5):1329–1340, 2002. Hughes IA: Intersex. BJU International 90:769–776, 2002. Joint LWPES/ESPE CAH Working Group, Writing Committee: Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. J Clin Endocrinol Metab 87:4098–4053, 2002. Kuttenn F, Couillin P, Girard F, et al.: Late-onset adrenal hyperplasia in hirsutism. N Engl J Med 313:224–231, 1985. Lajic S, Wedell A, Bui TH, et al.: Long-term somatic follow-up of prenatally treated children with congenital adrenal hyperplasia. Trends Endocr Metab 9:284–289, 1998.

CONGENITAL ADRENAL HYPERPLASIA Levine LS: Congenital adrenal hyperplasia. Pediatr Rev 21:159–170, 2000. Lo JC, Grumbach MM: Pregnancy outcomes in women with congenital virilizing adrenal hyperplasia. Endocrinol Metab Clin North Am 30:207–229, 2001. Merke DP, Cutler GB: New approaches to the treatment of congenital adrenal hyperplasia. JAMA 277:1073–1076, 1997. Meyer-Bahlburg HF: Gender and sexuality in classic congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 30:155–171, 2001. Miller WL: Molecular biology of steroid hormone synthesis. Endocr Rev 9:295–318, 1998. Miller WL: Congenital adrenal hyperplasia in the adult patient. Adv Intern Med 44:155–173, 1999. New MI: Steroid 21-hydroxylase deficiency (congenital adrenal hyperplasia). Am J Med 98:2S–8S, 1995. New MI: Antenatal diagnosis and treatment of congenital adrenal hyperplasia. Curr Urol Rep 2:11–18, 2001. New MI: Prenatal treatment of congenital adrenal hyperplasia. The United States experience. Endocrinol Metab Clin North Am 30:1–13, 2001. New MI, Putnam A: 21-hydroxylase deficiency. Gene Reviews, 2002. http://www.genetests.org New MI, Wilson RC: Genetic Disorders of the Adrenal Gland. In Rimoin DL, Connor JM, Pyeritz RE, Korf BR (eds): Emery and Rimoin’s Principles and Practice of Medical Genetics, 4th ed, Vol 2, Chapter 84, pp 2277–2314, 2002. New MI, Carlson A, Obeid J, et al.: Extensive personal experience. Prenatal diagnosis for congenital adrenal hyperplasia. J Clin Endocrinol Metab 86:5651–5657, 2001. Pang S: Congenital adrenal hyperplasia. Endocrinol Metab Clin 26: 853–891, 1997. Pang S, Shook MK: Current status of neonatal screening for congenital adrenal hyperplasia. Curr Opin Pediatr 9:419–423, 1997. Pang S, Wallace MA, Hofman L, et al.: Worldwide experience in newborn screening for classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Pediatrics 81:866–874, 1988. Ritzén EM: Prenatal treatment of congenital adrenal hyperplasia: a commentary. Trends Endocr Metab 9:293–295, 1998. Ritzén EM: Prenatal dexamethasone treatment of fetuses at risk for congenital adrenal hyperplasia: benefits and concerns. Semin Neonatol 6:357–362, 2001.

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Schnitzer JJ, Donahoe PK: Surgical treatment of congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 30:137–154, 2001. Speiser PW: Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Endocrinol Metab Clin North Am 30:31–59, 2001. Speiser PW, New MI: Prenatal diagnosis and management of congenital adrenal hyperplasia. Clin Perinatol 21:631–645, 1994. Speiser PW, White PC: Congenital adrenal hyperplasia. N Engl J Med 349:776–788, 2003. Speiser PW, Dupont B, Rubinstein P, et al.: High frequency of nonclassical steroid 21-hydroxylase deficiency. Am J Hum Genet 37:650–667, 1985. Stikkelbroeck NM, Hermus AR, Braat DD, et al.: Fertility in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Obstet Gynecol Surv 58:275–284, 2003. Therrell BL: Newborn screening for congenital adrenal hyperplasia. Endocrinol Metab Clin 30:15–30, 2001. Therrell BLJ, Berenbaum SA, Manter-Kapanke V, et al.: Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia. Pediatrics 101:583–590, 1998. Wedell A: Molecular approaches for the diagnosis of 21-hydroxylase deficiency and congenital adrenal hyperplasia. Clin Lab Med 16:125–137, 1996. Wedell A: Molecular genetics of congenital adrenal hyperplasia (21-hydroxylase deficiency): implications for diagnosis, prognosis and treatment. Acta Paediatr 87:159–164, 1998. White PC: Congenital adrenal hyperplasias. Best Pract Res Clin Endocrinol Metab 15:17–41, 2001. White PC, Speiser PW: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 21:245–291, 2000. White PC, New MI, Dupont B: Congenital adrenal hyperplasia. (first of two parts). N Engl J Med 316:1519–1524, 1987. White PC, New MI, Dupont B: Congenital adrenal hyperplasia (second of two parts). N Engl J Med 316:1580–1586, 1987. Wilson T: Congenital adrenal hyperplasia. Emedicine, 2004. http://www. emedicine.com Woelfle J, Hoepffner W, Sippell WG, et al.: Complete virilization in congenital adrenal hyperplasia: clinical course, medical management and diseaserelated complications. Clin Endocrinol 56:231–238, 2002.

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Fig. 2. A newborn with congenital adrenal hyperplasia showing ambiguous genitalia. Newborn screening from filter paper showed total 17OHP of >240 ng/mL (normal 80 IU/mL) c. Thrombocytopenia (2 mg/dL) e. Anemia f. Elevated CSF protein (>120 mg/dL) g. Abnormal CT scan (most common neurologic sign and the most sensitive predictor for mental retardation) i. White matter lucencies ii. Ventriculomegaly iii. Intracranial calcifications (usually periventricular) iv. Destructive encephalopathy v. Brain atrophy vi. Neuronal migration disorders 2. Evidence of infection with CMV a. 4-fold rise in antiCMV IgG titers b. Seroconversion from negative to positive c. Sensitivity of the CMV IgM assays (50–90%). The IgM titers may not become positive during acute infection 3. Viral isolation a. The most sensitive method to diagnose CMV infection b. Culture of CMV from virtually all body fluids, including saliva and urine of the newborn, semen, and cervicovaginal secretions c. Detection of CMV within the first 3 weeks of life: considered proof of congenital CMV infection 4. Identification of CMV DNA through PCR (sensitivity of 75–100%)

GENETIC COUNSELING 1. Recurrence risk a. Preconceptional immunity to CMV provides substantial protection against intrauterine transmission and severe fetal infection

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b. Presence of maternal humoral antibody: conferring no fetal protection in subsequent reinfection or reactivation 2. Prenatal diagnosis a. Prenatal ultrasonography i. Intrauterine growth retardation ii. Microcephaly iii. Ventriculomegaly iv. Periventricular calcifications v. Intrahepatic calcifications vi. Nonimmune hydrops vii. Fetal Ascites viii. Pericardial effusion ix. Hepatosplenomegaly x. Echogenic bowel xi. Cardiomegaly xii. Oligohydramnios xiii. Placentomegaly b. Prenatal diagnosis of congenital CMV infection by combined detection of CMV-DNA and CMV-IgM in fetal blood or by combined testing of AF and fetal blood for CMV-DNA and IgM antibodies (sensitivity of 100%) c. Negative results of CMV culture or PCR in the amniotic fluid cannot formally exclude intra-uterine infection d. Prenatal diagnosis of CMV infection remains a ‘longstanding problem still seeking a solution’ as long as no assistance (treatment or prevention) can be offered to the pregnant women 3. Management a. Prevention i. Complicated because both primary and secondary maternal infections give rise to disease in the offspring and absence of characteristic symptoms in CMV-infected mothers excludes clinical recognition of at-risk pregnancies ii. Routine screening of pregnant patients for CMV status: not currently recommended because no effective antiviral therapy is available during gestation and also there is no means to predict the outcome in an infected fetus iii. Risk to CMV infection for women in high-risk environments (day-care centers, nurseries, elementary schools, or health care facilities) iv. Strict hygiene practices for seronegative women to reduce the risk for the infection b. No pharmaceutic regimens available for treatment of maternal and fetal CMV infections. Treatment with antiviral agents (ganciclovir, foscarnet) is limited to severe infections (CMV retinitis) in immunocomromised patients and not currently used in pregnancy c. A live attenuated CMV vaccine i. Live vaccines may bear a serious risk when transmittable to the fetus ii. Concerns for reactivation (reinfection), viral shedding in breast milk and cervix, and oncogenesis

REFERENCES Ahlfors K, Ivarsson S-A, Harris S: Report on a long-term study of maternal and congenital cytomegalovirus infection in Sweden. Review of prospective studies available in the literature. Scand J Infect Dis 31:443–457, 1999.

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American Academy of Pediatrics Report of the Committee on Infectious Diseases: Toxoplasmosis. Red Book 2000, pp 583–586. Bale JF Jr, Blackman JA, Sato Y: Outcome in children with symptomatic congenital cytomegalovirus infection. J Child Neurol 5:131–136, 1990. Beksaç MS, Saygan-Karamürsel B, Ustaçelebi S, et al.: Prenatal diagnosis of intrauterine cytomegalovirus infection in a fetus with non-immune Hydrops fetalis. Acta Obstet Gynecol Scand 80:762–765, 2001. Berenberg W, Nankervis G: Long-term follow-up of congenital cytomegalovirus disease of infancy. Pediatrics 46:403–410, 1970. Bodéus M, Hubinont C, Bernard P, et al.: Prenatal diagnosis of human cytomegalovirus by culture and polymerase chain reaction: 98 pregnancies leading to congenital infection. Prenat Diagn 19:314–317, 1999. Boppana SB, Pass RF, Britt WJ, et al.: Symptomatic congenital cytomegalovirus infection: neonatal morbidity and mortality. Pediatr Infect Dis J 11:93–99, 1992. Boppana SB, Fowler KB, Vaid Y, et al.: Neuroradiographic findings in the newborn period and long-term outcome in children with symptomatic congenital cytomegalovirus infection. Pediatrics 99:409–414, 1997. Boppana SB, Fowler KB, Britt WJ, et al.: Symptomatic congenital cytomegalovirus infection in infants born to mothers with preexisting immunity to cytomegalovirus. Pediatrics 104:55–60, 1999. Brown HL, Abernathy MP: Cytomegalovirus infection. Semin Perinatol 22: 260–266, 1998. Byrne PJ, Silver MM, Gilbert JM, et al.: Cyclopia and congenital cytomegalovirus infection. Am J Med Genet 28:61–65, 1987. Casteels A, Naessens A, Gordts F, et al.: Neonatal screening for congenital cytomegalovirus infections. J Perinat Med 27:116–121, 1999. Cline MK, Bailey-Dorton C, Cayelli M: Maternal infections. Diagnosis and management. Primary Care: Clin Offic Pract 27:13–33, 2000. Coats DK, Demmler GJ, Paysse EA, et al.: Ophthalmologic findings in children with congenital cytomegalovirus infection. Am Assoc Pediatr Ophthalmol Strabism 4:110–116, 2000. Conboy TJ, Pass RF, Stagno S, et al.: Early clinical manifestations and intellectual outcome in children with symptomatic congenital cytomegalovirus infection. J Pediatr 111:342–348, 1987. Demmler GJ. Infectious Disease Society of America and Centers for Disease Control: summary of a workshop on surveillance for congenital cytomegalovirus disease. Rev Infect Dis 13:315–329, 1991. Demmler GJ: Congenital cytomegalovirus infection and disease. Adv Pediatr Infect Dis 11:135–162, 1996. Enders G, Bäder U, Lindemann L, et al.: Prenatal diagnosis of congenital cytomegalovirus infection in 189 pregnancies with known outcome. Prenat Diagn 21:362–377, 2001. Fowler KB, Stagno S, pass RF, et al.: The outcome of congenital cytomegalovirus infection in relation to maternal antibody status. N Enl J Med 326:663–667, 1992. Fowler KB, McCollister FP, Dahle AJ, et al.: Progressive and fluctuating sensorineural hearing loss in children with asymptomatic congenital cytomegalovirus infection. J Pediatr 130:624–630, 1997. Gaytant MA, Steegers EAP, Semmekrot BA, et al.: Congenital cytomegalovirus infection: review of the epidemiology and outcome. Obstet Gynecol Surv 57:245–256, 2002. Guerra B, Lazzarotto T, Quarta S, et al.: Prenatal diagnosis of symptomatic congenital cytomegalovirus infection. Am J Obstet Gynecol 183:476–482, 2000.

Guyton TB, Ehrlich F, Blanc WA, et al.: New observations in generalized cytomegalic-inclusion disease of the newborn: report of a case with chorioretinitis. N Engl J Med 257:803–807, 1957. Hicks T, Fowler K, Richardson M, et al.: Congenital cytomegalovirus infection and neonatal auditory screening. J Pediatr 123:779–782, 1993. Istas AS, Demmler GJ, Dobbins JG, and the National Congenital Cytomegalovirus Disease Registry Collaborating Group Surveillance for congenital cytomegalovirus disease: a report from the National Congenital Cytomegalovirus Disease registry. Clin Infect Dis 20:665–670, 1995. Kuhlmann RS, Autry AM: An approach to nonbacterial infections in pregnancy. Clin Fam Pract 3(2): June 2001. Lazzarotto T, Varani S, Guerra B, et al.: Prenatal indicators of congenital cytomegalovirus infection. J Pediatr 137:90–95, 2000. Liesnard C, Donner C, Brancart F, et al.: Prenatal diagnosis of congenital cytomegalovirus infection: prospective study of 237 pregnancies at risk. Obstet Gynecol 95:881–888, 2000. McCracken GH Jr, Shinefield HR, Cobb K, et al.: Congenital cytomegalovirus infection disease: a longitudinal study of 20 patients. Am J Dis Child 117:522–539, 1969. Metz MB: Eye manifestations of intrauterine infections. Ophthalmol Clin N Am 14:521–531, 2001. Miklos G, Orban T: Ophthalmic lesions due to cytomegalic inclusion disease. Ophthalmologica 148:98–106, 1964. Nelson CT, Demmler GJ, Istas AS, et al.: Early prediction of neurodevelopmental outcome in symptomatic congenital cytomegalovirus (CMV) infection. Pediatr Res 39:180A, 1993. Noyola DE, Demmler GJ, Griesser C, et al.: Early predictors of neurodevelopmental outcome in symptomatic . J Pediatr 138:325–331, 2001. Pass RF: Cytomegalovirus infection. Pediatrics in Review 23:163–169, 2002. Pass RF, Stagno S, Myers GJ, Alford CA: Outcome of symptomatic congenital cytomegalovirus infection: results of long-term longitudinal follow-up. Pediatrics 66:758–762, 1980. Perlman JM, Argyle C: Lethal cytomegalovirus infection in preterm infants: Clinical, radiological, and neuropathological findings. Ann Neurol 31:64–68, 1992. Ramsy MEB, Miller E, Peckhan CS: Outcome of confirmed symptomatic congenital cytomegalovirus infection. Arch Dis Child 66:1068–1069, 1991. Roach ES, Sumner TE, Volverg FM, et al.: Radiological case of the month. Am J Dis Child 137:799, 1983. Stagno S: Cytomegalovirus. In Remington JS, Klein JO (eds): Infectious Diseases of the Fetus & newborn Infant. Philadelphia, WB Saunders, 312–353, 1995. Stagno S, Pass RF, Dworsky ME, et al.: Congenital cytomegalovirus infection: The relative importance of primary and recurrent maternal infection. N Engl J Med 306:945–949, 1982. Stagno S, Pass RF, Cloud G, et al.: Primary cytomegalovirus infection in pregnancy. Incidence, transmission to fetus and clinical outcome. JAMA 256:1904–1908, 1986. Williamson WD, Desmond MM, LaFevers N, et al.: Symptomatic congenital cytomegalovirus infection, disorders of language, learning, and hearing. Am J Dis Child 136:902–905, 1982. Yow MD, Williamson DW, Leeds LJ, et al.: Epidemiologic characteristics of cytomegalovirus infection in mothers and their infants. Am J Obstet Gynecol 158:1189–1195, 1988.

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Fig. 2. Photomicrograph of the kidney (macerated fetus, 16 weeks gestation). Even though the tissue is macerated, many cytomegalic inclusion bodies are demonstrable. Coronal section of the brain (frontal lobe) showing ventricular hemorrhage and focal encephalomalacia (chalky white discoloration) due to cytomegalovirus infection.

Fig. 1. A neonate with blue berry muffin skin lesions (generalized purpura) due to cytomegalovirus infection. He died 20 hours after birth. CMV inclusions were noted in kidneys, lungs, liver, pancreas, thyroid, brain and eyes, and also in the urine. Photomicrograph of the kidney shows many tubular epithelial cells containing large cytomegalic inclusion bodies.

Fig. 3. Photomicrograph of premature lung of a different patient showing a single large cytomegalic inclusion body.

Fig. 4. One cytomegalic inclusion body in the urine sediment in another patient.

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Fig. 7. Skull radiographs of another patient with congenital CMV infection showing microcephaly and typical intracranial ventricular subependymal calcifications.

Fig. 5. A macerated stillborn with hydrops fetalis from congenital CMV infection.

Fig. 6. An infant with CNS involvement and chorioretinitis from congenital CMV infection.

Fig. 8. An adult with congenital CMV infection showing mental retardation and intracranial calcifications by CT scan.

Congenital Generalized Lipodystrophy Congenital generalized lipodystrophy (CGL), also called Berardinelli-Seip syndrome (BSCL), is an extremely rare genetic disorder characterized by extreme paucity of adipose tissue from birth, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis, and early onset of diabetes. Its prevalence is estimated to be less than 1 in 12 million people.

GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. Existence of two loci in a gene for congenital generalized lipodystrophy (Berardinelli-Seip congenital lipodystrophy) a. Congenital generalized lipodystrophy type 1 i. Identification of the aberrant gene, 1-acylglycerol3-phosphate O-acyltransferase 2 (AGPAT2) in patients from several pedigrees in which the lipodystrophy was linked to chromosome 9q34 ii. Several homozygous or compound heterozygous mutations in the AGPAT2 gene identified in affected patients iii. AGPAT2 (1-acylglycerol-3-phosphate O-acyltransferase 2) a) Encodes the enzyme AGPAT2 that is responsible for the production of an important intermediate in the synthesis of triglycerides or fat b) Mutations of AGPAT2: may cause CGL by inhibiting the fat synthesis and storage in adipocytes (fat cells) b. Congenital generalized lipodystrophy type 2 i. Identification of another disease locus (BSCL2) which is mapped to chromosome 11q13 ii. Identification of mutations of BSCL2 gene in all families linked to 11q13 iii. BSCL2 (Seipin) gene a) Highly expressive in the brain and testis b) Encodes a protein whose function remains unknown 3. Several other genes are responsible for different types of inherited lipodystrophies: a. Lamin A/C (LMNA) gene in familial partial lipodystrophy Dunnigan variety (autosomal dominant familial partial lipodystrophy) mapped to 1q21–22 b. PPAR-γ (peroxisome proliferator-activated receptor-γ) gene in autosomal dominant familial partial lipodystrophy 4. Cause a. CGL is caused by mutations in BSCL2, AGPAT2, and other as yet unmapped genes b. This genetic heterogeneity is also accompanied by phenotypic heterogeneity 5. Proposed pathogenesis: genetic defect results in poor growth and development of metabolically active adipose tissue with preservation of mechanical disposition of the adipose tissue

CLINICAL FEATURES 1. Extreme paucity (near complete absence) of adipose tissue from birth, resulting in a generalized muscular appearance (an essential diagnostic criterion) 2. Characteristic features during early childhood a. Accerated linear growth b. Voracious appetite c. Increased basal metabolic rate (hypermetabolism) d. Advanced bone age 3. Acanthosis nigricans (dark velvety pigmentation of the skin) a. Common occurrence b. Usually appears by age 8 c. May be widespread, involving the neck, axillae, groin, and trunk d. Can eventually cause skin tag formation 4. Umbilical hernia: common 5. Hepatosplenomegaly a. Almost universal presence of hepatomegaly from fatty liver, ultimately leading to cirrhosis b. Splenomegaly common 6. Acromegaloid appearance a. Enlarged hands and feet b. Prominent mandible 7. Premature thelarche and adrenarche 8. Affected women a. Virilization (clitoromegaly and hirsutism) b. Oligo-amenorrhea c. Polycystic ovaries in postpubertal female patients d. Successful pregnancy rare 9. Affected males with normal reproductive potential 10. Multiple focal lytic lesions in the appendicular bones in postpubertal patients 11. Severe fasting and postprandial hyperinsulinemia and marked hypertriglyceridemia resulting in chylomicronemia, eruptive xanthomas, acute pancreatitis and predisposing to premature atherosclerosis 12. Abnormal glucose intolerance and diabetes mellitus develop during puberty or early adolescence. Diabetic nephropathy and nephropathy may develop during adulthood 13. Rare hypertrophic cardiomyopathy 14. Mental retardation in a few patients

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1. Clinical laboratory work-up a. Marked insulin resistance b. Severe hyperinsulinemia c. Nonketotic insulin-resistant diabetes mellitus d. Hypertriglyceridemia with low serum high-density lipoprotein (HDL) and cholesterol concentration e. Chylomicronemia f. Markedly low plasma leptin levels

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2. MRI (confirmatory) and necropsy a. An extreme paucity of subcutaneous and intermuscular fat i. Intraabdominal sites (omental, mesenteric, and retroperitoneal areas) ii. Thoracic cavity (retrosternal, epicardial, and superior mediastinal areas) iii. Bone marrow iv. Parathyroid glands b. In contrast, a peculiar distribution of normal amounts of adipose tissue over whole body i. Orbits ii. Crista galli iii. Palms iv. Soles v. Scalp vi. Perineum vii. Vulva viii. Epidural area ix. Pericalyceal regions of the kidney x. Periarticular regions (knee, hip, shoulder, elbow, wrist, and ankle joints) xi. Some fat localizes in breasts, tongue, and buccal region 3. Skeletal radiography: multiple focal lytic lesions appear in appendicular skeletons after puberty 4. Echocardiography to detect hypertrophic cardiomyopathy 5. Molecular genetic analysis of mutations in BSCL2 (Seipin) gene and AGPAT2 gene

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not increased unless the spouse is a carrier or affected 2. Prenatal diagnosis: not reported 3. Management (Garg, 2004) a. Cosmetic management i. Facial reconstruction with free flaps, transposition of facial muscle, and silicone or other implants in the cheeks ii. Liposuction or lipectomy for removal of excessive facial or neck fat iii. Etretinate and fish oil may improve acanthosis in some patients b. Diet i. Avoidance of weight gain to reduce the risk of developing diabetes and dyslipidemia ii. Need sufficient energy to allow for growth and maturation in childhood c. Hypoglycemic drugs i. Require rigorous glycemic control ii. Require large dose of insulin to control hyperglycemia and prevent long-term complications of diabetes, such as nephropathy, retinopathy, neuropathy, and possibly atherosclerosis d. Lipid-lowering drugs i. Fibrates and, if needed, n-3 polyunstaurated fatty acids

ii. Avoid estrogens for oral contraception or postmenopausal hormone replacement therapy in women because it can accentuate hypertriglyceridemia e. Clinical trial of adipocytes hormone leptin-replacement therapy has shown a marked reduction in the blood glucose and lipids and reverse hepatic steatosis, allowing discontinuation of several medications

REFERENCES Afifi AK, Mire-Salman J, Najjar S: The myopathology of congenital generalized lipodystrophy light and electron microscopic observations. Johns Hopkins Med J (Suppl) 139:61–68, 1976. Agarwal AK, Arioglu E, De Almeida S, et al.: AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat Genet 31:21–23, 2002. Agarwal AK, Barnes RI, Garg A: Genetic basis of congenital generalized lipodystrophy. Int J Obes Relat Metab Disord 2003. Agarwal AK, Garg A: Congenital generalized lipodystrophy: significance of triglyceride biosynthetic pathways. Trends Endocrinol Metab 14: 214–221, 2003. Agarwal AK, Simha V, Oral EA, et al.: Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy. J Clin Endocrinol Metab 88:4840–4847, 2003. Berardinelli W: An undiagnosed endocrinometabolic syndrome: report of 2 cases. J Clin Endocrinol Metab 14:193–204, 1954. Brunzell JD, Shankle SW, Bethune JE: Congenital generalized lipodystrophy accompanied by cystic angiomatosis. Ann Intern Med 69:501–516, 1968. Cao H, Hegele R: Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Genet 9:109–112, 2000. Chandalia M, Garg A, Vuitch F, et al.: Postmortem findings in congenital generalized lipodystrophy. J Clin Endocrinol Metab 80:3077–3081, 1995. Downes GB, Copeland NG, Jenkins NA, et al.: Structure and mapping of the G protein gamma3 subunit gene and divergently transcribed novel gene, gng3lg. Genomics 53:220–230, 1998. Fleckenstein JL, Garg A, Bonte FJ, et al.: The skeleton in congenital generalized lipodystrophy: evaluation using whole-body radiographic surveys, magnetic resonance imaging and technetium-99m bone scintigraphy. Skel Radiol 21:381–386, 1992. Garg A: Peculiar distribution of adipose tissue in patients with congenital generalized lipodystrophy. J Clin Endocrinol Metab 75:358–361, 1992. Garg A: Lipodystrophies. Am J Med 108:143–152, 2000. Garg A: Acquired and inherited lipodystrophies. N Engl J Med 350:1220–1234, 2004. Garg A, Wilson R, Barnes R, et al.: A gene for congenital generalized lipodystrophy maps to human chromosome 9q34. J Clin Endocrinol Metab 84:3390–3394, 1999. Gomes KB, Fernandes AP, Ferreira ACS, et al.: Mutations in the Seipin and AGPAT2 genes clustering in consanguineous families with BerardinelliSeip congenital lipodystrophy from two separate geographical regions of Brazil. J Clin Endocrinol Metab 89:357–361, 2004. Guell-Gonzales JR, De Acosta OM, Alavez-Matin E, et al.: Bone lesions in congenital generalized lipodystrophy. Lancet 2:104–105, 1971. Heathcote K, Rajab A, Magré J, et al.: Molecular analysis of Berardinelli-Seip congenital lipodystrophy in Oman. Evidence for multiple loci. Diabetes 51:1291–1293, 2002. Helm TN: Lipodystrophy. Cutis 67:163–164, 2001. Huseman CA, Johanson AJ, Varma MM, et al.: Congenital lipodystrophy. II. Association with polycystic ovarian disease. J Pediatr 95:72–74, 1979. Magré J, Delepine M, Khallouf E, et al.: Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet 28:365–370, 2001. Magré J, Delépine M, Van Maldergem L, et al.: Prevalence of mutations in AGPAT2 among human lipodystrophies. Diabetes 52:1573–1578, 2003. McLean RH, Hoefnagel D: Partial lipodystrophy and familiar C3 deficiency. Hum Hered 30:149–154, 1980. Oral EA, Simha V, Ruiz E, et al.: Leptin-replacement therapy for lipodystrophy. N Engl J Med 346:570–578, 2002.

CONGENITAL GENERALIZED LIPODYSTROPHY Petersen KF, Oral EA, Dufour S, et al.: Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 109:1345–1350, 2002. Premkumar A, Chow C, Bhandarkar P, et al.: Lipoatrophic-lipodystrophic syndromes. AJR 178:311–318, 2002. Rajab A, Heathcote K, Joshi S, et al.: Heterogeneity for congenital generalized lipodystrophy in seventeen patients from Oman. Am J Med Genet 110:219–225, 2002. Reed WB, Dexter R, Corley C, et al.: Congenital lipodystrophic diabetes with acanthosis nigricans. Arch Dermatol 91:326–334, 1965. Rheuban KS, Blizzard RM, Parker MA, et al.: Hypertrophic cardiomyopathy in total lipodystrophy. J Pediatr 109:301–302, 1986. Savage DB, O’Rahilly S: Leptin: a novel therapeutic role in lipodystrophy. J Clin Invest 109:1285–1286, 2002. Seip M: Lipodystrophy and gigantism with associated endocrine manifestations: a new diencephalic syndrome? Acta Paediatr Scand 48:555–574, 1959.

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Seip M, Tryqstad O: Generalised lipodystrophy. Arch Dis Child 38: 447–453, 1963. Seip M, Trygstad O: Generalized lipodystrophy, congenital and acquired (lipoatrophy). Acta Paediatr Suppl 413:2–28, 1996. Senior B, Gellis SS: Syndromes of total lipodystrophy and of partial lipodystrophy. Pediatrics 33:593–612, 1964. Shackleton S. Lloyd DJ, Jackson SNJ: LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nat Genet 24:153–156, 2000. Van Maldergem L, Magré J, Khallouf TE, et al.: Genotype–phenotype relationships in Berardinelli-Seip congenital lipodystrophy. J Med Genet 39:722–733, 2002. Westvik J: Radiological features in generalized lipodystrophy. Acta Paediatr (Suppl) 413:44–51, 1996. Wilson TA, Alford BA, Morris L: Cerebral computed tomography in lipodystrophy. Arch Neurol 39:733, 1982.

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Fig. 1. An infant with congenital generalized lipodystrophy showing extreme paucity (near complete absence) of adipose tissue from birth, resulting in a generalized prominent muscular appearance

Congenital Hydrocephalus Hydrocephalus is one of the most common CNS developmental disorders. The incidence of congenital hydrocephalus is estimated as 3 per 1000 live births. Hydrocephalus is defined as an increase in the cerebral spinal fluid (CSF) volume within the ventricular system independent of the actual head circumference.

GENETICS/BASIC DEFECTS 1. Physiology of CSF production and absorption a. Production of CSF: by choroid plexus of lateral ventricles b. Pathway of CSF flow i. From lateral ventricles to third ventricle through foramen of Monro ii. From third ventricle to fourth ventricle through aqueduct of Sylvius iii. Out of the ventricular system: from fourth ventricle to spinal subarachnoid spaces through foramen of Magendie or to the basal cisterns through two lateral foramina of Luschka c. Site of CSF resorption into venous system: primarily through superior sagittal sinus via arachnoid granulations 2. Types and causes of hydrocephalus a. Overproduction of CSF: usually caused by choroid plexus tumors (very rare) b. Noncommunicating hydrocephalus i. Mechanical obstruction within the ventricular system causing impaired CSF absorption a) Foramen of Monro b) Aqueduct of Sylvius c) The fourth ventricle and its outlet channels ii. Causes a) Tumors b) Cysts c) Inflammatory scarring d) Intraventricular hemorrhage e) Rarely genetic disorders c. Communicating hydrocephalus i. Obstruction distally at the arachnoid granulations causing impaired absorption into blood stream ii. Causes a) Meningitis b) Trauma c) Intraventricular hemorrhage 3. Etiology of congenital hydrocephalus a. Tumors blocking CSF pathway i. Benign tumors such as choroid plexus papilloma ii. Malignant tumors b. CNS malformations/syndromes i. Congenital atresia of the foramina of Monro, Magendie or Luschka ii. Dandy-Walker syndrome 221

a) b) c) d)

Atresia of the foramina of the 4th ventricle Dilation of 4th ventricle Extreme Dolichocephaly Sac formation at the caudal end of the cerebellum filling the posterior cranial fossa iii. Aqueductal stenosis iv. X-linked hydrocephalus: Bickers-Adams syndrome characterized by: a) Stenosis of the aqueduct of Sylvius b) Severe mental retardation c) An adduction-flexion deformity of the thumb v. Chiari II malformation vi. Cerebellar agenesis vii. Neural tube defects a) Meningomyelocele b) Encephalocele viii. Other Mendelian conditions with congenital hydrocephalus a) Walker-Warburg syndrome b) Hydrolethalus syndrome c) Meckel syndrome d) Smith-Lemli-Opitz syndrome c. Chromosome abnormalities i. Trisomy 13 ii. Trisomy 18 iii. Trisomy 9 and 9p (mosaic) iv. Triploidy v. Other aneuploidies d. Skeletal dysplasias i. Achondroplasia ii. Craniosynostosis syndromes such as Crouzon syndrome or Apert syndrome iii. Fanconi anemia iv. Hurler or Hunter syndromes e. Infections i. Congenital CMV infection ii. Congenital toxoplasmosis iii. Congenital rubella infections iv. Congenital syphilis v. Meningitis vi. Ventriculitis vii. Abscess f. Vascular malformation g. In utero intraventricular hemorrhage h. Birth trauma i. Destructive lesions i. Hydranencephaly ii. Porencephaly iii. Perinatal leukomalacia 4. Familial (X-linked) aqueductal stenosis (HSAS: hydrocephalus-stenosis of the aqueduct of Sylvius sequence) a. X-linked recessive inheritance b. Linked to chromosome Xq28

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c. Mutations in L1-CAM, the major gene for X-linked hydrocephalus (accounting for 7–27% of all male cases) d. L1-CAM, a neuronal surface glycoprotein, has been implicated in neuronal migration and axon fasciculation 5. Traits known to be due to allelic mutations of L1-CAM a. HSAS b. MASA i. Mental retardation ii. Aphasia iii. Shuffling gait iv. Adducted thumbs c. SP1 (complicated spastic paraparesis, type 1) d. MR-CT (mental retardation-clasped thumbs) e. ACC-DCC (agenesis or dysgenesis of the corpus callosum) 6. Pathogenesis of hydrocephalus-induced brain dysfunction: complex a. Chronic ischemia in white matter related to changes in intracranial pressure and in the vasculature b. Physical damage to periventricular axons with disconnection of neurons c. Alterations in the extracellular chemical environment of neurons

CLINICAL FEATURES 1. Children 2 years a. Symptoms and signs more related to increased intracranial pressure due to inability of cranium to expand sufficiently to offset the mounting volume of CSF b. Headaches c. Nausea d. Vomiting e. Lethargy f. Loss of milestones g. School performance and behavioral change h. Sunsetting of the eyes i. Sixth cranial nerve palsy j. Papilledema

3. Natural history of untreated childhood hydrocephalus: poor. Handicaps resulting directly from hydrocephalus include the following: a. Disturbances in motor abilities, particularly gait b. Impaired cognitive development c. Hypothalamic dysfunction with delayed growth and short stature 4. X-linked neurological syndromes a. HSAS (hydrocephalus-stenosis of the aqueduct of Sylvius sequence) i. Hydrocephalus ii. Macrocephaly iii. Adducted thumbs iv. Spasticity v. Agenesis of the corpus callosum vi. Mental retardation b. MASA syndrome i. Mental retardation ii. Aphasia iii. Shuffling gait iv. Adducted thumbs v. Hydrocephalus

DIAGNOSTIC INVESTIGATIONS 1. Fundoscopic examination a. Bilateral papilledema secondary to high intracranial pressure b. Normal finding in some cases of acute hydrocephalus 2. Lumbar puncture for measuring intracranial pressure a. Avoid if an increase in intracranial pressure is suspected due to obstruction since relief of pressure may cause herniation of the brainstem b. Perform only after imaging studies ruling out an obstruction 3. TORCH titers on the infant and mother if intrauterine infection is suspected 4. Chromosome analysis in cases of associated multiple congenital anomalies 5. Cranial sonography (provided anterior fontanelle is still open) a. Ventriculomegaly b. Intraventricular hemorrhage 6. CT scans a. Ventriculomegaly b. Cerebral edema c. Mass lesions i. Colloid cyst of the third ventricle ii. Thalamic tumor iii. Pontine tumor 7. MRI a. Ventriculomegaly b. Mass lesions c. Associated brain anomalies i. Agenesis of the corpus callosum ii. Chiari malformations iii. Disorders of neuronal migration iv. Vascular malformations 8. Molecular genetic diagnosis to identify L1CAM mutations, identified in 22.4% (15/67) of sporadic cases of clinically or prenatally suspected L1-disease

CONGENITAL HYDROCEPHALUS

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Sporadic: low (4%) ii. Multifactorial trait (e.g., neural tube defect or in female infants with congenital hydrocephalus due to stenosis of the aqueduct of Sylvius): low recurrence risk (5%) for subsequent sibling; 10% risk if there are two affected siblings iii. Autosomal recessive traits (e.g., Dandy-Walker syndrome): 25% affected; 50% carriers; 25% normal iv. X-linked hydrocephalus: 50% of brothers affected and 50% of sisters carriers if the mother is a carrier; negligible in males with “sporadic” hydrocephalus representing a new X-linked mutation b. Patient’s offspring i. Sporadic: low (4%) ii. Multifactorial trait: 3–4.5% recurrence risk iii. Autosomal recessive traits: not increased unless the spouse is a carrier or affected iv. X-linked hydrocephalus: all daughters will be carriers in case of an affected father 2. Prenatal diagnosis a. Ultrasonography i. Fetal ventriculomegaly ii. Additional CNS malformations iii. Extracerebral malformations b. Sonographic findings in HSAS or MASA syndromes i. Male fetus ii. Hydrocephalus iii. Hypoplasia or agenesis of the corpus callosum iv. Bilateral adducted thumbs c. Amniocentesis i. α-fetoprotein and cholinesterase determination from amniotic fluid for neural tube defects ii. Chromosome analysis for suspected chromosomal disorder d. Molecular genetic diagnosis i. DNA diagnosis often requested in families with ‘isolated’ hydrocephalus case due to high rate of de novo mutations, small family size, and the improved sensitivity of prenatal ultrasound scanning ii. Molecular diagnosis of prenatally suspected L1 spectrum disorders, even in cases without positive family history 3. Management a. Folic acid intake before and during the first trimester reduces the incidence of neural tube defects, thereby the incidence of hydrocephalus b. Shunting CSF from the ventricles i. Ventriculoperitoneal shunting (VP) devices with pressure-controlled valves under the scalp close to the burr hole ii. Ventriculopleural shunt iii. Ventriculoatrial shunt iv. Frontal or parietal ventriculostomy v. Does not completely reverse the pathologic alterations in the brain and, unfortunately, treatment

223

by shunting is associated with frequent complications c. Major complication associated with shunt treatment: 81% of children with shunts suffer at least one and usually several malfunctions necessitating hospitalization i. Shunt obstruction ii. Valve malfunction iii. Disconnection iv. Hematoma v. Overdrainage vi. Outgrown shunt vii. Shunt fracture viii. Shunt-related infections, most often caused by staphylococcus aureus, with unexplained fever or frank meningitis ix. Signs of increased intracranial pressure with headache, lethargy, and vomiting x. Abdominal complications a) Peritonitis b) Perforation of an abdominal organ c) Peritoneal cysts d) Development of hydroceles in boys xi. Seizures xii. Allergic reaction to material

REFERENCES Aronyk KE: The history and classification of hydrocephalus. Nerosurg Clin North Am 4:599–609, 1993. Barkovich AJ, Edwards MS: Applications of neuroimaging in hydrocephalus. Pediatr Neurosurg 18:65–83, 1992. Bradley WG Jr: Diagnostic tools in hydrocephalus. Nerosurg Clin North Am 12:661–684, 2001. Burton BK: Recurrence risks for congenital hydrocephalus. Clin Genet 16:47–53, 1979. Del Bigio MR: Future directions for therapy of childhood hydrocephalus: a view from the laboratory. Pediatr Neurosurg 34:172–181, 2001. Del Bigio MR: Pathophysiologic consequences of hydrocephalus. Nerosurg Clin North Am 12:639–649, 2001. Dias MS, Li V: Pediatric surgery for the primary care pediatrician, Part II. Pediatric neurosurgical disease. Pediatr Clin N Amer 45:1539–1578, 1998. Epstein F: How to keep shunts functioning, or ‘the impossible dream’. Clin Neurosurg 32:608–631, 1985. Fernell E, Uvebrant P, von Wendt L: Overt hydrocephalus at birth-origin and outcome. Childs Nerv Syst 3:350–353, 1987. Finckh U, Gal A: Prenatal molecular diagnosis of L1-spectrum disorders. Prenat Diagn 20:744–745, 2000. Futagi Y, Suzuki Y, Toribe Y, et al.: Neurodevelopmental outcome in children with fetal hydrocephalus. Pediatr Neurol 27:111–116, 2002. Golden JA, Bonnemann CG: Developmental Structural Disorders. In Goetz (ed): Textbook of Clinical Neurology. 1st Ed. WB Saunders, 1999, Ch 28, pp 510–537. Habib Z: Genetics and genetic counselling in neonatal hydrocephalus. Obstet Gynecol Surv 36:529–534, 1981. Hamid RKA, Newfield P: Pediatric neuroanesthesia. Hydrocephalus. Anesthesiol Clin North Am 19:207–218, 2001. Harrod MJE, Friedman JM, Santos-Ramos R, et al.: Etiologic heterogeneity of fetal hydrocephalus diagnosed by ultrasound. Am J Obstet Gynecol 150:38–40, 1984. Hord E-D: Hydrocephalus. E-Med J, 2002. Hudgins RJ, Edwards MS, Goldstein R, et al.: Natural history of fetal ventriculomegaly. Pediatrics 82:692–697, 1988. Jouet M, Rosenthal A, Armstrong G, et al.: X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene. Nat Genet 7:402–407, 1994. Kanev PM, Park TS: The treatment of hydrocephalus. Nerosurg Clin North Am 4:611–619, 1993.

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Kestle JRW: Pediatric hydrocephalus: current management. Neurol Clin 21:883–895, 2003. Kirpatrick M, Engleman H, Minns RA: Symptoms and signs of progressive hydrocephalus. Arch Dis Child 64:124–128, 1989. Milhorat T: Hydrocephalus: Pathophysiology and clinical features. Neurosurgery 3:3625–3632, 1996. Pattisapu JV: Etiology and clinical course of hydrocephalus. Nerosurg Clin North Am 12:651–659, 2001. Pomili G, Donti GV, Carrozza LA, et al.: MASA syndrome: ultrasonographic evidence in a male fetus. Prenat Diagn 20:1012–1014, 2000. Pudenz RH: The surgical treatment of hydrocephalus—an historical review. Surg Neurol 15:15–26, 1981. Rickert CH, Paulus W: Tumors of the choroid plexus. Microscopy Res Technique 52:104–111, 2001. Rosseau GL, McCullough DC, Joseph AL: Current prognosis in fetal ventriculomegaly. J Neurosurg 77:551–555, 1992. Sahrakar K, Pang D: Hydrocephalus. E-Med J, 2002.

Schrander-Stumpel C, Fryns J-P: Congenital hydrocephalus: nosology and guidelines for clinical approach and genetic counselling. Eur J Pediatr 157:355–362, 1998. Senat MV, Bernard JP, Delezoide A, et al.: Prenatal diagnosis of hydrocephalusstenosis of the aqueduct of Sylvius by ultrasound in the first trimester of pregnancy. Report of two cases. Prenat Diagn 21:1129–1132, 2001. Sztriha L, Vos YJ, Verlind E, et al.: X-linked hydrocephalus: a novel missense mutation in the L1CAM gene. Pediatr Neurol 27:293–296, 2002. Thompson NM, Fletcher JM, Chapieski L, et al.: Cognitive and motor abilities in preschool hydrocephalics. J Clin Exp Neuropsychol 13:245–258, 1991. Váradi V, Tóth Z, Török O, et al.: Heterogeneity and recurrence risk for congenital hydrocephalus (ventriculomegaly): a prospective study. Am J Med Genet 29:305–310, 1988. Weller S, Gärtner J: Genetic and clinical aspects of X-linked hydrocephalus (L1 disease): Mutations in the L1CAM gene. Hum Mutat 18:1–12, 2001.

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Fig. 3. Prenatal ultrasound at 33 weeks showing markedly dilated lateral ventricles Fig. 1. A child with hydrocephalus which was shunted.

Fig. 4. CT scan of the head of a patient showing ventriculomegaly with congenital hydrocephalus.

Fig. 5. CT scan of the head of a patient after ventriculoperitoneal shunt. Fig. 2. An adult with severe congenital hydrocephalus and mental retardation.

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Fig. 6. MRI of the brain of a patient showing hydrocephalus due to aqueduct stenosis.

Fig. 7. CT scans of the brain of a patient showing dilatation of the lateral ventricles with stretching of corpus callosum and cortical atrophy.

Congenital Hypothyroidism All forms of congenital hypothyroidism occur in 1 in 4000 live births worldwide. The dysgenetic form affects twice as many females as males. It is the most prevalent congenital endocrine disease. The incidence is approximately 1 in 32,000 in Blacks and 1 in 2000 in Hispanics.

GENETICS/BASIC DEFECTS 1. Inheritance a. Thyroid dysgenesis i. The most frequent cause of congenital hypothyroidism (85% of cases) ii. Morphological classification a) Ectopic thyroid gland: the most frequent malformation, observed most frequently at the base of the tongue b) Athyreosis (absence of any detectable thyroid tissue) c) Hypoplasia (partially absent thyroid) iii. Sporadic in most cases iv. Genetic factors contributing to the development of thyroid dysgenesis in 2% of cases with a positive familial history v. Molecular defects clarified only in few cases of thyroid dysgenesis a) TSH-receptor gene (thyroid hypoplasia, “apparent athyrosis”) b) Transcription factors: TTF-1 (hypothyroidism, chorea, choreoathetosis, respiratory distress), TTF-2 (thyroid hypoplasia, cleft palate, choanal atresia, curly hair, developmental delay), PAX-8 (thyroid hypoplasia, ectopy) c) NKX2A (athyrosis, hypoplasia, normally developed gland, choreoathetosis, pulmonary problems, mental retardation, pituitary abnormalities) b. Autosomal recessive defects of thyroid hormone biosynthesis with identification of the following candidate genes for congenital hypothyroidism i. Thyroid peroxidase (TPO) gene a) A hemoprotein responsible for tyrosine iodination and coupling b) Intriguing role of TPO mutations in the development of thyroid tumor ii. Sodium-iodide symporter gene iii. Thyroglobulin (Tg) gene iv. Pendrin gene c. Autosomal dominant transmission of congenital hypoplasia due to loss-of-function mutation of PAX-8 2. Etiology of thyroidal congenital hypothyroidism a. Disorders in development of the thyroid gland (85% of cases with congenital hypothyroidism) 227

3.

4.

5.

6.

i. Absent thyroid ii. Under-development with migration failure iii. Under-development with normal migration b. Disorders in thyroid hormone synthesis (10–20%) i. TSH hypo-responsiveness (TSH receptor abnormalities) ii. Defects in iodide transport from circulation into the thyroid cells iii. Defects in iodide transport from the thyroid cell to the follicular lumen, often combined with inner ear deafness (Pendred syndrome, sensorineural hearing loss and goiter) iv. Defects in the synthesis of hydrogen peroxide v. Defects in the oxidation of iodide, iodination and iodothyronine synthesis vi. Defects in processes involved in the synthesis or degradation of thyroglobulin vii. Defects in iodine recycling Etiology of central (hypothalamic or pituitary) congenital hypothyroidism a. Disorders in development and/or function of the hypothalamus b. Disorders in development and/or function of the pituitary glands c. Disorders in development and/or function of the hypothalamus and pituitary glands Transient form of primary congenital hypothyroidism a. Occurs in 5–10% of infants detected by newborn screening b. Represents about 5% of cases with congenital hypothyroidism c. Etiology i. Mothers with chronic autoimmune thyroiditis: transplacental passage of maternal TSH-receptor blocking antibodies leading to inhibition of TSH action on the infant’s thyroid gland until the maternal antibodies disappear ii. Antithyroid drugs taken by pregnant women with thyroid autoimmune disease iii. Maternal dietary iodide deficiency iv. Maternal dietary goitrogen ingestion v. Exposure to excess iodine in the perinatal period a) Use of iodinated disinfectants b) Use of contrast agents Down syndrome: congenital hypothyroidism occurs approximately 28 times more common among infants with Down syndrome than in the general population with an incidence of 1% detected by newborn screening Pathogenesis of mental retardation in congenital hypothyroidism: due to the central role of thyroid hormones in brain development, which takes place during fetal life and early postnatal life up to the 2nd or 3rd year of age

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CLINICAL FEATURES 1. Most newborn are asymptomatic 2. Severe dysgenetic and athyrotic hypothyroidism a. Early symptoms i. Feeding problems ii. Constipation iii. Growth failure iv. Hoarse cry b. Signs and symptoms in infants and toddlers i. Delayed linear growth ii. Hypotonia iii. Decreased activity iv. Lethargy v. Prolonged jaundice vi. Bradycardia vii. Hypothermia viii. Cold to touch ix. Dry/puffy/thick skin x. Sparse hair xi. Characteristic craniofacial appearance a) Coarse facial feature b) Puffy eyes c) Myxedematous facies d) Large fontanelles e) A broad, flat nose f) Pseudohypertelorism g) Large, protruding tongue xii. Delayed tooth eruption xiii. Occasional cardiomegaly xiv. Protuberant abdomen with umbilical hernia xv. Constipation xvi. Poor nail growth xvii. Delayed return of the deep tendon reflexes xviii. Irreversible growth failure and mental retardation

3. 4. 5.

DIAGNOSTIC INVESTIGATIONS 1. Newborn screening a. Successful identification of infants with congenital hypothyroidism b. Enables early diagnosis and treatment of infants and prevention of mental retardation c. Newborn screening measures either TSH or T4 in neonatal blood placed on filter paper d. Confirmation with a serum sample if the filter paper result is abnormal i. Primary congenital hypothyroidism a) Low serum T4 levels b) Elevated serum TSH ii. Hypopituitary hypothyroidism a) Low total T4 levels b) Low or normal TSH iii. Thyroxine-binding globulin (TBG) deficiency a) Low total T4 but normal serum free T4 levels b) Normal TSH 2. Laboratory diagnosis a. Thyroid function tests i. Elevated serum TSH ii. Low serum T4 levels b. Determine antithyroglobulin and antithyroid peroxidase antibodies if indicated

6. 7.

c. Determine TBG levels for suspected TBG deficiency Radiography for bone age Ultrasonography, considered as the best noninvasive method for the anatomical assessment of the thyroid gland Radionuclide scan (thyroid scintigraphy) using 99mTc or 123I a. To demonstrate the presence of ectopic thyroid tissue or thyroid aplasia b. Iodide transport defect i. Low or absent uptake of 123I ii. Response to therapeutic doses of potassium iodide c. Defective organification of iodide i. Rapid uptake of 123I ii. Marked decrease in thyroid radioactivity when perchlorate or thiocyanate is administered 2 hours after administering radioiodine iii. Occasional sensorineural hearing loss (Pendred syndrome) d. Iodotyrosine-coupling defect i. Rapid uptake of 123I ii. No discharge by perchlorate iii. Very high thyroid gland content of monoiodotyrosine (MIT) and diiodotyrosine (DIT) iv. Virtually undetectable T4 and T3 v. Adequately iodinated thyroglobulin e. Defects in thyroglobulin gene expression and thyroglobulin secretion i. Elevated uptake of 123I ii. No discharge by perchlorate iii. Abnormal serum iodoproteins iv. Elevated protein-bound/ T4 iodine ratio v. Low or borderline serum thyroglobulin f. Iodotyrosine deiodinase defect i. Rapid uptake and turnover of 123I ii. Elevated serum and urinary iodotyrosines (MIT, DIT) iii. Response to iodine supplementation Intelligence quotient (IQ) measurement for testing neuropsychological progress and outcome Molecular genetic diagnosis by sequencing of select exons to identify mutations

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Sporadic cases: low recurrence risk ii. Autosomal recessive inheritance: 25% iii. Autosomal dominant inheritance: low recurrence risk unless a parent is affected b. Patient’s offspring i. Sporadic cases: low recurrence risk ii. Autosomal recessive inheritance: low recurrence risk unless the spouse carries the recessive gene iii. Autosomal dominant inheritance: 50% 2. Prenatal diagnosis a. Ultrasonography and percutaneous fetal blood sampling i. Detection of fetal goiter a) A rare yet potentially dangerous condition b) A large goiter may cause hyperextension of the neck of the fetus caused by a large goi-

CONGENITAL HYPOTHYROIDISM

ter, resulting in malpresentation and complicate labor and delivery c) Possibility of compressing the trachea and asphyxiating the neonate after birth ii. Fetal blood sample a) Elevated TSH b) Low T4 b. Amniocentesis i. Determination of TSH concentration (markedly elevated TSH level) in amniotic fluid in the second trimester for the offspring of a couple both known to have an iodide (iodothyronine synthesis) enzymatic organification defect ii. Affected fetus with markedly increased TSH level in the amniotic fluid sample for the trimester c. Molecular genetic diagnosis possible by sequencing of select exons on fetal DNA for previously identified mutations in a research laboratory 3. Management a. Sodium L-thyroxine i. The treatment of choice ii. Early therapy (within 14 days) with appropriate doses of thyroxine (about 10 mcg/kg/day) will prevent any brain damage even in case of evidence of fetal hypothyroidism, since thyroxine of maternal origin will reach and protect the fetus iii. Avoid over treatment to prevent the following adverse effects a) Premature cranial suture fusion b) Acceleration of growth and skeletal maturation c) Problems with temperament and behavior b. X-linked dominant thyroxine-binding globulin deficiency (causing a low total T4 but normal free T4): no need for thyroid hormone replacement c. Intrauterine treatment of fetus with a large goiter i. Indicated because of the morbidity associated with compression of the trachea and mechanical interferences during delivery ii. Intra-amniotic administration of levothyroxine presents the least invasive approach to fetal treatment a) Rapid decrease in the fetal goiter size b) Normalization of fetal thyroid function d. Intrauterine treatment of fetus affected with iodide organification defect with synthroid

REFERENCES American Academy of Pediatrics AAP Section on Endocrinology and Committee on Genetics, and American Thyroid Association Committee on Public Health: Newborn screening for congenital hypothyroidism: recommended guidelines. Pediatrics 91:1203–1209, 1993. Abuhamad AZ, Fisher DA, Worsof SL, et al.: Antenatal diagnosis and treatment of fetal goitrous hypothyroidism: case report and review of the literature. Ultrasound Obstet Gynecol 6:368–371, 1995. Abramowicz MJ, Duprez L, Parma J, et al.: Familial congenital hypothyroidism due to inactivating mutation of the thyrotropin receptor causing profound hypoplasia of the thyroid gland. J Clin Invest 99:3018–3024, 1997. Abramowicz MJ, Vassart G, Refetoff S: Probing the cause of thyroid dysgenesis. Thyroid 7:325–336, 1997. Agrawal P, Ogilvy-Stuart A, Lees C: Intrauterine diagnosis and management of congenital goitrous hypothyroidism. Ultrasound Obstet Gynecol 19:501–505, 2002.

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Ambrugger P, Stoeva I, Biebermann H, et al.: Novel mutations of the thyroid peroxidase gene in patients with permanent congenital hypothyroidism. Eur J Endocrinol 145:19–24, 2001. Bargagna S, Canepa G, Costagli C, et al.: Neuropsychological follow-up in early-treated congenital hypothyroidism: a problem-oriented approach. Thyroid 10:243–249, 2000. Beltroy E, Umpaichitra V, Gordon S, et al.: Two infants who have coarse facial features and growth and developmental delay. Pediatr Rev 24:16–21, 2003. Biebermann H, Liesenkotter KP, Emeis M, et al.: Severe congenital hypothyroidism due to a homozygous mutation of the betaTSH gene. Pediatr Res 46:170–173, 1999. Bourgeois MJ, Varma S: Congenital hypothyroidism. http://www. emedicine.com Castanet M, Polak M, Bonaiti-Pellie C, et al.: Nineteen years of national screening for congenital hypothyroidism: familial cases with thyroid dysgenesis suggest the involvement of genetic factors. J Clin Endocrinol Metab 86:2009–2014, 2001. Clifton-Blight RJ, Wentworth J, Heinz P, et al.: Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia. Nat Genet 18:399–401, 1998. Coyle B, Reardon W, Herbrick JA, et al.: Molecular analysis of the PDS gene in Pendred syndrome. Hum Mol Genet 7:1105–1112, 1998. Davidson KM, Richards DA, Schatz DA, et al.: Successful in utero treatment of fetal goiter and hypothyroidism. N Engl J Med 234:543–546, 1991. Delange F: Neonatal screening for congenital hypothyroidism: results and perspectives. Horm Res 48:51–61, 1997. De Vijlder JJM: Primary congenital hypothyroidism: defects in iodine pathways. Eur J Endocrinol 149:247–256, 2003. Fisher DA: Fetal thyroid function diagnosis and management of fetal thyroid disorders. Cog 40:16–31, 1997. Grüters A, Jenner A, Krude H: Long-term consequences of congenital hypothyroidism in the era of screening programmes. Best Pract Res Clin Endocrinol Metab 16:369–382, 2002. Hirsch M, Josefsberg Z, Schoenfeld A, et al.: Congenital hereditary hypothyroidism—prenatal diagnosis and treatment. Prenat Diagn 10:491–496, 1990. Kohn LD, Suzuki K, Hoffman WH, et al.: Characterization of monoclonal thyroid-stimulating and thyrotropin binding-inhibiting autoantibodies from a Hashimoto’s patients whose children had intrauterine and neonatal thyroid disease. J Clin Endocr Metab 82:3998–4004, 1997. Kopp P: Perspective: genetic defects in the etiology of congenital hypothyroidism. Endocrinology 143:2019–2024, 2002. Kreisner E, Camargo-Neto E, Maia CR, et al.: Accuracy of ultrasonography to establish the diagnosis and aetiology of permanent primary congenital hypothyroidism. Clin Endocrinol (Oxf) 59:361–365, 2003. LaFranchi S: Congenital hypothyroidism: etiologies, diagnosis, and management. Thyroid 9:735–740, 1999. Macchia PE: Recent advances in understanding the molecular basis of primary congenital hypothyroidism. Mol Med Today 6:36–42, 2000. Macchia PE, De Felice M, Di Lauro R: Molecular genetics of congenital hypothyroidism. Curr Opin Genet Dev 9:289–294, 1999. Macchia PE, Lapi P, Krude H, et al.: PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nat Genet 19:83–86, 1998. Medeiros-Neto G, Bunduki V, Tomimori E, et al.: Prenatal diagnosis and treatment of dyshormonogenetic fetal goiter due to defective thryoglobulin synthesis. J Clin Endocrinol Metab 82:4239–4242, 1997. Noia G, De Santis M, Tocci A, et al.: Early prenatal diagnosis and therapy of fetal hypothyroid goiter. Fetal Diagn Ther 7:138–143, 1992. Perelman AH, Johnson RL, Clemons RD, et al.: Intrauterine diagnosis and treatment of fetal goitrous hypothyroidism. J Clin Endocrinol Metab 71:618–621, 1990. Schwingshandl J, Donaghue K, Luttrell B, et al.: Transient congenital hypothyroidism due to maternal thyrotrophin binding inhibiting immunoglobulin. J Paediatr Child Health 29:315–318, 1993. Smith DW, Klein AM, Henderson JR, et al.: Congenital hypothyroidism—signs and symptoms in the newborn period. J Pediatr 87:958–962, 1975. Van Naarden Braun K, Yeargin-Allsopp M, Schendel D, et al.: Long-term developmental outcomes of children identified through a newborn screening program with a metabolic or endocrine disorder: a population-based approach. J Pediatr 143:236–242, 2003. Vilain C, Rydlewski C, Duprez L, et al.: Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of PAX8. J Clin Endocrinol Metab 86:2345–238, 2001.

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Fig. 1. A neonate with congenital hypothyroidism showing coarse facial features, hypotonia and umbilical hernia.

Fig. 2. A twin affected with congenital hypothyroidism (left) shows coarse facial features. The normal co-twin is on the right.

Congenital Muscular Dystrophy Congenital muscular dystrophy (CMD) refers to a group of genetic disorders in which weakness and an abnormal muscle biopsy are present at birth.

(POMGnT1) gene which is mapped to chromosome 1p32-p34 b) Sharing features with Fukuyama CMD c) Milder phenotype with survival ranging from early childhood to the seventh decade iii. Walker-Warburg syndrome a) Caused by mutation in the protein O-mannosyltransferase-1 (POMT1) gene b) Similar to muscle-eye-brain disease c) Comparatively more severe leading to death in the first few months of life iv. Other CMD with neuronal migration defects

GENETICS/BASIC DEFECTS 1. Inheritance a. Genetic heterogeneity b. Autosomal recessive in general 2. Classification a. Merosin—negative (laminin α2 deficient) CMD (complete or partial) i. Chromosome locus: 6q22–q23 ii. Caused by mutations of the laminin α2-chain (LAMA2) gene iii. “Classical CMD”: deficient in merosin, the α2 chain of laminin-2, a major constituent of the basal lamina of skeletal muscle fibers linking the extracellular matrix to the dystrophin-associated proteins and integrins iv. A milder phenotype caused by partial deficiency of merosin b. Merosin-positive CMD consisting of a genetically more heterogeneous group i. Rigid spine syndrome a) Caused by mutations in the selenoprotein N1 (SEPN1) gene which is mapped to chromosome 1p35–p36 b) Early onset of hypotonia c) Rigidity of the spine d) Scoliosis ii. Ullrich syndrome: congenital muscular dystrophy with proximal joint contractures and distal joint laxity iii. Pure CMD: either with normal or deficient levels of laminin-α2 (merosin) iv. Other merosin-positive CMD a) Merosin-positive CMD with mental retardation b) Merosin-positive CMD with cerebellar hypoplasia c. Merosin-positive CMD with mental retardation and neuronal migration disorders i. Fukuyama CMD a) Chromosome locus: 9q31–q33 b) FCMD gene encodes fukutin c) Fukutin gene defect represents a novel mutation with a retrotransposal insertion of tandemly repeated sequences on chromosome 9q31-q33 ii. Muscle-eye-brain disease a) Caused by mutation in the protein O-mannoside N-acetylglucosaminyltransferase-1

CLINICAL FEATURES

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1. Typical features a. Floppy infant b. Low muscle tone c. Contractures d. Muscle weakness i. Tends to be stable over time ii. Complications of dystrophy becoming more sever with time 2. Merosin-negative CMD a. Demonstrating clinical homogeneity i. Severe hypotonia ii. Multiple contractures iii. Delayed developmental milestones iv. Normal mentation v. Variable degrees of central hypomyelination seen on neuroimaging b. Patients with complete merosin deficiency i. Typically presenting as floppy infants ii. May or may not require ventilatory assistance iii. Most patients stabilize and able to continue developing without mechanical ventilation iv. Feeding difficulty leading to recurrent aspiration and poor nutrition in some patients v. The best motor milestone achieved: standing with support vi. Unable to ambulate vii. Cognitive development a) Generally normal b) Mental retardation in patients with brain anomalies viii. Epilepsy c. Patients with partial merosin deficiency i. Wide clinical spectrum a) Marked hypotonia at birth, contractures, and severely delayed motor milestones b) Limb-girdle muscular dystrophy-like presentation in the teen

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c) An adult-onset proximal limb-girdle weakness with elevated CK concentration ii. White matter abnormalities by MRI in all patients with documented merosin gene mutations 3. Merosin-positive CMD a. Rigid spine disease i. Onset in infancy ii. Axial muscle weakness iii. Early rigidity of the spine iv. Prominent nasal voice v. Nocturnal respiratory insufficiency vi. Early respiratory failure b. Ullrich disease i. Proximal contractures ii. Distal joint laxity iii. Delayed motor milestones a) Ability to walk in some cases b) Wheelchair dependent in majority of cases iv. Normal intelligence c. Pure CMD i. Normal intelligence ii. Normal brain imaging d. Other merosin-positive CMD 4. Merosin-positive CMD with mental retardation and neuronal migration defects a. Fukuyama CMD i. An autosomal recessive disorder ii. Prevalent in Japan iii. Early onset (before nine months) iv. Muscle weakness v. Accompanied by joint contractures vi. Hypotonia/hypokinesia vii. Severe mental retardation viii. Epilepsy ix. Eye anomalies a) Myopia b) Congenital nystagmus c) Cortical blindness d) Optic atrophy e) Choreoretinal degeneration x. Brain anomalies (cobblestone lissencephaly; type 2 lissencephaly) a) Micropolygyria b) Pachygyria c) White matter lucency d) Minor cerebellar alterations (cortical dysplasia b. Muscle-eye-brain disease i. An autosomal recessive disorder ii. Mimics Walker-Warburg syndrome but overall changes tend to be much milder iii. Present as a floppy infant with suspected blindness iv. Severe mental retardation v. Extensive neuronal migration disorder a) Pachygyria and polymicrogyria b) Brain stem hypoplasia c) Cerebellar dysgenesis d) Hydrocephalus

vi. Muscle involvement: typical features of muscular dystrophy with ongoing de- and regeneration vii. Normal expression of laminin α2 c. Walker-Warburg syndrome i. An autosomal recessive disorder ii. Type II lissencephaly a) Micropolygyric ‘cobblestone’ cortex b) Extensive white matter abnormalities c) Hydrocephaly with enlarged ventricles d) Brainstem hypoplasia e) Hypoplasia of the cerebellum, particularly the cerebellar vermis iii. Ocular dysgenesis a) Megacornea b) Buphthalmos c) Corneal clouding d) Cataracts e) Abnormal vitreous f) Retinal hypopigmentation g) Hypoplasia of the optic nerve h) Clinically blind iv. Muscular dystrophy a) Variable in severity: ranges from myopathy with increased variation of fiber size to severe, end-stage muscular dystrophy b) Well preserved expression of laminin α2 v. Complete lack of psychomotor development (severe mental retardation) for those who survive for some years

DIAGNOSTIC INVESTIGATIONS 1. Elevated serum creatine kinase (CPK) levels 2. Brain MRI with variety of findings a. Pachygyria (with normal cognitive function) b. Cerebellar hypoplasia (with normal cognitive function but delay of speech development) c. Cerebellar cysts (in connection with pure CMD) d. Abnormal white matter signal (in connection with pure CMD of merosin-deficient type) e. Large lissencephalic changes f. Hydrocephalus 3. EMG: the motor units show myopathy with small amplitude and duration 4. Muscle biopsy a. Dystrophic or myopathic pattern b. Varying degrees of muscle fiber degeneration and replacement of muscle fibers by connective tissue and fat c. In the severe merosin-deficient form of CMD: very few muscle fibers left d. Immunohistochemic staining for merosin i. Normal in most of the subgroups of CMD ii. Deficient or totally lacking in CMD with merosin deficiency iii. Merosin is deficient in 5% of patients with Fukuyama type CMD 5. Molecular genetic analyses a. Fukuyama CMD: sequencing of entire coding region or select exons of FCMD gene

CONGENITAL MUSCULAR DYSTROPHY

b. Muscle-eye-brain disease: sequencing of entire coding region or select exons or targeted mutation analysis of POMGnT1 gene c. Walker-Warburg syndrome: sequencing of entire coding region or select exons or mutation scanning of POMT1 gene

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% (autosomal recessive) b. Patient’s offspring: i. Many individuals not living long enough to reproduce ii. All offspring are carriers iii. Recurrence risk to offspring probably less than 1% 2. Prenatal diagnosis a. Available for pregnancies at 25% risk for complete merosin deficiency by linkage analysis, provided complete merosin deficiency has been documented in the muscle of the proband b. Prenatal diagnosis by DNA mutation analysis is available for pregnancies at increased risk of Fukuyama MD, muscle-eye-brain disease, or Walker-Warburg MD by analysis of fetal DNA, obtained by amniocentesis or CVS, provided both disease-causing alleles of an affected family member have been identified 3. Management a. No definitive treatment available b. General approaches i. Weight control to avoid obesity ii. Physical therapy and stretching exercises a) To promote mobility b) To prevent contractures iii. Using mechanical devices to help ambulation and mobility iv. Surgical interventions for scoliosis and foot deformity v. Medications for seizure control vi. Respiratory aids as needed vii. Social and emotional support

REFERENCES Aida N: Fukuyama congenital muscular dystrophy: a neuroradiologic review. J Magn Reson Imaging 8:317–326, 1998. Allamand V, Guicheney P: Merosin-deficient congenital muscular dystrophy, autosomal recessive (MDC1A, MIM#156225, LAMA2 gene coding for alpha2 chain of laminin). Eur J Hum Genet 10:91–94, 2002. Brockington M, Sewry CA, Herrmann R, et al.: Assignment of a form of congenital muscular dystrophy with secondary merosin deficiency to chromosome 1q42. Am J Hum Genet 66:428–435, 2000. Brockington M, Blake DJ, Prandini P, et al.: Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha2 deficiency and abnormal glycosylation of alpha-dystroglycan. Am J Hum Genet 69:1198–1209, 2001. Brockington M, Yuva Y, Prandini P, et al.: Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C. Hum Mol Genet 10:2851–2859, 2001. Caro PA, Scavina M, Hoffman E, et al.: MR imaging findings in children with merosin-deficient congenital muscular dystrophy. AJNR Am J Neuroradiol 20:324–326, 1999.

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Chijiiwa T, Nishimura M, Inomata H, et al.: Ocular manifestations of congenital muscular dystrophy (Fukuyama type). Ann Ophthalmol 15:921–923, 926–928, 1983. Cormand B, Avela K, Pihko H, et al.: Assignment of the muscle-eye-brain disease gene to 1p32–p34 by linkage analysis and Homozygosity mapping. Am J Hum Genet 64:126–135, 1999. Cormand B, Pihko H, Bayés M, et al.: Clinical and genetic distinction between Walker-Warburg syndrome and muscle-eye-brain disease. Neurology 56:1059–1069, 2001. De Stefano N, Dotti MT, Villanova M, et al.: Merosin positive congenital muscular dystrophy with severe involvement of the central nervous system. Brain Dev 18:323–326, 1996. Donner M, Rapola J, Somer H: Congenital muscular dystrophy: a clinicopathological and follow-up study of 15 patients. Neuropadiatrie 6:239–258, 1975. Dubowitz V: 68th ENMC international workshop (5th international workshop): On congenital muscular dystrophy, 9–11 April 1999, Naarden, The Netherlands. Neuromuscul Disord 9:446–454, 1999. Dubowitz V: Congenital muscular dystrophy: an expanding clinical syndrome. Ann Neurol 47:143–144, 2000. Echenne B: Congenital muscular dystrophy of a non-Fukuyama type. Brain Dev 10:397, 1988. Eeg-Olofsson KE: Congenital muscular dystrophy. Care of children and families. Scand J Rehabil Med Suppl 39:53–57, 1999. Farina L, Morandi L, Milanesi I, et al.: Congenital muscular dystrophy with merosin deficiency: MRI findings in five patients. Neuroradiology 40:807–811, 1998. Flanigan KM, Kerr L, Bromberg MB, et al.: Congenital muscular dystrophy with rigid spine syndrome: a clinical, pathological, radiological, and genetic study. Ann Neurol 47:152–161, 2000. Fukuyama Y, Ohsawa M: A genetic study of the Fukuyama type congenital muscular dystrophy. Brain Dev 6:373–390, 1984. Fukuyama Y, Osawa M, Suzuki H: Congenital progressive muscular dystrophy of the Fukuyama type-clinical, genetic and pathological considerations. Brain Dev 3:1–29, 1981. Gordon E, Hoffman EP, Pegoraro E: Congenital muscular dystrophy overview. Gene Reviews 2004. (http://www.genetests.org) Guicheney P, Vignier N, Helbling-Leclerc A, et al.: Genetics of laminin alpha 2 chain (or merosin) deficient congenital muscular dystrophy: from identification of mutations to prenatal diagnosis. Neuromuscul Disord 7:180–186, 1997. Guicheney P, Vignier N, Zhang X, et al.: PCR based mutation screening of the laminin alpha2 chain gene (LAMA2): application to prenatal diagnosis and search for founder effects in congenital muscular dystrophy. J Med Genet 35:211–217, 1998. Helbling-Leclerc A, Zhang X, Topaloglu H, et al.: Mutations in the laminin alpha 2-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy. Nat Genet 11:216–218, 1995. Hillaire D, Leclerc A, Faure S, et al.: Localization of merosin-negative congenital muscular dystrophy to chromosome 6q2 by homozygosity mapping. Hum Mol Genet 3:1657–1661, 1994. Jones R, Khan R, Hughes S, et al.: Congenital muscular dystrophy: the importance of early diagnosis and orthopaedic management in the long-term prognosis. J Bone Joint Surg Br 61:13–17, 1979. Kobayashi O, Hayashi Y, Arahata K, et al.: Congenital muscular dystrophy: Clinical and pathologic study of 50 patients with the classical (Occidental) merosin-positive form. Neurology 46:815–818, 1996. Kondo E, Saito K, Toda T, et al.: Prenatal diagnosis of Fukuyama type congenital muscular dystrophy by polymorphism analysis. Am J Med Genet 66:169–174, 1996. Kondo-Iida E, Kobayashi K, Watanabe M, et al.: Novel mutations and genotypephenotype relationships in 107 families with Fukuyama-type congenital muscular dystrophy (FCMD). Hum Mol Genet 8:2303–2309, 1999. Kondo-Iida E, Saito K, Tanaka H, et al.: Molecular genetic evidence of clinical heterogeneity in Fukuyama-type congenital muscular dystrophy. Hum Genet 99:427–432, 1997. Leyten QH, Gabreels FJ, Joosten EM, et al.: An autosomal dominant type of congenital muscular dystrophy. Brain Dev 8:533–537, 1986. Leyten QH, Gabreels FJ, Renier WO, et al.: Congenital muscular dystrophy: a review of the literature. Clin Neurol Neurosurg 98:267–280, 1996. Leyten QH, Gabreels FJ, Renier WO, et al.: Congenital muscular dystrophy. J Pediatr 115:214–221, 1989.

