Atlas of Genodermatoses [3 ed.] 9780367643966, 9780367643973, 9781003124351

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Atlas of Genodermatoses Genodermatoses are often considered rare diseases seldom seen by practicing clinicians, and as a result, professionals often have little experience or confidence with their diagnosis when they are called upon for a clinical case. This text presents a comprehensive illustrated overview of almost 200 inherited diseases of the skin, hair and nails. Examples have been expanded, with new images added to provide clear examples, alongside coherent and comprehensive explanations to enable clinicians to easily identify and source relevant information. This resource encompasses a varied range of skin diseases, providing accessible and in-depth information to help familiarize clinicians. The entry for each disease provides the background, followed by common characterizations, manifestations, laboratory findings, genetics, cutaneous and extracutaneous findings, differential diagnosis, an overview of complications and recommended follow-ups. Authored by dermatologists and geneticists, this is an atlas of scientific research which updates established information with current studies and references. In its third edition, this text becomes an invaluable resource for dermatologists and paediatricians.

Atlas of Genodermatoses Third Edition

Gianluca Tadini, MD

Paediatric Dermatology Unit, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy

Michela Brena, MD

Paediatric Dermatology Unit, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy

Lidia Pezzani, MD

Paediatric Unit ASST Papa Giovanni XXIII, Bergamo, Italy Clinical Genetics Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy

Francesca Besagni, MD

Dermatology Unit – IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Italy

Third edition published 2024 by CRC Press 2385 NW Executive Center Drive, Suite 320, Boca Raton FL 33431 and by CRC Press 4 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN CRC Press is an imprint of Taylor & Francis Group, LLC © 2024 Taylor & Francis Group, LLC First edition published by Taylor & Francis 2006 Second edition published by CRC Press 2015 This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have been made to publish reliable data and information, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. The publishers wish to make clear that any views or opinions expressed in this book by individual editors, authors or contributors are personal to them and do not necessarily reflect the views/opinions of the publishers. The information or guidance contained in this book is intended for use by medical, scientific or health-care professionals and is provided strictly as a supplement to the medical or other professional’s own judgement, their knowledge of the patient’s medical history, relevant manufacturer’s instructions and the appropriate best practice guidelines. Because of the rapid advances in medical science, any information or advice on dosages, procedures or diagnoses should be independently verified. The reader is strongly urged to consult the relevant national drug formulary and the drug companies’ and device or material manufacturers’ printed instructions, and their websites, before administering or utilizing any of the drugs, devices or materials mentioned in this book. This book does not indicate whether a particular treatment is appropriate or suitable for a particular individual. Ultimately it is the sole responsibility of the medical professional to make his or her own professional judgements, so as to advise and treat patients appropriately. The authors and publishers have also attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged, please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, access www.copyright.com or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. For works that are not available on CCC please contact [email protected] Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Names: Tadini, Gianluca, author, editor. | Brena, Michela, author, editor. | Pezzani, Lidia, author, editor. | Besagni, Francesca, author, editor. Title: Atlas of genodermatoses / edited by Gianluca Tadini, Michela Brena, Lidia Pezzani, Francesca Besagni. Description: Third edition. | Boca Raton : CRC Press, 2023. | Includes bibliographical references and index. Identifiers: LCCN 2023031149 (print) | LCCN 2023031150 (ebook) | ISBN 9780367643966 (hardback) | ISBN 9780367643973 (paperback) | ISBN 9781003124351 (ebook) Subjects: MESH: Skin Diseases--genetics | Atlas Classification: LCC RL120.G45 (print) | LCC RL120.G45 (ebook) | NLM WR 17 | DDC 616.5/042--dc23/eng/20240124 LC record available at https://lccn.loc.gov/2023031149 LC ebook record available at https://lccn.loc.gov/2023031150 ISBN: 9780367643966 (hbk) ISBN: 9780367643973 (pbk) ISBN: 9781003124351 (ebk) DOI: 10.1201/9781003124351 Typeset in Warnock Pro by KnowledgeWorks Global Ltd.

CONTENTS Foreword ................................................................................................................................................................................................................................xi Preface .................................................................................................................................................................................................................................. xii Acknowledgements .......................................................................................................................................................................................................... xiii List of Contributors ...........................................................................................................................................................................................................xiv Illustration Credits .............................................................................................................................................................................................................xv 1. Epidermolysis Bullosae ...............................................................................................................................................................................................1 Definition .......................................................................................................................................................................................................................1 Epidemiology ................................................................................................................................................................................................................1 Epidermolytic epidermolysis bullosa (EEB) ..........................................................................................................................................................1 Junctional epidermolysis bullosa (JEB) ...................................................................................................................................................................8 Dermolytic epidermolysis bullosa (DEB)..............................................................................................................................................................14 Kindler syndrome ......................................................................................................................................................................................................21 2. Acantholytic Diseases ...............................................................................................................................................................................................24 Darier disease .............................................................................................................................................................................................................24 Hailey-Hailey disease ................................................................................................................................................................................................27 3. Ichthyoses ....................................................................................................................................................................................................................30 Non-syndromic ichthyoses ......................................................................................................................................................................................30 Autosomal dominant congenital ichthyoses .......................................................................................................................................................31 Autosomal recessive congenital ichthyoses (ARCI) ...........................................................................................................................................35 Keratinopathic ichthyoses........................................................................................................................................................................................46 Loricrin keratoderma ................................................................................................................................................................................................54 Klick syndrome ..........................................................................................................................................................................................................54 Erythrokeratoderma variabilis et progressiva (EKVP) ......................................................................................................................................54 Pityriasis rotunda.......................................................................................................................................................................................................57 Ichthyosis cribriformis .............................................................................................................................................................................................58 Peeling skin syndromes (PSS) .................................................................................................................................................................................58 PLACK syndrome ......................................................................................................................................................................................................60 Keratolytic winter erythema ...................................................................................................................................................................................62 Syndromic ichthyoses ...............................................................................................................................................................................................62 Syndromic X-linked ichthyosis ...............................................................................................................................................................................62 Netherton syndrome .................................................................................................................................................................................................63 SAM syndrome...........................................................................................................................................................................................................66 ErythroKeratoderma cardiomyopathy (EKC) syndrome ..................................................................................................................................68 Neonatal inflammatory skin and bowel disease type 1 (NISBD1) ..................................................................................................................68 EGFR-related Ichthyosis ...........................................................................................................................................................................................69 Sjögren-Larsson syndrome ......................................................................................................................................................................................69 Refsum disease ...........................................................................................................................................................................................................71 Trichothiodystrophy (TTD) ....................................................................................................................................................................................72 Ichthyosis follicularis with atrichia and photophobia (IFAP)/keratosis follicularis spinulosa decalvans (KFSD)...............................72 BRESEK/BRESHECK syndrome ............................................................................................................................................................................74 X-linked dominant chondrodysplasia punctata..................................................................................................................................................75 KID syndrome ............................................................................................................................................................................................................77 Ichthyosis hypotrichosis syndrome (IHS) ...........................................................................................................................................................77 Ichthyosis-hypotrichosis-sclerosing cholangitis syndrome (IHSC) ..............................................................................................................78 MEDNIK syndrome ..................................................................................................................................................................................................79 Keratitis-ichthyosis-deafness autosomal recessive (KIDAR) ...........................................................................................................................80 Gaucher disease type II ............................................................................................................................................................................................80 Multiple sulfatase deficiency (MSD)......................................................................................................................................................................81 CEDNIK syndrome ...................................................................................................................................................................................................82 Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome ...................................................................................................................82 Autosomal recessive keratoderma, ichthyosis and deafness (ARKID) syndrome.......................................................................................83 Dorfman-Chanarin syndrome................................................................................................................................................................................83 Ichthyosis prematurity syndrome ..........................................................................................................................................................................84 Neu-Laxova syndrome ..............................................................................................................................................................................................85 UDP-glucose ceramide glucosyltransferase associated collodion baby .......................................................................................................86 Cutaneous ceramidopathies ....................................................................................................................................................................................86 KDSR-related phenotypes ........................................................................................................................................................................................88 v

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Contents Ferro-cerebro-cutaneous syndrome ......................................................................................................................................................................89 Congenital disorders of glycosylation associated with ichthyosis ..................................................................................................................89 Sphingosine lyase insufficiency syndrome (SPLIS) ............................................................................................................................................90

4. Palmoplantar Keratodermas ...................................................................................................................................................................................91 Definition .....................................................................................................................................................................................................................91 Diffuse hereditary PPKs: no associated features.................................................................................................................................................91 Diffuse hereditary PPKs: with associated features .............................................................................................................................................95 Focal hereditary PPKs: no associated features ..................................................................................................................................................103 Focal hereditary PPKs: with associated features ..............................................................................................................................................104 Papular hereditary PPK: no associated features ...............................................................................................................................................107 Papular hereditary PPKs: with associated features ..........................................................................................................................................109 Pachydermoperiostosis ...........................................................................................................................................................................................110 PPK congenital alopecia syndrome ......................................................................................................................................................................111 Keratin 16-related PPK ...........................................................................................................................................................................................112 5. Other Disorders of Keratinization .......................................................................................................................................................................113 Kyrle’s disease ...........................................................................................................................................................................................................113 Autoinflammatory keratinization diseases (AiKDs) .......................................................................................................................................114 6. Poikilodermas and Aging Syndromes .................................................................................................................................................................121 Xeroderma pigmentosum (XP) .............................................................................................................................................................................121 Clericuzio-type poikiloderma with neutropaenia ............................................................................................................................................123 Kindler syndrome ....................................................................................................................................................................................................125 Bloom syndrome ......................................................................................................................................................................................................125 Rothmund-Thomson syndrome............................................................................................................................................................................125 Dyskeratosis congenita (DC) ................................................................................................................................................................................ 126 Hereditary sclerosing poikiloderma ....................................................................................................................................................................129 POIKTMP syndrome ............................................................................................................................................................................................. 130 LIPHAK syndrome (LTV1-associated inflammatory poikiloderma with hair abnormalities and acral keratoses) .......................................................................................................................................................................132 Trichothiodystrophy syndrome (TTD) ...............................................................................................................................................................132 Aging syndromes .....................................................................................................................................................................................................135 Werner syndrome ....................................................................................................................................................................................................135 Cockayne syndrome ................................................................................................................................................................................................136 Acrogeria....................................................................................................................................................................................................................137 Kitamura disease......................................................................................................................................................................................................138 Dowling-Degos disease...........................................................................................................................................................................................139 Laminopathies ..........................................................................................................................................................................................................140 Hutchinson-Gilford syndrome .............................................................................................................................................................................140 Restrictive dermopathy ..........................................................................................................................................................................................142 Atypical progeroid syndromes (APSs) ................................................................................................................................................................143 7. Hair Diseases ............................................................................................................................................................................................................146 Non-syndromic forms of congenital hypotrichosis .........................................................................................................................................146 Syndromic forms of congenital hypotrichosis ..................................................................................................................................................153 Congenital hypertrichosis..................................................................................................................................................................................... 154 Congenital complex syndromes with hypertichosis ........................................................................................................................................155 Cantu syndrome.......................................................................................................................................................................................................156 Cornelia de Lange syndrome.................................................................................................................................................................................156 Barber-Say syndrome ..............................................................................................................................................................................................156 Pili torti ......................................................................................................................................................................................................................156 Pili annulati ...............................................................................................................................................................................................................158 Menkes disease .........................................................................................................................................................................................................159 Trichothiodystrophy ...............................................................................................................................................................................................160 Silvery hair syndrome .............................................................................................................................................................................................160 Loose anagen syndrome .........................................................................................................................................................................................161 Alopecia areata .........................................................................................................................................................................................................162 Ulerythema ophryogenes .......................................................................................................................................................................................163 Triangular alopecia .................................................................................................................................................................................................164 8. Nail Disorders ...........................................................................................................................................................................................................165 Twenty nail dystrophy ............................................................................................................................................................................................165 Pachyonychia congenita .........................................................................................................................................................................................166 Nail-patella syndrome ............................................................................................................................................................................................168

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Iso-Kikuchi syndrome ............................................................................................................................................................................................170 Leuconychia ..............................................................................................................................................................................................................171 Yellow nail syndrome ..............................................................................................................................................................................................171 Witkop syndrome ....................................................................................................................................................................................................172 Pterygium inversum unguis ..................................................................................................................................................................................172 Congenital malalignment of the great toenail ..................................................................................................................................................172 DOORS syndrome ...................................................................................................................................................................................................173 9. Neurocutaneous Syndromes .................................................................................................................................................................................174 Neurofibromatosis type 1 (NF1) ...........................................................................................................................................................................174 Legius syndrome ......................................................................................................................................................................................................188 Noonan syndrome (NS) ..........................................................................................................................................................................................188 Cardiofaciocutaneous (CFC) syndrome .............................................................................................................................................................191 Costello syndrome ...................................................................................................................................................................................................192 Mosaic RASopathies ...............................................................................................................................................................................................193 Schwannomatoses ...................................................................................................................................................................................................194 Neurofibromatosis type 2 related schwannomatosis .......................................................................................................................................194 LZTR1 and SMARCB1-related schwannomatosis ...........................................................................................................................................196 Tuberous sclerosis (TS)...........................................................................................................................................................................................197 10. Epidermal Nevi and Epidermal Nevus Syndromes ......................................................................................................................................... 206 EN and related syndromes .................................................................................................................................................................................... 206 Phacomatosis pigmentokeratotica .......................................................................................................................................................................215 Phacomatosis Pigmento-Eccrina ..........................................................................................................................................................................217 Waxy keratosis..........................................................................................................................................................................................................218 Papular EN with Skyline basal cell layer (PENS) nevus and related syndrome ........................................................................................ 220 Porokeratotic eccrine ostial and dermal duct nevus (PEODDN)..................................................................................................................222 Nevoid follicular mucinosis .................................................................................................................................................................................. 224 CHILD syndrome ................................................................................................................................................................................................... 225 White sponge hyperplasia of the mucosae ........................................................................................................................................................ 226 11. Ectodermal Dysplasias and Related Disorders ................................................................................................................................................. 228 Ectodermal dysplasias............................................................................................................................................................................................ 228 Hypohidrotic ED (HED) ........................................................................................................................................................................................ 228 p63-related EDs ....................................................................................................................................................................................................... 236 Tricho-dento-osseous syndrome .........................................................................................................................................................................239 Witkop’s syndrome ................................................................................................................................................................................................. 240 Ellis-Van Creveld-Weyers acrofacial dysostosis (EVC-WAD) complex .......................................................................................................241 Nectinopathies ........................................................................................................................................................................................................ 242 Further complex syndromes with ED signs ...................................................................................................................................................... 244 Connexins-related syndromes ............................................................................................................................................................................. 246 Ectodermal dysplasia-skin fragility syndrome................................................................................................................................................. 250 Pure hair-nail ectodermal dysplasia ....................................................................................................................................................................251 Trichorhinophalangeal syndrome........................................................................................................................................................................252 Incontinentia pigmenti ...........................................................................................................................................................................................253 Naegeli–Franceschetti syndrome........................................................................................................................................................................ 258 Focal dermal hypoplasia .........................................................................................................................................................................................259 MIDAS syndrome ....................................................................................................................................................................................................262 12. Disorders of Connective Tissue ........................................................................................................................................................................... 263 Ehlers-Danlos syndromes (EDSs)........................................................................................................................................................................ 263 Classical EDS type (cEDS) .................................................................................................................................................................................... 263 Classical-like EDS type (clEDS) ........................................................................................................................................................................... 265 Cardiac-Valvular EDS (cvEDS) ............................................................................................................................................................................ 266 EDS hypermobility type (hEDS).......................................................................................................................................................................... 266 EDS vascular type (vEDS) ..................................................................................................................................................................................... 267 EDS kyphoscoliotic type (kEDS) ..........................................................................................................................................................................269 EDS arthrochalasia type (aEDS) ...........................................................................................................................................................................270 EDS dermatosparaxis type (dEDS) ......................................................................................................................................................................271 EDS other rarer types..............................................................................................................................................................................................272 Cutis laxa syndromes ..............................................................................................................................................................................................273 Autosomal dominant CL (ADCL) ........................................................................................................................................................................273 Autosomal recessive CL (ARCL) ..........................................................................................................................................................................274 Geroderma osteodysplasticum (GO)...................................................................................................................................................................276 MACS syndrome ......................................................................................................................................................................................................277

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Contents Pseudoxanthoma elasticum (PXE) .......................................................................................................................................................................278 Urbach-Wiethe disease .......................................................................................................................................................................................... 280 Marfan syndrome (MFS) ........................................................................................................................................................................................281 Loeys-Dietz syndrome (LDS) ............................................................................................................................................................................... 283 Arterial tortuosity syndrome (ATS) ................................................................................................................................................................... 284 Stickler syndrome ................................................................................................................................................................................................... 285 Connective tissue nevi ........................................................................................................................................................................................... 286 Buschke-Ollendorff syndrome............................................................................................................................................................................. 287 Melorheostosis......................................................................................................................................................................................................... 288 Elastosis perforans serpiginosa............................................................................................................................................................................ 288 Congenital symmetric circumferential skin creases (CSCSC) ..................................................................................................................... 289 Hyaline fibromatosis syndrome ........................................................................................................................................................................... 289 Cutaneous mastocytosis ........................................................................................................................................................................................291 Dermochondrocorneal dystrophy ........................................................................................................................................................................291 GNAS-related syndromes: Osteoma (osteomatosis) cutis (OC), progressive osseous heteroplasia (POH) and Albright’s hereditary osteodystrophy (AHO) ....................................................................................................................................................292 Cutis verticis gyrata (CVG)................................................................................................................................................................................... 294 Atrophoderma of Moulin.......................................................................................................................................................................................295

13. Fatty Tissue Anomalies ..........................................................................................................................................................................................297 Launois-Bensaude syndrome ................................................................................................................................................................................297 Congenital generalized lipodystrophy (CGL) ....................................................................................................................................................298 Partial lipodystrophy.............................................................................................................................................................................................. 299 Lipomas, familial multiple lipomatosis and nevus lipomatosus .................................................................................................................. 300 Sebocystomatosis .................................................................................................................................................................................................... 300 14. Aplasia Cutis ............................................................................................................................................................................................................ 302 15. Disorders of Pigmentation .................................................................................................................................................................................... 306 Oculocutaneous albinisms ................................................................................................................................................................................... 306 X-Linked ocular albinism ......................................................................................................................................................................................311 Cross syndrome ........................................................................................................................................................................................................312 Hermansky-Pudlak syndrome (HPS) ..................................................................................................................................................................313 Pigmentary mosaicism (PM) .................................................................................................................................................................................314 Syndromic pigmentary mosaicism ......................................................................................................................................................................317 TFE3-related Pigmentary Mosaicism .................................................................................................................................................................317 Borjeson-Forssman-Lehmann syndrome ...........................................................................................................................................................318 RHOA-related pigmentary mosaicism ................................................................................................................................................................318 TUBB3-related pigmentary mosaicism ..............................................................................................................................................................319 Familial progressive hyper-hypopigmentation ................................................................................................................................................ 320 Terminal osseous dysplasia with pigmentary defects .....................................................................................................................................321 mTOR-related syndromic pigmentary mosaicism ...........................................................................................................................................321 Piebaldism .................................................................................................................................................................................................................323 Waardenburg syndrome .........................................................................................................................................................................................324 McCune-Albright syndrome .................................................................................................................................................................................326 MELAS syndrome ...................................................................................................................................................................................................328 Melanocytic nevi and related syndromes...........................................................................................................................................................328 Segmental lentiginosis ............................................................................................................................................................................................331 OTA nevus................................................................................................................................................................................................................ 334 Dermal melanocytosis (DM) .................................................................................................................................................................................335 Cutis tricolor ............................................................................................................................................................................................................ 336 Dyschromatosis symmetrica hereditaria ...........................................................................................................................................................337 16. Vascular Disorders ..................................................................................................................................................................................................339 Fast-flow malformations ........................................................................................................................................................................................339 Slow-flow malformations ...................................................................................................................................................................................... 343 Cobb syndrome ....................................................................................................................................................................................................... 347 Other syndromes with prominent vascular signs ........................................................................................................................................... 348 von Hippel-Lindau syndrome .............................................................................................................................................................................. 348 Anemic nevus .......................................................................................................................................................................................................... 349 Angioma serpiginosum (AS) ................................................................................................................................................................................ 350 Cutis marmorata telangiectatica congenita.......................................................................................................................................................351 Microcephaly–capillary malformation.............................................................................................................................................................. 354 Phacomatosis pigmentovascularis ...................................................................................................................................................................... 354 Adams-Oliver syndrome ....................................................................................................................................................................................... 356

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Hereditary haemorrhagic telangiectasia (HHT).............................................................................................................................................. 357 Maffucci syndrome................................................................................................................................................................................................. 358 Blue rubber bleb angioma syndrome...................................................................................................................................................................359 Glomuvenous malformations............................................................................................................................................................................... 360 Generalized essential telangiectasia....................................................................................................................................................................361 Lymphatic malformations and lymphoedema syndromes .............................................................................................................................362 Lymphatic malformations......................................................................................................................................................................................362 Net-like superficial lymphatic malformation ................................................................................................................................................... 363 Lymphoedema syndromes .................................................................................................................................................................................... 363 Primary intestinal lymphangiectasia ................................................................................................................................................................. 365 Hypotrichosis-lymphoedema-telangiectasia syndrome (HLTS).................................................................................................................. 366 Generalized cyanosis, phlebectases and soft skin syndrome ....................................................................................................................... 367 Vascular tumours.................................................................................................................................................................................................... 368 Haemangioma syndromes .....................................................................................................................................................................................369 CADASIL ...................................................................................................................................................................................................................371 17. Metabolic Diseases ..................................................................................................................................................................................................372 Porphyrias..................................................................................................................................................................................................................372 Porphyria cutanea tarda (PCT) and hepatoerythropoietic porphyria (HEP) .............................................................................................372 Erythropoietic protoporphyria (EPP) ..................................................................................................................................................................375 Congenital erythropoietic porphyria (CEP) ......................................................................................................................................................377 Hereditary coproporphyria (HCP) and harderoporphyria .............................................................................................................................379 Variegate porphyria (VP) .......................................................................................................................................................................................379 Acrodermatitis enteropathica .............................................................................................................................................................................. 380 Fabry disease .............................................................................................................................................................................................................382 Sea-blue histiocytosis............................................................................................................................................................................................. 383 Cerebrotendinous xanthomatosis ....................................................................................................................................................................... 384 Prolidase deficiency ................................................................................................................................................................................................ 386 Methylmalonic aciduria .........................................................................................................................................................................................387 Alkaptonuria ............................................................................................................................................................................................................ 388 18. Complex Malformative Syndromes with Distinctive Cutaneous Signs ..................................................................................................... 390 Rubinstein–Taybi syndrome................................................................................................................................................................................. 390 Cornelia de Lange syndrome (CdLS) ..................................................................................................................................................................391 KBG syndrome .........................................................................................................................................................................................................392 Coffin–Siris syndrome ............................................................................................................................................................................................393 Orofaciodigital syndromes (OFDS) .....................................................................................................................................................................394 Branchio-oculo-facial (BOF) syndrome ............................................................................................................................................................ 396 Barber–Say syndrome .............................................................................................................................................................................................398 Turner syndrome .....................................................................................................................................................................................................398 Down syndrome (trisomy 21) ............................................................................................................................................................................... 400 Pallister–Killian syndrome................................................................................................................................................................................... 400 Encephalocraniocutaneous lipomatosis (ECCL) ..............................................................................................................................................401 Growth retardation, alopecia, pseudoanodontia and optical atrophy (GAPO) syndrome .................................................................... 403 Cantu syndrome...................................................................................................................................................................................................... 404 Zimmermann–Laband syndrome (ZLS) ........................................................................................................................................................... 404 Woodhouse–Sakati syndrome ............................................................................................................................................................................. 406 Apert syndrome ...................................................................................................................................................................................................... 407 H Syndrome ............................................................................................................................................................................................................. 408 Poland syndrome .................................................................................................................................................................................................... 409 Kabuki syndrome .....................................................................................................................................................................................................410 Congenital insensitivity to pain (CIP).................................................................................................................................................................411 Primary cutaneous amyloidosis............................................................................................................................................................................413 Frank–Ter Haar–Borrone syndrome ...................................................................................................................................................................414 Familial comedones.................................................................................................................................................................................................415 Triple A syndrome ...................................................................................................................................................................................................416 Gómez–Lopez–Hernández syndrome ................................................................................................................................................................417 Axenfeld-Rieger syndrome ....................................................................................................................................................................................418 19. Immunodeficiency Disorders ................................................................................................................................................................................419 Primary immunodeficiency syndromes..............................................................................................................................................................419 Ataxia–telangiectasia .............................................................................................................................................................................................419 Chediak-Higashi syndrome .................................................................................................................................................................................. 420 Cartilage-hair hypoplasia.......................................................................................................................................................................................421

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Contents Chronic granulomatous disease .......................................................................................................................................................................... 422 Chronic mucocutaneous candidiasis ................................................................................................................................................................. 423 APECED syndrome ................................................................................................................................................................................................ 424 Hyper-IgE syndromes ............................................................................................................................................................................................ 424 Hereditary Angioedema ........................................................................................................................................................................................ 426 Omenn syndrome-severe combined immunodeficiencies ............................................................................................................................ 426 Common variable immunodeficiency ................................................................................................................................................................ 429 Wiskott-Aldrich syndrome ................................................................................................................................................................................... 429 Immunoglobulin deficiencies............................................................................................................................................................................... 430 Cyclic neutropenia ...................................................................................................................................................................................................432 Leukocyte adhesion deficiencies ..........................................................................................................................................................................432 DiGeorge syndrome ............................................................................................................................................................................................... 433 Fanconi anaemia ..................................................................................................................................................................................................... 433

20. Autoinflammatory Diseases ................................................................................................................................................................................. 435 Interferonopathies .................................................................................................................................................................................................. 435 SAVI syndrome........................................................................................................................................................................................................ 436 Familial chilblain lupus/Aicardi-Goutières complex ......................................................................................................................................437 X-Linked reticulate pigmentary disorder with systemic manifestations (XLRPD) ................................................................................. 440 Other rarer interferonopathies ............................................................................................................................................................................ 442 Monogenic autoinflammatory diseases ............................................................................................................................................................. 442 CARD14 gene-related diseases ............................................................................................................................................................................ 446 APLAID syndrome ................................................................................................................................................................................................. 446 NLRC4-related autoinflammatory disorder ..................................................................................................................................................... 447 VEXAS syndrome ................................................................................................................................................................................................... 447 Familial keratosis lichenoides chronica ............................................................................................................................................................. 448 EGFR-related autoinflammatory syndrome ..................................................................................................................................................... 449 21. Overgrowth Syndromes ........................................................................................................................................................................................ 450 PIK3CA-related syndromes (PROS) .................................................................................................................................................................. 450 Proteus syndrome ................................................................................................................................................................................................... 456 Beckwith-Wiedemann syndrome (BWS) .......................................................................................................................................................... 458 22. Genodermatoses Related to Malignancy ........................................................................................................................................................... 460 Basal cell carcinoma syndrome (BCCS) ............................................................................................................................................................ 460 Bazex-Dupré-Christol syndrome .........................................................................................................................................................................461 Rombo syndrome .................................................................................................................................................................................................... 462 Constitutional mismatch repair deficiency syndromes ................................................................................................................................. 463 Gardner syndrome.................................................................................................................................................................................................. 465 Peutz-Jeghers syndrome ........................................................................................................................................................................................ 466 PTEN-opathies ........................................................................................................................................................................................................ 468 Howel–Evans syndrome .........................................................................................................................................................................................470 Cutaneous leiomyomatosis ....................................................................................................................................................................................471 Multiple endocrine neoplasia (MEN) syndrome type 2B ...............................................................................................................................472 Carney complex........................................................................................................................................................................................................474 Birt-Hogg-Dubé syndrome ....................................................................................................................................................................................475 Cyld cutaneous syndrome......................................................................................................................................................................................475 Bloom syndrome ......................................................................................................................................................................................................477 Epidermodysplasia verruciformis (EV) ...............................................................................................................................................................477 Hereditary progressive mucinous histiocytosis................................................................................................................................................479 23. Cutaneous Mosaicism............................................................................................................................................................................................ 480 Definition and introduction ................................................................................................................................................................................. 480 Patterns of clinical manifestation of skin mosaicism ..................................................................................................................................... 482 Dydymosis twin spots ............................................................................................................................................................................................ 488 Mechanisms of inheritance of mosaicism......................................................................................................................................................... 490 24. Genodermatoses in Dark Skin ............................................................................................................................................................................. 498 25. Dermoscopy in Genodermatoses ........................................................................................................................................................................ 506 Index ....................................................................................................................................................................................................................................514

FOREWORD It is really great news to welcome the third edition of the Atlas of Genodermatoses by Prof. Gianluca Tadini and coworkers. There have been many advances in the field of genodermatosis since the last edition was published more than 7 years ago, and certainly an updated version of this work was really worth producing. Having had the pleasure to meet Prof. Gianluca Tadini, listen to his lectures and discuss intriguing cases together, I can testify that this book is a faithful reflection of Prof. Tadini’s wisdom, expertise and meticulousness. This atlas is a must-read piece not only for those who want to get into the field of genodermatoses, but also for specialists and experts who search for quick answers for patients with unusual genetic skin diseases. As is well known, this book is easy to read, comprehensive and updated, and contains an impressive number

of high-quality pictures. The clinical images are highly demonstrative of the conditions that are treated and represent a most valuable diagnostic tool for dermatologists dealing with genetic skin disorders. A complete reading of the book is highly recommended, especially for those who are in the process of creating a knowledge building in the subject. In today’s world, where the immediate acquisition of information prevails, slow reading and comprehension of this book, along with retention of its beautiful pictures, will provide readers with the pleasure of solid and lasting learning. Antonio Torrelo Head, Department of Dermatology Hospital Infantil Niño Jesús Madrid, Spain

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PREFACE After a further second decade, we are ready to deliver this third edition of our Atlas of Genodermatoses in the lineage of the Milan School of Paediatric Dermatology on behalf of Professor Ferdinando Gianotti and Ruggero Caputo. The run to discover new diseases (new phenotypes and genotypes) has reached tremendous results. In this edition, as in the past two, we tried to describe all the published genodermatoses, but we are sure that some phenotypes have been forgotten and we apologize for that. The general layout remains the same, but we preferred to eliminate photographic legends maintaining only references in the text, to avoid repetition and to force the reader to adhere to the concise lecture of the text, as occurred in the first edition. We used the dyadic approach to describe the diseases: 1. A recognizable distinct phenotype description 2. The gene that is mutated

xii

For example, TGM1-related autosomal recessive ichthyosis or KRAS-related epidermal nevus; we consider these two elements (phenotype and genotype) as a single specific entity. Only for didactic reasons are some eponyms still present as descriptors, but we hope that in the future (perhaps in the fourth edition of the Atlas…) we’ll arrive at a complete molecular taxonomy. Some new classifications are reported (i.e., ectodermal dysplasias and epidermolysis bullosae) that are developed by a consensus of experts to clearly designate the groups of genetic skin disorders to have common, worldwide accepted nomenclature of phenotypes and related genes. We hope that our three-year effort will be useful for students, trainees and colleagues showing interest in genodermatoses.

ACKNOWLEDGEMENTS First of all, we have to thank patients and their families to whom the Atlas is dedicated. We are grateful to all the colleagues that contributed with photographs and expertise that are acknowledged in the specific chapter of photographic references. In particular, we also thank Dr Federica Dassoni and Dr Iria Neri for the contribution in their chapters. A special thanks to the colleagues of the Paediatric Dermatology Unit of the Policlinic Hospital of Milan (Dr Riccardo Cavalli, Stefano Cambiaghi, Lucia Restano Cassulini and Cristiana Colonna) and all the students and trainees that supported us in the last 10 years; in particular, we want to thank Beatrice Carcano for her assistance. We are grateful for their knowledge and dedication: Amy Paller (Chicago, USA), John McGrath (London, England), Eli Sprecher (Tel Aviv, Israel), Cristina Has and Judith Fisher (Freiburg, Germany), Rudolph Happle (Marburg, Germany), Antonio Torrelo and Angela Hernández-Martin

(Madrid, Spain), Vinzenz Oji and Heiko Traupe (Heidelberg, Germany), Smail Hadji-Rabia and Christine Bodemer (Paris, France), Maurice van Steensel (Singapore), Peter Itin (Basel, Switzerland), Ramon Grimalt (Barcelona, Catalunya). Not forgetting our Italian friends, especially: Maya El Hachem, Andrea Diociaiuti, Andrea Paradisi, Giovanna Zambruno, Daniele Castiglia and Alessandro Terrinoni (Rome), Marco Castori (San Giovanni Rotondo), Francesco Brancati (L’Aquila), Michele Callea (Florence), Marina Colombi and Alessandro Plebani (Brescia). We also want to remember the late Marcel Jonkman (Groningen, Netherlands), Mauro Paradisi (Rome), Marco Simonacci (Recanati) and Adrián-Martín Pierini (Buenos Aires, Argentina). Gianluca Tadini received a grant from the United For Fighting Ichthyoses (UFFI) Society for the redaction of the Atlas.

xiii

LIST OF CONTRIBUTORS Federica Dassoni Dermatology Unit San Gerardo Hospital ASST Monza, Italy Martina Mussi Dermatology Unit IRCCS Azienda Ospedaliero Universitaria di Bologna Bologna, Italy and Department of Medical and Surgical Sciences Alma Mater Studiorum University of Bologna Bologna, Italy Iria Neri Dermatology Unit IRCCS Azienda Ospedaliero Universitaria di Bologna Bologna, Italy and Department of Medical and Surgical Sciences Alma Mater Studiorum University of Bologna Bologna, Italy

xiv

Francesco Salamone Dermatology Unit IRCCS Azienda Ospedaliero Universitaria di Bologna Bologna, Italy and Department of Medical and Surgical Sciences Alma Mater Studiorum University of Bologna Bologna, Italy

ILLUSTRATION CREDITS The authors are grateful to the following colleagues for their kind permission to reproduce their illustrations in the Atlas:

Dr. Federica Dassoni, Dermatology Unit, San Gerardo Hospital, ASST Monza, Italy.

Dr. Bernard Ackerman, New York University, New York, USA.

Dr. Anja De Moor, Department of Dermatology, University of Antwerp, Belgium.

Professor William Bacon, Department of Dentofacial Ortho­ pedics, University of Strasburg, Strasbourg, France. Professor Eulalia Baselga, Multidisciplinary Vascular Anomalies Unit, Department of Dermatology, Sant Joan de Déu Hospital, Barcelona, Spain. Dr. Samantha Berti and Dr. Giordana Coronella, Division of Dermatology, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy. Dr. Gianfranco Biolcati, Porphyria Centre, San Gallicano Institute, San Gallicano Hospital, Roma, Italy.

Dr. Enzo Di Iorio and Dr. Paolo Raffa, The Veneto Eye Bank Foundation, Venice, Italy. Dr. Andrea Diociaiuti, Dermatology Unit, Bambino Gesù Children’s Hospital, Rome, Italy. Professor Robin Eady, Department of Dermatology, St. John’s Institute of Dermatology, King’s College, London, UK. Dr. Maya El Hachem, Dermatology Unit, Bambino Gesù Children’s Hospital, Rome, Italy.

Dr. Claudine Blanchet-Bardon, Hôpital S. Louis, Paris, France.

Dr. Silvia Esposito and Dr. Veronica Saletti, Istituto Neurologico Besta, Milan, Italy.

Dr. Valeria Boccaletti, Dermatology Unit, University of Brescia, Brescia, Italy.

Dr. Daniele Fanoni and Professor Emilio Berti, Department of Dermatology, University of Milan, Milan, Italy.

Dr. Vinicio Boneschi, Department of Dermatology, University of Milan, Milan, Italy.

Dr. Claudio Feliciani, Dermatology Unit, University of Parma, Parma, Italy.

Professor Giovanni Borroni, Department of Dermatology, University of Pavia, Pavia, Italy.

Dr. Anna Belloni Fortina and Dr. Laura Gnesotto, Pediatric Dermatology Unit, University of Padova, Italy.

Dr. Mariangela Bosoni, Department of Pediatrics, Sacco Hospital, University of Milan, Milan, Italy.

Dr. Michele Gaffuri, Otolaryngology Department, University of Milan, Milan, Italy.

Dr. Lucia Brambilla, Department of Dermatology, University of Milan, Milan, Italy.

Dr. Giulia Genoni, Neonatal Pathology, Novara Hospital, Novara, Italy.

Professor Hugo Cabrera and Dr. Patricia Della Giovanna, Department of Dermatology, University of Buenos Aires, Argentina.

Dr. Tommaso Gobello, Istituto Dermopatico dell’Immacolata, IDI, Rome, Italy.

Dr. Michele Callea, Pediatric Dentistry and Special Dental Care Unit, Meyer Children’s University Hospital IRCCS, Florence, Italy. Dr. Stefano Cambiaghi, Pediatric Dermatology Unit, University of Milan, Milan, Italy. Dr. Marco Castori, Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy. Dr. Riccardo Cavalli, Pediatric Dermatology Unit, University of Milan, Milan, Italy.

Dr. Massimo Gola, Allergological and Occupational Dermatology Unit, University of Florence, Florence, Italy. Dr Antoni Gostynski, Department of Dermatology, Maastricht University Medical Centre+, Maastricht, The Netherlands. Professor Rudolph Happle, Department of Dermatology, Medical Center - University of Freiburg, Freiburg, Germany. Professor Christina Has, Department of Dermatology, University Medical Center Freiburg, Freiburg, Germany.

Professor Marina Colombi, Department of Genetic, University of Brescia, Brescia, Italy.

Professor Hans Christian Hennies, Center for Dermatogenetics, Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.

Professor Bruno Dallapiccola, Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy.

Professor Herbert Hönigsmann, Department of Dermatology, University of Wien, Wien, Austria.

xv

xvi

Illustration Credits

Historical Archives of Istituto Neurologico Carlo Besta, Milan, Italy.

Professor Enrico Nunzi, Department of Dermatology, University of Genoa, Italy.

Dr. Michel Janier, Hôpital S. Louis, Paris, France.

Dr. Laura Pantaleoni, Istituto Neurologico Besta, Milan, Italy.

Professor Marcel Jonkman, Department of Dermatology, University of Groningen, Groningen, the Netherlands.

Dr. Andrea Paradisi, UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli - IRCCS, Rome, Italy.

Dr. Ariana Kariminejad, Kariminejad-Najmabadi Pathology and Genetics Center, Shahrak Gharb, Tehran, Iran. Dr. Merel Klaassens, Pediatric Intensive Care Unit, Maastricht University Medical Center, Maastricht, the Netherlands. Dr. Pablo Lapunzina, Section of Medical and Molecular Genetics, Instituto de Genética Médica y Molecular, Hospital Universitario La Paz, Autónoma University of Madrid, Madrid, Spain.

Dr. Mauro Paradisi, Department of Experimental Medicine, University of Tor Vergata, Rome, Italy. Professor Annalisa Patrizi, Department of Dermatology, University of Bologna, Bologna, Italy. Professor Adrián-Martín Pierini, Dermatology Service, Hospital de Pediatría Juan P. Garrahan, Buenos Aires, Argentina.

Dr. Hiram Larangeira de Almeida Jr., Departments of Dermatology at Santa Casa de Porto Alegre, Pelotas, Brazil.

Professor Mario Pippione, Dermopathology Unit, Gradenigo Hospital, Turin, Italy.

Professor Lidia Larizza, Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Milano, Italy.

Professor Nelida Pizzi de Parra, Department of Dermatology, Universitad de Cuyo, Mendoza, Argentina.

Professor Margarita Larralde and Dr. Maria Pia Boldrini, Pediatric Dermatology Department, Hospital Ramos Mejía, Buenos Aires, Argentina. Dr. Wiebke Ludwig-Peitsch, Department of Dermatology, University Medical Center Mannheim, Mannheim, Germany. Dr. Siranoush Manoukian, Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. Professor. Angelo Valerio Marzano, Department of Dermatology, University of Milan, Milan, Italy. Professor José Maria Mascarò, Department of Dermatology, Hospital Clinic, Barcelona, Spain. Professor John McGrath, Department of Dermatology, St. John’s Institute of Dermatology, King’s College, London, UK. Dr. Bodo Melnik, Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Germany. Dr. Laura Milazzo, Department of Infectious Diseases, L. Sacco Hospital, ASST Fatebenefratelli-Sacco, Milan, Italy.

Professor Alessandro Plebani, Pediatrics Clinic, Spedali Civili di Brescia, University of Brescia, Brescia, Italy. Dr. Attilio Pocchini, Department of Dermatology, University of Milan, Milan, Italy. Dr. Giulia Pomero, Terapia Intensiva Neonatale-Neonatologia, Ospedale S. Croce e Carle, Cuneo, Italy. Dr. Pawinee Rerknimitr, Dermatology Unit, Department of Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand. Dr. Lucia Restano, Pediatric Dermatology Unit, University of Milan, Milan, Italy. Professor Franco Rongioletti, School of Medicine, Vita-Salute San Raffaele University, Dermatology Clinic, IRCCS San Raffaele Hospital, Milan, Italy. Professor Ramon Ruiz-Maldonado, University of Mexico City, Mexico, Hospital Districto Federal, Mexico City, Mexico. Dr. Jorge L. Sanchez, Private Practice, Hato Rey, San Juan, Puerto Rico.

Dr. Arti Nanda, As’ad Al-Hamad Dermatology Center, Al-Sabah Hospital, Kuwait City, Kuwait.

Dr. Paolo Sbraccia and Professor Giuseppe Novelli, Department of Systems Medicine, Medical School, University of Rome Tor Vergata, Rome, Italy.

Professor Kenji Naritomi, Graduate School of Medicine, University of Okinawa, Nishihara, Okinawa, Japan.

Dr. Sylvia Schauder, Department of Dermatology, University of Göttingen, Germany.

Dr. Iria Neri, Dermatology Unit, IRCCS Azienda OspedalieroUniversitaria di Bologna, Bologna, Italy.

Dr. Carmelo Schepis, Oasi Research Institute-IRCCS, Troina, Italy.

Professor Paolo Nucci, Ophthalmology Unit, San Giuseppe Hospital, IRCCS Multimedica, Milan, Italy.

Professor Holm Schneider, Center for Ectodermal Dysplasias & Department of Pediatrics, University Hospital Erlangen, Erlangen, Germany.

Illustration Credits Dr. Angelo Selicorni, Pediatria, ASST Lariana, S. Fermo della Battaglia, Como, Italy. Dr. Jan Cezary Sitek, Department of Dermatology, Oslo University, Oslo, Norway. Professor Eli Sprecher, Division of Dermatology, Tel Aviv Sourasky Medical Center, Department of Human Molecular Genetics and Biochemistry, School of Medicine, Tel-Aviv University, Tel Aviv, Israel. Professor Omar Boudghene Stambouli, School of Medicine Aboubakr Belkaid, Tlemcen, Algerie. Professor Peter Steijlen, Department of Dermatology, Maastricht University Medical Centre+, Maastricht, The Netherlands. Dr. Mariam Tajir, Department of Medical Genetics, University of Rabat, Rabat, Morocco. Professor Yasushi Tomita, Department of Dermatology, Nagoya University Graduate School of Medicine, Showa-Ku, Japan. Professor Antonio Torrelo, Department of Dermatology, Hospital Infantil Universitario del Niño Jesús, Madrid, Spain. Dr. Antonella Tosoni and Dr. Manuela Nebuloni, Pathology Unit, L. Sacco Hospital, University of Milan, Milan, Italy. Professor Antonella Tosti, Department of Dermatology, University of Miami, Miami, Forida.

xvii Professor Jouni Uitto, Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA. Dr Hassan Vahidnezhad, Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA. Professor Maurice A.M. van Steensel, Institute of Medical Biology (IMB)/Skin Research Institute of Singapore (SRIS), Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore. Dr. Ana Vega, Fundación Pública Gallega de Medicina XenómicaSERGAS, Grupo de Medicina Xenómica-USC, Santiago de Compostela, Spain. Dr. Francesco Viola, Ophthalmology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy. Dr. Giovanna Zambruno, Genetics and Rare Diseases Research Division, Bambino Gesù Children’s Hospital, Rome, Italy. Dr. Abraham Zlotogorski, Department of Dermatology, The Center for Genetic Diseases of the Skin and Hair, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

1

EPIDERMOLYSIS BULLOSAE Definition Epidermolysis bullosa (EB) is a group of heterogeneous genetic disorders characterized by skin fragility, with formation of blisters, erosions and wounds of skin and mucous membranes in response to minor mechanical trauma. Disease-causing variants in 20 different genes account for the genetic and allelic heterogeneity of EB, and they code for intracellular, transmembrane or extracellular proteins (Table 1.1). In 2019, leading experts reviewed and improved the previous classification introducing the concept of “genodermatosis with skin fragility” and describing new variants. Other disorders with skin fragility, where blisters are only a minor part of the clinical picture or are not seen because skin cleavage is very superficial, are classified as separate categories (discussed later in this Atlas) (Table 1.2). As can be seen in the literature, the denominations simplex and dystrophic are commonly used, but we prefer to define EB regarding simply the site of the cleavage, abandoning the denomination of simplex and dystrophic that are, in our opinion, aspecific; i.e., we refuse to call simplex a group of disorders in which there are potentially lethal variants. If the term epidermolytic does not fit to all subtypes of EB in which the site of cleavage is intraepithelial (basal or suprabasal), we prefer this term to clearly underline the localization of blisters. In analogy, we believe that in the current classification, the term dystrophic is meaningless: we failed to find an exact definition of dystrophy that could fit with the subtypes of EB due to a genetic defect in COL7A1 gene.

Schematic drawing 1.1 shows the molecular basis of the different types of EB.

Epidemiology Overall prevalence is 11.1 million live births, with an incidence of 1:51.000 live births in the United States; data in Italy are superimposable.

Epidermolytic epidermolysis bullosa (EEB) or epidermolysis bullosa simplex This form is characterized by cleavage within the basal layer of keratinocytes.

Common epidermolytic epidermolysis bullosa subtypes

The common EEB subtypes comprise localized (previously known as Weber-Cockayne), intermediate (previously known as EEB generalized intermediate, EEB Köbner) and severe EEB (previously known as EEB generalized severe, EEB Dowling-Meara).

Main cutaneous manifestations

• Skin blistering begins at birth in severe and intermediate EEB, and at birth or in early infancy in localized EEB. The intraepidermal blistering is superficial, leading to erosions and crusts, and is enhanced by heat, humidity and sweating. The tendency to blister diminishes in adolescence when it may become localized to the hands and feet. Blisters may heal with hyperpigmentation (EB nevi)

TABLE 1.1  Classical Types of EB Level of Skin Cleavage

EB Type

Inheritance

Mutated Gene(s)

Targeted Protein(s)

Intraepidermal

EB epidermolytic

Autosomal dominant

KRT5, KRT14 PLEC KLHL24 KRT5, KRTI4 DST

Keratin 5, keratin 14 Plectin Kelch-Iike member 24 Keratin 5, keratin 14 Bullous pemphigoid antigen 230 (BP230) (syn. BPAGle, dystonin) Exophilin-5 (syn. synaptotagmin-like protein homolog lacking C2 domains b, Slac2-b) CD151 antigen (syn. tetraspanin 24) Plectin Laminin 332 Type XVII collagen Integrin α6β4 Integrin α3 subunit Type VII collagen Type VII collagen Fermitin family homolog 1 (syn. kindlin-1)

Autosomal recessive

EXPH5 (syn. SLAC2B)

Junctional

Junctional EB

Dermal

Dermolytic EB

Mixed

Kindler EB

DOI: 10.1201/9781003124351-1

AD/AR Autosomal recessive

Autosomal dominant Autosomal recessive Autosomal recessive

CD151 (syn. TSPAN24) PLEC LAMA3, LAMB3, LAMC2 COL17A1 ITGA6, ITGB4 ITGA3 COL7A1 COL7A1 FERMT1 (syn. KINDI)

1

Atlas of Genodermatoses

2 TABLE 1.2  Level of Skin Cleavage

Disorder Name

Inheritance

Mutated Gene(s)

Targeted Protein(s)

Peeling skin disorders Intraepidermal

Peeling skin disorders

Autosomal recessive

Erosive disorders Intraepidermal

TGM5 CSTA CTSB SERPINB8 FLG2 CDSN CAST DSG1 SPINK5

Transglutaminase 5 Cystatin A Cathepsin B Serpin protease inhibitor 8 Filaggrin 2 Corneodesmosin Calpastatin Desmoglein 1 LEKTI

Erosive skin fragility disorders

Autosomal recessive

DSP JUP PKP1 DSC3 DSG3

Desmoplakin Plakoglobin Plakophilin 1 Desmocollin 3 Desmoglein 3

Autosomal dominant Autosomal recessive Autosomal dominant

KRT1, KRT10, KRT2 KRT10 KRT6A, KRT6B, KRT6C, KRT16, KRT17

Keratin 1, 10, 2 Keratin 10 Keratin 6A, 6B, 6C, 16, 17

Autosomal recessive

PLOD3

Lysyl hydroxylase 3

Hyperkeratotic disorders with skin fragility Intraepidermal

Keratinopathic ichthyoses

Intraepidermal

Pachyonychia congenita

Connective tissue disorder with skin fragility Dermal

Syndromic connective tissue disorder with skin fragility

SCHEMATIC DRAWING 1.1 

Epidermolysis Bullosae

Fig. 1.1  • In severe EEB, skin fragility is very prominent at birth, and congenital ulcerated areas on hands and feet as well as nail involvement are common. In the neonatal period, large tense blisters can occur after minimal mechanical trauma or spontaneously. The condition may be life threatening in the first year of life. This subtype has been defined by the herpetiform (arciform) pattern of blisters, a crustingnecrotic aspect of the lesions that are often associated or preceded by inflammatory plaques (Figures 1.1 and 1.2) and by clumping of keratin intermediate filaments as shown by transmission electron microscopy • Blistering is generalized, but less severe in intermediate EEB (Figure 1.3)

3

Fig. 1.3  • Blisters are mainly restricted to the hands and feet in localized EEB (Figures 1.4 and 1.5) • Palmoplantar keratoderma occurs in all three common EEB subtypes (Figures 1.6 and 1.7). It develops gradually, is painful, may reduce mobility and may strongly impair quality of life; confluent palmoplantar keratoderma is mostly seen in severe EEB

Fig. 1.4 

Fig. 1.2 

Fig. 1.5 

Atlas of Genodermatoses

4 Extracutaneous involvement

• Gastro-oesophageal reflux may occur in infancy in severe EEB, often needing medical treatment • Growth retardation is common in infants with severe EEB • There is no primary involvement of extracutaneous organs

Genetics and pathogenesis

Fig. 1.6 

• Autosomal dominant inheritance • Monoallelic missense, nonsense, frameshift or splice site pathogenic variants, or in-frame deletions in KRT5 or in KRT14 genes, with a high rate (about 30%) of de novo mutations • Semidominant inheritance and variable penetrance of pathogenic variants have been reported • Digenic occurrence of pathogenic variants in both KRT5 and KRT14 has been reported • Pathogenic variants located in the keratin 5 or 14 genes with variable locations outside the helix initiation and termination regions lead to localized EEB, while those located in the helix initiation or termination motifs lead to severe EEB • Keratin 14 pathogenic variants affecting codon 125 (p.R125C, p.R125L or p.R125H) are common “hot spot mutations” and are associated with severe EEB • The keratin 5 amino acid substitution, p.E477K, has been associated with a very severe course and even a lethal outcome in the neonatal period. Some pathogenic variants in keratin 14, such as p.M119T and c.1246del, have also been correlated with a very severe clinical course

Rare EEB phenotypes EEB with mottled pigmentation Main clinical manifestations

Fig. 1.7  • Milia may occur in the first weeks of life • The oral mucosa is usually involved in infants with severe EEB (Figure 1.8) • Nails may be thick and dystrophic • Hair is not affected

Fig. 1.8 

• Skin blistering starts at birth and is generalized, of intermediate severity • Mottled or reticulate pigmentation develops gradually (Figure 1.9) • Focal keratoses of the palms and soles and dystrophic, thickened nails occur over time

Fig. 1.9 

Epidermolysis Bullosae

5

Genetics and pathogenesis

• Autosomal dominant inheritance • The keratin 5 monoallelic pathogenic variant c.74C>T, p.P25L typically causes this phenotype, but cases with other variants in KRT5, KRT14 or EXPH5 have been reported

EEB migratory circinate erythema Main clinical manifestations

• Multiple vesicles are present from birth onwards and acquire over time a typical circinate migratory pattern on an erythematous background; post-inflammatory hyperpigmentation develops gradually and may have a mottled pattern (Figure 1.10) • Nails may be dystrophic

Genetics and pathogenesis

• Autosomal dominant inheritance • Monoallelic pathogenic variants in KRT5 which affect the variable 2 domain and result in frameshift and elongated keratin 5 polypeptide cause this phenotype

Rare EEB subtypes EEB intermediate with cardiomyopathy Main clinical manifestations

• Extensive skin defects on the extremities are present at birth and heal with hypo- and hyperpigmentation and skin atrophy, initially resembling burn-like scars (Figure 1.11). Skin blistering diminishes in adulthood, but fragility persists, with erosions occurring after minimal mechanical trauma • Diffuse or focal plantar keratoderma • Nail thickening and onychogryphosis • Diffuse alopecia has been reported in some adult patients • Dilated cardiomyopathy has been reported in young adulthood

Genetics and pathogenesis

• Autosomal dominant inheritance • Monoallelic pathogenic variants in the translation initiation codon of KLHL24, coding for the kelch-like member 24, cause this disorder; the protein encoded is a ubiquitin ligase substrate receptor, and its mutation causes an increased ubiquitin and degradation of keratin 14, which leads to skin fragility and a potentially life-threatening form of EB • High rate (50%) of de novo mutations

Fig. 1.10 

Fig. 1.11 

Follow-up and therapy

• Laboratory screening (pro-BNP, creatine kinase, creatine kinase myocardial band [MB]) should be started as early as the age of 2 years, with yearly follow-ups. If pathologic values are found, cardiologic examination, ECG and cardiac ultrasound should be performed

Recessive EEB intermediate or severe with keratin 14 or 5 pathogenic variants Main clinical manifestations

• Skin blistering starts at birth and is generalized and severe in most cases (Figure 1.12). No improvement of cutaneous fragility is expected with age. Healing of lesions leads to post-inflammatory hyperpigmentation (Figure 1.13) • Absence of keratin 5 leads to widespread blisters, erosions and early lethality

Genetics and pathogenesis

• Autosomal recessive inheritance • Biallelic nonsense, missense or frameshift KRT14 pathogenic variants • Biallelic loss-of-function or missense KRT5 pathogenic variants

Fig. 1.12 

Atlas of Genodermatoses

6

Fig. 1.13 

Fig. 1.15 

EEB localized or intermediate with BP230 deficiency Main clinical manifestations

Genetics and pathogenesis

• Skin blistering starts at birth or in childhood and is mostly localized to acral extremities (Figures 1.14 and 1.15) • Plantar keratoderma • Nail dystrophy

• Autosomal recessive inheritance • Biallelic loss-of-function pathogenic variants in DST lead to absence of BP230 and cause this subtype • BP230 or BPAG-1 is also known as the epithelial isoform of bullous pemphigoid antigen 1 and is one of the components of hemidesmosomes • The DST (dystonin) gene encodes the coiled-coil domain of BP230: mutations of this gene have been found to cause a subset of EB, leading to the loss of hemidesmosomal inner plaques and skin fragility

EEB localized or intermediate with exophilin 5 deficiency Main clinical manifestations

• Generalized skin blistering starts at birth or in infancy (Figures 1.16 and 1.17) • Blistering tendency may diminish with age, while crusts and scabs reflect the fragility of the skin (Figure 1.18) • Mild mottled pigmentary changes may develop

Genetics and pathogenesis

• Autosomal recessive inheritance • Biallelic loss-of-function pathogenic variants in EXPH5 lead to absence of exophilin 5 and cause this subtype

EEB intermediate with PLEC pathogenic variants Main clinical manifestations

Fig. 1.14 

• Skin blistering starts at birth, is mainly acral but may be widespread • Plantar keratoderma • Dystrophic thickened nails, sometimes onychogryphosis • No muscular dystrophy

Epidermolysis Bullosae

7 Genetics and pathogenesis

• Autosomal dominant or recessive inheritance • The autosomal dominant subtype is characterized by a mild course, mainly acral erosions and post-lesional violaceous and hypopigmented macules. Very few cases with autosomal recessive subtype have been published yet, all of intermediate severity • The monoallelic PLEC pathogenic variant, c.5998C>T, p.R2000W causes the autosomal dominant subtype previously known as EEB Ogna (founder effect in Norway population) • Biallelic pathogenic variants in the exon 1a of the PLEC1a isoform (expressed in skin, but not in muscles), in particular, c.46C>T, p.R16*, cause the autosomal recessive subtype

Fig. 1.16 

EEB intermediate with muscular dystrophy Main clinical manifestations

• Generalized skin blistering starts at birth and is of intermediate severity (Figure 1.19). Blistering tendency diminishes with age • Focal plantar keratoderma • Nail dystrophy • Mucosal involvement including oral, oesophagus, ocular and urethral/bladder mucosae is common • Granulation tissue and stenosis of the upper respiratory tract and hoarseness may occur • Dental anomalies • Muscular dystrophy starts at a variable age, ranging from infancy to adulthood, usually life-limiting; obviously it tends to overwhelm skin lesions regarding the course and the prognosis of the disease • Cardiomyopathy may be associated

Genetics and pathogenesis Fig. 1.17 

Fig. 1.18 

• Autosomal recessive inheritance • Biallelic loss-of-function pathogenic variants in PLEC coding for plectin cause this phenotype. They result in lack of immunoreactivity for plectin and a plane of cleavage deep within the basal pole of the basal keratinocytes and neuromuscular plaques

Fig. 1.19 

Atlas of Genodermatoses

8 EEB severe with pyloric atresia Main clinical manifestations • • • • •

Widespread full-thickness congenital absence of skin Pyloric atresia Involvement of the oral mucosa Anaemia and growth retardation Possible lethal course

Genetics and pathogenesis

• Autosomal recessive inheritance • Biallelic loss-of-function pathogenic variants in PLEC cause this phenotype

EEB localized with nephropathy with CD151 deficiency

Only a few individuals with this subtype have been reported so far in the literature

Main clinical manifestations

• Skin blistering starts at birth and is widespread primarily in the pretibial area but also scattered on other parts of the body, particularly those exposed to trauma • Facial freckling, poikiloderma and atrophy of the skin, also acrogeria of the backs of the hands on the sun-exposed areas reported in one case (Figure 1.20) • Erosions of the oral mucous membranes • Nail dystrophy (Figure 1.21)

Fig. 1.21  • • • •

Early-onset alopecia Nasolacrimal duct stenosis Oesophageal webbing and strictures Nephropathy manifesting with proteinuria

Genetics and pathogenesis

• Autosomal recessive inheritance • Biallelic loss-of-function pathogenic variants in CD151, coding for the CD151 antigen cause this EEB subtype

Junctional epidermolysis bullosa (JEB) This form is characterized by cleavage through the lamina lucida of the cutaneous basement membrane zone (BMZ)

Common JEB subtypes

The two major subtypes of JEB are severe JEB (previously known as JEB generalized severe, Herlitz JEB, with a lethal course) and intermediate JEB (previously known as JEB generalized intermediate, non-Herlitz JEB)

Main cutaneous manifestations

• In both major forms of JEB, blistering begins at birth or shortly afterwards. Blisters tend to rupture, leaving erosions that can become extensive (Figure 1.22). Areas of ulcerated skin may be present at birth, most commonly on

Fig. 1.20 

Fig. 1.22 

Epidermolysis Bullosae

Fig. 1.23 

•

•

• • • •

the lower limbs or dorsa of the feet and ankles. Blisters and ulcers may heal with atrophic scarring and variable hypoor hyperpigmentation In severe JEB, blisters may be few the first couple weeks of life and tend to occur on the buttocks, elbows and around the nails. Wounds may become chronic with a bed of friable granulation tissue, commonly affecting the face, ears and distal digits (Figures 1.23–1.25) Involvement of the oral mucosa occurs in both subtypes, but severe JEB is typical laryngeal mucosal involvement with blistering, erosions, granulation tissue and scarring, giving rise to hoarseness, stridor and peculiar aphonic crying, with a potentially life-threatening airway obstruction Intermediate JEBs show a less severe clinical phenotype (Figures 1.26–1.28) In intermediate JEB, nails are usually lost or dystrophic with atrophy, thickening or ridging of the nail plate (Figure 1.29) JEB due to COL17A1 mutations are associated with scarring alopecia and diffuse hair loss (Figures 1.30–1.32) and very fragile skin (Figure 1.33) Ocular involvement with corneal blistering and erosions is common, with pannus formation, scarring and symblepharon that may follow blistering

Fig. 1.24 

9

Fig. 1.25 

Fig. 1.26 

Fig. 1.27 

Atlas of Genodermatoses

10

Fig. 1.28 

Fig. 1.30 

Fig. 1.29  • Involvement of the genitourinary tract can occur • Development of cutaneous squamous cell carcinoma (SCC) can occur in adulthood in intermediate JEB (Figure 1.34). In patients affected by laminin 332 mutations, a totally spare cutaneous area of the foot is clearly visible (Figures 1.34 and 1.35) • EB naevi may occur in patients with intermediate JEB (Figures 1.36 and 1.37)

Extracutaneous involvement

• Infants with severe JEB usually develop profound failure to thrive despite adequate nutritional intake • Anaemia is common in severe JEB and, to a lesser extent, in intermediate JEB with widespread cutaneous involvement

Fig. 1.31  • Severe JEB usually results in death in the first 24 months due to failure to thrive, airway involvement or sepsis • Dental enamel defects occur in all individuals with JEB. Monoallelic pathogenic variants in COL17A1, LAMA3 or LAMB3 can cause dental pitting and hypoplastic amelogenesis imperfecta (Figure 1.38)

Epidermolysis Bullosae

11

Fig. 1.32 

Fig. 1.34 

Fig. 1.33 

Fig. 1.35 

Atlas of Genodermatoses

12

Fig. 1.39 

Genetics and pathogenesis

Fig. 1.36 

• Autosomal recessive inheritance • In severe JEB: biallelic nonsense, frameshift or splice site pathogenic variants in LAMA3, LAMB3 or LAMC2 • The most common pathogenic variant causing severe JEB is located in the LAMB3 gene and leads to a premature termination codon, p.R635; in addition, there are some recurrent population-specific LAMB3 variants, such as c.3228+1G>A, c.1133-22G>A • In intermediate JEB: biallelic missense, nonsense, frameshift or splice site pathogenic variants in LAMA3, LAMB3 or LAMC2; biallelic missense, nonsense, frameshift or splice site pathogenic variants in COL17A1 • Revertant mosaicism is relatively frequent in inter­ mediate JEB, particularly those with COL17A1 mutations (Figure 1.39)

Other JEB subtypes JEB with pyloric atresia Main clinical manifestations

Fig. 1.37 

Fig. 1.38 

• Full-thickness skin loss over extensive areas of the head, trunk and limbs at birth (Figure 1.40) • Skin loss can cause deformity of structures such as the ears and nose. Severe phenotypes can present with rudimentary ears

Fig. 1.40 

Epidermolysis Bullosae

Fig. 1.41 

13

Fig. 1.42 

• Nail dystrophy and loss • Pyloric atresia is usually evident within the first days/week of life (Figure 1.41); possible atresia at other gastrointestinal sites e.g., duodenal or anal • Usually lethal within the first few weeks of life despite surgical correction of pyloric atresia • Milder, non-lethal forms have less severe skin and nail involvement, but with frequent genitourinary tract involvement

Genetics and pathogenesis

• Biallelic loss-of-function, splice site or missense pathogenic variants in ITGA6 or ITGB4 result in a severe and rapidly lethal phenotype • ITGA6 and ITGB4 code respectively for integrin-α6 and integrin-β4, crucial components of the hemidesmosomes (see Schematic drawing 1.1) • Biallelic loss-of-function, missense, splice site or in-frame deletion mutations in ITGB4 result in reduced β4 integrin expression with a non-lethal form of JEB with pyloric atresia • Biallelic mutations in ITGB4 may result in JEB without pyloric atresia

JEB laryngo-onycho-cutaneous (LOC) syndrome Main clinical manifestations

• Onset of skin fragility from birth with blistered areas leaving erosions and granulation tissue (much more than severe JEB) (Figure 1.42) • Predilection for the face and neck (Figure 1.43) • Nail dystrophy and loss with granulation tissue of the nail beds (Figure 1.44)

Fig. 1.43  • Conjunctival and eyelid granulation tissue leading to symblepharon, scarring and impaired vision • Laryngeal granulation tissue leading to respiratory obstruction, which can be lethal • Severe anaemia is a major feature due to bleeding from granulating wounds

Atlas of Genodermatoses

14 Genetics and pathogenesis

• Most reported cases result from homozygous loss-of-function pathogenic variants in ITGA3 • Missense ITGA3 mutations reported in milder cases surviving to later childhood

Other JEB phenotypes JEB localized Main clinical manifestations

• Limited cutaneous fragility and blistering, often only acral • Variable nail dystrophy and mucosal involvement • Variable dental enamel defects • Normal hair

Fig. 1.44 

Genetics and pathogenesis

• Autosomal recessive inheritance • Most cases in Punjabi Muslim individuals with a homozygous founder single nucleotide insertion mutation in exon 39 of LAMA3, which is specific to the LAMA3A isoform • Compound heterozygosity for mutations in LAMA3A and LAMA3 result in a similar JEB-LOC phenotype

JEB with interstitial lung disease and nephrotic syndrome (ILNEB, interstitial lung disease, nephrotic syndrome and epidermolysis bullosa) Main clinical manifestations

• Variable cutaneous features with absence or presence of skin fragility from infancy (Figure 1.45) • Dystrophic nails and sparse hair • Interstitial lung disease and nephrotic syndrome predominate the phenotype and determine the prognosis

Genetics and pathogenesis

• Autosomal recessive inheritance • Homozygous or compound heterozygous pathogenic variants in COL17A1, LAMA3, LAMB3, LAMC2, ITGB4 and ITGA3

JEB inversa Main clinical manifestations • • • •

Onset of blistering from birth in flexural sites Atrophic scarring Dental enamel abnormalities Variable nail loss

Genetics and pathogenesis

• Pathogenic variants associated with residual expression of laminin 332

JEB late onset Main clinical manifestations • • • •

Onset of skin fragility in childhood often starting acrally Progressive fragility with age Healing with skin atrophy and loss of dermatoglyphs Scarring leading to flexion contractures of the fingers and reduction of mouth opening may occur with age • Variable dental enamel and nail involvement

Genetics and pathogenesis

• Autosomal recessive inheritance • Biallelic pathogenic variants in COL17A1, specifically the missense variant c.3908G>A, p.R1303Q, cause this phenotype

Dermolytic epidermolysis bullosa or dystrophic epidermolysis bullosa (DEB) This form is characterized by cleavage just beneath the lamina densa in the most superficial portion of the dermis.