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Lopate G: Congenital muscular dystrophy. EMedicine (www.emedicien.com) McMenamin JB, Becker LE, Murphy EG: Congenital muscular dystrophy: a clinicopathologic report of 24 cases. J Pediatr 100:692–697, 1982. Mendell JR: Congenital muscular dystrophy: searching for a definition after 98 years. Neurology 56:993–994, 2001. Misugi N: Light and electron microscopic studies of congenital muscular dystrophy. Brain Dev 2:191–199, 1980. Moghadaszadeh B, Desguerre I, Topaloglu H, et al.: Identification of a new locus for a peculiar form of congenital muscular dystrophy with early rigidity of the spine, on chromosome 1p35–36. Am J Hum Genet 62:1439–1445, 1998. Muntoni F, Guicheney P: 85th ENMC International Workshop on Congenital Muscular Dystrophy. 6th International CMD Workshop. 1st Workshop of the Myo-Cluster Project ‘GENRE’. 27–28th October 2000, Naarden, The Netherlands. Neuromuscul Disord 12:69–78, 2002. Naom I, Sewry C, D’Alessandro M, et al.: Prenatal diagnosis in merosin-deficient congenital muscular dystrophy. Neuromuscul Disord 7:176–179, 1997. Nass D, Goldberg I, Sadeh M: Laminin alpha2 deficient congenital muscular dystrophy: prenatal diagnosis. Early Hum Dev 55:19–24, 1999. Nissinen M, Helbling-Leclerc A, Zhang X, et al.: Substitution of a conserved cysteine-996 in a cysteine-rich motif of the laminin alpha2-chain in congenital muscular dystrophy with partial deficiency of the protein. Am J Hum Genet 58:1177–1184, 1996.

Philpot J, Sewry C, Pennock J, et al.: Clinical phenotype in congenital muscular dystrophy: correlation with expression of merosin in skeletal muscle. Neuromuscul Disord 5:301–305, 1995. Santavuori P, Leisti J, Kruus S: Muscle, eye, and brain disease: a new syndrome. Neuropaediatrie 8(suppl):553–558, 1977. Sombekke BH, Molenaar WM, van Essen AJ, et al.: Lethal congenital muscular dystrophy with arthrogryposis multiplex congenita: three new cases and review of the literature. Pediatr Pathol 14:277–285, 1994. Takai Y, Tsutsumi O, Harada I, et al.: Prenatal diagnosis of Fukuyama-type congenital muscular dystrophy by microsatellite analysis. Hum Reprod 13:320–323, 1998. Toda T, Segawa M, Nomura Y, et al.: Localization of a gene for Fukuyama type congenital muscular dystrophy to chromosome 9q31–33. Nat Genet 5:283–286, 1993. Toda T, Kobayashi K, Kondo-Iida E, et al.: The Fukuyama congenital muscular dystrophy story. Neuromuscular Dis 10:153–159, 2000. Tomé FM, Evangelista T, Leclerc A, et al.: Congenital muscular dystrophy with merosin deficiency. C R Acad Sci III 317:351–357, 1994. Topaloglu H, Renda Y, Yalaz K, et al.: Classification of congenital muscular dystrophy. J Pediatr 117:166–167, 1990. Voit T: Congenital muscular dystrophies: 1997 update. Brain Dev 20:65–74, 1998. Yoshioka M, Kuroki S: Clinical spectrum and genetic studies of Fukuyama congenital muscular dystrophy. Am J Med Genet 53:245–250, 1994.

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Fig. 1. An infant with congenital muscular dystrophy showing hypotonic frog-leg posture, the chest deformity due to weakness of the intercostal muscles, and contractures of joints.

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Congenital Toxoplasmosis Acute infection in a pregnant woman with Toxoplasma gondii can result in an infected infant. In the United States, the incidence of congenital toxoplasmosis is estimated to be 1 in 1000 to 1 in 10,000 births and approximately 400–4000 cases of congenital toxoplasmosis occur each year.

7.

GENETICS/BASIC DEFECTS

9.

1. Toxoplasma gondii a. A protozoan parasite b. The causative agent of toxoplasmosis, a common infection throughout the world with estimated 1 billion people infected worldwide c. Life cycle: exists in three forms i. The oocysts, or soil form ii. The tachyzoite, or active infectious form iii. The tissue cyst, or latent form 2. Hosts a. Cats i. The primary host ii. Maintain the intestinal-epithelial sexual cycle of toxoplasma development with the production of oocysts b. All other animals (humans, birds, rodents, and domestic animals) i. The intermediate or secondary hosts ii. Have an extraintestinal asexual cycle with resultant parasitemia and the production of tissue cysts 3. Routes by which Toxoplasma is transmitted to humans a. Principal routes i. Acquired a) Ingestion of raw or inadequately cooked infected meat (beef, pork, or lamb) b) Ingestion of oocysts, an environmentally resistant form of the organism that cats pass in their feces and human exposure to cat litter or contaminated soil (from gardening or unwashed fruits or vegetables) ii. Congenital: transplacental infection of unborn fetus by the newly infected mother b. Rare routes i. Blood and blood product transfusion ii. Organ transplant iii. Laboratory accident c. No evidence of direct human to human transmission other than from mother to fetus 4. 70% of the obstetric population with negative antibodies: at risk for transmission to the fetus 5. Congenital toxoplasmosis usually occurs as a result of primary maternal infection 6. Maternal-fetal transmission rate depends on gestational age at the time of maternal infection a. 90% in the last few weeks of pregnancy Severity of the fetal infection inversely related to gestational age: the earlier infections being the most severe Untreated maternal infections: about 50% of cases transmit to the fetus An immunocompetent woman previously infected are considered immune and will not transmit T. gondii to her offspring. Toxoplasma infection leads to life-long immunity with the presence of T. gondii-specific IgG antibodies. Acute toxoplasmosis in the adult is often asymptomatic and usually does not result in complications Reactivation can occur in immunocompromised pregnant woman (i.e., HIV) leading to parasitemia and fetal infection

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1. Unpredictable manifestations in the fetus and in the newborn 2. Maternal infections a. Generally asymptomatic in immunocompetent mothers b. Subtle symptoms in about 15–20% of infected mothers i. Cervical lymphadenopathy: the most common clinical manifestation ii. Fatigue iii. Flu-like symptoms c. In immunocompromised mothers i. Chorioretinitis ii. Encephalitis iii. Pneumonitis iv. Myocarditis d. Maternal infections early in pregnancy i. Less likely to be transmitted to the fetus than infections later in pregnancy ii. More likely to be severe than later infections 3. Fetal infections a. Usually resulting from a primary maternal infection with risk of developing congenital abnormalities. Reactivation of T. gondii in an immunocompromised patient can render the fetus susceptible to infection b. Infectivity: The incidence and severity of the fetal infection depend on the gestational age at the time of the maternal infection. The later the gestation, the higher the infectivity. However, the postnatal sequelae is severer when infection occurs early in gestation 4. Natural history of congenital toxoplasmosis a. Free of symptoms at birth in vast majority of cases with congenital infection (70–90% of cases) b. About 15% of the infected children with signs or symptoms at birth or neonatal period i. Maculopapular rash ii. Generalized lymphadenopathy iii. Hepatosplenomegaly iv. Jaundice

CONGENITAL TOXOPLASMOSIS

v. Thrombocytopenia vi. Consequences of intrauterine meningoencephalitis a) CSF abnormalities b) Hydrocephalus c) Microcephaly d) Chorioretinitis e) Seizures vii. Signs of the “classic triad” (hydrocephalus, intracranial calcifications, and chorioretinitis) without systemic signs of disease c. Sequelae during childhood or early adult life in 50–90% of cases i. Learning disability ii. Visual impairment iii. Chorioretinitis: the most frequent congenital manifestation and is progressive in >80% of patients by 20 years of age iv. Mental retardation v. Hearing loss d. Eye manifestations i. Strabismus (33%) ii. Nystagmus (27%) iii. Microphthalmia (13%) iv. Phthisis (4%) v. Microcornea (19%) vi. Cataract (10%) vii. Active vitritis (11%) viii. Active retinitis (11%) ix. Chorioretinal scars (79%) x. Optic atrophy (20%) e. Severely affected congenital infection i. Die in utero ii. Die within a few days of life

DIAGNOSTIC INVESTIGATIONS 1. Serological testing a. IgM antibodies i. Produced one to two weeks after an infection ii. Levels detectable for years after the acute infection b. IgG antibodies i. Levels peak approximately 2 months after the initial infection ii. Remain positive for life c. IgA antibodies i. Parallels IgM production ii. Peak levels occur approximately 2 months after the initial infection and then rapidly decline d. IgE antibodies i. Detected early after an acute infection ii. Usually present for 4–8 months iii. May provide useful information regarding the timing of an acute infection 2. Detection of antibodies to toxoplasmosis in the neonatal period a. Specific T. gondii IgM antibody i. A positive IgM antibody in the newborn: diagnostic of congenital toxoplasmosis ii. A negative IgM antibody in the newborn does not exclude the diagnosis and may be due to the following reasons:

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a) Lack of production of IgM b) Waning of the IgM response by the time of birth c) Insensitivity of the assay iii. A positive IgM antibody in the mother a) Associated with recent maternal infection b) Would support the diagnosis of congenital toxoplasmosis b. Specific T. gondii IgA antibody: more sensitive test than IgM antibodies c. Neonatal screening with IgM or IgA antibodies fails to detect majority of children with congenital toxoplasmosis when the maternal infection occurred before the 20 weeks of pregnancy 3. Definitive postnatal diagnosis of congenital toxoplasmosis a. Detection of parasites in material collected from the newborn (blood, cerebrospinal fluid, or other clinical material) by inoculation into mice or tissue culture b. Detection of persisting specific IgG antibodies at the age of 1 year c. Reappearance of specific IgG antibodies in the child after cessation of postnatal antibiotic therapy d. Diffuse cerebral calcifications and hydrocephalus detected by radiography, ultrasonography, CT scan, or MRI of the brain 4. Other diagnostic evaluation of the infants a. Physical examination b. Dilated retinal examination c. Examination of the cerebrospinal fluid i. Protein ii. Glucose iii. Cell count iv. Antibody determination d. Audiologic screen e. Examination of the placenta i. Evidence of infection, although the gross appearance may not parallel the severity of fetal disease ii. Inoculation of the placental tissue into mice or tissue culture to attempt isolation of the parasite

GENETIC COUNSELING 1. Recurrence risk: women with previous infection not at risk for delivering a fetus with congenital toxoplasmosis unless immunosuppressed 2. Prenatal diagnosis a. Seroconversion during pregnancy i. Absence of specific Toxoplasma gondii IgG antibodies in the first serum sample obtained during gestation ii. Detection of specific IgG and IgM antibodies in the follow-up sample at a later prenatal visit or at birth b. Suggestive but not diagnostic signs by prenatal ultrasonography i. Ventriculomegaly: the most common sonographic finding in utero ii. Intracranial calcifications iii. Hydrops iv. Microcephaly v. Choroid plexus cysts

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vi. Growth retardation vii. Hepatomegaly viii. Splenomegaly ix. Ascites x. A thickened placenta c. Prenatal diagnosis of acute infection in the fetus i. Amniocentesis or cordocentesis a) Detection of parasites in amniotic fluid or in fetal blood by inoculation into tissue culture or mice b) Detection of anti-Toxoplasma gondii IgM, IgA, and IgE antibodies in the fetal blood. The diagnosis of fetal T. gondii infection before 22 weeks using cordocentesis is not possible because fetal IgM or IgA may not be produced before 22 weeks’ gestation. c) Detection of T. gondii DNA (B1 gene) by gene amplification in amniotic fluid: more accurate and faster diagnosis of congenital toxoplasmosis ii. Chorionic villus sampling not helpful because it will show placental but not fetal infection 3. Management a. Prevention of toxoplasma infection i. Cook meat to a safe temperature to kill toxoplasma ii. Peel or thoroughly wash fruits and vegetables before eating iii. Clean cooking surfaces and utensils after they have contacted raw meat, poultry, seafood, or unwashed fruits or vegetables iv. Avoid changing cat litter during pregnancy or use gloves and wash hands thoroughly v. Do not feed raw or undercooked meat to cats and keep cats inside to prevent acquisition of Toxoplasma by eating infected prey vi. Avoid risk factors for T. gondii infection including careful adherence to simple hygienic measures during pregnancy (decrease Toxoplasma infection by 60%) b. Treat Toxoplasma infection with spiramycin, pyrimethamine, sulfonamides, and folinic acid i. Reduce sequelae of congenital infection by treating the mother as soon as possible after the serologic screening program identifies the infection ii. Treat infected neonates: sooner the treatment, the better the outcome c. Newborn screening for Toxoplasma-specific IgM allows the identification and treatment of subclinical cases so that the sequelae of infection with toxoplasmosis may be prevented or attenuated

REFERENCES Alford CA Jr, Stagno S, Reynolds DW: Congenital toxoplasmosis: clinical, laboratory, and therapeutic considerations with special reference to subclinical disease. Bull NY Acad Med 50:160–181, 1974.

American Academy of Pediatrics Report of the Committee on Infectious Diseases: Toxoplasmosis. Red Book 2000, pp 583–586. Antsaklis A, Daskalakis G, Papantoniou N, et al.: Prenatal diagnosis of congenital toxoplasmosis. Prenat Diagn 22:1107–1111, 2002. Bale JF Jr: Congenital infections. Neurol Clin 20:1039–1060, 2002. Beasley DM, Egerman RS: Toxoplasmosis. Semin Perinatol 22:332–338, 1998. Black MW, Boothroyd JC: Lytic cycle of Toxoplasma gondii. Microbiol Mole Biol Rev 64:607–623, 2000. Daffos F, Forestier F, Capella-Pavlovsky M, et al.: Prenatal management of 746 pregnancies at risk for congenital toxoplasmosis. N Engl J Med 318:271–275, 1988. Desmonts G, Couvreur J: Congenital toxoplasmosis: A prospective study of 378 pregnancies. N Engl J Med 290:1110–1116, 1974. Foulon W, Pinon J-M, Stray-Pedersen B, et al.: Prenatal diagnosis of congenital Toxoplasmosis: a multicenter evaluation of different diagnostic parameter. Am J Obstet Gynecol 181: 1999. Foulon W, Villena I, Stray-Pedersen B, et al.: Treatment of toxoplasmosis during pregnancy: a multicenter study of impact on fetal transmission and children’s sequelae at age 1 year. Am J Obstet Gynecol 190:410–415, 1999. Fricker-Hidalgo H, Pelloux H, Muet F, et al.: Prenatal diagnosis of congenital toxoplasmosis: comparative value of fetal blood and amniotic fluid using serological techniques and cultures. Prenat Diagn 17:831–835, 1997. Guerina NG, Hsu H-W, Meissner HC, et al.: Neonatal serologic screening and early treatment for congenital Toxoplasma Gondii infection. N Engl J Med 330:1858–1863, 1994. Hall SM: Congenital toxoplasmosis. Brit Med J 305:291–297, 1992. Hezard N, Marx-Chemla C, Foudrinier F, et al.: Prenatal diagnosis of congenital toxoplasmosis in 261 pregnancies. Prenat Diagn 17:1047–1054, 1997. Hohlfeld P, Daffos F, Thulliez P, et al.: Fetal toxoplasmosis: outcome of pregnancy and infant follow-up after in utero treatment. J Pediatr 115:765–769, 1989. Hohlfeld P, Dafos F, Costa JM, et al.: Prenatal diagnosis of congenital toxoplasmosis with a polymerase-chain-reaction test on amniotic fluid. N Engl J Med 331:695–699, 1994. Hovakimyan A, Cunningham ET Jr: Ocular toxoplasmosis. Ophthalmol Clin N Amer 15:327–332, 2002. Jones J, Lopez A, Wilson M: Congenital toxoplasmosis. Am Fam Physician 67:2131–2138, 2000. Kuhlmann RS, Autry AM: An approach to nonbacterial infections Lopez A, Dietz VJ, Wilson M, et al.: Preventing congenital toxoplasmosis. Morbidity Mortality Weekly Report 49(RR-2):57, 2000. Lopez A, Dietz VJ, Wilson M, et al.: Preventing congenital toxoplasmosis. Morbidity Mortality Weekly Report 49(RR-2), 2000. Lynfield R, Eaton RB: Teratogen update: congenital toxoplasmosis. Teratology 52:176–180, 1995. Metz MB: Eye manifestations of intrauterine infections. Ophthalmol Clin N Am 14:521–531, 2001. Naessens A, Jenum PA, Pollak A, et al.: Diagnosis of congenital toxoplasmosis in the neonatal period: a multicenter evaluation. J Pediatr 135:714–719, 1999. Pataki, Meszner Z, Todorova R: Congenital toxoplasmosis. Int Pediatr 15:33–36, 2000. Patel DV, Holfels EM, Vogel NP, et al.: Resolution of intracranial calcifications in infants with treated congenital toxoplasmosis. Radiology 199:433–440, 1996. Remington JS: Toxoplasmosis in the adult. Bull N Y Acad Med 50:211–227, 1974. Roizen N, Swisher CN, Stein MA, et al.: Neurologic and developmental outcome in treated congenital toxoplasmosis. Pediatrics 95:11–20, 1995. Sever JL, Ellenberg JH, Ley AC, et al.: Toxoplasmosis: Maternal and pediatric findings in 23,000 pregnancies. Pediatrics 82:181–192, 1988. Wilson CB, Remington JS: What can be done to prevent congenital toxoplasmosis? Am J Obstet Gynecol 138:357–363, 1980.

CONGENITAL TOXOPLASMOSIS

Fig. 1. A newborn died of congenital generalized toxoplasma infection. The heart showed myocarditis with presence of toxoplasma cyst (arrow) (H & E, ×400)

Fig. 2. Toxoplasma cyst seen in high magnification (arrow) (H & E, ×1000)

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Fig. 4. A small area of resolving acute toxoplasmic retinochoroiditis adjacent to a larger area of healed congenital toxoplasmosis scar.

Fig. 5. Satelitte lesions of acute exacerbation of toxoplasmic retinochoroiditis adjacent to a larger scar of healed congenital ocular toxoplasmosis.

Fig. 3. Mild acute chorionitis associated with toxoplasma infection. A toxoplasma cyst was found in chorionic plate of the placental disc (H & E, ×1000) Fig. 6. Diffusely scattered punctate cerebral calcifications secondary to congenitally acquired toxoplasmosis

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Fig. 7. An adult with congenital toxoplasmosis who had mental retardation, seizures, and chorioretinitis. CT of the brain showed scattered multiple foci of intracerebral calcifications.

Conjoined Twins Conjoined twins are incompletely separated monozygotic twins. They have long fascinated both medical profession and lay public. Such events are rare and occur in 1/50,000 to 1/100,000 births and one in 400 sets of monozygotic twins. It is a complication of monochorionic twinning at 13 to 15 days after conception.

GENETICS/BASIC DEFECTS 1. Conjoined twins a. Rare variants of monozygotic, monochorionic twins b. Two theories of con-joined twin formation i. Resulting from the secondary union of two originally separate monovular embryonic discs ii. Resulting from an incomplete separation of the inner cell mass at around 13–15 days of gestation of the monovular twins c. Twins can be conjoined at any site from the cranium downward to the sacrococcygeal region d. Approximately 60% are stillborn e. Female predominance: approximately 3:1 female-tomale ratio 2. Embryologic classification of conjoined twins a. Ventral (87%) i. Rostral (48%) a) Cephalopagus 11% b) Thoracopagus 19% c) Omphalopagus 18% ii. Caudal (11%) (ischiopagus) iii. Lateral (28%) (parapagus) b. Dorsal (13%) i. Craniopagus (5%) ii. Rachipagus(2%) iii. Pygopagus (6%) 3. Anatomic classifications of conjoined twins, based on how the body axes of the twins are mutually oriented in the embryonic disc a. Notochordal axes facing each other i. Ventro-ventral a) Thoracopagus b) Xiphopagus c) Omphalopagus ii. Cranial ventro-vental (cephalothoracopagus) iii. Caudal ventro-ventral (ischiopagus) iv. Cranial end-to-end (craniopagus) v. Caudal end-to-end (pygopagus) b. Notochordal axes facing side-by-side i. Dicephalus ii. Diprosopus 4. Anatomic classifications of conjoined twins, based on how the subsequent events of migration, growth, and body folding result in different types of conjoined twins a. Dipygus b. Fetus-in-fetu 241

i. A fetiform mass located within a basically normal fetus ii. Inclusion of a monozygotic diamniotic twin within the bearer is the best explanation 5. Duplicitas symmetros (symmetrical conjoined twins resulting from incomplete fission of the uniovum) a. Terata Katadidyma (twins joined at the lower part of the body and double above) i. Dicephalus (twins with 2 separate heads and necks side by side with 1 body; lateral conjugation) ii. Diprosopus (twins with 2 faces side by side, 1 head, and 1 body) iii. Ischiopagus (twins joined by the inferior margins of the coccyx and sacrum with 2 completely separate spinal columns; caudal conjugation) iv. Pygopagus (twins joined by posterior surfaces of the coccyx and sacrum, back to back; posterior conjugation) v. Craniothoracopagus vi. Ileothoracopagus b. Terata anadidyma (twins joined at the upper part of the body and double below) i. Craniopagus (twins joined at the top of cranial vaults; cephalic conjugation) ii. Dipygus (twins with 1 head, 1 thorax, 1 abdomen, and double pelvis with or without 2 sets of external genitalia and up to 4 legs; lateral conjugation) iii. Syncephalus (twins joined by the face; the faces turn laterally) c. Tera anakatadidyma (twins joined by the midportion of the body) i. Omphalopaus (twins joined from the umbilicus to xiphoid cartilage; anterior conjugation) ii. Xiphopagus (twins joined at xiphoid process) iii. Rachipagus (twins joint by the vertebral column; back to back) iv. Thoracopagus (twins joined at the chest wall; anterior conjugation) 6. Duplicatas asymmetros (asymmetrical conjoined twins resulting from unequal and incomplete fission of the uniovum and unequal placental circulation to twins) a. Cephalic conjugation i. Craniopagus parasiticus ii. Janus parasiticus iii. Epignathus heteropagus b. Anterior conjugation i. Thoracopagus parasiticus ii. Epigastrius c. Posterior conjugation i. Ischiopagus parasiticus ii. Pyopagus parasiticus iii. Sacral parasiticus

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CLINICAL FEATURES 1. Thoracopagus twins a. Represents 40% of conjoined twins b. Conjoined at the thoracic region c. Face to face d. Associated congenital heart defects i. Present in 75% of cases ii. Presence of varying degree of pericardial sac fusion iii. A conjoined heart with two ventricles and a varying number of atria (most frequent abnormality) iv. Ventricular septal defect in virtually all patients 2. Omphalopagus twins (fused umbilical region)/Xiphopagus twins (fused xiphoid process of sternum) a. Constitutes one third of all types of conjoined twins b. The most readily separable conjoined twins since their union may involve only skin and portions of the liver, occasionally including portions of the sternum c. Most omphalopagus twins joined by a skin bridge that contains liver and bowel d. Conjoined liver in 81% e. Conjoined sternal cartilage in 26% f. Conjoined diaphragm in 17% g. Conjoined genitourinary tract in 3% h. Malformations of the abdominal wall (usually omphalocele) in at least one of the twins in 33% i. Congenital heart defects in at least one of the twins in 25% i. Ventricular septal defects ii. Tetralogy of Fallot j. Concordant congenital heart defects in only one out of 9 sets of twins 3. Pygopagus twins a. Constitutes 19% of conjoined twins b. Conjoined at sacrum (buttocks and lower spine) c. Most commonly back-to-back (face away from each other) d. May share part of the sacral spinal canal e. May share common rectum and anus f. Often with fused genitalia 4. Ischiopagus twins a. Constitutes 6% of conjoined twins b. Conjoined back-to-back at the coccyx c. Often with a common large pelvic ring formed by the union of the two pelvic girdles d. May have 4 legs (ischiopagus tetrapus) e. May have three legs (ischiopagus tripus) f. Frequently share the lower gastrointestinal tract i. Intestines joined at the terminal ileum ii. Emptying into a single colon g. May have a single bladder and urethra h. Displaced anus i. Common vaginal anomalies j. Common rectovaginal communications 5. Craniopagus twins (fused at the cranial vault) (2%) a. Classification according to the area of junction i. Frontal craniopagus ii. Parietal craniopagus (most common)

6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

16.

17.

18.

iii. Temporal craniopagus iv. Occipital craniopagus b. Classification based on surgical and prognostic purposes i. Partial type (brains separated by bone or dura with each brain having separate leptomeninges) ii. Complete type (presence of cerebral connection) Rachiopagus twins (fused upper spinal column; back to back) Pygodidymus twins (fused cephalothoracic region; duplicate pelves and lower extremities) Pygopagus twins/pygomelus twins (joined back-to-back at the sacrum; additional limb or limbs at or near buttock) Iniopagus twins/craniopagus occipitalis twins (fused head, at parasitic occipital region) Epicomus twins/craniopagus parasiticus twins (smaller, parasitic twin joined to larger autosite at occiput) Monocephalus twins (single head with 2 bodies) Diprosopus twins (single body with 2 faces) Dicephalus twins (symmetric body with 2 heads) Dipygus parasiticus twins (head and thorax completely merged; pelvis and lower extremities duplicated) Cephalopagus conjoined twins a. The rarest type of conjoined twins b. Fused from the top of the head to the umbilicus c. Presence of two faces on the opposite sides of the head with one face usually being rudimentary d. Separation of the lower abdomen e. With 4 arms and 4 legs f. Prognosis dismal dependent on the following factors i. Presence of associated anomalies ii. Degree of fusion of the intracranial, intrathoracic and/or intra-abdominal structures iii. Extent of venous connections Epigastric heteropagus twins a. A rare type of conjoined twinning b. Resulting from an ischemic atrophy of one fetus at an early stage of gestation c. Pelvis and lower limbs of the ischemic fetus (incomplete parasitic twin; heteropagus) attached to the epigastrium of the well-developed fetus (the autosite) Fetus in fetu a. The parasites embodied in the autosite, usually within cranial, thoracic, and abdominal cavities during the developmental process of the asymmetrical conjoined twins b. Most likely arise from inclusion of a monochorionic, diamniotic, monozygotic twin within the bearer due to anastomoses of vitillene circulation Prognosis a. A high mortality rate i. Nearly 40% are stillborn ii. 1/3 die within 24 hours of birth iii. No prospect of survival when complex cardiac union is present b. Causes of death i. Severely abnormal conjoined heart ii. Pulmonary hypoplasia due to distortion of fused thoracic cages

CONJOINED TWINS

19. Examples of historically famous conjoined twins a. So-called Biddenden Maids (1100–1134) in England i. Probably pyopagus twins ii. Their famous image imprinted on the “cakes” iii. Walks with their arms around each other b. Chang and Eng Bunker (1811–1874) from Bangkok and settled in the USA (“Siamese twins”) i. Later married to twin girls ii. Fathered 22 children c. Blazˇek sisters (1878–1922) from Bohemia i. 2 heads ii. 4 arms iii. 4 legs iv. Partially fused torso v. Combined reproductive organs vi. Delivered an infant through a single vagina but the gestation had occurred in the uterus of one of the twins

DIAGNOSTIC INVESTIGATIONS 1. Prenatal echocardiography a. Presence and extent of cardiac conjunction b. Associated cardiac defects 2. Prenatal radiography 3. Prenatal ultrasonography (including transvaginal twodimensional sonography), especially three-dimensional sonographic examinations (The surface-rendered image of the conjoined twin and its demonstration on an axially rotating cine loop facilitates explanation of the precise nature of the abnormalities, especially in the case of cephalothoracopagus conjoining) 4. CAT scan and MRI of the abdomen and the chest a. Anatomy of the heart b. Anatomy of the livers c. Anatomy of the genitourinary systems 5. Gastrointestinal contrast studies to demonstrate the presence and level of conjunction of the intestinal tract 6. Ventrally fused conjoined twins a. Prenatal radiography/ultrasonography i. Fetal body parts on the same level ii. Constant relative fetal position iii. Fetal extremities in unusual proximity iv. Face-to-face fetal position v. Bibreech, less commonly bicephalic presentation vi. Hyperextension of one or both cervical spines b. Prenatal ultrasonography i. Nonseparable continuous external skin contour ii. Single heart sound by Doppler iii. Solitary large liver and heart iv. Multiple shared omenta v. Solitary umbilical cord with >3 vessels 7. Cephalothoracopagus a. Prenatal radiographic criteria i. Both fetal heads at the same level ii. Backward fusion of the cervical spines iii. A narrow space between lower cervical and upper thoracic spines iv. No change in fetal relative positions after maternal movement

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b. Prenatal sonographic criteria i. Fusion of the skulls, face, thorax, and upper abdomen ii. Fetal body parts at the same level iii. Constant relative fetal motion iv. Fetal extremities in unusual positions v. Breech position vi. Hyperextension of both cervical spines vii. Nonseparable external skin contour viii. A solitary umbilical cord with multiple vessels ix. Polyhydramnios x. Two actively beating hearts xi. Two sets of pelves, limbs and spine

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not higher according to family study b. Patient’s offspring: report of delivery of a healthy male infant to the pygopagus Blazˇek sisters 2. Prenatal diagnosis a. Radiography b. 2D/3D ultrasonography: prenatal diagnosis made as early as 10–12 weeks’ gestation c. Transcervical embryoscopy for first trimester embryonic evaluation of conjoined twins after a missed abortion 3. Management a. Early prenatal diagnosis: highly desirable, given the extremely poor prognosis of some types of conjoined twins b. Psychological and prognosis counseling c. Accurate preoperative investigation d. A team approach e. Previous experience f. Meticulous operative and postoperative management g. Substantial mortality rate related to the underlying conditions h. High likelihood of success if major associated anomalies are absent i. Options of obstetrical management i. Continue the vaginal delivery and deliver the twins intact ii. Deliver the twins vaginally after intrauterine separation or a destructive procedure iii. Cesarean section and deliver the twins intact iv. Cesarean section and deliver the twins after intrauterine separation or destruction j. Anesthetic management for separating operations i. Extensive cross circulation a) Through a liver bridge b) Common cerebral venous sinus ii. Mechanical problems a) One anesthetist required for each infant b) A third anesthetist to look after intravenous infusions and monitors c) A fourth anesthetist to look after massive blood loss, circulatory collapse or other catastrophic occurrence iii. Anticipate complex congenital heart defects that was not diagnosed preoperatively

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REFERENCES Awashi M, Narlawar R, Hira P, et al.: Fetus in fetu. Rare cause of a lump in an adult’s abdomen. Aust Radiol 45:354–356, 2001. Bega G, Wapner R, Lev-Toaff A, et al.: Diagnosis of conjoined twins at 10 weeks using three-dimensional ultrasound: a case report. Ultrasound Obstet Gynecol 16:388–390, 2000. Benirschke K, Temple WW, Bloor CM: Conjoined twin: nosologic and congenital malformation Birth Defects 15:179–192, 1978. Benirschke K: Sonographic diagnosis of conjoined twinning. Ultrasound Obstet Gynecol 1:241, 1998. Biswas A, Chia D, Wong YC: Three-dimensional sonographic diagnosis of cephalothoracopagus janiceps twins at 13 weeks. Ultrasound Obstet Gynecol 18:289, 2001. Bonilla-Musoles F, Machado LE, Osborne Nat Genet, et al.: Two-dimensional and three-dimensional sonography of conjoined twins. J Clin Ultrasound 30:68–75, 2002. Chen C-P, Lee C-C, Liu F-F, et al.: Prenatal diagnosis of cephalothoracopagus janiceps monosymmetros. Prenat Diagn 17:384–388, 1997. Chou SY, Liang SJ, Wu CF, et al.: Sacral parasite conjoined twin. Obstet Gynecol 98:938–940, 2001. Edmonds LD, Layde PM: Conjoined twins in the United States. 1970–1977. Teratology 25:301–308, 1982. Gilbert-Barness E, Debich-Spicer D, Opitz JM: Conjoined twins: morphogenesis of the heart and a review. Am J Med Genet 120A:568–582, 2003. Gore RM, Filly RA, Parer JT: Sonographic antepartum diagnosis of conjoined twins. Its impact on obstetric management. JAMA 247:3351–3353, 1982. Guttmacher AF: Biographical notes on some famous conjoined twins. Birth Defects Original Article Series III(1):10–17, 1967. Guttmacher AF, Nichols BL: Teratology of conjoined twins. Birth Defects Orig Artic Ser 3(1):3–9, 1967. Harper RG, Kenigsberg K, Sia CG, et al.: Xiphopagus conjoined twin: a 300year review of the obstetric, morphopathologic, neonatal, and surgical parameters. Am J Obstet Gynecol 137:617–629, 1980. Herbert WNP, Cefalo RC, Koontz WL: Perinatal management of conjoined twins. Am J Perinatal 1:58–63, 1983. Keats AS, Cave PE, Slataper EL, et al.: Conjoined twins-A review of anesthetic management for separating operations. Birth Defects Original Article Series III(1):80–88, 1967. Knox JS, Webb AJ: The clinical features and treatment of fetus in fetu: two case reports and review of literature. J Pediatr Surg 10:483–489, 1975. Kuroda K, Kamei Y, Kozuma S, et al.: Prenatal evaluation of cephalopagus conjoined twins by means of three-dimensional ultrasound at 13 weeks of pregnancy. Ultrasound Obstet Gynecol 16:264–266, 2000. Lam YH, Sin SY, Lam C, et al.: Prenatal sonographic diagnosis of conjoined twins in the first trimester: two case reports. Ultrasound Obstet Gynecol 11:289–291, 1998.

Maymon R, Halperin R, Weinraub Z, et al.: Three-dimensional transvaginal sonography of conjoined twins at 10 weeks: a case report. Ultrasound Obstet Gynecol 11:292–294, 1998. Machin GA: Multiple pregnancies and conjoined twins. In Gilbert-Barness E (ed.): Potter’s Pathology of the Fetus and Infant. St. Louis, Mosby, 1997, Ch 9, pp 281–321. Nastanski F, Downey EC: Fetus in fetu: a rare cause of a neonatal mass. Ultrasound Obstet Gynecol 18:72–75, 2001. Petit T, Raynal P, Ravasse P, et al.: Prenatal sonographic diagnosis of a twinning Epigastric heteropagus. Ultrasound Obstet Gynecol 17:534–535, 2001. Rudolph AJ, Michaels JP, Nichols BL: Obstetric management of conjoined twins. Birth Defects Original Article Series III(1):28–37, 1967. Sanders SP, Chin AJ, Parness IA, et al.: Prenatal diagnosis of congenital heart defects in thoracoabdominally conjoined twins. N Engl J Med 313:370–374, 1985. Sills ES, Vrbikova J, Kastratovic-Kotlica B: Conjoined twins, conception, pregnancy, and delivery: A reproductive history of the pygopagus Blazˇek sisters (1878–1922). Am J Obstet Gynecol 185:1396–1402, 2001. Spencer R: Anatomic description of conjoined twins: a plea for standardized terminology. J Pediatr Surg 31:941944, 1996. Spencer R: Theoretical and analytical embryology of conjoined twins: Part I: Embryogenesis. Clin Anat 13:36–53, 2000. Spencer R: Theoretical and analytical embryology of conjoined twins: Part II: Adjustments to union. Clin Anat 13:97–120, 2000. Spencer R: Parasitic conjoined twins: external, internal (fetuses in fetu and teratomas), and detached (acardiacs). Clin Anat 14:428–444, 2001. Spitz L, Kiely EM: Experience in the management of conjoined twins. Brit J Surg 89:1188–1192, 2002. Tan A, Lee S-L: Prenatal diagnosis of parasitic twins using three-dimensional ultrasound: a case report. Ultrasound Obstet Gynecol 20:192–193, 2002. Tongsong T, Chanprapaph P, Pongsatha S: First-trimester diagnosis of conjoined twins: a report of three cases. Ultrasound Obstet Gynecol 14:434–437, 1999. Van Den Brand SF, Nijhuis JG, Van Dongen PW: Prenatal ultrasound diagnosis of conjoined twins. Obstet Gynecol Surv 49:656–662, 1994. Weingast GR, Johnson ML, Pretorius DH, et al.: Difficulty in sonographic diagnosis of cephalothoracopagus. J Ultrasound Med 3:421–423, 1984. Wilcox DT, Quinn FM, Spitz L, et al.: Urological problems in conjoined twins. Brit J Urol 81:905–910, 1998. Yin CS, Chen W-H, Wei RY-C, et al.: Transcervical embryoscopic diagnosis of conjoined twins in a ten-week missed abortion. Prenat Diagn 18:626–628, 1998. Zimmermann AA: Embryological and anatomic considerations of conjoined twins. Birth Defects 3:18–27, 1967.

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Fig. 1. The conjoined twins are joined at the level of abdomen from umbilicus to the xiphoid cartilage (xiphoomphalopagus). This type of conjoined twins is the one most amenable to successful surgical correction because the incidence of complex anatomical anomalies is low. Left twin was successfully separated from the right twin who succumbed shortly after surgery to multiple congenital anomalies including exstrophy of the cloaca, left Bochdalek hernia, hypoplastic kidney, hypoplastic lungs, imperforate anus, and a large sacral meningomyelocele.

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Fig. 3. These twins are thoraco-omphalopagus, connected at the thorax and upper abdomen. The heart showed complex anomalies with a common atrium and a single ventricle. Therefore, separation of the twins was not attempted.

Fig. 4. The radiograph of the twins in Fig. 3 showing the connection at the thorax and the upper abdomen.

Fig. 2. Prenatal ultrasound (A) detected the above conjoined twins with a shared liver (CAB) and separate hearts, stomach, pelvis, and extremities. One fetus was noted to have a meningomyelocele (M). The magnified view (B) shows part of the shared liver and meningomyelocele.

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Fig. 5. Dicephalic conjoined twins. Two separate heads, two separate necks, and only one body are evident. The twins shared a common pericardium with complex cardiac anomalies, a common aorta at the level of iliac arteries, a common small intestine and other GI tract distally, a common bladder and urethra drained from a single kidney from each twin, and single normal female genitalia with normally placed fallopian tubes and ovaries. Surgical separation of the twins was deemed impossible and was not attempted.

Fig. 7. A stillbirth with dicephalic conjoined twins.

Fig. 8. A set of dicephalic conjoined twin embryos at 6–7 weeks of gestation.

Fig. 6. The radiograph of the above-conjoined twins showing separate heads, vertebrae, and upper GI tract. There is one pericardium sac and a fused liver.

Corpus Callosum Agenesis/Dysgenesis Agenesis/dysgenesis of the corpus callosum is among the most common brain developmental malformation with a wide spectrum of associated clinical and pathologic abnormalities. The prevalence and clinical significance are uncertain. It is estimated to be 0.3–0.7% in the general population and 2–3% in the developmentally disabled.

GENETICS/BASIC DEFECTS 1. Markedly heterogeneous etiology of agenesis/dysgenesis of the corpus callosum a. Sporadic in most cases b. Environmental factors i. Alcoholism ii. Maternal rubella iii. Maternal diabetes c. A multifactorial trait d. As a part of autosomal dominant syndrome i. Agenesis/dysgenesis of the corpus callosum ii. Apert syndrome iii. Basal cell nevus syndrome iv. Miller-Dieker syndrome v. Rubinstein-Taybi syndrome vi. Tuberous sclerosis e. As a part of autosomal recessive syndrome i. Agenesis/dysgenesis of the corpus callosum ii. Agenesis/dysgenesis of the corpus callosum with thrombocytopenia iii. Acrocallosal syndrome iv. Andermann syndrome a) Agenesis/dysgenesis of the corpus callosum with peripheral neuropathy b) Mapping of the gene to a 5-cm region in chromosome 15q13-15 v. Cerebro-oculo-facio-skeletal (COFS) syndrome vi. Cogan syndrome (ocular motor apraxia) vii. Craniotelencephalic dysplasia viii. Dincsoy syndrome a) Multiple midline malformations b) Limb abnormalities c) Hypopituitarism ix. Fukuyama congenital muscular dystrophy x. Hydrolethalis syndrome xi. Joubert syndrome (cerebellar vermis agenesis) xii. Leprechaunism xiii. Lowry-Wood syndrome a) Epiphyseal dysplasia b) Microcephaly c) Nystagmus xiv. Meckel-Gruber syndrome xv. Microcephalic osteodysplastic primordial dwarfism type I/III xvi. Neu-Laxova syndrome 247

xvii. Opitz G syndrome xviii. Peters plus syndrome a) Peters anomaly b) Short-limb dwarfism xix. Shapiro syndrome (recurrent hypothermia) xx. Smith-Lemli-Opitz syndrome xxi. Toriello-Carey syndrome a) Agenesis/dysgenesis of the corpus callosum b) Facial anomalies c) Robin sequence xxii. Vici syndrome a) Agenesis/dysgenesis of the corpus callosum b) Immunodeficiency c) Cleft lip/palate d) Cataract e) Hypopigmentation xxiii. Walker-Warburg syndrome a) Hydrocephalus b) Agyria c) Retinal dysplasia xxiv. Warburg micro syndrome a) Microcephaly b) Microphthalmia c) Cerebral malformations d) Other anomalies f. As a part of X-linked syndrome i. Agenesis/dysgenesis of the corpus callosum ii. Agenesis/dysgenesis of the corpus callosum with Hirschsprung disease iii. Agenesis/dysgenesis of the corpus callosum with hypohidrotic ectodermal dysplasia iv. Aicardi syndrome (retinovertebral anomalies in females) v. ATR-X syndrome (X-linked alpha thalassemia mental retardation syndrome) vi. Craniofrontonasal syndrome vii. Curatolo syndrome a) Agenesis/dysgenesis of the corpus callosum b) Chorioretinal abnormality viii. FG syndrome a) Mental retardation b) Large head c) Imperforate anus d) Congenital Hypotonia e) Partial agenesis/dysgenesis of the corpus callosum ix. HSAS syndrome (hydrocephalus due to congenital stenosis of aqueduct of Sylvius) x. Lenz dysplasia a) Microphthalmia/anophthalmia b) Associated anomalies xi. Lujan-Fryns syndrome

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a) X-linked mental retardation b) Marfanoid habitus xii. MASA syndrome a) Mental retardation b) Aphasia c) Shuffling gait d) Adducted thumbs xiii. MLS syndrome a) Microphthalmia b) Linear skin defects xiv. Opitz G syndrome xv. OFD I xvi. Proud syndrome a) X-linked syndrome b) Seizures c) Acquired micrencephaly d) Agenesis/dysgenesis of the corpus callosum xvii. XLIS syndrome (X-linked lissencephaly) g. As a part of unknown-genesis syndrome i. Calloso-genital dysplasia ii. Delleman (oculocerebrocutaneous) syndrome iii. Frontonasal dysplasia iv. Opitz C trigonocephaly syndrome v. Sebaceous nevus syndrome h. As a part of metabolic disorders i. Adenylosuccinase deficiency ii. Adipsic hypernatremia iii. β-hydroxyisobutyryl coenzyme A deacyclase deficiency iv. Glutaric aciduria type II v. Histidinemia vi. Hurler syndrome vii. Leigh syndrome viii. Menkes syndrome ix. Neonatal adrenoleukodystrophy x. Nonketotic hyperglycinemia xi. Pyruvate dehydrogenase deficiency xii. Zellweger syndrome i. Associated chromosome abnormalities i. Trisomy 18 ii. Trisomy 8 iii. Trisomy 21 iv. Trisomy 22 v. Other trisomies vi. Deletions vii. Translocations viii. Duplications j. Agenesis of the corpus callosum with interhemispheric cyst: a heterogeneous group of disorders that have in common callosal agenesis and extraparenchymal cysts, both of which are among the commonest CNS malformations k. Incidental finding in normal individuals (isolated dysgenesis of the corpus callosum) 2. Embryogenesis of the corpus callosum a. Development of the corpus callosum i. A late event in cerebral ontogenesis ii. Taking place between 12–18 weeks of gestation b. An important brain commissure connecting the cerebral hemispheres

c. Essential for efficient cognitive function d. Failure of development of the commissural fibers connecting the cerebral hemispheres produces dysgenesis or agenesis of the corpus callosum e. Diagnosis of agenesis: a challenge even for expert sonologists, particularly prior to 20 weeks of gestation 3. Types of agenesis a. Complete agenesis: commonly regarded as a malformation deriving from faulty embryogenesis b. Type I agenesis i. Not associated with other disorder ii. Usually absent or associated with mild neurologic manifestations c. Type II agenesis i. Associated with other migrational, genetic, and chromosomal disorders ii. Usually associated with severe neurologic manifestations d. Partial agenesis i. Referred to as dysgenesis ii. Either a true malformation or a disruptive event occurring at any time during pregnancy iii. Missing caudad portion (splenium and body) to varying degrees 4. Agenesis/dysgenesis of the corpus callosum a. Without other associated brain anomalies b. Frequently associated with other brain anomalies i. Defects of septum pellucidum and fornix ii. Hydrocephalus iii. Dandy-Walker malformation iv. Interhemispheric cyst v. Holoprosencephaly vi. Porencephaly vii. Polymicrogyria viii. Macrogyria ix. Cortical heterotopia and atrophy x. Lipoma xi. Encephalocele xii. Hypoplasia of cerebellum c. Frequently associated other anatomical anomalies i. Congenital heart defects ii. Costovertebral defects iii. Gastrointestinal anomalies iv. Genitourinary anomalies

CLINICAL FEATURES 1. Craniofacial abnormalities a. Microcephaly b. Macrocephaly 2. Developmental anomalies a. Nonspecific mental retardation b. Developmental delay c. Learning disabilities d. Behavioral disorder e. Mental retardation f. Failure to thrive 3. Infantile spasms/seizures 4. Signs and symptoms related to type I and type II agenesis a. Type I

CORPUS CALLOSUM AGENESIS/DYSGENESIS

i. Variable intelligence: normal to mild or moderate mental retardation ii. Seizure disorder iii. Impaired visual, motor, and/or bimanual coordination iv. Mild impairment of crossed tactile localization and skills requiring matching of visual patterns b. Type II i. Mental retardation ii. Seizures iii. Hydrocephaly iv. Microcephaly v. Hemiparesis vi. Diplegia vii. Spasticity viii. Failure to thrive

DIAGNOSTIC INVESTIGATIONS 1. Psychometric tests a. Difficulties in motor coordination b. Difficulties in inter-hemispheric transfer of tactile information c. Difficulties in some areas of memory d. A marked difference in verbal IQ and performance IQ in children 2. EEG for seizure activities 3. CT and/or ultrasound of the brain a. Absence of the corpus callosum b. Absence of septum pellucidum c. Increased separation of the lateral ventricles d. Marked separation of the slit-like anterior horns of the lateral ventricles and dilatation of the occipital horns creating the typical ‘rabbit’s ear’ or ‘tear drop’ appearance e. Upward displacement of the third ventricle f. Evidence of other migration disorders 4. Coronal radiographs showing a pathognomonic bat-wing ventricular pattern 5. Karyotyping for underlying chromosomal disorder 6. Metabolic studies for underlying inborn error of metabolism

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: depending on the etiology and the mode of inheritance i. Isolated Agenesis/dysgenesis of the corpus callosum: recurrence risk not increased ii. Environmental factor: recurrence risk not increased by avoiding the environmental factor iii. Autosomal recessive inheritance: 25% of siblings affected, 50% siblings carriers, and 25% of siblings normal iv. Autosomal dominant inheritance: recurrence risk not increased unless a parent is affected in which case the recurrence risk is 50% v. X-linked recessive inheritance a) Carrier mother (50% of brothers affected; 50% of sisters carriers)

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b) Affected father (all brothers normal, all sisters carriers) vi. X-linked dominant inheritance a) Affected mother (50% of brothers and sisters affected) b) Affected father (all brothers normal; all sisters affected) vii. Chromosomal disorder: recurrence risk increased, especially if a parent carries a balanced translocation b. Patient’s offspring i. Environmental factor: recurrence risk not increased by avoiding the environmental factor ii. Autosomal recessive inheritance: recurrence risk not increased unless the spouse is also a carrier in which case the recurrence risk is 50% iii. Autosomal dominant inheritance: 50% iv. X-linked recessive inheritance a) Carrier female (50% of sons affected, 50% of daughters carriers) b) Affected male (all sons normal, all daughters carriers) v. X-linked dominant inheritance a) Affected female (50% of sons and daughters affected) b) Affected male (all sons normal, all daughters affected) vi. Chromosomal disorder: recurrence risk increased, especially if a parent carries a balanced translocation 2. Prenatal diagnosis a. Ultrasonography i. Prenatal detection of the agenesis of the corpus callosum usually not possible before 22 weeks of gestations ii. Direct demonstration of the absence or partial absence of the corpus callosum iii. Failure to visualize the cavum septum pellucidum iv. Third ventricle lying between widely separated lateral ventricles due to absent corpus callosum v. Lateral ventricles more parallel to the midline than usual vi. A cyst arising from the superior aspect of the third ventricle communicating with the lateral ventricles vii. Vertical orientation of the gyri with agenesis instead of normal horizontal alignment viii. Colpocephaly (locally dilated occipital horns of the lateral ventricle) forming an appearance on axial views similar to bulls’ horns ix. Absence of pericallosal artery x. Up to 50% of cases with other associated anatomic defects xi. Variable developmental outcome on prenatal detection of an isolated agenesis of the corpus callosum b. MRI i. Allows more detailed visualization of the fetal brain than ultrasonography

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ii. Constitutes a useful additional procedure after ultrasonographic diagnosis or suspicion of corpus callosum agenesis c. Amniocentesis recommended for karyotyping as there is 10–20% risk of aneuploidy associated with the agenesis of the corpus callosum d. Prenatal counselling for ultrasonically diagnosed fetal agenesis of the corpus callosum remains very difficult, as giving precise information on outcome is impossible. The following observation, however, may be of help in prenatal counseling: i. Isolated agenesis/dysgenesis of the corpus callosum (in the absence of other sonographically detectable anomalies) carrying apparent excellent prognosis a) 85% chance of a normal developmental outcome b) 15% risk of handicap ii. Agenesis/dysgenesis of the corpus callosum with other associated anomalies: poor outcome 3. Management a. Identification of actual deficits resulting from the absence of such a major structure (corpus callosum): clearly an issue b. Multidisciplinary team approach to intervention programs c. Anticonvulsants for seizures d. Management based on the underlying etiology

REFERENCES Achiron R, Achiron A: Development of the human fetal corpus callosum: a high-resolution, cross-sectional sonographic study. Ultrasound Obstet Gynecol 18:343–347, 2001.

Barkovich AJ, Simon EM, Walsh CA: Callosal agenesis with cyst. A better understanding and new classification. Neurology 56:220–227, 2001. Bennett GL, Bromley B, Benacerraf BR: Agenesis of the corpus callosum: prenatal detection usually is not possible before 22 weeks of gestation. Radiology 199:447–450, 1996. Casaubon LK, Melanson M, Lopes-Cendes I, et al.: The gene responsible for a severe form of peripheral neuropathy and agenesis of the corpus callosum maps to chromosome 15q. Am J Hum Genet 58:28–34, 1996. da-Silva EO: Callosal defect, microcephaly, severe mental retardation, and other anomalies in three sibs. Am J Med Genet 29:837–843, 1988. D’Ercole C, Girard N, Cravello L, et al.: Prenatal diagnosis of fetal corpus callosum agenesis by ultrasonography and magnetic resonance imaging. Prenat Diagn 18:247–253, 1998. Dobyns WB: Absence makes the search grow longer. (Editorial) Am J Hum Genet 58:7–16, 1996. Finlay DC, Peto T, Payling J, et al.: A study of three cases of familial related agenesis of the corpus callosum. J Clin Exp Neuropsychol 22:731–742, 2000. Gupta JK, Lilford RJ: Assessment and management of fetal agenesis of the corpus callosum. Prenat Diagn 15:301–312, 1995. Lacey, DJ: Agenesis of the corpus callosum. Clinical features in 40 children. Am J Dis Child 139:953–955, 1985. Loeser JD, Alvord EC: Agenesis of the corpus callosum. Brain 91:553–570, 1968. Moutard M-L, Kieffer V, Feingold J, et al.: Agenesis of corpus callosum: prenatal diagnosis and prognosis. Child Nerv Syst 19:471–476, 2003. Pilu G, Hobbins JC: Sonography of fetal cerebrospinal anomalies. Prenat Diagn 22:321–330, 2002. Pilu GL, Sandri F, Perolo A, et al.: Sonography of fetal agenesis of the corpus callosum: a survey of 35 cases. Ultrasound Obstet Gynecol 3:318–329, 1993. Probst FP: Agenesis of the corpus callosum. Acta Radiol 331 (Suppl):1–150, 1973. Serur D, Jeret JS, Wisniewski K, et al.: Agenesis of the corpus callosum: clinical, neuroradiological and cytogenetic studies. Neuropediatrics 19: 87–91, 1988. Vergani P, Ghidini A, Strobelt N, et al.: Prognostic indicators in the prenatal diagnosis of agenesis of the corpus callosum. Am J Obstet Gynecol 170:753–758, 1994.

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Fig. 1. An infant (ages 3 months and 16 months) with agenesis of the corpus callosum and interhemispheric cyst, illustrated by MRI.

Craniometaphyseal Dysplasia Craniometaphyseal dysplasia (CMD) is a rare craniotubular bone dysplasia in which sclerosis of the skull is associated with abnormal modeling of the metaphyses of the long bones.

GENETICS/BASIC DEFECTS 1. Genetic heterogeneity a. Autosomal dominant form [also called CMD, Jackson type (CMDJ)]: i. CMDJ locus mapped to 5p15.2–p14.1 within a region harboring the human homolog (ANKH) of the mouse progressive ankylosis (ank) gene ii. ANK protein: spans the outer cell membrane and shuttles inorganic pyrophosphate, a major inhibitor of physiologic and pathologic calcification, bone mineralization and bone resorption b. Autosomal recessive form i. Rare ii. Ill-defined iii. Probably heterogeneous iv. Often difficult to diagnose with precision v. Autosomal recessive CMD locus mapped to 6q21–22 2. Basic defects a. Autosomal dominant form: caused by mutations in the human homolog of the mouse progressive ankylosis gene (ANKH) b. Autosomal recessive form i. May involve dysfunctional osteoclasts because reported metabolic responses of affected children to therapy with calcitonin and clacitrol ii. Osteoclast-like cells derived from the bone marrow shown to lack expression of the osteoclast vacuolar proton pump

CLINICAL FEATURES 1. Autosomal dominant form a. General features i. Good general health ii. Normal intelligence iii. Normal stature b. Bony overgrowth of the facial bone resulting in the typical facies: i. Frontal bossing ii. Hypertelorism iii. Paranasal bossing (30% of cases in childhood) a) May be present during infancy b) Tends to regress with age c) Virtually absent by adolescence and early adulthood d) May be associated with some degree of nasal obstruction and frequent mouth breathing 252

iv. Mild to moderate mandibular prognathism v. An open mouth secondary to bony encroachment of the nasal passages vi. Malalignment of the teeth vii. Grotesque hyperostosis of the facial bones viii. Decreased facial movement c. Bony overgrowth of the cranial foramina resulting in the following features: i. Cranial nerve paralysis ii. Nystagmus iii. Optic atrophy iv. Facial palsy (30% of cases) a) Common but variable b) May be unilateral or bilateral c) May occur at any age d) The involvement often fluctuant in early childhood e) May be permanent in adulthood v. Deafness (50% of cases) a) Due to compromised auditory nerve and inner ear by bone overgrowth b) May be unilateral or bilateral c) Often “mixed” in type due to chronic otitis media and upper respiratory tract infection secondary to minor anatomical abnormalities of the airway and sinuses d) Usually partial and rarely profound vi. Less commonly reported conditions a) Compression of the cerebellar tonsils and medulla secondary to a narrowed foramen magnum b) Obstruction of Eustachian tube c) Obstruction of nasolacrimal duct d) Obstruction of nasal passages e) Raised intracranial pressure: rare instances of a potentially lethal rise in intracranial pressure due to hyperostosis of the calvarium d. Abnormal modeling of the metaphyses of the long bones i. Metaphyseal widening of the long and short tubular bones ii. Thin cortical layer iii. Coarse trabeculations e. Clinical and radiographic features improved in later childhood in the dominant form 2. Autosomal recessive form a. Similar to, but more severe than, those seen in the dominant form b. An increasing severity with age c. Progressive overgrowth and craniofacial deformity i. Very severe facial distortion ii. A thick bony wedge over the bridge of the nose iii. Dystopia canthorum

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iv. Ocular hypertelorism v. Enlarged malar prominences and mandible (marked prognathism) vi. Wide alveolar ridge vii. Narrowed nasal passages leading to mouth breathing viii. Dental abnormalities d. Abnormal modeling of the metaphyses of the long bones i. Gradual, club-shaped widening of the metaphyses ii. Thin cortex and undermineralized medullary bone 3. Differential diagnosis a. Pyle disease (metaphyseal dysplasia) i. Frequently confused with craniometaphyseal dysplasia. In Pyle disease, metaphyseal flaring occurs but there is minimal involvement of the skull ii. Autosomal recessive inheritance b. Craniodiaphyseal dysplasia i. Most severe thickening, distortion, and enlargement of the craniofacial region ii. Characterized by diaphyseal endostosis iii. Does not exhibit metaphyseal flaring iv. Inheritance likely autosomal recessive c. Frontometaphyseal dysplasia i. A pronounced bony supra-orbital ridge ii. Hirsutism iii. Long-bone alterations iv. Conductive deafness d. Camurati-Engelmann disease (progressive diaphyseal dysplasia) i. Presence of excess subperiosteal bone in the diaphyses of the long bone ii. Normal metaphyses iii. Rare craniofacial involvement e. Van Buchem disease (hyperostosis corticalis generalisata) i. Dense and thickened craniofacial skeleton ii. Generalized cortical thickening of the long bones mainly due to endosteal bone apposition

DIAGNOSTIC INVESTIGATIONS 1. Normal serum calcium, phosphorous and alkaline phosphatase 2. Radiographic features a. Autosomal dominant form: age-related radiographic features i. Characteristic hyperostosis and sclerosis of the skull ii. Paranasal bony bossing, most evident in early childhood iii. May be present with prognathism and asymmetry iv. Characteristic nonsclerotic widening of the metaphyses of the tubular bones: a major radiographic feature a) Most obvious at the lower end of the femur b) An “Erlenmeyer flask” configuration in childhood

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c) A “club” shape in adulthood b. Autosomal recessive form: severe radiographic manifestations i. Increasing severity with age ii. Sclerosis and hyperostosis of the calvarium, the base of the skull, and the facial bones and mandible iii. Increased bone deposition on the walls of the paranasal sinuses iv. Underpneumatization of mastoid cells v. Gradual, club-shaped widening of the metaphyses vi. Thin cortex and undermineralized medullary bone 3. Gross pathological features a. Thickened “ivory-hard” facial and cranial bones b. Narrow cranial foramina c. Narrowing of the nasal chambers and posterior choanae 4. Histological features a. Compact laminar cortical bone with dilated Haversian canals containing osteoblasts b. No osteoclasts identified in the periosteal or endosteal layers c. An increased amount of ground substance and excessive formation of subperiosteal and subendosteal bone 5. Molecular genetic analysis for mutations in the human homolog of the mouse progressive ankylosis gene (ANKH)

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Autosomal dominant form: 50% risk if one parent is affected, otherwise risk not increased ii. Autosomal recessive form: 25% b. Patient’s offspring i. Autosomal dominant form: 50% ii. Autosomal recessive form: not increased unless the spouse is also a carrier in which case there is 50% recurrence risk 2. Prenatal diagnosis: has not been reported 3. Management a. Medical treatment attempted with the following two hormones i. Calcitonin: has an inhibitory effect on bone formation ii. Calcitriol a) Stimulates resorption of bone by promoting osteoclast formation b) Partial resolution of facial nerve paralysis, increased size of the cranial nerve foramina, and demineralization of the cranial base during treatment of one patient with high doses of calcitriol b. Hearing aids for hearing loss c. Psychological support for facial disfigurement

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d. Surgical treatment with mixed results i. Resection of dysplastic bone arduous because it is highly mineralized with a consistency like thick ivory ii. Craniofacial reduction performed with some difficulty iii. Optic canal decompression for progressive visual loss iv. Facial nerve decompression v. Middle ear exploration and implantation of total ossicular replacement prosthesis for conductive hearing loss vi. Foramen magnum decompression for cervicomedullary encroachment

REFERENCES Beighton P: Craniometaphyseal dysplasia (CMD), autosomal dominant form. J Med Genet 32:370–374, 1995. Beighton P, Hamersma H, Horan F: Craniometaphyseal dysplasia—variability of expression within a large family. Clin Genet 15:252–258, 1979. Boltshauser E, Schmitt B, Wichmann W, et al.: Cerebellomedullary compression in recessive craniometaphyseal dysplasia. Neuroradiology 38 Suppl 1:S193–S195, 1996. Bricker SL, Langlais RP, van Dis ML: Dominant craniometaphyseal dysplasia. Literature review and case report. Dentomaxillofac Radiol 12:95–100, 1983. Carnevale A, Grether P, del Castillo V, et al.: Autosomal dominant craniometaphyseal dysplasia. Clinical variability. Clin Genet 23:17–22, 1983. Chandler D, Tinschert S, Lohan K, et al.: Refinement of the chromosome 5p locus for craniometaphyseal dysplasia. Hum Genet 108:394–397, 2001. Cheung VG, Boechat MI, Barrett CT: Bilateral choanal narrowing as a presentation of craniometaphyseal dysplasia. J Perinatol 17:241–243, 1997. Cole DE, Cohen MM Jr: a new look at craniometaphyseal dysplasia. J Pediatr 112:577–579, 1988. Cooper JC: Craniometaphyseal dysplasia: a case report and review of the literature. Br J Oral Surg 12:196–204, 1974. Day RA, Park TS, Ojemann JG, et al.: Foramen magnum decompression for cervicomedullary encroachment in craniometaphyseal dysplasia: case report. Neurosurgery 41:960–964, 1997. Fanconi S, Fischer JA, Wieland P, et al.: Craniometaphyseal dysplasia with increased bone turnover and secondary hyperparathyroidism: therapeutic effect of calcitonin. J Pediatr 112:587–591, 1988.

Gorlin RJ, Spranger J, Koszalka MF: Genetic craniotubular bone dysplasias and hyperostoses: a critical analysis. Birth Defects Orig Art Ser V(4):79–95, 1969. Gorlin RJ, Koszalka MF, Spranger J: Pyle’s disease (familial metaphyseal dysplasia). A presentation of two cases and argument for its separation from craniometaphyseal dysplasia. J Bone Joint Surg Am 52:347–354, 1970. Iughetti P, Alonso LG, Wilcox W, et al.: Mapping of the autosomal recessive (AR) craniometaphyseal dysplasia locus to chromosome region 6q21–22 and confirmation of genetic heterogeneity for mild AR spondylocostal dysplasia. Am J Med Genet 95:482–491, 2000. Jackson WPU, Albright F, Drewry G, et al.: Metaphyseal dysplasia, epiphyseal dysplasia, diaphyseal dysplasia, and related conditions. I. Familial metaphyseal dysplasia and craniometaphyseal dysplasia: their relation to leontiasis ossea and osteopetrosis: disorders of ‘bone remodeling’. Arch Intern Med 94:871–885, 1954. Key LL Jr, Volberg F, Baron R, et al.: Treatment of craniometaphyseal dysplasia with calcitriol. J Pediatr 112:583–587, 1988. Kietzer G, Paparella MM: Otolaryngological disorders in craniometaphyseal dysplasia. Laryngoscope 79:921–941, 1969. Martin FW: Otorhinological aspects of craniometaphyseal dysplasia. Clin Otolaryngol 4:67–76, 1979. Millard DR Jr, Maisels DO, Batstone JH, et al.: Craniofacial surgery in craniometaphyseal dysplasia. Am J Surg 113:615–621, 1967. Nürnberg P, Thiele H, Chandler D, et al.: Heterozygous mutations in ANKH, the human ortholog of the mouse progressive ankylosis gene, result in craniometaphyseal dysplasia. Nat Genet 28:37–41, 2001. Nürnberg P, Tinschert S, Mrug M, et al.: The gene for autosomal dominant craniometaphyseal dysplasia maps to chromosome 5p and is distinct from the growth hormone-receptor gene. Am J Hum Genet 61:918–923, 1997. Penchaszadeh VB, Gutierrez ER, Figueroa E: Autosomal recessive craniometaphyseal dysplasia. Am J Med Genet 5:43–55, 1980. Puri P, Chan J: Craniometaphyseal dysplasia: ophthalmic features and management. J Pediatr Ophthalmol Strabismus 40:228–231, 2003. Reichenberger E, Tiziani V, Watanabe S, et al.: Autosomal dominant craniometaphyseal dysplasia is caused by mutations in the transmembrane protein ANK. Am J Hum Genet 68:1321–1326, 2001. Shea J, Gerbe R, Ayani N: Craniometaphyseal dysplasia: the first successful surgical treatment for associated hearing loss. Laryngoscope 91:1369–1374, 1981. Yamamoto T, Kurihara N, Yamaoka K, et al.: Bone marrow-derived osteoclastlike cells from a patient with craniometaphyseal dysplasia lack expression of osteoclast-reactive vacuolar proton pump. J Clin Invest 91:362–367, 1993.

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Fig. 1. A girl with craniometaphyseal dysplasia showing characteristic craniofacial features consisting of hypertelorism, broadening nasal base with paranasal bossing, short nose, and prominent facial bones.

Cri-Du-Chat Syndrome Cri-du-chat syndrome is a chromosome 5p deletion syndrome first describe by Lejeune et al. in 1963. The incidence is estimated to be approximately 1 in 15,000–50,000 births. The prevalence among mentally retarded individuals is approximately 1.5 in 1000.

GENETICS/BASIC DEFECTS 1. Cause a. Caused by deletion of short arm of chromosome 5 (5p15.2–15.3) i. De novo deletion (80%): paternally derived deletions in 80% of cases ii. Familial rearrangement (12%) iii. Mosaicism (3%) iv. Rings (2.4%) v. De novo translocation (3%) b. A high-resolution physical and transcription map generated a 3.5-Mb region of 5p15.2 that is associated with the Cri du chat syndrome region 2. Genotype–phenotype correlation a. Deletion of 5p15.3 results in a cat-like cry and speech delay b. Deletion of 5p15.2 results in the distinct facial features associated with the syndrome as well as the severe mental and developmental delay 3. Hemizygosity of δ-catenin (CTNND2, mapped to 5p15.2), reported to be associated with severe mental retardation in cri-du-chat syndrome 4. Deletion of the telomerase reverse transcriptase (TERT) gene (mapped at 5p15.33) and haploinsufficiency of telomere maintenance is probably a genetic element contributing to the phenotypic changes in cri-du-chat syndrome

CLINICAL FEATURES 1. Characteristic mewing cry a. A high-pitched monochromatic cry with subtle dysmorphism and neonatal complications: commonly observed in infants with this syndrome b. Observed in many infants with Cri-du-chat syndrome c. Not associated with other aneuploidies d. Usually considered diagnostic e. Loss of the characteristic cry by age 2 years in one third of children 2. Clinical findings during infancy a. Low birth weight b. Hypotonia c. Microcephaly d. Poor sucking/swallowing difficulties e. Need for incubator care f. Respiratory distress 256

g. h. i. j. k. l. m.

Jaundice Pneumonia Dehydration Failure to thrive/growth retardation Early ear infections Severe cognitive, speech and motor delays Facial features i. Round face with full cheek ii. Hypertelorism iii. Epicanthal folds iv. Down-slanting palpebral fissures v. Strabismus vi. Flat nasal bridge vii. Down-turned mouth viii. Micrognathia ix. Low-set ears n. Cardiac defects i. VSD ii. ASD iii. PDA iv. Tetralogy of Fallot o. Short fingers p. Single palmar creases q. Less frequent features i. Cleft lip and palate ii. Preauricular tags and fistulas iii. Thymic dysplasia iv. Gut malrotation v. Megacolon vi. Inguinal hernia vii. Dislocated hips viii. Cryptorchidism ix. Hypospadias x. Rare renal malformations a) Horseshoe kidneys b) Renal ectopia or agenesis c) Hydronephrosis xi. Clinodactyly of the fifth fingers xii. Talipes equinovarus xiii. Pes planus xiv. Syndactyly of the second and third fingers and toes xv. Oligosyndactyly xvi. Hyperextensible joints 3. Clinical findings in childhood a. Severe mental retardation b. Developmental delay c. Microcephaly d. Hypertonicity e. Premature graying of the hair f. Small, narrow and often asymmetric face g. Dropped-jaw h. Open-mouth expression secondary to facial laxity

CRI-DU-CHAT SYNDROME

i. j. k. l. m.

4.

5.

6.

7.

Short philtrum Malocclusion of the teeth Scoliosis Short third-fifth metacarpals Chronic medical problems i. Upper respiratory tract infections ii. Otitis media iii. Severe constipation iv. Hyperactivity Clinical findings in late childhood and adolescence a. Coarsening of facial features b. Prominent supraorbital ridges c. Deep-set eyes d. Hypoplastic nasal bridge e. Affected females reaching puberty and developing secondary sex characteristics and menstruate at the usual time f. Small testis and normal spermatogenesis in males Dermatoglyphics a. Transverse flexion creases b. Distal axial triradius c. Increased whorls and arches on digits Behavioral profile a. Hyperactivity b. Aggression c. Tantrums d. Stereotypic and self-injurious behavior e. Repetitive movements f. Hypersensitivity to sound g. Clumsiness h. Obsessive attachments to objects i. Able to communicate needs and interact socially with others j. Autistic-like features and social withdrawal: more characteristic of individuals who have a 5p deletion as the result of an unbalanced segregation of a parental translocation Prognosis a. Ability of many children to develop some language and motor skills b. Ability of these children to attain developmental and social skills observed in 5- to 6-year-old children, although their linguistic abilities are seldom as advanced c. Older, home-reared children i. Usually ambulatory ii. Able to communicate verbally or through gestural sign language iii. Independent in self-care skills.

DIAGNOSTIC INVESTIGATIONS 1. Conventional cytogenetic studies. The size of the 5p deletion may vary from the entire short arm to only 5p15. A small deletion of 5p may be missed by a conventional cytogenetic technique 2. High-resolution cytogenetic studies are required for a smaller 5p deletion 3. Molecular cytogenetic studies using fluorescent in situ hybridization (FISH)

4.

5. 6.

7. 8.

9.