Common DEB subtypes

Fig. 1.45 

Major subtypes of DEB include localized dermolytic dominant EB (previously encompassing nails only, pretibial and acral dermolytic dominant epidermolysis [DDEB]), intermediate DDEB (previously known as generalized DDEB), intermediate recessive

Epidermolysis Bullosae

15

dermolytic EB (previously known as RDEB generalized intermediate, non-Hallopeau-Siemens RDEB) and severe RDEB (previously RDEB generalized severe, Hallopeau-Siemens RDEB).

Main cutaneous manifestations

• In localized DDEB, the onset of skin fragility is usually from birth or early childhood and is limited in anatomical extent (Figure 1.46). This may be predominantly acral in distribution or just affect the nails with progressive dystrophy and loss, mainly of the toenails. Some individuals have a predominantly pretibial distribution of blistering and scarring; in this form, symptoms may not develop until later childhood or adulthood • Intermediate DDEB manifests with more generalized skin fragility, scarring and milia from birth or early childhood, with a predilection for bony prominences including the elbows, knees, ankles and dorsa of the hands and feet (Figures 1.47 and 1.48) • Clinical manifestations in intermediate RDEB tend to be more severe (Figures 1.49–1.51) • Skin blistering in severe RDEB is widespread and manifests from birth with significant fragility from minor skin trauma (Figure 1.52): a peculiar presentation at birth of extensive erosions with deep loss of epidermis and dermis,

Fig. 1.48 

Fig. 1.46 

Fig. 1.49 

Fig. 1.47 

especially involving pretibial areas and the dorsa of the feet, leading in some patient to scarring deformities of the feet, formerly known as Bart’s syndrome; it can also occur in other forms of DEB, JEB or EEB • From infancy, blistering is more marked over bony prominences (Figure 1.53) and causes extensive scarring, which can lead to flexion contractures of the large joints • Progressive pseudosyndactyly (digital fusion), flexion contractures and distal resorption of the digits lead to mitten deformities of the hands and feet (Figures 1.54 and 1.55)

Atlas of Genodermatoses

16

Fig. 1.50 

Fig. 1.53 

Fig. 1.51 

Fig. 1.54 

Fig. 1.52 

Fig. 1.55 

Epidermolysis Bullosae

17

Fig. 1.58  Fig. 1.56  • Severe inflammatory skin background characterizes many RDEB patients (Figures 1.56 and 1.57) • The development of aggressive cutaneous SCC is very common and a frequent cause of death in severe RDEB, increasing in incidence from the teen years onwards, arising in areas of repeated trauma, wounds and scarring (Figures 1.58). The risk of developing SCC is also increased in intermediate DDEB, RDEB and, to a lesser extent, localized DDEB, but is less common than in severe RDEB and occurs later in adulthood • EB naevi may occur • The oral mucosa may be involved in all forms of DEB with blistering, erosions and scarring, but changes are most extensive and marked in severe RDEB

Fig. 1.57 

• In severe RDEB, progressive scarring leads to microstomia and ankyloglossia (Figure 1.59), which can result in dental overcrowding, malalignment and the development of secondary caries • Oesophageal blistering and scarring are common in severe and intermediate forms of DEB. Left untreated, progressive strictures can significantly limit oral nutritional intake • Recurrent blistering and fissuring around the anal area are common in all forms of DEB, particularly the more severe types, and may exacerbate constipation • Involvement of the conjunctiva and cornea in severe and intermediate DEB is common, leading to corneal erosions, scarring, pannus, symblepharon formation and reduced visual acuity • Urethral strictures may occur in more severe forms of RDEB

Fig. 1.59 

Atlas of Genodermatoses

18 • Nail dystrophy and loss secondary to trauma are common in all forms of DEB. In severe RDEB, nails are usually lost progressively during the first several years of life • Scarring alopecia and crusting are common with increasing age in severe RDEB

Extracutaneous involvement

• Nutritional impairment is common in severe RDEB and may also occur in intermediate forms of DEB; it results from reduced intake due to factors such as microstomia, dental caries and oesophageal stricture disease, in combination with increased metabolic demands due to chronic wounds, infection and inflammation • Constipation is common in DEB due to pain on defecation resulting from anal fissuring and blistering, exacerbated by poor intake of fibre-rich foods when intake is compromised • A mixed picture of anaemia due to iron deficiency and inflammation is common in severe RDEB • Osteopenia, osteoporosis and vertebral fractures are common in severe RDEB and may be due to reduced mobility, chronic inflammation, vitamin D and calcium deficiency and pubertal delay • Renal impairment and failure may occur in severe RDEB as a result of acute kidney injury, post-streptococcal glomerulonephritis, renal amyloid or IgA nephropathy • Cardiomyopathy may rarely arise in severe RDEB; aetiology is probably multifactorial including micronutrient deficiency, iron overload, drugs and viral causes

Genetics and pathogenesis

• All forms of dermolytic EB are caused by mutations in the COL7A1 gene • DDEB: autosomal dominant inheritance. Monoallelic missense, splice site or deletion mutations in COL7A1 • Intermediate RDEB: autosomal recessive inheritance. Biallelic missense, nonsense, deletion, insertion, small insertion/deletion or splice site mutations • Severe RDEB: autosomal recessive inheritance. Biallelic nonsense, splice site, deletion, insertion, small insertion/deletion or missense mutations. Mutations usually result in null alleles • The most common recurrent “hot spot” COL7A1 mutation is c.425A>G at the donor splice site of exon 3. Other frequently encountered or population-specific RDEB mutations are c.6527dup, c.497dup, p.R2069C, c.682+1G>A, p.R578, p.R2063W, p.R185, p.R1933, c.6269_6270delC, c.4233delT • Revertant mosaicism has been described in RDEB through a variety of mechanisms including COL7A1 somatic mutation and intragenic crossover (Figure 1.60) • Forward non-revertant mosaicism has been demonstrated in RDEB with a germline COL7A1 frameshift mutation and a somatic splice site mutation • Somatic mosaicism for a dominant glycine substitution mutation in COL7A1 has been identified in the parent of an individual with DDEB • DDEB is most commonly caused by missense mutations, resulting in a glycine substitution around the hinge region of the collagenous triple helix of COL7A1. Less commonly, glycine substitution mutations are recessive, only giving rise to an RDEB disease phenotype when inherited in trans with a second COL7A1 mutation • Compound heterozygosity for a loss-of-function mutation on one COL7A1 allele and a non-loss-of-function mutation

Fig. 1.60  on the second allele usually results in an intermediate RDEB phenotype • Homozygosity or compound heterozygosity for truncating COL7A1 mutations usually results in severe RDEB

Rare DEB phenotypes DDEB pruriginosa and RDEB pruriginosa Main clinical manifestations

• Usually presents initially as localized or intermediate DDEB or RDEB in childhood and early adulthood • Characterized by intensely pruritic, excoriated violaceous papules or linear plaques and scars, particularly on the lower legs, thighs and arms, which can become more progressive from adolescence through adulthood (Figures 1.61 and 1.62) • Nail dystrophy and milia are common • May co-exist with non-pruriginosa DEB within families

Fig. 1.61 

Epidermolysis Bullosae

19 • Scarring and milia occur at sites of blistering • Skin fragility improves spontaneously and may resolve completely over the first year or two of life, although nail dystrophy, particularly of the toenails, may persist throughout life

Genetics and pathogenesis

• Autosomal dominant or autosomal recessive • COL7A1 missense mutations, especially glycine substitutions, are most commonly associated, but in-frame deletion, premature termination codon and alternative splicing mutations are also described • Characteristic intraepidermal retention of type VII collagen on immunohistochemistry and stellate bodies in dilated rough endoplasmic reticulum on transmission electron microscopy (Figure 1.63). These changes tend to improve in parallel with phenotypic improvement

RDEB inversa Main clinical manifestations

Fig. 1.62 

Genetics and pathogenesis

• Autosomal dominant or autosomal recessive inheritance • Monoallelic or biallelic mutations in COL7A1, similar to those identified in non-pruriginosa DDEB or RDEB without identification of a specific genotype-phenotype correlation for the pruriginosa phenotype

DDEB self-improving and RDEB self-improving (bullous dermolysis of the newborn) Main clinical manifestations

• Skin blistering presents at or shortly after birth, usually on the extremities • Severe erosions with loss of epidermis and dermis on the lower limbs may be visible at birth

Fig. 1.63 

• In the neonatal period and childhood, skin blistering is usually generalized and of intermediate severity • From adolescence to early adulthood, a predilection for flexural sites develops, specifically in the axillae, groin, perianal area and natal cleft. In women, there may be marked vulvovaginal and inframammary skin blistering • Mucosal disease with blistering and scarring in the mouth and oesophagus is characteristic • Involvement of the external auditory canal may lead to narrowing or complete occlusion • Nail involvement is common

Genetics and pathogenesis

• Autosomal recessive inheritance • Usually results from compound heterozygosity for a lossof-function COL7A1 mutation in combination with a missense mutation; specific glycine and arginine substitutions have been suggested as causative for this specific phenotype

Atlas of Genodermatoses

20 RDEB localized Main clinical manifestations

• Skin fragility usually presents at or shortly after birth, but may rarely be of late onset in adulthood • Blistering is limited in extent; it may affect predominantly the hands and feet, but in others may be restricted to the pretibial area • Nail dystrophy and loss are common • Oral and oesophageal mucosal involvement are usually mild or absent

Genetics and pathogenesis

• Autosomal recessive inheritance • Compound heterozygosity for COL7A1 missense, splice site and frameshift mutations described

Dominant and recessive compound heterozygous DEB Main clinical manifestations

• Severe skin and mucosal fragility presenting from birth indistinguishable from severe RDEB • May have a family history of DDEB

Genetics

• Compound heterozygosity for a dominant COL7A1 glycine substitution mutation and a recessive mutation on the second allele

Recessive DEB temperature-sensitive (“bathing-suit”)

A personal observation of a severe RDEB diffuse phenotype at birth, with progressive centripetal localization of the lesions only in warmer skin areas (trunk), totally sparing face and limbs, mimicking a bathing-suit dress (Figure 1.64). A similar phenotype is already described in literature in “bathing-suit” ichthyosis due to temperature-sensitive TGM1 mutations (see Figures 3.20 and 3.21).

Follow-up for all forms of EB

• Check every 3–6 months for clinical status (especially for skin cancer) • Blood examinations for haemoglobin, electrolytes and proteins • Bacteriological samples for infections • Radiography for hands and feet deformities and mineralometry (osteoporosis) • Radiography for oesophageal strictures • Two scores have been published, iscorEB and EB disease activity and scarring index (EBDASI): the first revealed to be a sensitive tool in differentiating between EB types and across the clinical spectrum of severity, whereas the second index scores activity responsive to therapy separately from scarring. • Recently, a quality-of-life questionnaire based on patient input was developed in Italy and is currently under validation • Multidisciplinary approach: • Odontostomatological for caries and oral erosions • Paediatrics for anaemia, renal insufficiency and nutrition • Physiotherapy for hands, feet and joints • Plastic and hand surgeons for correction of pseudosyndactyly • Urologist and gynaecologist for urethral and vulvar restrictions • Interventional endoscopist for oesophageal dilatation • Psychological support for patients and families

Differential diagnosis (all type of EB) • • • • • • •

Keratinopathic ichthyoses Dyskeratosis congenita (infancy) Pachyonychia congenita (infancy) Neonatal bacterial infections Congenital syphilis Congenital autoimmune bullous diseases Congenital insensitivity to pain syndrome

Therapy • • • • • • • • • • •

Antiseptic local therapy Special dressings and gauzes Antibiotic therapy, local and systemic Pain management Human recombinant erythropoietin and iron for anaemia Vaccines (especially for varicella and measles) Individualized, specific dietary regimen Gastrostomy for severe cases Surgical treatment for scars on the hands (and feet) Surgical treatment for skin tumours Platelet-rich plasma gel derived from umbilical cord for the treatment of ulcers (neonatal localized aplasia cutis-like presentation of former Bart’s syndrome) • Dupilumab for DEB pruriginosa

Targeted therapies

In recent years, attention has turned to the potential for newer targeted treatment options for EB.

Gene therapy for EEB:

Fig. 1.64 

• Small molecular weight compounds have been used in EEB with mutations in the KRT5 and KRT14 genes, associated with increased IL-1b expression, with consequences on blister formation • Diacerein, an inhibitor of IL-1b, induced significant reduction in blistering

Epidermolysis Bullosae

21

Kindler syndrome

For JEB: • LAMB3 cDNA under control of a cytomegalovirus (CMV) promoter was delivered to patient-derived JEB keratinocytes by a retroviral vector • In one report, a recombinant adenoassociated virus (rAAV) with a hybrid serotype (rAAV-DJ), which is able to mediate homologous recombination (HR) at high efficiencies in human keratinocytes, was used to correct a homozygous point mutation in the splice acceptor site of exon 44 in LAMA3 • Non-viral methods have also been used to correct LAMB3-deficient keratinocytes. A transposon plasmid containing LAMB3 cDNA and a blasticidin resistance gene under the control of the CMV promoter was delivered to β3-deficient JEB keratinocytes with an SB transposase plasmid • Clustered regularly interspaced short palindromic repeats (CRISPR) associated to protein 9 (Cas9) was recently used to correct β3-deficient JEB keratinocytes

Cutaneous manifestations

• Skin blistering begins at birth and is generalized with predilection for the extremities (Figures 1.65 and 1.66). The tendency to blister decreases with age

for DEB: • Gene therapy with topical gel containing replicationdefective herpes simplex virus type 1 (HSV1) vector encoding full-lenght human COL7A1 gene has been approved by FDA for patients 6 months and older with DEB and is available for patients in the United States • GENEGRAFT: combines gene-corrected keratinocytes and fibroblasts into a skin equivalent that then can be grafted to the patient’s skin. It has been approved by FDA • Betulin-derived ointment enhanced wound healing in EB following topical application, approved by EMA for JEB and DEB • Gene repair: correction of the mutations by CRISPR/Cas9 editing technology supported with development of inducible pluripotent stem cells (iPSCs) that, after gene correction, can be differentiated into keratinocytes or fibroblasts and used for graft development • Allele-specific therapies: the prerequisite for the development of allele-specific therapies for EB is the specific knowledge of the types and positions of the mutations within the mutant gene • Protein replacement therapy: preclinical studies demonstrated that recombinant type VII collagen intravenously injected into COL7A1 knock-out mice homed into the skin, enhancing wound healing and prolonging the lifespan of these mice. Based on information derived from such studies, this approach is currently on the way to clinical application • Cell-based therapies: cell-based therapies have particularly focused on stem cells with the notion that they could home to the skin and be coached to synthesize basement membrane components to enhance the repair of the molecular defect • Mesenchymal stem cell: intradermal injection as well as intravenous infusion, with clinical improvement initially reported in a limited number of patients

Fig. 1.65 

Fig. 1.66  • Skin atrophy and poikiloderma start on the dorsal aspects of the hands and on the neck during childhood and extend to the entire integument (Figures 1.67 and 1.68) • Photosensitivity is of variable severity (Figure 1.69) • Bullous and erosive lesions on lips and oral cavity starting in young adulthood may have a severe course and can lead to SCC (Figure 1.70) • Oesophageal strictures are peculiar in these patients, worsening with age both in severity and time of recurrence, and require frequent endoscopic dilatation

Atlas of Genodermatoses

22

Fig. 1.67 

Fig. 1.68 

Fig. 1.70 

Fig. 1.71  • Gingivitis with tooth loss, gingival hyperplasia and colitis in a few cases • Urogenital strictures are rare • Ectropion, corneal erosions • Nail dystrophy • SCC are a frequent complication, especially in those patients who work outdoors (Figure 1.71); carcinomas in other regions are rare

Genetics and pathogenesis

Fig. 1.69 

• Autosomal recessive inheritance • Biallelic FERMT1 pathogenic variants (nonsense, frameshift, splicing, large deletions, in regulatory regions, missense), mostly leading to the absence of kindlin-1, an actin cytoskeleton and a focal adhesion-associated molecule • Interestingly, this protein acts with a double role, structural and functional: the first as a component of cytoskeleton of basal cells, and the second as a DNA-repair of UV-induced damage. These actions explain both the skin fragility, the poikilodermatous changes and the neoplastic susceptibility • Some FERMT1 pathogenic variants are recurrent or population-specific

Epidermolysis Bullosae • Revertant mosaicism has been reported mainly in patients with particular frameshift mutations within nucleotide repeats • The absence of kindlin-1 is associated with variable disease severity that is determined by additional factors. An in-frame deletion of one amino acid, p.R100del, leading to residual kindlin-1 expression and function lead to a mild Kindler EB phenotype

Differential diagnosis • • • •

EB Rothmund–Thomson syndrome Xeroderma pigmentosum Dyskeratosis congenita

Follow-up and therapy

• Photoprotection • Detection of early precancerous stages and surgery of squamous cell carcinomas in the skin and mucosae • Oesophageal endoscopy and dilatations

Bibliography Boccaletti V, Zambruno G, Castiglia D, et al. Recessive bullous dermolysis of the newborn in preterm siblings with a missense mutation in type VII collagen. Pediatr Dermatol. 2015;32:e42–e47. Colombo EA, Spaccini L, Volpi L, et al. Viable phenotype of ILNEB syndrome without nephrotic impairment in siblings heterozygous for unreported integrin alpha3 mutations. Orphanet J Rare Dis. 2016;11:136. Fine J-D, Bruckner-Tuderman L, Eady RAJ, et al. Inherited epidermolysis bullosa: Updated recommendations on diagnosis and classification. J Am Acad Dermatol. 2014;70:1103–1126. Gostynska KB, Nijenhuis M, Lemmink H, et al. Mutation in exon 1a of PLEC, leading to disruption of plectin isoform 1a, causes autosomal-recessive skin-only epidermolysis bullosa simplex. Hum Mol Genet. 2015;24:3155–3162. Guerrero-Aspizua S, Conti CJ, Escamez MJ, et al. Assessment of the risk and characterization of non-melanoma skin cancer in Kindler syndrome: Study of a series of 91 patients. Orphanet J Rare Dis. 2019;14:183. Has C, Küsel J, Reimer A, et al. The position of targeted next-generation sequencing in epidermolysis bullosa diagnosis. Acta Derm Venereol. 2018;98:437–440. Hubbard LD, Mayre-Chilton K. Retrospective longitudinal study of osteoporosis in adults with recessive dystrophic epidermolysis bullosa. Clin Case Rep. 2019;7:58–63. Kim E, Harris A, Hyland V, Murrell DF. Digenic inheritance in epidermolysis bullosa simplex involving two novel mutations in KRT5 and KRT14. Br J Dermatol. 2017;177:262–264. Knöbel M, O’Toole EA, Smith FJD. Keratins and skin disease. Cell Tissue Res. 2015;360:583–589. Kyrova J, Kopeckova L, Buckova H, et al. Epidermolysis bullosa simplex with muscular dystrophy. Review of the literature and a case report. J Dermatol Case Rep. 2016;10:39–48. Lai-Cheong JE, Moss C, Parsons M, et al. Revertant mosaicism in Kindler syndrome. J Invest Dermatol. 2012;132:730–732.

23 Lalor L, Titeux M, Palisson F, et al. Epidermolysis bullosa simplexgeneralized severe type due to keratin 5 p.Glu477Lys mutation: Genotype-phenotype correlation and in silico modeling analysis. Pediatr Dermatol. 2019;36:132–138. Maier K, He Y, Esser PR, et al. Single amino acid deletion in kindlin-1 results in partial protein degradation which can be rescued by chaperone treatment. J Invest Dermatol. 2016;136:920–929. Masunaga T, Ogawa J, Akiyama M, et al. Compound heterozygosity for novel splice site mutations of ITGA6 in lethal junctional epidermolysis bullosa with pyloric atresia. J Dermatol. 2017;44:160–166. Pasmooij AM, Nijenhuis M, Brander R, Jonkman MF. Natural gene therapy may occur in all patients with generalized non-Herlitz junctional epidermolysis bullosa with COL17A1 mutations. J Invest Dermatol. 2012;132:1374–1383. Reimer A, Hess M, Schwieger-Briel A, et al. Natural history of growth and anaemia in children with epidermolysis bullosa: A retrospective cohort study. Br J Dermatol. 2019. doi:10.1111/bjd.18475. Reimer A, Schwieger-Briel A, He Y, et al. Natural history and clinical outcome of junctional epidermolysis bullosa generalized intermediate due to a LAMA3 mutation. Br J Dermatol. 2018;178:973–975. Saleva M, Has C, He Y, et al. Natural history of Kindler syndrome and propensity for skin cancer - case report and literature review. J Dtsch Dermatol Ges. 2018;16:338–341. Schwieger-Briel A, Fuentes I, Castiglia D, et al. Epidermolysis Bullosa Simplex with KLHL24 Mutations Is Associated with Dilated Cardiomyopathy. J Invest Dermatol. 2019;139:244–249. Smith CEL, Poulter JA, Brookes SJ, et al. Phenotype and variant spectrum in the LAMB3 form of amelogenesis imperfecta. J Dent Res. 2019;98:698–704. Tadini G, Guez S, Pezzani L, et al. Preliminary evaluation of cord blood platelet gel for the treatment of skin lesions in children with dystrophic epidermolysis bullosa. Blood Transf. 2014;29: 1–6. Tolar J, McGrath JA, Xia L, et al. Patient-specific naturally gene-reverted induced pluripotent stem cells in recessive dystrophic epidermolysis bullosa. J Invest Dermatol. 2014;134:1246–1254. Turcan I, Pasmooij AMG, Van den Akker PC, et al. Association of epidermolysis bullosa simplex with mottled pigmentation and EXPH5 mutations. JAMA Dermatol. 2016;152:1137–1141. Vahidnezhad H, Youssefian L, Saeidian AH, et al. KRT5 and KRT14 mutations in epidermolysis bullosa simplex with phenotypic heterogeneity, and evidence of semidominant inheritance in a multiplex family. J Invest Dermatol. 2016;136:1897–1901. Vahidnezhad H, Youssefian L, Saeidian AH, et al. Recessive mutation in tetraspanin CD151 causes Kindler syndrome-like epidermolysis bullosa with multi-systemic manifestations including nephropathy. Matrix Biol. 2018;66:22–33. van den Akker PC, Mellerio JE, Martinez AE, et al. The inversa type of recessive dystrophic epidermolysis bullosa is caused by specific arginine and glycine substitutions in type VII collagen. J Med Genet. 2011;48:160–167. Watson KD, Schoch JJ, Beek GJ, Hand JL. Compound heterozygosity of dominant and recessive COL7A alleles in a severely affected patient with a family history of dystrophic epidermolysis bullosa: Clinical findings, genetic testing, and treatment implications. Pediatr Dermatol. 2017;34:166–171. Youssefian L, Vahidnezhad H, Barzegar M, et al. The kindler syndrome: A spectrum of FERMT1 mutations in Iranian families. J Invest Dermatol. 2015;135:1447–1450.

2

ACANTHOLYTIC DISEASES Darier disease Synonym

Darier-White disease, keratosis follicularis.

Epidemiology

The prevalence of approximately 1/55.000 to 1/100.000 in the general population

Age of onset

• The lesions usually occur before the third decade, but early onset is not rare (Figure 2.1) • Sunlight, heat, sweating, occlusion and stress often exacerbate the skin lesions

Cutaneous findings

• Malodorous warty, greasy, yellow-to-brown, hyperkeratotic papules on the seborrheic areas of the chest, upper back, forehead, scalp, nasolabial folds and ears (Figures 2.2–2.5). Frequently, they tend to flow into plaques with a high risk of acquiring secondary infections, particularly in folded areas (Figure 2.6)

Fig. 2.3 

Fig. 2.4  Fig. 2.1 

Fig. 2.2  24

Fig. 2.5 

DOI: 10.1201/9781003124351-2

Acantholytic Diseases

25

Fig. 2.8 

Fig. 2.6  • Guttate leukodermatous macules • Papules may appear on mucosal membranes, mainly oral, pharynx, vulva and rectum: whitish oral mucosal lesions in a cobblestone pattern • Gingival hyperplasia and macroglossia • Palmoplantar punctate keratoses or pits (Figures 2.7 and 2.8) • Nail abnormalities are characterized by longitudinal white or red lines with ridges and distal V-shaped notches on the nail surface (Figure 2.9) • 10% of cases are localized forms, example of type 1 segmental mosaicism (Figures 2.10) • Acrokeratosis verruciform of Hopf is merely a variant characterized by skin colored to brown flat-topped papules of the dorsal hands and feet, similar to flat warts (Figure 2.11) • Rare linear comedo-like cases have been described

Fig. 2.7 

Fig. 2.9 

Fig. 2.10 

Atlas of Genodermatoses

26

premature termination codons (PTC) or aberrant splicing (37%) • Segmental distribution of lesions is possible (type 1 mosaicism), as well as a loss of heterozygosity due to a somatic mutation (type 2 superimposed mosaicism)

Differential diagnosis • • • •

Seborrheic dermatitis Hailey-Hailey disease Grover’s disease Paraneoplastic form

Course

• Patients with Darier have a high prevalence of Staphylococcus aureus colonization in lesional skin (68%) (Figure 2.12) and nares (47%), fungal infection (mostly candida species, more rarely dermatophytes), virus (herpes simplex virus) (Figure 2.13) • After the fourth decade, lesions can assume a verrucous and cobblestone appearance (Figure 2.14)

Follow-up and therapies

Fig. 2.11 

Extracutaneous findings

• Mechanical stress at the predilection sites, especially the intertriginous areas, should be decreased by wearing loose cotton clothing and weight loss • Superinfections must be treated early after swabs on the infected areas • Topical emollients and keratolytic ointment (urea, glycerin or lactic acid, retinoids, tacalcitol, 5-fluorouracil); short therapy with topical corticosteroids • Systemic treatment with acitretin (0.2–0.3 mg/kg/body weight)

• Susceptibility to neuropsychiatric dysfunction, in particular severe psychiatric illness, schizophrenia, mental retardation, epilepsy and mood disorders • Diabetes-like metabolic phenotype • Cardiopathy, heart failure, cardiac valvular flaps involvement (bacterial endocarditis) • Corneal, bone, pulmonary and urogenital abnormalities (post-infections nephritis) • Renal abnormalities as renal agenesis, polycystic kidneys or horseshoe kidneys • Gonadal hypoplasia, testicular agenesis

Laboratory findings

• Skin biopsy specimen shows in the epidermis the presence of well-defined hyperparakeratotic areas of different size, dyskeratosis with corps rounds and grains and focal acantholysis with suprabasal cleft formation

Genetics and pathogenesis

• Autosomal dominant caused by mutations in the ATP2A2 gene, encoding sarcoendoplasmic reticulum Ca2+-ATPase isoform 2 (SERCA2), an adenosine triphosphate-dependent calcium pump that transfers calcium from the cytosol to the calcium-rich lumen of the endoplasmic reticulum, causing abnormalities in desmosomes formation • De novo mutations have been reported in up to 68% of the patients • Most mutations described are missense mutations, in-frame deletions or insertions (63%). Other mutations will cause

Fig. 2.12 

Acantholytic Diseases

27 Bibliography

Fig. 2.13  • In severe cases, oral corticosteroids over a limited period of time (prednisolone initially 0.5 mg/kg body weight) • Doxycycline 100 mg per day for its anti-inflammatory effect, low-dose oral Naltrexone (5 mg per day) and magnesium 200 mg per day • Intralesional injections of botulinum toxin A (50–100 IU per site) to eliminate sweat as a trigger factor • Ablative therapies: CO2 laser, Er:YAG laser • Psychiatric, cardiologic, endocrinologic comorbidity needs consultation • Conventional photodynamic therapy • Biologic drugs such as baricitinib may get improvement in itch and sleep disturbances

Fig. 2.14 

Ahanian T, Curman P, Leong IUS, Brismar K, Bachar-Wikstrom E, Cederlöf M, Wikstrom JD. Metabolic phenotype in Darier disease: A cross-sectional clinical study. Diabetol Metab Syndr. 2020;12:12. Bachar-Wikström E, Wikström JD. Darier disease—A multi-organ condition? Acta Derm Venereol. 2021;101(4):adv00430. Digby SS, Hald M, Arendrup MC, Hjort SV, Kofoed K. Darier disease complicated by terbinafine-resistant trichophyton rubrum: A case report. Acta Derm Venereol. 2017;97(1):139–140. Genedy R, Taha A. Acrokeratosis verruciformis of Hopf: Dermoscopic and histopathological study of two siblings. Clin Exp Dermatol. 2021;46(7):1313–1314. Gordon-Smith K, Green E, Grozeva D, Tavadia S, Craddock N, Jones L. Genotype-phenotype correlations in Darier disease: A focus on the neuropsychiatric phenotype. Am J Med Genet B Neuropsychiatr Genet. 2018;177(8):717–726. Leis JMB, Negre GS, Ibarguren APM, Pinto PH. Response of Darier disease following treatment with baricitinib. JAMA Dermatol. 2022;158(6):699–701. Matsuoka LY, Wortsman J. Renal involvement in Darier disease. J Am Acad Dermatol. 2016;75(6):e235. Phillips D, Gumparthy K, Farrar CW, Karumanchery R, Tan BB. Localized Darier disease: Three cases of type 1 segmental mosaicism. Clin Exp Dermatol. 2022;47(1):167–169. Shwetha V, Sujatha S, Yashoda Devi BK, Rakesh N, Pavan Kumar T, Priyadharshini R, Krishnamurthy Y. Spectrum of features in Darier’s disease: A case report with emphasis on differential diagnosis. J Oral Biol Craniofac Res. 2019;9(2):215–220. Soenen A, Saint-Jean M, Daguzé J, Peuvrel L, Quéreux G, Dréno B. Combination of alitretinoin and topical 5-fluorouracil in Darier disease. JAAD Case Rep. 2018;5(1):75–77.