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a. Allow the diagnosis to be made in the patients with very small deletions b. Use genetic markers that have been precisely localized to the area of interest c. The absence of a fluorescent signal from either the maternal or paternal chromosome 5p regions: indicative of monosomy for that chromosomal region Skeletal radiographs a. Microcephaly b. Retromicrognathia c. Cranial base malformations i. Reduced cranial base angle ii. Malformed sella turcica and clivus d. Disproportionately short third, fourth, and fifth metacarpals and disproportionately long second, third, fourth, and fifth proximal phalanges (frequent) Echocardiography to rule out structural cardiac malformations MRI of the brain a. Atrophic brainstem, middle cerebellar peduncles and cerebellar white matter b. Possible hypoplasia of cerebellar vermis with enlargement of the cisterna magna and 4th ventricle Swallowing study for feeding difficulty Comprehensive evaluation for receptive and expressive language. Most children have better receptive language than expressive language Developmental testing and referral to early intervention and appropriate school placement

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Recurrence risk for a de novo case is 1% or less ii. Rare recurrences in chromosomally normal parents: most likely the result of gonadal mosaicism for the 5p deletion in one of the parents iii. The risk is substantially high if a parent is a balanced carrier of a structural rearrangement. Risk should be assessed based on the type of structural rearrangement and its pattern of segregation b. Patient’s offspring: female patients are fertile and can deliver viable affected offspring, with an estimated recurrence risk of 50% 2. Prenatal diagnosis by amniocentesis, CVS, and PUBS for chromosome analysis to detect 5p deletion 3. Management a. Supportive care. No treatment exists for the underlying disorder b. Appropriate treatment for chronic medical problems i. Upper respiratory tract infections ii. Otitis media iii. Severe constipation c. Using the relatively good receptive skills to encourage language and communicative development rather than relying on traditional verbal methods d. Early intervention programs i. Physical therapy ii. Occupational therapy iii. Speech therapy

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e. Introduction to sign language, an effective means of developing communication skills (50% of children are able to use sign language to communicate) f. Behavior modification programs to successfully managing hyperactivity, short attention span, low threshold for frustration, and self-stimulatory behaviors (eg, head-banging, hand-waving) g. Surgical interventions i. Correction of congenital heart defects if indicated ii. Medical problems involving minor malformations such as strabismus and clubfoot iii. Gastrostomy in infancy to protect airway of patients with major feeding difficulties iv. Orchiopexy for undescended testes v. Issues important to anesthetic plan a) Anatomical abnormalities of the airway b) Congenital heart disease c) Hypotonia d) Mental retardation e) Temperature maintenance

REFERENCES Aoki S, Hata T, Hata K, et al.: Antenatal sonographic features of cri-du-chat syndrome. Ultrasound Obstet Gynecol 13:216–217, 1999. Baccichetti SE, Lenzini L, Artifoni D, et al.: Terminal deletion of the short arm of chromosome 5. Clin Genet 34:219–223, 1988. Brislin RP, Stayer SA, Schwartz RE: Anaesthetic considerations for the patient with cri du chat syndrome. Paediatr Anaesth 5: 139–141, 1995. Cerruti Mainardi P, Guala A, Pastore G, et al.: Psychomotor development in Cri du Chat Syndrome. Clin Genet 57:459–461, 2000. Chen H: Cri-du-chat syndrome. http://www.emedicine.com Church DM, Bengtsson U, Nielsen KV, et al.: Molecular definition of deletions of different segments of distal 5p that results in distinct phenotypic features. Am J Hum Genet 56:1162–1172, 1995. Church DM, Yang J, Bocian M, et al.: A high-resolution physical and transcript map of the Cri du Chat region of human chromosome 5p. Genome Res 7:787–801, 1997. Clarke DJ, Boer H: Problem behaviors associated with deletion Prader-Willi, Smith-Magenis, and Cri du chat syndrome. Am J Ment Retard 103: 264–271, 1998. Collins MS, Cornish K: A survey of the prevalence of stereotypy, self-injury and aggression in children and young adults with Cri du Chat syndrome. J Intellect Disabil Res 46:133–140, 2002. Cornish KM, Munir F: Receptive and expressive language skills in children with cri-du-chat syndrome. J Commun Disord 31:73–80; quiz 80–81, 1998. Cornish KM, Pigram J: Developmental and behavioural characteristics of cri du chat syndrome. Arch Dis Child 75:448–450, 1996. Dykens EM, Clark DJ: Correlates of maladaptive behavior in individuals with 5p- (cri du chat) syndrome. Dev Med Child Neurol 39:752–756, 1997. Fengen K, Niebuhr E: Measurements of hand radiographs from 32 Cri-du-chat probands. Radiology 1978; 129:137–141. Fankhauser L, Brundler AM, Dahoun S: Cri-du-chat syndrome diagnosed by amniocentesis performed due to abnormal maternal serum test. Prenat Diagn 18:1099–1100, 1998.

Gersh M, Goodart SA, Pasztor LM: Evidence for a distinct region causing a cat-like cry in patients with 5p deletions. Am J Hum Genet 56: 1404–1410, 1995. Gersh M, Grady D, Rojas K: Development of diagnostic tools for the analysis of 5p deletions using interphase FISH. Cytogenet Cell Genet 77: 246–251, 1997. Goodart SA, Simmons Arch Dermatol, Grady D, et al.: A yeast artificial chromosome contig of the critical region for cri-du-chat syndrome. Genomics 24:63–68, 1994. Hodapp RM, Wijma CA, Masino LL: Families of children with 5p- (cri du chat) syndrome: familial stress and sibling reactions. Dev Med Child Neurol 39:757–761, 1997. Kjaer I, Niebuhr E: Studies of the cranial base in 23 patients with cri-du-chat syndrome suggest a cranial developmental field involved in the condition. Am J Med Genet 82:6–14, 1999. Manning KP: The larynx in the cri du chat syndrome. J Laryngol Otol 91:887892, 1977. Mainardi PC, Perfumo C, Cali A, et al.: Clinical and molecular characterization of 80 patients with 5p deletion: genotype-phenotype correlation. J Med Genet 38:151–158, 2001. Marinescu RC, Johnson EI, Dykens EM, et al.: No relationship between the size of the deletion and the level of developmental delay in Cri-Du-Chat syndrome. Am J Med Genet 86:66–70, 1999. Marinescu RC, Johnson EI, Grady D, et al.: FISH analysis of terminal deletions in patients diagnosed with cri-du-chat syndrome. Clin Genet 56:282–288, 1999. Martinez JE, Tuck-Muller CM, Superneau D: Fertility and the cri du chat syndrome. Clin Genet 43:212–214, 1993. Medina M, Marinescu RC, Overhauser J, et al.: Hemizygosity of δ-catenin (CTNND2) is associated with severe mental retardation in cri-du-chat syndrome. Genomics 63:157–164, 2000. Niebuhr E: The cat cry syndrome (5p-) in adolescents and adults. J Ment Defic Res 15 Pt 4:277–291, 1971. Niebuhr E: The Cri du Chat syndrome: epidemiology, cytogenetics, and clinical features. Hum Genet 44: 227–275, 1978. Overhauser J, McMahon J, Oberlender S: Parental origin of chromosome 5 deletions in the cri-du-chat syndrome. Am J Med Genet 37: 83–86, 1990. Overhauser J, Huang X, Gersh M: Molecular and phenotypic mapping of the short arm of chromosome 5: sublocalization of the critical region for the cri-du-chat syndrome. Hum Mol Genet 3:247–252, 1994. Perfumo C, Mainardi PC, Cali A, et al.: The first three mosaic cri du chat syndrome patients with two rearranged cell lines. J Med Genet 37:967–972, 2000. Romano C, Ragusa RM, Scillato F, et al.: Phenotypic and phoniatric findings in mosaic cri du chat syndrome. Am J Med Genet 39:391–395, 1991. Saito N, Ebara S, Fukushima Y, et al.: Progressive scoliosis in cri-du-chat syndrome over a 20-year follow-up period: a case report. Spine 26:835–837, 2001. Stefanou EG, Hanna G, Foakes A, et al.: Prenatal diagnosis of cri du chat (5p-) syndrome in association with isolated moderate bilateral ventriculomegaly. Prenat Diagn 22:64–66, 2002. Tullu MS, Muranjan MN, Sharma SV, et al.: Cri-du-chat syndrome: clinical profile and prenatal diagnosis. J Postgrad Med 44:101–104, 1998. Van Buggenhout GJ, Pijkels E, Holvoet M, et al.: Cri du chat syndrome: changing phenotype in older patients. Am J Med Genet 90:203–215, 2000. Wilkins LE, Brown JA, Wolf B: Psychomotor development in 65 home-reared children with cri-du-chat syndrome. J Pediatr 97:401–405, 1980. Wilkins LE, Brown JA, Nance WE: Clinical heterogeneity in 80 home-reared children with cri du chat syndrome. J Pediatr 102: 528–533, 1983. Zhang A, Zheng C, Hou M, et al.: Deletion of the telomerase reverse transcriptase gene and haploinsufficiency of telomere maintenance in Cri du chat syndrome. Am J Hum Genet 72:940–948, 2003.

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Fig. 2. Cri-du-chat syndrome in an older child and a teenager showing a long and narrow face.

Fig. 1. Two infants with cri-du-chat syndrome. Note a round face with full cheeks, hypertelorism, epicanthal folds, and apparently low-set ears.

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Fig. 3. G-banded karyotypes with 5p deletion in two children with cri-du-chat syndrome.

Fig. 4. FISH of an interphase cell and a metaphase spread with two orange signals (LSI SpectrumOrange, D5S721) and one green signal (LSI SpectrumGreen, D5S23 chromosome 5p15.2-specific probe) indicating deletion of 5p15.2.

Crouzon Syndrome In 1912, Crouzon described the hereditary syndrome of craniofacial dysostosis in a mother and son. He described the triad of calvarial deformities, facial anomalies, and exophthalmos. Crouzon syndrome is characterized by premature closure of calvarial and cranial base sutures as well as those of the orbit and maxillary complex (craniosynostosis). Other clinical features include hypertelorism, exophthalmos, strabismus, beaked nose, short upper lip, hypoplastic maxilla, and relative mandibular prognathism. Prevalence is 1 per 60,000 (approximately 16.5 per 1,000,000) live births. Crouzon syndrome makes up approximately 4.8% of all cases of craniosynostosis.

iv. Maxillary hypoplasia v. Occasional upper airway obstruction

CLINICAL FEATURES

GENETICS/BASIC DEFECTS 1. Inheritance a. An autosomal dominant disorder with i. Complete penetrance ii. Variable expressivity b. Sporadic in 50% of patients resulting from new mutations 2. Cause a. Mutations in the fibroblast growth factor receptor-2 (FGFR2) gene which is mapped to 10q25–q26 b. Mutations reported in the third immunoglobulins-like domain c. Different mutations detected in both exon IIIa and exon IIIc. Most of these mutations are missense, although several different mutations leading to alternative splicing have been recognized d. Crouzon syndrome exhibits locus heterogeneity with causal mutations in FGFR2 and FGFR3 in different affected individuals e. Crouzon syndrome with acanthosis nigricans: always due to an Ala391Glu mutation within the transmembrane region of the FGFR3 gene 3. Pathophysiology a. Premature synostosis of the coronal, sagittal, and occasional lambdoidal sutures i. Begins in the first year of life ii. Completed by the second or third year b. Degree of deformity and disability determined by the order and rate of suture fusion c. After fusion of a suture i. Growth perpendicular to that suture becoming restricted ii. Fused bones acting as a single bony structure d. Compensatory growth occurring at the remaining open sutures to allow continued brain growth e. Multiple sutural synostoses often extend to premature fusion of the skull base sutures causing the following effects i. Midfacial hypoplasia ii. Shallow orbit iii. A foreshortened nasal dorsum 261

1. History a. Presence of mildly affected individuals in the family b. Craniofacial abnormalities often present at birth and may progress with time c. Decreased mental function in approximately 12% of the patients d. Headaches (29%) and failing vision due to elevated intracranial pressure e. Visual disturbance results from corneal injury due to exposed conjunctivitis and keratitis f. Conductive deafness common due to ear canal stenosis or atresia g. Causes of upper airway obstruction i. Septal deviation ii. Mid-nasal abnormalities iii. Choanal abnormalities iv. Nasopharyngeal narrowing h. Meniere disease i. Seizures (12%) 2. Skull and face a. Craniosynostosis i. Onset: commonly seen during the first year ii. Usually completing by the second or third year iii. Coronal suture most commonly involved iv. Acrocephaly v. Brachycephaly vi. Turricephaly vii. Oxycephaly viii. Flat occiput ix. High prominent forehead with or without frontal bossing x. Ridging of the skull usually palpable b. Cloverleaf skull i. Rare ii. Occurring in most severely affected individuals iii. Flattened sphenoid bone iv. Shallow orbits v. Hydrocephalus (progressive in 30%) vi. Midface (maxillary) hypoplasia 3. Eyes a. Exophthalmos (proptosis) (100%) secondary to shallow orbits resulting in frequent exposure conjunctivitis or keratitis b. Ocular hypertelorism (100%) c. Divergent strabismus d. Rare occurrence i. Nystagmus ii. Iris coloboma

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iii. Aniridia iv. Anisocoria v. Microcornea vi. Megalocornea vii. Cataract viii. Ectopia lentis ix. Blue sclera x. Glaucoma xi. Luxation of the eye globes xii. Blindness from optic atrophy Nose a. Beaked appearance (parrot-like nose) b. Compressed nasal passage c. Choanal atresia or stenosis d. Deviated nasal septum Mouth a. Mandibular prognathism b. Overcrowding of upper teeth c. Malocclusions d. V-shaped maxillary dental arch e. Narrow, high, or cleft palate and bifid uvula f. Oligodonti g. Macrodontia h. Peg-shaped i. Widely spaced teeth Ears a. Narrow or absent ear canals b. Deformed middle ears c. Mild to moderate hearing losses Other skeletal a. Cervical fusion (18%), C2-C3 and C5-C6 b. Block fusions involving multiple vertebrae c. Subluxation of the radial heads d. Ankylosis of the elbows Acanthosis nigricans (5%) a. Detectable after infancy b. The hallmark of these lesions i. A darkened, thickened skin with accentuated markings ii. A velvety feel CNS a. Chronic tonsillar herniation (approximately 73%). Of these, 47% have progressive hydrocephalus b. Syringomyelia c. Mental retardation (3%)

DIAGNOSTIC INVESTIGATIONS 1. Skull radiographs a. Synostosis: the coronal, sagittal, lambdoidal, and metopic sutures may be involved b. Craniofacial deformities c. Digital markings of skull d. Basilar kyphosis e. Widening of hypophyseal fossa f. Small paranasal sinuses g. Maxillary hypoplasia with shallow orbits 2. Cervical radiographs a. Butterfly vertebrae b. Fusions of the vertebral bodies and the posterior elements

3.

4.

5. 6.

i. Cervical fusions in approximately 18% of patients ii. C2-C3 and C5-C6 affected equally iii. Block fusions may involve multiple vertebrae Limb radiographs a. Metacarpophalangeal analysis b. Subluxation of the radial head Computed tomography (CT) scan: comparative 3dimensional reconstruction analysis of the calvaria and cranial bases to precisely define the pathologic anatomy and to permit specific operative planning Magnetic resonance imaging (MRI) Used to demonstrate occasional corpus callosum agenesis and optic atrophy Molecular analysis a. FGFR2 mutations in more than 50% of patients (FGFR2 mutations also observed in Apert syndrome, Pfeiffer syndrome, and Jackson-Weiss syndrome) b. FGFR3 ala391-to-glu mutation in all patients with associated acanthosis nigricans

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased unless a parent is affected or with germinal mosaicism b. Patient’s offspring: 50% 2. Prenatal diagnosis a. Prenatal ultrasonography i. Exophthalmos ii. Ocular hypertelorism b. Identification of the disease-causing FGFR2 mutation using i. CVS in the first trimester ii. Amniocentesis in the second trimester iii. Preimplantation genetic diagnosis 3. Management a. Medical care i. No specific medical therapy available ii. Nasal continuous positive airway pressure device to relieve airway obstruction iii. Management of speech b. Surgical care i. Stage reconstruction to coincide with facial growth patterns, visceral function, and psychosocial development ii. Early craniectomy with frontal bone advancement most often indicated to prevent or treat increased intracranial pressure because newborns with Crouzon syndrome develop multiple suture synostosis and fused synchondrosis iii. Fronto-orbital and midfacial advancements to help in the cosmetic reconstruction of facial dysmorphisms iv. A new technique, craniofacial disjunction, followed by gradual bone distraction (Ilizarov procedure) has been reported to produce complete correction of exophthalmos and improvement in the functional and aesthetic aspects of the middle third of the face without the need for bone graft in patients aged 6–11 years v. Shunting procedures for hydrocephalus

CROUZON SYNDROME

vi. Tracheostomy for airway compromise vii. Myringotomy to drain middle ear secretions secondary to distorted nasopharynx viii. Orthodontic management

REFERENCES Anderson PJ, Evans RD: Metacarpophalangeal analysis in Crouzon syndrome. Am J Med Genet 80:439, 1998. Anderson PJ et al.: Hand anomalies in Crouzon syndrome. Skeletal Radiol 26:113–115, 1997 Anderson PJ, Hall C, Evans RD: The cervical spine in Crouzon syndrome. Spine 22:402–405, 1997. Beck R, Sertie AL, Brik R, et al.: Crouzon syndrome: association with absent pulmonary valve syndrome and severe tracheobronchomalacia. Pediatr Pulmonol 34:478–481, 2002. Bresnick S, Schendel S: Crouzon’s disease correlates with low fibroblastic growth factor receptor activity in stenosed cranial sutures. J Craniofac Surg 6:245–248, 1995. Cinalli G, Renier D, Sebag G: Chronic tonsillar herniation in Crouzon’s and Apert’s syndromes: the role of premature synostosis of the lambdoid suture. J Neurosurg 83:575–782, 1995. Cohen MM: An etiologic and nosologic overview of craniosynostosis syndromes. BDOAS 11(2):137, 1975. Cohen MM Jr: Craniosynostosis: Diagnosis, Evaluation, and Management. New York, Raven Press, 1986. Cohen MM Jr: Craniosynostoses: phenotypic/molecular correlations [editorial] [see comments]. Am J Med Genet 56:334–339, 1995. Cohen MM Jr: An etiologic and nosologic overview of craniosynostosis syndromes. Birth Defects Orig Artic Ser ?(2):137–189, 1975. Cohen MM Jr: Craniosynostosis update 1987. Am J Med Genet Suppl 4:99–148, 1988. Cohen MM Jr, Kreiborg S: Birth prevalence studies of the Crouzon syndrome: comparison of direct and indirect methods. Clin Genet 41:12–15, 1992. Cohen MM Jr, MacLean RE: Craniosynostosis: Diagnosis, Evaluation, and Management. 2nd ed., Oxford University Press, New York, 1999. Crouzon O: Dysostose cranio-faciale hereditaire. Bull Mem Soc Med Hosp Paris 33:545–555, 1912 David DJ, Sheen R: Surgical correction of Crouzon syndrome. Plast Reconstr Surg 85:344–3, 1990. Dodge HW, et al.: Craniofacial dysostosis: Crouzon’s disease. Pediatrics 23:98–106, 1959. Glaser RL et al.: Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome. Am. J. Hum. Genet. 66: 768–777, 2000 Golabi M, et al.: Radiographic abnormalities of Crouzon syndrome. A survey of 23 cases Proc Greenwood Genet Ctr 3:102, 1984. Gorry MC, Preston RA, White GJ: Crouzon syndrome: mutations in two splice forms of FGFR2 and a common point mutation shared with JacksonWeiss syndrome. Hum Mol Genet 4:1387–1390, 1995. Harper JC, Wells D, Piyamongkol W, et al.: Preimplantation genetic diagnosis for single gene disorders: experience with five single gene disorders. Prenat Diagn 22:525–533, 2002. Hollway GE, Suthers GK, Haan EA: Mutation detection in FGFR2 craniosynostosis syndromes. Hum Genet 99:251–255, 1997.

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Jabs EW, Li X, Scott AF: Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2 [published erratum appears in Nat Genet 9:451, 1995]. Nat Genet 8:275–279, 1994. Jarund M, Lauritzen C: Craniofacial dysostosis: airway obstruction and craniofacial surgery. Scand J Plast Reconstr Surg Hand Surg 30:275–279, 1996. Kaler SG. et al.: Radiologic hand abnormalities in fifteen cases of Crouzon syndrome. J Cranio Genet Dev Biol 2:205–214, 1982. Kreiborg S: Crouzon syndrome: a clinical and roentgencephalometric study. Scan J Plast Reconstr Surg Suppl 18, 1–198, 1981. Leo MV, Suslak L, Ganesh VL, et al.: Crouzon syndrome: prenatal ultrasound diagnosis by binocular diameters. Obstet Gynecol 78:906–908, 1991. Liptak GS, Serletti JM: Pediatric approach to craniosynostosis [published erratum appears in Pediatr Rev 20:20, 1999.]. Pediatr Rev 19:352; quiz 359, 1998. Menashe Y, et al.: Exophthalmus-prenatal ultrasonic features for diagnosis of Crouzon syndrome. Prenatal Diagn 9:805–808, 1989. Meyers GA, Day D, Goldberg R: FGFR2 exon IIIa and IIIc mutations in Crouzon, Jackson-Weiss, and Pfeiffer syndromes: evidence for missense changes, insertions, and a deletion due to alternative RNA splicing. Am J Hum Genet 58:491–498, 1996. Meyers GA, Orlow SJ, Munro IR: Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans. Nat Genet 11:462–464, 1995. Meyers GA, et al.: Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans. Nature Genet 11:462–464, 1995. Navarrete C, et al.: Germinal mosaicism in Crouzon syndrome. A family with three affected siblings of normal parents. Clin Genet 40:29–34, 1991. Oldridge M et al.: Mutations in the third immunoglobulin domain of the fibroblast growth factor receptor-2 gene in Crouzon syndrome. Hum Mol Genet 4 (6): 1077–1082, 1995 Park WJ, Meyers GA, Li X: Novel FGFR2 mutations in Crouzon and JacksonWeiss syndromes show allelic heterogeneity and phenotypic variability. Hum Mol Genet 4:1229–1233, 1995. Preston RA et al.: A gene for Crouzon craniofacial dysostosis maps to the long arm of chromosome 10. Nature Genet 7:149–153, 1994. Reardon W, Winter RM, Rutland P: Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nat Genet 8:98–103, 1994. Bobertson MM, Reynolds HT: Crouzon’s disease (craniofacial dysostosis). A neuropsychiatric presentation. S Afr Med J 49:7–10, 1975. Rollnick BR et al.: Germinal mosaicism in Crouzon syndrome. Clin Genet 33:145–150, 1988. Rutland P, Pulleyn LJ, Reardon W: Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes [see comments]. Nat Genet 9:173–176, 1995. Schwartz M, Kreiborg S, Skovby F: First-trimester prenatal diagnosis of Crouzon syndrome. Prenat Diagn 16:155–158, 1996. Tessier P: The definitive plastic surgical treatment of the severe facial deformities of craniofacial dysostosis: Crouzon’s and Apert’s disease. Plast Reconst Surg 48:419–442, 1971. Turvy TA, et al.: Multidisciplinary management of Crouzon syndrome. J Am Dent Assoc 99:205–209, 1979. Wilkes D, Rutland P, Pulleyn LJ: A recurrent mutation, ala391glu, in the transmembrane region of FGFR3 causes Crouzon syndrome and acanthosis nigricans. J Med Genet 33:744–748, 1996. Wilkie AO, Slaney SF, Oldridge M: Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome [see comments]. Nat Genet 9:165–172, 1995.

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Fig. 2. A neonate with Crouzon syndrome showing typical craniofacial features with tracheostomy in place for the respiratory problem.

Fig. 1. Two children with Crouzon syndrome showing proptosis secondary to shallow obits and hypertelorism.

Fig. 3. A father and a daughter with Crouzon syndrome showing characteristic craniofacial features.

Cystic Fibrosis Cystic fibrosis (CF) is the most common Caucasian lethal genetic disorder (with gene frequency of 1 in 25) in the United States, where 4–5% of population have at least one CF allele. CF affects approximately 1 in 2500 live births among Caucasians, 1 in 17,000 among African-Americans, and 1 in 90,000 among Asians.

CLINICAL FEATURES

GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal recessive b. CF gene mapped to chromosome 7q31.2 2. Molecular defect a. Caused by a single gene defect on chromosome 7 that encodes a cAMP-regulated chloride channel known as the cystic fibrosis transmembrane conductance regulator (CFTR) i. CFTR usually resides in the apical membrane of epithelial cells lining the airway, biliary tree, intestines, vas deferens, sweat ducts, and pancreatic ducts. ii. Insufficient fluid secretion secondary to inability of CFTR to transport chloride ion at the above sites causes higher viscidity of the protein portions of the secretions and obstructing the ducts, leading to plugging and dysfunction at the organ level iii. CFTR also regulates the activity of other proteins that conduct ions and affects intracellular regulatory processes at the cellular level b. Presence of close to 1000 different disease-causing mutations of the CFTR gene i. Deletion mutations including delta F508 which, observed in over 70% of patients with CF, have a deletion of three contiguous base pairs resulting in the loss of a single amino acid, phenylalanine at codon 508) ii. Missense mutation (single base pair exchange within a normal length CFTR protein) iii. Nonsense mutations (exchange of a single base pair resulting in premature termination of the protein) iv. Frameshift mutations (the deletions or insertion of a single base pair) c. Genotype–phenotype correlations i. Phenotypic presentation of the disease: probably related to the underlying genetic abnormality ii. Patients with homozygous delta F508 typically have respiratory distress and malabsorption iii. Patients with less severe variations of the disease or typical CF with borderline normal sweat tests may have other haplotypes

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1. Classic clinical triad a. Exocrine pancreatic insufficiency b. Chronic obstructive pulmonary disease c. Elevation of sodium and chloride concentration in sweat 2. Chronic sino-pulmonary disease a. Varying widely in age of onset and rate of progression b. Clinical course i. Newborn with CF with histologically normal respiratory systems ii. First few months of age a) Epithelial chloride channel defect, leading to abnormal respiratory secretions, bronchopulmonary infections, and airway obstruction b) Clinical manifestations including cough, wheezing, retractions, and tachypnea c. Persistent endobronchial infection and inflammation with typical CF pathogens i. Staphylococcus aureus a) Responsible for the majority of lung disease when CF was first described b) Commonly isolated in the first year of life from the sputum of patients with CF c) Typically controlled by antibiotic therapy d) Currently only 10% of adult patients with CF are chronically colonized by the pathogen ii. Mucoid and non-mucoid pseudomonas aeruginosa a) The most prevalent of the pathogens in CF, causing chronic infection in up to 90% of adults and 80% of children b) Initial colonization with nonmucoid forms c) Subsequent conversion to mucoid variants iii. Hemophilus influenzae a) Commonly seen in babies b) Rarely encountered in the adults iv. Other pulmonary pathogens a) Burkholderia cepacia b) Aspergillus c) Mycobacteria d) Respiratory viruses d. Upper airway disease i. Opacified or maldeveloped sinuses ii. Nasal polyps (up to 26% of patients) iii. Sinusitis a) Facial pain b) Swelling c) Tenderness d) Air-fluid levels on radiograph

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e. Pulmonary exacerbations i. Persistent cough and sputum production ii. Increased dyspnea iii. Reduction in pulmonary function iv. Increased hemoptysis: a life-threatening complication but fatal hemoptysis is rare v. Digital clubbing vi. Changes in chest radiographic findings vii. Bronchiolitis viii. Increased rales or rhonchi ix. Decreased air exchange x. Increased use of accessory muscles of respiration xi. Spontaneous pneumothorax (5–8%), a lifethreatening complication xii. Obstructive airway disease, leading to respiratory insufficiency associated with bronchiectasis 3. Gastrointestinal abnormalities a. Intestine i. Meconium ileus at birth a) An obstruction of the distal ileum or proximal colon with thickened, viscous meconium in 15–20% of CF patients developed in utero in the second trimester b) Virtually diagnostic of CF ii. Meconium peritonitis (rupture of the intestine secondary to complete obstruction) iii. Meconium plug syndrome in the newborn infants, a more benign condition characterized by blockage of the colon iv. Distal intestinal obstruction syndrome later in childhood, adolescence, or adulthood (10%), presenting as crampy abdominal pain, usually with decreased stooling v. Rectal prolapse occurring in less than 1% of patients but may be the presenting symptom, particularly in infants vi. Occasional intussusception vii. Gastroesophageal reflux b. Pancreas i. Pancreatic exocrine insufficiency a) Failure of the pancreas to produce sufficient digestive enzymes to allow breakdown and absorption of fats and protein b) Obstruction of the pancreatic duct in utero with resultant progressive loss of exocrine pancreatic acini and their function c) A hallmark of the disease, occurring in 90% of patients by 1 year of age d) Leads to frequent, bulky, foul-smelling, oily stools e) Steatorrhea (presence of excessive undigested fat in the stool) f) Failure to thrive is commonly in the patients with CF ii. Recurrent pancreatitis in few patients iii. CF-related diabetes mellitus, rare before 10 years of age c. Liver i. Prolonged obstructive jaundice in a few affected infants, presumably secondary to obstruction of

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7.

8.

extrahepatic bile ducts by thick bile along with intrahepatic bile stasis ii. Chronic hepatic disease manifested by clinical or histologic evidence of focal biliary cirrhosis or multi-lobular cirrhosis Genitourinary manifestations a. Congenital bilateral absence of the vas deferens in most males i. Leading to azoospermia ii. A significant cause of infertility b. Infertility common in women i. Due to increased amounts of thick mucus in the cervical canal ii. An increased incidence of amenorrhea iii. Occasional patients carrying pregnancies to term without significant respiratory deterioration Skeletal manifestations a. Hypertrophic pulmonary osteoarthropathy i. Rarely seen in children with CF ii. Increasing frequency with increasing age and severity of disease b. Triad of skeletal manifestations i. Clubbing of fingers and toes ii. Arthritis iii. Periosteal new bone formation Nutritional abnormalities a. Failure to thrive, a common manifestation during infancy and beyond b. Poor appetite c. Weight loss d. Fatigue e. Prone to heat prostration f. Hypoproteinemia with or without edema, anemia, and deficient fat-soluble vitamins A, D, E, and K g. Peripheral neuropathy secondary to deficient vitamin E h. Delayed puberty largely due to nutritional factors i. Potentially lethal protein-energy malnutrition in some infants j. Development of some degree of malabsorption by 4 years of age in roughly 85% of patients Salt losing syndromes a. Acute salt depletion b. Chronic hypochloremic or hyponatremic alkalosis c. Excessive salt loss in the sweat potentially fatal for patients exposed to moderate heat or during prolonged hot weather Prognosis a. Respiratory failure: the leading cause of death in CF and occurs eventually in nearly all patients b. Current median survival: approximately 35 years in the United States c. Current data suggesting a lifespan exceeding 50 years for those diagnosed and treated early

DIAGNOSTIC INVESTIGATIONS 1. Newborn screening a. Measuring blood immunoreactive trypsinogen in dried blood spots i. Elevated levels in most CF infants (85–90% sensitive)

CYSTIC FIBROSIS

ii. Associated with a relatively large number of false positive results iii. Diagnosis must be confirmed by sweat tests or genotyping (CF multimutational analysis) b. Use DNA-based testing on dried blood spots by CFTR multimutational analysis 2. Sweat test a. The traditional method of CF diagnosis b. Reliably identifies the vast majority of patients with CF who have multiorgan involvement including the lungs and pancreas c. Using pilocarpine iontophoresis technique to produce sweat for chloride analysis d. Sweat chloride concentrations i. >60 mEq/L, observed in: a) CF patients with clinical manifestation of chronic pulmonary disease and/or pancreatic insufficiency b) CF patients with positive family history c) Untreated Addison disease d) Ectodermal dysplasia e) Certain types of glycogen storage diseases f) Untreated hypothyroidism g) A few normal adults ii. 95% Presymptomatic/preconceptional genetic testing: molecular characterization in familial and in sporadic cases

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sibling i. Risk not increased unless a parent is affected or has gonadal mosaicism ii. Possibility of germ-line mosaicism in a clinically normal parent: recurrence risk based on the percentage of the germ-line mosaicism b. Patient’s offspring i. Risk: 50% of inheriting the disease with extremely variable disease manifestations ii. Risk of having a child with NF1 in a patient affected with segmental NF1: small but greater than the general population risk. Segmental neurofibromatosis is believed to be due to

NEUROFIBROMATOSIS I

somatic mosaicism for a mutation in the NF gene. The mutation occurred postconceptionally and present in the limited population of cells. Gonadal cells may or may not have a mutation 2. Prenatal diagnosis a. Influence of knowledge of the disease in the reproductive decisions of affected individuals i. Interest in prenatal test by 41% of the subjects considering becoming pregnant ii. Only 10% considering terminating an affected pregnancy b. Prenatal diagnosis of NF1 difficult to be made in the past due to the following reasons i. Large size of the NF1 gene ii. Lack of any hotspots where the mutations arise iii. Variable expression even within members of a family with NF1 iv. Lack of a tight genotype–phenotype correlation v. High spontaneous mutation rate c. Currently available prenatal diagnosis i. Direct characterization of the mutation from a parent affected by NF1 ii. Analysis of the genomic DNA mutation from the fetus either by amniocentesis or CVS iii. Indirect linkage analysis to familial cases using informative polymorphic markers iv. Protein truncation test v. Fluorescence in situ hybridization d. Molecular diagnosis, unfortunately, cannot predict clinical expression of the disease in the fetus 3. Management a. Developmental assessment in children b. Medical management for itching, pain, depression, and other psychological and social problems c. Treatment of hypertension depending on the etiology i. Pheochromocytomas ii. Renal artery stenosis d. Surgical resection of tumors i. Resection of neurofibromas pressing on vital structures, obstructing vision, or rapidly growing lesions causing irritation, discomfort, and pain ii. Plexiform neurofibromas: extremely difficult to approach surgically and often recur after resection because of residual cells resting deeply in the soft tissues iii. Resection of spinal cord tumors: quite difficult but often is necessary to prevent progressive paraplegia or quadriplegia e. Surgical treatment of disfigurement i. Excision of multiple neurofibromas ii. Reconstructive surgery for plexiform neurofibromas f. Orthopedic care indicated for rapidly progressive scoliosis and for some severe bony defects g. Treatment of congenital pseudarthrosis of the tibia: challenging i. Bracing mainly of early treatment before fracture develops

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ii. A knee-ankle-foot-orthosis when weight bearing iii. Intramedullary rod fixation, often in combination with autogenous bone grafting of the pseudarthrosis site h. Complications of genetic counseling i. Intrafamilial variability (wide variation of phenotype even between members of the same family) ii. Presence of gonadal mosaicism in a phenotypically normal parent i. Advise high-risk pregnancy care to pregnant patient with neurofibromatosis i. Maternal hypertension ii. Aggravating features of neurofibromatosis

REFERENCES American Academy of Pediatrics Committee on Genetics: Health supervision for children with neurofibromatosis. Pediatrics 96:368–372, 1995. Ars E, Kruyer H, Gaona A, et al.: Prenatal diagnosis of sporadic neurofibromatosis type 1 (NF1) by RNA and DNA analysis of a splicing mutation. Prenat Diagn 19:739–742, 1999. Barker D, Wright E, Nguyen K, et al.: Gene for von Recklinghausen neurofibromatosis is in the pericentromeric region of chromosome 17. Science 236:1100–1102, 1987. Benjamin CM, Colley A, Donnai D, et al.: Neurofibromatosis type 1 (NF1): knowledge, experience, and reproductive decisions of affected patients and families. J Med Genet 30:567–574, 1993. Blickstein I, Lancet M, Shoham Z: The obstetric perspective of neurofibromatosis. Am J Obstet Gynecol 158:385–388, 1988, Comment in 161:501, 1989. Brasfield RD, DasGupta TK: Van Recklinghausen’s disease. A clinicopathological study. Ann Surg 175:86–104, 1972. Carey J: Health supervision and anticipatory guidance for children with genetic disorders (including specific recommendations for trisomy 21, trisomy 18, and neurofibromatosis I). Pediatr Clin North Am 39:25–53, 1992. Carey JC, Laub JM, Hall BD: Penetrance and variability in neurofibromatosis: A genetic study of 60 families. Birth Defects 15(5B):271, 1979. Carey JC, Baty BJ, Johnson JP, et al.: The genetic aspects of neurofibromatosis. Ann New York Acad Sci 486:45–56, 1986. Cnossen MH, Moon KGM, Garssen MPJ, et al.: Minor disease features in neurofibromatosis type 1 (NF1) and their possible value in diagnosis of NF1 children 1 year to 5 years i. Hepatomegaly ii. Portal hypertension 803

d. >5 year i. Hepatomegaly ii. Hypertension iii. Renal insufficiency iv. Portal hypertension e. Predominance of renal abnormalities in younger children f. Predominance of hepatic disease in older children and adolescents g. Tendency of inverse relative degrees of kidney and liver involvement i. Children with severe renal disease usually with milder hepatic disease ii. Children with severe hepatic disease with milder renal impairment 5. “Potter” phenotype developed in affected fetuses a. Pulmonary hypoplasia, often incompatible with life b. Characteristic face i. Short and snubbed nose ii. Deep eye creases iii. Micrognathia iv. Low-set flattened ears c. Deformities of the spine and limbs (clubfoot) 6. Renal manifestations a. Frequent loss of concentrating ability of the kidney b. Common recurrent urinary tract infections c. Proteinuria d. Hematuria e. Creatinine clearance improving early but declining progressively during adolescence f. Hypertension early in life but usually regresses g. Enlarged kidneys h. End-stage renal disease 7. Hepatic manifestations a. Congenital hepatic fibrosis i. Invariably present but only occasionally do hepatic symptoms predominate ii. Two predominant features characterizing the liver in ARPKD a) Bile ducts: abnormally/irregularly formed, often increased in number, and dilated intrahepatic bile ducts b) Portal tracts: enlarged and fibrotic iii. Normal hepatic parenchyma iv. Hepatocellular function almost always normal in affected patients, even when they have relatively severe portal tract disease v. Not by itself a diagnostic (not pathognomonic) sign. Congenital hepatic fibrosis has been observed in the following situations: a) Meckel-Gruber syndrome b) Vaginal atresia c) Tuberous sclerosis

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POLYCYSTIC KIDNEY DISEASE, AUTOSOMAL RECESSIVE TYPE

d) Juvenile nephronophthisis e) Rarely autosomal dominant polycystic kidney disease b. Caroli disease i. Congenital hepatic fibrosis accompanied by a non-obstructive dilation of the intrahepatic bile ducts ii. Clinical risk of secondary complications a) Stone formation b) Recurrent cholangitis: may result from ectatic bile ducts c) Hepatic abscesses d) Rare cholangiocarcinoma c. Hepatomegaly d. Portal hypertension i. The most common sequelae of congenital hepatic fibrosis ii. Splenomegaly iii. Variceal bleeding iv. Hypersplenism a) Leukopenia b) Thrombocytopenia c) Anemia d) Increased susceptibility to infections resulting from leukopenia associated with splenic sequestration e. Ascending cholangitis i. Presumably caused by entry of nonsterile gastrointestinal contents into the dilated intrahepatic bile ducts ii. Common in patients with macroscopically dilated bile ducts iii. Clinical features a) Abdominal pain b) Fever c) Elevation in levels of hepatic enzymes iv. Tends to recur v. May lead to hepatic abscess formation, sepsis, and death 8. Cerebral aneurysm, a common feature of ADPKD, reported in an adult with ARPKD 9. Prognosis a. 30–50% of affected neonates die shortly after birth in respiratory insufficiency due to pulmonary hypoplasia b. Recent trend with improved prognosis c. 67% of children who survive the newborn period with life-sustaining renal function at 15 years of age

DIAGNOSTIC INVESTIGATIONS 1. Radiography in neonates and infants with moderate to severe renal disease a. Smoothly enlarged kidneys because of the numerous dilated collecting ducts b. Abdominal distension c. Gas-filled bowel loops often deviated centrally d. Pulmonary hypoplasia and small thorax in the baby with severe kidney disease e. Pneumothorax common at birth following assisted ventilation

2. Ultrasonography a. Absence of renal cysts in both parents as demonstrated by ultrasound examination b. Neonatal ultrasonography with more marked renal cystic disease i. Massive enlarged kidneys ii. Increased echogenicity of entire parenchyma iii. Loss of corticomedullary differentiation iv. Loss of central echo complex v. Small macrocysts vi. Usually small bladder vii. Increased hepatic echogenicity, mainly in medulla c. Ultrasonography in children with more prominent hepatic fibrosis i. Massive kidney enlargement ii. Increased hepatic echogenicity, mainly in medulla iii. Macrocysts a) Less than 2 cm in diameter b) Tend to become larger and more numerous over time iv. Enlarged echogenic liver v. Hepatic cysts vi. Pancreatic cysts vii. Splenomegaly secondary to portal hypertension viii. Hepatofugal-flow duplex and color-flow Doppler 3. CT scan a. Nonenhanced CT: smooth, enlarged, and low attenuating kidneys, likely the reflection of the large fluid volume in the dilated ducts b. CT with contrast i. Kidneys with a striated pattern representing accumulation of contrast material in the dilated tubules ii. Linear opacifications representing retention of contrast medium in dilated medullary collecting ducts iii. Macrocysts appearing as well-circumscribed rounded lucent defects iv. Time of delay in visualizing the contrast medium in the kidneys, proportionate to the severity of renal impairment 4. Ultrasonography and magnetic resonance cholangiography to investigate the presence of an extent of Caroli disease in children with autosomal recessive polycystic kidney disease 5. MRI of affected children (perinatal, neonatal and infantile course) a. Kidney appearance i. Enlarged, humpy but still reniform in shape ii. Homogeneously grainy parenchyma b. Signal intensity i. Hypointense on T1-W spin-echo sequences ii. Hyperintense on T2-W turbo-spin-echo sequences c. RARE (rapid acquisition with relaxation enhancement)-MR-urography i. Hyperintense, linear radial pattern seen in the cortex and medulla representing the characteristic microcystic dilatation of collecting ducts ii. Possible few circumscribed small subcapsular cysts

POLYCYSTIC KIDNEY DISEASE, AUTOSOMAL RECESSIVE TYPE

6. Histopathology of the kidney a. Radially arranged cylindrical and fusiform ducts are present throughout renal medulla and cortex, due to a generalized dilatation of collecting ducts b. The portal tracts of the liver are enlarged and contain abundant fibrous tissue and many cistern-like dilated bile ducts. The abnormal changes are the result of ductal plate malformation 7. Molecular diagnosis a. Linkage analysis of the affected family using 6p21 markers demonstrating linkage to the ARPKD1 gene with the affected proband b. 33 different mutations detected on 57 alleles (Rossetti et al., 2003) i. 51.1% in ARPKD ii. 32.1% in congenital hepatic fibrosis/Caroli disease) iii. Two frequent truncating mutations a) 9689delA (9 alleles) b) 589insA (8 alleles) iv. Mutation detection rate a) High in severely affected patients (85%) b) Lower in moderate severe ARPKD (41.9%) c) Low, but significant, in adults with congenital hepatic fibrosis/Caroli disease (323.1%) v. Complications for the prospects for gene-based diagnostics a) Large gene size b) Marked allelic heterogeneity c) Clinical diversity of the ARPKD phenotype c. Direct DNA analysis available clinically

b. c. d.

e. f.

g.

h.

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not increased (theoretical risk 0.7%) 2. Prenatal diagnosis a. Ultrasonography in most severely affected fetuses i. Enlarged, echogenic kidneys ii. Dilated collecting ducts iii. Characteristic hepatic ductal plate malformation iv. A small or nonvisualized bladder v. Oligohydramnios attributable to poor fetal renal output vi. Unreliable especially in early pregnancy b. Mutation scanning of PKHD1 is available clinically by analysis of fetal DNA obtained from amniocentesis or CVS. Both disease-causing alleles of an affected family member must be identified or likage has been established in the family before prenatal testing can be performed. The ARPKD locus mapped to proximal chromosome 6p allowing haplotype-based prenatal diagnosis in “at-risk” family with a previously affected child in whom prior family studies have identified informative linked markers. An absolute prerequisite for these studies is an accurate diagnosis of ARPKD in the previously affected sib 3. Management a. Initial management of affected infants to focus on stabilization of respiratory function. Mechanical ventilation

i.

j.

805

may be necessary to treat both pulmonary hypoplasia and respiratory compromise from massively enlarged kidneys Water and electrolyte balance Peritoneal dialysis may be required for neonates with oliguria or anuria within the first days of life Vigorous treatment of systemic hypertension with antihypertensive agents i. ACE inhibitors ii. Calcium channel blockers iii. Beta-blockers iv. Judicious use of diuretics (eg, thiazides, loop diuretics) Antibiotics for treatment of urinary tract infections Management of renal osteodystrophy in children with ARPKD and chronic renal insufficiency i. Calcium supplements ii. Phosphate binders iii. 1,25-dihydroxyvitamin D3 to suppress parathyroid hormone (PTH) iv. Erythropoietin (EPO) a) Increases hemoglobin levels b) Improves the overall well-being of the child Potential use of recombinant human growth hormone therapy to improve the growth of children with uremia Therapeutic options available for the treatment of portal hypertension in children i. Conservative management ii. Control of variceal bleeding a) Sclerotherapy effective in controlling bleeding b) Banding of varices c) Placement of portosystemic shunts occasionally necessary to reduce bleeding and the formation of additional varices iii. Prompt management with antibiotics and, when indicated, surgical drainage to help reduce morbidity and mortality associated with ascending cholangitis iv. Splenectomy for hypersplenism v. Liver transplantation in patients with severe hepatic dysfunction or chronic cholangitis Replacement therapy for renal failure i. Renal dialysis ii. Renal transplant Combined liver/kidney transplantation

REFERENCES Bergmann C, Senderek J, Sedlacek B, et al.: Spectrum of mutations in the gene for autosomal recessive polycystic kidney disease (ARPKD/PKHD1). J Am Soc Nephrol 14:76–89, 2003. Dell KM: Autosomal recessive polycystic kidney disease. Gene Reviews; 2003. http://genetests.org. Guay-Woodford LM, Desmond RA: Autosomal recessive polycystic kidney disease: the clinical experience in North America. Pediatrics 111:1072–1080, 2003. Herrin JT: Phenotypic correlates of autosomal recessive (infantile) polycystic disease of kidney and liver: criteria for classification and genetic counseling. Prog Clin Biol Res 305:45–54, 1989. Jamil B, McMahon LP, Savige JA, et al.: A study of long-term morbidity associated with autosomal recessive polycystic kidney disease. Nephrol Dial Transplant 14:205–209, 1999.

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Jung G, Benz-Bohm G, Kugel H, et al.: MR cholangiography in children with autosomal recessive polycystic kidney disease. Pediatr Radiol 29:463–466, 1999. Kern S, Zimmerhackl LB, Hildebrandt F, et al.: Rare-MR-urography—a new diagnostic method in autosomal recessive polycystic kidney disease. Acta Radiol 40:543–544, 1999. Lederman HM, Hurth PJ: Polycystic kidney disease. http://www.emedicine.com Lieberman E, Salinas-Madrigal L, Gwinn JL, et al.: Infantile polycystic disease of the kidneys and liver: clinical, pathological and radiological correlations and comparison with congenital hepatic fibrosis. Medicine 50:277–318, 1971. Lilova M, Kaplan BS, Meyers KE: Recombinant human growth hormone therapy in autosomal recessive polycystic kidney disease. Pediatr Nephrol 18:57–61, 2003. Lonergan GJ, Rice RR, Suarez ES: Autosomal recessive polycystic kidney disease: radiologic-pathologic correlation. Radiographics 20:837–855, 2000. Pèrez L, Torra R, Badenas C, et al.: Autosomal recessive polycystic kidney disease presenting in adulthood. Molecular diagnosis of the family. Nephrol Dial Transplant 13:1273–1276, 1998. Rossetti S, Torra R, Coto E, et al.: A complete mutation screen of PKHD1 in autosomal-recessive polycystic kidney disease (ARPKD) pedigrees. Kidney Int 64:391–403, 2003.

Roy S, Dillon MJ, Trompeter RS, et al.: Autosomal recessive polycystic kidney disease: long-term outcome of neonatal survivors. Pediatr Nephrol 11:302–306, 1997. Stein-Wexler R, Jain K: Sonography of macrocysts in infantile polycystic kidney disease. J Ultrasound Med 22:105–107, 2003. Sumfest JM, Burns MW, Mitchell ME: Aggressive surgical and medical management of autosomal recessive polycystic kidney disease. Urology 42:309–312, 1993. Zerres K, Becker J, Mucher G, et al.: Autosomal recessive polycystic kidney disease. Contrib Nephrol 122:10–16, 1997. Zerres K, Hansmann M, Mallmann R, et al.: Autosomal recessive polycystic kidney disease. Problems of prenatal diagnosis. Prenat Diagn 8:215–229, 1988. Zerres K, Mucher G, Bachner L, et al.: Mapping of the gene for autosomal recessive polycystic kidney disease (ARPKD) to chromosome 6p21-cen. Nat Genet 7:429–432, 1994. Zerres K, Mucher G, Becker J, et al.: Prenatal diagnosis of autosomal recessive polycystic kidney disease (ARPKD): molecular genetics, clinical experience, and fetal morphology. Am J Med Genet 76:137–144, 1998. Zerres K, Rudnik-Schoneborn S, Senderek J, et al.: Autosomal recessive polycystic kidney disease (ARPKD). J Nephrol 16:453–458, 2003. Zerres K, Rudnik-Schoneborn S, Steinkamm C, et al.: Autosomal recessive polycystic kidney disease. J Mol Med 76:303–309, 1998.

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Fig. 2. Photomicrograph of a kidney of a neonate (37 weeks gestation) with ARPKD showing markedly dilated collecting ducts in the medulla (top) and the cortex (bottom). The infant also had intrahepatic bile duct proliferation and mild cystic changes, and pulmonary hypoplasia.

Fig. 3. Photomicrograph of the liver of a 2-year-old girl with congenital hepatic fibrosis, consistent with ARPKD. Note the irregularly dilated branching bile ducts. There is abundant fibrous connective tissue in this enlarged portal tract.

Fig. 1. A newborn with ARPKD showing Potter facies. The spongy appearing cut surface of a kidney from the same patient is due to generalized dilatation of the collecting ducts in both cortex and medulla.

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Fig. 4. Two neonates with ARPKD showing markedly distended abdomen.

Fig. 5. Kidneys in another neonate with ARPKD.

Prader-Willi Syndrome Prader-Willi syndrome is a neurogenetic disorder characterized by hypotonia and feeding difficulties in infancy, followed by hyperphagia, hypogonadism, mental retardation, and short stature. It was the first recognized microdeletion syndrome identified with high-resolution chromosome analysis, the first recognized human genomic imprinting disorder, and the first recognized disorder resulting from uniparental disomy. The incidence of Prader-Willi syndrome is approximately 1/10,000 to 1/15,000 individuals.

GENETICS/BASIC DEFECTS 1. Inheritance a. Usually sporadic events (de novo deletions of 15q11-q13) b. Rare familial transmission (balanced translocations involving 15q11-q13) (AGC) d) E145K (exon 2) observed in a phenotypically unusual HGPS iii. Mutations in LMNA also cause the following different recessive and dominant disorders: a) Emery-Dreifuss muscular dystrophy type 1 (EMD1) (autosomal dominant) b) Emery-Dreifuss muscular dystrophy type 2 (EMD2) (autosomal recessive) c) A familial dilated cardiomyopathy and conduction system defects (CMD1A) (autosomal dominant) d) Dunnigan type familial partial lipodystrophy (FPLD) (autosomal dominant) e) Limb girdle muscular dystrophy type 1B (LGMD1B) (autosomal dominant) f) Charcot-Marie-Tooth disorder type 2B1 (CMT2B1) (autosomal recessive axonal neuropathy) g) Mandibuloacral dysplasia (MAD) (autosomal recessive)

CLINICAL FEATURES

815

1. General features a. Normal appearance at birth b. Normal intelligence and personality c. High-pitched voice 2. Growth a. Profound growth failure/failure to thrive starting around 6 month to one year of age b. Extreme short stature c. No rapid growth during puberty d. Markedly diminished subcutaneous fat, especially on the face and limbs e. Absent sexual maturation 3. Skin a. Unremarkable at birth b. Generalized non-pitting edema suggestive of scleroderma shortly after birth

816

4.

5.

6.

7.

PROGERIA

c. “Sclerodermatous” skin over lower abdomen and proximal thighs, in which irregular bumps give appearance of lipodystrophy d. Becoming thin, dry, taut, and shiny in some areas, but lax and wrinkled in others, most commonly over the fingers and toes, by the second year e. Striking loss of subcutaneous tissue f. Prominent venous pattern g. Easy bruising h. Diminished eccrine sweating in some cases i. Progressive freckle-like hyperpigmentation (most evident in sun-exposed areas) and thickened sclerotic areas (usually on the lower parts of the trunk or thighs) after several years Hair a. Partial alopecia progressing to generalized alopecia often beginning at birth or in the first year and becoming prominent by the end of the second year b. Few remaining hairs: white or blond, fine, and fuzzy c. Body hair as well as scalp and facial hair: equally affected Nails a. Short, thin, and dystrophic fingernails and toenails b. Koilonychia (spoon nails) c. Onychogryphosis (deformed overgrowth of the nails) A striking facies after few months of life a. Typical “plucked-bird” appearance related to disproportionate craniofacial growth b. Disproportionately large cranium c. Relatively small face d. Prominent eyes e. Prominent scalp veins f. Sparse to absent scalp hair (alopecia, balding, hypotrichosis) g. Absent eyebrows and eyelashes h. Thin lips i. Circumoral cyanosis j. Protruded ears with absent earlobes k. “Beaked”, pinched nose with sculptured tip l. Micrognathia Teeth a. Anodontia/hypodontia, especially permanent teeth b. Delayed and incomplete dentition c. Discoloration (yellowish brownish) d. Crowded, rotated, displaced, overlapped, and maloccluded, especially the anterior teeth e. High incidence of caries f. Poor oral hygiene/gingivitis g. Irregularity in size and shape of the odontoblasts h. Delayed in ossification of the crown of the permanent teeth i. Narrow pulp chambers and root canals j. Reticular atrophy of pulp k. Calcification along the nerve fibers and the vascular walls l. Irregular width of predentin, secondary dentin and cemetum m. Osteoclastic resorption at apical portion n. Incompletely formation of roots of deciduous molars

8. Endocrine manifestations a. Incomplete sexual maturation b. Occasional hypoplastic nipples 9. Cardiovascular disease. a. Premature severe atherosclerosis b. Premature coronary artery disease c. Death from coronary artery disease frequent and may occur before 10 years of age d. Angina pectoris e. Myocardial infarction f. Congestive heart failure g. Epidural hematoma formation after a mild head injury possibly due to progressive atherosclerosis of intracranial vessels 10. Musculoskeletal abnormalities a. Generalized osteoporosis with pathologic fractures b. Marked delay in bone-healing after fractures c. Short/dystrophic clavicles d. Coxa valga e. Arthropathy f. Avascular necrosis of the femoral capital epiphysis g. Distal phalangeal osteolysis h. Delayed closure and persistently patent anterior fontanelle i. Joint contractures with contracted hands, elbows, and knees j. Dislocation of the hip k. Mild flexion of the knees resulting in a wide-gaited horse-riding stance and wide-based shuffling gait l. Short, tapered distal phalanges m. Thin limbs n. Muscle atrophy 11. Prognosis a. Absence of other factors associated with aging such as cancers, cataracts, and senility (not considered to be a phenocopy of normal aging) b. Death due to cardiovascular abnormalities in approximately 75% of patients c. Main cause of death due to cardiovascular complications i. Myocardial infarction ii. Congestive heart failure d. Other causes of death i. Marasmus ii. Inanition iii. Convulsions iv. Accidental head trauma due to thinned cortical bones e. Average life expectancy: 13 years (7–27 years)

DIAGNOSTIC INVESTIGATIONS 1. Histopathology a. Skin lesions indistinguishable from scleroderma i. Progressive hyalinization of dermal collagen (hyaline fibrosis) ii. Loss of subcutaneous tissue iii. Decreased sebaceous and sweat glands and hair follicles

PROGERIA

b. Bone lesions i. Osteoporosis ii. Osteolysis prominent in distal phalanges and clavicles iii. Skeletal dysplasia manifesting as coxa plana, coxa valga, and attenuated diaphyses with dystrophic metaphyses iv. Avascular hip necrosis v. Nonunion of fractures vi. Hip dislocations c. Cardiovascular lesions i. Severe, progressive atherosclerosis with widely variable age of clinical manifestation ii. Presence of atherosclerotic plaques in the large and small arteries iii. Calcifications in the mitral and aortic valves as well as aorta, coronary, cerebral, subclavian, and axillary arteries iv. Myocardial ischemia and infarction resulting from the coronary artery disease v. Diffuse interstitial myocardial fibrosis vi. Ventricular dilatation and hypertrophy d. Increased lipofuscin in the brain, adrenal cortex, kidney, testis, liver, and heart e. Gonads i. Aspermatogenesis in males ii. Presence of primordial follicles and corpora albicans in females with evidence of ovulation f. Arterial biopsy i. Premature atherosclerosis ii. Subintimal fibrosis 2. Radiography a. Widespread degenerative changes of bone in the first or second year of life b. Skull and facial bones i. Craniofacial disproportion ii. Patent fontanelles iii. Wormian bones with fractures iv. Facial bone hypoplasia v. Mandibular hypoplasia with dental crowding vi. Delayed and abnormal dentition c. Thorax i. Clavicular resorption ii. Rib tapering d. Long bones i. Indentations ii. Attenuated cortices iii. Widened metaphyses iv. Coxa valga v. Genu valgum e. Phalanges i. Distal resorption, one of the hallmarks of the disease ii. Radiolucent terminal phalanges (acro-osteolysis) f. Other i. Osteoporosis ii. Fish-mouthed vertebral bodies iii. Soft-tissue loss 3. Blood chemistry for hyperlipidemia a. Increased low-density lipoprotein levels

4.

5.

6.

7.

8.

817

b. Increased β-lipoprotein and pre-β-lipoprotein levels of high-density lipoprotein c. Increased serum cholesterol levels Metabolic work-up: inconsistent results a. Insulin resistance b. Abnormal collagen formation c. Increased metabolic rate: could be the cause of the failure to thrive seen in progeria d. Elevated growth hormone levels Urine test a. Excessive excretion of glycosaminoglycans b. Excessive excretion of hyaluronic acid (unreliable) Cultured skin fibroblasts a. Exhibit 76.1% DNA repair capacity compared to normal b. Decreased cell growth in culture c. Short telomeres d. Whether aging is the consequence of shortened telomeres with reduced cell replication, impaired telomerase activity, or the culmination of the effects of reactive oxygen species is uncertain Immunofluorescence of cultured fibroblasts with antibodies directed against lamin A demonstrating visible abnormalities of the nuclear membrane in many cells Molecular genetic analysis: polymerase chain reaction amplification of all of the exons of the LMNA gene, followed by direct sequencing

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. The lamin A gene mutations not found in patient’s parents suggesting that it occurs spontaneously in each patient and does not pass from parent to child ii. Recurrence risk very low, estimated at 1 in 500 with each subsequent pregnancy due to germ line mutations iii. Rare reports of siblings with progeria from consanguineous or nonconsanguineous marriages iv. Reported cases of monozygous twins with progeria b. Patient’s offspring: inability of patients to reproduce 2. Prenatal diagnosis: possible in families in which the diseasecausing mutation has been identified in a family member 3. Management a. Regular diet b. Combined nutritional treatment and growth hormone treatment i. Improve growth ii. Increase the levels of growth factors iii. Paradoxically result in a decreased BMR iv. Response decreases over time v. Do not prevent the progression of atherosclerotic disease c. Early and definitive surgical intervention for symptomatic oral pathosis i. Abnormal facial morphology ii. Dermal inelasticity

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PROGERIA

iii. Potential anaesthetic difficulties iv. Progressive ongoing deterioration in the medical condition d. Orthopedic cares for musculoskeletal abnormalities i. Routine treatment of fractures ii. Conservative treatment for hip dislocation. Avoid surgery if possible iii. Routine physical therapy to maintain joint range of motion e. Management of cardiovascular complications i. Routine anticongestive therapy for congestive heart failure ii. Nitroglycerin for angina iii. Low doses of aspirin help delay heart attacks and strokes

REFERENCES Abdenur JE, Brown WT, Friedman S, et al.: Response to nutritional and growth hormone treatment in progeria. Metabolism 46:851–856, 1997. Ackerman J, Gilbert-Barness E: Hutchinson-Gilford progeria syndrome: a pathologic study. Pediatr Pathol Mol Med 21:1–13, 2002. Arai T, Yamashita M: An abnormal dentition in progeria. Paediatr Anaesth 12:287, 2002. Badame AJ: Progeria. Arch Dermatol 125:540–544, 1989. Baker PB, Baba N, Boesel CP: Cardiovascular abnormalities in progeria: case report and review of the literature. Arch Pathol Lab Med 105:384–386, 1981. Batstone MD, Macleod AW: Oral and maxillofacial surgical considerations for a case of Hutchinson-Gilford progeria. Int J Paediatr Dent 12:429–432, 2002. Beauregard S, Gilchrest BA: Syndromes of premature aging. Dermatol Clin 5:109–121, 1987. Brown WT, Gordon LB, Collins FS: Hutchinson-Gilford progeria syndrome. Gene Reviews, 2004. http://www.genetests.org Cao H, Hegele RA: LMNA is mutated in Hutchinson-Gilford progeria (MIM 176670) but not in Wiedemann-Rautenstrauch progeroid syndrome (MIM 264090). J Hum Genet 48:271–274, 2003. Cooke JV: The rate of growth in progeria. J Pediatr 42:26–37, 1953 Danes BS: Progeria: a cell culture study on aging. J Clin Invest 50:2000–2003, 1971. De Sandre-Giovannoli A, Bernard R, Cau P, et al.: Lamin a truncation in Hutchinson-Gilford progeria. Science 300:20–55, 2003. DeBusk FL: The Hutchinson-Gilford progeria syndrome. Report of 4 cases and review of the literature. J Pediatr 80:697–724, 1972. Delahunt B, Stehbens WE, Gilbert-Barness E, et al.: Progeria kidney has abnormal mesangial collagen distribution. Pediatr Nephrol 15:279–285, 2000. Eriksson M, Brown WT, Gordon LB, et al.: Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423:293–298, 2003. Faivre L, Van Kien PK, Madinier-Chappat N, et al.: Can Hutchinson-Gilford progeria syndrome be a neonatal condition? Am J Med Genet 87:450–452; discussion 453–454, 1999. Fossel M: Human aging and progeria. J Pediatr Endocrinol Metab 13 Suppl 6:1477–1481, 2000. Fukuchi K, Katsuya T, Sugimoto K, et al.: LMNA mutation in a 45 year old Japanese subject with Hutchinson-Gilford progeria syndrome. J Med Genet 41:e67, 2004. Gabr M: Progeria Review of the literature with report of a case. Arc Pediatr 71:35–46, 1954. Gabr M, Hashem N, Hashem M, et al.: Progeria, a pathologic study. J Pediatr 57:70–77, 1960. Giannotti A, Digilio C, Mingarelli R, et al.: Progeroid syndrome with characteristic facial Appearance and hand anomalies in father and son. Am J Med Genet 73:227–229, 1997.

Gilford H: Progeria: a form of senilism. Practitioner 73:188–217, 1904. Gillar PJ, Kaye CI, McCourt JW: Progressive early dermatologic changes in Hutchinson-Gilford progeria syndrome. Pediatr Dermatol 8:199–206, 1991. Guarente L: Link between aging and the nucleolus. Genes Dev 11:2449–2455, 1997. Hamer L, Kaplan F, Fallon M: The musculoskeletal manifestations of progeria. A literature review. Orthopedics 11:763–769, 1988. Ishii T: Progeria: autopsy report of one case, with a review of pathologic findings reported in the literature. J Am Geriatr Soc 24:193–202, 1976. Jansen T, Romiti R: Progeria infantum (Hutchinson-Gilford syndrome) associated with scleroderma-like lesions and acro-osteolysis: a case report and brief review of the literature. Pediatr Dermatol 17:282–285, 2000. Jimbow K, Kobayashi H, Ishii M, et al.: Scar and keloid like lesions in progeria. An electron-microscopic and immunohistochemical study. Arch Dermatol 124:1261–1266, 1988. Khalifa MM: Hutchinson-Gilford progeria syndrome: report of a Libyan family and evidence of autosomal recessive inheritance. Clin Genet 35:125–132, 1989. Liessmann CD: Anaesthesia in a child with Hutchinson-Gilford progeria. Paediatr Anaesth 11:611–614, 2001. Luengo WD, Martinez AR, Lopez RO, et al.: Del(1)(q23) in a patient with Hutchinson-Gilford progeria. Am J Med Genet 113:298–301, 2002. Makous N, Friedman S, Yakovac W, et al.: Cardiovascular manifestations in progeria. Report of clinical and pathologic findings in a patient with severe arteriosclerotic heart disease and aortic stenosis. Am Heart J 64:334–346, 1962. Miki T, Morishima AK, Nakura J: The genes responsible for human Progeroid syndromes. Intern Med 39:327–328, 2000. Moen C: Orthopaedic aspects of progeria. J Bone Joint Surg Am 64:542–546, 1982. Monu JU, Benka-Coker LB, Fatunde Y: Hutchinson-Gilford progeria syndrome in siblings. Report of three new cases. Skeletal Radiol 19:585–590, 1990. Mounkes LC, Kozlov S, Hernandez L, et al.: A Progeroid syndrome in mice is caused by defects in A-type lamins. Nature 423:298–301, 2003. Nguyen NH, Mayhew JF: Anaesthesia for a child with progeria. Paediatr Anaesth 11:370–371, 2001. O’Brien ME, Weiss AS: A novel β(1–4) galactosyltransferase gene silent mutation (594C>T) associated with Hutchinson-Gilford progeria. Hum Mutat 17:355, 2001. Ozonoff MB, Clemett AR: Progressive osteolysis in progeria. Am J Roentgenol Radium Ther Nucl Med 100:75–79, 1967. Park WY, Hwang CI, Kang MJ, et al.: Gene profile of replicative senescence is different from progeria or elderly donor. Biochem Biophys Res Commun 282:934–939, 2001. Parkash H, Sidhu SS, Raghavan R: Hutchinson-Gilford progeria: familial occurrence. Am J Med Genet 36:431–433, 1990. Reichel W, Garcia-Bunuel R: Pathologic findings in progeria: myocardial fibrosis and lipofuscin pigment. Am J Clin Pathol 53:243–253, 1970. Rodríguez JI, Péez-Alonso P, Funes R, et al.: Lethal neonatal HutchinsonGilford progeria syndrome. Am J Med Genet 82:242–248, 1999. Rodriguez JI, Perez-Alonso P: Diagnosis of progeria syndrome is the only one possible. Am J Med Genet 87:453–454, 1999. Rosenbloom AL, Kappy MS, DeBusk FL, et al.: Progeria: insulin resistance and hyperglycemia. J Pediatr 102:400–402, 1983. Runge P, Asnis MS, Brumley GW, et al.: Hutchinson-Gilford progeria syndrome. South Med J 71:877–879, 1978. Sarkar PK, Shinton RA: Hutchinson-Guilford progeria syndrome. Postgrad Med J 77:312–317, 2001. Shiraishi I, Hayashi S, Hirai E, et al.: Fatal pulmonary hypertension associated with an atypical case of Hutchinson-Gilford progeria. Pediatr Cardiol 22:530–533, 2001. Talbot NB, Butler AM, Pratt EL, et al.: Progeria. Clinical, metabolic and pathologic studies on a patient. Am J Dis Child 69:267–279, 1945 Thomson J, Forfar JO: Progeria report of a case and review of the literature. Arch Dis Child 25:224–234, 1950. Yu QX, Zeng LH: Progeria: report of a case and review of the literature. J Oral Pathol Med 20:86–88, 1991.

PROGERIA

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Fig. 1. A boy with progeria showing short stature, senile appearance, small face in comparison with large cranial vault (craniofacial disproportion), alopecia with prominent scalp veins, absent eyelashes and eyebrows, prominent eyes, beaklike nose, mandibular hypoplasia, absent earlobes, contracted hands, elbows, and knees, short tapered terminal phalanges, enlarged joints, and dry brittle hypoplastic nails.

Prune Belly Syndrome 2. Pathogenesis: abdominal wall hypoplasia as a nonspecific lesion resulting from fetal abdominal distension of various causes 3. Terminologies a. Prune belly: a descriptive term for a wrinkled and flaccid abdominal wall secondary to stretched skin, soft tissues, and muscles of the abdomen b. Prune-belly syndrome generally used to indicate the condition having prune belly, cryptorchidism, and abnormalities of the urinary tract 4. Causes of urine flow impairment/obstruction a. Renal causes i. Pelvi-ureteric junction anomaly ii. Vesico-ureteric junction anomaly iii. Posterior urethral valves iv. Duplex systems v. Ureterocele/ectopic ureter vi. Urethral atresia vii. Cloacal anomaly viii. Vesico-ureteric reflux ix. Megaureter x. Megacystis microcolon xi. Hypoperistalsis syndrome b. Extrarenal causes i. Sacrococcygeal teratoma ii. Hydrometacolpos iii. Other pelvic masses

In 1895, Parker described the congenital triad of deficient abdominal musculature, cryptorchidism, and urinary tract abnormalities. Subsequently, the term “prune-belly syndrome” was coined for this condition based on the characteristic wrinkled appearance of the abdomen. The incidence of the syndrome is estimated to be 1 in 35,000 to 1 in 50,000 live births.

GENETICS/BASIC DEFECTS 1. Etiologies a. Questionable genetic inheritance i. Questionable autosomal dominant inheritance ii. Autosomal recessive inheritance suggested by some authors b. Fetal abdominal distension caused by urinary tract obstruction i. The most common cause of prune-belly syndrome ii. Urethral obstruction causing dilatation of the fetal bladder and upper tracts thereby attenuating the abdominal musculature iii. Spontaneous relief of the urethral obstruction in some cases prenatally decompresses the abdomen producing the shriveled, prune-like appearance of the baby’s abdomen iv. Persistent urethral obstruction causing huge distention of the urinary bladder, bilateral hydronephrosis and hydroureter complicated by oligohydramnios in more severe cases c. Fetal ascites from whatever cause: abdominal decompression during intrauterine life leading to prune belly appearance of the abdomen d. Prostatic hypoplasia resulting in a functional urethral obstruction leading to development of the prune-belly syndrome e. Primary mesodermal defect simultaneously affecting the formation of abdominal musculature and abnormalities in the lower urinary tract f. Rare association of chromosome abnormalities i. Trisomy 13 ii. Trisomy 18 iii. Turner syndrome with fetal ascites (pathogenetic mechanism thought to involve abdominal distention by ascites rather than by urinary obstruction) iv. Ring X chromosome lacking XIST v. Cat-eye syndrome vi. Rarely with trisomy 21 vii. Mosaic unbalanced chromosome constitution of chromosome 16 viii. Presence of a small additional chromosome fragment ix. Interstitial deletion of chromosome 1 [del(1) (q25q32)]

CLINICAL FEATURES

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1. Broad spectrum in severity 2. Nearly 95% of cases occurring in males 3. Abdomen a. Partial or complete absence of the abdominal musculature b. Thin/lax protruding abdominal wall c. Wrinkled abdominal skin d. Visible intra-abdominal intestinal patterns through thin abdominal wall 4. Genitourinary anomalies a. Bilateral cryptorchidism in males b. Urethral obstruction c. Dilated/hypertrophic bladder d. Dilated urethra, particularly the prostatic urethra e. Dilated/tortuous ureters f. Renal dysplasia/hypoplasia with cystic changes g. Hydronephrosis h. Absence or hypoplasia of the prostate i. Ventral body wall defects i. Cloacal exstrophy ii. Bladder exstrophy iii. Hypo/epispadias

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j. Potter sequence i. Oligohydramnios ii. Potter face iii. Pulmonary hypoplasia iv. Other deformations 5. Secondary malformations a. Gastrointestinal obstruction i. Malrotation ii. Atresia iii. Stenosis iv. Volvulus v. Splenic torsion vi. Imperforate anus vii. Anorectal agenesis b. Limb and other skeletal abnormalities believed to be the direct result of oligohydramnios with resultant fetal crowding i. Talipes equinovarus ii. Metatarsus adductus iii. Vertical talus iv. Hip dislocation v. Arthrogryposis vi. Pectus excavatum/carinatum vii. Congenital muscular torticollis viii. Infantile scoliosis ix. Severe leg maldevelopment a) Generalized hypoplasia b) Complete absence c) Terminal defects c. Cardiac malformations i. Tetralogy of Fallot ii. Ventriculoseptal defect d. Cleft lip e. Spina bifida f. Association with diverse chromosome syndromes i. Trisomy 13 ii. Trisomy 18 iii. Turner syndrome iv. Cat-eye syndrome v. Trisomy 21 vi. Others 6. Prognosis a. High mortality although compatible with long-term survival i. Stillbirth or death by one moth of age in 20% of cases ii. Death by the second year for additional 30% of cases b. Causes of death i. Renal failure secondary to renal dysplasia present at birth ii. Pulmonary complications including lung hypoplasia iii. Infection associated with urinary stasis or operative interventions

DIAGNOSTIC INVESTIGATIONS 1. Renal and bladder ultrasound 2. Contrast voiding cystourethrogram 3. Radiography

a. Hypoplastic lungs with flared lower ribs secondary to the distended abdomen b. Diffusely distended flanks c. Dilated/dysplastic calyces of the kidneys d. Markedly dilated/tortuous ureters e. Vertical and trabeculated bladder f. A wide and long posterior urethra g. Cryptorchidism 4. Histology of the abdominal wall a. Muscle atrophy (degeneration of already formed muscle), not of primitive muscle b. The finding supports the theory that the abdominal muscle hypoplasia is a nonspecific lesion, resulting from fetal abdominal distension of various causes 5. Chromosome analysis for multiple congenital anomalies

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased unless in autosomal recessive inheritance (which is still unclear) b. Patient’s offspring: not increased 2. Prenatal diagnosis by ultrasonography a. Signs of fetal abdominal laxity (characteristic abdominal appearance) associated with fetal urinary tract abnormalities i. Amniotic fluid wave produced by fetal movement ii. Sinusoidal undulation of the fetal anterior abdominal wall produced by tapping the maternal abdomen b. A distended bladder (megacystis) and ureters c. Cryptorchidism d. Oligohydramnios e. Fetal ascites f. Lung hypoplasia g. Associated anomalies i. Other renal anomalies (25%) ii. Extra-renal abnormalities (12%) a) Anorectal anomalies b) VATER syndrome c) Esophageal atresia d) Pattern compatible to specific chromosomal abnormality 3. Management a. Orchidopexy for cryptorchidism b. Treatment of vesicoureteral dysfunction i. Temporary diversion ii. Ureteral reconstruction c. Treatment of vesicourethral dysfunction i. Reduction cystoplasty ii. Internal urethrotomy iii. Megalourethra repair d. Abdominal wall reconstruction e. Vesico-amniotic shunt placement for suspected prenatal obstructive uropathy: remains controversial

REFERENCES Amacker EA, Grass FS, Hickey DE, et al.: An association of prune belly anomaly with trisomy 21. Am J Med Genet 23:919–923, 1986. Beckman H, Rehder H, Rauskolb R: Prune belly sequence associated with trisomy 13. Am J Med Genet 19:603–604, 1984.

PRUNE BELLY SYNDROME Bosman G, Reuss A, Nijman JM, et al.: Prenatal diagnosis, management and outcome of fetal uretero-pelvic junction obstruction. Ultrasound Med Biol 17:117–120, 1991. Burton BK, Dillerd RG: Prune belly syndrome: Observation supporting the hypothesis of abdominal over distention. Am J Med Genet 17:669–672, 1984. Christopher CR, Spinelli A, Severt D: Ultrasonic diagnosis of prune-belly syndrome. Obstet Gynecol 59:391–394, 1982. Cooperberg PL, Romalis G, Wright V: Megacystis (prune-belly syndrome): sonographic demonstration in utero. J Can Assoc Radiol 30:120–121, 1979. Drake DP, Stevens P, Eckstein HB: Hydronephrosis secondary to uretero-pelvic obstruction in children: a review of 14 years’ experience. J Urol 119:649–651, 1978. Eagle JF, Barret GS: Congenital deficiency of abdominal musculature with associated genitourinary anomalies: A syndrome. Report of 9 cases. Pediatrics 6:721–736, 1950. Freedman AL, Bukowski TP, Smith CA, et al.: Fetal therapy for obstructive uropathy: specific outcomes diagnosis. J Urol 156:720–724, 1996. Frydman M, Magenis RE, Mohandas TK, et al.: Chromosome abnormalities in infants with prune belly anomaly: Association with trisomy 18. Am J Med Genet 15:145–148, 1983. Genest DR, Driscoll SG, Bieber FR: Complexities of limb anomalies: the lower extremity in the “prune belly” phenotype. Teratology 44:365–371, 1991. Green NE, Lowery ER, Thomas R: Orthopaedic aspects of prune belly syndrome. J Pediatr Orthop 13:496–501, 1993. Harley LM, Chen Y, Rattner WH: Prune belly syndrome. J Urol 108:174–176, 1972. Ives EJ: The abdominal muscle deficiency triad syndrome-experience with ten cases. Birth Defects Original Article Series 10:127–135, 1974. Lattimer JK: Congenital deficiency of abdominal musculature and associated genitourinary anomalies. J Urol 79:343–352, 1958. Leeners B, Sauer I, Schefels J, et al.: Prune-belly syndrome: therapeutic options including in utero placement of a vesicoamniotic shunt. J Clin Ultrasound 28:500–507, 2000. Lubinsky M, Doyle K, Trunca C: The association of “prune-belly” with Turner’s syndrome. Am J Dis Child 134:1171–1172, 1980. Moerman P, Fryns JP, Goddeeris P: Prune belly syndrome, a secondary urethral functional obstruction due to prostatic hypoplasia. J Genet Hum 32:141–143, 1984.

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Moerman P, Fryns J-P, Goddeeris P, et al.: pathogenesis of the prune-belly syndrome: a functional urethral obstruction caused by prostatic hypoplasia. Pediatrics 73:470–475, 1984. Monie IW, Monie BJ: Prune belly syndrome and fetal ascites. Teratology 19:111–117, 1979. Mouriquand PDE, Whitten M, Pracros J-P: Pathophysiology, diagnosis and management of prenatal upper tract dilatation. Prenatal Diagn 21:942–951, 2001. Nunn IN, Stephens FD: The triad syndrome: A composite anomaly of the abdominal wall, urinary system, and testes. J Urol 86:782–784, 1961. Pagon RA, Smith DW, Shepard TH: Urethral obstruction malformation complex: a cause of abdominal muscle deficiency and the “prune belly”. J Pediatr 94:900–906, 1979. Parker RW: Absence of abdominal muscles in an infant-extensive degenerating nevus of bladder-gastric ulcer treated by laparotomy. Lancet 1:1252–1254, 1895. Osler W: Congenital absence of abdominal muscle with distended and hypertrophied urinary bladder. Bull Johns Hopkins Hosp 12:331, 1901. Pramanik AK, Altshuler G, Light IJ, et al.: Prune-belly syndrome associated with Potter (renal nonfunction) syndrome. Am J Dis Child 131:672–674, 1977. Qazi QH, Kaufman S, Sher J, et al.: Chromosomal anomaly in prune belly syndrome. Hum Genet 20:265–267, 1978. Rogers LW, Ostrow PT: The prune belly syndrome. Report of 20 cases and description of a lethal variant. J Pediatr 83:786–793, 1973. Scarbrough PR, Files B, Carroll AJ, et al.: Interstitial deletion of chromosome 1 [del(1)(q25q32)] in an infant with prune belly sequence. Prenat Diagn 8:169–174, 1988. Shimada K, Hosokawa S, Tohda A, et al.: Histology of the fetal prune belly syndrome with reference to the efficacy of prenatal decompression. Int J Urol 7:161–166, 2000. Stevenson RE, Schroer RJ, Collins J, et al.: Fetal ascites: the underlying cause for prune belly. Proc Greenwood Genet Ctr 6:16–21, 1987. Straub E ,Spranger J: Etiology and pathogenesis of the prune belly syndrome. Kidney Int 20:695–699, 1981. Tuch BA, Smith TK: Prune-belly syndrome. A report of twelve cases and review of the literature. J Bone Joint Surg 60A:109–111, 1978 Welch KJ, Kearney GP: Abdominal musculature deficiency syndrome: prune belly. J Urol 111:693–700, 1974. Woodhouse CR, Ransley PG, Innes-Williams D: Prune belly syndrome— report of 47 cases. Arch Dis Child 57:856–859, 1982.

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Fig. 1. A premature male neonate with prune-belly syndrome due to urethral atresia. He lived for 2 hours. There was a massive dilation and hypertrophy of the urinary bladder. Mild hydronephrosis was seen in one kidney but the second kidney was hypoplastic. The anterior abdominal wall showed muscle deficiency. Additional anomalies included imperforate anus with vesicorectal fistula, secundum type atrial septal defect of the heart, mild coarctation of the aorta, and bilateral talipes equinovarus.

Fig. 2. A male fetus with prune belly syndrome due to severe urethral stenosis. There were marked dilatation of the proximal urethra, bladder and bilateral ureters. Mild hydronephrosis and cystic renal dysplasia were seen in both kidneys. There were no other anomalies.

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Fig. 3. An infant with prune belly syndrome showing thin, flaccid abdominal wall through which intra-abdominal intestinal patterns are visible.

Fig. 5. A neonate with prune belly syndrome showing wrinkling abdominal wall due to multicystic kidneys. The infant also has duplicated great toes.

Fig. 4. A postmortem infant with prune belly syndrome showing flaccid and wrinkling abdominal wall with visible intestinal patterns.

Pseudoachondroplasia Pseudoachondroplasia is a type of short-limbed dwarfism, deriving its name from phenotypic similarity to achondroplasia. It is characterized by normal facies, short-limbed dwarfism, joint laxity, and epiphyseal and metaphyseal abnormalities in the growing child.

d. Chronic compression myelopathy secondary to habitual atlantoaxial dislocation 7. Extremities a. Bowing of the long bones b. Deformities of the lower limbs i. Secondary to ligamentous laxity ii. Ranging from genu varum (bowed legs), genu valgum (knock knees), and genu recurvatum iii. A “wind-swept deformity” (bow-leg on one side and knock-knee on the other side) c. Markedly shortened hands (without trident configuration) and feet d. Ulnar deviation of the wrist e. Flexion contractures of the elbow and knees f. Brachydactyly g. “Telescoping” fingers 8. Joint a. Lax ligament b. Premature osteoarthritis c. Contractures of the hips 9. Prognosis a. Good survival b. Early arthrosis, notably in the hip and knee joints c. Possible myelopathy secondary to atlantoaxial dislocations

GENETICS/BASIC DEFECTS 1. Inheritance a. Pseudoachondroplasia: autosomal dominant with complete penetrance b. Pseudoachondroplasia types II: autosomal recessive (small percentage of cases from parental gonadal mosaicism) 2. Cause a. Mutations in the gene encoding cartilage oligomeric matrix protein (COMP) on the centromeric region of 19p (19p13.1-p12) i. Deletions: Approximately 40–50% of cases of pseudoachondroplasia have deletion mutations in exon 13 of the COMP gene. ii. Specific base substitutions iii. Duplications b. Allelic to multiple epiphyseal dysplasia, which is also caused by COMP mutations c. All mutations associated with pseudoachondroplasia and multiple epiphyseal dysplasia: found in exons encoding the type III repeat region or C-terminal domain of COMP d. Mutations in extracellular matrix proteins, COMP, types II and IX collagens, and matrilin-3 i. Producing a spectrum of mild to severe chondrodysplasias characterized by epiphyseal and vertebral abnormalities ii. Disruption of protein processing and excessive accumulation of some of these proteins in the rough endoplasmic reticulum that appears to compromise cellular function

DIAGNOSTIC INVESTIGATIONS

CLINICAL FEATURES 1. 2. 3. 4.

Normal at birth Normal intelligence Normal craniofacial appearance Waddling gait and diminished linear growth at about 2 years of age 5. Rhizomelic short-limbed dwarfism a. Body proportion resembling achondroplasia b. Usually detectable at age 2–4 years 6. Spine a. Accentuated lumbar lordosis b. Scoliosis c. Kyphosis 826

1. Radiography a. Tubular bones i. Irregularities and fragmentations of the developing epiphyses ii. Shortened tubular bones iii. Brachydactyly iv. Delayed epiphyseal ossification (delayed bone age) v. Small phalangeal epiphyses (miniepiphyses) vi. Small, irregular carpal bones vii. Irregular, widened (frayed), mushroomed metaphyses viii. Coxa vara b. Pelvis i. Delayed ossification of the capital femoral epiphyses, which become flattened and small when ossified ii. Commonly observed sclerosis and irregularity of the acetabular roof c. Vertebrae i. Characteristic anterior beaking or tonguing (in lateral view of the lumbar spines) a) Due to delayed ossification of the annular epiphyses b) Vertebrae becoming more normal in appearance after puberty

PSEUDOACHONDROPLASIA

i. Characteristic platyspondyly in childhood ii. Kyphoscoliosis iii. Lumbar lordosis iv. Odontoid hypoplasia v. Atlantoaxial dislocations d. Ribs: spatulate 2. Histology of growth plates a. Irregular arrangement of chondrocytes without column formation b. Irregular provisional calcification c. Intracytoplasmic inclusions in chondrocytes 3. EM of chondrocytes a. Showing distinctive giant rough endoplasmic reticulum cisternae filled with punctuate material b. The material composed of alternating electron-lucent and electron-dense layers in a unique lamellar appearance 4. Molecular diagnosis a. Techniques i. Mutation screening in exons of the COMP gene using SSCP and sequence analysis ii. COMP mutation screening in RNA isolated from skin fibroblast cell line b. Particularly useful in adult patients where radiological diagnosis can be difficult

GENETIC COUNSELING 1. Recurrence risk a. Autosomal dominant inheritance i. Patient’s sibs a) 50% if one of the parent is affected b) Not increased if parents are normal ii. Patient’s offspring: 50% b. Autosomal recessive inheritance i. Patient’s sibs a) 25% for true autosomal recessive inheritance b) Slightly increased risk in case of parental gonadal mosaicism (depending on the degree of mosaicism) ii. Patient’s offspring: not increased unless the spouse is also carrying the gene 2. Prenatal diagnosis a. Prenatal ultrasonography unlikely to detect the skeletal changes, which will not manifest until about 2 years of age b. Prenatal diagnosis possible in the family at risk and the disease-causing COMP mutation has been characterized in an affected individual 3. Management a. Supportive b. Surgical correction of the leg deformities c. Hip replacement for severe hip contractures d. Cervical stabilization procedures for cervical cord compression with progressive neurologic symptoms and signs

REFERENCES Beck M, Lingnau K, Spranger J: Newly synthesized proteoglycans in pseudoachondroplasia. Bone 9:367–370, 1988. Briggs MD, Hoffman SMG, King LM, et al.: Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene. Nature Genet 10:330–336, 1995.

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Briggs MD, Rasmussen IM, Weber JL, et al.: Genetic linkage of mild pseudoachondroplasia (PSACH) to markers in the pericentromeric region of chromosome 19. Genomics 18:656–660, 1993. Briggs MD, Mortier GR, Cole WG, et al.: Diverse mutations in the gene for cartilage oligomeric matrix protein in the pseudoachondroplasia-multiple epiphyseal dysplasia disease spectrum. Am J Hum Genet 62:311–319, 1998. Briggs MD, Chapman KL: Pseudoachondroplasia and multiple epiphyseal dysplasia: mutation review, molecular interactions, and genotype to phenotype correlations. Hum Mutat 19:465–478, 2002. Byers PH: Molecular heterogeneity in chondrodysplasias. (Editorial) Am J Hum Genet 45:1–4, 1989. Cohn DH, Briggs MD, King LM, et al.: Mutations in the cartilage oligomeric matrix protein (COMP) gene in pseudoachondroplasia and multiple epiphyseal dysplasia. Ann N Y Acad Sci 785:188–194, 1996. Cooper RR, Ponseti IV, Maynard JA: Pseudoachondroplastic dwarfism. A rough-surfaced endoplasmic reticulum storage disorder. J Bone Joint Surg 55A:475–484, 1973. Cranley RE, Williams BR, Kopits SE, et al.: Pseudoachondroplastic dysplasia: five cases representing clinical, roentgenographic and histologic heterogeneity. Birth Defects Original Article Series 11(6):205–215, 1975. Deere M, Sanford T, Ferguson HL, et al.: Identification of twelve mutations in cartilage oligomeric matrix protein (COMP) in patients with pseudoachondroplasia. Am J Med Genet 80:510–513, 1998. Dennis NR, Renton P: The severe recessive form of pseudoachondroplasia. Pediatr Radiol 3:169–175, 1975. Ferguson Hl, Deere M, Evans R, et al.: Mosaicism in pseudoachondroplasia. Am J Med Genet 70:287–201, 1997. Hall JG: Pseudoachondroplasia. Birth Defects Orig Artic Ser 11:187–202, 1975. Hall JG, Dorst JP: Pseudoachondroplastic SED, recessive Maroteaux-Lamy type. Birth Defects Orig Art Ser V(4):254–259, 1969. Hall JG, Dorst JP, Rotta J, McKusick VA: Gonadal mosaicism in pseudoachondroplasia. Am J Med Genet 28:143–151, 1987. Hecht JT, Nelson LD, Crowder E et al.: Mutations in exon 17B of cartilage oligomeric matrix protein (COMP) cause pseudoachondroplasia. Nature Genet 10:325–329, 1995. Heselson NG, Cremin BJ, Beighton P: Pseudoachondroplasia: a report of 13 cases. Brit J Radiol 59:473–482, 1977. Ikegawa S, Ohashi H, Nishimura G, et al.: Novel and recurrent COMP (cartilage oligomeric matrix protein) mutations in pseudoachondroplasia and multiple metaphyseal dysplasia. Hum Genet 103:633–638, 1998. Kopits SE, Lindstrom JA, McKusick VA: Pseudoachondroplastic dysplasia: pathodynamics and management. In: Bergsma D (ed.): Skeletal Dysplasias. Amsterdam: Excerpta Medica (pub.) 1974, pp 341–| 352. Langer LO Jr, Schaefer GB, Wadsworth DT: Patient with double heterozygosity for achondroplasia and pseudoachondroplasia, with comments on these conditions and the relationship between pseudoachondroplasia and multiple epiphyseal dysplasia, Fairbank type. Am J Med Genet 47: 772–781, 1993. Maroteaux P, Stanescu R, Stanescu V, et al.: The mild form of pseudoachondroplasia. Eur J Pediatr 133:227–231, 1980. McKeand J, Rotta J, Hecht JT: Natural history study of pseudoachondroplasia. Am J Med Genet 63:406–410, 1996. Newman B, Donnah D, Briggs MD: Molecular diagnosis is important to confirm suspected pseudoachondroplasia. J Med Genet 37:64–65, 2000. Song HR, Lee KS, Li QW, et al.: Identification of cartilage oligomeric matrix protein (COMP) gene mutations in patients with pseudoachondroplasia and multiple epiphyseal dysplasia. J Hum Genet 48:222–225, 2003. Wynne-Davis R, Hall CM, Young ID: Pseudoachondroplasia: clinical diagnosis at different ages and comparison of autosomal dominant and recessive types: a review of 32 patients (26 kindreds). J Med Genet 23:425–434, 1986. Young ID, Moore JR: Severe pseudoachondroplasia with parental consanguinity. J Med Genet 22:150, 1985.

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Fig. 1. A girl with pseudoachondroplasia at 2 and half years (upper) with normal craniofacial appearance, mild short stature, and waddling gate and at 6 years (lowers) with short limbs, accentuated lumbar lordosis, and short stature.

Fig. 2. Radiographs of the spine show characteristic anterior beaking of the lumbar spine and mild scoliosis.

PSEUDOACHONDROPLASIA

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Fig. 3. Radiographs of the pelvis and lower extremities showing irregular, horizontal acetabular roof, delayed epiphyseal ossification, and wide mushroom-shape metaphyses. Fig. 5. Radiographs of the hands and feet show grossly disturbed metaphyseal and epiphyseal ossification, short and stubby tubular bones, somewhat widened metacarpals and metatarsals, and small and markedly irregular carpal and tarsal bones.

Fig. 4. Radiograph of the upper extremities showing markedly widened and defective metaphyseal and epiphyseal ossifications in the proximal humerus, distal radius and ulna.

R(18) Syndrome In 1962, Wang et al. reported the first observation of the ring chromosome 18.

GENETICS/BASIC DEFECTS 1. Caused by the presence of a ring chromosome 18 or mosaic ring chromosome 18 with a loss of 18p segment and a loss of 18q segment 2. Phenotypic variability depends on the extent of the deleted chromosome 8 segments 3. Rare occurrence of a ring chromosome 18 together with a duplication of a segment of chromosome 18 or with a marker chromosome

CLINICAL FEATURES 1. Clinical features of r(18) syndrome a. Growth and development i. Mental retardation ii. Hypotonia iii. Short stature b. Head/brain i. Microcephaly ii. Dolichocephaly iii. Holoprosencephaly iv. Cebocephaly v. Arhinencephaly c. Midface: flat d. Ears i. Asymmetric ii. Low-set iii. Atretic external ear canals iv. Prominent anti-helix e. Eyes i. Deep-set ii. Hypertelorism iii. Down slanting palpebral fissures iv. Epicanthal folds v. Nystagmus vi. Strabismus vii. Ptosis viii. Coloboma f. Nose i. Broad base ii. Depressed nasal bridge iii. Broad tip g. Mouth i. Micrognathia ii. Carp-like down-turned corners iii. Thin upper and lower lips iv. High/narrow palate v. Dental caries

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h. Neck: short i. Chest i. Pectus excavatum ii. Wide-spaced nipples j. Congenital heart defect i. PDA ii. PS iii. VSD iv. AS k. Abdomen i. Umbilical hernia ii. Inguinal hernia l. Genitourinary i. Male genitalia a) Cryptorchidism b) Hypoplastic scrotum c) Micropenis ii. Female genitalia: hypoplastic labia minora m. Musculoskeletal i. Spine: scoliosis ii. Hands a) Clinodactyly b) Camptodactyly c) Short fingers d) Long tapering fingers e) Proximally placed thumbs f) Single transverse palmar crease iii. Legs/feet a) Club feet (varus) b) Over-riding toes c) Long/broad toes d) Genu valgum n. Other features i. Hypothyroidism ii. Hypoparathyroidism iii. Growth hormone deficiency o. Atypical features i. Van der Woude syndrome ii. Insulin-dependent diabetes mellitus iii. Agammaglobulinemia 2. Most patients share the features of del(18q) syndrome, which are highly variable depending on the extent of the terminal or interstitial 18q deletion: a. Mental retardation b. Hypotonia c. Microcephaly d. Short stature e. Flat midface f. Carp-shaped mouth g. Prominent antihelix and antitragus h. Atretic/stenotic ear canals

832

R(18) SYNDROME

i. Proximally placed thumbs j. Long tapering digits k. Foot deformity l. Abnormal male genitalia 3. Some patients share the features of del(18p) syndrome, which are highly variable depending on the extent of the terminal or interstitial 18p deletion: a. Mental retardation b. Speech delay c. Hypotonia d. Short stature e. Midface defects including holoprosencephaly f. Ptosis of eyelids g. Small mandible h. Dental caries i. Short neck j. IgA deficiency 4. Some patients share the combined features of del(18p) syndrome and del(18q) syndrome

DIAGNOSTIC INVESTIGATIONS 1. Conventional cytogenetic studies a. Nonmosaic r(18) b. Mosaic r(18) 2. Molecular cytogenetic studies using fluorescence in situ hybridization (FISH) technique a. Ring chromosome positive for chromosome 18 centromeric probe b. Absence of 18q subtelomeric probe 3. Microdissection followed by FISH to determine the origin of the marker chromosome 4. Using a number of microsatellite markers to determine the parental origin and possible mode of formation of the r(18) 5. Low IgA

GENETIC COUNSELING 1. Recurrence risk a. Patient sibling: not increased in cases of de novo instances (majority of cases) b. Patient’s offspring i. Vertical transmission of ring chromosome 18 from a mother to her offspring reported ii. Mosaic monosomy 18 with familial ring chromosome 18 reported 2. Prenatal diagnosis by chromosome analysis from amniocentesis, CVS, and fetal blood 3. Management a. Mainly supportive b. Multidisciplinary team approach with physical, occupational, and speech therapies

c. Supportive treatment for chronic sinopulmonary infections associated with IgA deficiency d. Treat endocrine dysfunction, if present

REFERENCES Baumer A, Uzielli MLG, Guarducci S, et al.: Meiotic origin of two ring chromosomes 18 in a girl with developmental delay. Am J Med Genet 113:101–104, 2002. Christensen KR, et al. Ring chromosome 18 in mother and daughter. J Ment Defic Res 14:49–67, 1970. Cody JD, Ghidoni PD, DuPont BR, et al.: Congenital anomalies and anthropometry of 42 individuals with deletions of chromosome 18q. Am J Med Genet 85:455–462, 1999. De Grouchy J: The 18p-, 18q- and 18r-syndromes. Birth Defects Orig Artic Ser V(5):74–87, 1969. Donlan MA, Dolan CR: Ring chromosome 18 in a mother and son. J Med Genet 24:171–174, 1986. Eiben B, Unger M, Stoltenberg G, et al.: Prenatal diagnosis of monosomy 18 and ring chromosome 18 mosaicism. Prenat Diagn 12:945–950, 1992. Grouchy J de: The 18p-, 18q-, and 18r-syndromes. Birth Defects Original Article Series V(5):74–87, 1969. Jenderny J, Caliebe A, Beyer C, et al.: Transmission of a ring chromosome 18 from a mother with 46,XX/47,XX,+r(18) mosaicism to her daughter, resulting in a 46,XX,r(18) karyotype. J Med Genet 30:964–965, 1993. Karda SI, Wirth J, Mazurczak T, et al.: Clinical and molecular-cytogenetic studies in seven patients with ring chromosome 18. Am J Med Genet 101:226–239, 2001. Litzman J, Brysova V, Gaillyova R, et al.: Agammaglobulinaemia in a girl with a mosaic of ring 18 chromosome. J Paediatr Child Health 34:92–94, 1998. Los FJ, van den berg C, Braat PG, Ring chromosome 18 in a fetus with only facial anomalies. Am J Med Genet 66:216–220, 1996. Miller K, Pabst B, Ritter H, et al.: Chromosome 18 replaced by two ring chromosomes of chromosome 18 origin. Hum Genet 112:343–347, 2003. Schaub RL, Leach RJ, Cody JD: Reevaluation of frequencies of selected features in patients with the 18p syndrome. Am J Hum Genet 63 (Suppl A342): 1931, 1999. Stankiewicz P, Brozek I, Hélias-Rodzewicz Z, et al.: Clinical and molecularcytogenetic studies in seven patients with ring chromosome 18. Am J Med Genet 101:226–239, 2001. Stewart J, Go S, Ellis E, et al.: Absent IgA and deletions of chromosome 18. J Med Genet 7:11–19, 1970. Strathdee G, Zackai EH, Shapiro R, et al.: Analysis of clinical variation seen in patients with 18q terminal deletions. Am J Med Genet 59:476–483, 1995. Thies U, Bartels I, von Beust G, et al.: Prenatal diagnosis and fetopathological findings in a fetus with ring chromosome 18. Fetal Diagn Ther 13:315–320, 1998. Wertelecki W, Gerald PS: Clinical and chromosomal studies of the 18q- syndrome. J Pediatr 78:44–52, 1971. Wilson MG, Towner JW, Forsman I, et al.: Syndromes associated with deletion of the long arm of chromosome 18[del(18q)]. Am J Med Genet 3:155–174, 1979. Yardin C, Esclaire F, Terro F, et al.: First familial case of ring chromosome 18 and monosomy 18 mosaicism. Am J Med Genet 104:257–259, 2001. Zumel RM, Darnaude MT, Delicado A, et al.: The 18p-syndrome. Report of five cases. Ann Génét 32:160–163, 1989.

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Fig. 2. Chromosome analysis of the patient showed 46,XY,r(18), illustrated by a G-banded karyotype, a partial karyotype with idiograms, and FISH with whole chromosome 18 painting probe.

Fig. 1. A 4-year-old boy with de novo r(18) syndrome showing growth deficiency (prenatal and postnatal), speech delay, hypertelorism, downward slanting of the palpebral fissures, strabismus, slightly lowset ears, mild pectus carinatum, clinodactyly of the 5th fingers, and syndactyly of toes. He also has IgA deficiency.

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R(18) SYNDROME

Fig. 4. A boy with del(18q) showing hypotonia, ptosis of the eyelids, and carp-like mouth.

Fig. 3. A girl with del(18p) showing hypotonia, ptosis of the eyelids, and small mandible. The G-banded karyotype shows deletion of the short arm of a chromosome 18.

Retinoid Embryopathy Oral retinoids, isotretinoin (Accutane) and etretinate, uniquely effective in the treatment for severe cystic and keratinization disorders, are potent human teratogens.

2. Teratogenicity a. Isotretinoin i. Teratogenic during the first trimester fetal exposure within the therapeutic dose range ii. Has a short elimination half-life of about 20 hours iii. Recommended contraception period after cessation of therapy: one month iv. Risk of teratogenicity for isotretinoin a) Exposure within first trimester: about 28% b) Pregnancy occurring within one month after cessation of treatment: about 4% c) Pregnancy occurring after 1 month: The risk of fetal malformations returns to baseline (isotretinoin is no longer detectable in the maternal circulation) b. Etretinate i. Readily absorbed into adipose tissue and slowly released from it ii. Has a long elimination half-life (≥120 days) iii. Recommended contraception period after therapy: 2 years iv. Risk for teratogenicity for exposure to etretinate a) During pregnancy: about 26% b) Within 2 years of treatment cessation: about 2% c. Acitretin i. A shorter elimination half-life of 50 hours ii. Recommendation of a two-year contraception period after therapy for acitretin, as in some women there is conversion of acitretin to etretinate during therapy

GENETICS/BASIC DEFECTS 1. Synthetic retinoids (isotretinoin, etretinate, acitretin) a. Closely resemble naturally occurring vitamin A, which is essential for the maintenance of visual and reproductive function and for proliferation and differentiation of epithelial tissues b. Isotretinoin and etretinate i. Released in the United States and Europe in 1982 ii. Isotretinoin: uniquely effective in severe cystic acne iii. Etretinate (and acitretin): uniquely effective in severe psoriasis and other keratinization disorders which proved recalcitrant to all other therapies, account for their availability on prescription despite their teratogenicity c. Acitretin released later to replace etretinate as it is more rapidly eliminated from the body d. Adverse reactions i. Commonly reported adverse reactions: largely dose-related, of early onset, and reversible on discontinuation a) Dryness of the lips, mouth, and eyes b) Hair loss c) Pruitis ii. Less common and more severe, idiosyncratic reactions a) Altered vision b) Headache c) Joint and muscle pain d) Abnormally raised serum transaminases levels e) Serum lipid changes f) Increased serum triglyceriode and cholesterol levels g) An increase in low density/high density lipoprotein ratio iii. Rare reactions a) Mental depression b) Severe hepatitis c) Diffuse hyperostosis of the spine d) Benign intracranial hypertension e. Teratogenicity of retinoids i. Foreshadowed by animal studies with strong warnings against exposure during pregnancy ii. Believed to interfere with the activity and migration of cranial neural crest cells during development and thus cause craniofacial, thymic conotruncal heart and CNS malformations iii. Intellectual deficits

CLINICAL FEATURES

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1. Isotretinoin embryopathy a. Craniofacial abnormalities i. Microtia/anotia ii. Agenesis or marked stenosis of external ear canals iii. Hypertelorism iv. Depressed nasal bridge v. Micrognathia vi. Cleft palate vii. Low-set ears b. Central nervous system abnormalities i. Hydrocephalus ii. Dandy-Walker malformation iii. Microcephaly iv. Microophthalmia v. Cerebellar defects a) Hypoplasia b) Microdysgenesis vi. Cortical defects vii. Cortical blindness

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viii. Facial nerve palsy ix. Optic nerve hypoplasia x. Retinal defects xi. Spina bifida xii. Mental retardation c. Cardiovascular abnormalities i. Conotruncal malformations a) Transposition of the great vessels b) Tetralogy of Fallot c) Truncus arteriosus d) Double-outlet right ventricle e) Ventricular septal defect f) Atrial septal defect ii. Coarctation of the aorta iii. Interrupted aortic arch iv. Hypoplastic left ventricle v. Retroesophageal right subclavian artery d. Other abnormalities i. Thymic abnormalities a) Ectopia b) Hypoplasia c) Aplasia ii. Nystagmus iii. Decreased muscle tone iv. Hepatic abnormality v. Hydroureter vi. Simian crease vii. Limb reduction viii. An increased risk of spontaneous abortions (about 15%) but no long-term effects on fertility 2. Retinate embryopathy a. Craniofacial abnormalities i. Microtia ii. Micrognathia iii. Low set ears b. Central nervous system abnormalities i. Menigomyelocele ii. Anophthalmia iii. Brain defect c. Skeletal abnormalities i. Syndactyly ii. Shortened or absent digits iii. Club foot iv. Multiple synostosis

DIAGNOSTIC INVESTIGATIONS 1. 2. 3. 4.

Sonogram/CT/MRI of the brain for CNS anomalies Radiography/CT for auditory canal malformations Echocardiography for congenital heart defects Audiological assessment by brainstem auditory evoked response 5. Visual and somatosensory evoked potential to detect cortical response 6. Electroencephalography

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased unless the mother exposes to retinoid again during the pregnancy

b. Patient’s offspring: not increased unless exposure to retinoid during pregnancy 2. Prenatal diagnosis a. History of maternal exposure to retinoid b. Prenatal ultrasonography i. Craniofacial anomalies a) Microtia/anotia b) Anophthalmia/microphthalmia c) Other facial abnormalities ii. CNS anomalies a) Microcephaly b) Dandy-Walker malformation c) Hydrocephalus iii. Cardiac defects by fetal echocardiography iv. Skeletal abnormalities 3. Management a. Pregnancy Prevention Program, developed by the manufacturer and the US Food and Drug Administration since 1988, to prevent fetal exposure to the drug Accutane i. Distribute printed material to prescribing physicians to be used in educating their female patients about the serious teratogenic effects ii. Instruct physicians to delay therapy until the second or third day of the patient’s next normal menstrual period iii. Stress to patients the importance of using 2 forms of contraception concurrently iv. A consent form to be signed by female patients a) Acknowledging that they have been instructed through the program b) Aware of the need to use 2 forms of contraception during isotretinoin therapy c) Agree to undergo pregnancy testing before, during and after the therapy b. Adhere to strict prescription guidelines, but exposure during pregnancy still occurs. The most common reasons for unwanted or mistimed pregnancies with isotretinoin therapy are: i. Unsuccessful attempts at abstinence ii. Use of ineffective contraception iii. Inconsistent use of contraception iv. Unexpected sexual activity v. Contraceptive failure c. Surgical shunting for hydrocephalus d. Surgical repair of congenital heart defects e. Surgical reconstruction of the external ear canal and middle ear f. Orthopedic management of limb reduction g. Multi-disciplinary approach to multiple handicapped conditions

REFERENCES Atanackovic G, Koren G: Fetal exposure to oral isotretinoin: failure to comply with the Pregnancy Prevention Program. Canad Med Assoc J 160:1719–1720, 1999. Atanackovic G, Koren G: Young women taking isotretinoin still conceive. Role of physicians in preventing disaster. Can Fam Physician 45:289–292, 1999. Braun JT, Franciosi RA, Mastri AR, et al.: Isotretinoin dysmorphic syndrome. Lancet 1:506–507, 1984.

RETINOID EMBRYOPATHY Brinker A, Trontell A, Beitz J: Pregnancy and pregnancy rates in association with isotretinoin (Accutane). J Am Acad Dermatol 47:798–799, 2002. Chan A, Hanna M, Abbott M, et al.: Oral retinoids and pregnancy. Med J Aust 165:164–167, 1996. Dai WS, Hsu MA, Itri LM: Safety of pregnancy after discontinuation of isotretinoin. Arch Dermatol 125:362–365, 1989. Dai WS, LaBraico JM, Stern RS: Epidemiology of isotretinoin exposure during pregnancy. J Am Acad Dermatol 26:599–606, 1992. de la Cruz E, Sun S, Vangvanichyakorn K, et al.: Multiple congenital malformations associated with maternal isotretinoin therapy. Pediatrics 74:428–430, 1984. Ellis CN, Krach KJ: Uses and complications of isotretinoin therapy. J Am Acad Dermatol 45:S150–S157, 2001. Fernhoff PM, Lammer EJ: Craniofacial features of isotretinoin embryopathy. J Pediatr 105:595–597, 1984. Hansen RC: Accutane (isotretinoin) revisited: severe birth defects from acne therapy. Ariz Med 42:363–365, 1985. Holmes SC, Bankowska U, Mackie RM: The prescription of isotretinoin to women: is every precaution taken? Br J Dermatol 138:450–455, 1998. Jahn AF, Ganti K: Major auricular malformations due to Accutane (isotretinoin). Laryngoscope 97:832–835, 1987. Jones KL, Adams J, Chambers CD, et al.: Isotretinoin and pregnancy. JAMA 285:2079–2081, 2001. Kassis I, Sunderji S, Abdul-Karim R: Isotretinoin (Accutane) and pregnancy. Teratology 32:145–146, 1985. Koren G, Pastuszak A: How to ensure fetal safety when mothers use isotretinoin (Accutane). Can Fam Physician 43:216–219, 1997. Lammer EJ, Schunior A, Hayes AM, et al.: Isotretinoin dose and teratogenicity. Lancet 2:503–504, 1988. Lancaster PA: Teratogenicity of isotretinoin. Lancet 2:1254–1255, 1988.

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Mitchell AA, Van Bennekom CM: Accutane and pregnancy. J Am Acad Dermatol 49:1201–1202, 2003. Mitchell AA, Van Bennekom CM, Louik C: A pregnancy-prevention program in women of childbearing age receiving isotretinoin. N Engl J Med 333:101–106, 1995. Nau H: Teratogenicity of isotretinoin revisited: species variation and the role of all-trans-retinoic acid. J Am Acad Dermatol 45:S183–S187, 2001. Pastuszak A, Koren G, Rieder MJ: Use of the Retinoid Pregnancy Prevention Program in Canada: patterns of contraception use in women treated with isotretinoin and etretinate. Reprod Toxicol 8:63–68, 1994. Perlman SE, Leach EE, Dominguez L, et al.: “Be smart, be safe, be sure”. The revised Pregnancy Prevention Program for women on isotretinoin. J Reprod Med 46:179–185, 2001. Pochi PE, Ceilley RI, Coskey RJ, et al.: Guidelines for prescribing isotretinoin (Accutane) in the treatment of female acne patients of childbearing potential. Acne Subgroup, Task Force on Standards of Care. J Am Acad Dermatol 19:920, 1988. Rappaport EB, Knapp M: Isotretinoin embryopathy-a continuing problem. J Clin Pharmacol 29:463–465, 1989. Rizzo R, Lammer EJ, Parano E, et al.: Limb reduction defects in humans associated with prenatal isotretinoin exposure. Teratology 44:599–604, 1991. Shear NH: Oral isotretinoin: prescribers beware. Canad Med Assoc J 160:1723–1724, 1999. Stashower ME: Pregnancy rates associated with isotretinoin (Accutane) and the FDA. J Am Acad Dermatol 49:1202–1203, 2003. Strauss JS, Cunningham WJ, Leyden JJ, et al.: Isotretinoin and teratogenicity. J Am Acad Dermatol 19:353–354, 1988. Strauss JS, Leyden JJ, Lucky AW, et al.: Safety of a new micronized formulation of isotretinoin in patients with severe recalcitrant nodular acne: A randomized trial comparing micronized isotretinoin with standard isotretinoin. J Am Acad Dermatol 45:196–207, 2001.

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Fig. 1. An infant with isotretinoin embryopathy. The mother took accutane in the first trimester. Prenatal ultrasound examinations revealed intrauterine growth retardation, apparent ocular hypertelorism and flat nasal bridge, and Tetralogy of Fallot. Parents elected to continue the pregnancy. The infant was born with dysmorphic craniofacial features (microcephaly, hypertelorism, flat nasal bridge, microretrognathia, cleft palate, absent ear canals and anotia, duplicated thumb on the left hand, anteriorly placed anus, and Tetralogy of Fallot (illustrated in a drawing).

Rett Syndrome Rett syndrome, a neurodevelopmental disorder affecting girls almost exclusively, was first described by Rett in 1966. The disorder now bears his name and became widely known after a report of 35 cases by Hagberg et al. in 1983. The prevalence is estimated to be 1/10,000 ~ 1/15,000 female births; over 95% of cases arise de novo due to the fact that most females with Rett syndrome do not reproduce. Rett syndrome is considered to be one of the most common genetic causes of mental retardation in girls, second only to Down syndrome.

GENETICS/BASIC DEFECTS 1. Inheritance a. Sporadic cases (99.5%), occurring almost exclusively in females i. A de novo mutation in the child with Rett syndrome ii. Disease-causing mutation inherited from one parent who has somatic or germline mosaicism b. Several reports of familial recurrence support X-linked dominant inheritance with lethality in hemizygous males 2. The region of interest has been localized to Xq28 by linkage analysis from available familial cases 3. Caused by mutations in the MECP2 (methyl-CpG-binding protein 2) gene in Xq28 a. Result in a loss of function by either disrupting the methylated DNA-binding properties of the protein or interfering with its association with transcriptional co-repressors b. MECP2 mutations in sporadic or atypical cases i. Up to 80% of sporadic affected females ii. One third of the clinically atypical cases c. MECP2 mutations in familial cases (lower incidence) i. Germline mosaic mothers ii. Asymptomatic carrier mothers due to nonrandom patterns of X-inactivation. The pattern of X-inactivation most likely protects the mutation carriers from expression of the disease by preferential inactivation of the mutant MECP2 allele 4. Males with MECP2 mutations may suffer from severe neonatal encephalopathy and die from breathing difficulties before their second year. The almost absence of men with classic Rett syndrome suggests a lethal effect of the MECP2 mutation in hemizygous affected men. However, males with Rett syndrome are not always lethal, although neurologic impairment is slowly progressive and much more severe in men than in women a. Affected men have been reported in association with Klinefelter syndrome and somatic mosaicism b. Most MECP2 mutations have originated in the paternal germline. The paternal X MECP2 never passed on from father to their sons

c. Only way for a male to have Rett syndrome is a de novo mutation of a maternal X or inheritance of a MECP2 gene mutation from his mother d. Caution: some reported MECP2 mutations may actually represent genetic variant rather than true pathogenetic novel mutations in the MECP2 gene in males

CLINICAL FEATURES 1. Normal prenatal and perinatal history 2. Appropriate head circumference 3. Apparently normal psychomotor development until about 6 to 18 months of life in affected girls 4. Developmental milestones afterwards beginning to slow down and regress with loss of skills already achieved a. Deterioration of communicative skills b. Social withdrawal c. Loss of purposeful hand movement 5. Continued deterioration over the next few years a. Loss of language b. Poor motor function (truncal and gait apraxia/ataxia) c. Stereotypic hand movements (hand wringing and flapping) d. Deceleration of head growth (acquired microcephaly) e. Autistic behavior 6. Period of stabilization a. Severe psychomotor dysfunction b. Some patients may make small recoveries in contact and communication skills 7. Breathing difficulties a. Periodic apnea b. Hyperventilation c. Breath holding d. Forced explosion of air/saliva e. Bruxism 8. Swallowing difficulties 9. Dystonia and hand and foot deformities as affected girls grow older 10. Later development of scoliosis 11. Osteoporosis at risk for fractures 12. Seizures (epilepsy) in 50% affected females 13. Possible survival into adulthood without further deterioration 14. An increased risk for sudden, unexplained death a. Longer corrected QT intervals b. T-wave abnormalities c. Reduced heart rate 15. Rett syndrome variants (T in one copy of the MECP2 gene which predicts an amino acid change of arginine to a premature translation stop at codon 255 (R255X). This nonsense mutation was previously identified in multiple Rett syndrome patients as a disease-causing MECP2 mutation.

Rickets Normal bone mineralization requires adequate supplies of calcium and phosphate and normal vitamin D metabolism. Defective supply or function of any of these factors can cause rickets and osteomalacia.

GENETICS/BASIC DEFECTS 1. Causes a. Younger than 6 months of age i. Hypophosphatasia ii. Prematurity iii. Primary hyperparathyroidism iv. Maternal factors a) Vitamin D deficiency b) Poorly controlled hyperparathyroidism c) Poorly controlled renal insufficiency b. Older than 6 months of age i. Nutritional rickets in children a) Inadequate levels (deficiency) of vitamin D due to either inadequate oral intake or insufficient exposure to sunlight b) With resultant decreased calcium absorption in the small intestine c) Thereby decreasing the available calcium for epiphyseal cartilage and skeletal mineralization d) Secondary hyperparathyroidism due to limited calcium availability and attendant renal phosphate losses contributes to the bone and growth plate pathophysiology that lead to the clinical manifestations of rickets ii. Liver disease (impaired 25-vitamin D formation) a) Chronic liver diseases (extrahepatic biliary atresia, total parenteral nutrition, tyrosinemia) b) Anticonvulsant therapy iii. Malabsorption a) Celiac disease b) Inflammatory bowel disease c) Pancreatic insufficiency iv. Renal tubular insufficiency (hypophosphatemia) a) Vitamin D resistant rickets b) Vitamin D dependent rickets c) Fanconi syndrome d) Lowe syndrome e) Cystine storage disease v. Chronic renal disease (renal osteodystrophy) a) Pyelonephritis b) Polycystic kidney disease c) Chronic glomerulonephritis d) Renal tubular acidosis 844

2. Vitamin D deficiency rickets: caused by low endogenous vitamin D a. Selected pediatric populations at high risk for vitamin D deficiency i. Dietary factors (breast-fed infants with marginal calcium stores due to low levels of vitamin D in breast milk) ii. Skin pigmentation (African American children due to dark skin absorbing ultraviolet radiation less available for vitamin D production) iii. Sun screen application iv. Insufficient sun exposure (far northern latitudes, during the winter months, cultural traditions) b. Other predisposing factors i. Severe liver failure ii. Nephrotic syndrome iii. Severe malnutrition iv. Gastrointestinal diseases leading to malabsorption, including impaired fat absorption or enterohepatic recirculation 3. Familial hypophosphatemic rickets: caused by defect in reabsorption of phosphate in the proximal tubule, resulting in hypophosphatemia, defective bone mineralization, normocalcemic rickets and short stature a. Dominant X-linked hypophosphatemic rickets (also called vitamin D-resistant rickets) i. The gene locus: mapped to Xp22.1 ii. The gene responsible: phosphate regulating (PHEX) gene with homologies to endopeptidases in the X chromosome iii. Complete penetrance b. Autosomal dominant hypophosphatemic rickets i. The gene locus: mapped to 12p13 ii. Incomplete penetrance 4. Vitamin D-dependent rickets: caused by reduced activity of 25(OH)1-alphahydroxylase a. Vitamin D-dependent rickets type I (1-alpha-hydroxylase mutation): also known as hereditary pseudovitamin D deficiency rickets i. Autosomal recessive disorder ii. Commonly found in the French Canadian population iii. The gene locus mapped to chromosome 12q14 iv. Caused by mutation in the vitamin D 1-alphahydroxylase gene v. Impaired 1 alpha-hydroxylation in the renal proximal tubule that converts 25(OH)D to 1,25(OH)2D b. Vitamin D-dependent rickets type II (receptor mutation): also known as hereditary vitamin D-resistant rickets i. Autosomal recessive inheritance ii. Caused by mutations in the vitamin D receptor (VDR) that result in end-organ resistance to

RICKETS

active vitamin D (1,25-dihydroxyvitamin D) [1,25-(OH)2D3] iii. Major defect caused by the mutant VDR: a decrease of intestinal calcium and phosphate absorption which leads to decreased bone mineralization and rickets iv. The major biochemical distinction between type I and type II a) Low circulating 1,25(OH)2D levels in patients with type I b) High circulating 1,25(OH)2D levels in patients with type II

CLINICAL FEATURES 1. Rickets vs osteomalacia a. Rickets: occur only before fusion of the epiphyses b. Osteomalacia: occur in adults deficient in calcium, phosphate, or vitamin D 2. Signs of rickets in osseous tissues a. Craniotabes in newborn baby and young infant i. Softening of skull bones ii. May be present but not pathognomonic b. Frontal bossing in early infancy i. Expansion of cranial bones relative to facial bones ii. Also possibly due to hydrocephalus (“rickets hydrocephalus”) c. Fontanelle i. Delayed closure ii. Occasional intracranial hypertension d. Wrists: an apparent bracelet of bone around the wrist (specificity 81%) e. Rickety rosary: swollen costochondral junctions of ribs (specificity 64%) f. Skeletal deformities i. Particularly “bow legs” once the child is walking ii. Genu valgum generally not due to rickets iii. Spinal curvature most likely due to nonrickets cause iv. Narrowed pelvic outlet used to cause obstructed labor g. Brown tumor: rare fibrous-cystic osteitis associated with the secondary hyperparathyroidism h. Limb pain i. Bone pain and pseudoparalysis uncommon ii. Osteomalacia and the subperiosteal hematoma of scurvy: more likely causes of pain i. Teeth i. Delayed eruption of teeth ii. Enamel hypoplasia: greater susceptibility to caries in the first dentition 3. Nonosseous effect of vitamin D deficiency a. Symptomatic hypocalcemia with convulsions: particularly in young infants less than 6 months of age born to mothers with untreated osteomalacia, many of whom are subclinical cases b. Myopathy i. Proximal myopathy in infants and adolescents ii. Heart failure simulating cardiomyopathy with severe hypocalcemia iii. Responding to treatment for rickets and inotropes

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c. Myelofibrosis i. With pancytopenia or microcytic hypochromic anemia ii. Returning to normal when treated with vitamin D d. Possible link between early vitamin D deficiency and other disorders in later life i. Type I diabetes ii. Multiple sclerosis iii. Schizophrenia iv. Hear disease e. Intrauterine and infant growth: vitamin D supplement in the last trimester of pregnancy improves growth in utero and during infancy in some studies 4. Vitamin D deficiency rickets a. Not clinically apparent before 6 months of age because of prenatal stores of vitamin D imparted by the mother b. Decreased linear growth/short stature c. Poor weight gain/small for age d. Delayed development e. Incidental finding on radiograph or physical examinations f. Nonspecific musculoskeletal complaints g. Bowing of the legs h. Seizures i. Tetany j. Weakness k. Drowsiness l. Development of secondary hyperparathyroidism due to increasing severity of vitamin D deficiency, progressing to frank osteomalacia and fractures 5. Hereditary hypophosphatemic rickets a. X-linked dominant hypophosphatemic rickets i. Disease severity similar in males and females but differs among individuals (some patients with isolated hypophosphatemia; others with disabling severe bone disease) ii. The disease may persists into adulthood iii. Short stature iv. Rickets with resultant lower-extremity deformities v. Bone pain vi. Enthesopathy (calcification of tendons, ligaments, and joint capsules) vii. Dental abscesses viii. Cranial abnormalities and spinal stenosis in some severely affected individuals b. Autosomal dominant hypophosphatemic rickets i. Isolated renal phosphate wasting ii. Short stature iii. Impressive windswept deformity (valgus on one side and varus on the other side) iv. Marked tendency for fracture with or without trauma v. Delayed onset of disease in some patients vi. Patients who present as adults: osteomalacia with bone pain, weakness, and fractures 6. Vitamin D-dependent rickets a. Vitamin D-dependent rickets type I (hereditary pseudovitamin D deficiency rickets) i. Clinical presentation within the first few months of life

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ii. First clinical sign: acute or chronic hypocalcemia because the major physiologic role of 1,25-dihydroxyvitamin D is to promote intestinal calcium absorption iii. Hypocalcemic seizures as early as 4 weeks of age or usually before 2 years of age iv. Growth retardation v. Bowing of the extremities vi. Bone pain secondary to rickets and osteomalacia vii. Enamel hypoplasia and oligodentia viii. Hypocalcemia accompanied by secondary hyperparathyroidism resulting in hypophosphatemia and occasional aminoaciduria b. Vitamin D-dependent rickets type II (hereditary vitamin D-resistant rickets) i. Onset of disease: infancy or childhood ii. Major clinical findings: hypocalcemia and rickets due to defective intestinal calcium absorption leading to impaired mineralization of newly forming bone and preosseous cartilage iii. Rickets a) Often severe b) Usually exhibits within months of birth iv. Bone pain v. Muscle weakness vi. Hypotonia vii. Occasional convulsions from hypocalcemia viii. Often growth retarded ix. Enamel hypoplasia, oligodentia, and severe dental caries x. Hypocalcemia accompanied by secondary hyperparathyroidism results in hypophosphatemia and occasional aminoaciduria. xi. Pneumonia secondary to severe rickets of the chest wall and poor respiratory effort causes death in some infants xii. Alopecia a) Sparse body hair in many patients b) Alopecia totalis observed in some kindreds, including eyebrows and in some cases eyelashes

DIAGNOSTIC INVESTIGATIONS 1. Vitamin D deficiency rickets a. Decreased levels of 25-OH vitamin D (best screening test for vitamin D stores in otherwise healthy individuals) b. Normal or increased levels of 1,25 (OH)2 vitamin D c. Increased levels of parathyroid hormone d. Decreased levels of calcium (hypocalcemia) e. Decreased levels of phosphate (hypophosphatemia) 2. Vitamin D-resistant rickets a. Renal tubular phosphate leakage and subsequent hypophosphatemia in all affected individuals b. Normal levels of 25-OH vitamin D c. Normal or decreased levels of 1,25 (OH)2 vitamin D d. Normal or increased levels of parathyroid hormone e. Normal levels of calcium f. Decreased phosphate (hypophosphatemia)

3. Vitamin D-dependent rickets a. Elevated or normal levels of 25-OH vitamin D b. Low levels of 1,25 (OH)2 vitamin D in type I and elevated levels in type II c. Normal or increased levels of parathyroid hormone d. Normal or decreased levels of calcium e. Decreased levels of phosphorous (hypophosphatemia) f. Elevated serum alkaline phosphatase activity 4. Radiographic findings a. Cupping, fraying and widening of the metaphyses: a requirement for diagnosis of rickets b. Rachitic rosary (enlargement of the wrists, knees, and rib ends) c. Bowing of the lower extremities in the newly ambulating child d. Widening and irregularity of all the physes e. Osteopenia (decreased mineralization of the bone matrix) with blurred or nonapparent cortical outlines of the epiphyseal ossification centers f. Rib flaring g. Multiple fractures in various stages of healing h. Deformities caused by softening of bone or poor muscle tone i. Femoral bowing ii. Tibial bowing iii. Genu valgum (knock knees) i. Pelvis i. Coxa valga ii. Protrusio acetabuli j. Thorax: hourglass shape k. Skull i. Postural molding ii. Frontal bossing l. The zone of provisional calcification appearing as a dense metaphyseal band due to calcium deposit in response to vitamin D therapy i. Seen as early as 2–3 weeks after initiation of therapy in children with nutritional rickets ii. Seen after 2–3 months in children with renal rickets iii. Persistence of deformities caused by bone softening despite successful treatment 5. Histological findings a. Primary metabolic abnormality at the zone of provisional calcification b. Diminished calcification of cartilage columns in the metaphysis c. Continued osteoid production by osteoblasts, but ossification of the osteoid tissue is impaired because of insufficient calcium deposition d. Widened, irregularly calcified physis resulting from resorption of osteoid and calcium because of impaired osteoclast function e. Metaphyseal broadening or “cupping” likely caused by stress at sites of ligament attachment f. Splaying of cartilage cells peripherally g. Microfractures of the primary spongiosa by herniation of cartilage into this area 6. Molecular genetic diagnosis a. X-linked dominant hypophosphatemic rickets: sequencing of entire coding region

RICKETS

b. Autosomal dominant hypophosphatemic rickets: sequencing of entire coding region c. Pseudovitamin D deficiency rickets i. Sequencing of entire coding region ii. Sequencing of select exons d. Rickets-alopecia syndrome: sequencing of entire coding region

GENETIC COUNSELING 1. Recurrence risk: depend on the etiology a. Vitamin D deficiency rickets: recurrence risk high if conditions leading to vitamin D deficiency exist b. Autosomal recessive inheritance i. Patient’s sib: 25% ii. Patient’s offspring: not increased unless the spouse is a carrier or affected c. Autosomal dominant inheritance i. Patient’s sib: not increased unless a parent is affected ii. Patient’s offspring: 50% d. X-linked dominant inheritance i. Patient’s sib: not increased unless a parent is affected ii. Patient’s offspring a) Affected female: 50% of daughters and 50% of sons will be affected b) Affected male: All daughters will be affected and all sons will be normal 2. Prenatal diagnosis a. Fetal radiography, particularly in mothers with osteomalacia i. Poorly mineralized fetal bones ii. Thin cortices of the limb bones and penciled outlines of the vertebral bodies iii. Cupped tibial/radial metaphysis with indistinct border to the epiphyseal aspect b. Fetal echocardiography i. Atrial flutter with heart failure reported in a fetus affected with X-linked dominant hypophosphatemic rickets ii. Causal relationship in this case remained unknown c. Prenatal diagnosis by molecular analysis of cultured fetal cells obtained from CVS and amniocentesis in pregnant women from high-risk families to look for disease-causing mutation, previously identified in an affected individual i. X-linked dominant hypophosphatemic rickets: sequencing of entire coding region ii. Autosomal dominant hypophosphatemic rickets: sequencing of entire coding region iii. Pseudovitamin D deficiency rickets: sequencing of entire coding region and select exons iv. Hereditary vitamin D-resistant rickets a) [3H]1,25-(OH)2D3 binding b) Induction of 24-hydroxylase activity c) RFLP analyses v. Rickets-alopecia syndrome: sequencing of entire coding region

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3. Management a. Hypocalcemia and ‘simple rickets’ i. Hypocalcemia (early infancy) a) IV calcium gluconate to control continuing seizures b) Oral calcium daily c) Oral calciferol daily d) Look for evidence of rickets in the baby (radiographs of the knees and wrists) e) Look for maternal osteomalacia (elevated maternal alkaline phosphatase) f) Slowly withdraw treatment when the plasma calcium is normal g) Continue prophylactic vitamin D thereafter ii. Rickets without hypocalcemia (early infancy): oral calciferol daily for 2–4 months iii. Older infants, toddlers, and adolescents a) Oral calciferol b) Add oral calcium if dietary deficiency may be a factor c) Phosphorus not needed in simple rickets since phosphorus is abundant in the diet d) Necessary to supplement phosphorus for very preterm babies and in the phosphatewasting causes of rickets b. Vitamin D deficiency rickets i. Increase dietary intake of vitamin D a) The new recommended adequate intake of vitamin D by the National Academy of Sciences to prevent vitamin D deficiency in normal infants, children, and adolescents is 200 IU per day b) An intake of at least 200 IU per day of vitamin D will prevent physical signs of vitamin D deficiency and maintain serum 25hydroxy-vitmin D at or above 27.5 nmol/L ii. Increased sun exposure iii. Prevent other predisposing factors c. Vitamin D-resistant rickets i. Increase dietary intake of vitamin D ii. Increased sun exposure iii. Prevent other predisposing factors d. Vitamin D-dependent rickets: life-long treatment with 1-alpha-hydroxyvitamin D or 1,25-dihydroxyvitamin D e. Dominant X-linked hypophosphatemic rickets: treat bone lesions and impaired longitudinal growth i. Vitamin D supplement ii. Oral phosphate supplement: risks of stimulating secondary hyperparathyroidism

REFERENCES Al-Khenaizan S, Vitale P: Vitamin D-dependent rickets type II with alopecia: two case reports and review of the literature. Int J Dermatol 42:682–685, 2003. Begum R, Continho ML, Dormandy TL: Maternal malabsorption presenting congenital rickets. Lancet 1:1048–1052, 1968. Bishop N: Rickets today-children still need milk and sunshine. N Engl J Med 341:602–603, 1999. Carpenter TO: New perspectives on the biology and treatment of x-linked hypophosphatemic rickets. Pediatr Clin N Am 44:443–466, 1997. Currarino GD, Neuhauser EBD, Reyersbach Genet Counsel, et al.: Hypophosphatasia. Am J Roentgenol 78:392–419, 1957.

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DeLucia MC, Mitnick ME, Carpenter TO: Nutritional rickets with normal circulating 25-hydroxyvitamin D: a call for reexamining the role of dietary calcium intake in North American infants. J Clin Endocrinol Metab 88:3539–3545, 2003. DiMeglio LA, Econs MJ: Hypophosphatemic rickets. Rev Endocr Metab Disord 2:165–173, 2001. DiMeglio LA, White KE, Econs MJ: Disorders of phosphate metabolism. Endocrinol Met Clin 29:591–609, 2000. Econs MJ, Francis F: Positional cloning of the PEX gene: new insights into the pathophysiology of X-linked hypophosphatemic rickets. Am J Physiol 273:F489–F498, 1997. Felman KW, Marcuse EK, Springer DA: Nutritional rickets. Am Fam Physician 42:1311–1318, 1990. Gartner LM, Greer FR: Prevention of rickets and vitamin D deficiency: new guidelines for vitamin D intake. Pediatrics 111:908–910, 2003. Glorieux FH, Scriver CR, Reade TM, et al.: Use of phosphate and vitamin D to prevent dwarfism and rickets in X-linked hypophosphatemia. N Engl J Med 287:481–487, 1972. Greer FR: Osteopenia of Prematurity. Annu Rev Nutr 14:169–185, 1994. Institute of Medicine, Food and Nutrition Board, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Vitamin D. In: Dietary Reference Intakes for Calcium, phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy Press; 1997: 250–287. Joiner TA, Foster C, Shope T: The many faces of vitamin D deficiency rickets. Pediatr Rev 21:296–302, 2000. Kreiter SR, Schwartz RP, Kirkman HN Jr, et al.: Nutritional rickets in African American breast-fed infants. J Pediatr 137:153–157, 2000. Kruse K: Pathophysiology of calcium metabolism in children with vitamin Ddeficiency rickets. J Pediatr 126:736–741, 1995. Landing BH, Kamoshita S: Congenital hyperparathyroidism secondary to maternal hypoparathyroidism. J Pediatr 77:842–847, 1970. Levin TL, States L, Greig A, et al.: Maternal renal insufficiency: a cause of congenital rickets and secondary hyperparathyroidism, Pediatr Radiol 22:315–316, 1992.

Malloy PJ, Pike JW, Feldman D: The vitamin D receptor and the syndrome of hereditary 1,25-dihydroxyvitamin D-resistant rickets. Endocr Rev 20:156–188, 1999. Mancrieff H, Fadahunsi T: Congenital rickets due to maternal vitamin D deficiency. Arch Dis Child 49:810–811, 1974. Norman ME: Vitamin D in bone disease. Pediatr Clin N Am 229:947–971, 1982. Pitt MJ: Rachitic and osteomalacic syndromes. Radiol Clin N Amer 19:581–599, 1981. Pitt MJ: Rickets and osteomalacia are still around. Radiol Clin North Am 29:97–118, 1991. Russell JG, Hill LF: True fetal rickets. Br J Radiol 47:732–734, 1974. Schmitt CP, Mehls O: The enigma of hyperparathyroidism in hypophosphatemic rickets. Pediatr Nephrol 19:473–477, 2004. Schneider R: Radiologic methods of evaluating generalized osteopenia. Orthop Clin N Amer 15:631–651, 1984. Smith R: The pathophysiology and management of rickets. Orthop Clin North Am 3:601–621, 1972. States LJ: Imaging of metabolic bone disease and marrow disorders in children Teitelbaum SL: Pathological manifestations of osteomalacia and rickets. Clin Endocrinol Metab 9:43–62, 1980. Thakker RV, Davies KE, Read AP, et al.: Linkage analysis of two cloned DNA sequences, DXS197 and DXS207, in hypophosphatemic rickets families. Genomics 8:189–193, 1990. The HYP Consortium: A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nat Genet 11:130–136, 1995. Thomas MK, Demay MB: Vitamin D deficiency and disorders of vitamin D metabolism. Endocrinol Metab Clin 29:611–627, 2000. Vintzileos AM, Campbell WA, Soberman SM, et al.: Fetal atrial flutter and X-linked dominant vitamin D-resistant rickets. Obstet Gynecol 65:39S–44S, 1985. Wharton B, Bishop N: Rickets. Lancet 362:1389–1400, 2003. Weisman Y, Jaccard N, Legum C, et al.: Prenatal diagnosis of vitamin D-dependent rickets, type II: response to 1,25-dihydroxyvitamin D in amniotic fluid cells and fetal tissues. J Clin Endocrinol Metab 71: 937–943, 1990.

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Fig. 2. A boy with vitamin D resistant rickets showing short stature. The radiograph shows widening, cupping, and fraying of the distal radius and ulna. Fig. 1. An infant with healing nutritional rickets. The radiograph shows femoral bowing and a healing fracture with callus formation in the right femur.

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Fig. 4. Radiograph from a patient with renal rickets shows widening, cupping, and fraying of the distal radius and ulna.

Fig. 3. Another boy with vitamin D resistant rickets.

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Fig. 6. Three sisters with hypophosphatemic rickets showing short stature and bowed legs. They have an affected father.

Fig. 5. Photomicrograph of the humerus (top) and the rib (bottom) of a female neonate who lived 43 minutes. Broad cartilage columns with many large chondrocytes are present in the metaphysis. They have broad osteoid seams and are poorly ossified. The abnormal area corresponds to the radiographic metaphyseal irregular lucency. The findings are similar to those of hypophosphatasia, though the changes are milder. The cause of congenital rickets in this case is unknown. The mother did not have history of malabsorption, vitamin D intake deficiency, renal failure or preeclampsia.

Fig. 7. Two sisters and a brother with hypophosphatemic rickets showing short stature. The brother had severe short stature and bowed legs. The oldest sister had surgeries on her legs to correct the lower leg deformities. The middle sister was mildly affected. Their mother was affected.

Roberts Syndrome Roberts syndrome is a rare hereditary disorder characterized by symmetrical reduction of all limbs and a unique cytogenetic abnormality of premature centromere separation, which disrupts the process of chromatid pairing.

GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. Associated with unique cytogenetic abnormality: premature centromere separation a. Disrupts the process of chromatid pairing b. Responsible for the development of multiple structural anomalies observed in Roberts syndrome 3. Caused by mutations in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion

CLINICAL FEATURES 1. Craniofacial malformations: marked variability a. Bilateral cleft lip and cleft palate in severe cases b. No clefting of the lip or palate in some cases c. Hypertelorism secondary to widely spaced obits d. Ophthalmic manifestations i. Exophthalmos due to shallow orbits ii. Microphthalmia iii. Peter anomaly iv. Cloudy cornea v. Cataracts e. Wide nasal bridge f. Hypoplastic nasal alae g. Hemangiomata of the lip, nose, face, or forehead h. Micrognathia i. Dark scalp hair becomes thin and silvery blond 2. Limb defects a. Phenotype varies from a complete absence of arms and legs with rudimentary digits to mild growth reduction in the limbs. b. Limb reduction defects tend to be symmetric and more severely involved in the upper extremities than the lower extremities. c. Presence of phocomelia i. Tetraphocomelia: a prominent characteristic of the syndrome ii. Two deficient limbs in 11% of cases iii. No phocomelia in 2% of cases d. Often reduced number of fingers (oligodactyly) e. Radial aplasia or dysplasia common f. Lack of 1st metacarpal, thumb, or first phalanx 3. Other associated anomalies a. CNS anomalies i. Mental retardation ii. Microcephaly 852

iii. Hydrocephalus iv. Absent olfactory lobes v. Calcification of the basal ganglia vi. Encephalocele vii. Cranial nerve paralysis viii. Seizures b. Congenital heart defects i. Atrial septal defect ii. Patent ductus arteriosus iii. Pulmonic stenosis iv. Aortic stenosis v. AV canal defect c. Renal anomalies i. Polycystic kidneys ii. Dysplastic kidneys iii. Horseshoe kidney iv. Hydronephrosis v. Renal agenesis d. Gastrointestinal obstruction e. Splenogonadal fusion f. Cryptorchidism g. Enlarged phallus h. Failure to thrive i. Neoplasms i. Sarcoma botryoides ii. Malignant melanoma 4. Prognosis a. Severe cases i. Often resulting in spontaneous abortions or stillbirths ii. Few cases survive past one month of life b. Phenotypically milder cases i. Requiring minimal to full time care depending on the degree of mental retardation ii. May require surgical interventions to correct craniofacial and limb anomalies 5. Differential diagnosis a. SC phocomelia i. Clinical characteristics a) Tetraphocomelia b) Silvery blond hair c) Facial hemangioma d) Hypoplastic nasal alae ii. Originally thought to differ from Roberts syndrome by: a) Usual absence of midfacial clefting b) Prolonged survival c) Lesser degree of mental and physical retardation d) Relatively milder degree of phocomelia iii. Now considered to be the same entity as Roberts syndrome (Roberts-SC phocomelia syndrome)

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b. TAR syndrome i. Absent radii with thumbs present ii. Hypomegakaryocytic thrombocytopenia iii. Absent cleft palate

DIAGNOSTIC INVESTIGATIONS 1. Cytogenetics a. Distinctive abnormality of the constitutive heterochromatin (the RS effect): premature centromere separation (PCS) i. Detected in: a) Fibroblasts and lymphocytes in neonates b) Chorionic villi and amniocytes in the fetus ii. Consists of “puffing” or “repulsion” of the constitutive heterochromatin a) Chromosome puffing most obvious at the large heterochromatic regions of chromosomes 1, 9, and 16 b) Chromosome repulsion most evident at the short arms of the acrocentrics and the distal long arm of the Y chromosome iii. A “rail-road-track” or “tram-track” appearance of the sister chromatids due to the absence of a constriction at the centromere in several other chromosomes a) This phenomenon, called heterochromatin repulsion, is observed in cells of different tissue origin with several chromosomes in each metaphase showing a visible abnormality b) Most evident in chromosomes containing the largest amount of heterochromatin b. Sporadic aneuploidy noted with the pattern of aneuploidy different in each patient. The possible relationship between centromere “splaying” and aneuploidy has yet to be determined c. Normal karyotypes lacking any microdeletion or chromosomal rearrangement from either leukocytes or fibroblasts in about a fifth of all cases 2. Radiography for phocomelia evaluation a. Absence of the radius and fibula: the most common skeletal abnormalities in the upper and lower limbs b. Absent, short, deformed and /or hypoplastic ulna and tibia: the second most common bone defects c. Absent, short, deformed or hypoplastic humerus and femur: the third and least common abnormalities 3. Echocardiography for congenital heart defect 4. Renal ultrasound for renal anomalies 5. MRI of the brain for CNS anomalies

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not increased (not surviving to reproduction in severe cases) 2. Prenatal diagnosis for pregnancies at risk a. Ultrasonography i. Intrauterine growth retardation ii. Bilateral phocomelia (tetraphocomelia in majority of cases) of varying degree

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iii. Cleft lip and palate iv. Associate anomalies a) Hydrocephalus b) Congenital heart defects c) Renal anomalies b. Confirmed by characteristic disjunction of centromeres in amniocytes or CVS 3. Management a. Special education b. Cornea grafting c. Corrective surgery i. Cleft lip/palate ii. Limb defects d. Prosthetic devices i. For underdeveloped or missing limbs ii. Used to increase independence

REFERENCES Benzacken B, Savary JB, Manouvrier S, et al.: Prenatal diagnosis of Roberts syndrome: two new cases. Prenat Diagn 16:125–130, 1996. Concolino D, Sperli D, Cinti R, et al.: A mild form of Roberts/SC phocomelia syndrome with asymmetrical reduction of the upper limbs. Clin Genet 49:274–276, 1996. de Ravel TJ, Seftel MD, Wright CA: Tetra-amelia and splenogonadal fusion in Roberts syndrome. Am J Med Genet 68:185–189, 1997. Freeman MV, Williams DW, Schimke RN, et al.: The Roberts syndrome. Birth Defects Orig Artic Ser 10:87–95, 1974. Freeman MV, Williams DW, Schimke RN, et al.: The Roberts syndrome. Clin Genet 5:1–16, 1974. Fryns JP, Kleczkowska A, Moerman P, et al.: The Roberts tetraphocomelia syndrome: identical limb defects in two siblings. Ann Genet 30:243–245, 1987. German J: Roberts’ syndrome. I. Cytological evidence for a disturbance in chromatid pairing. Clin Genet 16:441–447, 1979. Herrmann J, Opitz JM: The SC phocomelia and the Roberts syndrome: nosologic aspects. Eur J Pediatr 125:117–134, 1977. Holden KR, Jabs EW, Sponseller PD: Roberts/pseudothalidomide syndrome and normal intelligence: approaches to diagnosis and management. Dev Med Child Neurol 34:534–539, 1992. Holmes-Siedle M, Seres-Santamaria A, Crocker M, et al.: A sibship with Roberts/SC phocomelia syndrome. Am J Med Genet 37:18–22, 1990. Hwang K, Lee DK, Lee SI, et al.: Roberts syndrome, normal cell division, and normal intelligence. J Craniofac Surg 13:390–394, 2002. Jabs EW, Tuck-Muller CM, Cusano R, et al.: Centromere separation and aneuploidy in human mitotic mutants: Roberts syndrome. Prog Clin Biol Res 318:111–118, 1989. Jabs EW, Tuck-Muller CM, Cusano R, et al.: Studies of mitotic and centromeric abnormalities in Roberts syndrome: implications for a defect in the mitotic mechanism. Chromosoma 100:251–261, 1991. Karabulut AB, Aydin H, Erer M, et al.: Roberts syndrome from the plastic surgeon’s viewpoint. Plast Reconstr Surg 108:1443–1445, 2001. Keppen LD, Gollin SM, Seibert JJ, et al.: Roberts syndrome with normal cell division. Am J Med Genet 38:21–24, 1991. Lenz WD, Marquardt E, Weicker H: Pseudothalidomide syndrome. Birth Defects 10:97–107, 1974. Lopez-Allen G, Hutcheon RG, Shaham M, et al.: Picture of the month. Roberts-SC phocomelia syndrome. Arch Pediatr Adolesc Med 150:645–646, 1996. Louie E, German J: Roberts’s syndrome. II. Aberrant Y-chromosome behavior. Clin Genet 19:71–74, 1981. Mann NP, Fitzsimmons J, Fitzsimmons E, et al.: Roberts syndrome: clinical and cytogenetic aspects. J Med Genet 19:116–119, 1982. Maserati E, Pasquali F, Zuffardi O, et al.: Roberts syndrome: phenotypic variation, cytogenetic definition and heterozygote detection. Ann Genet 34:239–246, 1991. Ota˜no L, Matayoshi T, Gadow EC: Roberts syndrome: first-trimester prenatal diagnosis. Prenat Diagn 16:770–771, 1996. Paladini D, Palmieri S, Lecora M, et al.: Prenatal ultrasound diagnosis of Roberts syndrome in a family with negative history. Ultrasound Obstet Gynecol 7:208–210, 1996.