Hailey-Hailey disease Synonym

Chronic benign familial pemphigus

Epidemiology

Estimated to be around 1:50.000

Age of onset

Early adulthood

Cutaneous findings

• Recurrent eruptions of vesicles and blisters on an erythematous background in intertriginous areas and other regions exposed to increased friction (Figures 2.15 and 2.16)

Fig. 2.15 

Atlas of Genodermatoses

28

Fig. 2.16 

Fig. 2.18 

Fig. 2.17  • Erosions, crusts and vegetant lesions may occur (Figures 2.17 and 2.18) • Pain, burning sensations and pruritus • Fetid body odor develops in bacterial superinfections • Nails show narrow and whitish longitudinal streaks or longitudinal leukonychia • Mucous membranes are not interested • Linear manifestations following the Blaschko lines both as segmental type 1 and type 2 variants confirmed by molecular genetics

Laboratory findings

• Suprabasal and intraepidermal cleavage, intracellular oedema and widespread acantholysis within the epidermis, resulting in a “dilapidated brick wall” appearance. Within the superficial dermis, a moderate perivascular lymphocytic infiltrate may be present. Chronic lesions show epidermal hyperplasia, parakeratosis and crusting. Necrotic keratinocytes and acantholytic keratotic cells are rarely observed. • Direct and indirect immunofluorescence shows negative findings

Genetics and pathogenesis

• Autosomal dominant disease • Mutation of the ATP2C1 gene, which encodes a calcium ATPase (hSPA1C) located on the Golgi apparatus, a Ca2+

and Mn2+ transporter that sequester proteins such as junctional proteins, causing imbalance of desmosomal component, resulting in acantholysis • Until now, 181 mutations throughout the ATP2C1 gene have been identified

Differential diagnosis • • • •

Bacterial and fungal infections Darier disease Pemphigus vulgaris and vegetans Transient acantholytic dermatosis of Grover’s disease

Course and complications

• Chronic relapsing course with flares • Superinfection with bacteria (S. aureus, Streptococcus pyogenes), fungi (Candida species) and virus (herpes simplex) may occur in erosive and macerated plaques • Squamous cell carcinomas may arise on chronic lesions in the genital region, especially after prolonged immunosuppressive therapy

Follow-up and therapy • • • • • • • • • •

Avoidance of friction, adhesive and occlusive dressings Topical antibacterial and antimycotic agents Topical corticosteroids and calcineurin inhibitors Topical cinacalcet 3% ointment Oral antibiotics and antimycotic drugs Low-dose naltrexone Magnesium supplementation Dapsone Oral retinoids Oral immunosuppressive drugs as corticosteroids, cyclosporine, methotrexate, azathioprine

Acantholytic Diseases • Procedural therapy as laser CO2, pulsed dye laser and photodynamic therapy • Dupilumab has been used as an alternative therapy. Further studies are necessary to evaluate the long-term efficacy of dupilumab for the treatment

Bibliography Alamon-Reig F, Serra-García L, Bosch-Amate X, Riquelme-Mc Loughlin C, Mascaró JM Jr. Dupilumab in Hailey-Hailey disease: A case series. J Eur Acad Dermatol Venereol. 2022;36(10):e776–e779. Ben Lagha I, Ashack K, Khachemoune A. Hailey-Hailey disease: An update review with a focus on treatment data. Am J Clin Dermatol. 2020;21(1):49–68. Edminister JR, Patel HA, Pixley JN, et al. Improvement of Hailey-Hailey disease with topical cinacalcet, 3%, ointment. JAMA Dermatol. 2023;159(6):669–671.

29 Nellen RG, Steijlen PM, van Steensel MA, Vreeburg M; European Professional Contributors, Frank J, van Geel M. Mendelian disorders of cornification caused by defects in intracellular calcium pumps: Mutation update and database for variants in ATP2A2 and ATP2C1 associated with Darier disease and Hailey-Hailey disease. Hum Mutat. 2017;38(4):343–356. Rogner DF, Lammer J, Zink A, Hamm H. Darier and Hailey-Hailey disease: Update 2021. J Dtsch Dermatol Ges. 2021;19(10):1478–1501. Shigehara Y, Shinkuma S, Fujimoto A, Saijo S, Abe R. Hailey-Hailey disease patient with a novel missense mutation in ATP2C1 successfully treated with minocycline hydrochloride. J Dermatol. 2018;45(11):e306–e308. von Felbert V, Hampl M, Talhari C, Engers R, Megahed M. Squamous cell carcinoma arising from a localized vulval lesion of HaileyHailey disease after tacrolimus therapy. Am J Obstet Gynecol. 2010;203(3):e5–e7.

3

ICHTHYOSES According to the conference held in 2009 in Sorèze, France, a consensus on the terminology and classification of ichthyoses was reached: the result of this discussion is a clinically based classification in which the diseases are referenced with the causative gene or genes.

The classification remains clinically based and distinguishes between syndromic and non-syndromic ichthyosis forms (Scheme 3.1). In the last few years, new causative genes have been found, arising the need of a new gene-based classification.

SCHEME 3.1

Non-syndromic ichthyoses (Table 3.1) TABLE 3.1: Inherited Ichthyoses—Non-syndromic Forms Disease

Mode of Inheritance

Gene(s)

IV ASPRV1-I XLI (Non-syndromic presentation) ARCI   Major types   HI   LI   CIE

Autosomal semidominant Autosomal dominant X-linked recessive

FLG ASPRV1 STS

Autosomal recessive Autosomal recessive Autosomal recessive

ABCA12, KDSR TGM1/NIPAL4b/ALOX12B/ABCA12/CYP4F22a/LIPNa/ SDR9C7/CASP14 ALOXE3/ALOX12B/ABCA12/CYPF22/ NIPAL4b/ TGM1/PNPLAl/CERS3/ LIPNa/SULT2B1

Autosomal recessive Autosomal recessive Autosomal recessive

TGM1, ALOX12B, ALOXE3, ABCA12 TGM1 TGM1

Autosomal dominant Autosomal dominant Autosomal dominant

KRT1/KRT10 KRT2 Revertant mosaicism KRT1/KRT10

Autosomal recessive Somatic mutations

KRT10 KRT1/KRT10

  Minor variants   SICI   Acral SICI   BSI Keratinopathic ichthyoses   Major types   EI   SEI   CRIE   Minor variants   AREI   Epidermolytic nevic

(Continued) 30

DOI: 10.1201/9781003124351-3

Ichthyoses

31

TABLE 3.1:  Inherited Ichthyoses—Non-syndromic Forms (Continued) Disease Other forms  LK  EKVP  PSS   PLACK syndrome   KLICK syndrome  PR

Mode of Inheritance

Gene(s)

Autosomal dominant Autosomal dominant/ recessive Autosomal recessive Autosomal recessive Autosomal recessive Autosomal dominant

LOR GJB3/GJB4/GJA1/LOR/KDSR/TRPM4/KRT83/ELOVL4 CHST8/SERPINB8/FLG2 (type A), CDSN (type B), TGM5/CSTA (acral PSS) CAST POMP ProFLG

Abbreviations: IV, ichthyosis vulgaris; XLI, X-linked ichthyosis; ARCI, autosomal recessive congenital ichthyosis; HI, harlequin ichthyosis; LI, lamellar ichthyosis; CIE, congenital ichthyosiform erythroderma; SICI, self-improving collodion ichthyosis; BSI, bathing-suit ichthyosis; EI, epidermolytic ichthyosis; SEI, superficial epidermolytic ichthyosis; CRIE, congenital reticular ichthyosiform erythroderma; AREI, autosomal recessive epidermolytic ichthyosis; LK, loricrin keratoderma; EKVP, erythrokeratoderma variabilis et progressiva; PSS, peeling skin syndrome; PLACK, peeling skin-leukonychia-acral keratoses-cheilitis-knuckle pads; KLICK, keratosis linearis-ichthyosis congenita-keratoderma; PR, pityriasis rotunda. Notes: Often delayed onset (in XLI mild scaling and erythroderma may be present already at birth). b Also known as ICHTHYN gene. c May indicate gonadal mosaicism, which can cause generalized EI in offspring generation. a

Autosomal dominant congenital ichthyoses Ichthyosis vulgaris (IV) Epidemiology

This is the most frequent disease in the group of ichthyoses, with a prevalence ranging from 1:100 to 1:3.000.

Age of onset

It may be visible shortly after birth, but more frequently, the clinical picture is more easily seen during the first year of life.

Cutaneous findings

• IV is characterized by very different clinical presentations that vary from slightly visible xerotic itchy skin to more severe pictures similar to those of mild autosomal recessive congenital ichthyoses (ARCI) (Figures 3.1 and 3.2) • The particular presentation is a combination of erythematous scaly cheeks and face (Figure 3.3), small grey to brownish scales covering all of the body including the folds, follicular hyperkeratosis and hyperlinearity of the palms and soles (Figure 3.4)

Extracutaneous symptoms

It is associated with a higher risk for the development of atopic diseases, such as atopic eczema and allergic rhinitis (Figure 3.5).

Course

This is a lifelong disease with some degree of seasonal changes.

Laboratory findings

• Histology shows a decrease or absence of stratum granulosum; the ultrastructure shows anomalies of keratohyalin granules • Allergy testing shows frequent positivity to nickel and other allergens

Genetics and pathogenesis

• IV is inherited as an autosomal semidominant trait • About two-thirds of patients have two filaggrin mutations with relatively serious disease; one-third of those with the disease have only one filaggrin mutation and a milder course

Fig. 3.1 

• The disease is related to loss-of-function mutations of the filaggrin gene (FLG), which cause anomalies in the synthesis of filaggrin and improper aggregation of keratin filaments in the cytosol, as well as the generation of much of the skin’s natural moisturizing factor. This leads to a reduction in skin hydration and excessive scaling • FLG mutations tend to be population-specific, with different and sometimes mutually exclusive mutations between Caucasian and Asian groups

Atlas of Genodermatoses

32

Fig. 3.4 

Fig. 3.2 

Fig. 3.5 

Therapy Fig. 3.3 

Differential diagnosis

Severe IV must be differentiated from ASPRV1-dominant ichthyosis, mild lamellar ichthyosis (ARCI) and from X-linked ichthyosis (XLI).

Follow-up

During childhood, allergological evaluation is mandatory in severe atopic patients.

Local therapy must be individualized, but mild keratolytic agents (e.g. urea, lactic acid) and emollients are recommended.

Bibliography Akiyama M. FLG mutations in ichthyosis vulgaris and atopic eczema: Spectrum of mutations and population genetics. Br J Dermatol. 2010;162(3): 472–477. Compton JG, DiGiovanna JJ, Johnston KA, et al. Mapping of the associated phenotype of an absent granular layer in ichthyosis vulgaris to the epidermal differentiation complex on chromosome 1. Exp Dermatol. 2002;11: 518–526.

Ichthyoses Fischer J, Bourrat E. Genetics of Inherited Ichthyoses and Related Diseases. Acta Derm Venereol. 2020;100(7):adv00096. Oji V, Tadini G, Akiyama M, et al. Revised nomenclature and classification of inherited ichthyoses: Results of the first ichthyosis consensus conference in Sorèze 2009. J Am Acad Dermatol. 2010;63(4):607–641. Thyssen JP, Godoy-Gijon E, Elias PM. Ichthyosis vulgaris—the filaggrin mutation disease. Br J Dermatol. 2013;168(6):1155–1166. Traupe H, Fischer J, Oji V. Nonsyndromic types of ichthyoses - an update. J Dtsch Dermatol Ges. 2014;12(2):109–121. doi: 10.1111/ ddg.12229.

ASPRV1-ichthyosis Epidemiology

10 cases have been described so far

Age of onset • At birth or within the first months of life • Collodion baby presentation is not reported

Cutaneous findings (Panel 3.1) • Patients present at birth or within the first months of life with scaling affecting the entire body, including the flexures, palms and soles • Erythema is absent or mild. Scaling improves, but doesn’t completely resolve, during warmer weather • Inability to perspire when scaling is severe • Palmoplantar keratoderma, with prominent scaling and accentuation of the creases, sometimes leading to constricting bands on the digits

33 Laboratory findings

Histology demonstrates acanthosis, compact orthohyperkeratosis, and a slightly expanded granular layer with coarse keratohyalin granules containing filaggrin.

Genetics and pathogenesis

• The disease is caused by deleterious missense mutations in the ASPRV1 gene, which encodes aspartic peptidase retroviral-like 1, also known as skin aspartic protease (SASPase) • ASPRV1 directly cleaves filaggrin, a process critical to epidermal integrity • Subjects with ASPRV1 mutations have aberrant protease function, with consequent excess of unprocessed filaggrin and a desquamation defect that manifests as thick scale and palmoplantar hyperkeratosis

Differential diagnosis

ASPRV1 ichthyosis should be differentiated mainly from lamellar ichthyosis (LI).

Course

Lifelong disease with some degree of seasonal changes.

Therapy

Pathogenesis-driven therapy might include keratolytic agents such as lactic acid and urea.

Bibliography Boyden LM, Zhou J, Hu R, et al. Mutations in ASPRV1 cause dominantly inherited ichthyosis. Am J Hum Genet. 2020;107(1):158–163

PANEL 3.1  Reprinted with permission (Boyden LM et al, Am J Hum Genet 2020)

Atlas of Genodermatoses

34 X-linked ichthyosis (XLI) Age of onset

• From birth to first month of life • It is the only type of ichthyosis that can be both syndromic and non-syndromic

Prevalence

About 1:1500 in males.

Cutaneous findings

• At birth, children may have a collodion baby phenotype, whereas later, dark, discrete, medium-sized scales, especially visible on the extensor surface (cobblestone appearance), are the hallmark of the disease (Figures 3.6–3.8). All surfaces are involved

Fig. 3.8  • At the site of major folds, the skin appears lighter in contrast to the nigricant aspect of the surrounding skin, implying false disease-free areas • In severe cases, the face shows dark, fine desquamation with underlying erythema (Figure 3.9). The scalp is covered by fine, dandruff-like scales • There is no follicular hyperkeratosis, but by contrast, some degree of rhomboidal palmoplantar hyperlinearity is present

Fig. 3.6 

Fig. 3.7 

Fig. 3.9 

Ichthyoses Extracutaneous findings (syndromic forms) • • • •

Cryptorchidism (10%) Short stature Corneal opacities Cognitive and behavioural disorders, including ADHD (up to 40% of patients), autism (up to 20%), epilepsy and cognitive impairment • Hypoanosmy (Kallmann’s syndrome, large deletions leading to complex contiguous gene syndromes) • Pregnancy and labour may be complicated

Laboratory findings

Steroid sulfatase (STS) enzyme deficiency can be detected in female carriers

Genetics and pathogenesis

• Large deletions of the gene encoding STS cause XLI. This enzyme plays a key role in the metabolism of membranerelated steroids, causing anomalies in the formation of the cornified envelope • STS activity is reduced in female carriers, who can have dry skin in winter as almost asymptomatic diseases carriers • Exceptional cases of XLI in women have been reported (Figures 3.10 and 3.11) • Point mutations in the same gene account for less than 10% of patients

35 Differential diagnosis

XLI must be differentiated from the milder cases of nigricans lamellar ichthyoses due to transglutaminase-1 gene mutations, which can have a similar presentation but have larger scales, and from IV cases in patients with dark skin or in males when there is no family history of the disease.

Course and complications

• The disease is present lifelong but dramatic amelioration during summer or after ultraviolet (UV) light exposure is highly characteristic of this disease. Xerosis and desquamation show remarkable improvement with topical therapy, whereas scalp scales tend to be resistant to treatments • Slow growth during childhood

Follow-up

• Cryptorchidism must be monitored and cured when necessary (orchiopexy) • Ophthalmological examination is advised when corneal anomalies are detected; rarely, corneal transplantation is necessary • Obstetric and genetic counselling for female carriers

Therapy

• UV radiation, either natural or lamp-originated • Mild keratolytic agents (urea) • Emollients

Bibliography

Fig. 3.10 

Cuevas-Covarrubias SA, Jimenez-Vaca AL, Gonzalez-Huerta LM, et al. Somatic and germinal mosaicism for the steroid sulfatase gene deletion in a steroid sufatase deficiency carrier. J Invest Dermatol. 2002;119:972–975. Fernandes NF, Janniger CK, Schwartz RA. X-linked ichthyosis: An oculocutaneous genodermatosis. J Am Acad Dermatol. 2010; 62(3):480–485. Nagtzaam IF, Stegmann AP, Steijlen PM, et al. Clinically manifest X-linked recessive ichthyosis in a female due to a homozygous interstitial 1.6-Mb deletion of Xp22.31. Br J Dermatol. 2012;166(4):905–907. Rodrigo-Nicolás B, Bueno-Martínez E, Martín-Santiago A, et al. Evidence of the high prevalence of neurological disorders in nonsyndromic X-linked recessive ichthyosis: A retrospective case series. Br J Dermatol. 2018;179(4):933–939.

Autosomal recessive congenital ichthyoses (ARCI)

Fig. 3.11 

• For this heterogeneous family of ichthyoses, a clinical terminology is still in use, dividing them in two subtypes, namely: • LI, defining a phenotype characterized by large, dark, adherent lamellae with absent or poorly marked erythema (lamellar ichthyoses) • Congenital ichthyosiform erythroderma (CIE), referring to patients showing marked erythema and fine- to medium-sized white-to-yellowish scales • Molecular characterization of most patients will allow us to obtain more precise genotype–phenotype correlations and to progressively abandon this categorization between LI and CIE.

Atlas of Genodermatoses

36 • In the majority of cases, ARCI at birth shows the collodion baby pattern, defined by a tight, shiny cast encasing the newborn that resolves progressively within the first months of life • No causative gene mutations can be found in approximately 10% of ARCI cases • A new ARCI classification system based on the identity of the causative genes is needed

Age of onset At birth.

Epidemiology

This recessively inherited group of diseases is very rare, with estimated incidence rates of 1:200.000–1:300.000.

Genetics

Molecular biology is performed in the majority of patients, searching for the 13 established loci (TGM1 gene, ALOXB12 and ALOXE3 genes, NIPAL4/ichthyin, ABCA12, CYP4F22, LIPN, PNPLA1, CERS3, SDR9C7, SULT2B, KDSR and CASP14).

Fig. 3.13 

Transglutaminase 1-related phenotypes

TGM1 mutations are the most common cause of ARCI: the majority consist of missense mutations located in the first twothirds of the gene. The most commonly reported TGM1 mutation has been the c.877-2A>G splice-site mutation, resulting in a premature stop codon. TGM1 encodes for the TGase-1 enzyme that cross-links proteins to form the cornified cell envelope, the final step of the skin differentiation process. ARCI patients with mutations in TGM1 have defects in skin barrier function due to the essential role of this enzyme for cornified cell envelope formation and normal epidermal barrier function. Skin ultrastructure shows a thin cornified cell envelope and disorganization of lamellar bilayers and cholesterol crystals.

Cutaneous findings

• The majority of patients show a collodion baby pattern at birth with a brownish-dark nigricans presentation, having large, dark, plate-like lamellae with or without erythematous underlying areas, accompanied by severe ectropion, eclabium and scalp involvement LI (Figures 3.12–3.14). • Infections and sepsis occur at perinatal and neonatal ages

Fig. 3.12 

Fig. 3.14  • Palmoplantar keratoderma is present (Figure 3.15). Residual scarring alopecia is possible, as well as nail dystrophy • Patients who had at least one mutation predicted to truncate TGase-1 are more likely to have severe hypohidrosis and overheating than those with TGM1-missense mutations only • A minority of patients are born as collodion babies with erythroderma and overlying fine, whitish scale CIE (Figure 3.16) • During adolescence and adulthood, different, less severe phenotypes are recognizable and are associated with variable underlying erythema. Scale colour may vary and very small, adherent, whitish scales may be visible, giving the highly characteristic translucency to the skin. Patients affected by TGM1 mutations are more likely to experience skin odour than other ARCI • Finally, the phenotype may change over time and after treatment

Ichthyoses

37 Therapy

Fig. 3.15 

• Sterile paraffin oil and control of the temperature and humidity in neonatal equipment • Ointments and creams to allow for the detachment of scales in a short period • Emollients • Keratolytic agents (urea, lactic acid, glycolic acid, propylene glycol) • Salicylic acid for palmoplantar sites • Calcipotriol • Oral retinoids (0.4–0.8 mg/kg/day) • Ophthalmological treatment • Topical N-acetylcysteine/carbocysteine (anti-proliferative effect) • Topical enzyme-replacement therapy based on sterically stabilized liposomes with encapsulated recombinant human TGM1 or a replication-defective herpes simplex virus type 1 (HSV1) vector encoding full-length human TGM1 are currently under development.

Self-healing collodion baby (SHCB), also called self-improving collodion ichthyosis (SICI) Cutaneous findings

• After a premature birth, babies are totally and firmly encased in a translucent, parchment-like film that is 1–2 mm deep that involves all of the body (Figure 3.17). There is ectropion and coarctation of the external ears. Eclabium and digital constrictions may be present. The underlying epidermis may be erythematous. The membrane begins a slow, progressive detachment in large lamellae (Figure 3.18)

Fig. 3.17  Fig. 3.16 

Extracutaneous symptoms and complications • • • • •

Nystagmus and corneal defects (due to ectropion) Hearing problems Neurologic abnormalities Failure to thrive Phalangeal malformations and reabsorption in severe cases

Differential diagnosis (LI and CIE) • • • • •

Keratinopathic ichthyosis Self-healing collodion baby (SHCB) Other ARCI due to different genes Severe dominant IV Syndromic ichthyoses

Fig. 3.18 

Atlas of Genodermatoses

38 “Bathing-suit” ichthyosis Cutaneous findings

Patients show a collodion membrane at birth with the subsequent development of a clinical picture that is characterized in the majority of subjects by large- or medium-sized yellowish to brown lamellae. Then, within the first year of life, the skin heals predominantly on the extremities (colder areas) but, by contrast, warmer skin areas (e.g., trunk and scalp) remain involved and show a localized form of LI (Figures 3.20 and 3.21), mimicking a bathing-suit dress. This presentation is also due to temperaturesensitive TGM1 mutations.

Fig. 3.19  that continues until the scales are totally faded. The large, firm crops on the scalp are the last to heal. This process takes 1–6 months to conclude, leaving the appearance of normal skin with some degree of translucency (Figure 3.19) • Partial relapses of the symptoms are often referred during febrile disease, especially in children

Genetics and pathogenesis

Fig. 3.20 

• The phenomenon is related to the re-activation of TGM1 mutated enzyme after birth. Peculiar TGM1-mutations during pregnancy, due to the temperature of amniotic fluid, cause secretion of an inactive TGM1 enzyme, causing a pathological skin differentiation and the related clinical presentation at birth (dynamic, temperature-dependent phenotype). The TGM1 mutation D490G has only been associated with SICI • Other gene defects may cause the SICI phenotype, namely, lipo-oxygenase genes (ALOX12B and ALOXE3) and ABCA12 mutations

Differential diagnosis

Despite the description of these cases as a self-healing disease, a collodion baby is to be considered a symptom and not a disease since many other diseases at birth may have a collodion baby presentation: • • • • • •

All ARCI XLI Keratinopathic ichthyoses Hypohidrotic ectodermal dysplasia Omenn syndrome Syndromic ichthyoses

Fig. 3.21 

Ichthyoses ABCA12-related phenotypes

ABCA12 is a keratinocyte-specific lipid transporter localized in lamellar granules: a loss of ABCA12 function leads to a defective lipid barrier in the stratum corneum, resulting in an ichthyotic phenotype. There is no apparent mutation hot spot in ABCA12, although mutations underlying the CIE phenotype are clustered in the region of the first ATP-binding cassette. ABCA12 mutations have been described in ARCI, including harlequin ichthyosis (homozygous null alleles with absent or minimal residual ABCA12 function, often in consanguineous parents) and CIE phenotype (compound heterozygous, missense mutations); since the latter has a much milder clinical phenotype than HI, this suggests that the type of ABCA12 variant has a major impact on the severity of the disease.

Harlequin ichthyosis (HI) Epidemiology

This disease is very rare; incidence is estimated in 1:300.000.

Cutaneous findings

• This disease shows a dramatic pattern represented by a thick (0.5–1 cm), compact, armour-like white-greyish shell that covers the entire body (Figure 3.22) • This cuirass is fixed and divided into irregular, quadrangular plates by deep fissures. These patterns grotesquely mimic the dress of the traditional Italian character named Harlequin (Figure 3.23). The whole body is so strongly enveloped that the baby is forced to lie in a flexed position

39 • Extreme ectropion, eclabium and an O-shaped mouth are visible, together with very severe auricular malformations (flattened ears) • The hair is enveloped by the cornified shell and the nails are deformed

Extracutaneous findings and complications

• Nystagmus and corneal opacities • Distal phalanges may be necrotic, owing to strictures that can cause auto-amputation • Osseous malformations of fingers • Xerostomia • Neurologic abnormalities and malformations • Superinfections, dehydration and sepsis are the most frequent causes of death in these patients

Course

• Without therapy, the disease is invariably lethal • When high-dose oral retinoid therapy is correctly administered, 50% of patients may survive. The cuirass of the survivors fades within 2–3 months and they develop an erythematous, scaly, very severe ichthyosis pattern with ectropion, abnormal external ears and alopecia (Figure 3.24) • The hands and feet are largely malformed, with osseous reabsorption (Figure 3.25) • Viral conjunctivitis as well as mycotic and bacterial skin infections may occur

Fig. 3.22 

Fig. 3.23 

Fig. 3.24 

Atlas of Genodermatoses

40

Fig. 3.25 

Laboratory findings

Fig. 3.26 

Ultrastructurally, abnormal lipid-containing droplets and vacuoles are seen in the cytoplasm of cornified cells and many abnormal immature lamellar granules are observed in the keratinocytes.

Genetics

• Only ABCA12 mutations have been reported so far (homozygous, stop-codon nonsense variants) • Recently, KDSR gene encoding for 3-ketodihydrosphingosine reductase, a key step in the de novo ceramide synthesis pathway, has been identified as a possible additional candidate gene for non-ABCA12 HI

Differential diagnosis Restrictive dermopathy.

Follow-up and therapy

• Intensive neonatal care is mandatory • The mortality rate is very high due to severe respiratory infections and sepsis, caused by both bacteria or Candida spp • Monitoring of temperature and humidity as well as sterile medications (vaseline) are recommended • A multidisciplinary approach is advised to cope with related problems, but the ophthalmologist, orthopaedic and neurologist play key roles in the first years of life • Physiotherapy may help with the correct development of posture and walking • The dermatologist is essential for the assessment of local emollients and for the management of oral retinoids • Oral retinoids at an initial dose of 1–2 mg/kg/day • Surgery for ectropion and hand and feet malformation • Emollients and keratolytic ointments

Fig. 3.27 

Other ABCA12-related phenotypes • Less severe heterozygous ABCA12 mutations lead to a clinical picture with collodion baby presentation that may evolve into either clinical pattern with slight underlying erythema and dark, large lamellae, or into a clinical presentation of a moderately severe phenotype with underlying erythema with fine, white to greyish, diffuse scales. Scalp and palmoplantar areas are normally involved, as well as ectropion. Distinguishing features rarely found in other ARCI phenotypes include tapered digits, hyperconvex nails and auricle malformation (Figures 3.26–3.28). • ABCA12 mutations may cause an ichthyosis with a progressive simmetric erythrokeratoderma (PSEK) phenotype

Fig. 3.28 

Extracutaneous symptoms and complications • Hypohidrosis • Eye problems • Hearing problems

A unique patient with blaschkoid CIE due to biallelic mutations, one inherited germline missense mutation and the other a postzygotic frameshift mutation in the ABCA12 gene has recently been reported. This was the first report of a proven biallelic mosaic

Ichthyoses

41 Patients may be born as an erythematous collodion baby and normally show a mild-to-moderate form with underlying erythema and whitish or light-brown lamellae (Figures 3.31–3.33). All patients with ALOX12B mutations show mild hyperkeratosis of the palms and soles with accentuated palmoplantar creases.

Fig. 3.31  Fig. 3.29 

Fig. 3.32 

Fig. 3.30  presentation of an autosomal recessive genodermatosis, called by the authors as “recessive mosaicism”. (Figures 3.29 and 3.30)

ALOX12B and ALOXE3-related ARCI ALOX12B and ALOXE3 encode the lipo-oxygenases 12R-LOX and eLOX-3, which are predominantly synthesized in the epidermis; these enzymes are part of the lipid metabolism pathway involved in the formation of ceramides from arachidonic acid and have a role in the regulation of the proliferation and differentiation of keratinocytes. All of the mutations are loss-of-function mutations, either impairing enzyme activity or ablating protein synthesis. Mutations in ALOX12B or ALOXE3 account for almost 15% of ARCI cases, as the second most common cause for ARCI.

Fig. 3.33 

Atlas of Genodermatoses

42 ALOXE3 and ALOX12B are related to rare self-improving collodion baby phenotypes. Loss-of-function of ALOXE3 may suppress the expression of the TGM5 mutation, possibly by upregulating the expression of a compensatory function with elevated corneodesmosin levels.

CYP4F22-related ARCI This is a cytochrome P450 protein coded by the FLJ39501 gene and has an important role in the same pathway of the lipo-oxygenase genes, necessary for the formation of acylceramides. Patients with CYP4F22 mutations usually are not born with collodion membranes, but later, they develop an LI phenotype, with fine, white or plate-like scale, mild-to-severe erythema and palmoplantar keratoderma (PPK) (Figures 3.34 and 3.35). A reticulate aspect of the plate-like scaling can be noticed.

Fig. 3.36 

NIPAL4-related ARCI

Fig. 3.34 

Fig. 3.35 

Also known as ichthyin, this membrane transporter likely functions as a Mg2+ transporter with roles in lipid processing and lamellar body formation, which are essential for the development of a normal skin barrier. Patients more resemble the CIE subtype, despite the fact that some patients clinically show the LI phenotype. The peculiar symptom in these patients is a pronounced yellowish palmoplantar keratoderma (Figures 3.36 and 3.37). Collodion membrane at birth and alopecia are significantly less common among patients with NIPAL4 mutations. Skin ultrastructure reveals a weak correlation with vesicular complexes, defective lamellar bodies and perinuclear membranes within stratum granulosum. Significant clinical variability without apparent variant correlation doesn’t allow a genotype–phenotype correlation. Recently, a consanguineous pedigree with phenotypical overlap between ARCI ichthyosis and erythrokeratoderma variabilis has been described as related to a novel missense homozygous mutation in the NIPAL4 gene (Figure 3.38).

Fig. 3.37 

Ichthyoses

43

Fig. 3.40  Fig. 3.38 

PNPLA1-related ARCI The PNPLA1 gene encodes patatin-like phospholipase domaincontaining 1, which is central to acylceramide biosynthesis. In a few pedigrees with mutations in the PNPLA1 gene, a phenotype characterized by collodion baby presentation at birth evolves into a clinical picture with fine or plate-like scale and variable erythema, mild facial lesions without ectropion, thick adherent scales on the scalp without alopecia and palmoplantar hyperlinearity (Figures 3.39–3.41). Nails are unaffected but, conversely, severe heat intolerance may be present. Clear genotype–phenotype associations for PNPLA1 are lacking.

Fig. 3.41 

CERS3-related ARCI

Fig. 3.39 

Ceramide synthase type 3 (CERS3) plays a crucial role in the synthesis of very-long-chain (VLC) ceramides in differentiating keratinocytes. In these patients, the epidermis shows a disturbance of epidermal differentiation with an earlier maturation and an impairment of epidermal barrier function. These mutations inactivating the function of CERS3 lead to a very rare phenotype represented by an erythematous collodion baby with severe ectropion and eclabium (Figure 3.42). After a short period of time, a clinical picture arises with underlying mild erythema and large yellowish to brown lamellae (Figure 3.43). With age, these patients show pronounced keratotic lichenification, leading to a prematurely aged appearance

Atlas of Genodermatoses

44

Fig. 3.42  Fig. 3.44  reductase family 9C, member 7 (SDR9C7), responsible for converting retinal into retinol; SDR9C7 deficiency leads to reduced keratinocyte migration, leading to abnormal skin barrier function. Patients show a relatively mild ichthyosis phenotype with generalized dry and scaly skin with mild local erythema, hyperlinearity of the palms and soles and PPK. The collodion baby at birth is a variable feature of the phenotype. Other findings such as susceptibility to fungal infections (skin and nails) and alopecia have been reported. No clear phenotype–genotype correlation has been found, and no significant difference exists among patients with missense versus nonsense mutations. Fig. 3.43 

SULT2B1-related ARCI

and the severe involvement of the scalp, and subsequently at school age, erythema is more pronounced and the scales become lighter. Severe heat intolerance is present. The application of lotions supplemented with VLC ceramides, especially acylceramides onto the skin of affected patients, would be a promising therapeutic approach to treat skin symptoms in these patients.