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Parry DM, Mulvihill JJ, Tsai S, et al.: SC phocomelia syndrome, premature centromere separation, and congenital cranial nerve paralysis in two sisters, one with malignant melanoma. Am J Med Genet 24:653–672, 1986. Qazi OH, Kassner EG, Masakawa A, et al.: The SC phocomelia syndrome: report of two cases with cytogenetic abnormality. Am J Med Genet 4:231–238, 1979. Roberts JB: A child with double cleft of lip and palate, protrusion of the intermaxillary portion of the upper jaw and imperfect development of the bones of the four extremities. Ann Surg 70:252–253, 1919. Robins DB, Ladda RL, Thieme GA, et al.: Prenatal detection of Roberts-SC phocomelia syndrome: report of 2 sibs with characteristic manifestations. Am J Med Genet 32:390–394, 1989. Römke C, Froster-Iskenius U, Heyne K, et al.: Roberts syndrome and SC phocomelia. A single genetic entity. Clin Genet 31:170–177, 1987. Sherer DM, Shah YG, Klionsky N, et al.: Prenatal sonographic features and management of a fetus with Roberts-SC phocomelia syndrome (pseudothalidomide syndrome) and pulmonary hypoplasia. Am J Perinatol 8:259–262, 1991.

Sinha AK, Verma RS, Mani VJ: Clinical heterogeneity of skeletal dysplasia in Roberts syndrome: a review. Hum Hered 44:121–126, 1994. Stioui S, Privitera O, Brambati B, et al.: First-trimester prenatal diagnosis of Roberts syndrome. Prenat Diagn 12:145–149, 1992. Stoll C, Levy JM, Beshara D: Roberts’s syndrome and clonidine. J Med Genet 16:486–487, 1979. Tomkins D, Hunter A, Roberts M: Cytogenetic findings in Roberts-SC phocomelia syndrome(s). Am J Med Genet 4:17–26, 1979. Tomkins DJ: Premature centromere separation and the prenatal diagnosis of Roberts syndrome. Prenat Diagn 9:450–452, 1989. Urban M, Opitz C, Bommer C, et al.: Bilaterally cleft lip, limb defects, and haematological manifestations: Roberts syndrome versus TAR syndrome. Am J Med Genet 79:155–160, 1998. Van Den Berg DJ, Francke U: Roberts syndrome: a review of 100 cases and a new rating system for severity. Am J Med Genet 47:1104–1123, 1993. Vega H, Waisfisz Q, Gordillo M, et al.: Roberts syndrome is caused by mutation in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion. Nature Genet Online 10 April 2005, pp. 1–3.

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Fig. 1. The G-banded metaphase spread from fibroblast culture of a male infant with Roberts syndrome showing characteristic heterochromatin separation: puffing of the centromeric heterochromatin of some chromosomes and splaying of the Yqh region (arrows). The patient had profound psychomotor retardation, corneal clouding, and tetraphocomelia.

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Fig. 2. A newborn with Roberts syndrome variant showing bilateral cleft lip and cleft palate, phocomelia, club hands with an appendage-like thumb on the right and a missing thumb on the left. The infant also had intrauterine growth retardation, hydrocephalus, cloudy cornea, AV canal heart defect, and normal lower extremities. Cytogenetic studies revealed no premature centromere separation. The mother took Diflucan during pregnancy and the teratogenic etiology was a possibility.

Robinow Syndrome In 1969, Robinow et al. described a new dwarfing syndrome characterized by mesomelic shortening of extremities, hemivertebrae, genital hypoplasia, and “fetal facies”. The incidence is estimated to be approximately 1 in 500,000.

2.

GENETICS/BASIC DEFECTS 1. Autosomal recessive form a. Phenotype tends to be more severe than the autosomal dominant form b. Caused by different homozygous missense, nonsense, and frameshift mutations of the ROR2 gene c. ROR2 gene i. Mapped to chromosome 9q22 ii. Encoding an orphan receptor tyrosine kinase 2 with orthologues in mouse and other species iii. Allelic to dominant brachydactyly type B (characterized by terminal deficiency of fingers and toes) 2. Autosomal dominant form: uncertain whether it is caused by mutations in ROR2 or caused by mutations in a different gene

3.

4.

CLINICAL FEATURES 1. Characteristic craniofacial appearance a. Early childhood i. Midfacial hypoplasia ii. Occasional midline capillary hemangioma iii. Eyes a) Marked hypertelorism b) Prominent eyes giving appearance of exophthalmos (pseudoexophthalmos) iv. A short upturned nose v. Mouth a) “Tented” upper lip having an inverted V appearance with tethering in the center b) Midline clefting of the lower lip c) Gum hypertrophy at birth d) Dental crowding/irregular teeth e) “Tongue tie” (ankyloglossia) resembling a bifid tongue when the tongue tie is marked vi. Ears a) Low set b) Simple c) Deformed pinna vii. Resemblance to a fetal face a) Relatively small face b) Laterally displaced eyes c) Forward pointing alae nasi d) “Fetal facies” becomes less prominent over time b. Adulthood i. Loss of fetal facial proportions 856

5.

6.

ii. Absent midfacial hypoplasia iii. Persistent hypertelorism with a broad nasal root and broad forehead Short stature a. Reduced birth length b. Not an universal finding with some reports of normal growth Limb abnormalities a. Mesomelic or acromesomelic limb shortening b. Shortening of the forearms more striking than the shortening of the legs c. Occasional Madelung deformity d. Hands/feet i. Brachydactyly with shortening of the distal phalanx and nail hypoplasia or dystrophy ii. Thumbs a) Displaced b) Occasionally bifid c) Partial cutaneous syndactyly d) Ectrodactyly (especially patients reported from Turkey) Other skeletal abnormalities a. Chest deformities b. Kyphoscoliosis c. Vertebral anomalies d. Rib defects e. Pectus excavatum f. Acrodysostosis g. Delayed bone age Genital hypoplasia a. Genital abnormalities: may be present at birth causing concern regarding gender assignment i. Males a) Micropenis b) Normal scrotum and testes ii. Females a) Reduced clitoral size b) Hypoplasia of the labia minor c) Associated vaginal atresia and hematocolpos iii. Onset of puberty normal in both sexes iv. Several reports of both male and female patients having normal children Congenital heart defects (15%) a. Severe pulmonary stenosis or atresia (the most common cardiac abnormalities) b. Atrial septal defect c. Ventricular septal defect d. Coarctation of the aorta e. Bicuspid aortic valve f. Tetralogy of Fallot g. Tricuspid atresia h. Double outlet right ventricle i. Patent ductus arteriosus

ROBINOW SYNDROME

7. Renal abnormalities a. Hydronephrosis (relatively common) b. Cystic dysplasia of the kidney 8. Developmental delay but intelligence is usually normal 9. Dermatoglyphics a. Absent interphalangeal creases b. Bilateral transverse creases c. Hypothenar whorl pattern 10. Clinical characteristics of recessive Robinow syndrome: more frequently manifests orthopedic involvement (vertebral/rib anomalies and more severe mesomelic brachymelia) than the dominant form a. Short stature b. Mesomelic and acromelic brachymelia c. Thick abnormally modeled radius and ulna d. Characteristic face i. Hypertelorism ii. Wide palpebral fissures iii. Broad based nose with everted nares iv. Large mouth v. Gum hypertrophy vi. Irregular and crowded teeth e. Costovertebral anomalies f. Endocrine dysfunction i. Empty sella ii. Partial insensitivity of Leydig cells to HCG iii. Low basal testosterone in prepubertal boys iv. Defective sex-steroid feedback mechanism g. Micropenis in males 11. Differential diagnosis of mesomelic dwarfism a. With Madelung deformity: dyschondrosteosis b. With malformations of long bones depending on various distribution/severity patterns and types of transmission i. Ulno-fibular a) With mild triangular deformity b) With extreme variety: Boomerang bone disease ii. Radio-tibial with “normal” fibula iii. Ulno-fibular-mandibular (Langer type, homozygous dyschondrosteosis) iv. Ulno-radio-fibular-tarsal with square, triangular or rhomboid tibia v. Ulno-radio-tibial with absent fibula c. With associated malformations of spine i. Robinow syndrome ii. Wegmann syndrome iii. Campallia and Martinelli syndrome iv. “Spondylo-epiphyso-metaphyseal” d. With acrodysplasia i. Acromesomelic dwarfism ii. Ellis-van Creveld syndrome iii. Grebe achondrogenesis

DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Skull i. Macrocephaly ii. Prominent forehead iii. Hypertelorism

2. 3. 4. 5.

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iv. Hypoplastic mandible v. Dental anomalies b. Spine/ribs: widespread fusion of thoracic vertebrae with frequent hemivertebrae and fusion of the ribs, resembling Jarcho-Levin syndrome (spondylocostal dysostosis) in severe cases (autosomal recessive form) i. Hemivertebrae and vertebral fusions ii. Fusion of ribs iii. Shortened interpeduncular distance c. Extremities (long bones): mesomelic shortening i. Upper extremities ii. Lower extremities iii. Ulna shorter than radius iv. Luxation of the radius d. Hands and feet i. Brachymesophalangism of fifth digits ii. Clinodactyly of the fifth digits iii. Shortening of other phalanges iv. Brachymetacarpism v. Fusion of carpal bones vi. Bifid terminal phalanges (splitting of one or more distal phalanges) vii. Fusion of phalanges viii. Retarded bone age Renal ultrasound for renal anomalies Echocardiography for congenital heart disease Growth hormone assay for possible growth hormone deficiency DNA mutation analysis by sequencing of entire coding region of ROR2 gene

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Autosomal dominant inheritance: not increased unless a parent is affected ii. Autosomal recessive inheritance: 25% b. Patient’s offspring i. Autosomal dominant inheritance: 50% ii. Autosomal recessive inheritance: not increased unless the spouse is a carrier 2. Prenatal diagnosis possible by ultrasonography: measure the length of the long bones and the ulna/humerus ratio for the fetus at risk. Prenatal diagnosis is also possible by sequencing of entire coding region of ROR2 gene on fetal DNA obtained by amniocentesis or CVS, provided disease-causing alleles have been previously identified in the proband. 3. Management a. Anticipate difficult intubation because of midfacial hypoplasia b. Orthopedic care for vertebral anomalies and hip dislocation c. Orthodontics for dental malalignment d. Surgery for cleft lip and palate, inguinal hernia and undescended testes e. Growth hormone therapy if associated with growth hormone deficiency f. Testosterone therapy for micropenis not proven useful g. Psychologic support

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REFERENCES Afzal AR, Rajab A, Fenske C, et al.: Linkage of recessive Robinow syndrome to a 4 cm interval on chromosome 9q22. Hum Genet 106:351–354, 2000. Afzal AR, Rajab A, Fenske C, et al.: Autosomal recessive Robinow syndrome is allelic to dominant brachydactyly type B and caused by loss of function mutations in ROR2. Nat Genet 25:419–422, 2000. Afzal AR, Jeffery S: One gene, two phenotypes: ROR2 mutations in autosomal recessive Robinow syndrome and autosomal dominant brachydactyly type B. Human Mutat 22:1–11, 2003. Al-Ata J, Paquet M, Teebi AS. Congenital heart disease in Robinow syndrome. Am J Med Genet 77:332–333, 1998. Atalay S, Ege B, Imamoglu A, et al.: Congenital heart disease and Robinow syndrome. Clin Dysmorphol 2:208–210, 1993. Butler MG, Wadlington WB: Robinow syndrome: report of two patients and review of literature. Clin Genet 31:77–85, 1987. Castells S, Chakurkar A, Qazi Q, et al.: Robinow syndrome with growth hormone deficiency: treatment with growth hormone. J Pediatr Endocrinol Metab 12:565–571, 1999. Giedion A, Battaglia GF, Bellini F, et al.: The radiological diagnosis of the fetal-face (= Robinow) syndrome (mesomelic dwarfism and small genitalia). Report of 3 cases. Helv Paediatr Acta 30:409–423, 1976. Kantaputra PN, Gorlin RJ, Ukarapol N, et al.: Robinow (fetal face) syndrome: report of a boy with dominant type and an infant with recessive type. Am J Med Genet 84:1–7, 1999. Kawai M, Yorifuji T, Yamanaka C, et al.: A case of Robinow syndrome accompanied by partial growth hormone insufficiency treated with growth hormone. Horm Res 48:41–43, 1997. Lee PA, Migeon CJ, Brown TR, et al.: Robinow’s syndrome. Partial primary hypogonadism in pubertal boys, with persistence of micropenis. Am J Dis Child 136:327–330, 1982.

Lovero G, Guanti G, Caruso G, et al.: Robinow’s syndrome: prenatal diagnosis. Prenat Diagn 10:121–126, 1990. Patton MA, Afzal AR: Robinow syndrome. J Med Genet 39:305–310, 2002. Percin EF, Guvenal T, Cetin A, et al.: First-trimester diagnosis of Robinow syndrome. Fetal Diagn Ther 16:308–311, 2001. Robinow M, Silverman FN, Smith HD. A newly recognized dwarfing syndrome. Am J Dis Child 117:645–651, 1969. Robinow M. The Robinow (fetal face) syndrome: a continuing puzzle. Clin Dysmorphol 2:189–198, 1993. Schorderet DF, Dahoun S, Defrance I, et al.: Robinow syndrome in two siblings from consanguineous parents. Eur J Pediatr 151:586–589, 1992. Soliman AT, Rajab A, Alsalmi I, et al.: Recessive Robinow syndrome: with emphasis on endocrine functions. Metabolism 47:1337–1343, 1998. Teebi AS: Autosomal recessive Robinow syndrome. Am J Med Genet 35:64–68, 1990. van Bokhoven H, Celli J, Kayserili H, et al.: Mutation of the gene encoding the ROR2 tyrosine kinase causes autosomal recessive Robinow syndrome. Nat Genet 25:423–426, 2000. (Erratum in Nat Genet 26:383, 2000.) Wadlington WB, Tucker VL, Schimke RN: Mesomelic dwarfism with hemivertebrae and small genitalia (the Robinow syndrome). Am J Dis Child 126:202–205, 1973. Webber SA, Wargowski DS, Chitayat D, et al.: Congenital heart disease and Robinow syndrome: coincidence or an additional component of the syndrome? Am J Med Genet 37:519–521, 1990. Wiens L, Strickland DK, Sniffen B, et al.: Robinow syndrome: report of two patients with cystic kidney disease. Clin Genet 37:481–484, 1990. Wilcox DT, Quinn FM, Ng CS, et al.: Redefining the genital abnormality in the Robinow syndrome. J Urol 157:2312–2314, 1997.

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Fig. 1. A child with Robinow syndrome showing prominent forehead, ocular hypertelorism, short upturned nose, pectus excavatum, penile hypoplasia, and acromesomelic shortening of the limbs.

Rubinstein-Taybi Syndrome In 1963, Rubinstein and Taybi described a new syndrome characterized by broad thumbs and toes, facial abnormalities, and mental retardation. The prevalence of Rubinstein-Taybi syndrome is estimated to be 1 in 100,000 to 125,000 live births in the Netherlands.

GENETICS/BASIC DEFECTS 1. Inheritance: autosomal dominant 2. Caused by deletions or heteroallelic mutations of CREBBP, the gene for cAMP responsive element binding (CREB) protein, which resides on chromosome 16p13.3. CREBBP is a large nuclear protein involved in transcription regulation, chromatin remodeling, and the integration of several different signal transduction pathways. The following mutations of CREBBP were reported in patients with RubinsteinTaybi syndrome: a. Chromosomal translocations/inversions b. Deletions at the microscopic and submicroscopic level c. Molecular mutations 3. Mutations in the CREBBP gene are responsible for: a. Rubinstein-Taybi syndrome b. t(8;16)-associated acute myeloid leukemia 4. No clear phenotypic differences observed between patients in which microdeletions or truncating mutations were found

CLINICAL FEATURES 1. Characteristic craniofacial features a. Microcephaly (35–94%) b. Prominent forehead c. Down-slanting palpebral fissures d. Apparent ocular hypertelorism e. High-arched or heavy eyebrows f. Long eyelashes g. Epicanthal folds h. Prominent nose with columella (lower margin of the nasal septum) below the alae nasi i. Malpositioned ears with dysplastic helices j. Grimacing smile k. Hypoplastic maxilla l. Mild retrognathia m. High arched palate 2. Skeletal abnormalities a. Thumbs i. Broad terminal phalanges ii. Severe radial angulation deformity (“hitch-hiker thumbs”) with abnormal shape of proximal phalanx, which prevents opposition and functional gripping strength b. Great toes i. Broad terminal phalanges 860

3. 4. 5. 6.

7.

ii. Angulation deformity with abnormal shape of proximal phalanx or first metatarsal iii. Duplicated proximal phalanx iv. Duplicated distal phalanx c. Short stature (78%) d. 5th finger clinodactyly e. Overlapping toes f. Broad terminal phalanges of other fingers g. Pelvic anomalies i. Flat acetabular angles ii. Flaring of the ilia iii. Notch in the ischia h. Stiff gait i. Lax ligaments j. Hyperextensible joints k. Vertebral anomalies i. Spina bifida ii. Kyphosis iii. Lordosis iv. Scoliosis l. Sternal or rib anomalies i. Premature fusion ii. Simian sternum iii. Pectus excavatum or carinatum iv. Forked ribs v. Cervical ribs vi. Fusion of the first and second ribs History of maternal polyhydramnios (39%) Hypotonia Developmental delay Variable mental retardation a. Severe in some patients b. Moderate degree in many patients c. Mild in some patients Behavioral/psychiatric disorders a. Childhood i. Short attention span ii. Impulsiveness iii. Clinically nonsignificant stereotype iv. Withdrawal v. Nonspecific ‘maladaptive behavior’ vi. Repetitive motions vii. Resistance to change viii. Distractibility ix. Aggressive outbursts x. Difficulty in sleeping b. Adulthood i. Mood disorders ii. Chronic motor tic disorder iii. Obsessive compulsive disorder iv. Depressive disorder v. Bipolar disorder vi. Tourette disorder

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8. 9.

10.

11.

12.

13.

14.

vii. Trichotillomania viii. Pervasive developmental disorder ix. Self-injurious behaviors x. Autistic features Seizures (27–28%) Ophthalmologic problems a. Strabismus (60–71%) with subsequent risk of amblyopia b. Refractive errors (41–56%) c. Lacrimal duct obstructions (38–47%) d. Ptosis (29–32%) e. Coloboma (9–11%) f. Duane retraction syndrome (8%) g. Ghost vessels h. Peters anomaly i. Optic nerve hypoplasia j. Cataracts k. Corneal opacities l. Congenital glaucoma m. Retinal abnormalities Dental manifestations (67%) a. Talon cusps of secondary dentition b. Crowding and malpositioned teeth c. Anterior and posterior crossbites secondary to a narrow palate or jaw size discrepancy d. Natal teeth e. Gingivitis f. Hypo/hyperdontia g. Increased rate of carries Upper airway obstruction during sleep due to: a. Hypotonia b. Anatomy of the oropharynx and airway i. Small nasal passages ii. Retrognathia iii. Micrognathia iv. Hypertrophy of the tonsils and adenoids v. Obesity Gastrointestinal problems a. Significant gastroesophageal reflux b. Feeding difficulties c. Constipation Congenital heart disease (24–38%) a. ASD b. VSD c. PDA d. Coarctation of the aorta e. Pulmonary stenosis f. Bicuspid aortic valve g. Pseudotruncus h. Aortic stenosis i. Hypoplastic left heart syndrome j. Complex congenital heart defects k. Dextrocardia l. Vascular rings m. Conduction problems Renal anomalies (52%) a. Hydronephrosis b. Duplications c. Vesicoureteral reflux d. Urinary tract infections

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e. Renal stones f. Nephrotic syndrome g. Neurogenic bladder 15. Cutaneous manifestations a. Tendency of keloid and hypertrophic scar formation b. Ingrown toenails c. Toenail paronychia (44%) d. Fingernail paronychia (9%) e. Pilomatrixomas f. Capillary hemangioma i. Forehead ii. Nape of the neck iii. Back g. Supernumerary nipples h. Hirsutism i. Transverse palmar creases j. Deep plantar crease between the first and second toes 16. Orthopedic problems a. Hypotonia b. Lax ligaments c. Tight heel cords d. Elbow abnormalities e. Legg-Perthes disease (3%) f. Dislocated patella (2.5%) g. Congenital hip dislocation (1.4%) h. Slipped capital femoral epiphysis (0.6%) i. Congenital or acquired scoliosis, kyphosis, and lordosis j. An increased risk of associated thickened filum terminale, tethering of the cord, and lipoma k. An increased risk of fractures 17. An increased risk of having benign and malignant tumors as well as leukemia and lymphoma a. Oligodendroglioma b. Medulloblastoma c. Neuroblastoma d. Meningioma e. Pheochromocytoma f. Nasopharyngeal rhabdomyosarcoma g. Leiomyosarcoma h. Seminoma i. Embryonal carcinoma j. Odontoma k. Choristoma l. Dermoid cyst m. Pilomatrixomas

DIAGNOSTIC INVESTIGATIONS 1. 2. 3. 4. 5. 6. 7. 8.

Developmental evaluation Echocardiography for cardiac defects Ophthalmologic examination Renal ultrasound Voiding cystourethrogram Hearing evaluation EEG abnormalities Radiography a. Hands i. Broad 1st distal phalanx ii. Broad 1st ray iii. Duplicated 1st distal phalanx

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iv. Delta-shaped proximal phalanges of the thumbs v. Mushroom-shaped distal phalanges vi. Angulation of the distal phalanges vii. Thin tubular bones viii. Delayed bone age (74%) b. Feet i. Broad 1st distal phalanx ii. Broad 1st ray iii. Duplicated 1st distal phalanx iv. Duplicated 1st proximal and distal phalanx v. Delta-shaped 1st proximal phalanx. A duplicated longitudinal bracketed epiphysis (“kissing delta” phalanx) always involve the proximal phalanx of the great toe vi. Angulation deformity of the hallux vii. Mushroom-shaped distal phalanges viii. Very small distal phalanges ix. Thin tubular bones x. Protruding calcaneus xi. Synostosis of cuneiform ossicles xii. Proximally split 5th metatarsal bone c. Limbs i. Thin tubular bones ii. Fractures iii. Patella luxations d. Spine i. Cervical hyperkyphosis ii. Lumbar hyperlordosis iii. Scoliosis iv. Spina bifida occulta: cervical or lumbosacral v. Spondylolisthesis vi. Irregular thoracic endplates e. Skull i. Microcephaly ii. Absent sinus frontalis iii. Deviated nasal septum iv. Steep skull base v. Abnormally-shaped sella turcica vi. Foramina parietale permagna vii. Prominent digital marking f. Thorax i. Narrow thoracic aperture ii. 11 ribs iii. Fusion of ribs iv. High diaphragm g. Pelvis i. Small iliac wings ii. Flaring iliac wings iii. Irregularly formed acetabulum iv. Symphysiolysis 9. Diagnosis of Rubinstein-Taybi syndrome a. Made primarily by clinical examination b. Confirmed by the presence of microdeletion 10. Cytogenetic analysis a. FISH analysis with cosmids from the CBP region to detect chromosome 16p13.3 b. Chromosome abnormalities i. t(2;16)(p13.3;p13.3) ii. t(7;16)(q34;p13.3) iii. Inv(16)(p13.3q13)

11. Mutation analysis of CREBBP gene a. SSCP b. Genomic sequencing c. Protein truncation test (10% of cases) d. Fluorescent in situ hybridization (FISH) probes i. Specific for chromosome region 16p13.3 ii. Containing regions of the cyclic AMP-responsive element-binding protein gene (CBP gene) iii. Microdeletions identified in approximately 10% of patients by five cosmid probes containing almost the entire gene

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 0.1% based on empiric data b. Patient’s offspring: as high as 50%, particularly in individuals with deletions 2. Prenatal diagnosis: possible for fetuses at risk using FISH on fetal cells obtained by amniocentesis or chorionic villus sampling, provided the FISH has identified a deletion in an affected family member 3. Management a. Early intervention programs i. Physical therapy ii. Occupational therapy iii. Speech therapy b. Management of gastroesophageal reflux c. Prophylaxis for subacute bacterial endocarditis for patients at risk d. Require assistance and training in self-help skills but can become self-sufficient in most self-help areas such as feeding, dressing, and toileting e. Special education f. Behavioral modification g. Surgery to correct a delta phalanx deformity h. Caution with general anesthesia in children i. Challenging to intubate due to airway anomalies a) Relatively anterior position of the larynx b) Easily collapsible laryngeal wall ii. Important to intubate due to the high risk of aspiration during induction and emergence iii. Presence of skeletal anomalies iv. Cardiac arrhythmia may result from use of cardioactive drugs a) Atropine b) Neostigmine c) Succinylcholine d) Suxamethonium

REFERENCES Allanson JE: Rubinstein-Taybi syndrome: the changing face. Am J Med Genet Suppl 6:38–41, 1990. Bartsch O, Wagner A, Hinkel GK, et al.: FISH studies in 45 patients with Rubinstein-Taybi syndrome: deletions associated with polysplenia, hypoplastic left heart and death in infancy. Eur J Hum Genet 7:748–756, 1999. Bartsch O, Locher K, Meinecke P, et al.: Molecular studies in 10 cases of Rubinstein-Taybi syndrome, including a mild variant showing a missense mutation in codon 1175 of CREBBP. J Med Genet 39:496–501, 2002. Baxter G, Beer J: Rubinstein-Taybi syndrome. Psychol Rep 70:451–456, 1992. Berry AC: Rubinstein-Taybi syndrome. J Med Genet 24:562–566, 1987.

RUBINSTEIN-TAYBI SYNDROME Blough RI, Petrij F, Dauwerse JG, et al.: Variation in microdeletions of the cyclic AMP-responsive element-binding protein gene at chromosome band 16p13.3 in the Rubinstein-Taybi syndrome. Am J Med Genet 90:29–34, 2000. Breuning MH, Dauwerse HG, Fugazza G, et al.: Rubinstein-Taybi syndrome caused by submicroscopic deletions within 16p13.3. Am J Hum Genet 52:249–254, 1993. Cantani A, Gagliesi D: Rubinstein-Taybi syndrome. Review of 732 cases and analysis of the typical traits. Eur Rev Med Pharmacol Sci 2:81–87, 1998. Carey JC, Curry CJR: Rubinstein-Taybi syndrome: new look at an “old” syndrome. Am J Med Genet (Suppl 6):2, 1990. Coupry I, Roudaut C, Stef M, et al.: Molecular analysis of the CBP gene in 60 patients with Rubinstein-Taybi syndrome. J Med Genet 39:415–421, 2002. Filippi G: The Rubinstein-Taybi syndrome. Report of 7 cases. Clin Genet 3:303–318, 1972. Giles RH, Petru F, Dauwerse HG, et al.: Constructions of a 1.2-Mb contig surrounding, and molecular analysis of the human CREB-binding protein (CBP/CREBBP) gene on chromosome 16p13.3. Genomics 42:96–114, 1997. Gotts EE, Liemohn WP: Behavioral characteristics of three children with the broad thumb-hallux (Rubinstein-Taybi) syndrome. Biol Psychiatry 12: 413–423, 1977. Hellings JA, Hossain S, Martin JK, et al.: Psychopathology, GABA, and the Rubinstein-Taybi syndrome: a review and case study. Am J Med Genet 114:190–195, 2002. Hennekam RC: Bibliography on Rubinstein-Taybi syndrome. Am J Med Genet Suppl 6:77–83, 1990. Hennekam RC: Rubinstein-Taybi syndrome: a history in pictures. Clin Dysmorphol 2:87–92, 1993. Hennekam RC, Baselier AC, Beyaert E, et al.: Psychological and speech studies in Rubinstein-Taybi syndrome. Am J Ment Retard 96:645–660, 1992. Hennekam RC, Lommen EJ, Strengers JL, et al.: Rubinstein-Taybi syndrome in a mother and son. Eur J Pediatr 148:439–441, 1989. Hennekam RC, Van Doorne JM: Oral aspects of Rubinstein-Taybi syndrome. Am J Med Genet Suppl 6:42–47, 1990. Hennekam RC, Stevens CA, Van de Kamp JJ: Etiology and recurrence risk in Rubinstein-Taybi syndrome. Am J Med Genet (Suppl 6):56–64, 1990. Hennekam RC, Van Den Boogaard MJ, Sibbles BJ, et al.: Rubinstein-Taybi syndrome in The Netherlands. Am J Med Genet (Suppl 6):17–29, 1990. Hennekam RC, Tilanus M, Hamel BC, et al.: Deletion at chromosome 16p13.3 as a cause of Rubinstein-Taybi syndrome: clinical aspects. Am J Hum Genet 52:255–262, 1993. Imaizumi K, Kuroki Y: Rubinstein-Taybi syndrome with de novo reciprocal translocation t(2;16)(p13.3;p13.3). Am J Med Genet 38:636–639, 1991. Imaizumi K, Kurosawa K, Masuno M, et al.: Chromosome aberrations in Rubinstein-Taybi syndrome. Clin Genet 43:215–216, 1993. Lacombe D, Saura R, Taine L, et al.: Confirmation of assignment of a locus for Rubinstein-Taybi syndrome gene to 16p13.3. Am J Med Genet 44:126–128, 1992. Levitas AS, Reid CS: Rubinstein-Taybi syndrome and psychiatric disorders. J Intellect Disabil Res 42 (Pt 4):284–292, 1998. Masuno M, Imaizumi K, Kurosawa K, et al.: Submicroscopic deletion of chromosome region 16p13.3 in a Japanese patient with Rubinstein-Taybi syndrome. Am J Med Genet 53:352–354, 1994. McGaughran JM, Gaunt L, Dore J, et al.: Rubinstein-Taybi syndrome with deletions of FISH probe RT1 at 16p13.3: two UK patients. J Med Genet 33:82–83, 1996.

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Miller RW, Rubinstein JH: Tumors in Rubinstein-Taybi syndrome. Am J Med Genet 56:112–115, 1995. Partington MW: Rubinstein-Taybi syndrome: a follow-up study. Am J Med Genet Suppl 6:65–68, 1990. Petrij F, Giles RH, Dauwerse HG, et al.: Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature 376:348–351, 1995. Petrij F, Dauwerse HG, Blough RI, et al.: Diagnostic analysis of the Rubinstein-Taybi syndrome: five cosmids should be used for microdeletion detection and low number of protein truncating mutations. J Med Genet 37:168–176, 2000. Petrij F, Dorsman JC, Dauwerse HG, et al.: Rubinstein-Taybi syndrome caused by a De Novo reciprocal translocation t(2;16)(q36.3;p13.3). Am J Med Genet 92:47–52, 2000. Petrij F, Giles RH, Breuning MH, et al.: Rubinstein-Taybi syndrome. In: Scriver CR, Beaudet al., Valle D, Sly WS, eds. The metabolic and molecular bases of inherited disease. 8th ed. Chapter 248, New York: McGrawHill, 2001:6167–6182. Rubinstein JH: The broad thumbs syndrome-Progress report 1968. Birth Defects Original Article Series 5(2):25–41, 1969. Rubinstein JH: Broad thumb-hallux (Rubinstein-Taybi) syndrome 1957-1988. Am J Med Genet Suppl 6:3–16, 1990. Rubenstein JH, Taybi H: Broad thumbs and facial abnormalities. Am J Dis Child 105:588–608, 1963. Rubinstein-Taybi syndrome. Papers presented at the 9th annual David W. Smith Workshop on Malformations and Morphogenesis. Oakland, 1988. Proceedings. Am J Med Genet (Suppl 6):1–131, 1990. Selmanowitz VJ, Stiller MJ: Rubinstein-Taybi syndrome. Cutaneous manifestations and colossal keloids. Arch Dermatol 117:504–506, 1981. Stevens CA: Rubinstein-Taybi syndrome. Gene Reviews. www.genetests.org Stevens CA, Bhakta MG: Cardiac abnormalities in the Rubinstein-Taybi syndrome. Am J Med Genet 59:346–348, 1995. Stevens CA, Carey JC, Blackburn BL: Rubinstein-Taybi syndrome: a natural history study. Am J Med Genet Suppl 6:30–37, 1990. Stirt JA: Anesthetic problems in Rubinstein-Taybi syndrome. Anesth Analg 60:534–536, 1981. Taine L, Goizet C, Wen ZQ, et al.: Submicroscopic deletion of chromosome 16p13.3 in patients with Rubinstein-Taybi syndrome. Am J Med Genet 78:267–270, 1998. Tommerup N, van der Hagen CB, Heiberg A: Tentative assignment of a locus for Rubinstein-Taybi syndrome to 16p13.3 by a de novo reciprocal translocation, t(7;16)(q34;p13.3). Am J Med Genet 44:237–241, 1992. van Genderen MM, Kinds GF, Riemslag FC, et al.: Ocular features in Rubinstein-Taybi syndrome: investigation of 24 patients and review of the literature. Br J Ophthalmol 84:1177–1184, 2000. Wallerstein R, Anderson CE, Hay B, et al.: Submicroscopic deletions at 16p13.3 in Rubinstein-Taybi syndrome: frequency and clinical manifestations in a North American population. J Med Genet 34:203–206, 1997. Wiley S, Swayne S, Rubinstein JH, et al.: Rubinstein-Taybi syndrome medical guidelines. Am J Med Genet 119A:101–110, 2003. Wood VE, Rubinstein JH: Surgical treatment of the thumb in the RubinsteinTaybi syndrome. J Hand Surg [Br] 12:166–172, 1987. Wood VE, Rubinstein J: Duplicated longitudinal bracketed epiphysis “kissing delta phalanx” in Rubinstein-Taybi syndrome. J Pediatr Orthop 19:603–606, 1999.

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Fig. 1. A patient with Rubinstein-Taybi syndrome at different ages (childhood and adulthood) showing typical facial appearance (prominent beaked nose with the columella below the alae nasi), broad thumbs, and broad/bifid great toes, which are illustrated by radiographs.

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Fig. 3. A young patient with Rubinstein-Taybi syndrome showing characteristic facies, broad thumbs, and great toes.

Fig. 2. An adult with Rubinstein-Taybi syndrome showing the characteristic facies and broad thumbs.

Schizencephaly Schizencephaly is a rare congenital brain malformation characterized by deep clefts of the cerebral mantle that extend from the cortical surface to the lateral ventricles. The conditions are often associated with convolutional anomalies such as polymicrogyria or nodular subependymal heterotopias.

ii. Type II (open-lip schizencephaly): Presence of a large defect, a holohemispheric cleft in the cerebral cortex filled with cerebral spinal fluid and lined by polymicrogyric grey matter d. Associated malformations commonly accompanying schizencephaly i. Mild hypoplasia of the corpus callosum ii. Total or nearly total absence of cavum septum pellucidum in 70–90% of patients with schizencephaly. 30–50% of patients show associated optic nerve hypoplasia on clinical examination (septo-optic dysplasia with schizencephaly) iii. Focal cortical dysplasia iv. Coloboma of the retina v. Hydrocephalus 4. Syndromes associated with schizencephaly a. Septo-optic dysplasia-schizencephaly syndrome i. Clinical features distinct from isolated septo-optic dysplasia ii. Significant global developmental delay and spastic motor deficits iii. Seizures and visual symptoms rather than with endocrine abnormalities b. Other rare schizencephaly syndromes i. Prenatal cytomegalovirus infection ii. Vascular disruption related to twinning c. Schizencephaly (plus polymicrogyria) as part of multiple congenital anomaly/mental retardation syndromes i. Adam-Oliver syndrome ii. Aicardi syndrome iii. Arima syndrome iv. Delleman (oculocerebrocutaneous ) syndrome v. Galloway-Mowat syndrome vi. Micro syndrome

GENETICS/BIRTH DEFECTS 1. Inheritance a. Isolated schizencephaly: mainly sporadic b. Rare reports of familial cases 2. Etiology a. A developmental defect in the blood vessels supplying the cerebral cortex i. Resulting in tissue death and cleft formation due to lack of oxygen (in utero vascular insufficiency) ii. With preferential location in the parasylvian regions following the frontoparietal distribution of the middle cerebral artery b. Mutations in the homeodomain gene Emx2 as a possible cause of some cases of schizencephaly i. At least some schizencephaly cases result from germline mutations ii. Emx2: expressed in restricted areas of the developing mammalian forebrain, including areas that develop into the cerebral cortex iii. Discovery of Emx2 mutations in both sporadic and familial cases of schizencephaly marking an important advance in establishing genetic causes for brain malformations iv. Lack of Emx2 mutations in most schizencephaly patients has increased the likelihood of other genes being involved 3. Schizencephaly a. Refers to gray matter lined clefts that extend through the entire hemisphere from the ependymal lining of the lateral ventricles to the pial covering of the cortex b. Cleft i. A cleft in cerebral mantle which communicates between the subarachnoid space laterally and ventricular system medially a) Unilateral or bilateral cleft b) Symmetric or asymmetric cleft ii. The sides of clefts generally lined with heterotopic gray matter (an abnormal accumulation of neurons) c. Two types of schizencephaly depending on the size of the area involved and the separation of the cleft lips i. Type I (closed-lip schizencephaly) a) Consisting of a fused cleft b) This fused pial-ependymal seam forms a furrow in the developing brain and is lined by polymicrogyric grey matter

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1. Clinical manifestations depend on the size and location of involved brain a. A narrow, unilateral cleft i. Usually present with seizures and mild focal neurological deficits ii. Otherwise developmentally normal b. Bilateral clefts i. Severe developmental delay ii. Early intractable epilepsy iii. Severe motor dysfunction 2. Clinical features a. Mental retardation (varying degree) b. Developmental delay: moderate to severe if the defects are large c. Microcephaly (varying degree) d. Hydrocephalus in some patients e. Hypotonia in the postnatal period

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f. g. h. i. j. k.

Motor difficulties Seizures in most patients Generalized spasticity Hemiparesis or quadriparesis Blindness secondary to optic nerve hypoplasia Prognosis depending on the size of the clefts and the degree of neurological deficits i. Patients with type I abnormalities a) Almost normal b) May have seizures and spasticity ii. Patients with smaller, unilateral clefts (clefts in only one hemisphere) a) Often paralyzed on one side of the body b) May have normal intelligence iii. Patients with type II abnormalities a) Mental retardation b) Seizures c) Hypotonia d) Spasticity e) Inability to walk or speak f) Blindness iv. Patients with bilateral open-lip schizencephaly generally with the worst clinical symptoms

DIAGNOSTIC INVESTIGATIONS 1. Ultrasonography of the brain to demonstrate closed-lip or open-lipped brain cleft communicating with lateral ventricle(s) 2. Magnetic resonance imaging (MRI) or computed tomography (CT) of the brain a. Open-lipped or closed-lipped schizencephaly b. Associated absence of the septum pellucidum and hypoplasia of the optic chiasm 3. Pathology a. Clefts most commonly in the Rolandic fissures b. Frequently associated with pachygyria, polymicrogyria or lissencephaly 4. Molecular genetic testing of EMX2 mutation for familial schizencephaly

GENETIC COUNSELING 1. Recurrence risk: low unless germline mutation is present in one of the parent 2. Prenatal diagnosis with ultrasonography to demonstrate brain clefts connecting to the lateral ventricles and with EMX2 gene mutation analysis of amniocytes and CVS to the end 3. Management a. Physical therapy b. Seizure control c. VP shunt for hydrocephalus

REFERENCES Aniskiewicz AS, Frumkin NL, Brady DE, et al.: Magnetic resonance imaging and neurobehavioral correlates in schinzencephaly. Arch Neurol 47:911–916, 1990. Barkovich AJ, Kjos BO: Schizencephaly: correlation of clinical findings with MR characteristics. Am J Neuroradiol 13:85–94, 1992.

Barkovich AJ, Kuzniecky RI, Jackson GD, et al.: Classification system for malformations of cortical development. Update 2001. Neurology 57:2168, 2001. Brunelli S, Faiella A, Capra V, et al.: Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly. Nature Genet 12:94–96, 1996. Byrd SE, Osborn RE, Bohan TP, et al.: The CT and MR evaluation of Migrational disorders of the brain. Part I. Lissencephaly and pachygyria. Pediatr Radiology 19:151–156, 1989. Capra V, De Marco P, Moroni A, et al.: Schizencephaly: Surgical features and new molecular genetic results. Eur J Pediatr Surg 6(Suppl 1):27–29, 1996. Ceccherini AF, Twining P, Variend S: Schizencephaly: antenatal detection using ultrasound. Clin Radiol 54:620–622, 1999. Chamberlain MC, Press GA, Bejar RF: Neonatal schizencephaly: comparison of brain imaging. Pediatr Neurol 6:382–387, 1990. Denis D, Maugey-Laulom B, Carles D, et al.: Prenatal diagnosis of schizencephaly by fetal magnetic resonance imaging. Fetal Diagn Ther 16:354–359, 2001. Denis D, Chateil JF, Brun M, et al.: Schizencephaly: clinical and imaging features in 30 infantile cases. Brain Dev 22:475–483, 2000. Faiella A, Brunelli S, Granata T, et al.: A number of schizencephaly patients including 2 brothers are heterozygous for germline mutations in the homeobox gene EMX2. Eur J Hum Genet 5:186–190, 1997. Granata T, Battaglia G, D’Incerti L, et al.: Schizencephaly: neuroradiologic and epileptologic findings. Epilepsia 37:1185–1193, 1996. Granata T, Farina L, Faiella A, et al.: Familial schizencephaly associated with EMX2 mutation. Neurology 48:1404–1406, 1997. Herman M, Rico S: Schizencephaly: Presentation in a 6-week-old boy with fetal death of co-twin. Int Pediatr 14:32–34, 1999. Haverkamp F, Zerres K, Ostertun B, et al.: Familial schizencephaly: further delineation of a rare disorder. J Med Genet 32:242–244, 1995. Hayashi N, Tsutsumi Y, Barkovich AJ: Morphological features and associated anomalies of schizencephaly in the clinical population: detailed analysis of MR images. Neuroradiology 44:418–427, 2002. Hilburger AC, Willis JK, Bouldin F, et al.: Familial schizencephaly. Brain Dev 15:234–236, 1993. Hosley MA, Abroms IF, Ragland RL: Schizencephaly: Case report of familial incidence. Pediatr Neurol 8:148–150, 1991. Klingensmith WC III, Cioffi-Ragan DT: Schizencephaly: Diagnosis and progression in utero. Radiology 159:617–618, 1986. Komarniski CA, Cyr DR, Mack LA, et al.: Prenatal diagnosis of schizencephaly. J Ultrasound Med 9:305–307, 1990. Kuban KC, Teele RL, Wallman J: Septo-optic-dysplasia-schizencephaly. Radiographic and clinical features. Pediatr Radiol 19:145–150, 1989. Landrieu P, Lacroix C: Schizencephaly, consequence of a developmental vasculopathy? A clinicopathological report. Clin Neuropathol 13:192–196, 1994. Lituania M, Passamonti U, Cordono MS, et al.: Schizencephaly: prenatal diagnosis by computed sonography and magnetic resonance imaging. Prenat Diagn 9:649–655, 1989. Lubinsky MS: Hypothesis: septo-optic dysplasia is a vascular disruption sequence. Am J Med Genet 69:235–236, 1997. Miller SP, Shevell MI, Patenaude Y, et al.: Septo-optic plus: A spectrum of malformations of cortical development. Neurology 54:1701–1703, 2000. Miller GM, Stears IC, Cuggenheim MA, et al.: The clinical and computerized tomographic spectrum of schinzencephaly in six patients. Neurology 32:A218–219, 1982. Miller GM, Stears IC, Cuggenheim MA, et al.: Schizencephaly: a clinical and CT study. Neurology 34:997–1001, 1984. Packard AM, Miller VS, Delgado MR: Schizencephaly: Correlations of clinical and radiologic features. Neurology 48:1427–1434, 1997. Pilu GL, Falco P, Perolo A, et al.: Differential diagnosis and outcome of fetal intracranial hypoechoic lesions: report of 21 cases. Ultrasound Obstet Gynecol 9:229–236, 1997. Robinson RO: Familial schizencephaly. Dev Med Child Neurol 33:1010–1012, 1991. Yakovlev PI, Wadsworth RC: Schizencephalies. A study of the congenital clefts in the cerebral mantle. I. Clefts with fused lips. J Neuropathol Exp Neurol 5:116–130, 1946. Yakovlev PI, Wadsworth RC: Schizencephalies. A study of the congenital clefts in the cerebral mantle. II. Clefts with hydrocephalus and lips separated. J Neuropathol Exp Neurol 5:169–206, 1946. Yoshida M, Suda Y, Matsuo I, et al.: Emx1 and Emx2 functions in development of dorsal telencephalon. Development 124:101–110, 1997.

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Fig. 2. An infant with schizencephaly with global delay and spastic quadriplegia. His MRI of the brain showed bilateral large open-lip schizencephaly in frontotemporal regions.

Fig. 1. An infant with asymmetric open-lip parietal schizencephaly, illustrated by MRI.

Fig. 3. MRI of the brain of another patient showing bilateral open-lip schizencephaly in the parietal regions in communication with a large cavity filled by cerebrospinal fluid.

Schmid Metaphyseal Chondrodysplasia Schmid metaphyseal chondrodysplasia (SMCD) is a mild hereditary chondrodysplasia resulting from growth plate cartilage abnormalities.

ii. Abnormal distal fibular metaphyses d. Wrist i. Abnormal distal radial metaphyses ii. Abnormal distal ulnar metaphyses e. Ribs: anterior cupping, splaying and sclerosis f. Wide metaphyses with cupping and fraying g. Short and stubby long bones h. Normal metacarpals and phalanges i. Normal spine 2. Histology: variable bone changes a. Mild sharp serrations of the metaphyses with increased density of the provisional zone of calcification b. Irregularity with flaring and fragmentation and widening of the growth plate 3. Molecular genetic analysis of COL10A1 mutation a. Mutation analysis b. Mutation scanning

GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal dominant b. Variable expression 2. Molecular pathogenesis a. SMCD: caused by heterozygous mutations in the gene (COL10A1 mapped to chromosome 6q21-q22) for Type X collagen, a short-chain collagen whose expression is largely restricted to the hypertrophic chondrocytes of growth plate cartilage i. Most mutations reside in the carboxylterminal globular domain (CN1) ii. Two mutations observed in a putative signal peptide cleavage site b. Growth plate abnormalities of SMCD: resulting from collagen X haploinsufficiency, a reduction by 50% in collagen X

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: low recurrence risk unless a parent is affected b. Patient’s offspring: 50% 2. Prenatal diagnosis by amniocentesis or CVS: can be offered to families at-risk for DMCD with a previously characterized disease-causing COL10A1 mutation 3. Management a. Supportive b. Orthopedic management of bowed legs: generally does not require orthopedic surgery

CLINICAL FEATURES 1. 2. 3. 4. 5. 6. 7. 8. 9.

Mild to moderate short-limbed dwarfism Bowed legs Waddling gait, often a presenting sign at second year Coxa vara Genu varum Exaggerated lumbar lordosis Flared anterior rib cage Leg pain during childhood Prognosis a. Radiological changes appearing early with a tendency to heal and change slowly with time, giving rise to mildly dwarfed patients b. Normal intelligence

DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Hip i. Abnormal acetabular roofs ii. Enlarged capital femoral epiphyses iii. Coxa vara iv. Femoral bowing v. Abnormal proximal femoral metaphyses b. Knee i. Abnormal distal femoral metaphyses ii. Abnormal proximal tibial metaphyses iii. Abnormal proximal fibular metaphyses c. Ankle i. Abnormal distal tibial metaphyses

REFERENCES Bateman JF, Freddi S, Nattrass G, et al.: Tissue-specific RNA surveillance? Nonsense-mediated mRNA decay causes collagen X haploinsufficiency in Schmid metaphyseal chondrodysplasia cartilage. Hum Mol Genet 12:217–225, 2003. Beluffi G, Fiori P, Notarangelo CD, et al.: Metaphyseal dysplasia type Schmid. Early X-ray detection and evolution with time. Ann Radiol (Paris) 26:237–243, 1983. Beluffi G, Fiori P, Schifino A, et al.: Metaphyseal dysplasia, type Schmid. Prog Clin Biol Res 104:103–110, 1982. Bonaventure J, Chaminade F, Maroteaux P: Mutations in three subdomains of the carboxy-terminal region of collagen type X account for most of the Schmid metaphyseal dysplasias. Hum Genet 96:58–64, 1995. Chan D, Jacenko O: Phenotypic and biochemical consequences of collagen X mutations in mice and humans. Matrix Biol 17:169–184, 1998. Chan D, Ho MS, Cheah KS: Aberrant signal peptide cleavage of collagen X in Schmid metaphyseal chondrodysplasia. Implications for the molecular basis of the disease. J Biol Chem 276:7992–7997, 2001. Chan D, Weng YM, Graham HK, et al.: A nonsense mutation in the carboxylterminal domain of type X collagen causes haploinsufficiency in Schmid metaphyseal chondrodysplasia. J Clin Invest 101:1490–1499, 1998. Dharmavaram RM, Elberson MA, Peng M, et al.: Identification of a mutation in type X collagen in a family with Schmid metaphyseal chondrodysplasia. Hum Mol Genet 3:507–509, 1994.

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SCHMID METAPHYSEAL CHONDRODYSPLASIA Dimson SB: Metaphyseal dysostosis type Schmid. Proc R Soc Med 61:1260–1261, 1968. Lachman RS, Rimoin DL, Spranger J: Metaphyseal chondrodysplasia, Schmid type. Clinical and radiographic delineation with a review of the literature. Pediatr Radiol 18:93–102, 1988. Matsui Y, Yasui N, Kawabata H, et al.: A novel type X collagen gene mutation (G595R) associated with Schmid-type metaphyseal chondrodysplasia. J Hum Genet 45:105–108, 2000. Miller SM, Paul LW: Roentgen observations in familial metaphyseal dysostosis. Radiology 83: 665–673, 1964. Milunsky J, Maher T, Lebo R, et al.: Prenatal diagnosis for Schmid metaphyseal chondrodysplasia in twins. Fetal Diagn Ther 13:167–168, 1998. Sawai H, Ida A, Nakata Y, et al.: Novel missense mutation resulting in the substitution of tyrosine by cysteine at codon 597 of the type X collagen gene

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associated with Schmid metaphyseal chondrodysplasia. J Hum Genet 43:259–261, 1998. Schmid F: Beitrag zur dysostosis enchondralis metaphysaria. Monatsschr Kinderheilk 97:393–397, 1949. Schmid TM, Linsenmayer TF: Immunohistochemical localization of short chain cartilage collagen (type X) in avian tissues. J Cell Biol 100:598–605, 1985. Wallis GA, Rash B, Sweetman WA, et al.: Amino acid substitutions of conserved residues in the carboxyl-terminal domain of the alpha 1(X) chain of type X collagen occur in two unrelated families with metaphyseal chondrodysplasia type Schmid. Am J Hum Genet 54:169–178, 1994. Wallis GA, Rash B, Sykes B, et al.: Mutations within the gene encoding the alpha 1 (X) chain of type X collagen (COL10A1) cause metaphyseal chondrodysplasia type Schmid but not several other forms of metaphyseal chondrodysplasia. J Med Genet 33:450–457, 1996. Warman ML, Abbott M, Apte SS, et al.: A type X collagen mutation causes Schmid metaphyseal chondrodysplasia. Nat Genet 5:79–82, 1993.

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SCHMID METAPHYSEAL CHONDRODYSPLASIA

Fig. 1. Three young children with Schmid metaphyseal chondrodysplasia showing short stature, lumbar lordosis, and bowing of the legs. Radiographs showed genu varum and metaphyseal widening with fraying and cupping. Epiphyses are normal.

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Seckel Syndrome In 1960, Seckel reported two personal cases and 13 cases from the literature of a clinical condition characterized by severe intrauterine and postnatal proportionate dwarfism, severe microcephaly, “bird-headed” profile with receding forehead and chin, large and beaked nose, severe mental retardation and other anomalies. Seckel syndrome (SCKL) is a rare heterogeneous type of primordial dwarfism with frequency of less than 1 in 10,000 live births.

GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. Genetic heterogeneity a. SCKL1: A gene for Seckel syndrome was mapped to human chromosome 3q22.1-q24 in two inbred Pakistani families originating from the same village i. The gene encoding ataxia-telangiectasia and Rad3-related protein (ATR) maps to the critical region to an interval of 5Mbp between markers D3S1316 and D3S1557 ii. A synonymous mutation in affected individuals was identified that alters ATR splicing iii. The mutation confers a phenotype including marked microcephaly and dwarfism b. SCKL2: Another gene locus was mapped to chromosome 18p11.31-q11.2 in one inbred Iraqi family c. SCKL3: A novel locus at 14q23 by linkage analysis in 13 Turkish families. The novel gene locus SCKL3 is 1.18 cM and harbors ménage a trios 1, a gene with a role in DNA repair

CLINICAL FEATURES 1. Broad interfamilial clinical heterogeneity 2. Growth a. Severe proportionate short stature of prenatal onset b. Severe postnatal growth deficiency c. Intrauterine growth retardation d. Low birth weight dwarfism 3. Mental retardation 4. Characteristic craniofacial features a. Cranial manifestations i. Severe microcephaly ii. Premature closure of cranial sutures b. Receding forehead c. “Bird-like” face d. Antimongoloid slant of palpebral fissures e. Large eyes f. Beak-like protrusion of the nose g. Narrow face h. Receding lower jaw (retrognathia) i. Micrognathia j. High-arched or cleft palate 874

k. Ears i. Low-set ii. Hypoplastic lobules l. Dental abnormalities i. Enamel hypoplasia ii. Missing permanent teeth iii. Precocious eruption of teeth iv. Microdontia v. Malocclusion vi. Taurodontism m. “Dysplastic” ears 5. Associated anomalies a. Ocular manifestations i. Severe myopia and astigmatism ii. Severe, early onset, bilateral retinal degeneration iii. Hypotelorism iv. Bilateral ptosis v. Microphthalmos vi. Megacornea vii. Glaucoma viii. Retrolental membrane ix. Macular coloboma x. Optic hypoplasia xi. Strabismus xii. Lens dislocation b. Skeletal defects i. Premature closure of cranial sutures ii. Dislocation of the radial head iii. Clinodactyly of the 5th fingers iv. Hip “dysplasia”/dislocation v. Retardation of ossification vi. Clubfoot vii. Hypoplastic patella viii. Scoliosis c. CNS anomalies i. Small cerebrum with simplified, apelike convolutional pattern (pongidoid micrencephaly) ii. Dysgenesis of cerebral cortex iii. Agenesis of corpus callosum iv. Cerebellar vermis hypoplasia v. Dorsal cerebral cyst vi. Arachnoid cyst vii. Dilated ventricles viii. Pachygyria ix. Agyria x. Intracranial aneurysms d. Endocrine abnormalities i. Pituitary gland abnormalities a) Delayed development b) Decreased adrenocorticotropic hormone production c) Decreased growth hormone production

SECKEL SYNDROME

d) Absence of adenohypophysis e) Hypophyseal hypoplasia f) Precocious puberty ii. Adrenal hypoplasia iii. Hirsutism e. Hematopoietic abnormalities i. Acute myelogenous leukemia ii. Refractory anemia with excess blasts iii. Pancytopenia iv. Fanconi anemia f. Urogenital abnormalities i. Males a) Cryptorchidism b) Hypoplasia of testis ii. Females a) Clitoromegaly b) Hypoplasia of labia majora g. Features of premature senility i. Receding hair ii. Redundant wrinkled skin on the palms h. Miscellaneous findings i. Congenital heart defects a) Patent ductus arteriosus b) Atrial septal defect c) Ventricular septal defects d) Atrioventricular canal defect ii. Multiple intestinal atresia 6. Seckel-like syndromes a. Microcephalic osteodysplastic primordial dwarfism type I i. Distinguished from Seckel syndrome by: a) Broad, low “dysplastic” pelvis with poor development of the acetabula b) Disproportionately short, broad bowing of humeri and femora with rather unremarkable metaphysis c) Agenesis of the corpus callosum and lissencephaly have also been noted ii. Classified as Seckel syndrome by Majewski and Goecke (1982) b. Microcephalic osteodysplastic primordial dwarfism type II: Differences from the Seckel syndrome include the following (mainly based on X-ray features): i. Short limbs with preferential distal involvement (disproportionate shortness of forearms and legs) in the first years of life ii. Brachymesophalangy iii. Brachymetacarpy I iv. Coxa vara v. Epiphysiolysis vi. Metaphyseal flaring with V-shaped distal femoral metaphyses c. Microcephalic osteodysplastic primordial dwarfism type III i. Alopecia ii. Seckel-like features a) Intrauterine growth retardation b) Microcephaly c) Receding forehead and chin d) Large ears

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e) Large prominent nose f) Platyspondyly g) Long dysplastic clavicles h) Hypoplasia of iliac wing and acetabula i) Broad femora iii. Currently considered to be the same entity as type I d. A variant of osteodysplastic bird-headed dwarfism described by Bangstad et al. (1989) i. Progressive ataxia ii. Primary gonadal insufficiency iii. Endocrine abnormalities a) Insulin-resistant diabetes mellitus b) Goiter e. Chromosome abnormalities i. Chromosome instability/breakage ii. Deletion 1q22–q24.3 iii. Interstitial deletion 2q33.3–q34 iv. Ring chromosome 4 mosaicism

DIAGNOSTIC INVESTIGATIONS 1. Hematological work-up indicated in selected patients a. Anemia b. Pancytopenia c. Acute myeloid leukemia 2. Endocrine work-up for pituitary and adrenal dysfunction 3. Radiography a. Microcephaly with a rather steeply sloping base of the skull b. Premature closure of the cranial sutures c. Delayed bone age d. Hip dysplasia e. Elbow dislocation f. Dislocation of the radial head g. Ivory epiphyses (dense sclerotic areas in the phalanges) h. Cone-shaped epiphyses i. Disharmonic bone development i. Hypoplasia of proximal radii and fibulae ii. Absence of epiphyseal ossification centers in fingers and toes 4. Neuropathology and CT/MRI of the brain a. Microcephaly b. Neuroglial ectopia c. Agenesis of the corpus callosum d. Micropolygyria e. Disproportion of the cerebrum and cerebellum f. Dysgenetic cerebral cortex g. Hypoplasia of the cerebellar vermis h. Dorsal cerebral cyst 5. Growth plate histology a. Normal column formation b. No structural abnormality of chondrocytes c. Decrease in cellularity of chondrocytes

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not likely to have offspring due to severe mental retardation

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2. Prenatal diagnosis possible by serial ultrasonography for families at risk for Seckel syndrome a. Severe intrauterine growth retardation b. Craniofacial abnormalities i. Microcephaly ii. Receding forehead iii. A prominent nose iv. Severe micrognathia c. Short limbs 3. Management a. Symptomatic b. Psychosocial support for mental retardation c. Dental cares d. Orthopedic cares e. Treatments for hematological abnormalities

REFERENCES Abou-zahr F, Bejjani B, Kruyt F AE, et al.: Normal expression of the Fanconi anemia proteins FAA and FAC and sensitivity to mitomycin C in two patients with Seckel syndrome. Am J Med Genet 83:388–391, 1999. Anderson CE, Wallerstein R, Zamerowski ST, et al.: Ring chromosome 4 mosaicism coincidence of oligomeganephronia and signs of Seckel syndrome. Am J Med Genet 72:281–285, 1997. Arnold SR, Spicer D, Kouseff B, et al.: Seckel-like syndrome in three siblings. Pediatr Dev Pathol 2:180–187, 1999. Bangstad HJ, Beck-Nielsen H, Hother-Neilsen O, et al.: primordial bird-headed nanisme associated with progressive ataxia, early onset insulin resistant diabetes, goiter, and primary gonadal insufficiency. A new syndrome. Acta Paediatr Scand 78:488–493, 1989. Bobabilla-Morales L, Corona-Rivera A, Corona-Rivera JR, et al.: Chromosome instability induced in vitro with mitomycin C in five Seckel syndrome patients. Am J Med Genet 123A:148–152, 2003. Børglum AD, Balslev T, Haagerup A, et al.: A new locus for Seckel syndrome on chromosome 18p11.31-q11.2. Eur J Hum Genet 9:753–757, 2001. Butler MG, Hall BD, Maclean RN, et al.: Do some patients with Seckel syndrome have hematological problems and/or chromosome breakage? Am J Med Genet 27:645–649, 1987. D’Angelo VA, Ceddia AM, Zelante L, et al.: Multiple intracranial aneurysms in a patient with Seckel syndrome. Childs Nerv Syst 14:82–84, 1998. De Elejalde MM, Elejalde BR: Visualization of the fetal face by ultrasound. J Craniofac Genet Dev Biol 4:251–257, 1984. Faivre L, Le Merrer M, Lyonnet S, et al.: Clinical and genetic heterogeneity of Seckel syndrome. Am J Med Genet 112:379–383, 2002. Featherstone LS, Sherman SJ, Quigg MH: Prenatal diagnosis of Seckel syndrome. J Ultrasound Med 15:85–88, 1996. Goodship J, Gill H, Carter J, et al.: Autozygosity mapping of a Seckel syndrome locus to chromosome 3q22. 1–q24. Am J Hum Genet 67:498–503, 2000.

Guirgis MF, Lam BL, Howard CW: Ocular manifestations of Seckel syndrome. Am J Ophthalmol 132:596–597, 2001. Harper RG, Orti E, Baker RK: Bird-headed dwarfs (Seckel’s syndrome). A familial pattern of developmental, dental, skeletal, genital, and central nervous system anomalies. J Pediatr 70:799–804, 1967. Kilinç MO, Ninis VN, Ug˘ur SA, et al.: Is the novel SCKL3 at 14q23 the predominant Seckel locus? Eur J Hum Genet 11:851–857, 2003. Majewski F, Goecke T: Studies of microcephalic primordial dwarfism I: approach to a delineation of the Seckel syndrome. Am J Med Genet 12:7–21, 1982. Majewski F, Ranke M, Schinzel A: Studies of microcephalic primordial dwarfism II: the osteodysplastic type II of primordial dwarfism. Am J Med Genet 12:23–35, 1982. Majewski F, Stoeckenius M, Kemperdick H: Studies of microcephalic primordial dwarfism III: an intrauterine dwarf with platyspondyly and anomalies of pelvis and clavicles—osteodysplastic primordial dwarfism type III. Am J Med Genet 12:37–42, 1982. Majewski F: Caroline Crachami and the delineation of osteodysplastic primordial dwarfism type III, and autosomal recessive syndrome. Am J Med Genet 44:203–209, 1992. Majewski F, Goecke TO: Microcephalic osteodysplastic primordial dwarfism type II: report of three cases and review. Am J Med Genet 80:25–31, 1998. Majoor-Krakauer DF, Wladimiroff JW, et al.: Microcephaly, micrognathia, and bird-headed dwarfism: prenatal diagnosis of a Seckel-like syndrome. Am J Med Genet 27:183–188, 1987. McKusick VA, Mahloudji M, Abbott MH, et al.: Seckel’s bird-headed dwarfism. N Engl J Med 277:279–286, 1967. Meinecke P, Passarge E: Microcephalic osteodysplastic primordial dwarfism type I/III in sibs. J Med Genet 28:795–800, 1991. Meinecke P, Schaefer E, Wiedemann HR, et al.: Microcephalic osteodysplastic primordial dwarfism: further evidence for identity of the so-called types I and III. Am J Med Genet 39:232–236, 1991. Nadjari M, Fasouliotis SJ, Ariel I, et al.: Ultrasonographic prenatal diagnosis of microcephalic osteodysplastic primordial dwarfism types I/III. Prenat Diagn 20:666–669, 2000. O’Driscoll M, Ruiz-Perez VL, Woods CG, et al.: A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet 33:497–501, 2003. Sauk JJ, Litt R, Espiritu CE, et al.: Familial bird-headed dwarfism (Seckel’s syndrome). J Med Genet 10:196–198, 1973. Seckel HPG: “Bird headed dwarfs: Studies in Developmental Anthropology Including Human Proportions.” Springfield, Ill: CC Thomas Publ. 1960. Shanske A, Caride DG, Menasse-Palmer L, et al.: Central nervous system anomalies in Seckel syndrome: report of a new family and review of the literature. Am J Med Genet 70:155–158, 1997. Syrrou M, Georgiou I, Paschopoulos M, et al.: Seckel syndrome in a family with three affected children and hematological manifestations associated with chromosome instability. Genet Couns 6:37–41, 1995. Thompson E, Pembrey M: Seckel syndrome: an overdiagnosed syndrome. J Med Genet 22:192–201, 1985.

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Fig. 2. An adult with Seckel syndrome showing severe short stature, mental retardation, extreme microcephaly, sloping forehead, a beaked nose, and retro/micrognathia.

Fig. 1. A girl with Seckel syndrome showing marked short stature, severe microcephaly, sloping forehead, “bird-headed” face, large eyes, beaked nose, and severe retro/micrognathia.

Severe Combined Immune Deficiency Severe combined immune deficiency (SCID) is a fatal, heterogeneous group of immune disorder, characterized by T-cell lymphopenia, a profound lack of cellular (T-cell) and humoral (B-cell) immunity and, in some cases, decreased NK-cell number and function. The incidence of SCID is estimated to be 1/100,000 live births.

GENETICS/BASIC DEFECTS 1. A heterogeneous syndrome of varied genetic origins a. X-linked type SCID (X-SCID) i. The most common type (50% of all patients with SCIDs) ii. A combined cellular and humoral immunodeficiency resulting from lack of T and natural killer (NK) lymphocytes and nonfunctional B lymphocytes iii. Caused by a mutation in the X-linked gene IL2RG, which encodes the common γ chain, γc (mapped on Xq13), of the leukocyte receptors for interleukin-2 and multiple other cytokines a) Significant frequency of de novo mutations accounting for 1/3rd of the cases b) Occurrence of maternal germline mosaicism iv. Atypical X-SCID: less frequently seen in patients with mutations that result in production of a small amount of gene product or a protein with residual activity b. Autosomal recessive type SCID i. Formerly known as Swiss-type agammaglobulinemia ii. Causes a) Adenosine deaminase deficiency (10–20% of all cases of SCID): the ADA gene mapped on chromosome 20q13.11 b) Purine nucleoside phosphorylase (PNP) deficiency: the PNP gene mapped on 14q13 c) Janus-associated kinase 3 (JAK3) deficiency causing autosomal recessive T–B+ SCID: the JAK3 gene mapped on 19p13 d) Interleukin (IL)-2 deficiency e) ZAP-70 protein tyrosine kinase (PTK) deficiency: ZAP-70 mapped on 2q12 f) Bare lymphocyte syndrome g) Reticular dysgenesis h) Omenn syndrome 2. Pathophysiology a. Varies among various forms of SCID b. Common endpoint in all forms of SCID i. Lack of T-cell function ii. Lack of B-cell function c. Cellular hallmarks differentiating various forms of SCID 878

i. X-linked SCID a) Absence or near absence of T cells (CD3+) and natural killer (NK) cells leading to lymphopenia b) Variable levels of B cells that produce no functional antibodies ii. JAK3 deficiency a) Absence or near absence of T cells (CD3+) and natural killer (NK) cells leading to lymphopenia b) Normal or high levels of B cells that produce no functional antibodies iii. ADA deficiency a) Death of T cells secondary to the accumulation of toxic metabolites in the purine salvage pathway leading to lymphopenia b) Decreased or absence of functional antibodies iv. PNP deficiency a) Death of T cells secondary to the accumulation of toxic metabolites in the purine salvage pathway leading to lymphopenia b) Normal number of circulating B cells with poor B-cell function, evidenced by the lack of antibody formation v. IL-2 deficiency a) Normal or near normal numbers of T cells (both CD4+ and CD8+) b) Decreased production of functional antibody vi. ZAP-70 PTK deficiency a) Absence of CD8+ T cells leading to lymphopenia b) No antibody formation vii. Bare lymphocyte syndrome a) Normal or mildly reduced lymphocyte count b) Decreased CD4+ T cells c) Normal or mildly increased CD8+ T cell numbers d) Normal or mildly decreased B-cell numbers with decreased antibody production viii. Reticular dysgenesis a) Absence of myeloid cells in the bone marrow leading to lymphopenia b) Presence of functioning red blood cells and platelets ix. Omenn syndrome a) Presence of normal or elevated T-cell numbers of maternal origin b) Usually undetectable B cells c) Presence of NK cells d) Markedly low total immunoglobulin level with poor antibody production e) Elevated eosinophils and total serum immunoglobulin E (IgE) level

SEVERE COMBINED IMMUNE DEFICIENCY

3. Molecular defects a. X-linked SCID i. Mutation of the common gamma chain of the IL receptors (IL-2R, IL-4R, IL-7R, IL-9R, IL-15R) resulting in loss of cytokine function ii. Loss of IL-2R function leading to the loss of a lymphocyte proliferation signal iii. Loss of IL-4R function leading to the inability of B cells to class switch iv. Loss of IL-7R function leading to the loss of an antiapoptotic signal resulting in a loss of T-cell selection in the thymus and also associated with the loss of a T-cell receptor v. Loss of IL-15R function leading to the ablation of NK cell development b. JAK3 deficiency i. JAK, a protein tyrosine kinase that associates with the common gamma chain of the IL receptors ii. Deficiency of JAK3 resulting in the same clinical manifestations as those of X-linked SCID c. ADA and PNP deficiencies i. Associated with enzyme deficiencies in the purine salvage pathway ii. Toxic metabolites responsible for the destruction of lymphocytes that cause the immune deficiency d. IL-2 deficiency i. Molecular defect unknown ii. Often associated with other cytokine production defects e. ZAP-70 PTK deficiency: caused by a mutation in the gene coding for this tyrosine kinase, which is important in T-cell signaling and is critical in positive and negative selection of T cells in the thymus f. Bare lymphocyte syndrome i. Deficiency of major histocompatibility complex (MHC) ii. Absent or decreased MHC type I levels iii. Decreased MHC type II levels on mononuclear cells g. Omenn syndrome: believed to be caused by a mutation impairing the function of immunoglobulin and TCR recombinase genes, such as RAG1 and RAG2 genes

CLINICAL FEATURES 1. Age of onset: 3–6 months of life 2. Usual presentation with infections due to lack of T-cell function a. Opportunistic organisms i. Pneumocystis carinii pneumonia ii. Systemic candidiasis iii. Atypical mycobacterium iv. Cryptosporidium v. Pneumococcus b. Recurrent infections c. Persistence of infections despite conventional treatment 3. Failure to thrive 4. Oral or diaper candidiasis 5. Dehydration from chronic diarrhea

6. 7. 8. 9. 10. 11. 12. 13. 14.