LIPN-related ARCI A late-onset form (from 5 years of age on) of recessive ichthyosis in a large consanguineous pedigree has been described as being related to decreased expression of LIPN in keratinocytes. LIPN encodes for lipase N, one of the six acid lipases known to be involved in triglyceride metabolism: despite the critical importance of this pathway, the exact function of this gene is still unknown. Patients are characterized by a pattern of dark, medium-sized lamellae that are especially visible on the extensor surfaces of arms and legs and generalized scaling (Figure 3.44). At 5 years of age, a female patient showed progressive erythema and fine white scales all over the body.

SDR9C7-related ARCI A further gene causative for ARCI phenotype have been identified in SDR9C7 which encodes the short chain dehydrogenase/

SULT2B1 is a member of the large cytosolic sulfotransferase superfamily that is engaged in the synthesis and metabolism of cholesterol in humans, affecting the regulation of epidermal proliferation in human skin. The loss of SULT2B1 also affects the proper expression of cornified envelope proteins, such as loricrin, involucrin and filaggrin, and impairs the differentiation process in human skin and, thereby, in the maintenance of a functional cutaneous permeability barrier. Affected individuals born as collodion babies showed a generalized very dry, scaly skin with severe itching and erythema at birth. A thicker, greyish skin is seen particularly on the knees, elbows and dorsal feet and hands, areas exposed to increased mechanical stress. Mild or non-affected skin was observed in the axilla, face, popliteal fossa and back, similar with XLI. No extracutaneous abnormalities have been reported.

CASP14-related ARCI A new gene was identified as a cause of ARCI in a consanguineous family, due to a mutation in the CASP14 gene. In contrast with other human caspases, CASP14 is not involved in apoptosis or inflammation, and is mainly expressed in all suprabasal layers of the epidermis, causing the degradation of filaggrin (FLG) monomers in the stratum corneum to free hygroscopic amino acids, the natural moisturizing factors (NMF) of the skin.

Ichthyoses

45

A mild ichthyotic phenotype has been reported without a collodion membrane at birth. The patient showed fine whitish scales over the whole body without erythema. No other symptoms, such as palmoplantar keratoderma, nail, hair or teeth anomalies, were observed.

Complications for all types of ARCI

• Risk of systemic infections, dehydration, respiratory problems and temperature dysregulation • In some patients, severe seronegative polyarthritis with early onset

Therapy for all ARCI

• Sterile paraffin oil and control of the temperature and humidity in neonatal equipment • Ointments and creams to allow for detachment of scales in a short period • Emollients • Keratolytic agents (urea, lactic acid, glycolic acid, propylene glycol) • Salicylic acid for palmoplantar sites • Calcipotriol • Topical retinoids • Oral cholecalciferol • Oral retinoids (0.4–0.8 mg/kg/day) • Periodic otolaryngologist for deep ear cleaning • Ophthalmological treatment (ocular lubrication, surgical/ non-surgical interventions) • Recent studies in literature showed Th17 immune skewing, as in psoriasis, across the spectrum of ichthyosis, suggesting that targeting this pathway might broadly reduce disease severity in terms of redness and itch; therefore, the use of secukinumab and ixekizumab may be a promising therapeutic approach in some selected cases.

Follow-up

• Hospitalization in the neonatal period is necessary to avoid major complications • Routine dermatological assessment for local keratolytic therapy and retinoid therapy • Psychological consultation for the patient and family • Ophthalmologist for follow-up of ectropion • Blood testing and radiography for oral retinoid therapy • Genetic counselling is required

Bibliography Akiyama M. ABCA12 mutations and autosomal recessive congenital ichthyosis: A review of genotype/phenotype correlations and of pathogenetic concepts. Hum Mutat. 2010;31(10):1090–1096. Aufenvenne K, Larcher F, Hausser I, et al. Topical enzyme replacement therapy restores transglutaminase 1 activity and corrects architecture of transglutaminase-1-deficient skin grafts. Am J Hum Genet. 2013;93(4):620–630. Charfeddine C, Laroussi N, Mkaouar R, et al. Expanding the clinical phenotype associated with NIPAL4 mutation: Study of a Tunisian consanguineous family with erythrokeratodermia variabilisLike Autosomal Recessive Congenital Ichthyosis. PLoS One. 2021;16(10):e0258777. DiGiovanna JJ, Robinson-Bostom L. Ichthyosis: Etiology, diagnosis, and management. Am J Clin Dermatol. 2003;4:81–95. Fachal L, Rodríguez-Pazos L, Ginarte M, et al. Identification of a novel PNPLA1 mutation in a Spanish family with autosomal recessive congenital ichthyosis. Br J Dermatol. 2014;170(4):980–982.

Freedman JC, Parry TJ, Zhang P, et al. Preclinical evaluation of a modified herpes simplex virus type 1 vector encoding human TGM1 for the treatment of autosomal recessive congenital ichthyosis. J Invest Dermatol. 2021;141(4):874–882.e6. Hasbani DJ, Hamie L, Eid E, Tamer C, Abbas O, Kurban M. Treatments for non-syndromic inherited ichthyosis, including emergent pathogenesis-related therapy. Am J Clin Dermatol. 2022; 23:853–867. Heinz L, Kim GJ, Marrakchi S, et al. Mutations in SULT2B1 cause autosomal-recessive congenital ichthyosis in humans. Am J Hum Genet. 2017;100(6):926–939. doi: 10.1016/j.ajhg.2017.05.007. PMID: 28575648; PMCID: PMC5473727. Hotz A, Kopp J, Bourrat E, et al. Meta-analysis of mutations in ALOX12B or ALOXE3 identified in a large cohort of 224 patients. Genes (Basel). 2021;12(1):80. Israeli S, Khamaysi Z, Fuchs-Telem D, et al. A mutation in LIPN, encoding epidermal lipase N, causes a late-onset form of autosomal-recessive congenital ichthyosis. Am J Hum Genet. 2011;88(4):482–487. Kirchmeier P, Zimmer A, Bouadjar B, Rösler B, Fischer J. Whole-exomesequencing reveals small deletions in CASP14 in patients with autosomal recessive inherited ichthyosis. Acta Derm Venereol. 2017;97(1):102–104. Lefferdink R, Rangel SM, Chima M, et al. Secukinumab responses vary across the spectrum of congenital ichthyosis in adults. Arch Dermatol Res. 2023; 315(2):305–315. Mohamad J, Nanda A, Pavlovsky M, Peled A, Malchin N, Malovitski K, Pramanik R, Weissglas-Volkov D, Shomron N, McGrath J, Sprecher E, Sarig O. Phenotypic suppression of acral peeling skin syndrome in a patient with autosomal recessive congenital ichthyosis. Exp Dermatol. 2020;29(8):742–748. Oji V, Tadini G, Akiyama M, et al. Revised nomenclature and classification of inherited ichthyoses: Results of the first ichthyosis consensus conference in Sorèze 2009. J Am Acad Dermatol. 2010;63(4):607–641. Radner FP, Marrakchi S, Kirchmeier P, et al. Mutations in CERS3 cause autosomal recessive congenital ichthyosis in humans. PLoS Genet. 2013;9(6):e1003536. Scott CA, Rajpopat S, Di WL. Harlequin ichthyosis: ABCA12 mutations underlie defective lipid transport, reduced protease regulation and skin-barrier dysfunction. Cell Tissue Res. 2013;351(2):281–288. Sugiura K, Takeichi T, Tanahashi K, et al. Lamellar ichthyosis in a collodion baby caused by CYP4F22 mutations in a non-consanguineous family outside the Mediterranean. J Dermatol Sci. 2013;72(2):193–195. Sun Q, Burgren NM, Cheraghlou S, et al. The genomic and phenotypic landscape of ichthyosis: An analysis of 1000 kindreds. JAMA Dermatol. 2022;158(1):16–25. Uitto J, Youssefian L, Saeidian AH, Vahidnezhad H. Molecular genetics of keratinization disorders-what’s new about ichthyosis. Acta Derm Venereol. 2020;100(7):adv00095. Vahlquist A, Bygum A, Gånemo A, et al. Genotypic and clinical spectrum of self-improving collodion ichthyosis: ALOX12B, ALOXE3, and TGM1 mutations in scandinavian patients. J Invest Dermatol. 2010;130(2):438–443. van Leersum FS, Seyger MMB, Theunissen TEJ, Bongers EMHF, Steijlen PM, van Geel M. Recessive mosaicism in ABCA12 causes blaschkoid congenital ichthyosiform erythroderma. Br J Dermatol. 2020;182(1):208–211. Wajid M, Kurban M, Shimomura Y, Christiano AM. NIPAL4/ichthyin is expressed in the granular layer of human epidermis and mutated in two Pakistani families with autosomal recessive ichthyosis. Dermatology. 2010;220(1):8–14. Youssefian L, Niaziorimi F, Saeidian AH, et al. Knockdown of SDR9C7 impairs epidermal barrier function. J Invest Dermatol. 2021;141(7): 1754–1764.e1.

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Keratinopathic ichthyoses Congenital reticular ichthyosiform erythroderma (CRIE) Synonyms

• Ichthyosis with confetti • Ichthyosis variegata

Epidemiology

Prevalence T KRT1 mutation in a case of annular epidermolytic ichthyosis. Pediatr Dermatol. 2018;35(6):e414–e415.

Fig. 3.73 

Superficial EI (SEI) Synonym

Ichthyosis bullosa of Siemens.

Epidemiology

There are no available data. The estimated prevalence is 1:500.000.

Age of onset At birth.

Clinical findings

• Milder than EI • At birth, a collodion-like presentation is possible • SEI is defined by a picture of superficial hyperkeratosis and erosions with rare bullae in the first years of life (Figure 3.73). The pattern of diffuse, fine scaling and the contemporaneous presence of desquamative oval-shaped ridges is called mauserung and is typical of SEI (Figures 3.74 and 3.75) • The frequency of the symptoms decreases with growth • No palmoplantar keratoderma • Hypertrichosis • Nails can be dystrophic • These patients may have a discomforting, sweetish, macerative odour • Infections by pyogenes bacteria

Fig. 3.74 

Laboratory findings

On histology, SEI shows hyperkeratosis, acanthosis and epidermolytic changes to the upper spinous and granular layers only.

Genetics and pathogenesis

• The disease is due to mutations in the keratin 2 gene and is autosomal dominant. KRT2 is expressed in the final steps of differentiation, in the uppermost epidermal layers. These mutations cause instability of the keratin network and abnormalities in the formation of the corneocyte envelope

Fig. 3.75 

Atlas of Genodermatoses

54 • The skin of SEI patients is usually fragile and the outer layers of the epidermis have the tendency to peel off, producing localized superficial denuded areas • Recently, three cases of epidermolytic nevi (EN) due to somatic mutations in KRT2 have been described

Differential diagnosis • EI • Ichthyoses

Synonyms

• Mendes da Costa’s disease • Genodermatosis en cocarde • Gottron’s syndrome

Epidemiology 200 µmol/L (normal T (p.Arg266Ter) in the last exon

Course and complications

• Bacterial/fungal superinfection can be present

Follow-up and therapy

Fig. 4.7 

• • • • • •

Keratolytics Retinoids Calcipotriol Antifungal Aluminium potassium sulphate Topical gentamicin as nonsense suppression (readthrough)

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Fig. 4.9  • Vaspin deficiency is associated with increased kallikrein 7 activity, and concomitantly decreased expression of desmoglein-1 and corneodesmosin, which may contribute to the development of keratoderma and peeling skin, respectively

Follow-up and therapy • Keratolytics • Retinoids • Calcipotriol

Bibliography

Fig. 4.8 

Bibliography Huang C, Yang Y, Huang X, Zhou Z. Nagashima-type palmoplantar keratosis: Clinical characteristics, genetic characterization, and clinical management. Biomed Res Int. 2021;2021:8841994. Thomas BR, O’Toole EA. Diagnosis and management of inherited palmoplantar keratodermas. Acta Derm Venereol. 2020;100(7):adv00094. Xiao T, Liu Y, Wang T, Ren J, Xia Y, Wang X. Two novel mutations of SERPINB7 in eight cases of Nagashima-type palmoplantar keratosis in the Chinese population. J Dermatol. 2022;49(5):539–544.

Serpina12 PPK Age of onset

At birth or within first months of life.

Cutaneous findings

• Erythematous diffuse hyperkeratosis of the palms and soles with peripheral peeling (Figure 4.9), extending to the Achilles tendon area and to the anterior part of the leg

Laboratory findings

Histopathology shows marked orthohyperkeratosis, acanthosis and an intact granular layer.

Genetics and pathogenesis

• Autosomal recessive • Loss-of-function mutations in the SERPINA12 gene, encoding vaspin, which is part of the SERPIN family of serine peptidase inhibitors and is predominantly expressed in skin, with a role in the maintenance of normal epidermal differentiation

Mohamad J, Sarig O, Malki L, et al. Loss-of-function variants in SERPINA12 underlie autosomal recessive palmoplantar keratoderma. J Invest Dermatol. 2020;140(11):2178–2187.

Mal De Meleda Synonym

Keratoderma palmoplantaris transgrediens

Age of onset

From birth to the third year of life

Cutaneous findings

• Diffuse, ivory-yellow sharply demarcated PPK developing on the erythematous base and extending to the backs of the hands and feet with a glove and sock distribution: transgrediens and progrediens keratoderma (Figures 4.10–4.12) • Hyperkeratotic plaques causing maceration and malodour • Lesions on the elbows and knees • Perioral hyperkeratosis and erythema • Subungual keratosis and nail abnormality (koilonychia and pachyonychia) • Flexion contractures can occur and constrictive bands can lead to spontaneous amputation

Laboratory findings

• Histopathologic findings: hyperorthokeratosis, hypergranulosis and acanthosis with pseudospongiosis • Bone radiography

Palmoplantar Keratodermas

95 Genetics and pathogenesis

Fig. 4.10 

• Autosomal recessive inheritance • Caused by mutations in the ARS gene encoding the SLURP-1 protein that belongs to a superfamily of receptors and secreted proteins that participate in signal transduction, immune cell activation and cellular adhesion • SLURP-1 stimulates nicotinic acetylcholine receptors, which regulate keratinocyte growth; when SLURP-1 is not functioning, it is thought that there is a reduction in keratinocyte apoptosis regulation • SLURP-1 acts as a neuromodulator, which is probably relevant in the modulation of the proliferation of the keratinocytes and in preventing inflammatory cascades determined by TNF-α, thus explaining both the hyperproliferative and the inflammatory phenotypes of the disease • Female heterozygotes can also present with a mild phenotype

Differential diagnosis

• Vohwinkel syndrome • Papillon-Lefevre syndrome • Olmsted syndrome

Course and complications • • • • • •

The disease is slowly progressive with a normal lifespan. Pseudoainhum with amputation of fingers Secondary infections (mycotic) Painful fissures Flexion contractures of fingers Predisposition to skin malignancies is rarely described

Follow-up and therapy • • • • •

Oral retinoids Keratolytics Bacterial/fungal superinfection treatment Surgery for pseudoainhum Biological therapy (ixekizumab) may be a potential strategy

Bibliography

Fig. 4.11 

Chhabra G, Verma P, Sharma S. Mal de Meleda palmoplantar keratoderma with pseudoainhum. Skinmed. 2021;19(5):383–384. Pospischil I, Enzelsberger K, Gross S, Hoetzenecker W, Fischer TW. Mal de Meleda: Diagnostic work-up and therapy with low-dose acitretin. Acta Derm Venereol. 2022;102:adv00758.

Keratolytic winter erythema See Chapter 3.

Diffuse hereditary PPKs: with associated features Keratoderma hereditaria mutilans Synonym

Vohwinkel syndrome.

Age of onset Infancy.

Cutaneous findings

Fig. 4.12 

• Hyperkeratosis of the palms and soles with a characteristic honeycomb appearance (Figures 4.13 and 4.14) • Star-shaped keratotic plaques on the dorsa of the hands and feet, elbows, knees and knuckles (Figure 4.15)

Atlas of Genodermatoses

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Fig. 4.13 

Fig. 4.16  Fig. 4.14 

• Myopathy • Cognitive impairment • Epilepsy (very rare)

Laboratory findings

• Histopathology: hyperkeratosis, marked parakeratosis, hypergranulosis, and acanthosis (not diagnostic) • Radiography of phalanges

Genetics and pathogenesis

Fig. 4.15  • Constricting fibrous bands (pseudoainhum) encircling the digits of the hands and feet with possible auto-amputation (Figures 4.15 and 4.16) • Occasional scarring alopecia

Extracutaneous findings

• Hearing loss of varying severity (related to non-ichthyotic classical presentation and with connexin 26 mutations) • Spastic paraplegia

• Autosomal dominant fashion, occasionally recessive • Mutations in the GJB2 gene encoding connexin 26 (epithelial-mesenchymal interaction protein) are related to classical dominant pedigrees with severe sensorineural deafness • Gap junctions are present in the skin and inner ear; mutations in junction genes lead to abnormal keratinocyte differentiation/growth and dysfunctional inner ear potassium ion recycling required for hearing • G59R loss-of-function mutation in connexin 30 (GJB6) is linked to Vohwinkel syndrome, whereas Bart-Pumphrey variant (knuckle pads, leukonychia and deafness) is a further eponym describing a syndromic presentation due to connexin 26 and 30 mutations (Figures 4.17 and 4.18) • Non-syndromic presentation of Bart-Pumphrey may be due also to GJA1 (connexin 43) mutations • Mutations in gene encoding for loricrin with abnormality of a structural component of cornified envelope and diffuse ichthyotic presentation are responsible for cases of keratoderma mutilans unrelated to deafness

Palmoplantar Keratodermas

97 Loricrin keratoderma (LK) Synonyms

• Camisa syndrome • Honeycomb PPK with ichthyosis

Age of onset

At birth or during infancy.

Cutaneous findings

• Diffuse honeycomb-like PPK with or without digital constriction (pseudoainhum) (Figures 4.19 and 4.20) • Mild generalized congenital ichthyosis (Figure 4.21) • Collodion baby has been reported • Prominent knuckle pads

Extracutaneous findings Hearing is intact. Fig. 4.17 

Laboratory findings

Parakeratotic hyperkeratosis with hypergranulosis and nuclear accumulation of mutant loricrin.

Fig. 4.18 

Differential diagnosis

• Olmsted syndrome • Pachyonychia congenita • Mal de Meleda

Fig. 4.19 

Course

There is persistent keratoderma with loss of digits around the second decade.

Follow-up and therapy

• Normal lifespan • Oral and topical retinoids may prevent loss of digits and disability • Keratolytics • Surgical release of constriction bands

Bibliography Mercy P, Singh A, Ghorpade AK, Das MN, Upadhyay A, Keswani N. Vohwinkel syndrome with mental retardation. Indian J Dermatol Venereol Leprol. 2013;79(5):725. Saleh D, Tanner LS. Vohwinkel syndrome. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022 Jan.

Fig. 4.20 

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Bibliography Montero-Vilchez T, Martinez-Lopez A, Rodriguez-Tejero A, SalvadorRodriguez L, García-Durá E, Molina-Leyva A, Arias-Santiago S. Loricrin keratoderma: Description of a novel mutation, systematic review and meta-analysis between genotypic and phenotypic features. J Dtsch Dermatol Ges. 2020;18(11):1316–1321. Nomura T. Recombination-induced revertant mosaicism in ichthyosis with confetti and loricrin keratoderma. J Dermatol Sci. 2020;97(2):94–100. doi: 10.1016/j.jdermsci.2019.12.013. Epub 2019 Dec 31. PMID: 31928837.

Huriez syndrome Synonyms

• PPK with sclerodactyly • Sclerotylosis

Age of onset

At birth or in infancy.

Cutaneous findings

• Scleroatrophy of the hands with sclerodactyly (main feature) (Figures 4.22 and 4.23) • PPK (main feature) (Figure 4.24), with red skin and the more severe involvement in palms than the soles • Nail changes consisting of hypoplasia, ridging, clubbing and white discolouration • Palmar hypohidrosis (50%)

Fig. 4.21 

Genetics and pathogenesis

• Autosomal dominant inheritance • Four different mutations in the loricrin gene (LOR) have been reported to date, with all mutations being single base-pair insertions: the unique mutations in the glycine-rich domain of the mutant LOR form arginine-rich nuclear localization sequences disrupts differentiation of keratinocytes • The heterogeneous phenotypes of LK might be related to differences in the intensity of LOR expression or to polymorphisms in the LOR gene • Revertant mosaicism developing numerous revertant skin patches has been described in LK, as well as in ichthyosis with confetti (see Chapter 3)

Fig. 4.22 

Differential diagnosis Vohwinkel syndrome.

Follow-up and therapy • • • • •

Normal lifespan Retinoids may prevent loss of digits and disability Keratolytics Surgical release of constriction bands Vascular endothelial growth factor 2 receptor inhibitors may have a role in the future

Fig. 4.23 

Palmoplantar Keratodermas

Fig. 4.24  • Atrophic plaques on the dorsa of the hands and fingers and sclerodermatous appearance • Poikiloderma-like changes of the nose • Telangiectasia on the lips

Extracutaneous findings

• Flexion contractures of the little finger • Normal teeth

Laboratory findings

Histopathologic findings: Hyperorthokeratosis and slight acanthosis; mild dermal fibrosis; absence of Langerhans’ cells in the involved skin.

Genetics and pathogenesis

• Autosomal dominant inheritance • Aploinsufficiency in the SMARCAD1 gene, an ATPdependent chromatin remodeller of the Snf2 ATPase family • Huriez syndrome, adermatoglyphia and Basan syndrome are allelic disorders due to SMARCAD1 mutations with variable expressivity • Palmoplantar hyperkeratosis with squamous cell carcinoma (SCC) of skin and sex reversal is similar to Huriez syndrome as it is a mild PPK with sclerodactyly and nail hypoplasia, predisposition for cutaneous SCC and laryngeal SCC; periodontitis with loss of teeth may be present. Autosomal recessive, caused by mutations in the RSPO1 gene, which is responsible for stabilizing β-catenin in the Wnt signalling pathway, which antagonizes SRY/SOX9 actions for sex determination. A characteristic feature is the female-tomale sex reversal seen in females with karyotype 46, XX. WNTs are related to female sex development (as in SERKAL syndrome, a very rare non-cutaneous disorder with female sex reversal) and to normal epithelial development, causing other hereditary skin disorders, such as Goltz syndrome and WNT-related ectodermal dysplasias (see Chapter 11) • A homozygous variant in the SASH1 gene has been identified in a consanguineous Moroccan family with two affected siblings presenting an abnormal pigmentation pattern (hypo- and hyperpigmented macules of the trunk and face and areas of reticular hypo- and hyperpigmentation of the extremities), alopecia, PPK, ungueal dystrophy and recurrent spinocellular carcinoma; heterozygous

99

Fig. 4.25  SASH1 variants are known to cause autosomal-dominant dyschromatosis (see Chapter 15)

Differential diagnosis

• Werner syndrome • Kindler syndrome • Schöpf-Schulz-Passarge syndrome

Course and complications

• Lesions persist unchanged throughout life. • 100-fold increased risk of developing SCC in the affected skin during the third or fourth decade of life (main feature) (Figure 4.25)

Follow-up and therapy

• Lifelong follow-up is necessary because the higher risk of skin cancer and consequent mortality of affected individuals • Retinoids may be helpful for the PPK and prevention of SCC • Early surgical excision of suspicious lesions • Chemotherapy, immunotherapy and cemiplimab for SCC

Bibliography Courcet JB, Elalaoui SC, Duplomb L, et al. Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma. Eur J Hum Genet. 2015;23(7):957–962. Dellambra E, Cordisco S, Delle Monache F, et al. RSPO1-mutated keratinocytes from palmoplantar keratoderma display impaired differentiation, alteration of cell-cell adhesion, EMT-like phenotype and invasiveness properties: Implications for squamous cell carcinoma susceptibility in patients with 46XX disorder of sexual development. Orphanet J Rare Dis. 2022;17(1):275. Günther C, Lee-Kirsch MA, Eckhard J, et al. SMARCAD1 haploinsufficiency underlies Huriez syndrome and associated skin cancer susceptibility. J Invest Dermatol. 2018;138(6):1428–1431. Loh AYT, Špoljar S, Neo GYW, et al. Huriez syndrome: Additional pathogenic variants supporting allelism to SMARCAD syndrome. Am J Med Genet A. 2022;188(6):1752–1760. Tallapaka K, Venugopal V, Dalal A, Aggarwal S. Novel RSPO1 mutation causing 46,XX testicular disorder of sex development with palmoplantar keratoderma: A review of literature and expansion of clinical phenotype. Am J Med Genet A. 2018;176(4):1006–1010.

Atlas of Genodermatoses

100 Olmsted syndrome Epidemiology

Less than 100 cases have been published; the prevalence is likely to be less than 1/1.000.000.

Age of onset

Either soon after birth or in childhood.

Cutaneous findings

• Bilateral symmetric transgrediens PPK: the keratoderma is thick and sharply demarcated with deep, painful fissures and surrounded by an erythematous rim; ainhum-like constrictions of digits may lead to spontaneous amputation (Figures 4.26–4.28) • Periorificial keratotic plaques (Figures 4.29 and 4.30) • The plaques are symmetrical, yellow-brown in colour and sharply demarcated • Alopecia • Nail dystrophy (Figure 4.31) • Hyperhidrosis of palms and soles • Hyperkeratotic linear streaks • Keratosis pilaris • Leukokeratosis

Fig. 4.28 

Fig. 4.29 

Fig. 4.26 

Fig. 4.30 

Extracutaneous findings

Fig. 4.27 

• • • • • •

Teeth dystrophy Joint laxity Osteoporosis Growth retardation Corneal anomalies Immunodeficiency and lung cancer have been reported

Palmoplantar Keratodermas

101 • Mal de Meleda • Keratoderma hereditaria mutilans (Vohwinkel syndrome)

Course

The disease is slowly progressive with increasing keratoderma of the palms and soles. Melanoma and SCC may appear in hyperkeratotic areas.

Follow-up and therapy

The ever-increasing hyperkeratosis results in:

Fig. 4.31 

Laboratory findings

Histopathologic features of PPK are not diagnostic. Immunohistochemical studies have identified cytokeratin abnormalities that consist of staining involving the entire thickness of the epidermis with cytokeratin AE1 (normally, this cytokeratin only stains the basal layer).

• Progressive contractures of fingers • Difficulty in walking or grasping • Cosmetic disfigurement • Treatment in general is difficult with variable response to systemic retinoids • Topical anti-inflammatories can be helpful for hyperkeratosis and itching • Surgery with excision and grafting of the keratoderma can lead to more favourable long-term outcomes • Erlotinib, the EGFR inhibitor, may represent an effective and novel treatment for pain and PPK in patients with OS and TRPV3 mutations • An attempt to formulate a stable 0.2% erlotinib cream has been reported

Genetics and pathogenesis

• Autosomal dominant, autosomal recessive, semi-dominant and X-linked recessive (XLR) forms have been described caused by mutations in different genes • TRPV3 gene mutation, encoding a protein involved in calcium entry associated with the TGF-α/EGFR signalling complex that orchestrates keratinocyte terminal differentiation. Functional studies of the human mutations have shown that these are gain-of-function mutations that promote calcium influx and apoptosis, thereby providing a link between TRPV3 and the clinical features of abnormal keratinization. • Missense mutations in the MBTPS2 gene are involved in the X-linked form of Olmsted syndrome. MBTPS2 is a membrane-bound transcription factor protease that activates, by intramembranous trimming in conjunction with the protease MBTPS1, regulatory factors involved in sterol control of transcription and in cellular stress responses. Missense mutations in MBTPS2 have been associated with IFAP/KFSD syndrome and BRESEK/BRESHECK syndrome • There is no obvious clinical difference between OS caused by TRPV3 and MBTPS2 mutations despite the mode of inheritance • Recently another gene has been linked to Olmsted syndrome: monoallelic nonsense mutations in PERP gene, encoding p53 effector related to PMP-22 (PERP), tetraspan member protein that is both an apoptosis mediator and a component of epidermal desmosomes and other cell junctions

Differential diagnosis

• Acrodermatitis enteropathica (periorificial lesions) • Hidrotic ectodermal dysplasia (Clouston syndrome) • Pachyonychia congenita

Bibliography Duchatelet S, Boyden LM, Ishida-Yamamoto A, et al. Mutations in PERP cause dominant and recessive keratoderma. J Invest Dermatol. 2019; 139(2):380–390. Youssefian L, Khodavaisy S, Khosravi-Bachehmir F, et al. Ichthyosis, psoriasiform dermatitis, and recurrent fungal infections in patients with biallelic mutations in PERP. J Eur Acad Dermatol Venereol. 2022;36(3):472–479. Nguyen D, Secrétan PH, Cotteret C, et al. Stability and formulation of erlotinib in skin creams. Molecules. 2022;27(3):1070. Spitz KE, Chu L, Lawley LP. Treatment of TRPV3 mutation-associated Olmsted syndrome with erlotinib. JAAD Case Rep. 2022;25: 83–85.

Papillon-Lefevre syndrome Synonyms

• PPK with periodontitis • Diffuse keratoderma with periodontopathy

Epidemiology

About 300 cases have been reported worldwide.

Age of onset

Between 6 months and 4 years of age.

Cutaneous findings

• Diffuse transgrediens palmoplantar erythrokeratoderma (main feature) (Figures 4.32 and 4.33) • Erythematous scaly lesions over the knees, elbows and interphalangeal joints (Figure 4.34) • Palmoplantar hyperhidrosis with fetid odour • Bacterial skin infections

Atlas of Genodermatoses

102 Extracutaneous findings

• Rapidly progressive periodontitis and severe alveolar bone destruction leading to early loss of both deciduous and permanent teeth (main feature) (Figures 4.35 and 4.36) • Mild physical and mental retardation • Calcifications of dura mater and falx cerebri • Pyogenic liver abscesses

Laboratory findings

• Histopathological findings are non-specific • Cranial radiography and orthopantomography • Impaired leukocyte function involving chemotactic and phagocytic activity

Genetics and pathogenesis Fig. 4.32 

• Autosomal recessive inheritance • The mutated gene is called CTSC, coding for the cathepsin C protein, which is involved in protein degradation and proenzyme activation, expressed in the palms, soles, alveolar bone and keratinized gingiva • Haim-Munk syndrome in an allelic condition, characterized also by arachnodactyly, onychogryphosis and acro-osteolysis

Fig. 4.33 

Fig. 4.35 

Fig. 4.34 

Fig. 4.36 

Palmoplantar Keratodermas

103

Differential diagnosis

• Mal de Meleda disease • Olmsted syndrome • Schöpf-Schulz-Passarge syndrome

Course

• Increased susceptibility to infections (20%) • Persistent keratoderma with winter worsening

Follow-up and therapy

• Cutaneous and dental lesions may improve with oral retinoids • Specialist dental care • Low-dose tetracycline may be helpful for gingivitis, even at subtherapeutic doses • Keratolytic agents • Dimethyl fumarate, used in psoriasis, could be a new valid option for treating PPK in resistant cases

Bibliography

Fig. 4.37 

Adamski Z, Burchardt D, Pawlaczyk-Kamieńska T, Borysewicz-Lewicka M, Wyganowska-Świątkowska M. Diagnosis of Papillon-Lefèvre syndrome: review of the literature and a case report. Postepy Dermatol Alergol. 2020;37(5):671–676. Al-Omair A, Alharbi M, Almesfer A. Dimethyl fumarate for treating Papillon-Lefèvre syndrome. JAAD Case Rep. 2022;31:19–22. Balestri R, Magnano M, Savoia F, Patrizi A, Neri I. Alitretinoin for palmoplantar keratodermas: A novel case and review of the literature. Dermatol Ther. 2019;32(2):e12794. Upadhyaya JD, Pfundheller D, Islam MN, Bhattacharyya I. PapillonLefèvre syndrome: A series of three cases in the same family and a literature review. Quintessence Int. 2017;48(9):695–700.

CEDNIK syndrome See Chapter 3.

ARKID syndrome See Chapter 3.

Focal hereditary PPKs: no associated features Striate keratoderma Synonym

Brunauer-Fuchs’ disease.

Age of onset

Plantar involvement is usually focal and starts early in life (i.e., first or second year), whereas the palmar changes follow.

Cutaneous findings

• Linear keratotic lesions along the palmar surfaces of the fingers (Figure 4.37) • Diffuse pattern (keratotic plaques) on the soles (Figure 4.38)

Laboratory findings

Histopathologic findings include orthokeratotic hyperkeratosis and acantholysis of keratinocytes pointing to a desmosomal mutation.

Genetics and pathogenesis

• Autosomal dominant inheritance • Striated PPK type 1: due to heterozygous mutations of the DSG1 gene, coding for desmoglein 1, a major component of desmosomes

Fig. 4.38  • Striated PPK type 2: due to a mutation of the DSP1 gene, coding for desmoplakin, resulting in a premature termination codon with alteration in the intercellular adhesion • Striated PPK type 3: due to the KRT1 gene mutations that disrupt the intermediate filament network • If patients exhibit woolly/curly hair or abnormal dentition, associated cardiomyopathy should be considered (see Naxos-Carvajal syndrome later in the chapter) • A case of acantholytic dyskeratotic epidermal naevus associated with striate PPK carrying a heterozygous DSG1 mutation has been reported, suggesting a type-2 segmental mosaicism

Differential diagnosis Other PPKs.

Course

Stable lesions are increased by mechanical trauma.

Follow-up and therapy • Keratolytics • Oral retinoids

Atlas of Genodermatoses

104 Bibliography Blecic AS, Pernin J, Jonca N, et al. Acantholytic dyskeratotic epidermal naevus and striate palmoplantar keratoderma associated with DSG1 mutation: Evidence for segmental type 2 mosaicism. J Eur Acad Dermatol Venereol. 2021;35(6):e385–e387. Vodo D, O’Toole EA, Malchin N, et al. Striate palmoplantar keratoderma resulting from a missense mutation in DSG1. Br J Dermatol. 2018;179(3):755–757. Wan H, Dopping-Hepenstal PJ, Gratian MJ, et al. Striate palmoplantar keratoderma arising from desmoplakin and desmoglein 1 mutations is associated with contrasting perturbations of desmosomes and the keratin filament network. Br J Dermatol. 2004;150(5):878–891.

Focal hereditary PPKs: with associated features See Chapter 22.

Howel-Evans syndrome

Fig. 4.40 

Tyrosinaemia type II Synonym

Richner-Hanhart syndrome.

Age of onset

From early infancy to childhood.

Cutaneous findings

• Circumscribed, painful arched hyperkeratotic lesions on the palms and soles mainly located on the fingertips, where they show a peculiar glyphic pattern (Figures 4.39 and 4.40), hypothenar or thenar eminences and weight-bearing plantar surfaces (plaque-like lesions), leading to impaired ambulation (Figure 4.41) • Hyperkeratotic plaques on the elbows and knees • Linear keratotic plaque on the lips (Figure 4.42) • Hyperhidrosis • Leukokeratosis of the tongue • Abnormalities of the hair shafts can be detected in some patients (Figure 4.43)

Fig. 4.39 

Fig. 4.41 

Fig. 4.42 

Palmoplantar Keratodermas

105 Course

Without a special diet, the disease is progressive and death occurs before adulthood.

Follow-up and therapy

• The dietary regimen must be continued for the patient’s entire life. Early dietary intervention may prevent or limit cutaneous and ocular manifestations, but not mental retardation, and may prolong life • Low-tyrosine and low-phenylamine diet as early as possible • Systemic retinoids

Bibliography

Fig. 4.43 

Ghalamkarpour F, Niknezhad N, Niknejad N. Familial Richner-Hanhart syndrome: Report of a sibling with incomplete presentation. Dermatol Ther. 2020;33(6):e14072. Rossi LC, Santagada F, Besagni F, Cambiaghi S, Colombo E, Brena M, Tadini G. Palmoplantar hyperkeratosis with a linear disposition along dermatoglyphics: A clue for an early diagnosis of tyrosinemia type II. G Ital Dermatol Venereol. 2017;152(2):182–183. Thibault LP, Mitchell GA, Parisien B, Hamel P, Blanchard AC. An infant with bilateral keratitis: From infectious to genetic diagnosis. Am J Case Rep. 2022;23:e937967.

See Chapter 8.

Pachyonichia congenita

Palmoplantar Keratoderma-Cardiomyopathy Synonym

• Naxos-Carvajal syndromes

Epidemiology Fig. 4.44 

Very few pedigrees have been reported since the first family on the island of Naxos, Greece and from Ecuador (Carvajal).

Extracutaneous findings

Age of onset

• Corneal erosions and ulcerations developing within the first months of life lead to severe keratosis and blindness (Figure 4.44) • Intellectual disability and neurological signs in 50% of patients

Laboratory findings

• Increased tyrosine levels in plasma and urine due to deficiency of hepatic tyrosine aminotransferase deficiency • Histopathologic findings: marked orthohyperkeratosis and hypergranulosis, acantholysis (not diagnostic) • Ultrastructural findings: intracytoplasmic tyrosine crystals

Genetics and pathogenesis

• Autosomal recessive disorder • Disease caused by mutations of the tyrosine aminotransferase gene (TAT) that cause a deficiency of the hepatic enzyme tyrosine aminotransferase, leading to the accumulation of tyrosine in all tissues

Differential diagnosis

• Other painful PPKs • Skin and eye manifestations absent in tyrosinaemia I

• • • • •

Cardiac defects at birth (Carvajal) Woolly, curly hair since early childhood Plantar defects during childhood Palmar hyperkeratosis during adolescence Arrhythmogenic right ventricular cardiomyopathy in early adulthood (Naxos) with 100% penetrance

Cutaneous findings

• Thick and yellowish plantar keratoderma, especially over the pressure areas (Figures 4.45 and 4.46), and striated palmar keratoderma in others (Figure 4.47) • Hyperkeratotic and even painful hyperkeratotic lesions over the interphalangeal joints • Acanthosis nigricans • Diffuse xerosis and follicular hyperkeratosis may be present • Palmoplantar hyperhidrosis • Dredding with curly and difficult-to-comb hair that is light brown, soft, and matted (Figure 4.48) • Other body hair is sparse • Hypo/oligodontia is rarely reported in autosomal dominant pedigrees

Atlas of Genodermatoses

106

Fig. 4.45 

Fig. 4.48 

Extracutaneous findings

• Mild-to-very-severe heart defects (left ventricular or biventricular cardiomyopathy in Carvajal syndrome, right ventricular cardiomyopathy mimicking arrhythmogenic right ventricular dysplasia in Naxos syndrome) • Increased risk of sudden-death mortality • Hypo/oligodontia is rarely reported in autosomal dominant pedigrees with desmoplakin mutations

Laboratory investigations

Fig. 4.46 

• Echocardiography may reveal early ventricular dysfunction • Scanning electron microscopy reveals flattening and twisting of hair shafts • Histological examination may show epidermal acantholysis in samples derived from palmo-plantar biopsies

Genetics and pathogenesis

Fig. 4.47 

• Autosomal recessive inheritance (Naxos), both recessive and dominant (Carvajal) • Naxos syndrome: mutations of the JUP gene encoding plakoglobin, a molecule that contributes to the desmosomal structure, are demonstrated in some pedigrees. Plakoglobin is present in epidermal and neuromuscular structures (i.e., as plectin does), directly causing both epidermal and cardiac defects • JUP gene anomalies are also involved in cases of lethal skin fragility and in skin fragility-wooly-hair syndrome without cardiomyopathy • Carvajal syndrome: autosomal dominant and recessive; the causal gene is DSP gene, encoding a further component of desmosome, desmoplakin. Carvajal syndrome is like Naxos, although the cardiomyopathy presents earlier in the teens and is usually biventricular

Palmoplantar Keratodermas • The KANK2 gene can cause woolly hair, hypotrichosis and a PPK without cardiac involvement. KANK2 encodes the steroid receptor coactivator (SRC)-interacting protein (SIP), which sequesters SRCs in the cytoplasm and controls transcription activation of steroid receptors, among others, also of the vitamin D receptor (VDR) and important components of epidermal differentiation • Patients with a striate keratoderma/PPK and woolly hair should have cardiac investigations. Family members should also be screened as these can have autosomal recessive or autosomal dominant inheritance

107 Cutaneous findings

• Numerous yellow-to-dark brown, 2–10 mm, round, isolated asymptomatic keratotic papules with a central keratinic plug (Figures 4.49–4.51) • Lesions may be represented by tiny plugs confined to palmar and digital creases, seen mostly in the Black population (Figure 4.52) • Occasional nail abnormalities: longitudinal fissuring, onychogryphosis and onychomadesis • Diffuse xerosis

Other desmosomal genodermatoses are listed below: • Desmocollin-2 is related to wooly hair, keratoderma, cardiomyopathy phenotype • Desmoglein-1 mutations in striate PPK and Unna–Thost– Vorner phenotypes • Desmoglein 4 mutations in recessive monilethrix and localized recessive hypotrichosis • Corneodesmosin is related to recessive hypotrichosis simplex and to dominant generalized peeling skin syndrome • Plakophilin 1 described in skin fragility-ectodermal dysplasia syndrome (see Chapter 11)

Differential diagnosis

• Isolated, uncombable and woolly hair • Other PPKs

Fig. 4.49 

Course

• Cardiac fibromuscular dysplasia may lead to right-side cardiac failure in some pedigrees • High risk of sudden death • Lifelong skin defects

Follow-up and therapy

• Early echocardiography for monitoring right-sided cardiac defects • Acitretin therapy for palmoplantar changes • Keratolytics and emollients for hyperkeratosis and xerosis

Bibliography Sun Q, Wine Lee L, Hall EK, Choate KA, Elder RW. Hair and skin predict cardiomyopathies: Carvajal and erythrokeratodermia cardiomyopathy syndromes. Pediatr Dermatol. 2021;38(1):31–38. Yao JV, Winship I. More than meets the eye: Palmoplantar keratoderma and arrhythmogenic right ventricular cardiomyopathy in a patient with loss of the DSP gene. JAAD Case Rep. 2020;6(9):804–806.

Fig. 4.50 

Papular hereditary PPK: no associated features Punctate PPK Synonyms

• Keratosis palmaris and plantaris punctata • Buschke-Fischer-Brauer disease

Epidemiology

1 in 100.000 people.

Age of onset

Usually from the second to the fourth decade of life.

Fig. 4.51 

Atlas of Genodermatoses

108

Bibliography Bukhari R, Alhawsawi W, Radin AA, Jan HD, Al Hawsawi K, Al Ahmadi M. Punctate palmoplantar keratoderma: A case report of type 1 (Buschke-Fischer-Brauer Disease). Case Rep Dermatol. 2019;11(3):292–296. Harjama L, Karvonen V, Kettunen K, et al. Hereditary palmoplantar keratoderma - phenotypes and mutations in 64 patients. J Eur Acad Dermatol Venereol. 2021;35(9):1874–1880. Hasegawa A, Hayashi R, Shimomura Y, Hirashima M, Abe R. Only plantar lesion of punctate palmoplantar keratoderma with a novel missense mutation in the AAGAB gene: Two Japanese familial case reports and review of reported mutations. J Dermatol. 2021;48(12):1926–1930.

Fig. 4.52 

Extracutaneous findings

• Rarely associated with malignancies such as breast cancer, prostatic carcinoma, Hodgkin’s disease, colonic adenocarcinomas and metastatic non-small-cell carcinoma of the lung • Atopy • Spastic paralysis • Ankylosing spondylitis

Laboratory findings

• Histopathologic findings include marked hyperkeratosis, hypergranulosis and acanthosis with a mild inflammatory dermal infiltrate around the dermal vessels • Ultrastructural analysis of lesional skin shows mild acanthosis, a reduction in the granular cell layer and compact orthokeratosis. In basal keratinocytes, a large increase in the number of small vesicles close to the cell membrane is detectable, with a prominent dilatation of the Golgi apparatus. These ultrastructural features are consistent with a defect in vesicle transport

Acrokeratoelastoidosis Synonym

Inverse papular acrokeratosis.

Age of onset

Childhood or adolescence.

Cutaneous findings

• Small, yellowish, firm, smooth, translucent, asymptomatic crateriform papules characteristically localized on the boundary between the dorsal and palmar or plantar skin and on the dorsa of the fingers; often confluent to form plaques (Figures 4.53 and 4.54) • Occasional hyperhidrosis

Genetics and pathogenesis

• Autosomal dominant inheritance with variable penetrance • The causal gene in one-third of patients is AAGAB, which encodes the α- and γ-adaptin-binding protein p34, involved in recycling of EGFR proteins, and impairment in this function leads to keratinocyte proliferation • An additional disease-associated gene is COL14A1, which encodes collagen XIV (CXIV) a fibril-associated collagen with an interrupted triple helix. It interacts with the fibril surface and regulates fibrillogenesis. The CXIV receptor is a chondroitin sulphate variant of CD44; the adherence with hyaluronic acid plays an important role in the regulation of keratinocyte proliferation

Fig. 4.53 

Differential diagnosis

• Punctate porokeratosis • Basal cell nevus syndrome • Acrokeratosis verruciformis

Course

• This is a slowly progressive disease • Periodic follow-up is recommended

Follow-up and therapy • Keratolytics • Oral retinoids

Fig. 4.54 

Palmoplantar Keratodermas

109

Laboratory findings

• Histopathologic findings include epidermal hypertrophy with acanthosis and marked hyperkeratosis, as well as coarse fragmentation of the elastic fibres in the reticular dermis • Electron microscopic studies show that fibroblasts within the reticular dermis are reduced in number and contain abnormally dense granules, representing precursors of elastin fibres in or near the plasma membrane

Genetics and pathogenesis

• Autosomal dominant inheritance, occasionally sporadic • Possible linkage to chromosome 2

Differential diagnosis • • • •

Focal acral hyperkeratosis Keratoelastoidosis marginalis of the hands Acrokeratosis verruciformis Degenerative collagenous plaques of the hands

Course

• Slow, gradual increase of the lesions over several years • Rapid extension in pregnancy

Follow-up and therapy • Keratolytics • Oral retinoids • Erbium laser

Bibliography Dumont M, Hickman G, Hovnanian A, Bagot M, Bourrat E, Petit A. "African" acral keratoderma: Further evidence for a single entity. A retrospective study of 42 patients. Ann Dermatol Venereol. 2022:S0151-9638(22)00081-3. Sonthalia S, Aboobacker S. Acrokeratoelastoidosis. 2022 May 11. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. Żychowska M, Batycka-Baran A, Baran W. Acrokeratoelastoidosis as an example of marginal popular acrokeratoderma with prominent elastorrhexis. Postepy Dermatol Alergol. 2019;36(6):772–774.

Fig. 4.55 

Papular hereditary PPKs: with associated features Cole disease Synonym

Punctate keratoderma, patchy hypopigmentation, and cutaneous calcification.

Epidemiology

Following the initial description in 1976, less than 20 cases have been reported.

Age of onset

Usually within the first year of life, rarely at birth.

Cutaneous findings

• Punctate keratoderma (Figure 4.55) • Ovalar or irregularly shaped hypopigmented macules, particularly on the arms and legs, sparing the trunk or acral areas, that are 1–3 cm wide (Figure 4.56) • Calcinosis cutis (in a minority of patients) • Transient plantar blisters in a single report

Fig. 4.56 

Atlas of Genodermatoses

110

Pachydermoperiostosis

Extracutaneous findings

• Early-onset calcific multiple tendinopathies • Less frequently, microcalcifications in the mammary glands and internal organs

Laboratory findings

• Skin biopsies from plantar regions show aspecific acanthosis, hyperorthokeratosis and hyper- granulosis • Biopsies from hypopigmented macules reveal normal numbers of melanocytes and a normal melanin content in the melanocytes, but a low melanin content in keratinocytes and hyperkeratosis • At the ultrastructural level, melanocytes are replete with melanosomes in the cytoplasm and dendrites but, by contrast, keratinocytes appear with a paucity of these specific organelles

Genetics and pathogenesis

• Autosomal dominant inheritance • Heterozygous mutations in the ENPP1 gene, encoding ectonucleotide pyrophosphatase/phosphodiesterase 1, which is responsible for the generation of pyrophosphate, a potent inhibitor of mineralization, leading to calcification • The mutations affect the somatomedin-B-like domain of the protein that is involved in insulin signalling that may interact with epidermal growth factor in the epidermal homeostasis, explaining the hyperkeratosis • The insulin pathway also regulates melanosome uptake via PAR-2, leading to hypopigmentation • Biallelic mutations of ENPP1 are demonstrated in other recessive conditions with ectopic calcification or abnormal calcium metabolism, such as generalized arterial calcification of infancy (GACI), autosomal recessive hypophosphataemic rickets type 2 (ARHR2) and pseudoxanthoma elasticum (PXE)

Course and prognosis

The disease is stable during life, with a normal life expectancy.

Follow-up and therapy

• X-rays and echotomography to detect ectopic calcifications in the tendons and internal organs • Survey of glycaemia and mineral metabolism

Synonyms

• Primary hypertrophic osteoarthropathy (PHO) • Touraine-Solente-Golé syndrome

Age of onset

The age of disease onset has a bimodal distribution, the initial peak being in the first year of life and the other during puberty; male:female ratio 9:1.

Cutaneous findings

• Soft-tissue hypertrophy resulting in marked thickening and furrowing of the skin of the face, eyelids (coarse facial features, 60%) and scalp (cutis verticis gyrate, 24%) • Increased seborrhoea (33%) • Thickening of the skin of the hands and feet with hyperhidrosis (24%) (Figure 4.57) • Watch glass appearance of the nails (90%) • Papular mucinosis

Extracutaneous findings

• Digital clubbing (89%) and spade-like enlargement of the hands and feet due to soft-tissue hyperplasia and periosteal proliferation (radiologically evident in 97% of patients) • Cylindrical thickening of the legs and forearms • Peptic ulcer • Mental retardation • Gynecomastia • Extramedullary haematopoiesis • SCC

Laboratory findings

• Radiographic examination: prominent periostosis of the metatarsals, metacarpals and long bones of the limbs • Histopathology findings: marked thickening of the dermis with hypertrophy of collagen and an increase of acid mucopolysaccharide

Genetics and pathogenesis

• Both autosomal dominant and recessive inheritance • The HPGD gene, which encodes 15-hydroxy-prostaglandin dehydrogenase, is associated with the disease

Differential diagnosis • • • •

Other punctate keratoderma Progressive osseous heteroplasia Tuberous sclerosis Pityriasis rotunda

Bibliography Eytan O, Morice-Picard F, Sarig O, et al. Cole disease results from mutations in ENPP1. Am J Hum Genet. 2013;93(4):752–757. Ralph D, Levine MA, Richard G, Morrow MM, Flynn EK, Uitto J, Li Q. Mutation update: Variants of the ENPP1 gene in pathologic calcification, hypophosphatemic rickets, and cutaneous hypopigmentation with punctate keratoderma. Hum Mutat. 2022;43(9): 1183–1200.

PLACK syndrome See Chapter 3.

Fig. 4.57 

Palmoplantar Keratodermas

111

• HPGD is the enzyme responsible for the breakdown of PGE2 in the pulmonary vasculature, to induce transcription of VEGF in osteoblasts and stimulates bone formation; it activates endothelial cells, which increase transcription of VEGF and promote local angiogenesis • The SLCO2A1 gene, encoding prostaglandin transporter, is involved, especially in Japanese patients • SLCO2A1 is also associated to another rare disease, chronic enteropathy with multiple small intestine ulcers

Differential diagnosis

• Acromegaly • Lepromatous leprosy • Secondary pachydermoperiostosis

Course and complications

• PHO is a self-limiting illness, and the disease becomes stationary or resolves spontaneously after the active phase during adolescence years • The complications of hypertrophic osteoarthropathy itself are limited to pain and loss of range of motion from oedema and periostitis

Follow-up and therapy

Fig. 4.58 

• Surgical reductive procedures of the scalp and skin of the face and eyelids may be performed for cosmetic reasons • COX-2 inhibitors • Bisphosphonates for refractory bone pain

Bibliography Krugh M, Vaidya PN. Hypertrophic Osteoarthropathy. 2022 Nov 7. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. Long B, Tang H, Zhao X, He T, Tang M, Wan P. Chronic enteropathy associated with SLCO2A1-associated primary hypertrophic osteoarthropathy in a female patient. Clin Res Hepatol Gastroenterol. 2022;46(9):102021. Xu Y, Zhang Z, Yue H, Li S, Zhang Z. Monoallelic mutations in SLCO2A1 cause autosomal dominant primary hypertrophic osteoarthropathy. J Bone Miner Res. 2021;36(8):1459–1468.

PPK congenital alopecia syndrome Epidemiology

Only 18 cases have been reported so far.

Age of onset

Fig. 4.59 

At birth or within the first months of life.

Cutaneous findings • • • • •

• • • •

Hair may be present at birth, but disappears in a short time Generalized non-cicatricial atrichia (Figure 4.58) Possibly, vellus hair in localized areas Severe progressive PPK with thickening especially visible at the lateral and medial aspects of palms and soles (Figure 4.59) Transgrediens pattern involving the extensor surfaces of fingers with scales and erythema leading progressively to severe contractures and scleroderma-like pattern of hands (Figure 4.60) Pseudoainhum Mild onychodystrophy Absence of eyebrows and eyelashes Diffuse keratosis pilaris with ulerythema ophryogenes

Fig. 4.60 

Atlas of Genodermatoses

112 Extracutaneous findings

• Early-onset cataracts • Agenesis of the corpus callosum

Genetics and pathogenesis

• The condition is inherited in both dominant (type 1) and recessive (type 2) mode of inheritance • Dominant forms seem to be less severe • The LSS gene, encoding for lanosterol synthase (LSS), which functions in the cholesterol biosynthesis pathway by converting (S)-2,3-oxidosqualene to lanosterol, has been found as causative gene

Differential diagnoses • • • • •

KFSD Clouston-KID syndromes Olmsted syndrome WNT10-related ED Hypotrichosis Osteolysis Periodontitis PPK syndrome: atrichia/hypotrichosis, PPK, dystrophic nails, periodontitis • Lelis syndrome: atrichia, PPK, hypohidrosis, pigmented lesions, oligodontia • Alves syndrome: hypotrichosis, follicular hyperkeratosis, kyphoscoliosis, cataracts

Bibliography Castori M, Morlino S, Sana ME, et al. Clinical and molecular characterization of two patients with palmoplantar keratoderma-congenital alopecia syndrome type 2. Clin Exp Dermatol. 2016;41(6):632–635. Yang F, Jiang X, Zhu Y, et al. Biallelic variants in Lanosterol Synthase (LSS) cause palmoplantar keratoderma-congenital alopecia syndrome type 2. J Invest Dermatol. 2022;142(10):2687–2694.e2.

Keratin 16-related PPK Synonym

Keratosis palmoplantaris nummularis.

Age of onset

During infancy, when the patient assumes an erect position and starts walking.

Clinical findings

• Bilateral islands of hyperkeratosis mainly involving the soles at sites of maximum pressure, with severe painful sensation upon pressure (Figure 4.61) • Sometimes linear disposition of the hyperkeratosis, mimicking a striate PPK • Similar lesions, often smaller and less painful, on the palms • Nail anomalies: leukonychia, thickening of the toenails, koilonychia and platonychia

Fig. 4.61 

Extracutaneous findings Polydactyly (rare).

Laboratory findings

Histopathologic findings: local epidermolytic hyperkeratosis (in nearly all patients).

Genetics and pathogenesis

Autosomal dominant inheritance due to KRT16 mutations.

Differential diagnosis

• Clinically related to the palmoplantar lesions observed in Howel-Evans syndrome (see Chapter 22) • Tyrosinaemia type II • Pachyonychia congenita • Olmsted syndrome

Course

The lesions progress slowly, with worsening of both thickness and pain.

Follow-up and therapy

• The disease inevitably leads to invalidity. Oesophagus monitoring is absolutely necessary • Resistant to many treatments • Oral retinoids

Bibliography Cambiaghi S, Morel P. Hereditary painful callosities with associated features. Dermatology. 1996;193(1):47–49. Ryan P, Baird G, Benfanti P. Hereditary painful callosities: Case report and review of the literature. Foot Ankle Int. 2007;28(3):377–378.

5

OTHER DISORDERS OF KERATINIZATION Kyrle’s disease Synonym

Hyperkeratosis follicularis et parafollicularis in cutem penetrans.

Age of onset

• It is a rare cause of primary perforating dermatosis in children • The disease could also present in adulthood, more commonly in women between 30 and 50 years of age

Cutaneous findings

• Asymptomatic, scattered, generalized papular lesions (0.5–2 cm) with central hyperkeratotic cone-shaped plugs (Figure 5.1) • Follicular or extrafollicular papules (Figure 5.2) • Possible coalescence to form verrucous plaques (mainly extensor extremities) or linear arrangements (mainly antecubital and popliteal fossae) • Sparing of the mucous membranes and the palmar and plantar surfaces

Extracutaneous findings

• Diabetes mellitus • Chronic renal failure • Congestive cardiac failure

Fig. 5.2 

Histopathologic findings • • • •

Keratotic plug filling an epithelial invagination Parakeratosis in parts of the plug Basophilic cellular debris within the plug Granulomatous reaction in the surrounding dermis

Genetics and pathogenesis

• Autosomal recessive inheritance; rare reports of children affected, including two siblings, have been described • A case of co-occurrence of Kyrle’s disease and Flegel disease has been reported in a 6-year-old girl • Gene locus unknown • 67-kDa elastin receptors have been detected in the epidermis, eliminating altered elastic fibers (elastin–keratinocyte interaction) • Infectious agents (probably anaerobic bacteria) may play a role in the pathogenesis of the disease

Differential diagnosis • • • •

Elastosis perforans serpiginosa Flegel’s disease Reactive perforating collagenosis Perforating folliculitis

Course and prognosis

• The disease is chronic and persistent. There is a normal lifespan • An underlying metabolic disorder needs to be ruled out, since secondary metabolic causes of perforating dermatosis are a much more common occurrence

Follow-up and therapy

Fig. 5.1 

DOI: 10.1201/9781003124351-5

• • • •

Topical keratolytic agents and retinoids Oral retinoids CO2 laser Antimicrobial therapy 113

Atlas of Genodermatoses

114 Bibliography Alshami MA, Mohana MJ. A Case of infantile Kyrle-Flegel disease in a 6-year-old Yemeni girl. Case Rep Dermatol. 2016;8(1):5–9. Fujimoto N, Akagi A, Tajima S et al. Expression of the 67 kDa elastin receptor in perforating skin disorders. Br J Dermatol. 2002;146: 74–79. Viswanathan S, Narurkar SD, Rajpal A, Nagpur NG, Avasare SS. Rare presentation of Kyrle’s disease in siblings. Indian J Dermatol. 2008;53(2):85–87.

Autoinflammatory keratinization diseases (AiKDs) Inflammation caused by the hyper-activation of innate immunity due to genetic factors occasionally leads to inflammatory keratinization diseases of the skin: such inflammatory keratinization diseases with genetic autoinflammatory pathomechanisms, mainly localized in the epidermis and in the superficial dermis, are called “autoinflammatory keratinization diseases” (AiKDs). The clinical phenotypes of AiKDs are variable, and each disease has unique characteristic manifestations, although common clinical features are hyperkeratotic lesions with inflammation. Inflammatory keratinization diseases classified as AiKDs encompass pustular psoriasis (IL36RN mutations), pityriasis rubra pilaris type V (CARD14 mutations), porokeratoses (mutations in mevalonate pathway-related genes), KLICK syndrome (mutations in POMP gene) and hidradenitis suppurativa (mutations in γ-secretase genes) (see also Chapter 20)

Fig. 5.3 

Pityriasis rubra pilaris (PRP) Epidemiology

A few pedigrees have been described.

Age of onset

At birth or it appears during the first years of life.

Cutaneous findings

• Individual erythematous-scaling lesions merging to form large patches of involved skin with characteristic islands of sparing within affected tissue (Figure 5.3), with peculiar “dark salmon pink” colour of the lesions • Prominent involvement of the face (cheeks, chin and ears), with possible ectropion • Palmoplantar hyperkeratosis with progressive extension to the Achilles’ tendon areas (Figures 5.4 and 5.5) • As in psoriasis, extensor surfaces (Figure 5.6) are the preferred site, but erythroderma (Figure 5.7) is possible • Aspecific nail dystrophies and scalp involvement

Course and prognosis

Usually progressive and lifelong, the disease may stabilize or relapse, with long symptom-free intervals.

Laboratory findings

Histological features include alternating parakeratosis and orthokeratosis, hypergranulosis, broad thickening of the rete ridges, thick suprapapillary plates, follicular hyperkeratosis, lack of neutrophilic infiltration and limited vascular dilatation.

Fig. 5.4 

Other Disorders of Keratinization

Fig. 5.5 

115 • Sporadic PRP represent the vast majority of cases • The familial disease is caused by autosomal dominant gain-of-function heterozygous mutations in the CARD14 gene, which encodes caspase recruitment domain-containing protein 14, a known activator of nuclear factor kappa B (NF-κB) signalling. CARD14 is specifically expressed in the skin, and mutations modulate the NF-κB signalling pathway within keratinocytes and, ultimately, lead to aberrant immunological activation, especially the IL-23/Th17 pathway • Loss-of-function mutations in the CARD14 gene are associated with a severe variant of atopic dermatitis, decreased NF-κB signalling and concomitant dysregulation of critical innate immunity-associated mediators previously implicated in AD pathogenesis • CARD14-associated papulosquamous eruption (CAPE) is a proposed term that encompasses features ranging from psoriasis to PRP in association with CARD14 mutations. • The early onset of the disease, prominent facial involvement, family history of an autosomal dominant trait and poor response to conventional treatment are characteristics of CAPE that distinguish it from classical psoriasis and PRP • Revertant mosaicism has been described in PRP, and CARD14 mutations are repaired mainly via homologous recombination, preferentially under conditions of replication stress

Follow-up and therapy

Fig. 5.6 

• • • •

Keratolytics and emollients Systemic retinoids Calcipotriol Cyclosporine, methotrexate, and azathioprine may be useful in a minority of patients • There are reports of successful treatment with anti-TNFα agents (adalimumab, infliximab, etanercept) or interleukin (IL) inhibitors (ustekinumab and secukinumab); best responses have been described with ustekinumab

Differential diagnosis • • • • •

Psoriasis Seborrheic dermatitis Peeling skin syndrome Palmoplantar keratodermas Netherton syndrome

Bibliography

Fig. 5.7 

Genetics and pathogenesis

• The pathogenesis of PRP remains elusive: an infective aetiology and an association with defective vitamin A metabolism or vitamin A deficiency were proposed on the basis of clinical observations. However, based on clinical and pathological features, it is now classified as a papulosquamous disease, which, like psoriasis, is thought to result from abnormal activation of inflammatory pathways

Frare CP, Blumstein AJ, Paller AS, Pieretti L, Choate KA, Bowcock AM, Larralde M. CARD14-associated papulosquamous eruption (CAPE) in pediatric patients: Three additional cases and review of the literature. Pediatr Dermatol. 2021;38(5):1237–1242. Fuchs-Telem D, Sarig O, van Steensel MA, et al. Familial pityriasis rubra pilaris is caused by mutations in CARD14. Am J Hum Genet. 2012;91(1):163–170. Leger M, Newlove T, Robinson M, Patel R, Meehan S, Ramachandran S. Pityriasis rubra pilaris. Dermatol Online J. 2012;18(12):14. Miyauchi T, Suzuki S, Takeda M, Peh JT, Aiba M, Natsuga K, Fujita Y, Takeichi T, Sakamoto T, Akiyama M, Shimizu H, Nomura T. Altered replication stress response due to CARD14 mutations promotes recombination-induced revertant mosaicism. Am J Hum Genet. 2021;108(6):1026–1039.

Atlas of Genodermatoses

116 Nielsen RM, Gram SB, Bygum A. Identification of a pathogenic CARD14 mutation in a 70-year-old woman with pityriasis rubra pilaris: When genetic diagnosis influences choice of treatment strategy. BMJ Case Rep. 2021;14(1):e235287. Peña-Rosado A, Riera-Martí N, Expósito-Serrano V, Romaní J. Autoinflammatory keratinization diseases (AIKDs). Actas Dermosifiliogr (Engl Ed). 2021:S0001-7310(21)00208-8. English, Spanish.

Porokeratoses Porokeratoses are chronic keratoatrophodermas of different clinical forms that are histologically characterized by columns of porokeratosis termed “cornoid lamellae”.

Age of onset

Onset is usually in childhood; the actinic form appears in the third or fourth decade of life.