15. 16. 17. 18. 19.

20.

21. 22.

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Fevers Rashes Cough and congestion Increased reparatory rate and effort Absence of tonsils and lymph nodes Absence of lymphadenopathy or increased tonsillar tissue despite serious infections Pneumonias Sepsis Disseminated infections a. Salmonella b. Varicella c. Cytomegalovirus d. Epstein-Barr virus e. Herpes simplex virus f. BCG g. Vaccine strain (live) polio virus Recurrent sinopulmonary infections Recurrent skin infections Abscesses Poor wound healing Transplacental transfer of maternal lymphocytes to the infant prenatally or during parturition causing graft-vs-host disease (GVHD), characterized by: a. Erythematous skin rashes b. Hepatomegaly c. Lymphadenopathy ADA deficiency and PNP deficiency with later onset and miler or atypical clinical presentation a. Diagnosis suspected in patients with: i. Unexplained T-cell lymphopenia ii. Late manifestations of immunodeficiency a) Chronic pulmonary insufficiency b) History of autoimmunity and neurologic abnormalities c) Onset during the first two decades of life and even later b. Diagnosis confirmed by finding absent or very low enzyme activity in erythrocytes or in nucleated blood cells Lymphadenopathy or hepatosplenomegaly in Omenn syndrome or bare lymphocyte syndrome Prognosis a. Fatal if untreated b. Bone marrow transplantation or enzyme replacement to reconstitute the immune system compatible with long survival

DIAGNOSTIC INVESTIGATIONS 1. Blood workup a. Complete blood cell count with differential to detect lymphopenia b. Lymphocyte markers to obtain percentages and absolute counts i. CD3+ T cells ii. CD4+ T cells iii. CD8+ T cells iv. CD19+ T cells v. NK cell markers (CD16 and CD56)

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2.

3.

4.

5.

6.

SEVERE COMBINED IMMUNE DEFICIENCY

c. Immunoglobulin concentrations i. Low IgA and IgM ii. IgG a) Generally normal at birth b) Declines as maternally transferred IgG disappears by three months of age d. Lymphocyte functional tests i. Absence of responses to vaccines and infectious agents ii. Lacking T-cell responses to mitogens Chest X-ray a. Absent to small thymus shadow b. Pneumonia c. Typical cupping and flaring of the costochondral junction in patients with ADA deficiency Lymph node biopsy a. Paucity of T and B cells b. Lack of germinal centers Consider X-SCID in male infants with: a. Severe recurrent or persistent infections b. Infections not responding to ordinary treatment c. Infections caused by opportunistic pathogens d. Failure to thrive Confirmatory tests a. Determination of the ADA and PNP levels i. Lymphocytes ii. Erythrocytes iii. Fibroblasts b. X-inactivation studies to determine whether the SCID is X-linked c. Molecular genetic testing i. X-SCID a) Sequence analysis of the IL2RG coding region detecting a mutation in >99% of affected individuals b) Mutation analysis Carrier testing of X-SCID a. Testing for known family-specific IL2RG mutations b. Sequence analysis of the IL2RG coding region and splice regions c. Southern blot analysis used to detect large deletions and complex mutations if the family-specific mutation is not known and sequence analysis is uninformative d. X-chromosome inactivation studies on lymphocytes for at-risk females in whom sequence analysis and/or mutation analysis are not an option for carrier testing or are not informative, provided presence of the following two conditions: i. Skewed X-chromosome inactivation in lymphocytes ii. Nonskewed X-chromosome inactivation in another blood lineage such as granulocytes

GENETIC COUNSELING 1. Recurrence risk a. X-SCID i. Female germline mosaicism present if a woman has more than one affected son and the

disease-causing mutation in the IL2RG gene cannot be detected in her leukocytes ii. Over 50% of affected males do not have family history of early deaths in maternal male relatives iii. Patient’s sib if the mother is a carrier a) 50% of males sibs affected b) 50% of females sibs carriers iv. Patient’s sib is still at increased risk even if the disease-causing mutation has not been identified in the mother’s leukocytes since germline mosaicism has been demonstrated in this condition v. Patient’s offspring (offspring of affected males) a) 100% of daughters carriers b) None of sons affected b. Autosomal recessive SCID i. Patient’s sib: 25% ii. Patient’s offspring: not increased unless the spouse is a carrier in which case 25% of the offspring will be affected 2. Prenatal diagnosis a. X-SCID i. Determination on fetal cells obtained by CVS or amniocentesis ii. Analysis of DNA from fetal cells for the known disease-causing mutation, provided: a) Karyotype revealing 46,XY b) The disease-causing IL2RG mutation has been identified in a family member iii. Fetal blood sampling for immunological evaluation when the family-specific mutation is not known a) Lymphocytopenia b) Low numbers of T cells c) Poor T cell blastogenic responses to mitogens b. Autosomal recessive SCID i. JAK3 deficient SCID a) Immunophenotypic evaluation of cord blood cells at 18–20 weeks of gestation b) Direct gene analysis using chorionic villus sampling derived DNA in the first trimester ii. ADA deficiency: prenatal diagnosis established by measuring ADA enzyme activity in amniotic cells or chorionic villi 3. Management a. X-linked SCID and JAK3 PTK deficiency i. Fatal disease unless cured by bone marrow transplantation (BMT) a) The best results achieved by using an HLA-matched sibling as a donor (success rates of 97%) b) Using haploidentical T-cell depleted BMT from a parent (haploidentical family donors resulting in lower success rates of 52%): lifesaving for the majority of X-SCID patients who lack matched sibling ii. Monthly intravenous immunoglobulin replacement therapy required if B cells do not engraft iii. Report of in utero transplantation of hematopoietic progenitor cells allowing immune reconstitution in a fetus

SEVERE COMBINED IMMUNE DEFICIENCY

b.

c.

d.

e.

iv. Gene therapy a) Using autologous bone marrow stem/progenitor cells retrovirally transduced with a therapeutic gene b) Successful in reconstituting the immune system in patients with X-SCID c) Youngest two of the first ten infants treated in a French study developed leukemia due to retroviral insertional mutagenesis d) Currently a consideration only for those who are not candidates for bone marrow transplantation or have failed bone marrow transplantation ADA deficiency i. Usually fatal unless: a) Keeping affected children in protective isolation, or b) Reconstituting the immune system by bone marrow transplantation from a human leukocyte antigen (HLA)-identical sibling donor (therapy of choice but only available for a minority of patients) ii. Exogenous enzyme replacement primarily with polyethylene glycol-conjugated ADA replacement (PED-ADA) therapy a) Providing noncurative, life-saving treatment for ADA- SCID patients b) Increased peripheral T cell counts providing a source of T cells for gene correction not available without enzyme therapy c) Weight gain and decreased opportunistic infections in most patients d) Improved T cell function as measured by in vitro mitogen responses in most patients e) Recovery of consistent immune responses to specific antigens in fewer patients iii. The first genetic disorder treated by gene therapy: a clinical trial using retroviral mediated transfer of the adenosine deaminase (ADA) gene into the T cells of children with ADA- SCID a) Normalization of the number of blood T cells as well as many cellular and humoral immune responses b) Successful gene transfer into long-lasting progenitor cells, producing a functional multilineage progeny c) Safe and effective addition to treatment for some patients iv. Combined treatment with PEG-ADA and gene therapy PNP deficiency and bare lymphocyte syndrome: primarily with bone marrow transplantation when an appropriate donor is available IL-2 production defects: i. Primarily with intravenous IL-2 replacement ii. Alternatively with bone marrow transplantation when an appropriate donor is available Omenn syndrome i. Primarily with bone marrow transplantation when an appropriate donor is available

f.

g.

h. i.

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ii. Pretreatment ablative chemotherapy necessary because of maternal cell engraftment Bone marrow transplantation from a related donor: a life-saving and life-sustaining treatment for patients with any type of severe combined immune deficiency, even when there is no HLA-identical donor Two fetuses successfully treated with gene therapy in utero by an injection of haploidentical CD34+ cells for the γ chain deficiency Psychosocial support for the affected family Avoid live vaccines

REFERENCES Antoine C, Muller S, Cant A, et al.: Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968–99. Lancet 361:553–60, 2003. Arredondo-Vega FX, Santisteban I, Daniels S, et al.: Adenosine deaminase deficiency: genotype-phenotype correlations based on expressed activity of 29 mutant alleles. Am J Hum Genet 63:1049–1059, 1998. Belmont JW, Puck JM: T cell and combined immunodeficiency syndromes. In: Scriver DR, Beaudet al., Sly WS (eds) The Metabolic and Molecular Bases of Inherited Disease, 8 ed. McGraw-Hill, New York, 2001, pp 4751–4784. Blaese RM, Culver KW, Miller AD, et al.: T lymphocyte-directed gene therapy for ADA-SCID: initial trial results after 4 years. Science 270:475–480, 1995. Bordignon C, Notarangelo LD, Nobili N, et al.: Gene therapy in peripheral blood lymphocytes and bone marrow for ADA-immunodeficient patients. Science 270:470–475, 1995. Buckley RH, Schiff RI, Schiff SE, et al.: Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants. J Pediatr 130:378–387, 1997. Buckley RH, Schiff SE, Schiff RI, et al.: Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med 340:508–516, 1999. Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, et al.: Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 288:669–673, 2000. Davis J, Puck JM: X-linked severe combined immunodeficiency. http://www. geneclinics.org Fisher A: Severe combined immunodeficiencies. Immunodefic Rev 3:83–100, 1992. Fisher A, Hacein-Bey S, Le Deist F, et al.: Gene therapy for human severe combined immunodeficiencies. Immunity 15:1–4, 2001. French gene therapy group reports on the adverse event in a clinical trial of gene therapy for X-linked severe combined immune deficiency (X-SCID). Position statement from the European Society of Gene Therapy. J Gene Med 5:82–84, 2003. Gansbacher B: Report of a second serious adverse event in a clinical trial of gene therapy for X-linked severe combined immune deficiency (X-SCID). Position of the European Society of Gene Therapy (ESGT). J Gene Med 5:261–262, 2003. Gaspar HB, Gilmour KC, Jones AM: Severe combined immunodeficiencymolecular pathogenesis and diagnosis. Arch Dis Child 84:169–173, 2001. Hershfield MS: Enzyme replacement therapy of adenosine deaminase deficiency with polyethylene glycol-modified adenosine deaminase (PEG-ADA). Immunodeficiency 4:93–97, 1993. Hershfield MS: PEG-ADA replacement therapy for adenosine deaminase deficiency: an update after 8.5 years. Clin Immunol Immunopathol 76:S228–S232, 1995. Hershfield MS: PEG-ADA: an alternative to haploidentical bone marrow transplantation and an adjunct to gene therapy for adenosine deaminase deficiency. Hum Mutat 5:107–112, 1995. Hershfield MS, Mitchell BS: Immunodeficiency diseases caused by adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency. In Scriver CR, Beaudet al., Sly WS, Valle D (eds): The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001, Chapter 109, pp 2586–2588. Hoogerbrugge PM, van Beusechem VW, Fischer A, et al.: Bone marrow gene transfer in three patients with adenosine deaminase deficiency. Gene Ther 3:179–183, 1996.

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Kalman L, Lindegren ML, Kobrynski L, et al.: Mutations in genes required for T-cell development: IL7R, CD45, IL3RG, JAK3, RAG1, RAG2, ARTEMIS, and ADA and severe combined immunodeficiency: HUGE review. Genet Med 6:16–26, 2004. Myers LA, Patel DD, Puck JM, et al.: Hematopoietic stem cell transplantation for severe combined immunodeficiency in the neonatal period leads to superior thymic output and improved survival. Blood 99:872–8, 2002. Puck JM: Primary immunodeficiency diseases. JAMA 278:1835–1841, 1997. Puck JM, Middelton L, Pepper AE: Carrier and prenatal diagnosis of X-linked severe combined immunodeficiency: mutation detection methods and utilization. Hum Genet 99:628–633, 1997. Puck JM, Nussbaum RL, Conley ME: Carrier detection in X-linked severe combined immunodeficiency based on patterns of X chromosome inactivation. J Clin Invest 79:1395–400, 1987.

Rosen FS: Severe combined immunodeficiency: a pediatric emergency. J Pediatr 130:345–346, 1997. Secord EA: Severe combined immunodeficiency. http://www.emedicine.com. Emedicine 2002. Stephan JL, Vlekova V, Le Deist F, et al.: Severe combined immunodeficiency: a retrospective single-center study of clinical presentation and outcome in 117 patients. J Pediatr 123:564–72, 1993. Ting SS, Leigh D, Lindeman R, et al.: Identification of X-linked severe combined immunodeficiency by mutation analysis of blood and hair roots. Br J Haematol 106:190–194, 1999. Wengler GS, Lanfranchi A, Frusca T, et al.: In-utero transplantation of parental CD34 haematopoietic progenitor cells in a patient with Xlinked severe combined immunodeficiency (SCIDX1). Lancet 348: 1484–1487, 1996.

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Fig. 1. A healthy 9-year-old boy with ADA deficient SCID who has been receiving bi-weekly Adagen (Pegademase) injections since early infancy.

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Short Rib Polydactyly Syndromes Short rib-polydactyly syndromes (SRPS) are a heterogeneous group of recessively inherited lethal skeletal dysplasia. There are four classic subtypes: type I (Saldino-Noonan) (SRPS I), type II (Majewski) (SRPS II), type III (Verma-Naumoff) (SRPS III), and type IV (Beemer-Langer) (SRPS IV).

GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive in all four subtypes 2. Different subtypes of SRPS a. A great overlap of anomalies present among different subtypes contributing to diagnostic dilemmas in the short rib-polydactyly syndrome group b. Possibly represent a continuous spectrum with variable expressivity, suggested by some reports

CLINICAL FEATURES 1. SRPS I (Saldino-Noonan) a. Constant findings i. Severely shortened (flipper-like) limbs with postaxial polydactyly ii. Small/narrow thorax with short ribs and hypoplastic lungs iii. Protuberant abdomen iv. Early neonatal death b. Common findings i. Hydrops fetalis ii. Gastrointestinal abnormalities a) Esophageal atresia b) Short small intestine c) Malrotation of the bowel d) Imperforate anus e) Persistent cloaca f) Imperforate anus g) Pancreatic fibrosis and cysts iii. Cardiac malformations a) Transposition of the great vessels b) Coarctation of the aorta or hypoplastic aortic arch c) Ventricular septal defects d) Double-outlet left ventricle c. Occasional findings i. Oligohydramnios ii. Renal dysplasia/cystic disease iii. Abnormal genitalia a) Cryptorchidism b) Hypoplastic penis iv. CNS malformations a) Cerebellar hypoplasia b) Dandy-Walker malformation

884

v. Bifid epiglottis vi. Bifid tongue vii. Cleft upper lip 2. SRPS II (Majewski) a. Constant findings i. Extremely short limbs with pre/postaxial polydactyly of the hands and feet ii. Small/narrow chest with short ribs and pulmonary hypoplasia iii. Protuberant abdomen iv. Median cleft lip or pseudo-cleft of the upper and lower lip or cleft palate v. Epiglottis and larynx hypoplasia vi. Short/ovoid tibias with round ends vii. Presence of premature ossification centers viii. Early neonatal death b. Common findings i. Polyhydramnios ii. Hydrops fetalis iii. Ocular hypertelorism iv. Broad and flat nose v. Low-set ears vi. Ambiguous genitalia vii. Renal cystic disease c. Occasional findings i. Short small intestine ii. Malrotation of the bowel iii. Cardiac malformations iv. Dysplastic pancreas 3. SRPS III (Verma-Naumoff) a. Constant findings i. Severely shortened limbs with postaxial polydactyly ii. Small/narrow thorax with short ribs and hypoplastic lungs iii. Early neonatal death b. Common findings i. Hydrops fetalis ii. Short cranial base iii. Bulging forehead iv. Depressed nasal bridge v. Flat occiput vi. Renal cystic dysplasia c. Occasional findings i. Congenital heart defects a) Ventricular septal defect b) Situs inversus ii. Epiglottic hypoplasia iii. Intestinal malrotation iv. Cloacal developmental abnormalities and ambiguous genitalia

SHORT RIB POLYDACTYLY SYNDROMES

4. SRPS IV (Beemer-Langer) a. Constant findings i. Severely shortened limbs with or without postaxial polydactyly ii. Small/narrow thorax with short ribs and hypoplastic lungs iii. Early neonatal death b. Common findings i. Hydrops fetalis ii. Macrocephaly with frontal bossing iii. Ocular hypertelorism iv. Flat nasal bridge v. Cleft lip and palate vi. Protuberant abdomen c. Occasional findings i. CNS abnormalities a) Holoprosencephaly/absence of the corpus callosum/hydrocephalus b) Dandy-Walker cyst and/or arachnoid cyst c) Hypothalamic hamartomas ii. Lobulated tongue with hamartomas iii. Oral frenula iv. Congenital heart defects v. Malrotation of the intestine vi. Renal malformations a) Renal cystic dysplasia b) Atresia of the ureter with hydronephrosis and hydroureter vii. Omphalocele viii. Inguinal hernia

DIAGNOSTIC INVESTIGATIONS 1. Radiography a. SRPS I (Saldino-Noonan) i. Extreme micromelia with severely dysplastic pointed (or ragged) metaphyses of the long tubular bones, and absence of corticomedullary demarcation ii. Narrow thorax with short/horizontal ribs iii. Deficient ossification in calvarium, vertebrae, pelvis, and bones of the hands and feet iv. Small iliac bones with horizontal acetabulae v. Postaxial polydactyly vi. Short tibiae b. SRPS II (Majewski) i. Extreme micromelia with smooth rounded metaphyses ii. Extremely short horizontal ribs iii. Normal pelvis and vertebrae iv. Disproportionately shortened ovoid-shaped tibiae v. Pre- and post-axial polydactyly, syndactyly, and brachydactyly vi. Advanced skeletal ossification—advanced maturation of the proximal femora and humeri c. SRPS III (Verma-Naumoff) i. Extreme micromelia with severely dysplastic widened metaphyses (bones of the legs) and clear corticomedullary demarcation of the long tubular bones

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ii. iii. iv. v.

Extremely shortened and horizontal ribs Small and malformed vertebral bodies Shortened cranial base Short iliac bones with horizontal trident lower margin vi. Polydactyly d. SRPS IV (Beemer-Langer) i. Extreme micromelia with smooth metaphyseal margins ii. Extremely shortened and horizontal ribs iii. Small, poorly ossified vertebrae and increased intervertebral spaces iv. High clavicles and small scapulae v. Small iliac bones vi. Bowed radii and ulnae vii. Tibiae: well tabulated and longer than fibulae viii. Postaxial polydactyly 2. Histopathology/necropsy a. SRPS I (Saldino-Noonan) i. Markedly retarded and frequently deranged endochondral ossification. A large island of fibrous tissue may occupy the center of physeal growth zone. A premature ossification center may be seen in the epiphyseal resting cartilage. ii. Lungs: hypoplasia which is easily assessed by abnormally small size and low weight iii. Identify associated multiple congenital anomalies listed in the clinical features b. SRPS II (Majewski) i. Markedly retarded endochondral ossification. The chondrocytes in the physeal growth zones are markedly reduced in number and disorderly arranged. ii. Lungs: hypoplasia as in type I iii. Identify associated multiple congenital anomalies listed in the clinical features c. SRPS III (Verma-Naumoff) i. Markedly retarded endochondral ossification as in type II. A single patient showed chondrocytic inclusions which are PAS reactive and diastase resistant. ii. Lung: hypoplasia as in type I iii. Identify associated multiple congenital anomalies which are less common in this type d. SRPS IV (Beemer-Langer) i. Physeal growth zones showing a prominent but disorganized zone of hypertrophy. The vascuolar penetration of physeal cartilage is irregular. ii. Lungs: hypoplasia as in type I iii. Identify associated multiple congenital anomalies listed in the clinical features

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: the patients will not survive to reproductive age 2. Prenatal diagnosis: not always possible to differentiate the subtypes

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a. Ultrasonography for SRPS I (Saldino-Noonan) i. Short fetal limbs ii. Narrow thorax iii. Polydactyly iv. Pointed metaphyses v. Dysplastic cystic kidneys vi. Congenital heart defect vii. Genital anomalies b. Ultrasonography for SRPS II (Majewski) i. With a positive family history of Majewski syndrome a) Presence of short fetal limbs b) Other skeletal findings ii. Without a family history a) Short fetal limbs b) Disproportionately short tibia c) Very narrow fetal chest d) Short ribs e) Bilateral postaxial polydactyly of the hands and feet f) Median cleft lip and palate g) Polyhydramnios h) Hydrops i) Marked shortened humerus and femur j) Severe bowing and deformity of the bones of the lower leg and forearm k) Hypoplastic lungs l) Congenital heart defect m) Enlarged echogenic kidneys n) Genital anomalies c. Ultrasonography for SRPS III (Verma-Naumoff) i. Short fetal limbs ii. Small/narrow thorax iii. Short thin ribs iv. Polydactyly v. Widened metaphyses with marginal spurs vi. Micromelia d. Ultrasonography for SRPS IV (Beemer-Langer) i. Short fetal bones ii. Small/narrow thorax iii. Short thin ribs iv. Polydactyly e. Fetoscopy i. To identify fetus with SRPS phenotype ii. An invasive procedure currently replaced by ultrasonography 3. Management: supportive therapy only for these lethal entities

REFERENCES Beemer FA: Short-rib syndrome classification. Am J Med Genet Suppl 3:209–210, 1987. Beemer FA, Langer LO Jr, Klep-de Pater JM, et al.: A new short rib syndrome: report of two cases. Am J Med Genet 14:115–123, 1983.

Benacerraf BR: Prenatal sonographic diagnosis of short rib-polydactyly syndrome type II, Majewski type. J Ultrasound Med 12:552–555, 1993. Black IL, Fitzsimmons J, Fitzsimmons E, et al.: Parental consanguinity and the Majewski syndrome. J Med Genet 19:141–143, 1982. Chen H, Yang SS, Gonzalez E, Fowler M, Al Saadi A: Short rib-polydactyly syndrome, Majewski type. Am J Med Genet 7:215–222, 1980. Chen H, Mirkin D, Yang S: De novo 17q paracentric inversion mosaicism in a patient with Beemer-Langer type short rib-polydactyly syndrome with special consideration to the classification of short rib polydactyly syndromes. Am J Med Genet 53:165–171, 1994. Cooper CP, Hall CM: Lethal short-rib polydactyly syndrome of the Majewski type: a report of three cases. Radiology 144:513–517, 1982. Corsi A, Riminucci M, Roggini M, et al.: Short rib polydactyly syndrome type III: histopathogenesis of the skeletal phenotype. Pediatr Dev Pathol 5:91–96, 2002. Elçiog˘lu N, Karatekin G, Sezgin B, et al.: Short rib-polydactyly syndrome in twins: Beemer-Langer type with polydactyly. Clin Genet 50:159–163, 1996. Elçiog˘lu NH, Hall CM: Diagnostic dilemmas in the short rib-polydactyly syndrome group. Am J Med Genet 111:392–400, 2002. Golombeck K, Jacobs VR, von Kaisenberg C, et al.: Short rib-polydactyly syndrome type III: comparison of ultrasound, radiology, and pathology findings. Fetal Diagn Ther 16:133–138, 2001. Hennekam RC: Short rib syndrome—Beemer type in sibs. Am J Med Genet 40:230–233, 1991. Martinez-Frias ML, Bermejo E, Urioste M, et al.: Lethal short rib-polydactyly syndromes: further evidence for their overlapping in a continuous spectrum. J Med Genet 30:937–941, 1993. Meizner I, Bar-Ziv J: Prenatal ultrasonic diagnosis of short-rib polydactyly syndrome (SRPS) type III: a case report and a proposed approach to the diagnosis of SRPS and related conditions. J Clin Ultrasound 13:284–287, 1985. Meizner I, Bar-Ziv J: Prenatal ultrasonic diagnosis of short rib polydactyly syndrome, type I. A case report. J Reprod Med 34:668–672, 1989. Meizner I, Barnhard Y: Short-rib polydactyly syndrome (SRPS) type III diagnosed during routine prenatal ultrasonographic screening. A case report. Prenat Diagn 15:665–668, 1995. Motegi T, Kusunoki M, Nishi T, et al.: Short rib-polydactyly syndrome, Majewski type, in two male siblings. Hum Genet 49:269–275, 1979. Naumoff P, Young LW, Mazer J, et al.: Short rib-polydactyly syndrome type 3. Radiology 122:443–447, 1977. Richardson MM, Beaudet AL, Wagner ML, et al.: Prenatal diagnosis of recurrence of Saldino-Noonan dwarfism. J Pediatr 91:467–471, 1977. Sillence DO: Non-Majewski short rib-polydactyly syndrome. Am J Med Genet 7:223–229, 1980. Sillence D, Kozlowski K, Bar-Ziv J, et al.: Perinatally lethal short rib-polydactyly syndromes. 1. Variability in known syndromes. Pediatr Radiol 17:474–480, 1987. Toftager-Larsen K, Benzie RJ: Fetoscopy in prenatal diagnosis of the Majewski and the Saldino-Noonan types of the Short Rib-Polydactyly syndromes. Clin Genet 26:56–60, 1984. Yang SS, Lin CS, Al Saadi A, et al.: Short rib-polydactyly syndrome, type 3 with chondrocytic inclusions: report of a case and review of the literature. Am J Med Genet 7:205–213, 1980. Yang SS, Langer LO Jr, Cacciarelli A, et al.: Three conditions in neonatal asphyxiating thoracic dysplasia (Jeune) and short rib-polydactyly syndrome spectrum: a clinicopathologic study. Am J Med Genet Suppl 3:191–207, 1987. Yang SS, Roth JA, Langer LO Jr: Short rib syndrome Beemer-Langer type with polydactyly: a multiple congenital anomalies syndrome. Am J Med Genet 39:243–246, 1991.

SHORT RIB POLYDACTYLY SYNDROMES

Fig. 1. Radiograph of a neonate with Saldino-Noonan syndrome (SRPS I) showing extremely shortened horizontal ribs, very small and dysplastic vertebral bodies and iliac cones, and very short tubular bones with irregular metaphyses.

Fig. 2. Photomicrograph of femur (SRPS I) shows markedly retarded and disorganized physeal growth zone.

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Fig. 3. Photomicrograph of humerus (SRPS I) shows markedly disrupted physeal growth zone by a large cartilage canal-like vascular fibrous tissue. In addition, there is a large premature ossification center (upper one third of the picture).

Fig. 4. A neonate with Majewski syndrome (SRPS II) showed hydrops, a large head, hairy forehead, small, malformed, and low-set ears, telecanthus, short nose, a flat nasal bridge, a central cleft upper and lower lips, short neck, short and narrow chest, markedly distended abdomen with ascites, extremely short limbs with pre- and postaxial polydactyly, syndactyly, and brachydactyly.

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Fig. 5. Mouth of the neonate in Fig. 4 showing lobulated tongue and mucosal frenular.

Fig. 6. Ambiguous genitalia with a barely visible micropenis (SRPS II).

Fig. 8. Radiographs (SRPS II) showing extremely short, horizontal ribs, high clavicles, unremarkable spine and pelvis, premature ossification of the proximal epiphyses of the humeri, femora, and lateral cuboids. The tubular bones were extremely short, especially the mesomelic segments. The tibiae were disproportionately short and oval in shape.

Fig. 7. Hands and feet showed pre and postaxial polydactyly, syndactyly, and brachydactyly (SRPS II).

SHORT RIB POLYDACTYLY SYNDROMES

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Fig. 11. Photomicrograph of renal cortex showing many dilated glomeruli and mildly cystic renal tubules (SRPS II).

Fig. 9. Respiratory system (necropsy) (SRPS II) showing a small larynx with hypoplastic epiglottis (arrow) and remarkably small and hypoplastic lungs. The patient’s thymus is juxtaposed for comparison.

Fig. 10. Photomicrograph of tibia cartilage (SRPS II) (Hematoxylineosin, ×108) showing a markedly stunted and disorganized physeal growth zone.

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Fig. 12. Radiographs of the skeletal system (SRPS III) showing extremely short and horizontal ribs, small dysplastic vertebral bodies and ilia, short tubular bones with widened metaphyses with longitudinal spurs

Fig. 13. Photomicrograph of the cartilage of the iliac crest (SRPS III) showing retardation and disorganization of physeal growth zone.

Fig. 14. Higher magnification of the chondrocytes in the resting cartilage and the physeal zone of proliferation frequently show cytoplasmic inclusions (PAS after diastase digestion) (SRPS III).

SHORT RIB POLYDACTYLY SYNDROMES

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Fig. 16. Radiograph of another premature neonate (SRPS IV) showing extremely short and horizontal ribs, small dysplastic vertebral bodies, small iliac wings, and short tubular bone.

Fig. 15. A fetus with Beemer-Langer syndrome showing macrocephaly, cystic hygroma, severe micro/retrognathia with cleft palate, low-set and malformed ears, short limbs, narrow thorax, protuberant abdomen with an omphalocele, and polydactyly. The radiographs show short, horizontal ribs, small scapulae, relatively poorly ossified vertebral bodies, small ilia, short tubular bones with absence of metaphyseal spicules, bowed radii and ulnae, and postaxial polydactyly. The ultrasonograph shows porencephalic cyst. The fetus also had a de novo paracentric inversion of chromosome 17q (q12;q25).

Fig. 17. Physeal growth zone of femur showing prominent but disorganized zone of hypertrophy (SRPS IV).

Sickle Cell Disease Sickle cell disease is the most common single gene disorder in Afro Americans, affecting approximately one in 375 persons of African ancestry. The frequency of sickle cell trait is about 8% in the United States blacks. Sickle blood cells have an increased resistance to malaria. Protection from malaria helps maintain the high prevalence of the sickle gene in areas where malaria is endemic.

ii. Hb C iii. Hb DLos Angels iv. Hb E v. Hb Lepore vi. Hb OArab vii. Hb CHarlem viii. Hb Quebec-Chori 4. Pathophysiology of sickle cell disease a. Hemolysis: the shortened survival of SS red blood cells results from the following two apparently independent properties of Hb S: i. Propensity of the concentrated Hb to polymerization resulting in: a) Morphologic sickling b) RBC dehydration c) A marked decrease in RBC deformability ii. Hemoglobin S instability b. Erythropoiesis i. Submaximal erythropoietic response ii. Abnormally low affinity for oxygen of SS cells iii. Response of the red cells’ glycolytic metabolism to hypoxia

GENETICS/BASIC DEFECTS 1. Inheritance: autosomal recessive 2. Caused by a point mutation at the second nucleotide of codon 6 of the β-globin gene. The base change of A to T causes the amino acid substitution of valine for glutamic acid (GAG to GTG) a. Immediate consequence of the mutation: Deoxygenated hemoglobin S polymerizes and distorts the shape of the red blood cell, causing vaso-occlusion in the small vessels b. Adverse effects of sickle hemoglobin on the red cell membrane i. Oxidative damage ii. Cellular dehydration iii. Abnormal phospholipid asymmetry iv. Increased adherence to endothelial cells c. Results of cellular abnormalities i. Shortened red cell lifespan causing a lifelong hemolytic anemia ii. Intermittent episodes of vascular occlusion causing tissue ischemia and acute and chronic organ dysfunction 3. Sickle cell disease a. Sickle cell anemia (homozygous sickle cell disease, Hb SS) i. Accounts for 60–70% of sickle cell disease in the US ii. The most common form of sickle cell disease iii. Caused by inheritance of hemoglobin S from both parents b. Other clinically significant sickle cell disorders caused by coinheritance of a sickle gene with a gene for: i. β-thalassemia: a) The β-thalassemias are divided into β+thalassemia (in which some β globin chains are produced) and β0-thalassemia (in which there is no β chain synthesis) b) Clinical pictures of patients with hemoglobin S β+-thalassemia and S β0-thalassemia resembles sickle cell disease rather than thalassemia, because the sickle β globin predominates in the presence of underproduction of normal β globin

CLINICAL FEATURES

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1. Infection a. The most immediate risk for infants diagnosed with sickle cell disease b. Prone to many bacterial infections, especially from encapsulated organisms, because of lack of splenic function resulting from progressive infarction of the spleen due to sickling of the red cells 2. Hemolysis a. Chronic anemia: Hemolytic anemia develops around three months of age. b. Jaundice (indirect hyperbilirubinemia) c. Aplastic crises i. Erythrocyte production by the bone marrow may pause temporarily in children with sickle cell disease. ii. Human parvovirus 19 infection responsible for 80% of aplastic crises d. Cholelithiasis i. Prone to develop pigmented gallstones due to large load of bilirubin from hemoglobin breakdown (chronic hemolysis) ii. Presenting symptoms: severe recurrent right upper quadrant pain, episode of cholecystitis, common duct obstruction, or pancreatitis e. Delayed growth and sexual maturation 3. Vaso-occlusion due to occlusion of the microcirculation by rigid red cells and consequent tissue anoxia and infarction

SICKLE CELL DISEASE

a. Recurrent acute pain i. Dactylitis (hand and foot syndrome) occurs in 25–45% of the patients and can be the earliest manifestation of sickle cell disease. The syndrome is rare after 4 years of age. It is believed to be due to infarction of the red marrow and associated periosteal inflammation. The clinical manifestations are fever and painful swelling of the hands or feet or both ii. Musculoskeletal pain iii. Abdominal pain b. Functional asplenia i. The proportion of children with Hb SS who are functionally asplenic: 1 year (28%), 2 years (58%), 3 years (78%), and 5 years (94%) ii. At risk for fulminant septicemia and meningitis with pneumococci and other encapsulated bacteria and death during the first 3 years of life in most patients with Hb SS c. Splenic sequestration (10–30% of children with Hb SS most commonly between 6 months and 3 years of life) i. Sudden massive collection of blood in the spleen due to sickle cells blocking outflow ii. Rapid enlargement of the spleen causing acute fall of the hemoglobin level of more than 2 g/dL, despite a persistently elevated reticulocyte count iii. Mild to moderate thrombocytopenia caused by sequestered platelets iv. Symptoms a) Acute pallor b) Lethargy c) Increased thirst d) Abdominal fullness e) Tachycardia f) Tachypnea v. May be associated with other complications of sickle cell disease, such as acute chest syndrome, vaso-occlusive pain, bacterial infection, stroke, or aplastic crisis vi. Increased tendency of recurrence (50%) vii. High mortality (second leading cause of death in children with sickle cell anemia) d. Acute chest syndrome i. Appearance of a new pulmonary infiltrate on chest radiography ii. Causes a) Infection (bacterial pneumonia, atypical bacterial pneumonia by Mycoplasma or Chlamydia, viral pneumonia, Parvovirus B19) b) Pulmonary vascular occlusion (in situ pulmonary thrombosis, fat embolism, peripheral thromboembolism) c) Hypoventilation/atelectasis (thoracic bony infarction, abdominal pain, opioids) d) Pulmonary edema (intravenous fluids, opioids, pulmonary vascular injury) e) Bronchospasm iii. Presenting with varying degrees of fever, cough, tachypnea, pleuritic chest pain, and/or hypoxemia

e.

f.

g.

h.

i.

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iv. Occurs in more than 50% of pediatric patients with Hb SS v. The second leading cause for hospitalization vi. Predispose to chronic restrictive lung disease with pulmonary hypertension and cor pulmonale (important causes of morbidity and mortality in adulthood) Stroke i. Caused by complete occlusion or severe narrowing of large cerebral vessels ii. Occurs in 7–8% of children with Hb SS after the first year of life, less commonly in children with Hb SC and sickle beta-thalassemia iii. Presenting symptoms a) Hemiparesis b) Monoparesis c) Aphasia d) Dysphasia e) Seizures f) Semicoma g) Coma h) Transient ischemic attack iv. High rate of recurrence (60–90% have a second stroke within 3 years without transfusion therapy) v. Silent cerebral infarctions in 10–20% of children with Hb SS without clinically apparent neurologic event Chronic nephropathy: an important cause of mortality in adult patients i. Hematuria a) Persistent microscopic (asymptomatic) hematuria: one of the most prevalent features of the disease b) Gross hematuria ii. Significant proteinuria (30%) iii. Papillary necrosis iv. Hyposthenuria and enuresis: inability to concentrate urine resulting in a high incidence of enuresis v. Nephrotic syndrome (40%) vi. Renal infarction vii. Pyelonephritis viii. Renal medullary carcinoma ix. Hypertension (2–6% in patients with Hb SS) x. Renal failure (5–18%) Priapism (painful erection) i. Affects about 2/3 of male patients ii. Recurrent attacks eventuate in impotence in 50% of the patients Bone disorders i. Dactylitis (hand-foot syndrome) ii. Bone infarction: manifestations include pain, tenderness, and frequently swelling at the involved site(s) iii. Aseptic necrosis of the long bones: manifestations include pain or limitation of motion in the hip, shoulder, or other joints, and during walking and climbing stairs Proliferative retinopathy

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SICKLE CELL DISEASE

j. Leg ulcers i. Most common cutaneous complication in sickle cell anemia ii. Causing pain, physical disfigurement, social isolation, vocational adversity, and high utilization of health care resources iii. Most common in the ankle area over the medial or lateral malleoli, less common over the dorsum of the foot and near the Achilles tendon iv. Universal secondary infections (Staphylococcus aureus and Pseudomonas aeruginosa most common pathogens) k. Osteomyelitis i. Salmonella (most common cause) ii. Staphylococcus aureus l. Transfusional hemosiderosis 4. Prognosis a. Natural history of sickle cell anemia conducted before mandated newborn screening programs: 15% of children die from acute infections or acute anemic events in the first five years of life b. Hb SC disease i. Clinical manifestations milder than Hb SS disease ii. Mild hemolytic anemia iii. Risk of overwhelming sepsis and death: less than that in Hb SS disease because of the later onset of splenic dysfunction iv. Risk of splenic sequestration up to young adulthood v. Splenomegaly vi. Vaso-occlusion vii. Proliferative retinopathy viii. Aseptic necrosis of femoral head c. Early infectious morbidity and mortality in Hb SS and sickle β0-thalassemia preventable by: i. Presymptomatic diagnosis by neonatal screening ii. Extensive parental education iii. Prophylactic penicillin for infants with Hb SS and Sβ0-thalassemia (125 mg by mouth twice a day begun between 2 months and three years of age and 250 mg twice daily until at least 5 years of age) iv. Timely immunizations (all routine immunizations in a timely fashion; new heptavalent conjugated pneumococcal vaccine administered at 2 months of age; influenza virus vaccines yearly after 6 months of age; meningococcal vaccine for children with splenic dysfunction) v. Prompt medical evaluation and management of febrile illness d. Sickle cell disease and pregnancy: Affected pregnant women are at risk for: i. Crisis ii. Toxemia iii. Pyelonephritis iv. Thrombophlebitis v. Spontaneous abortion e. Progress toward specific therapies i. Transfusion therapy ii. Bone marrow transplantation iii. Hydroxyurea

DIAGNOSTIC INVESTIGATIONS 1. Laboratory studies a. CBC count i. CBC and reticulocyte counts to document anemia and brisk marrow response ii. Peripheral blood smear to document presence of sickled erythrocytes, target cells, and HowellJolly body (indicating functional asplenism) iii. Differential white cell count iv. Arterial blood gases to reflect the severity of pulmonary crises v. Hemoglobin electrophoresis to document Hb SS or Hb S with another mutant hemoglobin in compound heterozygotes vi. Liver function tests, BUN, creatinine, and serum electrolytes vii. Fetal hemoglobin 2. Imaging studies a. Radiography i. Performed in patients with respiratory symptoms ii. To detect areas of infarction for painful bones b. MRI to detect areas of avascular necrosis for the femoral and humeral heads and to distinguish osteomyelitis from bony infarction c. Abdominal sonogram to document spleen size and the presence of biliary stones d. Transcranial Doppler ultrasonography useful in selecting patients at risk for stroke 3. Sickle cell anemia (Hb SS) a. Relative clinical severity i. Markedly severe hemolysis ii. Markedly severe vasoocclusion b. Neonatal screening: hemoglobins FS c. Hemoglobin electrophoresis i. Hb A: 0% ii. Hb S: 80–95% iii. Hb F: 2–20% iv. Hb A2: 90%) b) Cardiomegaly (>90%) c) Edematous placenta (90%) d) Ascites (>90%) e) Oligohydramnios (82%) f) Subcutaneous edema (75%) g) Decreased fetal movement (74%) h) Cord edema (63%) i) Enlarged umbilical vessel (62%) j) Pericardial or pleural effusion (15%) ii. Molecular hydridization technique to detect complete absence of α-genes in fetal amniocytes in a pregnancy at risk for homozygous α-thalassemia-1 and the hydrops fetalis syndrome iii. Quantitative polymerase chain reaction for the rapid prenatal diagnosis of homozygous αthalassemia (Hb Barts hydrops fetalis) b. β-thalassemia i. Available to couples who are carriers of βthalassemia and their hemoglobin gene mutations have been identified by DNA analysis ii. Direct DNA analysis by molecular hybridization methods for the presence of the thalassemia mutation from fetal cells obtained by amniocentesis and chorionic villus biopsy iii. DNA analysis of fetal nucleated RBCs from maternal peripheral blood iv. Approach to prenatal diagnosis complicated by presence of the heterogeneity of thalassemia mutations

THALASSEMIA

3. Management a. α-thalassemia i. No therapy necessary for patients with αthalassemia trait ii. Avoid exposure to oxidant medications (e.g., iron, sulfonamides) which accelerate precipitation of Hb H and exacerbate hemolysis iii. Prompt treatment of infection especially in postsplenectomy iv. Hb H disease a) Folate supplementation b) Chronic transfusion therapy (consider iron chelation therapy to avoid iron overloading) c) Splenectomy in rare instances of hypersplenism d) Allogeneic bone marrow transplantation limited to the most severely affected patients v. Bart hemoglobinopathy a) Usually result in neonatal death b) Patients rarely salvaged by intrauterine transfusions and subsequent stem cell transplantation b. β-thalassemia i. No specific therapy required for β-thalassemia trait ii. Regular blood transfusions iii. Iron chelation with Desferrioxamine to eliminate the iron overload secondary to multiple blood cell transfusions and to increase iron absorption iv. Bone marrow transplantation a) From an HLA-identical sib b) Outcome dependent on pretransplantation clinical conditions, specifically the presence of hepatomegaly, extent of liver fibrosis and magnitude of iron accumulation c) Risk of chronic graft-vs-host disease of variable severity: 5–8% v. Cord blood transplantation a) Human umbilical cord blood contains hematopoietic stem cells capable of reconstituting bone marrow. b) Possibility of using cord blood obtained from unrelated donors with a decrease in the incidence of graft-vs-host disease vi. Attempts to increase Hb F production by following agents: variable without substantial effects a) 5-azacytidine b) Erythropoietin c) Butyrate compounds d) Hydroxyurea

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vii. Hematopoietic stem cells to correct the molecular defect by transfer of a normal gene via a suitable vector or by homologous recombination: currently under investigation

REFERENCES Abramson SD: ‘Common’ uncommon anemias. Am Fam Physician 59:851– 858, 1999. Cao A, Galanello R: Beta-thalassemia. Gene Reviews. 2003. http://www. genetests.org Cao A, Rosatelli MC, Monni G, et al.: Screening for thalassemia: a model of success. Obstet Gynecol Clin 29:305–328, 2003. Carr S, Rubin L et al.: Intrauterine therapy for homozygous alpha-thalassemia. Obstet Gynecol 85:876, 1995. Chen H: Genetic testing & counseling for hemoglobinopathies. In Chen H (ed): Ohio Department of Health. The Resource Manual for hemoglobinopathies. An Essential Guide for Health Professionals. 1992, pp 97–107. Cheung M-C, Goldberg J, Kan Y: Prenatal diagnosis of sickle cell anaemia and thalassemia by analysis of fetal cells in maternal blood. Nature Genet 14:264, 1996. Dozy AM, Kan YW, Forman EN et al.: Antenatal diagnosis of homozygous & alpha thalassemia. JAMA 241:1610, 1979. Dumars KW, Boehm G, Eckman JR, et al.: Practical guide to the diagnosis of thalassemia. Am J Med Genet 62:29–37, 1996. Giardini C, Lucarelli G: Bone marrow transplantation for beta-thalassemia. Hematol Oncol Clin North Am 13:1059–1064, 1999. Irwin JJ: Anemia in children. Am Fam Physician 64:1379–1386, 2001. Kan YW, Schwartz E, Nathan DG: Globin chain synthesis in the alpha thalassemia syndrome. J Clin Invest 45:2515, 1968. Kan YW, Golbus MS, Klein P, et al.: Successful application of prenatal diagnosis in a pregnancy at risk for homozygous β-thalassemia. N Engl J Med 292:1096–1099, 1975. Kan YW, Lee KY, Furbetta M, et al.: Polymorphism of DNA sequence in the β-globin gene region: application to prenatal diagnosis of b-thalassemia in Sardinia. N Engl J Med 302:185–188, 1980. Kelly P, Kurtzberg J, Vichinsky E, et al.: Umbilical cord blood stem cells: application for the treatment of patients with hemoglobinopathies. J Pediatr 130:695–703, 1997. Lawson JP: Thalassemia. eMedicine. 2001. http://www.emedicine.com Locatelli F, Rocha V, Reed W, et al.: Related umbilical cord blood transplantation in patients with thalassemia and sickle cell disease. Blood 101:2137–2143, 2003. Lucarelli G, Giardini C, Baronciani D: Bone marrow transplantation in thalassemia. Semin Hematol 32:297–303, 1995. Rucknagel DL: Microcytosis and the thalassemias. In Chen H (ed): Ohio Department of Health. The Resource Manual for hemoglobinopathies. An Essential Guide for Health Professionals. 1992, pp 15–18. Sackey K: Hemolytic anemia: Part 2. Pediatr Rev 20:204–208, 1999. Schwartz E, Benz EJ Jr: The thalassemia syndromes. In Hoffman R, Benz EJ Jr, Shattil SJ, et al. (eds): Hematology. Basic Principles and Practice. New York: Churchill Livingstone, pp 368–392. Segel GB, Hirsh MG, Feig SA: Managing anemia in pediatric office practice: Part 1. Pediatr Rev 23:75–84, 2002. Tongson T, Wanapirak C, Srisomboon J, et al.: Antenatal sonographic features of 100 alpha-thalassemia hydrops fetalis fetuses. J Clin Ultrasound 24:73–77, 1998. Yaish HM: Thalassemia. eMedicine. 2001. http://www.emedicine.com

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Fig. 1. Peripheral blood smear from a 58-year-old woman with microcytic anemia and frequent target cells (codocytes). Hemoglobin electrophoresis showed an AA pattern with an increased hemoglobin A2 (5.8% by HPLC) consistent with β+-thalassemia trait.

Fig. 2. Peripheral blood smear from a patient with alpha thalassemia minor shows hypochromia, target cells (arrows), and anisopoikilocytosis (Wright Giemsa stain, ×1000).

Thanatophoric Dysplasia Thanatophoric dysplasia was originally described by Maroteaux et al. in 1967. The term “thanatophoric” was coined to mean “death bearing” in Greek. Thanatophoric dysplasia is probably the most common lethal neonatal dwarfism with an estimated incidence of 0.2–0.5 per 10,000 births.

GENETICS/BASIC DEFECTS 1. Genetic heterogeneity a. Sporadic in most cases b. A new autosomal dominant mutation c. Caused by mutations in the transmembrane domains of the fibroblast growth factor receptor 3 (FGFR3) 2. Having the most extreme micromelia and the most extensive craniofacial involvement, compared to two other short limb skeletal dysplasias (achondroplasia and hypochondroplasia) which are also caused by mutations of FGFR3 3. Pathogenesis for the phenotypic features of thanatophoric dysplasia a. Normal function of FGFR3: to regulate endochondral ossification by “putting the brakes on growth” b. “Gain-of-function” type of known mutations on FGFR3 i. Primarily affect the cranial base and nasal capsule (endochondral bones) ii. With secondary effect on membrane bones which articulates with endochondral bones 4. Two major forms (TD1, TD2) of thanatophoric dysplasia, postulated based on subtle differences in skeletal radiographs and the underlying genetic mutation a. TD1 i. Curved femora ii. Very flat vertebral bodies iii. Very few TD1 patients with cloverleaf skull iv. Molecular defect consisting of a stop codon mutation or missense mutation in the extracellular domain of the FGFR3 protein, resulting in a newly created cysteine residue (Arg248Cys, most common) b. TD2 i. Straight femora ii. Taller vertebral bodies iii. Most TD2 patients with cloverleaf skull (severe craniosynostosis) iv. Molecular defect consisting of a single nucleotide substitution resulting in replacement of lysine with glutamine at position 650 (Lys650Glu) in the tyrosine kinase 2 domain of the receptor

CLINICAL FEATURES 1. Unique and homogeneous clinical features observed in patients with TD1 955

2. General features a. Virtually lethal neonatally b. A few reports with survival up to 4–5 years of age with aggressive neonatal intervention i. Markedly limited growth potential ii. Markedly delayed cognitive development iii. Respiratory insufficiency iv. Neurologic abnormalities v. Long-term medical care and chronic ventilator dependence 3. Craniofacial features a. Head i. Disproportionally large (macrocephaly) ii. Frontal bossing iii. With or without cloverleaf (Kleeblattschdel) anomaly of the skull resulting from premature closure of cranial sutures b. Facial features i. Bulging eyes ii. Hypertelorism iii. Severely depressed or indented nasal bridge 4. Short neck 5. Chest a. Extremely narrow b. Constricted thoracic cage c. Reduced size of the thoracic cavity d. Short ribs e. Hypoplastic lungs 6. Protuberant abdomen 7. Limbs a. Extremely short b. Thickened skin c. Excessive skin folds d. Usually outstretched arms e. Externally rotated legs with abducted thighs f. Syndactyly 8. Early death in most children secondary to: a. Chest constriction and consequent respiratory insufficiency b. Foramen magnum stenosis resulting in failure of respiratory control 9. A few children with longer survival (up to 9–10 years) a. Respiratory insufficiency i. Reduced chest circumference ii. Upper cervical cord compression resulting from a diminutive foramen magnum b. Markedly limited growth potential c. Markedly delayed cognitive development d. Seizures e. Hearing loss f. Additional CNS anomalies i. Hydrocephalus ii. Polymicrogyria

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iii. Neuronal heterotopia iv. Megalencephaly v. Cerebral Gyral disorganization vi. Hippocampal malformation vii. Temporal lobe malformations viii. Nuclear dysplasia ix. Abnormal axonal bundles x. Cerebellar hypoplasia in the small posterior fossa xi. Partial agenesis of the corpus callosum xii. Spinal stenosis xiii. Hyperreflexia xiv. Clonus g. Acanthosis nigricans, an associated rare skin disorder 10. Differential diagnosis a. Achondroplasia i. Autosomal dominant disorder ii. Rhizomelic shortening of the bones, less prominent than thanatophoric dysplasia iii. Macrocrania iv. Heterozygous achondroplasia a) Compatible with normal life span b) Normal intelligence v. Homozygous achondroplasia with two affected parents b. Campomelic dysplasia i. Autosomal recessive disorder ii. Typical anterior bowing of the lower limbs iii. Hypoplastic fibula iv. Hypoplastic scapulae v. A sex reversal phenomenon (phenotypical female with male karyotype) c. Osteogenesis imperfecta type II and type III i. Varying degree of bone demineralization ii. Shortened long bones with multiple fractures iii. Blue sclerae iv. Polyhydramnios frequently associated with type II d. Hypophosphatasia i. Demineralization of bone tissue ii. Lack of calcification of the fetal skull iii. Mild to moderate shortening of limb bones iv. Difficult to differentiate from osteogenesis imperfecta if fractures are present e. Achondrogenesis i. Severe Micromelia ii. Poor ossification of the vertebral bodies, cranium, pelvis and sacrum iii. Narrow and shortened thorax iv. Frequent complications with fetal hydrops and hydramnios f. Short rib-polydactyly and other rare skeletal dysplasia syndromes

DIAGNOSTIC INVESTIGATIONS 1. Radiographic features a. Skull i. Relatively large calvarium ii. A small foramen magnum iii. Trilobed skull with a towering calvarium and bitemporal bulging in the cloverleaf skull type (type 2)

b. Ribs i. Very short ribs with cupped anterior ends ii. Short ribs (type 2) c. Vertebrae i. Flat vertebral bodies (platyspondyly) ii. Increasing interverteral disc space iii. “Inverted U-shaped or H-shaped” vertebral bodies iv. Narrow interpedunculate distance at the lumbar level v. Taller vertebral bodies (type 2) d. Pelvis i. Short ii. Small sacrosciatic notches e. Tubular bones i. Extremely shortened long bones of the limbs ii. Rhizomelic shortening of the limbs iii. Flared metaphyses iv. “Telephone-receiver”-like curved femora in the noncloverleaf type v. Relatively straight femora (type 2) 2. Histologic features a. Generalized disruption of endochondral ossification i. Hallmark of the histologic findings ii. Physeal growth zone shows minimal proliferation and hypertrophy of chondrocytes with absence of column formation. iii. Lateral overgrowth of metaphyseal bone around the physis iv. Mesenchymal cells extending inward from the perichondrium as a narrow band at the periphery of the physeal zone (the so-called fibrous band) v. Increased vascularity of the resting cartilage b. Brain i. Neuronal migration abnormalities of the temporal lobe ii. Hydrocephalus iii. Partial agenesis of the corpus callosum iv. Upper cord compression v. Spinal stenosis 3. DNA mutation analysis of FGFR3 a. TD1 i. 742C→T (Arg248Cys): most common ii. Tyr373Cys iii. Ser249Cys iv. Other missense mutations v. Stop-codon mutations b. TD2: missense mutation of 1948A→G (Lys650Glu) in TD2

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: about 2% b. Patient’s offspring: not surviving to reproduction 2. Prenatal diagnosis a. Ultrasonography i. Hydramnios in most cases ii. Megacephaly with or without cloverleaf-shaped skull iii. Progressive hydrocephaly

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iv. Hypoplastic thorax disproportionately small in relation to the abdomen v. Small chest and lung measurement to predict severe pulmonary hypoplasia vi. Short ribs vii. Short limbs with curved “telephone handleshaped” or straight femurs viii. Excessive skin giving fetus a “boxer’s face” appearance ix. Flattened vertebrae with increased intervertebral spaces, giving the vertebral bodies the form of an “H” b. Prenatal radiography for documenting characteristic skeletal anomalies c. DNA mutation analysis of FGFR3 in fetal cells from amniocentesis or CVS 3. Management a. Limited intervention i. Appropriate because of the inevitable lethal outcome ii. Aggressive neonatal management, at times, not even resulting in short-term survival b. Debatable issues about the level of intensity of medical care for unanticipated long-term survival i. Long-term medical care ii. Chronic ventilator support iii. Requiring extensive health maintenance measures iv. Anticipate frequent medical exacerbations requiring recurrent hospitalizations v. Possibility of lethal complication, an ever present concern vi. Special education programs for the longer survivals

REFERENCES Baker KM, Olson DS, Harding CO, et al.: Long-term survival in typical thanatophoric dysplasia type 1. Am J Med Genet 70:427–436, 1997. Bonaventure J, Rousseau F, Legeai-Mallet L, et al.: Common mutations in the gene encoding fibroblast growth factor receptor 3 account for achondroplasia, hypochondroplasia and thanatophoric dysplasia. Acta Paediatr Suppl 417:33–38, 1996. Bonaventure J, Rousseau F, Legeai-Mallet L, et al.: Common mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene account for achondroplasia, hypochondroplasia, and thanatophoric dwarfism. Am J Med Genet 63:148–154, 1996. Chen CP, Chern SR, Shih JC, et al.: Prenatal diagnosis and genetic analysis of type I and type II thanatophoric dysplasia. Prenat Diagn 21:89–95, 2001. Chen CP, Chern SR, Chang TY, et al.: Second trimester molecular diagnosis of a stop codon FGFR3 mutation in a type I thanatophoric dysplasia fetus following abnormal ultrasound findings. Prenat Diagn 22:736–737, 2002. Cohen MM, Jr: Achondroplasia, hypochondroplasia and thanatophoric dysplasia: clinically related skeletal dysplasias that are also related at the molecular level. Int J Oral Maxillofac Surg 27:451–455, 1998. Coulter CL, Leech RW, Brumback RA, et al.: Cerebral abnormalities in thanatophoric dysplasia. Childs Nerv Syst 7:21–26, 1991. De Biasio P, Prefumo F, Baffico M, et al.: Sonographic and molecular diagnosis of thanatophoric dysplasia type I at 18 weeks of gestation. Prenat Diagn 20:835–837, 2000.

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Horton WA, Hood OJ, Machado MA, et al.: Abnormal ossification in thanatophoric dysplasia. Bone 9:53–61, 1988. International Working Group on Constitutional Diseases of Bone. International nomenclature and classification of the osteochondrodysplasias (1997). Am J Med Genet 79:376–382, 1998. Isaacson G, Blakemore KJ, Chervenak FA: Thanatophoric dysplasia with cloverleaf skull. Am J Dis Child 137:896–898, 1983. Langer LO, Jr, Yang SS, Hall JG, et al.: Thanatophoric dysplasia and cloverleaf skull. Am J Med Genet Suppl 3:167–179, 1987. Lemyre E, Azouz EM, Teebi AS, et al.: Bone dysplasia series. Achondroplasia, hypochondroplasia and thanatophoric dysplasia: review and update. Can Assoc Radiol J 50:185–197, 1999. Machado LE, Bonilla-Musoles F, Osborne Nat Genet: Thanatophoric dysplasia. Ultrasound Obstet Gynecol 18:85–86, 2001. MacDonald IM, Hunter AG, MacLeod PM, et al.: Growth and development in thanatophoric dysplasia. Am J Med Genet 33:508–512, 1989. Maroteaux P, Lamy M, Robert J-M: Le nanisme thanatophore. Presse Med 49:2519–2524, 1967. Martinez-Frias ML, Ramos-Arroyo MA, Salvador J: Thanatophoric dysplasia: an autosomal dominant condition? Am J Med Genet 31:815– 820, 1988. Nerlich AG, Freisinger P, Bonaventure J: Radiological and histological variants of thanatophoric dysplasia are associated with common mutations in FGFR-3. Am J Med Genet 63:155–160, 1996. Norman AM, Rimmer S, Landy S, et al.: Thanatophoric dysplasia of the straight-bone type (type 2). Clin Dysmorphol 1:115–120, 1992. Orioli IM, Castilla EE, Barbosa Neto JG: The birth prevalence rates for the skeletal dysplasias. J Med Genet 23:328–332, 1986. Partington MW, Gonzales-Crussi F, Khakee SG, et al.: Cloverleaf skull and thanatophoric dwarfism. Report of four cases, two in the same sibship. Arch Dis Child 46:656–664, 1971. Passos-Bueno MR, Wilcox WR, Jabs EW, et al.: Clinical spectrum of fibroblast growth factor receptor mutations. Hum Mutat 14:115–125, 1999. Rousseau F, Saugier P, Le Merrer M, et al.: Stop codon FGFR3 mutations in thanatophoric dwarfism type 1. Nature Genet 10:11–12, 1995. Rousseau F, el Ghouzzi V, Delezoide AL, et al.: Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type 1 (TD1). Hum Mol Genet 5:59–512, 1996. Schild RL, Hunt GH, Moore J, et al.: Antenatal sonographic diagnosis of thanatophoric dysplasia: a report of three cases and a review of the literature with special emphasis on the differential diagnosis. Ultrasound Obstet Gynecol 8:62–67, 1996. Spranger J, Maroteaux P: The lethal osteochondrodysplasias. Adv Hum Genet 19:1–103, 1990. Stensvold K, Ek J, Hovland AR: An infant with thanatophoric dysplasia surviving 169 days. Clin Genet 29:157–159, 1986. Tavormina PL, Shiang R, Thompson LM, et al.: Thanatophoric dysplasia (types 1 and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat Genet 9:321–328, 1995. Tonoki H: A boy with thanatophoric dysplasia surviving 212 days. Clin Genet 32:415–416, 1987. Vajo Z, Francomano CA, Wilkin DJ: The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: the achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans. Endocrine Rev 21:23–29, 2000. Weber M, Johannisson T, Thomsen M, et al.: Thanatophoric dysplasia type I: new radiologic, morphologic, and histologic aspects toward the exact definition of the disorder. J Pediatr Orthop B 7:1–9, 1998. Wilcox WR, Tavormina PL, Krakow D, et al.: Molecular, radiologic, and histopathologic correlations in thanatophoric dysplasia. Am J Med Genet 78:274–281, 1998. Wongmongkolrit T, Bush M, Roessmann U: Neuropathological findings in thanatophoric dysplasia. Arch Pathol Lab Med 107:132–135, 1983. Yang SS, Heidelberger KP, Brough AJ, et al.: Lethal short-limbed chondrodysplasia in early infancy. Perspect Pediatr Pathol 3:1–40, 1976.

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Fig. 1. Front views of 3 infants showing frontal bossing, flat facies, short neck, micromelia, and small chest.

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Fig. 3. Lateral radiographic views of the spines in two infants with typical TD1 showing extreme platyspondyly and short ribs.

Fig. 2. AP radiographic views of three infants with typical findings of TD1 showing profound platyspondyly, decreased thoracic volume, characteristic pelvic configuration, micromelia, and so-called “telephone receiver” femoral bowing.

Fig. 4. Gross appearance of a femur resembling “telephone-receiver”.

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Fig. 5. Prenatal radiographs of two fetuses affected with thanatophoric dysplasia showing platyspondyly, short ribs, and micromelia.

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Fig. 6. Thanatophoric dysplasia in identical twin fetuses. The pregnancy was terminated following ultrasonographic diagnosis at 22 weeks gestation. The placenta was diamniotic monochorionic, consistent with monozygotic pregnancy. Fig. 8. Photomicrograph of the cartilage-bone junction, cloverleaf skull type of thanatophoric dysplasia. The physeal growth zone is markedly retarded and disorganized. Similar changes are seen in the classic type thanatophoric dysplasia. A partially ossified cartilage canal is present at the center of physis. It is more prominent in size and number in cloverleaf type than in classic type.

Fig. 7. Thanatophoric dysplasia with cloverleaf skull in a neonate. The head is large and trilobed. The narrow chest and rhizomelic shortening of limbs are similar to those of classic thanatophoric dysplasia. Radiograph revealed platyspondyly and small ilium that are similar to those of classic thanatophoric dysplasia (not shown). However, the femur is straight and not as curved as seen in the classic type.

Thrombocytopenia-Absent Radius Syndrome Thrombocytopenia-absent radius (TAR) syndrome is a congenital malformation syndrome characterized by bilateral absence of the radii and congenital thrombocytopenia.

GENETICS/BASIC DEFECTS 1. Genetic inheritance: autosomal recessive inheritance, based on the following observations a. Families with at least two affected children born to unaffected parents b. Rare instances of association with consanguinity 2. Etiology of thrombocytopenia: unknown but is considered to be the result of a decreased production of platelets from the bone marrow 3.

CLINICAL FEATURES 1. Thrombocytopenia (100%) a. May be transient b. Symptomatic in over 90% of cases within the first four months of life i. Purpura ii. Petechiae iii. Epistaxis iv. Gastrointestinal bleeding a) Hematemesis b) Melena v. Hemoptysis vi. Hematuria vii. Intracerebral bleeding c. More severe thrombocytopenia can be precipitated by stress, infection, gastrointestinal disturbances, or surgery d. Platelet count tends to rise as the child gets older and may approach normal levels in adulthood (spontaneous improvement of platelet counts after one year) 2. Upper extremity anomalies (100%) a. Bilateral absence of the radius (100%): the most striking skeletal manifestation b. Hand anomalies i. Presence of the thumbs (100%) a) An important clinical feature distinguishing TAR syndrome from other disorders featuring radial aplasia, which are usually associated with absent thumbs b) Relatively functional thumbs c) Thumbs often adducted d) Thumbs often hypoplastic ii. Radially deviated iii. Limited extension of the fingers iv. Hypoplasia of the carpal and phalangeal bones c. Associated ulnar anomalies i. Usually short ii. Usually malformed 962

4.

5.

6.

7.

iii. Absent ulna a) Absent bilaterally in about 20% of cases b) Absent unilaterally in about 10% of cases d. Associated humeral anomalies i. Often abnormal in about 50% of cases ii. Absent humeri in about 5–10% of cases (rare phocomelia) e. Associated shoulder and arm anomalies i. One arm shorter than the other in about 15% of cases ii. Hypoplasia of muscles and soft tissue in the arm and shoulder iii. Abnormal shoulder joint secondary to abnormal humeral head Lower limb anomalies (47%) a. Correlation exists between the severity of skeletal changes in the lower limbs and the severity of abnormalities of the upper limbs b. Variable involvement but usually milder than the upper limbs i. Dislocation of the patella and/or of the hips ii. Knee involvement a) Dysplasia: rare severe knee dysplasia due to agenesis of cruciate ligaments and menisci b) Ankylosis c) Subluxation iii. Hip dislocation iv. Coxa valga v. Absent tibiofibular joint vi. Femoral or tibial torsion vii. Lower limb phocomelia viii. Valgus and varus foot deformities ix. Abnormal toe placement x. Severe cases with lower limb phocomelia Cow’s milk intolerance (62%) a. Presentation symptoms i. Persistent diarrhea ii. Failure to thrive b. Thrombocytopenia episodes i. Precipitated by introduction of cow’s milk ii. Relieved by its exclusion from the diet Urogenital anomalies (23%) a. Horseshoe kidney b. Absent uterus Cardiac anomalies (22–33%) a. Tetralogy of Fallot b. Atrial septal defect c. Ventricular septal defect Other associated congenital anomalies a. Facial capillary haemangiomata in the glabella region b. Micrognathia c. Cleft palate d. Intracranial vascular malformation

THROMBOCYTOPENIA-ABSENT RADIUS SYNDROME

e. Sensorineural hearing loss f. Epilepsy g. Other skeletal anomalies i. Scoliosis ii. Cervical rib iii. Fused cervical spine iv. Short stature h. Neural tube defect 8. Prognosis a. Variable clinical course among patients b. Survival related to the severity and duration of thrombocytopenia c. Good prognosis after surviving the first year of life d. Early diagnosis and treatment with platelet therapy minimize mortality risks e. Mental retardation secondary to intracranial bleed (7%) f. Good hand and upper extremity functions, especially if bilateral radial aplasia is the only skeletal abnormality 9. Differential diagnosis a. Holt-Oram syndrome i. An autosomal dominant condition caused by mutations in the TBX5 gene ii. Often with a family history of heart and limb defects iii. Absence of the thumb associated with radial aplasia iv. Absence of thrombocytopenia b. Roberts syndrome i. An autosomal recessive trait ii. Pre- and postnatal growth retardation iii. Facial clefting iv. Genitourinary abnormalities v. Limb defects involving upper or lower limbs or both vi. Characteristic chromosome abnormality in the majority (79%) of cases a) Premature centromeric separation (PCS) b) “Puffing” of the chromosomes caused by repulsion of the heterochromatic regions near the centromeres of chromosomes 1, 9, and 16 with splaying of the short arms of the acrocentric chromosomes and of distal Yp.33 c) Evidence of abnormal mitosis vii. Postulated that TAR syndrome and Roberts syndrome might be part of the same condition with TAR syndrome being the milder and Roberts the severer variants c. Fanconi anemia i. An autosomal recessive disorder ii. Bone marrow failure iii. Skeletal defects iv. Cutaneous pigmentation v. Microcephaly vi. Short stature vii. May present with thrombocytopenia viii. Upper limb abnormalities also involve the radial ray ix. Hypoplastic thumbs may be accompanied by radial hypoplasia but absence of the radius is associated with absence of the thumbs

d.

e.

f.

g.

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x. Spontaneous chromosome breakage, a consistent feature of Fanconi anemia and is a reliable diagnostic test Aase syndrome i. Radial hypoplasia ii. Triphalangeal thumbs iii. Hypoplastic anemia, similar to Blackfan-Diamond syndrome iv. Thrombocytopenia not a feature Thalidomide embryopathy i. May present with radial anomalies of the upper limb ii. Malformations of the lower limbs showing a less consistent pattern iii. Diagnosed based on: a) Phenotype b) History of exposure to thalidomide during pregnancy c) Increasing use of thalidomide as a therapeutic agent for the treatment of conditions such as Beçhet’s disease, graft vs host disease, multiple myeloma, and Kaposi’s sarcoma Rapadilino syndrome i. Absent thumbs and radial aplasia/hypoplasia ii. Patellar aplasia/hypoplasia iii. Cleft palate Other syndromes with limb reduction abnormalities predominantly involving the upper extremities i. Adams-Oliver syndrome a) Transverse limb defects b) Aplasia cutis congenita c) Growth deficiency ii. Aglossia-adactylia a) Absence/hypoplasia of digits b) Absence/hypoplasia of the tongue iii. Amniotic band sequence a) Limb constriction or amputation b) Asymmetric facial clefts c) Cranial defects d) Compression deformities iv. CHILD syndrome a) Unilateral hypomelia b) Ichthyosiform erythroderma c) Cardiac septal defect v. Cornelia de Lange syndrome a) Micromelia b) Growth deficiency c) Facial dysmorphism vi. Femur-fibula-ulnar syndrome a) Femoral/fibular defects associated with malformations of the arms b) Amelia c) Peromelia at the lower end of the humerus d) Humeroradial synostosis e) Defects of the ulna and ulnar rays vii. Poland anomaly a) Unilateral defect of pectoralis major muscle b) Ipsilateral limb abnormalities viii. VATER association (vertebral, anal, tracheoesophageal, renal and radial anomalies)

964

THROMBOCYTOPENIA-ABSENT RADIUS SYNDROME

ix. Weyers ulnar ray/oligodactyly syndrome a) Deficient ulnar and fibular rays b) Oligodactyly c) Hydronephrosis h. Megakaryocytic aplasia i. Amegakaryocytic thrombocytopenia ii. Congenital hypoplastic thrombocytopenia with microcephaly iii. Thrombocytopenia associated with trisomy 13 and trisomy 18

DIAGNOSTIC INVESTIGATIONS 1. Hematological studies a. Blood platelet counts: thrombocytopenia b. Anemia secondary to bleeding c. Eosinophilia d. Leukemoid reaction i. Reported in about 60–70% of patients during the first year of life ii. White blood counts >35,000 per mm3 with a shift to the left, particularly with the stress and infections iii. Usually associated with worse thrombocytopenia and often with hepatosplenomegaly e. Bone marrow aspirates i. Normal or hypercellular bone marrow ii. Hypomegakaryocytic thromobocytopenia ( Br J Oral Maxillofacial Surg 24:137–142, 1986. Mercuri LG: The Hecht, Beals and Wilson syndrome. J Oral Maxillofac Surg 39:53–56, 1981. O’Brien PJ, Gropper PT, Tredwell SJ, et al.: Orthopaedic aspects of the trismus pseudocamptodactyly syndrome. J Pediatr Orthop 4:469–471, 1984. Robertson RD, Spence MA, Sparkes RS, et al.: Linkage analysis with the trismus-pseudocamptodactyly syndrome. Am J Med Genet 12:115–120, 1982. Seavello J, Hammer GB: Tracheal intubation in a child with trismus pseudocamptodactyly (Hecht) syndrome. J Clinic Anesth 11:254–256, 1999. Ter Haar BGA, Van Hoof RF: The trismus-pseudocamptodactyly syndrome. J Med Genet 11:41–49, 1974. Tsukahara M, Shinozaki F, Kajii T: Trismus-pseudocamptodactyly syndrome in a Japanese family. Clin Genet 28:247–250, 1985. Wilson RV, Gaines DL, Brooks A, et al.: Autosomal dominant inheritance of shortening of the flexor profundus muscle-tendon unit with limitation of jaw excursion. Birth Defects 5(3):99–102, 1969. Yamashita D-DR, Amet GF: trismus-pseudocamptodactyly syndrome. J Oral Surg 38:625–630, 1980. Vaghadia H, Blackstock D: Anaesthetic implications of the trismus pseudocamptodactyly syndrome (Dutch-Kentucky or Hecht-Beals) syndrome. Can J Anaesth 35:80–85, 1988.