Clinical forms Porokeratosis of Mibelli (plaque porokeratosis)

• Classic form of porokeratosis • Small asymptomatic keratotic papules enlarging gradually to form plaques with a raised, wall-like border that resembles a dyke, and an atrophic depressed centre (Figures 5.8) • Solitary or a few lesions ranging in size from millimetres to many centimetres (giant porokeratosis) (Figure 5.9)

Fig. 5.10  • Predilection for the face and extremities, including the palms and soles (Figure 5.10) • Fingernails and toenails may also be involved

Linear porokeratosis

• Linear, unilateral or whorled coalescent keratotic papules, distributed along Blaschko’s lines, most commonly on the extremities (Figures 5.11 and 5.12) • Loss of heterozygosity is relatively common, revealing exacerbation of the disease and, rarely, malignant transformation

Punctate palmoplantar porokeratosis (Mantoux)

• Multiple 1–2 mm seed-like keratotic plugs on palms and soles, surrounded by a thin, raised border (Figures 5.13 and 5.14) • It gradually progresses to involve other areas of the skin with DSP-like (where DSP is disseminated superficial porokeratosis) plaques

Disseminated superficial porokeratosis

Fig. 5.8 

Fig. 5.9 

Widespread, uniform lesions not exceeding 1 cm in diameter occurring in both sun-exposed and non-sun-exposed areas (Figures 5.15 and 5.16).

Fig. 5.11 

Other Disorders of Keratinization

Fig. 5.12 

117

Fig. 5.15 

Fig. 5.13  Fig. 5.16 

Disseminated superficial actinic porokeratosis

• Numerous pruritic papular lesions, enlarging centrifugally, confined to sun-exposed areas • Sparing of the palms, soles and mucosal surfaces • Exacerbations during the summer (Figure 5.17) • Solar facial porokeratosis could be considered as a mild form of this variant

Extracutaneous findings

Fig. 5.14 

• Immunosuppression (immunosuppression-induced porokeratosis) mainly revealed by transplantations (heart, kidney and bone marrow) • Autoimmune diseases

Atlas of Genodermatoses

118

• Linear porokeratosis: (inflammatory) linear verrucous epidermal nevi, lichen striatus, linear lichen planus and linear psoriasis • Punctate palmoplantar porokeratosis: nevoid basal cell carcinoma syndrome, Darier disease, pitted keratolysis and punctate palmoplantar keratoderma • Disseminated superficial porokeratosis: lichenoid pityriasis and solar keratosis

Course and prognosis

• The disease is chronic and slowly progressive, with worsening after sun exposure • About 10% of patients may develop squamous cell and basal cell carcinomas; these are most common in the giant and linear forms

Fig. 5.17 

Laboratory findings

Histopathologic features include the presence of cornoid lamellae (i.e., columns of parakeratosis beneath which the granular zone is thinned) and, in the spinous zone, there are vacuolated and dyskeratotic cells, a thinned epidermis and superficial perivascular lymphocytic infiltrates.

Genetics and pathogenesis

• Autosomal dominant diseases; many sporadic cases have been reported • Most patients with porokeratosis have a heterozygous germline mutation in genes that encode enzymes of the mevalonate pathway, mevalonate kinase (MVK), mevalonate diphosphodecarbolylase (MVD), phosphomevalonate kinase (PMVK) or farnesyl diphosphate synthase (FDPS), in both familial and sporadic cases; MVK has a role in regulating calcium-induced keratinocyte differentiation and could protect keratinocytes from the apoptosis induced by type A ultraviolet radiation • Porokeratosis skin lesions are induced by second-hit genetic changes in individuals who carry a pathogenic germline variant in a heterozygous manner, which is triggered by various factors, such as actinic radiation, immunosuppression, trauma or infective agents • One of the major second-hit mechanisms is somatic homologous recombination, resulting in copy neutralLOH (Figure 23.37 is an example of type II mosaicism with loss of heterozygosity [LOH]). • The timing of this second-hit somatic mutation explains the difference in skin lesion distribution and onset: a prenatal second hit in a precursor cell of a clone expanding in a linear pattern along Blaschko’s lines induces LP skin lesions, whereas a post-natal second hit occurring independently (over time due to UV-induced DNA damage) in the epidermis induces DSAP skin lesions • Mevalonate kinases recessive mutations are also responsible for MK-associated diseases, a heterogeneous group of conditions called autoinflammatory diseases, resulting from mutations in genes of the innate immune system (mevalonic aciduria, hereditary recurrent fever) (see also Chapter 20)

Differential diagnosis

• Porokeratosis of Mibelli: granuloma annulare, warts and elastosis perforans serpiginosa

Follow-up and therapy

• Propensity for neoplastic change requires accurate observation • Avoid sun exposure

Therapy is unsatisfactory:

• Topical sunscreens, keratolytics, topical retinoids, topical steroids, 5-fluorouracil and imiquimod • Cryotherapy, photodynamic therapy (PDT), CO2 laser and dermabrasion • Oral retinoids • Topical 2% cholesterol/lovastatin therapy has been successful studied as a pathogenesis-based therapy that replaces deficient end products (cholesterol, an essential mevalonate pathway end-product) and prevents accumulation of potentially toxic precursors

Bibliography Atzmony L, Khan HM, Lim YH, et al. Second-Hit, Postzygotic PMVK and MVD mutations in linear porokeratosis. JAMA Dermatol. 2019;155(5):548–555. Atzmony L, Lim YH, Hamilton C, et al. Topical cholesterol/lovastatin for the treatment of porokeratosis: A pathogenesis-directed therapy. J Am Acad Dermatol. 2020;82(1):123–131. Pini M, Balice Y, Tavecchio S, Crippa D. Eruptive disseminated porokeratosis following bone marrow transplantation for acute lymphoblastic leukemia in a child. J Dermatol. 2012;39(4):403–404. Sertznig P, von Felbert V, Megahed M. Porokeratosis: Present concepts. J Eur Acad Dermatol Venereol. 2012;26(4):404–412. Shiiya C, Aoki S, Nakabayashi K, Hata K, Amagai M, Kubo A. Linear and disseminated porokeratosis in one family showing identical and independent second hits in MVD among skin lesions, respectively: A proof-of-concept study. Br J Dermatol. 2021;184(6): 1209–1212. Touitou I. Twists and turns of the genetic story of mevalonate kinaseassociated diseases: A review. Genes Dis. 2021;9(4):1000–1007.

KLICK syndrome Synonyms

• Keratosis linearis with ichthyosis congenita and sclerosing keratoderma syndrome • Stellate epidermolytic hyperkeratosis

Epidemiology

Fewer than 20 reports in the literature, with only several pedigrees.

Other Disorders of Keratinization

119

Age of onset At birth.

Cutaneous findings

• Collodion presentation • Generalized erythema and ichthyosiform dermatosis • In antecubital and popliteal fossae, progressive eruption of linear stellate grouping of hyperkeratotic streaks (Figures 5.18 and 5.19) • Cerebriform appearance of knees and elbows (Figure 5.20) • Marked erythema and thickening on the dorsa of the hands (Figure 5.21) and feet • Palmoplantar keratoderma with constricting bands around the fingers (pseudoainhum)

Course and prognosis

The disease is slowly progressive.

Fig. 5.20 

Fig. 5.21 

Laboratory findings

Fig. 5.18 

• Histological examination of the skin shows hypertrophy and irregular hyperplasia of the spinous, granular and horny epidermal layers • Upon ultrastructural examination, there are small foci of acantholysis, but without massive clumping or perinuclear shells as evident in classic epidermolytic ichthyosis (EI) or Curth-Macklin disease

Genetics and pathogenesis

Fig. 5.19 

• Autosomal recessive • It is associated with a single-nucleotide deletion located in the 5’ UTR (untranslated region) of POMP, a ubiquitously expressed protein that functions as a chaperone for proteasome maturation of the standard proteasome and the immunoproteasome • Proteasome deficiency results in increased epidermal endoplasmic reticulum stress, a process that is known to cause aggregations of misfolded proteins. These protein aggregates limit normal cellular functions and can explain the disturbed terminal epidermal differentiation in KLICK syndrome • Since POMP is also known to be a causative gene for proteasome-associated autoinflammatory syndrome (PRAAS2), characterized by papulo-erythematous skin lesions (face, trunk and extremities), panniculitis, necrotizing lesions

Atlas of Genodermatoses

120 and early-onset combined immunodeficiency and immunodeficiency, KLICK syndrome has been included in a spectrum of proteasome-associated phenotypes grouped under the umbrella term “autoinflammatory keratinization disease” (AiKD).

Follow-up and therapy

• Emollients and keratolytic agents may be useful, as well as calcipotriol • Retinoid systemic therapy can show significant improvement

Differential diagnosis • • • •

ARCI Keratitis-ichthyosis-deafness (KID) syndrome Loricrin keratoderma Epidermolytic ichthyosis, Curth-Macklin variant

Bibliography Dahlqvist J, Klar J, Tiwari N, et al. A single-nucleotide deletion in the POMP 5’ UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis. Am J Hum Genet. 2010;86(4):596–603. Takeichi T, Akiyama M. KLICK Syndrome Linked to a POMP Mutation Has Features Suggestive of an Autoinflammatory Keratinization Disease. Front Immunol. 2020;11:641. Vahlquist A, Ganemo A, Pigg M, et al. The clinical spectrum of congenital ichthyosis in Sweden: A review of 127 cases. Acta Derm Venereol (Stockh). 2003;213(Suppl):34–47.

6

POIKILODERMAS AND AGING SYNDROMES Definition of poikiloderma: Poikiloderma is defined as a patchy skin appearance caused by atrophy, telangiectasia and mottled hypo/hyperpigmented macules. Papules, mild xerosis and petechiae may be associated. Poikiloderma is initially restricted to sun-exposed areas and is slowly progressive to non-exposed areas. Inherited skin disorders presenting with poikiloderma a. With photosensitivity: Xeroderma pigmentosum Clericuzio-type poikiloderma with neutropaenia Kindler syndrome (see Chapter 1) Bloom syndrome (see Chapter 22) b. Without photosensitivity: Rothmund-Thomson syndrome Dyskeratosis congenita Hereditary sclerosing poikiloderma (Weary type) HSP with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP)

TABLE 6.1  XP type

Gene

Photosensitivity

XP-A XP-B XP-C XP-D XP-E XP-F XP-G XP-V

DDB1 ERCC3 Endonuclease ERCC2 DDB2 ERCC4 Endonuclease

+++ ++ to +++ ++ to +++ ++ + ++ +++ ++ to +++

Polymerase-η

Cancer Proneness +++ +++ ++ Melanoma + Rare Few or absent Few or absent Late onset ++

+, mild; ++, moderate; +++, severe. Abbreviations: ERCC, excision-repair cross-complementing genes; DDB, DNA damage-binding protein; XP, xeroderma pigmentosum.

Xeroderma pigmentosum (XP) Synonym

De Sanctis-Cacchione syndrome for XP-A.

Epidemiology 1–9/1.000.000.

Age of onset

• First signs of the disease may appear as soon as first ultraviolet (UV) exposure occurs • Skin malignancies usually after the second year of life

Cutaneous findings

The different types of XP can be subdivided into seven complementation groups and one “variant” related to their different molecular origins, as reported in Table 6.1, but they share the following symptoms: • Photosensitivity (severe to extreme) • Freckling on photoexposed areas (Figure 6.1) • Progressive premature aging with poikilodermatous changes (atrophy, lentigo and telangiectasias) (Figures 6.2 and 6.3) • The risk of skin cancer development under 20 years of age is 1000-fold compared to healthy individuals of the same age • Basal cell carcinomas, squamous cell carcinomas and melanoma (in decreasing order) in photoexposed areas, lips, tongue and, rarely, oral and nasal mucosa (Figure 6.4) • Disfiguring cancer on the face can cause loss of nasal pyramid, orbital structures or external ears, as occurs with repeated surgery (Figures 6.5 and 6.6) • Rarely, skin angiosarcomas

DOI: 10.1201/9781003124351-6

Fig. 6.1  In particular: XPA: early photosensitivity, severe sunburn, lentigines, hypopigmented macules, atrophy, late onset skin cancers (Figure 6.3) XPB: lentigines, severe sunburn, hypopigmented macules, actinic damage, skin cancers (Figure 6.2) 121

Atlas of Genodermatoses

122

Fig. 6.4 

Fig. 6.2 

Fig. 6.5 

Fig. 6.6 

Fig. 6.3 

XPC: non-severe sunburn, high incidence of skin cancers, lentigines, atrophy, photophobia and conjunctivitis (Figures 6.4 and 6.7) XPD: severe sunburn, lentigines, hypopigmented macules, atrophy and actinic damage, skin cancer (Figure 6.1) XPE: non-severe sunburn, late onset of skin signs (lentigines, atrophy), higher incidence of skin cancer (Figure 6.6)

Poikilodermas and Aging Syndromes

123 • • • •

Ataxia telangiectasia Erythropoietic protoporphyria Gunther’s disease Kindler syndrome

Course and prognosis

• Life expectancy is greatly reduced: 90% at 13 years of age, 80% at 25 years of age and 70% at 40 years of age • Metastatic skin cancer occurs invariably in all patients

Follow-up and therapy

Fig. 6.7  XPF: sunburn after minimal exposure, minor incidence of skin cancer XPG: severe sunburn, lentigines, hypopigmented macules XPV: less severe symptoms of sunburn reaction and minor incidence of skin cancer

Extracutaneous findings

Extracutaneous signs may be very variable among the different groups of XP, but patients share common symptoms: • Photophobia, conjunctival cancer, blepharitis, corneal opacities and blindness • Twenty-five percent of XP patients show neurologic involvement of different degrees, with low IQ • Ataxia, abnormal reflex with paresis and progressive central deafness • Microcephaly, growth retardation and abnormal sexual development in a minority of patients • Increased risk for internal malignancies

Genetics and pathogenesis

• XP is inherited as an autosomal recessive disease • Clinical and cellular photosensitivity is due to the inability to repair UV-induced DNA damage • Two different DNA-repair processes are defective in XP: the classic nuclear excision repair, divided into two subpathways called “the global genome repair system” and “transcription-coupled repair and translation synthesis” (see Table 6.1)

Differential diagnosis

• Hereditary polymorphic light eruption • Rothmund-Thomson syndrome

• Photoexposure is strictly forbidden • Chemical and physical sunscreens • Adequate sunglasses, shirts, caps, and gloves as well as appropriate facemasks are mandatory • Window screens are required at home, at school and in the car • Psychosociological support for patients and families • Frequent dermatological survey to prevent precancers and skin cancers in skin and visible mucosae • Surgical excision of precancers and skin cancers • Plastic reconstructive surgery on the face • Tests for haematological and visceral internal malignancies • Frequent ophthalmological consultations • Therapy with systemic retinoids in the chemoprevention of non-melanoma skin cancers (NMSCs) is reported, but no guidelines exist on the type of retinoid to use, the dosage and the duration of this preventive treatment • Immunotherapy and target therapy for melanoma and NMSC

Bibliography Bettoli V, Zauli S, Virgili A. Retinoids in the chemoprevention of nonmelanoma skin cancers: Why, when and how. J Dermatolog Treat. 2013;24(3): 235–237. Brambullo T, Colonna MR, Vindigni V, Piaserico S, Masciopinto G, Galeano M, Costa AL, Bassetto F. Xeroderma Pigmentosum: A genetic condition skin cancer correlated-A systematic review. Biomed Res Int. 2022;2022:8549532. Hadj-Rabia S, Oriot D, Soufir N, et al. Unexpected extra-dermatological findings in 31 patients with xeroderma pigmentosum type C. Br J Dermatol. 2013;168(5):1109–1113. Lucero R, Horowitz D. Xeroderma pigmentosum. 2022 Sep 22. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022. PMID: 31855390. Rubatto M, Merli M, Avallone G, et al. Addendum: Immunotherapy in Xeroderma Pigmentosum: A case of advanced cutaneous squamous cell carcinoma treated with cemiplimab and a literature review. Oncotarget. 2022;13:985. Zhou X, Khan SG, Tamura D, et al. Abnormal XPD induced nuclear receptor transactivation in DNA repair disorders: Trichothiodystrophy and xeroderma pigmentosum. Eur J Hum Genet. 2012;21(8):831–837.

Clericuzio-type poikiloderma with neutropaenia Epidemiology

Less than 30 cases have been reported in the literature.

Age of onset

First months/years of life.

Atlas of Genodermatoses

124

• Growth retardation • Elevated lactate dehydrogenase and ferritin • Transient thrombocytopenia and/or leukopaenia

Course and complications

• Infective episodes became less frequent during adolescence and adult age • Increased risk of cancer is reported (squamous cell carcinoma and osteosarcoma)

Laboratory findings

• Bone marrow smears shows abnormal maturation of neutrophil lineage, with increased numbers of immature cells, but no abnormal clonality • Increase of enzymes such as LDH and CPK without any muscle involvement • Elevated serum ferritin

Fig. 6.8 

Cutaneous findings

• Very early photosensitivity • Papular erythematous rash during the first months of life typically with acral pattern and progressively spreading to the face and neck, evolving into poikiloderma (Figure 6.8). Mucous membranes are unaffected • Palmoplantar keratoderma • Pachyonychia • Milia, verrucous lesions and atrophic scars

Extracutaneous findings

• Persistent severe neutropaenia, less common thrombocytopenia and lymphopenia • Recurrent pulmonary infections, otitis media and sinusitis • Short stature, growth retardation • Dysmorphic features such as midface hypoplasia, hypertelorism, frontal bossing, depressed nasal bridge and prognathism (Figure 6.9) • Hepatosplenomegaly • Non-descended or retractile testes • Dental dysplasia • Lacrimal duct obstruction

Genetics and pathogenesis

• Autosomal recessive • The disease is due to mutations in the USB1 (C16orf57) gene. The encoded protein is significantly expressed in the myeloid lineage, where is thought to be important for the maturation of neutrophils but also in keratinocytes, melanocytes and fibroblasts • The USB1 gene codes for a long-sought 3–5′ RNA exonuclease that post-transcriptionally trims oligouridine tails of U6 molecule, which is involved in the pre-mRNA splicing within the spliceosome, suggesting the existence of sophisticated cellular pathways involved in surveillance and stabilization of m-RNA components as U6 • USB1 forms a complex with the RECQL4 gene (involved in Rothmund-Thomson syndrome pathogenesis) and SMAD4, a TGF-beta signal transductor (see also Haemorrhagic telangiectasia syndrome, Chapter 16)

Differential diagnosis

• Rothmund-Thomson syndrome • Dyskeratosis congenita

Follow-up and therapy

• Careful bone marrow smear examination and follow-up for the haematologic disease are needed to check the onset of myelodysplasia or leukaemic transformation • Interferon-γ has been found to improve phagocyte NADPH oxidase activity

Bibliography

Fig. 6.9 

Bilgic Eltan S, Sefer AP, Karakus İS, Ozen A, Karakoc-Aydiner E, Baris S. Lymphopenia with Low T and NK Cells in a Patient with USB1 Mutation, Rare findings in clericuzio-type poikiloderma with neutropenia. J Clin Immunol. 2021;41(5):1106–1111. Shchepachev V, Azzalin CM. The Mpn1 RNA exonuclease: Cellular functions and implication in disease. FEBS Lett. 2013;587(13):1858–1862. Suter AA, Itin P, Heinimann K, et al. Rothmund-Thomson Syndrome: Novel pathogenic mutations and frequencies of variants in the RECQL4 and USB1 (C16orf57) gene. Mol Genet Genomic Med. 2016;4(3):359–366. Van Hove JLK, Jaeken J, Proesmans M, et al. Clericuzio type poikiloderma with neutropenia is distinct from Rothmund–Thomson syndrome. Am J Med Genet. 2005;132A:152–158.

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125

Wang L, Clericuzio C, Larizza L. Poikiloderma with Neutropenia. 2017 Oct 26. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022.

Kindler syndrome See Chapter 1.

Bloom syndrome See Chapter 22.

Rothmund-Thomson syndrome Synonym

Hereditary congenital poikiloderma

Epidemiology

This is a rare disease, with fewer than 400 cases described in the literature

Age of onset

A few months to 2 years after birth

Cutaneous findings

• Erythema and oedema appear first and are located mainly in sun-exposed areas, together with photosensitivity • Progression of symptoms may reveal severe telangiectasias, rare blisters and hypo- and hyperpigmented macules, giving the characteristic poikilodermatous, mild atrophic pattern to UV- exposed areas (Figures 6.10 and 6.11)

Fig. 6.10 

Fig. 6.11  • Macules may extend to non-exposed areas late in childhood (Figure 6.12) • Keratoses occur on the dorsa of the hands and can transform into basal and squamous cell carcinoma (5–15% of patients) • Hair is sparse and coarse as well as eyebrows and eyelashes • Total alopecia after the second decade (Figure 6.10) • Less common symptoms are: • Aspecific nail dystrophies • Cutaneous calcinosis, osteoma cutis (trauma induced) • Porokeratosis

Fig. 6.12 

Atlas of Genodermatoses

126 Extracutaneous findings

• Facies with hypotrophy of malar areas and hypertelorism • Short stature and skeletal abnormalities (radius and hand bones) • Early-onset cataracts, potentially leading to blindness (30%) • Chronic vomiting and diarrhoea during infancy • Benign and malignant haematologic abnormalities, including isolated anaemia and neutropaenia, myelodysplasia, aplastic anaemia and leukaemia, have been reported • Occasional hypogonadism and low fertility in a quarter of patients • Hypodontia • Mental retardation described • Osteosarcoma in 30% of patients

Genetics and pathogenesis

• The disease is autosomal recessive and is due to mutations in the RECQL4 helicase gene, which is involved in DNA repair, replication and chromosome integrity • The predisposition to cancer correlates with the accumulation of transcriptionally active nuclear p53, because normal p53–RECQL4 binding leads to the masking of the nuclear localization signal of p53 • RECQL4 is also implicated in telomere maintenance • Those with truncating mutations are at increased risk of developing osteosarcoma • A minority of Rothmund-Thomson patients show mutations in the ANAPC1 gene which encodes for the APC1 protein that is part of the anaphase-promoter/cyclosome complex. Patients with ANAPC1 mutations do not develop osteosarcoma

Martin-Giacalone BA, Rideau TT, Scheurer ME, Lupo PJ, Wang LL. Cancer risk among RECQL4 heterozygotes. Cancer Genet. 2022;262–263:107–110. doi: 10.1016/j.cancergen.2022.02.001. Epub 2022 Feb 9. Rayinda T, van Steensel M, Danarti R. Inherited skin disorders presenting with poikiloderma. Int J Dermatol. 2021;60(11):1343–1353. doi: 10.1111/ijd.15498. Epub 2021 Mar 19. Wang LL, Plon SE. Rothmund-Thomson Syndrome. 1999 Oct 6 [updated 2020 Jun 4]. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle, WA: University of Washington; 1993–2022.

Dyskeratosis congenita (DC) Synonym

Zinsser-Cole-Engman syndrome

Epidemiology

This disease is rare. No further data are available

Age of onset

Generally, before puberty

Cutaneous findings

• Lacy, reticulated telangiectatic hyperpigmentation (poikilodermatous appearance) with interposed zones of hypopigmentation (100%) on the face, neck, trunk and upper thighs (Figures 6.13–6.15) • Atrophy and cyanosis of the dorsal aspects of the hands and feet (93%) (Figure 6.16)

Differential diagnosis

• XP (early phase) • Kindler syndrome • Ectodermal dysplasia

Course and prognosis

• Cutaneous symptoms are progressive during infancy and until adolescence, giving a poikilodermatous appearance, especially—but not exclusively—to the face and sunexposed areas • Squamous cell carcinomas are frequent • Increased risk of cancer, especially osteosarcoma • Life expectancy is reduced

Follow-up and therapy

• Photoprotection • Early detection of malignancies and their correction • Orthopaedic assessment of bone anomalies

Bibliography Ajeawung NF, Nguyen TTM, Lu L, et al. Mutations in ANAPC1, Encoding a scaffold subunit of the anaphase-promoting complex, cause rothmund-thomson syndrome type 1. Am J Hum Genet. 2019;105(3):625–630. Ghosh AK, Rossi ML, Singh DK, et al. RECQL4, the protein mutated in Rothmund–Thomson syndrome, functions in telomere maintenance. J Biol Chem. 2012;287(1):196–209.

Fig. 6.13 

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127

Fig. 6.17  Fig. 6.14 

• Hyperkeratosis and hyperhidrosis of the palms and soles (72%) (Figure 6.17) • Bullae and erosions are visible, especially during childhood and adolescence, or in sun-exposed areas (78%) (Figures 6.18 and 6.19) • Nail dystrophy (98%); longitudinal ridges, thinning (Figure 6.16) • Thin, lusterless, sparse hair, alopecia and early canities (51%) (Figure 6.20) • Leukokeratosis of the oral mucosa (87%) (Figure 6.21) and, less frequently, of the pharynx, anorectal and urogenital mucosae

Fig. 6.15 

Fig. 6.16 

Fig. 6.18 

Atlas of Genodermatoses

128 Extracutaneous findings

• Epiphora (i.e., persistent overflow of tears due to obstruction of lachrymal ducts) (78%), blepharitis and conjunctivitis • Early dental loss (63%) or extensive caries • Bone marrow failure, aplastic anaemia (>50%) with bleeding problems and purpura • Haematologic malignancies (acute myeloid leukaemia) • Squamocellular carcinomas of the face and neck, anorectal adenocarcinoma • Oesophageal diverticula and stenosis with dysphagia (59%) • Retardation of growth (50%) • Hypogonadism (40%) • Microcephaly, mental retardation (42%) • Macular amyloidosis • Osteoporosis • Pulmonary fibrosis

Laboratory findings

Fig. 6.19 

• • • • •

Blood count Bone marrow biopsy Accurate study of cellular immunity X-ray of bones Histopathological findings: • Skin: thinned epidermis, vacuolar alterations and sparse perivascular lymphocytic infiltrate • Mucous membranes: atypical keratinocytes with thickened ortho- and parakeratotic epithelium

Genetics and pathogenesis

Fig. 6.20 

Fig. 6.21 

• Approximately 10% of cases remaining genetically uncharacterized • The disease is caused by mutations in several genes (DKC1, TERC, TINF2, NHP2, NOP10, PARN, WRAP53, ACD, RTEL1, TERT). Seven of these are important in telomere maintenance either because they encode components of the telomerase enzyme complex (DKC1, TERC, TERT, NOP10, NHP2, and WRAP53) or the shelterin complex (TINF2) • X-linked DC: caused by mutations in the gene called DKC1 encoding a modulator (dyskerin) of the telomerase RNA and for ribosomal RNA processing. Dyskerin stability is regulated by SUMOylation, so mutations altering this process can lead to defects in telomere maintenance that are characteristic of DC • Autosomal dominant DC: to date, heterozygous mutations have been characterized: TERC, TERT, ACD, RTEL1, PARN and TINF2, a component of the shelterin complex that has protective activity on telomeres • Autosomal recessive DC (AR-DC): in a subset of AR-DC patients, biallelic mutations have been identified in TERT, NHP2, NOP10, RTEL1, ACD and NHP2, a component of the H/ACA ribonucleoprotein complex involved in ribosome biogenesis, pre-mRNA splicing and telomere maintenance. Mutations in the WRAP53 gene, coding for a telomerase holoenzyme protein that facilitates trafficking of telomerase to Cajal bodies, were reported • Mutations of CTC1 gene, POT1 and STN1 have been described • Mosaicism: in the X-linked form, somatic mosaicism is possible in carrier females due to lyonization. Revertant mosaicism is a recurrent event in DC caused by mutations in the TERC gene • True cutaneous type II segmental mosaicisms may be visible also in the AD form of DC (Figure 6.22)

Poikilodermas and Aging Syndromes

129 Bibliography

Fig. 6.22  • In addition, in the phenotypically severe variant of DC, Hoyeraal-Hreidarsson syndrome, affected individuals present additional features, such as bone marrow failure, cerebral hypoplasia and intrauterine growth retardation, resulting in an earlier onset of disease and a clinically poor prognosis • Revesz syndrome is another allelic severe form of DC

Differential diagnosis • • • • • •

Fanconi anaemia Epidermolysis bullosa Kindler syndrome Clericuzio syndrome Rothmund-Thomson syndrome White sponge hyperplasia of the mucosa

Course and prognosis

There is a poor prognosis. Death is the rule, often in the third decade of life: • Malignant neoplasms, most often squamous cell carcinomas of mucosal surfaces • Infection by opportunistic agents • This is an irreversible condition with high mortality owing to the failure of bone marrow and haematologic malignancies (mainly in the second or third decade of life)

Follow-up and therapy

• Close observation to detect early signs of bone marrow failure and malignant neoplasm • The anabolic steroid oxymetholone can produce improvement in haematopoietic function • Bone marrow transplantation. Recently, the adoption of non-myeloablative fludarabine-based protocols has allowed for successful engraftment in some patients, which is associated with fewer complications and lower toxicity • Oral retinoids • Transfusions

Allenspach EJ, Bellodi C, Jeong D, et al. Common variable immunodeficiency as the initial presentation of dyskeratosis congenita. J Allergy Clin Immunol. 2013;132(1):223–226. Brault ME, Lauzon C, Autexier C. Dyskeratosis congenita mutations in dyskerin SUMOylation consensus sites lead to impaired telomerase RNA accumulation and telomere defects. Hum Mol Genet. 2013;22(17):3498–3507. Garofola C, Nassereddin A, Gross GP. Dyskeratosis Congenita. 2022 Jun 27. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022. Jongmans MC, Verwiel ET, Heijdra Y, et al. Revertant somatic mosaicism by mitotic recombination in dyskeratosis congenita. Am J Hum Genet. 2012;90(3):426–433. Le Guen T, Jullien L, Touzot F, et al. Human RTEL1 deficiency causes Hoyeraal–Hreidarsson syndrome with short telomeres and genome instability. Hum Mol Genet. 2013;22(16):3239–3249. Ramos H, Aly MM, Balasubramanian SK. Late presentation of dyskeratosis congenita: Germline predisposition to adult-onset secondary acute myeloid leukemia. Hematol Rep. 2022;14(4):294–299. Tummala H, Walne A, Dokal I. The biology and management of dyskeratosis congenita and related disorders of telomeres. Expert Rev Hematol. 2022;15(8):685–696. Vulliamy TJ, Knight SW, Heiss NS, et al. Dyskeratosis congenita caused by a 3’ deletion: Germline and somatic mosaicism in a female carrier. Blood. 1999;94(4):1254–1260.

Hereditary sclerosing poikiloderma Synonym

“Weary type” hereditary sclerosing poikiloderma

Epidemiology

Near 30 cases described

Age of onset

Second-third year of life

Cutaneous findings

• Photosensitivity • Widespread poikiloderma with accentuation in flexural areas and over extensor bony prominences • Linear or reticular hyperkeratotic and sclerotic band (axillae, antecubital and popliteal fossae) • Palmoplantar sclerosing keratoderma • Less frequently, subcutaneous calcinosis

Extracutaneous signs • • • • •

Clubbing of fingers Micrognathia, mandibular anomalies “Slim” extremities Growth retardation, low stature Cardiovascular disease, Raynaud’s phenomenon

Laboratory findings

• Histopathology confirm the poikiloderma • Fragmentations of elastic fibres • Echotomographic cardiac valvular anomalies

Genetics and pathogenesis

• Autosomal dominant • It is uncertain if HSP is part of the spectrum of FAM111B mutations

Differential diagnosis

• Other poikilodermas • Kindler syndrome

Atlas of Genodermatoses

130 Course and Prognosis

• Progressive worsening of the skin signs • Linear flexural lesions develop during late infancy • Cardiopathy may occur in adulthood

Follow-up and therapy

• Cardiological assessment • No specific therapy for skin symptoms available

Bibliography DeMaria D, Mejia-Lopez E, Kelting SM, Soukoulis V. A case of familial calcific aortic and mitral stenosis in association with hereditary sclerosing poikiloderma. Cardiovasc Pathol. 2016;25(3):195–199. Grau Salvat C, Pont V, Cors JR, Aliaga A. Hereditary sclerosing poikiloderma of Weary: Report of a new case. Br J Dermatol. 1999;140(2):366–368. doi: 10.1046/j.1365-2133.1999.02684.x. Lee HJ, Shin DH, Choi JS, Kim KH. Hereditary sclerosing poikiloderma. J Korean Med Sci. 2012;27(2):225–227. doi: 10.3346/ jkms.2012.27.2.225. Epub 2012 Jan 27.

POIKTMP syndrome Synonyms

POIKiloderma, tendon contractures, myopathy, pulmonar fibrosis

PANEL 6.1A

Epidemiology

Less than 50 cases described.

Age of onset Early infancy.