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Fig. 1. Facial appearance of a child and his mother.

Fig. 3. Hands of the child and his mother demonstrating no contractures of fingers on neutral positions but flexion contractures of fingers on dorsiflexion. Interphalangeal webbings are also seen.

Fig. 2. Front and lateral views of the child and his mother illustrating maximal abilities to open their mouth.

Fig. 4. Marked flexion contractures of fingers on dorsiflexion in other relatives.

Trisomy 13 Syndrome In 1960, Patau et al. first recognized the relation of trisomy 13 to a clinical syndrome. Incidence is estimated to be 1/4000–1/10,000 live births.

GENETICS/BASIC DEFECTS 1. Trisomy 13 a. Mechanism: due to meiotic nondisjunction i. Maternal origin of the extra chromosome (90%) ii. Stage of nondisjunction: mostly maternal meiosis I (vs. meiosis II in trisomy 18) iii. Paternal origin of the extra chromosome (10%): The majority are primarily postzygotic mitotic errors. b. Frequency: 75% of cases 2. Translocation trisomy 13 a. Mechanism: de novo (75%) or familial transmission (25%) b. Frequency: 20% of cases c. Trisomy 13 due to t(13;13): The structural abnormalities are usually isochromosomes originating in mitosis. 3. Mosaic trisomy 13 a. Mechanism: due to postzygotic (postfertilization) mitotic nondisjunction b. Frequency: 5% of cases c. Variable phenotype from full trisomy to near normal d. Variable mental retardation with longer survival e. Trisomy 13/triploidy mosaicism: a rare event 4. Partial trisomy 13 a. Partial trisomy of proximal segment with nonspecific clinical features and little similarity to full trisomy 13 b. Partial trisomy of distal segment with specific clinical features

4.

5.

6.

7.

CLINICAL FEATURES 1. General a. Low birth weight b. Thrombocytopenia 2. CNS a. Severe mental retardation b. Holoprosencephaly c. Seizures d. Central apnea 3. Craniofacial abnormalities a. Microcephaly b. Wide sagittal sutures c. Wide fontanels d. Scalp defect (aplasia cutis congenita, 50%) e. Capillary hemangioma of the forehead f. Ocular abnormalities i. Microphthalmia/anophthalmia ii. Colobomas iii. Retinal dysplasia

8.

9.

10.

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g. Cleft lip/palate h. Abnormal auricles i. Low-set ears j. Sensorineural and conductive deafness k. Recurrent otitis media l. Abundant nuchal skin folds Cardiovascular abnormalities a. Ventricular septal defect b. Atrial septal defect c. Patent ductus d. Coarctation of the aorta e. Dextrocardia Gastrointestinal abnormalities a. Omphalocele b. Malrotation c. Umbilical hernia d. Inguinal hernia e. Accessory spleen f. Heterotopic pancreatic tissue g. Meckel’s diverticulum h. Diaphragmatic defects i. Large gallbladder Genitourinary abnormalities a. Polycystic kidneys b. Cryptorchidism c. Hypospadias d. Bicornuate uteri e. Abnormal fallopian tubes f. Hypoplastic ovaries Skeletal abnormalities a. Polydactyly b. Posterior prominence of heel c. Flexed fingers d. Hypoplasia of pelvis e. Shallow acetabulum f. Thin posterior ribs g. Flexion deformity of large joints h. Limb deficiency (5.3%) i. Radial aplasia j. Hyperconvex narrow fingernails Dermatoglyphics a. Transverse palmar crease b. t’ c. Hallucal arch fibular or loop tibial Others a. Thymic cyst b. Persistence of fetal hemoglobin Prognosis a. Majority of trisomy 13 conceptuses i. Abort during pregnancy ii. Stillborn b. 25% die by 24 hours of life

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TRISOMY 13 SYNDROME

c. 45% die by 1 month of life d. 60% die by 6 months of life e. 72% die by 1 year of age f. Usual mode of death: primary apnea g. Survivals up to 11 and 19 years old reported 11. Mosaic trisomy 13 a. The phenotype ranges i. Typical features of trisomy 13 ii. More mild mental retardation or even normal intellectual function (rare), milder physical features, and longer survival b. The range in clinical severity is likely due to the varying proportion of trisomy 13 cells and their distribution within the body 12. Partial trisomy 13 of the proximal segment a. Severe mental retardation b. Large nose c. Short upper lip d. Receding mandible e. Clinodactyly of the 5th fingers 13. Partial trisomy 13 of the distal segment a. Severe mental retardation b. Bushy eyebrows (synophrys) with long incurved lashed c. Frontal capillary hemangioma d. Long philtrum e. Prominent antihelix

DIAGNOSTIC INVESTIGATIONS 1. Cytogenetic studies a. Conventional technique b. FISH of interphase cells for rapid diagnosis c. Parental karyotyping in case of translocation trisomy 13 d. Trisomy 13 mosaicism 2. Echocardiography for cardiovascular anomalies 3. EEG: hypsarrhythmia 4. CT/MRI for central nervous system anomalies 5. Radiography a. Wide anterior fontanelle b. Presence of a cervical rib c. Absence of the 12th rib d. Anomalies of rib morphology e. Low acetabular angle f. Long distal phalanges g. Cranial bone abnormalities in case of holoprosencephaly h. Clefting of the vertebral bodies i. Abnormal postsphenoid component of the sphenoid bone j. Agenesis of the nasal bones 6. Placenta: Partial molar change of the placenta may rarely occur in Trisomy 13.

GENETIC COUNSELING 1. Recurrence risk a. Patient’s, sib i. Trisomy 13: about 1 in 4000 ii. De novo translocation: about 1 in 4000

iii. Familial translocation: 5–15% iv. Mosaicism: 1 in 4000 b. Patient’s offspring: not surviving to reproductive age 2. Prenatal diagnosis a. Prenatal ultrasonography: prevalence of ultrasound abnormalities (91%) i. General a) IUGR (48%) b) Single umbilical artery c) Polyhydramnios (15%) d) Oligohydramnios (12%) ii. Cranium and CNS abnormalities (58%) a) Holoprosencephaly (39%) b) Neural tube defects c) Lateral ventricular dilatation without holoprosencephaly (9%) d) Enlarged cisterna magna or Dandy-Walker variant (15%) e) Microcephaly (12%) f) Linear branching echogenicity of the thalamus or basal ganglia (representing vasculopathy) g) Choroid plexus cyst iii. Facial anomalies a) Cyclopia b) Proboscis c) Hypotelorism d) Hypoplastic midface e) Cleft lip/palate (36%) f) Micrognathia iv. Neck anomalies a) Nuchal thickening b) Cystic hygroma c) Hydrops d) Lymphangiectasia v. Chest/cardiac abnormalities a) Diaphragmatic hernia b) Ventricular septal defect c) Hypoplastic left heart d) Echogenic chorda tendineae (30%) vi. Renal abnormalities (33%) a) Echogenic kidneys b) Pyelectasis c) Enlarged kidneys d) Hydronephrosis vii. Abdominal abnormalities a) Omphalocele b) Echogenic bowel (6%) c) Bladder exstrophy viii. Limb abnormalities (33%) a) Clenched and overlapping digits b) Polydactyly c) Radial aplasia d) Short femur length e) Talipes equinovarus f) Rocker bottom feet b. Chromosome analyses i. Amniocentesis ii. CVS, followed by amniocentesis

TRISOMY 13 SYNDROME

iii. Fetal cells isolated from maternal blood using either flow sorting or magnetic sorting c. Dilemma for genetic counseling with trisomy 13 mosaicism i. Infrequent occurrence ii. Single cell pseudomosaicism (3.3%) iii. Multiple-cell pseudomosaicism (4%) iv. Often represents pseudomosaicism or confined placental mosaicism v. True fetal mosaicism (in the context of low-level single-digit percentage mosaicism): not necessarily associated with congenital defects and/or mental abnormalities vi. An optimistic approach in case of normal ultrasonography and absence of trisomy 13 cells in the fetal blood vii. Possibility of adverse phenotype and intellectual function in case of true low-level fetal mosaicism 3. Management a. Feedings i. Nasal tube feeding ii. Oral gastric tube feeding iii. Gastrostomy feeding b. Nissan fundoplication for gastroesophageal reflux c. Risk for anesthesia d. Early intervention programs e. Seizure control f. Monitor apneic spells g. Treat infections h. Symptomatic treatment for heart failure i. Cardiac operation rarely performed

REFERENCES Alizad A, Seward JB: Echocardiographic features of genetic diseases: part 7. Complex genetic disorders. J Am Soc Echocardiogr 13:707–714, 2000. Baty BJ, Blackburn BL, Carey JC: Natural history of trisomy 18 and trisomy 13: I. Growth physical assessment, medical histories, survival, and recurrence risk. Am J Med Genet 49:175–188, 1994. Baty BJ, Jorde LB, Blackburn BL: Natural history of trisomy 18 and trisomy 13: II. Psychomotor development. Am J Med Genet 49:189–194, 1994. Benacerraf BR, Miller WA, Frigoletto FD Jr: Sonographic detection of fetuses with trisomies 13 and 18: accuracy and limitations. Am J Obstet Gynecol 158:404–409, 1988. Brewer CM, Holloway SH, Stone DH, et al.: Survival in trisomy 13 and trisomy 18 cases ascertained from population based registers. J Med Genet 39:e54, 2002. Chabra S, Kriss VM, Pauly TH, et al.: Neurosonographic diagnosis of thalamic/basal ganglia vasculopathy in trisomy 13—An important diagnostic aid. Am J Med Genet 72:291–293, 1997. Colacino SC, Pettersen JC: Analysis of the gross anatomical variations found in four cases of trisomy 13. Am J Med Genet 2:31–50, 1978. Curtin WM, Marcotte MP, Myers LL, et al.: Trisomy 13 appearing as a mimic of a triploid partial mole. J Ultrasound Med 20:1137–1139, 2001. Delatycki M, Gardner RJ: Three cases of trisomy 13 mosaicism and a review of the literature. Clin Genet 51:403–407, 1997. Delatycki MB, Pertile MD, Gardner RJ: Trisomy 13 mosaicism at prenatal diagnosis: dilemmas in interpretation. Prenat Diagn 18:45–50, 1998. Eubanks SR, Kuller JA, Amjadi D, et al.: Prenatal diagnosis of mosaic trisomy 13: a case report. Prenat Diagn 18:971–974, 1998. Goldstein H, Nielsen KG: Rates and survival of individuals with trisomy 13 and 18. Data from a 10-year period in Denmark. Clin Genet 34:366–372, 1988.

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Hahnemann JM, Vejerslev LO: European collaborative research on mosaicism in CVS (EUCROMIC)—fetal and extrafetal cell lineages in 192 gestations with CVS mosaicism involving single autosomal trisomy. Am J Med Genet 70:179–187, 1997. Hansen CB, Fergestad JM, Barnes A, et al.: An analysis of heart surgery in children with trisomy 18, 13. J Med Invest 48:47A, 2000. Has R, Ibrahimogˇlu L, Ergene H, et al.: partial molar appearance of the placenta in trisomy 13. Fetal Diagn Ther 17:205–208, 2002. Hodes ME et al.: Clinical experience with trisomies 18 and 13. J Med Genet 15:48–60, 1978. Janiaux E, Halder A, Partington C: A case of partial mole associated with trisomy 13. Ultrasound Obstet Gynecol 11:62–64, 1998. Kjaer I, Keeling JW, Hansen BF: Pattern of malformations in the axial skeleton in human trisomy 13 fetuses. Am J Med Genet 70:421–426, 1997. Lehman CD, Nyberg DA, Winter TC III, et al.: Trisomy 13 syndrome: prenatal US findings in a review of 33 cases. Radiology 194:217–222, 1995. Martínez-Frías ML, Villa A, de Pablo RA, et al.: Limb deficiencies in infants with trisomy 13. Am J Med Genet 93:339–341, 2000. Moerman P, Fryns JP, van der Steen K, et al.: The pathology of trisomy 13 syndrome: a study of 12 cases. Hum Genet 80:349–356, 1988. Nyberg DA, Souter VL: Sonographic markers of fetal trisomies. J Ultrasound Med 20:655–674, 2001. Oosterwijk JC, Mesker WE, Ouwerkerk-van Velzen MCM, et al.: Prenatal diagnosis of trisomy 13 on fetal cells obtained from maternal blood after minor enrichment. Prenat Diagn 18:1082–1085, 1998. Patau K, Therman DG, Cameron AH, et al.: A new trisomic syndrome. Lancet 1:787–789, 1960. Pettersen JC et al.: An examination of the spectrum of anatomic defects and variations found in eight cases of trisomy 13. Am J Med Genet 3:183–210, 1979. Phelan MC, Rogers RC, Michaelis RC, et al.: Prenatal diagnosis of mosaicism for triploidy and trisomy 13. Prenat Diagn 21:457–460, 2001. Redheendran R, Neu RL, Bannerman RM: Long survival in trisomy 13 syndrome: 21 cases including prolonged survival in two patients 11 and 19 years old. Am J Med Genet 8:167–172, 1981. Robinson WP, Bernasconi F, Dutly F, et al.: Molecular studies of translocations and trisomy involving chromosome 13. Am J Med Genet 61:158–163, 1996. Rogers JF: Clinical delineation of proximal and distal partial 13q trisomy. Clin Genet 25:221–229, 1984. Schinzel A et al.: Further delineation of the clinical picture of trisomy for the distal segment of chromosome 13. Hum Genet 32:1–12, 1976. Smith K, Lowther G, Maher E, et al.: The predictive value of findings of the common aneuploidies, trisomies 13, 18 and 21, and numerical sex chromosome abnormalities at CVS: experience from the ACC U.K. Collaborative Study. Association of Clinical Cytogeneticists Prenatal Diagnosis Working Party. Prenat Diagn 19:817–826, 1999. Snijders RJ, Sebire NJ, Nayar R, et al.: Increased nuchal translucency in trisomy 13 fetuses at 10–14 weeks of gestation. Am J Med Genet 86:205–207, 1999. Taylor AI: Autosomal trisomy syndromes: A detailed study of 27 cases of Edwards’ syndrome and 27 cases of Patau’s syndrome. J Med Genet 5:227–241, 1968. Tharapel SA, Lewadowski RC, Tharapel AT, et al.: Phenotype–karyotype correlation in patients trisomic for various segments of chromosome 13. J Med Genet 23:310–315, 1986. Tongson T, Sirichotiyakul S, Wanapirak C, et al.: Sonographic features of trisomy 13 at midpregnancy. Int J Gynecol Obstet 76:143–148, 2002. Tuohy JF, James DK: Pre-eclampsia and trisomy 13. Br J Obstet Gynaecol 99:891–894, 1994. Warkany J et al.: Congenital malformations in autosomal trisomy syndromes. Am J Dis Child 112:502–517, 1966. Wallerstein R, Yu M-T, Neu RL, et al.: Common trisomy mosaicism diagnosed in amniocytes involving chromosomes 13, 18, 20 and 21: karyotype–phenotype correlations. Prenat Diagn 20:103–122, 2000. Wyllie JP, Wright MJ, Burn J, et al.: Natural history of trisomy 13. Arch Dis Child 71:343–345, 1994. Zoll B, Wolf J, Lensing-Hebben D, et al.: Trisomy 13 (Patau syndrome) with an 11-year survival. Clin Genet 43:46–50, 1993.

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Fig. 4. An infant with trisomy 13 showing microcephaly, forehead hemangioma, upslanted palpebral fissures, cleft lip/palate, and short neck. Fig. 1. An infant with trisomy 13 showing microcephaly, microphthalmia, forehead hemangioma, cleft lip/palate, and post-axial polydactyly.

Fig. 5. An infant with trisomy 13 showing scalp defect on the vertex.

Fig. 2. An infant with trisomy 13 showing microcephaly, microphthalmia, cleft lip/palate, and Omphalocele.

Fig. 6. A child with trisomy 13 associated with premaxillary dysgenesis, hypotelorism, cleft nose, and smooth philtrum. Fig. 3. Postaxial polydactyly of the hand and the feet in an infant with trisomy 13.

TRISOMY 13 SYNDROME

Fig. 7. An infant with trisomy 13-Klinefelter syndrome showing hypotelorism and a single nostril (holoprosencephaly).

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Fig. 9. Trisomy 13 karyotype (G-banded)

Fig. 10. Translocation trisomy 13 [t(13q;14q)].

Fig. 11. Trisomy 13 shown by FISH analysis of interphase cells with three copies of the green signal (LSI 13/SpectrumGreen) representing three chromosome 13s and two copies of the red signal representing two chromosome 21s (LSI 21/ SpectrumOrange). Fig. 8. A neonate with trisomy 13 showing similar facial features. In addition, the infant has polydactyly.

Trisomy 18 Syndrome Edwards et al. and Smith et al. independently described trisomy 18 syndrome in 1960. It is the second most common autosomal trisomy after trisomy 21. Prevalence is approximately 1 in 6000–8000 live births.

GENETICS/BASIC DEFECTS 1. Caused by an extra chromosome 18 resulting from nondisjunction in meiosis a. Maternal origin of an extra chromosome 18 in 90% of cases b. An error in maternal meiosis II is the most frequent cause of nondisjunction for chromosome 18, unlike all other human trisomies that have been studied, which show a higher frequency in maternal meiosis I. c. Increased incidence with advanced maternal age 2. Types of trisomy 18 a. Full trisomy 18 in 95% of cases b. Rare mosaicism and translocation cases: translocation trisomy giving rise to partial trisomy 18 syndrome 3. Preponderance of females with trisomy 18 in liveborns (sex ratio 0.63) (sex ratio defined as the number of males divided by the number of females) compared to fetuses diagnosed prenatally (sex ratio 0.90) indicating a prenatal selection against trisomy 18 males after the time of amniocentesis 4. The smallest extra region necessary for expression of serious anomalies of trisomy 18: Two critical regions, one proximal (18q12-q21.2) and one distal (18q22.3-qter), which work jointly to produce the typical trisomy 18 phenotype

CLINICAL FEATURES 1. Prenatal history a. Maternal polyhydramnios possibly related to defective fetal sucking and swallowing reflexes in utero b. Oligohydramnios secondary to renal defects c. Disproportionately small placenta d. Single umbilical artery e. Intrauterine growth retardation f. Weak fetal activity g. Fetal distress 2. Clinical history a. Apneic episodes b. Poor feeding c. Marked failure to thrive 3. Physical growth: profound growth retardation 4. Central nervous system (CNS) a. Inevitable profound delay in psychomotor development and mental retardation (100%) b. Neonatal hypotonia followed by hypertonia c. Jitteriness 990

d. Apnea e. Seizures f. Malformations i. Microcephaly ii. Cerebellar hypoplasia iii. Meningoencephalocele iv. Meningomyelocele v. Anencephaly vi. Hydrocephaly vii. Holoprosencephaly viii. Arnold-Chiari malformation ix. Hypoplasia or aplasia of the corpus callosum x. Defective falx cerebri xi. Frontal lobe defect xii. Abnormal gyri xiii. Migration defect xiv. Arachnoid cyst 5. Cranial a. Microcephaly b. Elongated skull c. Narrow bifrontal diameter d. Wide fontanels and cranial sutures e. Prominent occiput 6. Facial a. Microphthalmia b. Ocular hypertelorism c. Epicanthal folds d. Short palpebral fissures e. Iris coloboma f. Cataracts g. Corneal clouding h. Abnormal retinal pigmentation i. Short nose with upturned nares j. Choanal atresia k. Micrognathia/retrognathia l. Microstomia m. Narrow palatal arch n. Infrequent cleft lip and cleft palate o. Preauricular tags p. Low-set, malformed ears (faun-like with flat pinnae and a pointed upper helix) 7. Skeletal a. Severe growth retardation b. Characteristic hand posture, with clenched hands with the index finger overriding the middle finger and the fifth finger overriding the fourth finger c. Camptodactyly d. Radial hypoplasia or aplasia e. Thumb aplasia f. Syndactyly of the second and third digits g. Arthrogryposis h. Rocker-bottom feet with prominent calcanei i. Talipes equinovarus

TRISOMY 18 SYNDROME

j. k. l. m. n. o. p.

8.

9.

10.

11.

Hypoplastic nails Dorsiflexed great toes Short neck with excessive skin folds Short sternum Narrow pelvis Limited hip abduction Severe kyphoscoliosis and tendency to spontaneous fracture of long bones emerging later Cardiac malformations in more than 90% of infants with trisomy 18 a. Ventricular septal defects i. Present in about two-thirds of cases ii. Large defect unlikely to undergo spontaneous closure b. Polyvalvular heart disease (pulmonary and aortic valve defects) c. Double outlet right ventricle d. Atrial septal defects e. Patent ductus arteriosus f. Overriding aorta g. Coarctation of aorta h. Hypoplastic left heart syndrome i. Tetralogy of Fallot j. Transposition of great arteries k. Endocardial fibroelastosis l. Persistent left superior vena cava m. Absent right superior vena cava n. Dextrocardia Pulmonary a. Pulmonary hypoplasia b. Abnormal lobation of the lung Gastrointestinal a. Omphalocele b. Malrotation of the intestine c. Ileal atresia d. Common mesentery e. Meckel diverticulum f. Esophageal atresia with or without tracheoesophageal fistula g. Diaphragmatic eventration h. Prune belly anomaly i. Diastasis recti j. Abnormal lobulation of the liver k. Absent or hypoplasia of gallbladder l. Absent appendix m. Accessory spleens n. Exstrophy of cloaca o. Pyloric stenosis p. Common mesentery q. Megacolon r. Imperforate or malpositioned anus s. Pilonidal sinus t. Umbilical, inguinal or diaphragmatic hernias Genitourinary a. Micromulticystic kidneys b. Double ureters c. Megaloureters d. Hydroureters e. Hydronephrosis f. Horseshoe kidneys

991

g. h. i. j.

Ectopic kidney Unilateral renal agenesis Cryptorchidism, hypospadias and micropenis in males Hypoplasia of labia and ovaries, bifid uterus, hypoplastic ovaries and clitoral hypertrophy in females 12. Endocrine a. Thymic hypoplasia b. Thyroid hypoplasia c. Adrenal hypoplasia 13. Dermatoglyphics a. Increased number of simple arches (six or more) on the finger tips b. Transverse palmar crease c. Increased atd angle d. Clinodactyly of the fifth fingers with a single flexion crease 14. Prognosis a. Approximately 95–97.5% of conceptuses with trisomy 18 die in embryonic or fetal life b. Only 30% of live fetuses at mid-trimester amniocentesis surviving to term c. 5–10% of affected children survive beyond the first year d. Rare reports of long survival into 20’s e. High mortality rate secondary to cardiac and renal malformations, feeding difficulties, sepsis, and central apnea caused by CNS defects f. Severe psychomotor and growth retardation invariably present for those who survive beyond infancy g. Milder nonspecific phenotype in mosaic trisomy 18 correlates with the proportion of normal cells in the body

DIAGNOSTIC INVESTIGATIONS 1. Conventional cytogenetic study to detect full trisomy, mosaic trisomy, or rare translocation type trisomy 18 2. Echocardiography for cardiac anomalies 3. Barium swallow for gastrointestinal anomalies 4. Ultrasound for genitourinary anomalies 5. Skeletal radiography a. Phocomelia b. Absent radius c. Tight flexion of the fingers with second over the third and the fifth over the fourth d. Talipes equinovarus e. Short sternum f. Hemivertebrae g. Fused vertebrae h. Short neck i. Scoliosis j. Rib anomaly k. Dislocated hips 6. Histopathological study of temporal bone (auditory organ) a. External ear: arctation or atresia of external acoustic meatus (38%) b. Middle ear i. Anomalies of auditory ossicles (61%) a) Incus or malleus b) Stapes

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ii. Absence or aberration of tensor tympani muscle or its tendon (31%) iii. Complete absence or hypoplasia of stapedial muscle or its tendon (28%) c. Inner ear i. Hypoplasia of the ductus semicirculares (37%) ii. Shortened cochlea (22%) iii. Anomalies of stria vascularis (22%) iv. Absence or hypoplasia of lymphatic valve in utricle (21%) v. Enlargement of canaliculus cochleae (11%) d. Facial nerve: geniculate ganglion cells displaced into the internal auditory meatus (53%)

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. De novo full trisomy 18: 1% or less ii. Low grade parental mosaicism has been reported in two occasions in sporadic cases of trisomy 18 iii. A parent being a balanced carrier of a structural rearrangement: increased recurrence risk pending on the type of structural rearrangement and the pattern of segregation b. Patient’s offspring: unlikely to survive to reproduction 2. Prenatal diagnosis a. Prenatal screening in families without history of trisomy 18 using maternal serum markers i. Low human chorionic gonadotrophin (hCG) and low unconjugated estriol (uE3) in maternal serum during mid-trimester: useful predictors for an increased risk for trisomy 18. ii. Possible future first-trimester biochemical screening for trisomy 18: reduced levels of pregnancyassociated plasma protein A (PAPP-A) and free beta-human chorionic gonadotropin (beta-hCG) at 8–13 weeks gestation. The mean MOM in affected pregnancies was 0.25 for PAPP-A and 0.34 for free beta-hCG. iii. Screening for trisomy 18 using a combination of maternal age, PAPP-A and beta-hCG: reported to achieve a detection rate of 76.6% with a falsepositive rate of 0.5% b. Prenatal ultrasonography: the majority of fetuses with trisomy 18 have detectable structural abnormalities i. Oligohydramnios/polyhydramnios (12%) ii. Intrauterine growth retardation (29%) iii. Two-vessel umbilical cord (40%) iv. CNS a) Abnormally shaped fetal head (strawberry or lemon) (43%) b) Microcephaly c) Dandy-Walker malformation (posterior fossa enlargement associated with cerebellar hypoplasia) d) Enlarged cysterna magna e) Choroid plexus cysts (43%) f) Neural tube defects (9%) v. Micrognathia

vi. vii. viii. ix. x.

Thickened nuchal skin fold Cystic hygroma or lymphangiectasia (14%) Omphalocele (20%) Esophageal atresia Cardiac defects (37%): septal defects with polyvalvular disease xi. Renal anomalies (9%) a) Polycystic kidneys b) Horseshoe and ectopic kidneys. xii. Limb abnormalities a) Clenched hands with overlapping index finger (89%) b) Forehand and hand abnormalities such as a short radial ray c) Rocker-bottom feet d) Club feet c. Amniocentesis or CVS by conventional cytogenetic or FISH techniques i. Straight trisomy 18 ii. Trisomy 18 mosaicism: 54% risk for an abnormal outcome, including phenotypically abnormal offspring, IUGR, or fetal demise. The risk is increased with increasing percentage of amniotic fluid trisomic cell line d. Culturing fetal hematopoietic stem-progenitor cells from maternal blood during pregnancy: a new strategy holding great promise for noninvasive prenatal genetic diagnosis 3. Management a. Genetic counseling in prenatally diagnosed trisomy 18 i. Traumatic experience in the lives of all couples having a fetus with trisomy 18 ii. Emotional upheaval persisting for variable time periods after the diagnoses and the decisions concerning the pregnancy outcomes b. Medical care of trisomy 18 infants i. Supportive ii. Treat infections a) Otitis media b) Upper respiratory infections (bronchitis, pneumonia) c) Urinary tract infections iii. Nasogastric and gastrostomy supplementation for feeding problems iv. Orthopedic management of scoliosis secondary to hemivertebrae v. Primarily medical management of congenital heart disease vi. Diuretic and digoxin for congestive heart failure vii. Referral for early intervention including physical and occupational therapy viii. Psychosocial management: discuss implications, possible outcomes, and available supportive services in the community ix. Severe developmental delay exhibited by longterm survivors presenting the greatest challenge to parental coping during the childhood years x. Informed and empathetic care to families undergoing a complex grieving process that combines both the reactive grief predominant in chronic

TRISOMY 18 SYNDROME

illness and the preparatory grief associated with impending death c. Surgical care of trisomy 18 infants: Because of the extremely poor prognosis, surgical repair of severe congenital anomalies such as esophageal atresia or congenital heart defects is not likely to improve the survival rate of infants and should be discussed with families.

REFERENCES Adler B, Kushnick T: Genetic counseling in prenatally diagnosed trisomy 18 and 21: psychosocial aspects. Pediatrics 69:94–99, 1982. Alizad A, Seward JB: Echocardiographic features of genetic diseases: part 7. Complex genetic disorders. J Am Soc Echocardiogr 13:707–714, 2000. Bass HN, Fox M, Wulfsberg E, et al.: Trisomy 18 mosaicism: clues to the diagnosis. Clin Genet 22:327–330, 1982. Baty BJ, Blackburn BL, Carey JC: Natural history of trisomy 18 and trisomy 13: I. Growth, physical assessment, medical histories, survival, and recurrence risk. Am J Med Genet 49:175–188, 1994. Baty BJ, Jorde LB, Blackburn BL: Natural history of trisomy 18 and trisomy 13: II. Psychomotor development. Am J Med Genet 49:189–194, 1994. Benacerraf BR, Miller WA, Frigoletto FD Jr: Sonographic detection of fetuses with trisomies 13 and 18: accuracy and limitations. Am J Obstet Gynecol 158:404–409, 1988. Bersu ET, Ramirez-Castro JL: Anatomical analysis of the developmental effects of aneuploidy in man—the 18-trisomy syndrome: I. Anomalies of the head and neck. Am J Med Genet 1:173–193, 1977. Biagiotti R, Cariati E, Brizzi L: Maternal serum screening for trisomy 18 in the first trimester of pregnancy. Prenat Diagn 18: 907–913, 1998. Bugge M, Collins A, Petersen MB, et al.: Non-disjunction of chromosome 18. Hum Molec Genet 7:661–669, 1998. Carey J: Health supervision and anticipatory guidance for children with genetic disorders (including specific recommendations for trisomy 21, trisomy 18, and neurofibromatosis I). Pediatr Clin North Am 39:25–53, 1992. Carey JC: The trisomy 18 and 13 syndromes. In: Cassidy S, Allanson J: Management of Genetic Syndromes, Wiley, 2000. Chen H: Trisomy 18. Emedicine, 2001. http://emedicine.com Collins AL, Fisher J, Crolla JA: Further case of trisomy 18 mosaicism with a mild phenotype [letter]. Am J Med Genet 56:121–122, 1995. Edwards JH, Harnden DG, Cameron AH: A new trisomic syndrome. Lancet 1: 787–789, 1960. Embleton ND, Wyllie JP, Wright MJ: Natural history of trisomy 18. Arch Dis Child Fetal Neonatal Ed 75:F38–F41, 1996. Findlay I, Toth T, Matthews P: Rapid trisomy diagnosis (21, 18, and 13) using fluorescent PCR and short tandem repeats: applications for prenatal diagnosis and preimplantation genetic diagnosis. J Assist Reprod Genet 15: 266–275, 1998. Gardner RJM, Sutherland GR: Chromosome Abnormalities and Genetic Counselling. 2nd ed. Oxford University Press, Oxford, 1996. Gilbert-Barnes E: Chromosome Abnormalities. In Gilbert-Barnes E (ed): Potter’s Pathology of the Fetus and Infant. St Louis: Mosby 1997; Vol I:402–404. Gross SJ, Bombard AT: Screening for the aneuploid fetus. Obstet Gynecol Clin North Am 25:573–595, 1998. Hansen CB, Fergestad JM, Barnes A, et al.: An analysis of heart surgery in children with trisomy 18, 13. J Med Invest 48:47A, 2000. Hecht F, Bryant JS, Motulusky AG: The No. 17-18 (E) trisomy syndrome. J Pediatr 63:605–621, 1963.

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Hook EB, Lehrke R, Roesner A, et al.: Trisomy-18 in a 15-year-old female. Lancet 2:910–911, 1965. Huether CA, Martin RL, Stoppelman SM: Sex ratios in fetuses and liveborn infants with autosomal aneuploidy. Am J Med Genet 63:492–500, 1996. Kinoshita M, Nakamura Y, Nakano R: Thirty-one autopsy cases of trisomy 18: clinical features and pathological findings. Pediatr Pathol 9: 445– 457, 1989. Kjaer I, Keeling JW, Hansen BF: Pattern of malformations in the axial skeleton in human trisomy 18 fetuses. Am J Med Genet 65:332–336, 1996. Lam YH, Tang MH: Sonographic features of fetal trisomy 18 at 13 and 14 weeks: four case reports. Ultrasound Obstet Gynecol 13:366–369, 1999. Leporrier N, Herrou M, Herlicoviez M: The usefulness of hCG and unconjugated oestriol in prenatal diagnosis of trisomy 18. Br J Obstet Gynaecol 103:335–338, 1996. Mehta L, Shannon RS, Duckett DP, et al.: Trisomy 18 in a 13-year-old girl. J Med Genet 23:256–278, 1986. Nicolaidis P, Petersen MB: Origin and mechanisms of nondisjunction in human autosomal trisomies. Hum Reprod 13:313–319, 1998. Nicolaides KH, Azar G, Byrne D: Fetal nuchal translucency: Ultrasound screening for chromosome defects in the first trimester of pregnancy. Br Med J 304:704–707, 1992. Nyberg DA, Kramer D, Resta RG: Prenatal sonographic findings of trisomy 18: review of 47 cases. J Ultrasound Med 2:103–113, 1993. Nyberg DA, Souter VL: Sonographic markers of fetal trisomies. J Ultrasound Med 20:655–674, 2001. Ramirez-Castro JL, Bersu ET: Anatomical analysis of the developmental effects of aneuploidy in man—the 18-trisomy syndrome: II. Anomalies of the upper and lower limbs. Am J Med Genet 2:285–306, 1978. Ries MD, Ray S, Winter RB, et al.: Scoliosis in trisomy 18. Spine 15:1281–1284, 1990. Root S, Carey JC: Survival in trisomy 18. Am J Med Genet 1994 49:170–174, 1994. Shields LE, Carpenter LA, Smith KM: Ultrasonographic diagnosis of trisomy 18: is it practical in the early second trimester? J Ultrasound Med 17: 327–331, 1998. Smith A, Silink M, Ruxton T, et al.: Trisomy 18 in an 11-year-old child. J Ment Defic Res 22:277–286, 1978. Smith A, Field B, Learoyd BM: Trisomy 18 at 21 years. Am J Med Genet 34:338–339, 1989. Smith DW, Patau K, Therman E: A new autosomal trisomy syndrome: multiple congenital anomalies caused by an extra chromosome. J Pediatr 57: 338–345, 1960. Sumi SM: Brain malformations in the trisomy 18 syndrome. Brain 93:821–830, 1970. Surana RB, Bain HW, Conen PE: 18 trisomy in a 15-year-old girl. Am J Dis Child 123:75–77, 1972. Tadaki T, Kamiyama R, Okamura HO, et al.: Anomalies of the auditory organ in trisomy 18 syndrome: human temporal bone histopathological study. J Laryngol Otol 117:580–583, 2003. Taylor AI: Autosomal trisomy syndromes: a detailed study of 27 cases of Edwards’ syndrome and 27 cases of Patau’s syndrome. J Med Genet 5: 227–252, 1968. Van Dyke DC, Allen M: Clinical management considerations in long-term survivors with trisomy 18. Pediatrics 85:753–759, 1990. Wallerstein R, Yu M-T, Neu RL, et al.: Common trisomy mosaicism diagnosed in amniocytes involving chromosomes 13, 18, 20 and 21: karyotype-phenotype correlations. Prenat Diagn 20:103–122, 2000. Weber WW, Mamues P, Day R, et al.: Trisomy 17-18(E): studies in longterm survival with reports of two autopsied cases. Pediatrics 34:533– 541, 1964.

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Fig. 2. An infant with trisomy 18 showing small eyes, microstomia, low-set/malformed ears, and short neck.

Fig. 3. An infant with trisomy 18 showing micro/retrognathia, short neck, and characteristic finger grasping pattern.

Fig. 1. A fetus with trisomy 18 showing malformed and low-set ears, characteristic finger clenching pattern, spina bifida, hyperextended knee, and talipes equinovarus.

TRISOMY 18 SYNDROME

Fig. 4. Three infants with trisomy 18 showing reduction malformations of the upper extremities.

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Fig. 5. Two infants with trisomy 18 showing small eyes, micro/retrognathia, and low-set/malformed ears.

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Fig. 8. Translocation trisomy 18 karyotype [46,XX,+18,der(13)t(13;18) (q10;q10)].

Fig. 6. Typical hand grasping pattern (left) and rocker-bottom feet with prominent calcaneus (right) observed in trisomy 18.

Fig. 9. Trisomy 18 shown by FISH (CEP X/SpectrumGreen, CEP 18/SpectrumAqua, Vysis/Abbott) on an uncultured amniocyte. Three copies of the aqua signal are present in the cells (CEP 18). Two copies of the green signal (CEP X) confirm a female fetus.

Fig. 7. Trisomy 18 karyotype (47,XY,+18).

Tuberous Sclerosis Tuberous sclerosis is the second most common neurocutaneous syndrome after neurofibromatosis. The term “tuberous sclerosis” derived from the “tubers” (swellings or protuberances) and areas of “sclerosis” (hardening) of the cerebral gyri that calcifies with age. The classic description of the syndrome includes Bogt’s triad: mental retardation, seizures, and adenoma sebaceum (a misnomer) or facial angiofibromas. Tuberous sclerosis affects about one in 6000 newborns.

ii. Observed in 41% of all hamartomas including renal angiomyolipomas, cardiac rhabdomyomas and subependymal giant cell astrocytomas 4. Hamartin and tuberin a. Widely expressed in the brain b. May interact as part of a cascade pathway that modulates cellular differentiation, tumor suppression, and intracellular signaling 5. Mosaicism in tuberous sclerosis reported a. Somatic mosaicism: The mutation is not found in all cell lines b. Gonadal mosaicism: The mutation found only in gonadal cells and is therefore transmitted to offspring while parents are spared from any disease manifestation 6. Genotype-phenotype correlations a. Overlap of many clinical features exists among the patients with TSC1 and TSC2 mutations. b. Sporadic patients with TSC1 mutations i. On average, milder phenotypic manifestations compared with patients with TSC2 mutations ii. Lower frequencies of seizures iii. Lower frequencies of moderate-to-severe mental retardation iv. Fewer subependymal nodules and cortical tubers v. Less severe kidney involvement vi. No retinal hamartomas vii. Less severe facial angiofibroma c. Some features are rare or not seen at all in TSC1 patients i. Grade 2–4 kidney cysts or angiomyolipomas ii. Forehead plaques iii. Retinal hamartomas iv. Liver angiomyolipomas d. Both germline and somatic mutations are less common in TSC1 than TSC2 e. Patients without mutation i. Milder than patients with TSC2 mutations ii. Somewhat distinct from patients with TSC1 mutations

GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal dominant i. Almost complete penetrance ii. Extremely variable in its manifestations and severity b. Sporadic (new mutations) in two third of cases 2. Caused by mutations in either of the following two tuberous sclerosis complex (TSC) genes a. TSC1 i. Located on chromosome 9q34 ii. Encodes protein, hamartin (TSC1), a protein implicated in regulating cell adhesion via interactions with cortical actin filaments and a plasma membrane binding protein ezrin-radixin-moesin, part of a Rho-mediated signaling pathway iii. Approximately 50% of tuberous sclerosis families show linkage to TSC1. iv. Most described mutations in the TSC1 gene result in a truncated protein. b. TSC2 i. Located on chromosome 16p13.3 ii. Encodes protein, tuberin (TSC2), a protein implicated in regulating cytoplasmic vesicle transport to the cell membrane iii. Approximately 50% of families show linkage to TSC2. iv. Many mutations in the TSC2 gene are large (contiguous) deletions, which may involve the PKD1 gene, resulting in a severe phenotype called very early onset polycystic kidney disease. 3. Both TSC1 and TSC2 a. Have properties consistent with tumor suppressor genes functioning according to Knudson’s “two hit” hypothesis b. The clinical variability occurs secondary to the random nature of the second “hit” in individuals carrying a germline mutation. c. Loss of heterozygosity for TSC1 or TSC2 gene i. Suggests that one mutation is acquired embryonically and another is acquired later on somatically (2-hit hypothesis)

CLINICAL FEATURES

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1. Characteristic cutaneous features (virtually 100% of cases) a. Hypomelanotic macules (“ash-leaf spots”) (87–100% of cases) i. One of the earliest skin lesions (often present at birth) ii. Commonly on trunk and buttocks, rarely on the face, and best appreciated by the Wood’s fluorescence lamp iii. Not specific to tuberous sclerosis because they are seen in unaffected children

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iv. Smaller depigmented spots over the anterior shins: characteristically distributed in a “confetti” fashion (clustered skin lesions with a reticulated appearance) b. Shagreen patches (a form of collagenomas) (20–80%) i. Elevated discolored skin lesions commonly over lumbosacral region, observed in about 21% of patients ii. Age at presentation: birth to adulthood c. Facial angiofibromas (47–90%) i. One of the most common and specific cutaneous manifestations ii. Causing the most disfigurement among the skin lesions iii. Red to brown nodules, observed over the nose and cheeks in bilaterally symmetrical butterfly distribution. Rarely segmental tuberous sclerosis may present as unilateral facial angiofibromas iv. Age of presentation a) Usually appear after two years of age b) Increase in size and number of facial angiofibromas with time c) Observed in about 80% of adults with tuberous sclerosis v. Chance of small and discrete papules of facial angiofibromas to become confluent and fungating lesions vi. Presence of large fibromas without angiomatous appearance on the scalp or the forehead areas (forehead fibrous plaques) d. Periungual fibromas (17–87%): characteristically appear during puberty and persist through life e. Café au lait spots: seen in 15–30% of patients with tuberous sclerosis f. Molluscum fibrosum pendulum (skin tags) (23%) 2. CNS abnormalities (the most common manifestations of the disorder) a. Epilepsy i. The major neurologic manifestation, affecting 85% of patients ii. Onset usually at few months of age iii. Typically with initial classic hypsarrhythmia and infantile spasms, which transform into adulttype partial complex or tonic-clonic seizures iv. Carries a poor prognosis with congnitive impairment v. Intractable seizures b. Presence of cortical “tubers” i. A pathognomonic sign ii. Subependymal nodules (abnormal neuronal and glial elements): the most common cerebral lesion iii. Cortical or subcortical white matter tubers (70% of cases) a) Composed of abnormal giant astrocytes b) Found in 90% of patients with tuberous sclerosis c) Large cortical tubers may occasionally block the foramen of Monro resulting in hydrocephalus

3.

4.

5.

6.

c. Subependymal giant cell astrocytomas i. The most common CNS tumors (6–14%) ii. Subependymal nodules lining the ventricles may calcify iii. A radiologically confirmed cortical tuber or calcified subependymal nodule are highly suggestive of tuberous sclerosis iv. Rare malignant transformation of these astrocytomas, accounting for 25% of deaths in tuberous sclerosis d. Other abnormalities i. Cerebral atrophy ii. Cerebral infarct iii. Cerebral aneurysm iv. Arachnoid cyst Developmental disorders (>50%) a. Childhood i. Learning disabilities ii. Behavioral problems iii. Pervasive developmental disorder iv. Autism more common in childhood v. Hyperactivity or attention deficit hyperactivity disorder (ADHD) vi. Aggression b. Adulthood: Mental retardation present in less than 50% of the affected individuals Ocular involvement (at least 50% of the patients) a. Retinal and optic nerve astrocytic hamartomas (the most frequent manifestations) b. Retinal phakoma i. Astrocytomas of the retina ii. Often called “mulberry lesions” iii. Absence of the normal “red reflex” in the newborn suggests the presence of retinal phakoma. c. Visual loss resulting from: i. Macular hamartoma ii. Vitreous hemorrhage iii. Papilledema or optic atrophy secondary to intracranial tumors d. Rare sector hypopigmentation of the iris, vitiligo, or poliosis of the eyelid and eyelashes Dental involvement a. Pitting of the dental enamel i. Invariably present in the permanent teeth ii. Seen in the primary (deciduous) teeth (30%) iii. Rarely produce symptoms b. Gingival fibromas (50% of children; 70% of adults) Neoplasms affecting heart, kidneys, lungs, and other organ systems a. Cardiac rhabdomyomas i. The earliest diagnostic finding in some patients detected on prenatal sonography ii. Detected by echocardiography, rarely causing problems iii. Observed in two-thirds of affected children. However, more than 80% of children with cardiac rhabdomyomas have tuberous sclerosis. iv. Usually resolve spontaneously or regress with age

TUBEROUS SCLEROSIS

v. A rare cause of prenatal and neonatal cardiac failure, mostly from dysrhythmias vi. Rare tumor obstruction to cardiac valves or chambers b. Renal cysts or angiomyolipomas (70–80% of patients) i. Bilateral multiple renal angiomyolipomas (70%) a) Diagnostic of tuberous sclerosis b) Renal angiomyolipomas are benign tumors but contain vascular tissue, which may cause bleeding, hypovolemic shock, and renal failure ii. Epithelial cysts (20%) iii. Polycystic kidney disease (2–3%) iv. Rare occurrence of renal cell carcinoma (8 cm) in one sac (the recipient twin persistently has a distended bladder and produces a large amount of urine) b) Presence of oligohydramnios (largest pocket 0.4 predicting growth discordancy of at least 350 g iv. Ultrasound-guided fetal blood sampling a) Establishing the diagnosis of monozygosity when blood group studies are performed on both twins b) Allowing an accurate antenatal assessment of the inter-twin hemoglobin difference and consequently establishing the diagnosis of twin–twin transfusion c) Revealing the degree of fetal anemia in the donor twin c. Fetoscopy i. Plethora donor twin ii. Pale recipient twin 3. Management a. General approach i. Monochorionic twining at high risk for twin–twin transfusion syndrome ii. Requiring close obstetrical monitoring iii. Requiring specialized care in neonatal intensive care unit b. Post-partum therapies i. Directed towards the problems of each twin, such as prematurity, anemia, polycythemia, and hydrops fetalis ii. Severely anemic donor twin: requires packed red blood cell transfusions or partial exchange transfusions iii. Polycythemic recipient twin: requires partial exchange transfusion to lower serum hematocrit c. Prenatal therapies i. Treating the mother with digoxin with favorable results when the recipient twin is showing signs of cardiac failure ii. Serial amniodrainage (amnioreduction): currently the most widely used therapy because it is simple and requires commonly available skills and equipment a) Removing large volumes of amniotic fluid from the recipient twin’s sac b) Reducing the amniotic fluid volume, thereby reducing the risk of preterm labor or ruptured membranes c) Overall perinatal survival with serial aggressive amnioreduction: about 60% in uncontrolled published series

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d) Double survival rate (50%) and single survival rate (20%) in severe twin–twin transfusion syndrome presenting before 28 weeks of gestation e) Fail to address the underlying cause of twin–twin transfusion syndrome f) Complications: uterine contractions, premature rupture of membranes, chorioamnionitis, abruptio placenta, and inadvertent septostomy resulting in iatrogenic monoamniotic twins iii. Amniotic septostomy: intentionally puncturing the intertwine septum a) To create a hole in the intertwine membrane between the anhydramniotic donor’s sac and the hydramniotic recipient’s sac b) Restoring normal amniotic fluid pressure gradient, allowing fluid to move along a hydrostatic gradient from the hydramnios sac into the oligohydramnios sac c) Also an inadvertent occurrence during amnioreduction procedure d) Limited experience iv. Endoscopic laser coagulation of all placental vascular anastomoses a) Reduces and abolishes intertwine transfusion by ablating chorionic plate anastomoses, producing functionally dichorionic pregnancies b) Proponents arguing that the procedure reduces the risk of neurological injury in survivors c) Overall survival rate (58%) with single survival of 32% and double survival of 42% for cases presenting prior to 18 weeks d) Rare fetal complications (relationship to the procedure not established): aplasia cutis, limb necrosis, amniotic bands, and microphthalmia/ anophthalmia v. Selective feticide by cord occlusion (umbilical cord ligation): used as a last resort in cases in which both twins are at risk because of the serious condition of one twin a) Considered in case of monochorionic twin pregnancy in which one twin is a nonviable fetus, especially the condition is compromising the nonaffected fetus b) A typical example in twin reversed arterial perfusion sequence. The relatively normal twin risks high-output cardiac failure, complications of polyhydramnios and death in utero. c) Another example of twin–twin transfusion syndrome, in which one fetus has major congenital anomalies or in utero acquired abnormality, such as demonstrable cerebral lesions, terminal cardiac failure, or other conditions with a poor prognosis d) Benefits of selective termination of the affected twin: arrest the fetofetal transfusion process and protect the survivor

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vi. In general, twin–twin transfusion syndrome diagnosed before 26 weeks of gestation has significantly better survival rates and fewer neurological sequelae after laser ablation therapy than amnioreduction. Twin–twin transfusion syndrome diagnosed after 26 weeks can best be treated by amnioreduction or delivery.

REFERENCES Banek CS, Hecher K, Hackeloer BJ, et al.: Long-term neurodevelopmental outcome after intrauterine laser treatment for severe twin–twin transfusion syndrome. Am J Obstet Gynecol 188:876–880, 2003. Barss VA, Benacerraf BR, Frigoletto FD: Ultrasonographic determination of chorion type in twin gestation. Obstet Gynecol 66:779–783, 1985. Berghella V, Kaufmann M: Natural history of twin–twin transfusion syndrome. J Reprod Med 46:480–484, 2001. Bermúdez C, Becerra CH, Bornick PW, et al.: Placental types and twin–twin transfusion syndrome. Am J Obstet Gynecol 187:489–494, 2002. Blickstein I: The twin–twin transfusion syndrome. Obstet Gynecol 76:714–722, 1990. Chiang MC, Lien R, Chao AS, et al.: Clinical consequences of twin-to-twin transfusion. Eur J Pediatr 162:68–71, 2003. Cincotta RB, Fisk NM: Current thoughts on Twin–twin transfusion syndrome. Clin Obstet Gynecol 40:290–302, 1997. Crombleholme TM: The treatment of twin–twin transfusion syndrome. Semin Pediatr Surg 12:175–181, 2003. De Lia J, Emery MG, Sheafor SA, et al.: Twin transfusion syndrome: successful in utero treatment with digoxin. Int J Gynaecol Obstet 23:197–201, 1985. De Lia J, Fisk N, Hecher K, et al.: Twin-to-twin transfusion syndrome— debates on the etiology, natural history and management. Ultrasound Obstet Gynecol 16:210–213, 2000. Deprest JA, Audibert F, van Schoubroeck D, et al.: Bipolar coagulation of the umbilical cord in complicated monochorionic twin pregnancy. Am J Obstet Gynecol 182:340–345, 2000. Duncombe GJ, Dickinson JE, Evans SF: Perinatal characteristics and outcomes of pregnancies complicated by twin–twin transfusion syndrome. Obstet Gynecol 101:1190–1196, 2003.

Gardiner HM, Taylor MJ, Karatza A, et al.: Twin–twin transfusion syndrome: the influence of intrauterine laser photocoagulation on arterial distensibility in childhood. Circulation 107:1906–1911, 2003. Jauniaux E, Holmes A, Hyett J, et al.: Rapid and radical amniodrainage in the treatment of severe twin–twin transfusion syndrome. Prenat Diagn 21:471–476, 2001. Johnson JR, Rossi KQ, O’Shaughnessy RW: Amnioreduction versus septostomy in twin–twin transfusion syndrome. Am J Obstet Gynecol 185:1044–1047, 2001. Mari G, Detti L, Oz U, et al.: Long-term outcome in twin–twin transfusion syndrome treated with serial aggressive amnioreduction. Am J Obstet Gynecol 183:211–217, 2000. Quintero RA: Twin–twin transfusion syndrome. Clin Perinatol 30:591–600, 2003. Quintero RA, Morales WJ, Allen MH, et al.: Staging of twin–twin transfusion syndrome. J Perinatol 19:550–555, 1999. Quintero RA, Martinez JM, Bermudez C, et al.: Fetoscopic demonstration of perimortem feto-fetal hemorrhage in twin–twin transfusion syndrome. Ultrasound Obstet Gynecol 20:638–639, 2002. Quintero RA, Dickinson JE, Morales WJ, et al.: Stage-based treatment of twin–twin transfusion syndrome. Am J Obstet Gynecol 188:1333–1340, 2003. Ropacka M, Markwitz W, Blickstein I: Treatment options for the twin–twin transfusion syndrome: a review. Twin Res 5:507–514, 2002. Senat MV, Bernard JP, Loizeau S, et al.: Management of single fetal death in twin-to-twin transfusion syndrome: a role for fetal blood sampling. Ultrasound Obstet Gynecol 20:360–363, 2002. Seng YC, Rajadurai VS: Twin–twin transfusion syndrome: a five year review. Arch Dis Child Fetal Neonatal Ed 83:F168–170, 2000. Taylor MJ, Govender L, Jolly M, et al.: Validation of the Quintero staging system for twin–twin transfusion syndrome. Obstet Gynecol 100:1257–1265, 2002. Taylor MJ, Wee L, Fisk NM: Placental types and twin–twin transfusion syndrome. Am J Obstet Gynecol 188:1119; author reply 1119–1120, 2003. van Gemert MJ, Umur A, Tijssen JG, et al.: Twin–twin transfusion syndrome: etiology, severity and rational management. Curr Opin Obstet Gynecol 13:193–206, 2001. Wee LY, Fisk NM: The twin–twin transfusion syndrome. Semin Neonatol 7:187–202, 2002. Weiner CP, Ludomirski A: Diagnosis, pathophysiology, and treatment of chronic twin-to-twin transfusion syndrome. Fetal Diagn Ther 9:283–290, 1994.

TWIN–TWIN TRANSFUSION SYNDROME

Fig. 1. Diamniotic monochorionic twin placenta with features of twin–twin transfusion (the placental discs are not fused in this case): The placenta corresponding to the recipient twin (right) is small but plethoric and dark in color. The placenta of the donor twin (left) is large but anemic, pale and edematous. The amniotic sacs were removed at the margins of the placental discs. The root of the thin monochorionic septum between the two sacs is shown on the fetal surface (first picture). The color difference between the two placentas is better shown on the maternal surface (second picture).

Fig. 2. The donor twin (right) showing smaller and pallor and the recipient twin (left) showing larger and plethoric at birth.

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Ulnar-Mammary Syndrome Ulnar-mammary syndrome was originally described by Gilly in 1882 in a woman with mammary hypoplasia, inability to lactate, absence of the 3rd–5th digits and ulna. Later in 1978, Pallister et al. reported a complex malformation syndrome in a young woman with abnormal development of ulnar rays, forearms, mammary gland tissue, axillary apocrine glands, teeth, palate, vertebral column and urogenital system. Ulnar-mammary syndrome is a pleiotropic disorder affecting limb, apocrinegland, teeth, hair, and genital development.

GENETICS/BASIC DEFECTS 1. Inheritance: autosomal dominant with variable expression 2. A gene for ulnar-mammary syndrome mapped to chromosome 12q23-q24.1 3. Caused by mutations that disrupt the DNA-binding domain of the T-box gene, TBX3 4. Mutations in human TBX3 alter limb, apocrine, and genital development in ulnar-mammary syndrome 5. No obvious phenotypic differences between those who have missense mutations and those who have deletions or frameshifts

CLINICAL FEATURES 1. Posterior limb defects a. Widely variable b. Ulnar ray defects in most patients i. Hypoplasia of the terminal phalanx of the 5th digit ii. Hypoplasia or complete absence of the ulna and 3rd, 4th, 5th digits c. Postaxial digital duplications d. Camptodactyly e. Digital fusion 2. Apocrine gland abnormalities a. Mammary gland abnormalities: variable i. Hypoplasia to aplasia of the mammary glands and hypoplasia of the nipples ii. Accessory nipples iii. Inability to nipple feed iv. Normal breast development and lactation b. Decreased ability to sweat c. Reduced body odor d. Absent axillary perspiration e. Sparse axillary hair 3. Genital abnormalities: hypogenitalism a. Affected males i. Delayed puberty ii. Diminished to absent axillary hair iii. Micropenis iv. Cryptorchidism v. Small testes vi. Shawl scrotum vii. Reduced fertility

b. Affected females i. Diminished to absent axillary hair ii. Imperforate hymen in some affected females 4. Dental abnormalities a. Misplaced teeth b. Absent teeth c. Hypodontia 5. Other abnormalities a. Obesity b. Scanty lateral eyebrows c. Subglottic stenosis d. Pyloric stenosis e. Renal agenesis/malformation f. Pulmonary hypoplasia g. Inguinal hernia h. Anal atresia/stenosis i. Musculoskeletal abnormalities i. Short forearms ii. Hypoplastic humeri, scapulae, and clavicles iii. Hypoplastic pectoralis major muscles iv. Short, stiff, and crooked terminal phalanges of 4th–5th toes 6. Differential diagnosis a. Hand-foot-uterus syndrome i. Autosomal dominant disorder ii. Allelic to ulnar-mammary syndrome speculated iii. Manifestations similar to ulnar-mammary syndrome include the following: a) Digital hypoplasia b) Carpal fusion c) Supernumerary nipples d) Genital anomalies b. Split hand/split foot syndrome: a causal relationship to ulnar-mammary syndrome suggested c. Scalp-ear-nipple syndrome: overlapping manifestations with ulnar-mammary syndrome i. Mammary hypoplasia ii. Diminished axillary perspiration iii. Dental abnormalities iv. Digital syndactyly: characteristic limb anomaly found in this syndrome (vs limb deficiency or duplications in ulnar-mammary syndrome)

DIAGNOSTIC INVESTIGATIONS 1. Radiography a. Short and stiff 5th finger b. Absent 5th finger ray c. Absent 4th finger ray d. Absent 4th–5th finger rays e. Absent 3rd–5th finger rays f. Camptodactyly g. Hypoplastic/absent/deformed ulna

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h. Hypoplastic/absent/deformed radius i. Hypoplastic humerus, scapula, clavicle, and pectoralis major muscle j. Absent xiphisternum k. Postaxial polydactyly l. Short, stiff 4th and 5th toes 2. Endocrine investigations for hypogenitalism 3. Mutation analysis a. Missense mutations (L143P and Y149S) b. Nonsense mutation (Q360TER, S343TER) c. Splice-site mutations (IVS+1G to IVS2+1G) producing a truncated protein product d. Frameshift mutations of small duplications

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased unless a parent is affected b. Patient’s offspring: 50% 2. Prenatal diagnosis a. Ultrasonography and fetoscopy: possible to pregnancy at risk with presence of obvious fetal skeletal anomalies b. Mutation analysis of amniocytes and CVS: possible to families with identified mutation causing ulnarmammary syndrome 3. Management a. Orthopedic management of limb defects b. Orchiopexy for cryptorchidism c. Testosterone management for hyogonadism in male patients d. Bottle feeding of infants born to mothers who has hypoplastic or absent nipples

REFERENCES Bamshad M, Krakowiak PA, Watkins WS, et al.: A gene for ulnar-mammary syndrome maps to 12q23-q24.1. Hum Mol Genet 4:1973–1977, 1995. Bamshad M, Le T, Watkins WS, et al.: The spectrum of mutations in TBX3: genotype /phenotype relationship in ulnar-mammary syndrome. Am J Hum Genet 64:1550–1562, 1999. Bamshad M, Lin RC, Law DJ, et al.: Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome. Nat Genet 16:311–315, 1997. Bamshad M, Root S, Carey JC: Clinical analysis of a large kindred with the Pallister ulnar-mammary syndrome. Am J Med Genet 65:325–331, 1996.

Brummelkamp TR, Kortlever RM, Lingbeek M, et al.: TBX-3, the gene mutated in Ulnar-Mammary Syndrome, is a negative regulator of p19ARF and inhibits senescence. J Biol Chem 277:6567–6572, 2002. Carlson H, Ota S, Campbell CE, et al.: A dominant repression domain in Tbx3 mediates transcriptional repression and cell immortalization: relevance to mutations in Tbx3 that cause ulnar-mammary syndrome. Hum Mol Genet 10:2403–2413, 2001. Coll M, Seidman JG, Muller CW: Structure of the DNA-bound T-box domain of human TBX3, a transcription factor responsible for ulnar-mammary syndrome. Structure (Camb) 10:343–356, 2002. Davenport TG, Jerome-Majewska LA, Papaioannou VE: Mammary gland, limb and yolk sac defects in mice lacking Tbx3, the gene mutated in human ulnar mammary syndrome. Development 130:2263–2273, 2003. Edwards MJ, McDonald D, Moore P, et al.: Scalp-ear-nipple syndrome: additional manifestations. Am J Med Genet 50:247–250, 1994. Franceschini P, Vardeu MP, Dalforno L, et al.: Possible relationship between ulnar-mammary syndrome and split hand with aplasia of the ulna syndrome. Am J Med Genet 44:807–812, 1992. Froster GU, Baird PA: Upper limb deficiencies and associated malformations: a population-based study. Am J Med Genet 44:767–781, 1992. Gilly E: Absence complète des mamelles chez une femme mère: Atrophie du member superieur droit. Courrier Med 32:27–28, 1882. Gonzalez CH, Herrmann J, Opitz JM: Studies of malformation syndromes of man XXXXIIB: mother and son affected with the ulnar-mammary syndrome type Pallister. Eur J Pediatr 123:225–235, 1976. He M, Wen L, Campbell CE, et al.: Transcription repression by Xenopus ET and its human ortholog TBX3, a gene involved in ulnar-mammary syndrome. Proc Natl Acad Sci USA 96:10,212–10,217, 1999. Hecht JT, Scott CI: The Schinzel syndrome in a mother and daughter. Clin Genet 25:63–67, 1984. Pallister PD, Hermann J, Opitz JM: Studies of Malformation Syndromes in Man XXXXII: a pleiotropic dominant mutation affecting skeletal, sexual and apocrine-mammary development. Birth Defects Original Article Series XII(5):247–254, 1976. Rogers C, Anderson G: Hand-foot-uterus syndrome vs. ulnar-mammary syndrome in a patient with overlapping phenotypic features. Proc Greenwood Genet Ctr 14:17–20, 1995. Sasaki G, Ogata T, Ishii T, et al.: Novel mutation of TBX3 in a Japanese family with ulnar-mammary syndrome: implication for impaired sex development. Am J Med Genet 110:365–369, 2002. Schinzel A: Ulnar-mammary syndrome. J Med Genet 24:778–781, 1987. Schinzel A, Illig R, Prader A: The ulnar-mammary syndrome: an autosomal dominant pleiotropic gene. Clin Genet 32:160–168, 1987. Sherman J, Angulo MA, Sharp A: Mother and infant son with ulnar-mammary syndrome of Pallister plus additional findings. Am J Hum Genet 39:A82, 1986. van Bokhoven H, Jung M, Smits AP, et al.: Limb mammary syndrome: a new genetic disorder with mammary hypoplasia, ectrodactyly, and other Hand/Foot anomalies maps to human chromosome 3q27. Am J Hum Genet 64:538–546, 1999. Wollnik B, Kayserili H, Uyguner O, et al.: Haploinsufficiency of TBX3 causes ulnar-mammary syndrome in a large Turkish family. Ann Genet 45:213–217, 2002.

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Fig. 1. A newborn (A,B) with ulnar mammary syndrome showing ulnar hypoplasia (missing 4th and 5th fingers) (C), ectrodactyly, syndactyly, and hypoplasia of the breast and nipples (D). The infant also had cryptorchidism, anal atresia, pulmonary hypoplasia, pyloric stenosis and bilateral renal hypoplasia.

VATER (VACTERL) Association VATER association is an acronym for the following nonrandom association of defects: Vertebral defects, Anal atresia, Tracheoesophageal fistula with Esophageal atresia, and Renal or Radial defects. VACTERL association is an expanded acronym to include Cardiac defects and Limb defects. Diagnosis of VACTERL association is made if three out of seven above defects are present in an infant. The incidence is estimated to be 1.6 cases in 10,000 live births.

GENETICS/BASIC DEFECTS 1. Etiologic heterogeneity a. Isolated cases in most cases b. Reports of rare familial cases (single gene disorders) c. Reports of chromosome abnormality cases d. Recognized syndromes or phenotypes e. Observed more frequently in infants of diabetic mothers 2. Pathogenesis: suggestion of a defective mesodermal development during embryogenesis due to a variety of causes, leading to overlapping manifestations 3. Molecular basis of VACTERL association a. Report of a family in which a female infant was born and died at age 1 month due to renal failure. The mother and sister later developed classic mitochondrial cytopathy, associated with the A-to-G point mutation at nucleotide position 3243 of mitochondrial DNA. b. Mitochondrial NP 3243 point mutation considered not a common cause of VACTERL association c. Sonic hedgehog in the human: a possible explanation for the VATER association

CLINICAL FEATURES 1. Vertebral anomalies a. Hemivertebrae b. Fused vertebrae c. Hypersegmentation of the vertebrae d. Hypersegmentation of the ribs e. Scoliosis f. Sacral anomalies g. Incomplete pedicle h. Sternal anomalies 2. Anal and urachal anomalies a. Anal atresia with or without fistula b. Persistent urachus 3. Cardiac anomalies a. Ventricular septal defects b. Patent ductus arteriosus c. Tetralogy of Fallot d. Transposition of the great arteries 1025

4. 5. 6.

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e. Other cardiovascular anomalies i. Right aortic arch ii. Double aortic arch iii. Coarctation of the aorta iv. Dextrocardia v. Total anomalous pulmonary venous drainage vi. Left superior vena cava vii. Congenital mitral stenosis viii. Right anomalous coronary artery ix. Single umbilical artery Tracheoesophageal fistula Esophageal atresia Renal anomalies a. Renal agenesis/dysgenesis b. Ectopic kidney c. Horseshoe kidney d. Ureteral/urethral anomalies e. Hydronephrosis f. Renal ectopia g. Vesicoureteral reflux h. Posterior urethral valves i. Ureteropelvic junction obstruction Limb defects a. Radial aplasia/dysplasia b. Hypoplastic thumbs c. Triphalangeal thumb d. Preaxial polydactyly e. Syndactyly f. Radioulnar synostosis Other associated abnormalities a. Failure to thrive b. Short stature c. Wide cranial suture d. Large fontanel e. Potter facies f. Ear anomalies g. Cleft palate h. Gastrointestinal anomalies i. Malrotation ii. Meckel diverticulum iii. Duodenal atresia iv. Pyloric atresia v. Ileal atresia vi. Pancreatic heterotopia vii. Vermiform appendix agenesis viii. Omphalocele ix. Inguinal hernia i. Genital anomalies i. Hypospadias ii. Cryptorchidism iii. Bifid scrotum iv. Micropenis

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j. Neurological anomalies i. Tethered cord ii. Spinal dysrhaphia iii. Occipital encephalocele k. Anomalies more commonly associated with CHARGE association

DIAGNOSTIC INVESTIGATIONS 1. 2. 3. 4. 5. 6.

Radiography for vertebral and limb defects Echocardiography for congenital heart defects GI investigation for TE fistula or esophageal atresia Renal ultrasonography for renal dysplasia Urological evaluation of urogenital defects Chromosome analysis

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: low recurrence risk unless in a single gene disorder b. Patient’s offspring: low recurrence risk unless in a single gene disorder 2. Prenatal diagnosis by ultrasonography revealing multiple congenital anomalies compatible to VACTERL association a. Vertebral anomalies b. Anorectal anomalies c. Congenital hart defects d. TE fistula or esophageal atresia e. Renal anomalies f. Limb defects 3. Management a. Medical care b. Surgical care i. TE fistula and/or esophageal atresia ii. Major cardiac defects iii. Urogenital anomalies iv. Skeletal and limb defects

REFERENCES Arsic D, Qi BQ, Beasley SW: Hedgehog in the human: a possible explanation for the VATER association. J Paediatr Child Health 38:117–121, 2002.

Auchterlonie IA, White MP: Recurrence of the VATER association within a sibship. Clin Genet 21:122–124, 1982. Barnes JC, Smith WL: The VATER Association. Radiology 126:445–449, 1978. Botto LD, Khoury MJ, Mastroiacovo P, et al.: The spectrum of congenital anomalies of the VATER association: an international study. Am J Med Genet 71:8–15, 1997. Corsello G, Maresi E, Corrao AM, et al: VATER/VACTERL association: clinical variability and expanding phenotype including laryngeal stenosis. Am J Med Genet 44:813–815, 1992. Czeizel A, Ludanyi I: An aetiological study of the VACTERL-association. Eur J Pediatr 144:331–337, 1985. Damian MS, Seibel P, Schachenmayr W, Reichmann H, et al: VACTERL with the mitochondrial 3243 point mutation. Am J Med Genet 62:398–403, 1996. Fernbach SK, Glass RB: The expanded spectrum of limb anomalies in the VATER association. Pediatr Radiol 18:215–220, 1988. Heifetz SA: Requirements for the VATER association. Am J Dis Child 140:1098–1099, 1986. Iuchtman M, Brereton R, Spitz L, et al.: Morbidity and mortality in 46 patients with the VACTERL association. Isr J Med Sci 28:281–284, 1992. Khoury MJ, Cordero JF, Greenberg F, et al.: A population study of the VACTERL association: evidence for its etiologic heterogeneity. Pediatrics 71:815–820, 1983. Lubinsky MS: Current concepts: VATER and other associations: historical perspectives and modern interpretations. Am J Med Genet Suppl 2:6–16, 1986. Martinez-Frías ML, Frías JL: VACTERL as primary polytopic developmental field defects. Am J Med Genet 83:13–16, 1999. Martinez-Frias ML, Bermejo E, Frias JL: The VACTERL association: lessons from the Sonic hedgehog pathway. Clin Genet 60:397–398, 2001. McGahan JP, Leeba JM, Lindfors KK: Prenatal sonographic diagnosis of VATER association. J Clin Ultrasound 16:588–591, 1988. Miller OF, Kolon TF: Prenatal diagnosis of VACTERL association. J Urol 166:2389–2391, 2001. Quan L, Smith DW: The VATER association. Vertebral defects, Anal atresia, T-E fistula with esophageal atresia, Radial and Renal dysplasia: a spectrum of associated defects. J Pediatr 82:104–107, 1973. Say B, Greenberg D, Harris R, et al.: The radial dysplasia/imperforate anus/ vertebral anomalies syndrome (the VATER association): developmental aspects and eye findings. Acta Paediatr Scand 66:233–235, 1977. Smith DW: The VATER association. Am J Dis Child 128:767, 1974. Stone DL, Biesecker LG: Mitochondrial NP 3243 point mutation is not a common cause of VACTERL association. Am J Med Genet 72:237–238, 1997. Temtamy SA, Miller JD: Extending the scope of the VATER association: definition of the VATER syndrome. J Pediatr 85:345–349, 1974. Tongsong T, Wanapirak C, Piyamongkol W, et al.: Prenatal sonographic diagnosis of VATER association. J Clin Ultrasound 27:378–384, 1999. Weaver DD, Mapstone CL, Yu PL: The VATER association. Analysis of 46 patients. Am J Dis Child 140:225–229, 1986. Weber TR, Smith W, Grosfeld JL: Surgical experience in infants with the VATER association. J Pediatr Surg 15:849–854, 1980.

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Fig. 1. An infant with VATER association showing club hands, abnormally rotated left lower limb, fused/split ribs, hemivertebrae, radial aplasia on the right, and radioulnar fusion on the left elbow.

Fig. 2. A child with VATER association showing club hands and radial aplasia.

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Fig. 3. A male neonate with VATER association showing phocomelia, rudimentary external genitalia and anal atresia. Congenital heart anomalies (type 2 truncus arteriosus, tricuspid valve atresia, ventricular septal defect, large atrial septal defect), type 1 tracheoesophageal fistula, nonlobated lungs, agenesis of kidneys and ureters, malrotation of bowel and vesico-colonic fistula were demonstrated in the necropsy.

Von Hippel-Lindau Disease Von Hippel-Lindau disease (VHL) is a rare hereditary cancer syndrome. The prevalence is estimated as 1 in 85,000 with an incidence of 1 in 45,500 live births. b.

GENETICS/BASIC DEFECTS 1. Inheritance a. Autosomal dominant b. Reduced penetrance (95% penetrance at age 60) c. Positive family history in up to 80% of cases d. Sporadic new mutation in about 20% of cases e. Parental mosaicism described 2. Molecular pathogenesis of VHL disease a. VHL disease i. Caused by deletions or mutations in a tumor suppressor gene, the VHL gene ii. Two-hit theory of Knudson in a familial cancer syndrome such as VHL disease a) Prediction of the genotype of each neoplasm which consists of an allele with an inherited germ-line mutation and loss of the second wild-type allele through allelic deletion b) Loss of heterozygosity at chromosome 3p at the VHL gene region has been demonstrated in different VHL disease-associated tumors. iii. A germline mutation in the VHL gene a) Predisposes carriers to tumors in multiple organs b) Consistently detected in 100% of classic families with more than one affected family member or classic sporadic patients with multiple VHL-related tumors c) Missense mutations leading to an amino acid substitution in VHL gene product pVHL, observed in 40% of the families with an identified VHL gene germline mutation d) Microdeletions, insertions, splice site, and nonsense mutations, all predicted to lead to a truncated protein: observed in 30% of the families e) Large deletions including deletions encompassing the entire gene: account for the remaining 30% of the VHL gene germline mutations iv. Somatic mutations a) Independent somatic alteration of both alleles of the VHL tumor suppressor gene leading to tumorigenesis in nonfamilial (VHLrelated) tumors b) Somatic VHL gene mutations and allele loss: frequent events in sporadic clear cell

c.

d.

e.

renal cell carcinomas and sporadic central nervous system hemangioblastoma; uncommon in sporadic (i.e., nontumor syndrome associated) pheochromocytoma VHL gene i. Mapped on chromosome 3p25 ii. Involved in blood vessel formation by regulation of the activity of hypoxia-inducible factor (HIF)-1α Patients with VHL disease i. With a positive family history: have inherited an inactive VHL allele from an affected parent ii. Without a positive family history: have a parent who is mosaic for a VHL mutation, presumably as the result of a de novo mutation during early development Angiogenesis of VHL tumors: critical role of inactivation of VHL gene i. Overexpression of vascular endothelial growth factor (VEGF) resulting in hypervascularization ii. Negative regulation of hypoxia-inducible mRNAs including VEGF mRNA by VHL protein Tumor development in VHL disease i. Linked to inactivation or loss of the remaining wild-type VHL allele in a susceptible cell, leading to loss of the VHL gene product pVHL ii. Inactivation of VHL gene contributing to tumorigenesis of the VHL tumor since VHL protein is required for the down-regulation of transcription activity of certain genes

CLINICAL FEATURES

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1. Great variation in the clinical presentation with variable age of onset 2. Classification of VHL disease a. VHL type 1 i. Without pheochromocytoma ii. Truncating or null mutations in the VHL gene (deletions or frameshift, nonsense, or splice site mutations) observed in approximately 96–97% of patients with type 1 VHL b. VHL type 2 i. With pheochromocytomas ii. Missense mutations observed in 92–98% of patients with type 2 VHL c. Subtypes of type 2 VHL i. VHL type 2A a) VHL without predisposition to renal cell carcinoma and pancreatic neuroendocrine tumor b) Specific mutations (Y98H, Y112H, V116F, L188V) in the VHL gene conferring an increased risk for VHL disease

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ii. VHL type 2B a) VHL with predisposition to renal cell carcinoma and pancreatic neuroendocrine tumor b) Specific mutations (R167Q, R167W) in the VHL gene conferring an increased risk for VHL disease iii. VHL type 2C a) VHL with only pheochromocytoma manifestation b) Specific mutations (V155L, R238W) in the VHL gene conferring an increased risk for VHL disease 3. Tumors/cysts linked to VHL disease, typically develop in the 2nd, 3rd, and 4th decades of life a. Retinal angioma/hemangioblastoma i. Responsible for the first manifestation of VHL in 50% of the patients ii. Retinal lesions a) Formerly called retinal angiomas b) Histologically identical to hemangioblastomas c) Identified in about 70% of the patients d) Bilateral in about 50% of the patients e) Multiple in about 66% of the patients iii. Complications when the condition is unrecognized and untreated at early stage a) Majority of retinal angiomas eventually hemorrhage. b) Resulting in massive exudation and retinal detachment c) Ultimate development of neovascular glaucoma and blindness b. Cerebellar hemangioblastomas (80% of CNS hemangioblastoma) i. The most common initial manifestation (34.9%) ii. Cumulative occurrence: 60.2% iii. The most common cause of death (47.7%) iv. Symptoms and signs a) Headache b) Slurred speech c) Nystagmus d) Positional vertigo e) Labile hypertension (without pheochromocytoma) f) Vomiting g) Wide-based gait h) Dysmetria c. Spinal hemangioblastoma (20% of CNS hemangioblastoma) i. More specific for VHL disease ii. About 80% of cases are caused by VHL. iii. Cumulative occurrence (14.5%) iv. Symptoms and signs a) Pain b) Sensory and motor loss secondary to cord compression d. Renal lesions i. Renal cysts: Precursor lesions to clear cell renal carcinomas (75% of patients with VHL) which is a frequent cause of death

ii. Hemangioblastoma iii. Renal cell adenoma iv. Renal cell carcinoma (20–40%) e. Pheochromocytomas (tumor of adrenal medulla) i. Type 1 families a) Absence of pheochromocytomas b) Most type 1 families are affected by deletions or premature termination mutations. ii. Type 2 families (7–20% of families) a) Presence of pheochromocytomas b) Most type 2 families are affected by missense mutations. iii. Arg238trp and arg238gln mutations: associated with a 62% risk for pheochromocytoma iv. Location of tumors a) Usually located in one or both adrenal glands b) May present anywhere along the sympathetic axis in the abdomen or thorax (paragangliomas) or head and neck (chemodectomas) v. Symptoms and signs a) Sustained or episodic hypertension b) Asymptomatic f. Pancreatic lesions i. Type of lesions a) Simple pancreatic cysts b) Serous cystadenomas c) Pancreatic neuroendocrine tumors ii. Rarely causing endocrine or exocrine insufficiency unless the lesion is extensive iii. Occasionally causing biliary obstruction secondary to cysts in the head of the pancreas g. Liver lesions i. Hemangiomas ii. Cyst iii. Adenoma iv. Carcinoid of the common bile duct h. Splenic lesions i. Hemangiomas ii. Cyst i. Pulmonary lesions i. Hemangiomas ii. Cyst j. Bladder hemangioblastoma k. Endolymphatic sac tumors of the inner ears (labyrinth) i. Tinnitus or vertigo ii. Deafness l. Papillary cystadenomas of the epididymis in males i. Relatively common in males ii. Unilateral: rarely causing problem iii. Bilateral: infertility m. Papillary cystadenomas of the broad ligament in females: much less common n. Skin lesions i. Nevus ii. Café au lait spot o. Bone lesions i. Hemangioma ii. Cyst 4. Diagnosis of VHL disease usually made on clinical grounds

VON HIPPEL-LINDAU DISEASE

a. A positive family history of VHL disease plus one of the following lesion (hemangioblastoma or visceral lesion): i. Retinal hemangioblastoma ii. Cerebellar hemangioblastoma iii. Pheochromocytoma iv. Renal cell carcinoma v. Multiple pancreatic cysts b. A negative family history of VHL disease need one of the following: i. Two or more retinal or cerebellar hemangioblastomas ii. One hemangioblastoma plus one visceral tumor 5. Prognosis a. Life expectancy: 41 weeks) ii. Failure to thrive iii. Short stature (50%) iv. Hypothyroidism v. A premature and abbreviated pubertal growth spurt b. CNS i. Muscle hypotonia early ii. Muscle tone increases with age; hypertonia in some cases iii. Poor coordination iv. Awkward gait v. Chiari I malformation vi. Hyperreflexia of the lower extremities c. EENT i. Ocular findings a) Strabismus b) Hyperopia c) Stellate iris d) Retinal vessel tortuosity ii. Chronic otitis media iii. Dental abnormalities a) Hypodontia/Microdontia b) Malocclusion c) Overbite d) Excessive interdental spacing e) Small roots f) High incidence of caries iv. A hoarse or brassy voice d. GI i. Difficulty feeding ii. Gastroesophageal reflux/vomiting iii. Prolong colic iv. Bowel diverticula v. Hernias vi. Rectal prolapse vii. Constipation viii. Peptic ulcers e. Genitourinary (18%) i. Bladder diverticula: the most common defects

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ii. Renal artery stenosis iii. Renal agenesis iv. Duplicated kidneys v. Horseshoe kidney vi. Renal cysts vii. Nephrocalcinosis viii. Vesicouriteral reflux f. Orthopedic problems i. Low/hoarse voice ii. Hernias iii. Joint laxity mostly during infancy iv. Joint contractures may develop by childhood and adolescence (50%) v. Radioulnar synostosis vi. Kyphosis vii. Lordosis viii. Scoliosis ix. Hallux valgus x. Hypoplastic nails xi. Clinodactyly of 5th fingers

DIAGNOSTIC INVESTIGATIONS 1. Echocardiography for cardiac lesions 2. Ultrasonography a. Bladder and kidneys b. Intravascular ultrasound imaging: to detect vascular wall thickening with secondary lumen narrowing 3. Serum creatinine level 4. Blood calcium levels to detect hypercalcemia during early infancy 5. Thyroid function test 6. Ophthalmologic evaluation for strabismus and retinal vessel tortuosity 7. Urinalysis to detect hypercalcinuria 8. Renal ultrasound for possible nephrocalcinosis if hypercalcinuria is noted 9. Radiography: osteosclerosis of the metaphyses of long bones, the skull vault, or lamina dura of the alveolar bone in adolescence and adulthood, if overt hypercalcemia is present 10. Full cytogenetic studies a. Larger deletions detectable by standard cytogenetic techniques, especially by high-resolution chromosome analysis b. To rule out possible chromosomal rearrangements involving the 7q11.23 locus as well as any other cytogenetic abnormalities 11. Fluorescence in situ hybridization (FISH) with a cosmid probe corresponding to ELN for diagnostic testing a. 99% of the patients with a hemizygous submiroscopic deletion of 7q11.23 detectable by FISH b. Cases undetectable by FISH i. Rare cases with a smaller deletion which does not fully encompass the FISH probe ii. Cases with phenocopies of Williams syndrome with same clinical phenotype produced by mutation or deletion of other gene(s) iii. Cases with a Williams syndrome-like phenotype associated with various cytogenetic rearrangements

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WILLIAMS SYNDROME

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. Recurrence risk low (95% of deletions. Molecular cytogenetic studies using FISH allow the diagnosis to be made in patients with very small deletions or cryptic translocations. FISH uses genetic markers that have been precisely localized to the area of interest. The absence of signal from either the maternal or the paternal allele for the marker is indicative of monosomy for that chromosomal region. 4. Immune workup a. Common variable immunodeficiency b. Immunoglobulin A (IgA) and immunoglobulin G2 (IgG2) subclass deficiency c. IgA deficiency d. Impaired polysaccharide responsiveness e. Normal T-cell immunity 5. Radiography a. Delayed bone maturation b. Microcephaly c. Hypertelorism d. Micrognathia e. Anterior fusion of vertebrae f. Fused ribs g. Dislocated hips h. Proximal radioulnar synostosis i. Clubfeet 6. Echocardiography to detect heart defects 7. Renal ultrasound to detect renal anomalies

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8. MRI and CT scans to demonstrate underlying brain pathology including agenesis of corpus callosum and ventriculomegaly 9. EEG for seizure monitoring 10. Swallowing study for feeding difficulty 11. Comprehensive audiologic and otologic evaluation to rule out possible hearing impairment 12. Ophthalmologic examination 13. Developmental testing a. Speech and motor evaluation b. Appropriate psychometric evaluation

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib i. De novo deletion cases: no significant increased risk ii. Deletion resulting from a parental chromosomal rearrangement: increased risk for unbalanced product in offspring b. Patient’s offspring: reproduction unlikely due to mental retardation 2. Prenatal diagnosis available to families in which one parent is known to be a carrier of a chromosome rearrangement by amniocentesis, CVS, or PUBS a. Ultrasonography to detect in utero manifestation of distinct phenotype i. Severe intrauterine growth retardation ii. Microcephaly iii. Hypertelorism, usually with prominent glabella iv. Micrognathia v. Cleft lip and palate vi. Diaphragmatic hernia b. Chromosome analysis i. Conventional karyotyping ii. FISH iii. Whole chromosome painting 3. Management a. Multidisciplinary team approach i. Early intervention program to improve motor development, cognition, communication, and social skills ii. Speech, physical, and occupational therapies iii. Appropriate school placement b. Manage feeding difficulties and failure to thrive i. Gavage feeding ii. Gastrostomy iii. Occasional gastroesophageal fundoplication c. Anticonvulsants for seizure control d. Orthopedic care for skeletal abnormalities i. Clubfoot ii. Scoliosis iii. Kyphosis e. Care for possible immunodeficiency

REFERENCES Altherr MR, Wright TJ, Denison K, et al.: Delimiting the Wolf-Hirschhorn syndrome critical region to 750 kilobase pairs. Am J Med Genet 71: 47–53, 1997.

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Battaglia A, Carey JC: Wolf-Hirschhorn syndrome and Pitt-Rogers-Danks syndrome. Am J Med Genet 75:541, 1998. Battaglia A, Carey JC: Health supervision and anticipatory guidance of individuals with Wolf-Hirschhorn syndrome. Am J Med Genet (Semin Med Genet) 89:111–115, 1999. Battaglia A, Carey JC: Update on the clinical features and natural history of Wolf-Hirschhorn syndrome (WHS): experience with 48 cases. Am J Hum Genet 67(Suppl 2):127, 2000. Battaglia A, Carey JC, Cederholm P, et al.: Natural history of Wolf-Hirschhorn syndrome: experience with 15 cases. Pediatrics 103:830–836, 1999. Battaglia A, Carey JC, Wright TJ: Wolf-Hirschhorn (4p-) syndrome. Adv Pediatr 48:75–113, 2001. Chen H: Wolf-Hirschhorn syndrome. EMed J 2(3):March 27, 2003. Clemens M, Martsolf JT, Rogers JG, et al.: Pitt-Rogers-Danks syndrome: the result of a 4p microdeletion. Am J Med Genet 66:95–100, 1996. Dallapiccola B, Mandich P, Bellone E, et al.: Parental origin of chromosome 4p deletion in Wolf-Hirschhorn syndrome. Am J Med Genet 47:921–924, 1993. Dietze I, Fritz B, Huhle D, et al.: Clinical, cytogenetic and molecular investigation in a fetus with Wolf-Hirschhorn syndrome with paternally derived 4p deletion. Case report and review of the literature. Fetal Diagn Ther 19:251–260, 2004. Dufke A, Seidel J, Schoning M, et al.: Microdeletion 4p16.3 in three unrelated patients with Wolf-Hirschhorn syndrome. Cytogenet Cell Genet 91:81–84, 2000. Estabrooks LL, Breg WR, Hayden MR, et al.: Summary of the 1993 ASHG ancillary meeting “recent research on chromosome 4p syndromes and genes.” Am J Med Genet 55:453–458, 1995. Fang YY, Bain S, Haan EA, et al.: High resolution characterization of an interstitial deletion of less than 1.9 Mb at 4p16.3 associated with WolfHirschhorn syndrome. Am J Med Genet 71:453–457, 1997. Fryns J Pediatr, Smeets E, Devriendt K, et al.: Wolf-Hirschhorn syndrome with cryptic 4p16.3 deletion and balanced/unbalanced mosaicism in the mother. Ann Génét 41:73–76, 1998. Hanley-Lopez J, Estabrooks LL, Stiehm R: Antibody deficiency in WolfHirschhorn syndrome. J Pediatr 133:141–143, 1998. Hirschhorn K, Cooper HL, Firschein IL: Deletion of short arms of chromosome 4–5 in a child with defects of midline fusion. Humangenetik 1:479–482, 1965. Johnson VP, Mulder RD, Hosen R: The Wolf-Hirschhorn (4p-) syndrome. Clin Genet 10:104–112, 1976. Lazjuk GI, Lurie IW, Ostrowskaja TI, et al.: The Wolf-Hirschhorn syndrome. II. Pathologic anatomy. Clin Genet 18:6–12, 1980. Lesperance MM, Grundfast KM, Rosenbaum KN: Otologic manifestations of Wolf-Hirschhorn syndrome. Arch Otolaryngol Head Neck Surg 124:193–196, 1998. Lurie IW, Lazjuk GI, Ussova YI, et al.: The Wolf-Hirschhorn syndrome. I. Genetics. Clin Genet 17:375–384, 1980.

Ogle R, Sillence DO, Merrick A, et al.: The Wolf-Hirschhorn syndrome in adulthood: evaluation of a 24-yr-old man with a rec(4) chromosome. Am J Med Genet 65:124–127, 1996. Opitz JM: Twenty-seven-years follow-up in the Wolf-Hirschhorn syndrome [editorial]. Am J Med Genet 55:459–461, 1995. Pitt DB, Rogers JG, Danks DM: Mental retardation, unusual face, and intrauterine growth retardation: a new recessive syndrome? Am J Med Genet 19:307–313, 1984. Rauch A, Schellmoser S, Kraus C, et al.: First known microdeletion within the Wolf-Hirschhorn syndrome critical region refines genotype-phenotype correlation. Am J Med Genet 99:338–342, 2001. Roulston D, Altherr M, Wasmuth JJ, et al.: Confirmation of a suspected deletion 4p16 by fluorescent in situ hybridization (FISH) with a cosmid probe. Am J Hum Genet 49:274, 1991. Schlickum S, Moghekar A, Simpson JC, et al.: LETM1, a gene deleted in Wolf-Hirschhorn syndrome, encodes an evolutionarily conserved mitochondrial protein. Genomics 83:254–261, 2004. Shannon NL, Maltby FL, Rigby AS, et al.: An epidemiological study of Wolf-Hirschhorn syndrome: life expectancy and cause of mortality. J Med Genet 38:674–679, 2001. Sharathkumar A, Kirby M, Freedman M, et al.: Malignant hematological disorders in children with Wolf-Hirschhorn syndrome. Am J Med Genet 119A:194–199, 2003. Tachdjian G, Fondacci C, Tapia S, et al.: The Wolf-Hirschhorn syndrome in fetuses. Clin Genet 42: 281–287, 1992. Thomson P: Wolf-Hirschhorn syndrome. Review of the literature and three case studies. J Am Podiatr Med Assoc 88:192–197, 1998. Wieczorek D, Krause M, Majewski F, et al.: Effect of the size of the deletion and clinical manifestation in Wolf-Hirschhorn syndrome analysis of 13 patients with a de novo deletion. Eur J Hum Genet 8:519–526, 2000. Wilson MG, Towner JW, Coffin GS, et al.: Genetic and clinical studies in 13 patients with the Wolf-Hirschhorn syndrome [del(4p)]. Hum Genet 59:297–307, 1981. Wolf U, Reinwein H, Porsch R, et al.: Deficiency on the short arms of a chromosome No. 4. Humangenetik 1:397–413, 1965. Wright TJ, Ricke DO, Denison K, et al.: A transcript map of the newly defined 165 kb Wolf-Hirschhorn syndrome critical region. Hum Mol Genet 6:317–324, 1997. Wright TJ, Clemens M, Quarrell O, et al.: Wolf-Hirschhorn and Pitt-RogersDanks syndromes caused by overlapping 4p deletions. Am J Med Genet 75:345–350, 1998. Zollino M, Di Stefano C, Zampino G, et al.: Genotype-phenotype correlations and clinical diagnostic criteria in Wolf-Hirschhorn syndrome . Am J Med Genet 94:254–261, 2000. Zollino M, Lecce R, Fischetto R, et al.: Mapping the Wolf-Hirschhorn syndrome phenotype outside the currently accepted WHS critical region and defining a new critical region, WHSCR-2. Am J Hum Genet 72:590–597, 2003.

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Fig. 1. A patient with Wolf-Hirschhorn syndrome at different ages showing characteristic facial features consisting of prominent glabella, hypertelorism, beaked nose, and frontal bossing, collectively described as “Greek warrior helmet” facies.

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Fig. 2. A girl with WHS showing characteristic face and deletion of WHS locus (FISH).

WOLF-HIRSCHHORN SYNDROME

Fig. 3. Two children with WHS showing characteristic facial features of the syndrome.

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Fig. 5. Karyotype of the sister showing deletion of 4p, derived from the mother with balanced translocation (4p;8p) (partial karyotypes).

Fig. 4. Two siblings with WHS showing characteristic features of the syndrome.

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Fig. 6. Karyotype and FISH of another patient with Wolf-Hirschhorn syndrome.

Fig. 7. A fetus with WHS showing broad triangular-shaped nasal root and the flat facial profile resembling “Greek warrior helmet.” The radiographs show hypoplasia of the cervical vertebral bodies.

X-Linked Ichthyosis X-linked ichthyosis is a relatively common genetic disorder of keratinization. It is the second most common type of ichthyosis after vulgaris. The incidence is estimated to be between 1 in 2000 and 1 in 6000 male live births.

GENETICS/BASIC DEFECTS 1. Inheritance a. X-linked recessive b. Usually affects males only c. Transmitted by carrier females (about 1 in 2000 women are carriers of steroid sulfatase (STS) enzyme deficiency) d. Most apparently sporadic cases appear to be inherited based on biochemical analysis (as their mothers showed low values of STS enzyme activity) e. Reports of a few affected female patients. 2. Etiology a. Caused by a deficiency of STS enzyme b. The STS gene i. Mapped on the distal part of the short arm of the X chromosome (Xp22.3) ii. Close to the pseudoautosomal region iii. Unlike most X-chromosome genes, the STS gene escapes the X-inactivation process. 3. Molecular defects a. Deletion of the entire steroid sulfatase (STS) gene: the most common molecular defect in X-linked ichthyosis (XLI) patients (observed in 90% of patients) b. Partial deletion or point mutation (observed in 10% of patients) c. The deletion of STS gene may occasionally extend to involve neighboring genes (interstitial and terminal deletions of Xp22.3), resulting in a contiguous gene defect and may be associated with the following conditions. Depending on the length of the deletion, these disorders occur independently from each other or in combination as a contiguous gene syndrome. i. Kallmann syndrome (hypogonadotropic hypogonadism and anosmia) ii. X-linked chondrodysplasia punctata iii. Short stature iv. Mental retardation v. Ocular albinism vi. Ichthyosis

CLINICAL FEATURES 1. Cutaneous manifestation a. Generalized scaling of the skin (ichthyosiform hyperkeratosis) i. Early onset: usually at birth or within 4 months of life 1057

ii. Large, dark-brown polygonal scales a) Usually symmetrically distributed b) More prominent on the trunk and the extensor aspects of the limbs c) Usually the flexures less affected iii. Face usually free from scales, except in the preauricular areas, giving the classic “unwashed appearance,” which is considered by many to be pathognomonic iv. Sparing palms and soles in most cases b. Normal nails and hair c. Seasonal influence i. Improve during the summer ii. Worsen during dry, cold weather 2. Extracutaneous manifestations a. Corneal opacities i. The most common extracutaneus features ii. Secondary to deposits of cholesterol sulfate crystals iii. Asymptomatic (not affecting the visual acuity) iv. Occurring in the posterior capsule of Descemet’s membrane or the corneal stroma v. More frequent during the second and third decades of life vi. Observed in 10–50% of affected males and carrier females b. Cryptorchidism i. Occurring in 10–20% of patients (vs the incidence of cryptorchidism in the normal population of 1%) ii. Possible mechanisms a) A deficit in the STS enzyme b) A genetic disturbance located on the short arm of chromosome X close to the STS gene c. Patients at an increased risk of testicular cancer development d. CNS manifestations i. Epileptic seizures ii. Reactive psychological disorders e. Clinical manifestations as a part of the contiguous gene syndrome expression i. Kallmann syndrome ii. Short stature iii. Mental retardation iv. X-linked chondrodysplasia punctata f. Other rare manifestations i. Pyloric hypertrophy ii. Congenital abdominal wall defect iii. Acute lymphoblastic leukemia 3. Steroid sulfatase deficiency during pregnancy in carrier females a. Leads to an overall decrease in the levels of estrogen b. Causes poor cervical dilatation and prolonged labor c. Frequently necessitates a Caesarean section

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DIAGNOSTIC INVESTIGATIONS 1. Direct biochemical demonstration of STS deficiency (undetectable levels of STS activity) from the following tissue: a. Placenta b. Skin fibroblasts c. Leukocytes d. Keratinocytes 2. Demonstration of an increase in substrates of STS a. Dihydroepiandrosterone sulfate (DHEAS) b. Cholesterol sulfate 3. Electrophoresis: rapid migration of serum cholesterol sulfate (negatively charged and carried by low-density lipoprotein [LDL] particles) towards the positive pole during electrophoresis 4. Molecular genetic diagnosis yielding reliable results in most affected patients a. Detection of complete deletion of the STS gene in most patients i. Fluorescence in situ hybridization (FISH) ii. Southern blotting iii. Multiplex polymerase chain reaction (PCR) b. Partial deletion by FISH: may provide a false negative FISH result c. A very small number of cases carrying point mutations instead of deletions at the STS gene: undetectable by Southern blot or PCR d. Carrier detection i. STS enzyme assay ii. FISH technique especially useful in carrier detection since the enzymatic assay often provides inconclusive results

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib (given that the mother is a carrier) i. 50% of male sibs affected ii. 50% of female sibs carriers b. Patient’s offspring i. Affected male patients a) Male offspring normal b) All female offspring carriers ii. Affected female patients (heterozygous) a) 50% of male offspring affected b) 50% of female offspring carriers iii. Affected female patients (homozygous) a) All male offspring affected b) All female offspring carriers 2. Prenatal diagnosis a. Maternal plasma demonstrating low or undetectable estriol levels in routine maternal serum screening, which is associated with the following conditions: i. Placental steroid sulfatase deficiency ii. Fetal death iii. Miscarriages iv. Anencephaly v. Fetal adrenal hypoplasia vi. High-dose corticosteroid therapy

vii. Aneuploidies a) Down syndrome b) Triploidy viii. Smith-Lemli-Opitz syndrome in rare cases b. Maternal urine and plasma profiles of affected fetuses indicating a primary placental sulfatase deficiency (low estriol levels) c. Amniocentesis i. Elevated sulfated steroids in the amniotic fluid ii. FISH to detect deletion in one copy of X chromosome at region Xp22.3 using steroid sulfatase probe d. Skin biopsy through fetoscopy to measure sulfated steroid 3. Management a. Spontaneous improvement in most cases with age and during summer months and hardly require any treatment b. Attempt to diminish the abnormal cohesion of corneocytes by facilitating their separation in the milder forms i. Topical keratolytics ii. Emollients iii. Hydrating agents c. Retinoids for potential treatment in severely affected patients d. Liarozole, a imidazole derivative which inhibit cytochrome P450 to increase the level of endogenous retinoid acid by blocking its P450-dependent catabolism e. Examination of male patients to detect cryptorchidism which has an increased risk of testicular cancer

REFERENCES Ahmed MN, Killam A, Thompson KH, et al.: Unconjugated estriol as an indication for prenatal diagnosis of steroid sulfatase deficiency by in situ hybridization. Obstet Gynecol 92:687–689, 1998. Aviram-Goldring A, Goldman B, Netanelov-Shapira I, et al.: Deletion patterns of the STS gene and flanking sequences in Israeli X-linked ichthyosis patients and carriers: analysis by polymerase chain reaction and fluorescence in situ hybridization techniques. Int J Dermatol 39:182–187, 2000. Ballabio A, Bardoni B, Carrozo R, et al.: Contiguous gene syndromes due to deletions in the distal short arm of the human X chromosome. Proc Natl Acad Sci USA 86:10001–10005, 1989. Basler E, Grompe M, Parenti G, et al.: Identification of point mutations in the steroid sulfatase gene of three patients with X-linked ichthyosis. Am J Hum Genet 50:483–491, 1992. Bonifas JM, Epstein EH Jr: Detection of carriers for X-linked ichthyosis by Southern blot analysis and identification of one family with a de novo mutation. J Invest Dermatol 95:16–19, 1990. Bradshaw KD, Carr BR: Placental sulfatase deficiency: maternal and fetal expression of steroid sulfatase deficiency and X-linked ichthyosis. Obstet Gynecol Surv 41:401–413, 1986. Braunstein GD, Zeil FH, Allen A, et al.: Prenatal diagnosis of placental steroid sulfatase deficiency. Am J Obstet Gynecol 126:716–719, 1976. Casaroli Marano RP, Ortiz Stradtmann MA, Uxo M, et al.: Ocular findings associated with congenital X-linked ichthyosis. Ann Ophthalmol 23:167–172, 1991. Crawfurd MA: Review: genetics of steroid sulphatase deficiency and X-linked ichthyosis. J Inherit Metab Dis 5:153–163, 1982. Cuevas-Covarrubias SA, Jimenez-Vaca AL, Gonzalez-Huerta LM, et al.: Somatic and germinal mosaicism for the steroid sulfatase gene deletion in a steroid sulfatase deficiency carrier. J Invest Dermatol 119:972–975, 2002. Cuevas-Covarrubias SA, Kofman-Alfaro S, Orozco E, et al.: The biochemical identification of carrier state in mothers of sporadic cases of X-linked recessive ichthyosis. Genet Couns 6:103–107, 1995.

X-LINKED ICHTHYOSIS Cuevas-Covarrubias SA, Valdes-Flores M, Orozco E, et al.: Most “sporadic” cases of X-linked ichthyosis are not de novo mutations. Acta Derm Venereol 79:143–144, 1999. Glass IA, Lam RC, Chang T, et al.: Steroid sulphatase deficiency is the major cause of extremely low oestriol production at mid-pregnancy: a urinary steroid assay for the discrimination of steroid sulphatase deficiency from other causes. Prenat Diagn 18:789–800, 1998. Gohlke BC, Haug K, Fukami M, et al.: Interstitial deletion in Xp22.3 is associated with X linked ichthyosis, mental retardation, and epilepsy. J Med Genet 37:600–602, 2000. Hernandez-Martin A, Gonzalez-Sarmiento R, De Unamuno P: X-linked ichthyosis: an update. Br J Dermatol 141:617–627, 1999. Janniger CK, Schwartz RA: Ichthyosis, X-linked. Emedicine, 2001. http://www. emedicine.com Jasmi FA, Al-Khenaizan SA: X-linked ichthyosis and undescended tested. Int J Dermatol 41:614, 2002. Kashork CD, Sutton VR, Fonda Allen JS, et al.: Low or absent unconjugated estriol in pregnancy: an indicator for steroid sulfatase deficiency detectable by fluorescence in situ hybridization and biochemical analysis. Prenat Diagn 22:1028–1032, 2002. Keren DF, Canick JA, Johnson MZ, et al.: Low maternal serum unconjugated estriol during prenatal screening as an indication of placental steroid sulfatase deficiency and X-linked ichthyosis. Am J Clin Pathol 103:400–403, 1995. Lebo RV, Lynch ED, Golbus MS, et al.: Prenatal in situ hybridization test for deleted steroid sulfatase gene. Am J Med Genet 46:652–658, 1993. Lykkesfeldt G, Nielsen MD, Lykkesfeldt AE: Placental steroid sulfatase deficiency: biochemical diagnosis and clinical review. Obstet Gynecol 64:49–54, 1984. Mevorah B, Frenk E, Muller CR, et al.: X-linked recessive ichthyosis in three sisters: evidence for homozygosity. Br J Dermatol 105:711–717, 1981.

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Nomura K, Nakano H, Umeki K, et al.: A study of the steroid sulfatase gene in families with X-linked ichthyosis using polymerase chain reaction. Acta Derm Venereol 75:340–342, 1995. Okano M, Kitano Y, Yoshikawa K, et al.: X-linked ichthyosis and ichthyosis vulgaris: comparison of their clinical features based on biochemical analysis. Br J Dermatol 119:777–783, 1988. Paige DG, Emilion GG, Bouloux PM, et al.: A clinical and genetic study of X-linked recessive ichthyosis and contiguous gene defects. Br J Dermatol 131:622–629, 1994. Saeki H, Kuwata S, Nakagawa H, et al.: Deletion pattern of the steroid sulphatase gene in Japanese patients with X-linked ichthyosis. Br J Dermatol 139:96–98, 1998. Shapiro LJ: Steroid sulfatase deficiency and the genetics of the short arm of the human X chromosome. Adv Hum Genet 14:331–381, 388–389, 1985. Shapiro LJ, Yen P, Pomerantz D, et al.: Molecular studies of deletions at the human steroid sulfatase locus. Proc Natl Acad Sci USA 86:8477–8481, 1989. Traupe H, Happle R: Mechanisms in the association of cryptorchidism and X-linked recessive ichthyosis. Dermatologica 172:327–328, 1986. Watanabe T, Fujimori K, Kato K, et al.: Prenatal diagnosis for placental steroid sulfatase deficiency with fluorescence in situ hybridization: a case of X-linked ichthyosis. J Obstet Gynaecol Res 29:427–430, 2003. Wells RS, Kerr CB. Genetic classification of ichthyosis. Arch Dermatol 92:1–6, 1965. Wells RS, Jennings MC: X-linked ichthyosis and ichthyosis vulgaris. Clinical and genetic distinctions in a second series of families. JAMA 202:485–488, 1967. Zalel Y, Kedar I, Tepper R, et al.: Differential diagnosis and management of very low second trimester maternal serum unconjugated estriol levels, with special emphasis on the diagnosis of X-linked ichthyosis. Obstet Gynecol Surv 51:200–203, 1996.

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Fig. 1. A sporadic case of X-linked ichthyosis showing thick, large, polygonal, dark-brown scales involving the extensor.

Fig. 3. Abnormal FISH analysis showed a deletion in the steroid sulfatase critical region on the X chromosome [del(X)(p22.3p22.3)(STS-)] in a male fetus (upper photo). The case was ascertained because of undetectable UE3 from maternal serum screen. The lower photo (FISH) showed a normal XX control.

Fig. 2. X-linked ichthyosis affecting 3 boys in a family.

XXX Syndrome Females with a 47,XXX karyotype were first described by Jacobs et al. in 1959. The incidence of 47,XXX among female newborns is approximately 1 in 1000 live births.

i. ii. iii. iv. v.

Less well adapted With more stress With work, leisure, and relationship problems With a lower IQ With more psychopathology when contrasted with the comparison group c. Most 47,XXX women i. Self sufficient ii. Functioning reasonably well

GENETICS/BASIC DEFECTS 1. Etiology: an extra chromosome X is responsible for 47,XXX 2. Mechanism of the origin for the 47,XXX condition a. Almost all 47,XXX result from maternal nondisjunction b. Typically at meiosis I

DIAGNOSTIC INVESTIGATIONS 1. Chromosome analysis 2. Psychological and psychiatric evaluation when needed

CLINICAL FEATURES 1. No specific phenotype exists in 47,XXX females 2. A higher incidence of minor anomalies a. Epicanthal folds b. Upslanting palpebral fissures c. Ear abnormalities d. Clinodactyly 3. Growth and development a. Birth weights tend to be slightly lower than the general population. b. Taller in older children c. Relative microcephaly d. At risk for mild speech/language and motor delays and learning disabilities e. Intelligence i. Normal range ii. Lower intelligence quotients (10–15 points) in comparison to unaffected sibs 4. Gonadal structures and function a. Heterosexual b. Normal secondary sexual characteristics c. Normal menstruation d. Fertility usually normal e. Late menarche f. Occasional amenorrhea g. Premature ovarian failure h. Sterility with streak gonads 5. Congenital anomalies reported in a very small number of patients a. Urogenital tract abnormalities b. Brain abnormalities c. Skeletal abnormalities d. Congenital heart defects e. Craniofacial abnormalities 6. Adaptation status: variable a. At risk for intellectual and psychological problems b. 47,XXX women during adolescence and young adulthood

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased b. Patient’s offspring i. An increased risk of a cytogenetically abnormal child but the extent of the risk cannot yet be determined ii. Majority of offspring normal 2. Prenatal diagnosis by fetal karyotyping from amniocytes or CVS 3. Management a. Infancy/toddler: assess milestones b. Childhood i. Assess school performance ii. Provide intervention if needed a) Speech/language therapy b) Physical/occupational therapy c) Educational remediation c. Adolescence: usually no intervention needed d. Adult adulthood: annual physical examination

REFERENCES Barr ML, Sergovich FR, Carr DH, et al.: The triplo X female. Can Med Assoc J 101:247–258, 1969. Bender BG, Harmon RJ, Linden MG, et al.: Psychosocial competence of unselected young adults with sex chromosome abnormalities. Am J Med Genet 88:200–206, 1999. Chudley AE, Stoeber GP, Greenberg CR: Intrauterine growth retardation and minor anomalies in 47,XXX children. Birth Defects Orig Artic Ser 26:267–272, 1990. Dewhurst J: Fertility in 47,XXX and 45,X patients. J Med Genet 15:132–135, 1978. Evans JA, de von Flindt R, Greenberg C, et al.: A cytogenetic survey of 14,069 newborn infants. IV. Further follow up on the children with sex chromosome anomalies. Birth Defects Orig Artic Ser 18(4):169–184, 1982. Harmon RJ, Bender BG, Linden MG, et al.: Transition from adolescence to early adulthood: adaptation and psychiatric status of women with 47,XXX. J Am Acad Child Adolesc Psychiatry 37:286–291, 1998.

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Hassold T, Arnovitz K, Jacobs PA, et al.: The parental origin of the missing or additional chromosome in 45,X and 47,XXX females. Birth Defects Orig Artic Ser 26:297–304, 1990. Jacobs PA: The incidence and etiology of sex chromosome abnormalities in man. Birth Defects Orig Artic Ser XV(1):3–14, 1979. Linden MG, Bender BG, Harmon RJ, et al.: 47,XXX: what is the prognosis? Pediatrics 82:619–630, 1988. Linden MG, Bender BG, Robinson A: Genetic counseling for sex chromosome abnormalities. Am J Med Genet 110:3–10, 2002.

May KM, Jacobs PA, Lee M, et al.: The parental origin of the extra X chromosome in 47,XXX females. Am J Hum Genet 46:754–761, 1990. Ogata T, Matsuo M, Muroya K, et al.: 47,XXX male: A clinical and molecular study. Am J Med Genet 98:353–356, 2001. Pennington B, Puck M, Robinson A: Language and cognitive development in 47,XXX females followed since birth. Behav Genet 10:31–41, 1980. Robinson A, Lubs HA, Nielsen J, et al.: Summary of clinical findings: profiles of children with 47,XXY, 47,XXX and 47,XYY karyotypes. Birth Defects Orig Artic Ser 15:261–266, 1979.

XXX SYNDROME

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Fig. 2. A girl with 47,XXX showing normal phenotype.

Fig. 3. 47,XXX karyotype.

Fig. 1. A girl with 47,XXX at different ages showing normal phenotype.

XXXXX Syndrome 49,XXXXX (pentasomy X) is a rare sex chromosome aneuploidy. The birth prevalence of pentasomy X is estimated to be 1 in 85,000 females.

2. Craniofacial features a. Microcephaly b. Flattened occiput c. Epicanthus d. Upslanting palpebral fissures e. Ocular hypertelorism f. Uncoordinated eye movements g. Flat broad nose h. Cleft palate i. Low-set ears j. Malformed teeth 3. Skeletal abnormalities a. Short neck b. Lax joints c. Multiple dislocations i. Shoulders ii. Elbows iii. Hips d. Radioulnar synostosis e. Spinal abnormalities f. Clinodactyly of the 5th fingers g. Lower leg abnormalities i. Genu valgus ii. Talipes iii. Metatarsus varus h. Delayed bone age 4. Congenital heart defects a. Ventricular septal defect b. Patent ductus arteriosus 5. Abnormal lobulation of the lungs 6. Renal hypoplasia 7. Sexual development a. Delayed puberty b. Incomplete secondary sexual development c. Small uterus d. Hypoplastic/absent ovaries i. Composed mainly of stroma and atrophic follicles ii. Absence of ova iii. Unilateral absence of an ovary reported e. Reduced fertility 8. Normal external genitalia 9. Dermatoglyphics a. Finger-dermal-ridge hypoplasia and a low total ridge count, consistent with the inverse proportion between the number of X chromosomes and the total ridge count (exceptions exist) b. Transverse palmar creases

GENETICS/BASIC DEFECTS 1. Etiology: Three extra X chromosomes are responsible for the pentasomy X syndrome. 2. Occurrence of a 49,XXXXX complement: secondary to sequential non-disjunctions in meiosis I and meiosis II in the mother a. Involves the survival of both X chromosomes in a single oocytes through both meiotic divisions i. Once between homologous X chromosomes at the first meiosis ii. Twice between sister chromatids in both X chromosomes in the secondary oocytes at the second meiosis b. Followed by the fertilization by a sperm contributing the 5th chromosome X 3. Formation of four Barr bodies a. Lyon hypothesis i. Inactivation of all X chromosomes but one ii. Account for the viability of the X-chromosome aneuploidies b. Inactivation of four X chromosomes resulting in four Barr bodies 4. Effect of supernumerary X chromosomes: a direct relationship between the number of supernumerary X chromosomes and phenotypic abnormalities and mental retardation, with each additional chromosome increasing the severity a. Affects somatic development most significantly i. Skeletal abnormalities ii. Cardiovascular abnormalities b. Delays sexual development c. Affects cognitive development i. Severe mental retardation ii. Language delay (both expressive and receptive language) iii. Behavioral problems

CLINICAL FEATURES 1. Growth and development a. Prenatal growth retardation b. Small birth weight c. Low postnatal weight d. Failure to thrive e. Hypotonia f. Short stature g. Delayed psychomotor retardation h. Mental retardation

DIAGNOSTIC INVESTIGATIONS 1. Chromosome analysis a. 49,XXXXX karyotype b. Fluorescence in situ hybridization (FISH), using DNA probe for α-satellite sequence in chromosome 1064

XXXXX SYNDROME

X (DXZ1), reveals five signals representing the presence of XXXXX 2. Radiography a. Dislocations of the elbows and/or hips b. Radioulnar synostosis c. Clinodactyly

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased b. Patient’s offspring: not reported due to severe mental retardation 2. Prenatal diagnosis a. Ultrasonography: bilateral radioulnar synostosis b. Amniocentesis and CVS i. Chromosome analysis ii. FISH using DNA probe (DXZ1) applied to uncultured amniocytes 3. Management a. Physical/occupational therapy b. Speech therapy

REFERENCES Archidiacono N, Rocchi M, Valente M, et al.: X pentasomy: A case and review. Hum Genet 52:69–77, 1979. Brody J, Fitzgerald MG, Spiers ASD: A female child with five X chromosomes. J Pediatr 70:105–109, 1967. Deng H-X, Abe K, Kondo I, et al.: Parental origin and mechanism of formation of polysomy X: an XXXXX case and four XXXXY cases determined with RFLPs. Hum Genet 86:541–544, 1991.

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Dryer RF, Patil SR, Zellweger HU, et al.: Pentasomy X with multiple dislocations. Am J Med Genet 4:313–321, 1979. Fryns JP, Kleczkowska A, Petit P, et al.: X-chromosome polysomy in the female: personal experience and review of the literature. Clin Genet 23:341–349, 1983. Funderburk SJ, Valente M, Klisak I: Pentasomy X: report of patient and studies of X-inactivation. Am J Med Genet 8:27–33, 1981. Kassai R, Hamada I, Furuta H, et al.: Penta X syndrome: A case report with review of the literature. Am J Med Genet 40:51–56, 1991. Kesaree N, Woolley PV Jr: A phenotypic female with 49 chromosomes, presumably XXXXX. J Pediatr 63:1099–1103, 1963. Leal CA, Belmont JW, Nachtman R, et al.: parental origin of the extra chromosomes in polysomy X. Hum Genet 94:423–426, 1994. Linden MG, Bender BG, Robinson A: Sex chromosome tetrasomy and pentasomy. Pediatrics 96:672–682, 1995. Martini G, Carillo G, Catizone F, et al.: On the parental origin of the X’s in a prenatally diagnosed 49,XXXXX syndrome. Prenat Diagn 13:763–766, 1993. Monheit A, Francke U, Saunders B, et al.: The penta-X syndrome. J Med Genet 17:392–396, 1980. Myles TD, Burd L, Font G, et al.: Dandy-Walker malformation in a fetus with pentasomy X (49,XXXXX) prenatally diagnosed by fluorescence in situ hybridization technique. Fetal Diagn Ther 10:333–336, 1995. Sepulveda W, Ivankovic M, Be C, et al.: Sex chromosome pentasomy (49,XXXXY) presenting as cystic hygroma at 16 weeks’ gestation. Prenat Diagn 19:257–259, 1999. Sergovich F, Uilenberg C, Pozsony J: The 49,XXXXX chromosome constitution: similarities to the 49,XXXXY condition. J Pediatr 78:285–290, 1971. Silengo MC, Davi GF, Franceschini P: The 49XXXXX syndrome. Report of a case with 48XXXX/49XXXXX mosaicism. Acta Paediatr Scand 68:769–771, 1979. Toussi T, Hala F, Lesage R, et al.: Renal hypodysplasia and unilateral ovarian agenesis in the penta-X syndrome. Am J Med Genet 6:153–162, 1980.

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Fig. 1. The first reported case of 49,XXXXX at infancy (A) and adulthood (B) with 4 Barr bodies (C), two drumsticks in a polymorphonuclear leukocyte (D), and a karyotype of 49,XXXXX (E).

XXXXX SYNDROME

Fig. 2. A girl with 49,XXXXX syndrome at birth (A), 6 month (B), and 2 years 4 months (C).

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XXXXY Syndrome 49,XXXXY syndrome was first described by Fraccaro and Lindsten in 1960. The incidence is estimated to be approximately 1 in 85,000 newborn males.

GENETICS/BASIC DEFECTS 1. Etiology: Three extra X chromosomes are responsible for the 49,XXXXY syndrome. 2. Mechanism a. All four X chromosomes are of maternal in origin b. Resulting from successive nondisjunctions in maternal meiosis I and II c. Inactivation of three out of four X chromosomes results in three Barr bodies (Lyon hypothesis). 3. Effect of supernumerary X chromosomes: a direct relationship between the number of supernumerary X chromosomes and phenotypic abnormalities and mental retardation, with each additional chromosome increasing the severity a. Somatic development most significantly affected i. Skeletal abnormalities ii. Cardiovascular abnormalities b. Gonadal development in males: particularly susceptible to extra genetic material i. Addition of a single X chromosome to a 46,XY karyotype resulting in seminiferous tubal dysgenesis rendering infertile as such males with Klinefelter syndrome ii. Additional extra X chromosomes in polysomy X males such as 48,XXXY and 49,XXXXY can result in not only infertility but hypoplastic and malformed genitalia. c. Affects cognitive development i. Severe mental retardation ii. Language delay (both expressive and receptive language) iii. Behavioral problems

3. 4.

5.

6.

7.

8.

g. Micrognathia h. Prognathism i. High arched or cleft palate j. Irregular teeth implantation k. Malformed ears Webbed and short neck Congenital heart defects a. Patent ductus arteriosus b. Atrial septal defect c. Pulmonic stenosis d. Tetralogy of Fallot Skeletal abnormalities a. Short stature b. Proximal radio-ulnar dysostosis c. Vertebral anomalies d. Clinodactyly of the 5th fingers e. Coxa valga f. Genu valga g. Pes planus Genital abnormalities a. Hypoplastic male genitalia b. Micropenis c. Hypospadias d. Small testes e. Hypogonadism f. Infertility Dermatoglyphics a. Decrease in total finger ridge count b. Transverse palmar creases Psychological profile a. Timid and shy b. Emotional disturbances with low frustration level c. Strong reaction to minor changes d. Adaptive function higher than cognitive function

DIAGNOSTIC INVESTIGATIONS

CLINICAL FEATURES 1. Growth and development a. Growth retardation b. Severe speech impairment c. Varying degree of mental retardation 2. Craniofacial features a. Microcephaly b. A full, round face c. Ocular hypertelorism d. Upslanted palpebral fissures e. Epicanthus f. Broad nasal bridge

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1. Chromosome analysis showing 49,XXXXY 2. Radiography a. Elbows i. Proximal radio-ulnar dysostosis ii. Radio-ulnar dislocation without synostosis iii. Elongated upper radius iv. Wide, club-shaped proximal ulna b. Wrists and hands i. Elongated distal ulna ii. “Pseudoepiphyses” iii. Clinodactyly of the 5th fingers iv. Brachymesophalangia V v. Retarded bone age vi. Corner defect in capitate vii. Poor modeling of the 5th metacarpals

XXXXY SYNDROME

c. Pelvis and hips i. Coxa valga ii. Narrow iliac wings d. Knees i. Shallow intercondylar fossa ii. Genu valgum e. Ankles and feet i. Gap between the 1st and 2nd toes ii. Short wide distal phalanx of the great toes f. Skull i. Sclerotic cranial sutures ii. Thick cranial vault iii. Ocular hypertelorism iv. J-shaped sella v. Prognathism g. Spine i. Scoliosis ii. Thoracic kyphosis iii. Square vertebral bodies h. Sternum i. Thick ii. Abnormal segmentation 3. Echocardiography for congenital heart defects 4. Histology of testicular biopsies: dysgenesis of testicular germ cells and tubules leading to fibrosis

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased b. Patient’s offspring: no offspring due to infertility of the condition 2. Prenatal diagnosis a. Ultrasonographic markers i. Polyhydramnios ii. Cystic hygroma iii. Clubfoot iv. Micropenis b. Amniocentesis and CVS i. Chromosome analysis ii. FISH using DNA probe (DXZ1) applied to uncultured amniocytes

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3. Management a. Early intervention and stimulation programs i. Speech/language therapy ii. Physical/occupational therapy b. Testosterone replacement therapy

REFERENCES Chen C-P, Chern S-R, Chang C-L, et al.: Prenatal diagnosis and genetic analysis of X chromosome polysomy 49,XXXXY. Prenat Diagn 20:754–757, 2000. Curfs LM, Schreppers-Tijdink G, Wiegers A, et al.: The 49,XXXXY syndrome: clinical and psychological findings in five patients. J Ment Defic Res 34:277–282, 1990. Deng HX, Abe K, Kondo I, et al.: Parental origin and mechanism of formation of polysomy X: an XXXXX case and four XXXXY cases determined with RFLPs. Hum Genet 86:541–544, 1991. Galasso C, Arpino C, Fabbri F, et al.: Neurologic aspects of 49,XXXXY syndrome. J Child Neurol 18:501–504, 2003. Hecht F: Observations on the natural history of 49,XXXXY individuals. Am J Med Genet 13:335–336, 1982. Houston CS: Roentgen findings in the XXXXY chromosome anomaly. J Can Assoc Radiol 18:258–267, 1967. Karsh RB: Congenital heart disease in 49, XXXXY syndrome. Pediatrics 56:462–464, 1975. Kleczkowska A, Fryns J-P, Van den Berghe H: X-chromosome polysomy in the male. The Leuven experience 1966–1967, 1988. Kojima Y, Hayashi Y, Maruyama T, et al.: 49,XXXXY syndrome with hydronephrosis caused by intravesical ureterocele. Urol Int 63:212–214, 1999. Leal CA, Belmont JW, Nachtman R, et al.: parental origin of the extra chromosomes in polysomy X. Hum Genet 94:423–426, 1994. Linden MG, Bender BG ,Robinson A: Sex chromosome tetrasomy and pentasomy. Pediatrics 96:672–682, 1995. Lomelino CA, Reiss AL: 49,XXXXY syndrome: behavioural and developmental profiles. J Med Genet 28:609–612, 1991. Peet J, Weaver DD,Vance GH: 49,XXXXY: a distinct phenotype. Three new cases and review. J Med Genet 35:420–424, 1998. Rehder H, Fraccaro M, Cuoco C, et al.: The fetal pathology of the XXXXYsyndrome. Clin Genet 30:213–218, 1986. Schluth C, Doray B, Girard-Lemaire F, et al.: Prenatal sonographic diagnosis of the 49,XXXXY syndrome. Prenat Diagn 1177–1180, 2002. Sepulveda W, Ivankovic M, Be C, et al.: Sex chromosome pentasomy (49,XXXXY) presenting as cystic hygroma at 16 weeks’ gestation. Prenat Diagn 19:257–259, 1999. Villamar M, Benitez J, Fernandez E, et al.: Parental origin of chromosomal nondisjunction in a 49,XXXXY male using recombinant-DNA techniques. Clin Genet 36:152–155, 1989. Zaleski WA, Houston CS, Pozsonyi J, et al.: The XXXXY chromosome anomaly: report of three new cases and review of 30 cases from the literature. Can Med Assoc J 94:1143–1154, 1966.

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Fig. 2. A younger boy with 49,XXXXY showing a full, round face. He also has incontinentia pigmenti achromians. Fig. 1. An older boy with 49,XXXXY showing bilateral dislocation of the elbows, radio-ulnar synostosis and 3 Barr bodies (buccal smear).

XY Female XY females are completely sex-reversed individuals who are phenotypically females with 46,XY karyotype, failure to develop secondary sex characteristics, amenorrhea, and “streak gonads”. b.

GENETICS/BASIC DEFECTS 1. SRY gene and its mouse homologue, Sry a. The sex-determining region on the Y chromosome i. Mapped to the short arm of the Y chromosome ii. Encodes for a testis-determining factor (TDF) iii. Candidate gene narrowed down to a 35-kb interval on the Y chromosome adjacent to the pseudoautosomal boundary which contains a Y chromosomal-specific sequence, named SRY (sex-determining region Y gene) iv. Demonstration that mice transgenic for Sry developed into sex-reversed males despite an XX karyotype provided the confirmation of SRY being the TDF that directs the undifferentiated gonad into a testis b. Deletions or mutations occurring in the SRY i. Result in failure of testis development ii. Sex differentiation along the female pathway 2. Mechanism of male to female sex reversal (abnormalities of XY sex determination) a. Mutations in the SRY gene resulting in XY females with gonadal dysgenesis (vs translocation of this gene sequence to X chromosome giving rise to XX males) i. Increasing variety of unique mutations within SRY gene reported in patients with gonadal dysgenesis/XY reversal. These patients are, in general, normal 46,XY females with complete gonadal dysgenesis ii. SRY gene mutations noted in 15–20% of cases with complete gonadal dysgenesis a) Most mutations are located in the High Mobility Group (HMG) box b) De novo mutations affect only one individual in a family in the majority of cases c) Phenotypic variability is associated with different mutations iii. About one third of the SRY mutations reported are inherited. a) No apparent explanation available to explain why an inherited SRY mutation which results in sex reversal in the offspring is associated with a normal male phenotype in the father and sometime in brothers and uncles. b) Paternal mosaicism for the mutant SRY provides an explanation for the other familial cases of XY gonadal dysgenesis.

c.

d.

e.

iv. 80% of patients with sporadic or familial 46,XY gonadal dysgenesis lack a mutation or deletion of the SRY gene, indicating that other autosomal or X-linked genes have a role in sex determination. Sox9 i. Another gene involved in sex determination identified by positional cloning of a chromosomal breakpoint has been identified in the XY female with campomelic dysplasia, a condition in which three-quarters of XY patients show genital and gonadal malformations. ii. Belongs to a family of SRY-box related (SOX) genes which encode proteins with at least 60% amino acid homology to the HMG box of the SRY protein Atrx i. The gene responsible for the ATR-X syndrome causes α-thalassemia, severe mental retardation and multiple congenital anomalies which may include 46,XY gonadal dysgenesis and undermasculinization. ii. The C-terminal region of the protein has been lost in most cases where there has been gonadal dysgenesis associated with ATR-X syndrome. Deletions of variable portions of the short arm of chromosome 9 (DMRT-1 identified as a candidate gene) result in partial or complete gonadal dysgenesis in XY females Sex-reversing Xp duplication (Xp21)

CLINICAL FEATURES 1. 46,XY females (individuals with 46,XY complete gonadal dysgenesis) (Swyer Syndrome) a. Diagnosed usually not made until puberty when the patient presents with delayed pubertal development b. Unambiguous female phenotype with completely female external genitalia c. Gonadal dysgenesis (streak gonads) d. Well developed Mullerian structures e. Absence of testicular development f. Absence of Wolffian structures g. Absence of other somatic abnormalities h. Absence of secondary sexual characteristics i. Amenorrhea j. High risk of developing gonadal tumors i. Gonadoblastoma ii. Dysgerminoma 2. Differential diagnosis a. Individuals with 46,XY partial gonadal dysgenesis (also called 46,XY mixed gonadal dysgenesis or dysgenetic male pseudohermaphroditism)

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i. Majority of patients present in the newborn period for evaluation of ambiguous genitalia ii. Partial testicular determination. The extent of masculinization of the external genitalia depends on the extent of testicular differentiation. iii. Dysgenetic gonads iv. Presence of Mullerian and Wolffian structures v. Regarded as the clinical spectrum of 46,XY gonadal dysgenesis b. Individuals with 46,XY embryonic testicular regression syndrome (also called true agonadism or gonadal agenesis) i. A term used to describe the spectrum of genital anomalies resulting from regression of testis development from 8–14 weeks of gestation ii. Regression of the fetal testes between the 8–10 weeks of gestation a) Complete absence of gonads b) Rudimentary Mullerian and/or Wolffian ductal structure c) Hypoplastic uterus d) Female genitalia with/or without ambiguity iii. Regression of the testes after the critical period of male differentiation (around 12–14 weeks) a) Anorchia b) Partial testicular regression resulting in a male phenotype as in anorchia but with small rudimentary testes

DIAGNOSTIC INVESTIGATIONS 1. Karyotype analysis a. 46,XY in phenotypic females b. To exclude 45,X/46,XY and other forms of mosaicism, served to exclude the more common forms of gonadal dysgenesis 2. Molecular analysis for SRY gene a. Nucleotide substitutions (missense/nonsense) b. Deletions c. Insertions 3. Ultrasonography/laparotomy a. Complete gonadal dysgenesis i. Streak gonads ii. Presence of Mullerian ducts iii. Absence of Wolffian ducts b. Partial gonadal dysgenesis i. Dysgenetic gonads ii. Presence of Mullerian and Wolffian structures 4. Gonadal histology a. Streak gonads i. Absence of primordial follicles ii. Wavy ovarian stroma intermixed with fibrous tissue b. Gonadal tumors observed in about 30% of cases i. Gonadoblastomas: usually benign ii. Dysgerminoma iii. Embryonal carcinoma: more life-threatening 5. Biochemical findings a. Elevated levels of FSH and LH b. Low levels of estradiol c. No elevation of androgen levels

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: recurrence risk depending on whether the inheritance is X-linked recessive, male-limited autosomal dominant, or autosomal recessive b. Patient’s offspring: Patients are nonreproductive c. To rule out the disease in siblings because of the presence of familial aggregation. 2. Prenatal diagnosis: demonstration of the sexual discrepancy between fetal karyotype (XY) and ultrasonographic fetal phenotype a. To exclude sample error and placental mosaicism b. Detailed fetal ultrasound examination to check for syndromic gender discrepancy such as: i. Campomelic dysplasia (skeletal malformation) ii. Denys-Drash syndrome iii. Smith-Lemli-Opitz syndrome a) Microcephaly b) Abnormal cholesterol metabolism iv. Alfi syndrome a) Craniostenosis b) Trigonocephaly c) Multiple congenital anomalies c. Prenatal diagnosis possible by SRY analysis for XY gonadal dysgenesis (SRY-negative XY female and SRY-positive XY female) i. FISH using SRY probe on metaphase chromosomes ii. Sequencing of entire coding region 3. Management a. Removal of gonads to avoid malignancy b. Initiate cyclic hormonal therapy with estrogen and progesterone at puberty c. Psychological counseling i. Raise as a female ii. Increase patient’s knowledge about medical and surgical history and karyotype iii. Counseling for sexual function iv. Achievement of pregnancy in some patients following in vitro fertilization with a donor egg

REFERENCES Ahmed SF, Hughes IA: The genetics of male undermasculinization. Clin Endocr 56:1–18, 2002. Arn P, Chen H, Tuck-Muller CM, et al.: SRVX, a sex reversing locus in Xp21.2-p22.11. Hum Genet 93:389–393, 1994. Bardoni B, Zanaria E, Guioli S, et al.: A dosage sensitive locus at chromosome Xp21 is involved in male to female sex reversal. Nature Genet 7:497–501, 1994. Barr ML, Carr DH, Plunkett E R, et al.: Male pseudohermaphroditism and pure gonadal dysgenesis in sisters. Am J Obstet Gynec 99:1047–1055, 1967. Berkovitz GD: Abnormalities of gonad determination and differentiation. Semin Perinatol 16:289–298, 1992. Berta P, Hawkins JR, Sinclair AH, et al.: Genetic evidence equating SRY and the testis-determining factor. Nature 348:448–450, 1990. Bretelle F, Salomon L, Senat M-V, et al.: Fetal gender: antenatal discrepancy between phenotype and genotype. Ultrasound Obstet Gynecol 20:286–289, 2002. Calvan V, Bertini V, De Grandi A, et al.: A new submicroscopic deletion that refines the 9p region for sex reversal. Genomics 65:203–212, 2000.

XY FEMALE Cameron F, Sinclair AH: Mutations in SRY and SOX9: testis-determining genes. Hum Mutat 9:388–395, 1997. Davis RM: Localization of male-determining factors in man: A thorough review of structural anomalies of the Y chromosome. J Med Genet 18:161–195, 1981. Goodfellow PN, Lovell-Badge R: SRY and sex determination in mammals. Annu Rev Genet 27:71–92, 1993. Graves PE, Davis D, Erickson RP, et al.: Ascertainment and mutational studies of SRY in nine XY females. Am J Med Genet 83:138–139, 1999. Harley VR, Goodfellow PN: The biochemical role of SRY in sex determination. Mol Reprod Dev 39:184–193, 1994. Hawkins JR: Genetics of XY sex reversal. J Endocrinol 147:183–187, 1995. Hawkins JR, Taylor A, Berta P, et al.: Mutational analysis of SRY: nonsense and missense mutations in XY sex reversal. Hum Genet 88:471–475, 1992. Hawkins JR, Taylor A, Goodfellow PN, et al.: Evidence for increased prevalence of SRY mutations in XY females with complete rather than partial gonadal dysgenesis. Am J Hum Genet 51:979–984, 1992. Hines RS, Tho SPT, Zhang YY, et al.: Paternal somatic and germ-line mosaicism for a sex-determining region on Y (SRY) missense mutation leading to recurrent 46,XY sex reversal. Fertil Steril 67:675–679, 1997. Jacob PA, Ross A: Structural abnormalities of the Y chromosome in man. Nature 210:352–354, 1966. Jäger RJ, Anvret M, Hall K, et al.: A human XY female with a frame shift mutation in the candidate testis-determining gene SRY. Nature 348:452–454, 1990. Jordan BK, Jain M, Natarajan S, et al.: Familial mutation in the testis-determining gene SRY shared by an XY female and her normal father. J Clin Endocrinol Metab 87:3428–3432, 2002. Koopman P, Gubay J, Vivian N, et al.: Male development of chromosomally female mice transgenic for Sry. Nature 351:117–121, 1991. Kwok C, Weller PA, Guioli S, et al.: Mutations in SOX9, the gene responsible for campomelic dysplasia and autosomal sex reversal. Am J Hum Genet 57:1028–1036, 1995. Kwok C, Tyler-Smith C, Mendonca BB, et al.: Mutation analysis of the 2 kb 5' to SRY in XY females and XY Intersex subjects. J Med Genet 33:465–468, 1996. McDonald MT, Flejter W, Sheldon S, et al.: XY sex reversal and gonadal dysgenesis due to 9p24 monosomy. Am J Med Genet 73:321–326, 1997. McElreavey K, Fellous M: Sex determination and the Y chromosome. Am J Med Genet (Semin Med Genet) 89:176–185, 1999.

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McElreavey K, Vilain E, Abbas N, et al.: XY sex reversal associated with a deletion 5’ to the SRY “HMG box” in the testis-determining region. Proc Natl Acad Sci USA 89:11016–11020, 1992. McElreavey K, Vilain E, Barbauxz S, et al.: Loss of sequences 3’ to the testisdetermining gene, SRY, including the Y pseudoautosomal boundary associated with partial testicular determination. Proc Natl Acad Sci USA 93:8590–8594, 1996. Morerio C, Calvari V, Rosanda C, et al.: XY female with a dysgerminoma and no mutation in the coding sequence of the SRY gene. Cancer Genet Cytogenet 136:58–61, 2002. Nazareth HRS, Moreira-Filho CA, Cunha AJB, et al. antigens in 46,XY pure testicular dysgenesis. Am J Med Genet 3:149–154, 1979. Portuondo JA, Neyro JL, Barral A, et al.: management of phenotypic female patients with an XY karyotype. J Reprod Med 31:611–615, 1986. Sarafoglou K, Ostrer H: Familial sex reversal: a review. J Clin Endocrinol Metab 85:483–493, 2000. Sauer MV, Lobo RA, Paulson RJ: Successful twin pregnancy after embryo donation to a patient with 46,XY gonadal dysgenesis. Am J Obstet Gynecol 161:380–381, 1989. Schäffler A, Barth N, Winkler K, et al.: Identification of a new missense mutation (Gly95Glu) in a highly conserved codon within the high-mobility group box of the sex-determining region Y gene: report on a 46,XY female with gonadal dysgenesis and yolk-sac tumor. J Clin Endocrinol Metab 85:2287–2292, 2000. Simpson JL, Blgowidow N, Martin AO: XY gonadal dysgenesis: genetic heterogeneity based upon clinical observations, H-Y antigen status, and segregation analysis. Hum Genet 58:91–97, 1981. Sinclair AH, Berta P, Palmer MS, et al.: A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature 346:240–245, 1990. Swain A, Zanaria E, Hacker A, et al.: Mouse Dax1 expression is consistent with a role in sex determination as well as in adrenal and hypothalamus function. Nature Genet 12:404–409, 1996. Veitia R, Ion A, Barbaux S, et al.: Mutations and sequence variants in the testisdetermining region of the Y chromosome in individuals with a 46,XY female phenotype. Hum Genet 99:648–652, 1997. Vilain E, Jaubert F, Fellous M, et al.: Pathology of 46,XY pure gonadal dysgenesis: absence of testis differentiation associated with mutations in the testis-determining factor. Differentiation 52:151–159, 1993.

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Fig. 1. A patient with 46,XY female with gonadal dysgenesis at 42 years of age. Patient has short stature (4’6”), primary amenorrhea, lack of secondary sex characteristics (absent axillary hair, poor breast development), but normal female external genitalia. Laparotomy revealed absent Wolffian structures and presence of uterus and streak gonads which were excised.

XYY Syndrome In 1961, Sandberg described an XYY man. The incidence is estimated to be approximately 1 in 1000 live male newborns.

GENETIC COUNSELING 1. Recurrence risk a. Patient’s sib: not increased b. Patient’s offspring: Patient generally has chromosomally normal children, despite the high theoretical risk of aneuploidy. 2. Prenatal diagnosis: fetal karyotyping from amniocytes or CVS 3. Management a. The extra Y chromosome represents a risk factor for motor and language development, but the environment remains a primary force in shaping child’s development b. The increased frequency of prenatal detection of 47,XYY by amniocentesis necessitates the importance of making accurate information about the developmental prognosis of these individuals. c. Infancy and toddler: assess developmental milestones d. Childhood: assess school performance and provide intervention if needed e. Adolescence: no intervention needed f. Adulthood annual physical examination

GENETICS/BASIC DEFECTS 1. Caused by an additional Y chromosome in a male 2. Mechanisms of the extra Y chromosome in 47,XYY males a. Paternal nondisjunction at meiosis II after a normal chiasmate meiosis I (84%) b. Postzygotic mitotic error or nondisjunction at meiosis II after a nullichiasmate meiosis I (16%) 3. Spermatogenesis a. Normal spermatogenesis in majority of XYY males i. The supernumerary Y chromosome probably lost at the early stage of spermatogenesis ii. A large proportion of primary spermatocytes containing only one Y chromosome b. Altered spermatogenesis in a proportion of XYY males: Persistence of the supernumerary Y chromosome through meiotic prophase increases spermatocyte degeneration. 4. A higher incidence of the XYY complement in the institutions for the retarded, the mentally ill, the criminally insane, and the aggressive offender: controversial and biased

REFERENCES

CLINICAL FEATURES 1. Earlier observation of the association between the additional Y chromosome and aggressive behavior: considered to be due to selection bias and has since been challenged 2. No consistent physical stigmata or medical disorders 3. Growth and development a. Tall stature b. Larger tooth size c. At risk for mild speech/language and motor delays and learning disabilities 4. Intelligence a. Normal range b. IQ: 10–15 points lower than siblings 5. Behavioral profile a. Childhood temper tantrums b. No increased incidence of aggression c. Heterosexual 6. Normal reproduction 7. Normal adult adaptation 8. Low fertility

DIAGNOSTIC INVESTIGATIONS 1. Chromosome analysis to detect 47,XYY 2. Psychological and psychiatric evaluation when needed 3. Studies of sperm karyotypes or FISH analysis of sperm: The majority of sperm are chromosomally normal in 47,XYY men.

Abramsky L, Chapple J: 47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling. Prenat Diagn 17:363–368, 1997. Bender BG, Puck MH, Salbenblatt JA, et al.: The development of four unselected 47,XYY boys. Clin Genet 25:435–445, 1984. Court Brown WM: Males with an XYY sex chromosome complement. J Med Genet 5:341–359, 1968. Daly RF, Chun RW, Ewanowski S, et al.: The XYY condition in childhood: clinical observations. Pediatrics 43:852–857, 1969. Gabriel-Robez O, Delobel B, Croquette MF, et al.: Synaptic behaviour of sex chromosome in two XYY men. Ann Genet 39:129–132, 1996. Hoffman BF: Two new cases of XYY chromosome complement: and a review of the literature. Can Psychiatr Assoc J 22:447–455, 1977. Hsu LY, Shapiro LR, Hirschhorn K: Meiosis in an XYY male. Lancet 1:1173–1174, 1970. Linden MG, Bender BG, Robinson A: Genetic counseling for sex chromosome abnormalities. Am J Med Genet 110:3–10, 2002. Martin RH, Shi Q, Field LL: Recombination in the pseudoautosomal region in a 47,XYY male. Hum Genet 109:143–145, 2001. Money J, Franzke A, Borgaonkar DS: XYY syndrome, stigmatization, social class, and aggression: study of 15 cases. South Med J 68:1536–1542, 1975. Owen DR: The 47,XYY male: a review. Psychol Bull 78:209–233, 1972. Rives N, Simeon N, Milazzo JP, et al.: Meiotic segregation of sex chromosomes in mosaic and non-mosaic XYY males: case reports and review of the literature. Int J Androl 26:242–249, 2003. Robinson DO, Jacobs PA: The origin of the extra Y chromosome in males with a 47,XYY karyotype. Hum Mol Genet 8:2205–2209, 1999. Robinson A, Lubs HA, Nielsen J, et al.: Summary of clinical findings: profiles of children with 47,XXY, 47,XXX and 47,XYY karyotypes. Birth Defects Orig Artic Ser 15:261–266, 1979. Stewart DA, Netley CT, Park E: Summary of clinical findings of children with 47,XXY, 47,XYY, and 47,XXX karyotypes. Birth Defects Orig Artic Ser 18:1–5, 1982.

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Fig. 1. A 7-year-old boy with 47,XYY syndrome showing normal phenotype. Fig. 3. An adult with 47,XYY syndrome showing tall stature.

Fig. 2. A 13-year-old boy with XYY syndrome showing normal phenotype. He also has systemic carnitine deficiency and received Carnitol treatment.