Cutaneous findings

• Early photosensitivity, acute manifestations with facial erythema and transient bullous lesions (Panel 6.1A) • Progressive poikiloderma with atrophic lesions and late sclerodermiform changes (face; Panel 6.1A) • Palmoplantar hyperlinearity • Hypotrichosis and progressive scarring alopecia in late infancy • Eyebrows and eyelashes sparse or absent • Eczematous-psoriasiform lesions in adulthood (Panel 6.1B) • Late onset lymphoedema, cellulitis • Hypohidrosis • Hypo-hyperpigmented guttate or linear lesions

Extracutaneous signs

• Early onset myopathy with contractures (especially the “triceps surae”) • Diffuse progressive fatty myopathy • Pulmonary fibrosis • Exocrine pancreatic insufficiency

Reprinted with permission from Mercier S et al, Orphanet J Rare Dis 2015

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131

PANEL 6.1B 

Laboratory findings

Abnormal electromyography and pulmonary perfusion

Genetics and Pathogenesis

• Autosomal dominant • Missense mutations in FAM111B gene (serine protease)

Differential diagnosis

• Other poikilodermas with early photosensitivity • Erythropoietic porphyria

Course and prognosis

• Skin and extracutaneous symptoms worsen progressively with age • Pulmonary insufficiency is life-threatening in the fourthfifth decade of life

Follow-up and therapy

• No specific treatments available • Monitoring of pulmonary functions

Bibliography Mercier S, Küry S, Barbarot S. Hereditary Fibrosing Poikiloderma with Tendon Contractures, Myopathy, and Pulmonary Fibrosis. 2016 Oct 13 [updated 2021 Sep 9]. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews®[Internet]. Seattle, WA: University of Washington; 1993–2022. PMID: 27748098. Mercier S, Küry S, Salort-Campana E, Magot A, et al. Expanding the clinical spectrum of hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis due to FAM111B mutations. Orphanet J Rare Dis. 2015;10:135.

Atlas of Genodermatoses

132 Roversi G, Colombo EA, Magnani I, Gervasini C, Maggiore G, Paradisi M, Larizza L. Spontaneous chromosomal instability in peripheral blood lymphocytes from two molecularly confirmed Italian patients with Hereditary Fibrosis Poikiloderma: Insights into cancer predisposition. Genet Mol Biol. 2021;44(3):e20200332. Zhang Z, Zhang J, Chen F, Zheng L, Li H, Liu M, Li M, Yao Z. Family of hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis caused by a novel FAM111B mutation. J Dermatol. 2019;46(11):1014–1018. doi: 10.1111/13468138.15045. Epub 2019 Aug 7.

LIPHAK syndrome (LTV1-associated inflammatory poikiloderma with hair abnormalities and acral keratoses) A new form of cutaneous poikiloderma in two distinct families, associated with hair abnormalities and acral keratoses, is caused by homozygous mutations in the LTV1 gene, coding for one of the ribosome biogenesis factors that promote the assembly of the smaller ribosomal subunit. Clinical findings consist of acral reticulate poikilodermatous dyschromatosis, palmoplantar scaling, absent/sparse eyebrows and eyelashes, sparse hair without other ectodermal or haematological abnormalities. Extracutaneous findings include asymptomatic embryonal nuclear cataracts.

Fig. 6.24 

Bibliography Han JH, Ryan G, Guy A, Liu L, Quinodoz M, Helbling I, Lai-Cheong JE; Genomics England Research Consortium; Barwell J, Folcher M, McGrath JA, Moss C, Rivolta C. Mutations in the ribosome biogenesis factor gene LTV1 are linked to LIPHAK syndrome, a novel poikiloderma-like disorder. Hum Mol Genet. 2022;31(12):1970–1978.

Trichothiodystrophy syndrome (TTD) Synonym

Sulphur-deficient brittle hair syndrome.

Epidemiology

Estimated prevalence 1/800.000 in Europe.

Age of onset At birth.

Cutaneous findings

• Collodion baby presentation is frequent (Figure 6.23) • Dry, dull, brittle, unruly and broken hair (Figures 6.24–6.26)

Fig. 6.25 

Fig. 6.23 

• Partial or total alopecia of the scalp, eyelashes and eyebrows and subsequently of the secondary sexual hair (Figure 6.26) • Ichthyosis (Figure 6.27), eczema, follicular keratosis, cheilitis (Figure 6.28), telangiectasia, hypohidrosis, freckles and atopic dermatitis in 30% • Photosensitivity in more than 50% of patients • Dystrophic nails (Figure 6.29) with koilonychia, ridging, lamellar splitting and spotted leukonychia

Poikilodermas and Aging Syndromes

133

Fig. 6.28 

Fig. 6.26 

Fig. 6.29  • Bone lesions • Recurrent (pulmonary) immunodeficiency • Failure to thrive

infections

due

to

severe

Laboratory findings

Fig. 6.27 

Extracutaneous findings

• Neurologic symptoms: mental retardation, spasticity, paralysis, motor control impairment, pyramidal signs, hyperreflexia and party-behaviour appearance, with a broad spectrum of severity • Morphologic changes and dysmorphia: growth retardation with short stature, microcephaly, cranial dysplasia, micrognathia, protruding ears, dental abnormalities and high arched palate • Ocular lesions: cataracts, conjunctivitis, nystagmus, photophobia, retinal dystrophy and ectropion • Genital hypoplasia, cryptorchidism and hypospadias

• Amino acid analysis of the hair shaft: decrease in cystine and cysteine content • Light microscopy and electron microscopy: trichoschisis (transverse fractures through the hair shaft) and absence of cuticle (Figure 6.30) • Polarizing microscopy: presence of alternating light and dark bands (tiger-tail pattern) (Figure 6.31) that may be absent in the first year or two of life • Phototesting

Genetics and pathogenesis

• Autosomal recessive inheritance, except for the X-linkedrelated form due to mutations in the RNF113A gene • Photosensitive form of TTD is due to biallelic mutations in three genes encoding different subunits of the transcription initiating factors IIH (TFIIH), namely, and more frequently ERCC3, but also GTF2H5 and ERCC2. TFIIH play a pivotal role in both the starting of transcription and nucleotide excision repair

Atlas of Genodermatoses

134

single gene can (by different mutations and different loci in the same gene) cause different diseases. In fact, TTD patients do not show any susceptibility to cancer, and XP patients do not display a sulphur content deficit in their structural proteins. The XPD and XPB genes have been found to be mutated in the majority of patients affected by TTD • Different TTD phenotypes (severity of the disease) are related to the residual function of the XPD–B–TFIIH complex and are all mutations that can cause partial interference with the DNA repair system (the photosensitivity of TTD), but are not sufficient to cause susceptibility to cancer as occurs in the XP mutations that, conversely, do not interfere with the formation of a normal transcriptional complex • The TFIIH complex may be relevant in particular compartments, such as skin and central nervous system development genes, explaining the clinical features of hair anomalies, ichthyosis, and mental retardation • The novel X-linked form of non-photosensitive TTD is caused by nonsense mutations in the RNF113A gene. Clinically it is characterized by brittle, sulphur-deficient hair, microcephaly, profound intellectual disability, aged appearance, short stature, facial dysmorphism, seizures, an immunoglobulin deficiency, multiple endocrine abnormalities, cerebellar hypoplasia and partial absence of the corpus callosum, in the absence of cellular photosensitivity and ichthyosis. Obligate female carriers showed 100% skewed X-chromosome inactivation Fig. 6.30 

Differential diagnosis

The diagnosis of TTD, compared with Sjögren-Larsson, Menkes and Netherton diseases, is based on: • Hairs with low sulphur content • Trichoschisis • Tiger-tail pattern of hairs on polaroscopy

Course and prognosis

Strictly dependent on the severity of neurological manifestations and immune deficiency, but life expectancy is reduced.

Follow-up and therapy

• Photoprotection • Multidisciplinary approach • Symptomatic: prevention and treatment of pulmonary infections, application of emollients, physiotherapy, etc.

Fig. 6.31  • Seven genes are responsible of the non-photosensitive TTD forms: MPLKIP encoding the M-Phase-specific PLK1 interacting protein, GTF2E2 gene encoding for the general transcription factor II2 subunit 2, the X-linked RNF113A coding for X-linked ring-finger protein 113A and the four recently identified cysteinyl, threonyl, alanyl and methionyl-tRNA synthetase genes • At least two genes (XPB and XPD) that are responsible for two forms of XP, a disease characterized by DNA repair anomalies, also cause TTD phenotypes. Mutations that cause XP and TTD are different, demonstrating that a

Bibliography Corbett MA, Dudding-Byth T, Crock PA, et al. A novel X-linked trichothiodystrophy associated with a nonsense mutation in RNF113A. J Med Genet. 2015;52(4):269–274. DiGiovanna JJ, Randall G, Edelman A, et al. Debilitating hip degeneration in trichothiodystrophy: Association with ERCC2/XPD mutations, osteosclerosis, osteopenia, coxa valga, contractures, and osteonecrosis. Am J Med Genet A. 2022;188(12):3448–3462. Faghri S, Tamura D, Kraemer KH, Digiovanna JJ. Trichothiodystrophy: A systematic review of 112 published cases characterises a wide spectrum of clinical manifestations. J Med Genet. 2008;45(10):609–621. Ferri D, Orioli D, Botta E. Heterogeneity and overlaps in nucleotide excision repair disorders. Clin Genet. 2020;97(1):12–24.

Poikilodermas and Aging Syndromes Giglia-Mari G, Coin F, Ranish JA, et al. A new, tenth sub-unit of TFIIH is responsible for the DNA repair syndrome trichothiodystrophy group A. Nat Genet. 2004;36:714–719. Lanzafame M, Nardo T, Ricotti R, et al. TFIIH stabilization recovers the DNA repair and transcription dysfunctions in thermo-sensitive trichothiodystrophy. Hum Mutat. 2022;43:2222–2233. doi: 10.1002/humu.24488. Zhou X, Khan SG, Tamura D, et al. Brittle hair, develop-mental delay, neurologic abnormalities, and photosensitivity in a 4-year-old girl. J Am Acad Dermatol. 2010;63(2):323–328.

AGING SYNDROMES Werner syndrome Synonym

Adult progeria

Epidemiology

1/200.000. More frequent in Japan and Sardinia (founder effect)

Age of onset

Second and third decades of life

Cutaneous findings

Starting from the central years of the second decade, the patients prematurely develop pathologies that resemble traits of normal ageing, such as: • Progressive alopecia and canities • Sclerodermatous-like changes occur on the face, with loss of subcutaneous tissue (Figure 6.32)

135 • Poikilodermatous changes, including atrophy, mottled hyper- and hypopigmented macules and, less frequently, telangiectasias on the entire skin that develop with increasing age • Hyperkeratotic plaques and callosities over the elbows and knees, major joints and the palms and soles • Ulcerations occur due to ischemic changes at traumaprone sites • Mucosal atrophy in a minority of patients • Minor dystrophic nail changes

Extracutaneous findings

• Bird-like facies (Figure 6.32) • At puberty, growth retardation is visible; later, hypogonadism and reduced fertility is observed • Spindle-shaped extremities with sclerodactyly and progressive osteoporosis • Soft-tissue calcification • Severe atherosclerosis develops during the third decade of life, involving mainly cardiac valves and large vessels • Cataracts and glaucoma • High-pitched voice • Early diabetes • Increased incidence of both benign tumours and malignancies (sarcomas, melanomas)

Genetics and pathogenesis

• Autosomal recessive disorder • The Werner gene (WRN) codes for one of the five RECQ human helicases/exonucleases involved in DNA repair, replication, transcription and telomere maintenance • Mutations are found in >90% patients. The remnant 10% of patients may harbour LMNA mutations (see Laminopathies later in the chapter) and reveal an atypical Werner syndrome phenotype similar to LMNA-related cases, suggesting LMNA and WNR interactions within the nucleus • Cellular depletion of the WRN protein causes increased HIF-1 complex stabilization and activation that leads to the generation of mitochondrial reactive oxygen species

Differential diagnosis

• Laminopathies, progeroid syndromes • Rothmund-Thomson syndrome

Course and prognosis

The disease is rapidly progressive after the second decade of life. Heart diseases and malignancies are the major causes of death.

Bibliography

Fig. 6.32 

Labbé A, Lafleur VN, Patten DA, et al. The Werner syndrome gene product (WRN): A repressor of hypoxia inducible factor-1 activity. Exp Cell Res. 2012;318(14):1620–1632. Miller DE, Lee L, Galey M, et al. Targeted long-read sequencing identifies missing pathogenic variants in unsolved Werner syndrome cases. J Med Genet. 2022; 59(11):1087–1094. Rocha ML, Chicharo AT, Sequeira G, Teixeira V. Adult progeria: A new mutation in the WRN gene. BMJ Case Rep. 2022;15(11):e252646. doi: 10.1136/bcr-2022-252646.

Atlas of Genodermatoses

136 Takemoto M, Mori S, Kuzuya M, et al. Diagnostic criteria for Werner syndrome based on Japanese nationwide epidemiological survey. Geriatr Gerontol Int. 2012;13(2):475–481. Tsuge K, Shimamoto A. Research on Werner syndrome: Trends from past to present and future prospects. Genes (Basel). 2022;13(10): 1802.

Cockayne syndrome Epidemiology

Incidence is estimated at 1/200.000 in Western countries.

Age of onset

Age of onset is variable. Normally, CS children appear normal at birth, developing symptoms during childhood (CS type I). Nevertheless, a few patients may be affected from birth (CS type II) and another group may have a late or a very late onset of typical symptoms (CS type III).

Cutaneous findings • • • •

Thinning of the skin and hair Photosensitivity (Figure 6.33) Premature aging appearance Loss of subcutaneous adipose tissue

Extracutaneous findings

• Microcephaly with sunken eyes, beaked nose and prominent ears (Figures 6.34 and 6.35) • Short stature (cachectic dwarfism) • Progressive spastic quadriparesis with stooped posture and joint contractures • Mental retardation (demyelination, brain calcifications and severe neuronal loss) • Cerebellar ataxia • Progressive demyelinating peripheric disorder • Cataracts and retinitis pigmentosa • Overcrowded mouth with severe caries • Hearing loss • Osteoporosis

Fig. 6.34 

Laboratory findings

Magnetic resonance imaging may be useful for detecting the early phases of demyelination and/or brain calcification.

Fig. 6.35 

Genetics and pathogenesis

Fig. 6.33 

• Autosomal recessive • CS may be due to two different genes: ERCC6 and ERCC8 but, additionally, there are three different XP genes, namely, XPB, XBF and XPG, that can cause CS-like phenotypes. All of the genes involved in the pathogenesis of CS are related to the nucleotide excision repair mechanism that is responsible for the repair of DNA damage caused

Poikilodermas and Aging Syndromes

137

by UV radiation. The two involved genes may be related to other processes: lack of DNA repair caused by oxidative damage in active genes, methylation and demethylation processes and excessive cell death caused by apoptosis induced by blocked transcription. The lack of proneness to cancer of CS patients remains to be elucidated. • The ERCC6 gene is also related to other diseases: • De Sanctis-Cacchione syndrome (a variant of XP with severe neurologic involvement) • Cerebro-oculo-facial-skeletal syndrome may represent an allelic form of CS • UV-sensitivity syndrome, characterized by a high degree of photosensitivity with abnormal skin pigmentation, but not cancer proneness, with normal growth and development (a mild form of the disease?) • In addition, mitochondrial transcription was recently shown to be decreased in CS. Further defects in mitochondrial autophagy and mitophagy have been found

Differential diagnosis

• Other progeroid syndromes • Mitochondrial syndromes

Course and prognosis

The disease is inexorable and progressive with a greatly reduced life expectancy in 80% of those affected.

Fig. 6.36 

Follow-up and therapy • • • •

There is no specific treatment for the disease Neurological assessment is mandatory Orthopaedic devices are suggested for joint contractures Physiotherapy is suggested in milder cases

Bibliography Hennekam RCM. Pathophysiology of premature aging characteristics in Mendelian progeroid disorders. Eur J Med Genet. 2020;63(11):104028. Laugel V. Cockayne syndrome: The expanding clinical and mutational spectrum. Mech Ageing Dev. 2013;134(5–6):161–170. Scheibye-Knudsen M, Croteau DL, Bohr VA. Mitochondrial deficiency in Cockayne syndrome. Mech Ageing Dev. 2013;134(5–6):275–283. Spyropoulou Z, Papaspyropoulos A, Lagopati N, et al. Cockayne syndrome group B (CSB): The regulatory framework governing the multifunctional protein and its plausible role in cancer. Cells. 2021;10(4):866.

Acrogeria Synonym

Gottron’s acrogeria

Epidemiology

The disease is very rare: fewer than 25 cases have been reported in the literature, with a preponderance of female patients.

Age of onset

Early childhood

Cutaneous findings

• Non-progressive atrophy of the skin and subcutaneous tissue, mainly involving the distal parts of the extremities (Figures 6.36 and 6.37), rarely trauma induced ulcers • Fine hair

Fig. 6.37  • Cutaneous atrophy of the face (Figure 6.38) • Mottled-type hyperpigmentation of the acral skin, telangiectasia and bruising

Extracutaneous findings • Aged appearance • Intellectual disability • Joint hyperflexibility

Atlas of Genodermatoses

138

Maroofian R, Murdocca M, Rezaei-Delui H, et al. A novel in-frame deletion in ZMPSTE24 is associated with autosomal recessive acrogeria (Gottron type) in an extended consanguineous family. Clin Dysmorphol. 2018;27(3):88–90. Stembridge NS, Vandersteen AM, Ghali N, et al. Clinical, structural, biochemical and X-ray crystallographic correlates of pathogenicity for variants in the C-propeptide region of the COL3A1 gene. Am J Med Genet A. 2015;167A(8):1763–1772.

Kitamura disease Synonym

Familial reticular acropigmentation

Epidemiology

This disease is rare. Estimated prevalence 1/1.000.000.

Age of onset

Fig. 6.38 

First to fourth decades of life

• Growth failure during the first year of life • Corneal opacity • Radiologic anomalies (acro-osteolysis, wide sutures and fontanelles, Wormian bones, mandibular hypoplasia and avascular necrosis of the femoral heads)

Course and prognosis

As the patients are not usually afflicted by generalized atherosclerosis or myocardial diseases as seen in progeria, a normal lifespan can be expected.

Cutaneous findings

• Reticulate acral pigmentation affecting the dorsa of hands and feet (Figure 6.39) • Mild atrophy may be visible as well as palmoplantar pits and anomalies of dermatoglyphs • Palpable lesions are less frequent • Perioral punctate atrophoderma is described

Extracutaneous findings

There is mental retardation in some cases.

Laboratory findings

Laboratory findings

No abnormalities in laboratory studies.

At the ultrastructural examination, there is an increased number of normal melanosomes in the keratinocytes.

Genetics and pathogenesis

Genetics and pathogenesis

• The disease is autosomal recessive in the majority of familial cases • It has been reported mainly in females and almost all of the cases have been sporadic. Familial cases with a history of consanguinity have also been described, as well as cases affecting mother and child • The occurrence of acrogeria and metageria in members of one family indicate that these two disorders are related, and metageria could be regarded as a more severe variant of acrogeria • The disease is caused by mutations in COL3A1, ZMPSTE24 or LMNA genes

• Autosomal dominant inheritance • Reticulate acropigmentation of Kitamura is caused by mutations in ADAM10 gene encoding a zinc metalloprotease

Differential diagnosis • • • • •

Syndromic and non-syndromic lentiginoses Acropigmentation of DOHI Dowling-Degos disease Dyschromatosis universalis hereditaria Naegeli-Franceschetti syndrome

Differential diagnosis

• Ehlers-Danlos vascular type (EDS type IV) • Werner syndrome and other progeroid syndromes

Bibliography Ahmad SM, Majeed I. Familial acrogeria in a brother and sister. Indian J Dermatol Venereol Leprol. 2003;69(3):227–228. Blaszczyk M, Depaepe A, Nuytinck L, Glinska-Ferenz M, Jablonska S. Acrogeria of the Gottron type in a mother and son. Eur J Dermatol. 2000;10(1):36–40. Hadj-Rabia S, Mashiah J, Roll P, et al. A new lamin a mutation associated with acrogeria syndrome. J Invest Dermatol. 2014;134(8):2274–2277.

Fig. 6.39 

Poikilodermas and Aging Syndromes

139

Course and prognosis

The disease is progressive with age; pigmented lesions may involve neck, face and trunk.

Follow-up and therapy

• UV protection • Azelaic acid has been shown to be a potential treatment option

Bibliography Alshaikh H, Alsaif F, Aldukhi S. Clinical and Genetic Review of Hereditary Acral Reticulate Pigmentary Disorders. Dermatol Res Pract. 2017;2017:3518568. doi: 10.1155/2017/3518568. Kono M, Sugiura K, Suganuma M, et al. Whole-exome sequencing identifies ADAM10 mutations as a cause of reticulate acropigmentation of Kitamura, a clinical entity distinct from Dowling-Degos disease. Hum Mol Genet. 2013;22(17):3524–3533. Okamura K, Abe Y, Araki Y, Hozumi Y, Kawaguchi M, Suzuki T. Behavior of melanocytes and keratinocytes in reticulate acropigmentation of Kitamura. Pigment Cell Melanoma Res. 2016;29(2):243–246. Tang JC, Escandon J, Shiman M, Berman B. Presentation of reticulate acropigmentation of kitamura and Dowling– Degos disease overlap. J Clin Aesthet Dermatol. 2012;5(5):41–43.

Dowling-Degos disease Synonym

Galli-Galli disease

Epidemiology

Rare. No reports on prevalence

Age of onset

Usually second decade of life

Cutaneous findings

• Isolated or confluent hyperpigmented macules giving a reticulate appearance on the major folds (Figures 6.40 and 6.41)

Fig. 6.41  • Less frequently, hypopigmented lesions and mild atrophy are visible • Age-related progression of small pigmented follicular papules on major folds • Comedones and hidradenitis suppurativa (PSENEN, POFUT1 and NCSTN genes mutations) • Type II segmental mosaicism (POFUT1 mutation) has been described. Interestingly, second hit somatic mutation leads not only to a phenotypic augmentation but also to a different phenotype (hypopigmented Blaschko-linear streaks with follicular papules in a background of hyperpigmented patches on major folds)

Extracutaneous lesions

In some cases, intellectual impairment.

Laboratory findings

• At ultrastructural examination there is a disturbance of melanosome uptake in keratinocytes • Galli-Galli disease is traditionally mentioned when acantholysis is present at histological examination

Genetics and Pathogenesis

• KRT5 (keratin 5). Absence of K5 filaments may have a role in the uptake of melanosomes • POFUT1, POGLUT1, PSENEN and NCSTN genes mutations • These last four genes are part of the NOTCH signalling pathway that is important in maintaining homeostasis and cell fate during embryogenesis and in the differentiation of keratinocytes and melanocytes, resulting in abnormal uptake of melanosomes by keratinocytes

Differential diagnosis

• Naegeli-Franceschetti disease • Lentiginoses, acanthosis nigricans • Dyschromatosis universalis hereditaria

Course and prognosis Fig. 6.40 

The disease is progressive with age, lesions become confluent and darker with tendency to acne inversa and hidradenitis suppurativa in a subset of patients.

Atlas of Genodermatoses

140 Follow-up and therapy

• Adapalene and azelaic acid • Systemic retinoids • Surgery for vegetant lesions

Bibliography de Oliveira ASLE, de Siqueira RC, Nait-Meddour C, Tricarico PM, Moura R, Agrelli A, d’Adamo AP, Jamain S, Crovella S, de Fátima Medeiros Brito M, Boniotto M, Brandão LAC. A loss-of-function NCSTN mutation associated with familial Dowling Degos disease and hidradenitis suppurativa. Exp Dermatol. 2023 Nov;32(11):1935–1945. Kumar S, Borisov O, Maj C, Ralser DJ, Humbatova A, Hanneken S, Schmieder A, Groß J, Maintz L, Heineke A, Knuever J, Fagerberg C, Parmentier L, Anemüller W, Oji V, Tantcheva-Poór I, FölsterHolst R, Wenzel J, Krawitz PM, Frank J, Betz RC. Founder Variants in KRT5 and POGLUT1 Are Implicated in Dowling-Degos Disease. J Invest Dermatol. 2024 Jan;144(1):181–184.

LAMINOPATHIES Mutations in the A-type lamins A and C, two major components of the nuclear lamina, cause a large group of phenotypically different diseases collectively referred to as laminopathies, which affect nuclear lamins and consist of many different phenotypes, including cardiomyopathies, lipodystrophy syndromes, muscular dystrophies and Charcot-Marie-Tooth disease. Lamins are structural components of the nuclear membrane, but they are also essential for many nuclear functions, such as transcriptional regulation, DNA replication and repair, epigenetic modifications, chromatin remodelling and transition between euchromatin and heterochromatin conformation. Mutations in lamin genes lead to the accumulation of a non-functioning protein that causes cell death. Although LMNA gene mutations are known to cause laminopathies, the responsibility of the ZMPSTE24 gene mutations in these human diseases has also been recognized

Fig. 6.42 

Hutchinson-Gilford syndrome Synonyms

• Progeria • Hutchinson-Gilford progeria syndrome (HGPS)

Epidemiology

Estimated prevalence is 1 in 8.000.000 births. We have personally observed two cases in a 30-year survey.

Age of onset Early infancy

Cutaneous findings (Figures 6.42–6.47)

• Atrophic, scleroderma-like skin with progressive loss of subcutaneous fatty tissue • Epidermis has cigarette paper-like appearance • Venous network becomes clearly visible, especially on the upper trunk and face (facial cyanosis) • Hair is sparse from birth, but worsens within the first years of life to almost alopecic scalp with whitish-blond, thin hair • Aplasia cutis • Poikilodermatous-like changes with prominent hyper- and hypopigmented macules from childhood • Subcutaneous soft nodules (abdomen) have been reported in some patients

Fig. 6.43  • Aspecific nail changes • Absent or hypoplastic nipples have been described • Bird facies with sharp, thin nose and micrognathia with hydrocephalus-like appearance

Extracutaneous findings

• Cardiovascular anomalies (rapidly progressive atherosclerosis, early myocardial infarction and strokes, hypertension and congestive heart failure) • Low weight and stature and general growth failure

Poikilodermas and Aging Syndromes

Fig. 6.44 

141

Fig. 6.47  • Coxa valga is frequent, as well as flexural contractures in the major joints (horse rider gait) • Aseptic necrosis of bones reported, acro-osteolysis and osteoporosis • Sexual secondary characteristics absent • Delayed and abnormal dentitions • High-pitched voice

Complications and course

• Life expectancy is at the end of the second decade due to major cardiovascular events • Myocardial infarction within the first decade is frequent • Rapidly progressive poikilodermatous skin and hair changes • Normal development of intelligence

Laboratory findings

Optical and electron microscopy examinations show aspecific atrophic changes within the epidermis.

Genetics and pathogenesis

Fig. 6.45 

• The causative genes are LMNA, coding for lamins A and C, and ZMPSTE24, which codes for a zinc metalloprotease involved in the correct lamin A maturation pathway • The disease is usually caused by autosomal dominant or, less frequently, recessive mutations in the LMNA gene or autosomal recessive mutations in the ZMPSTE24 gene • The most common mutation leading to HGPS is a heterozygous de novo point mutation in exon 11 (c.1824C4T; p.Gly608Gly) of the LMNA gene. This deletion prevents complete processing of prelamin A, resulting in the accumulation of a farnesylated lamin A, known as progerin

Differential diagnosis • • • • • •

Fig. 6.46 

Rothmund-Thomson syndrome Cockayne syndrome Werner syndrome and other progerias Restrictive dermopathy (RD) Mandibuloacral dysplasia (MAD) Wiedemann-Rautenstrauch syndrome (a rare congenital anomalies/dysmorphic syndrome characterized by marked prenatal and post-natal growth retardation, decreased subcutaneous fat, hypotrichosis, relative macrocephaly and an unusual face. It is caused by bi-allelic variants in the POLR3A gene, which encodes a subunit of RNA polymerase III)

Atlas of Genodermatoses

142 Follow-up and therapy

• Cardiovascular support is mandatory. • Lonafarnib, a farnesyltransferase inhibitor originally developed to treat hepatitis D virus (HDV) infections, has been discovered to inhibit farnesyltransferase to prevent farnesylation and subsequent accumulation of progerin and progerinlike proteins in the nucleus and cellular cytoskeleton • Lonafarnib received first approval by FDA in November 2020 in USA to reduce the risk of mortality in HutchinsonGilford Progeria Syndrome (HGPS)

Bibliography Ahn J, Lee J, Jeong S, Jo I, Kang SM, Park BJ, Ha NC. Structural basis for the interaction between unfarnesylated progerin and the Ig-like domain of lamin A/C in premature aging disorders. Biochem Biophys Res Commun. 2022;637:210–217. Denecke J et al. A homozygous ZMPSTE24 null mutation in combination with a heterozygous mutation in the LMNA gene causes Hutchinson–Gilford progeria syndrome: Insights into the pathophysiology of HGPS. Hum Mutat. 2006;27(6):524–531. Hennekam RC. Hutchinson–Gilford progeria syndrome: Review of the phenotype. Am J Med Genet A. 2006;140:2603–2624. Lamis A, Siddiqui SW, Ashok T, Patni N, Fatima M, Aneef AN. Hutchinson-Gilford progeria syndrome: A literature review. Cureus. 2022;14(8):e28629. Mazereeuw-Hautier J, Wilson LC, Mohamme S, et al. Hutchinson– Gilford progeria syndrome: Clinical findings in three patients carrying the G608G mutation in LMNA and review of the literature. Br J Dermatol. 2007;156:1308–1314. Murtada SI, Mikush N, Wang M, et al. Lonafarnib improves cardiovascular function and survival in a mouse model of Hutchinson-Gilford progeria syndrome. Elife. 2023;12:e82728. Rahman MM, Ferdous KS, Ahmed M, Islam MT, Khan MR, Perveen A, Ashraf GM, Uddin MS. Hutchinson-Gilford progeria syndrome: An overview of the molecular mechanism, pathophysiology and therapeutic approach. Curr Gene Ther. 2021;21(3):216–229.

Fig. 6.48 

Restrictive dermopathy Synonyms

• Fetal akinesia deformation syndrome (FADS) • Tight skin contracture syndrome

Epidemiology

The disease is very rare. There are about 116 published cases.

Age of onset

Fig. 6.49 

At birth.

Cutaneous findings

• Skin is taut, thin, firm, and translucent (Figure 6.48) • Erosion in the major folds and erythema and scaling may be present (Figures 6.49 and 6.50)

Extracutaneous findings

• Dysmorphic facies with an open mouth and pinched nose (Figure 6.48) • Arthrogryposis • Acro-osteolysis • Flexion contractures of joints (Figures 6.49 and 6.50) • Pulmonary insufficiency due to thoracic stiffness and severely restricted movements • FADS sequence is represented by polyhydramnios, reduced fetal movements and dysmorphic facies • Prematurity and IUGR • Micrognathia (Figure 6.48)

Fig. 6.50 

Poikilodermas and Aging Syndromes Course and prognosis

• Restrictive dermopathy may be lethal in utero, perinatally (respiratory insufficiency) or usually within the first weeks of life due to major pulmonary complications • Skin defects also facilitate early infection and dehydration after fluid loss

Laboratory findings

• Flattening of the dermoepidermal junction and thinning of the dermis seen on conventional microscopy • Electron microscopy shows the lack of elastic fibres and the presence of dense dermal patches of collagen and fibroblasts with abundant endoplasmic reticulum and unusually small tonofilaments • Ultrasound during pregnancy may reveal characteristic features of FADS

Genetics and pathogenesis

• Autosomal recessive • Frameshift or nonsense homozygous or compound heterozygous mutations of the LMNA or ZMPSTE24 gene are expected to represent null alleles that cause complete loss of protein function • RD appears to result when ZMPSTE24 activity is completely lacking

143 Epidemiology

This disease is very rare. About 43 cases have been reported worldwide.

Age of onset

In preschool age.

Cutaneous findings • • • • •

Mottled hyperpigmentation Skin atrophy Scleroderma-like skin with subcutaneous calcifications MAD-A: acral lipodystrophy MAD-B, MADPS (MADaM): generalized lipodystrophy

Extracutaneous findings • • • • •

Post-natal growth retardation and failure to thrive Craniofacial anomalies (Figure 6.51) Micrognathia and teeth overcrowding Progeroid appearance Progressive skeletal abnormalities (mandibular and clavicular hypoplasia, acro-osteolysis, delayed closure of cranial sutures, low bone mass and joint contractures) with acral osteolysis (Figure 6.52)

Differential diagnosis

• Harlequin foetus and collodion presentations • Neu-Laxova syndrome

Bibliography Ahmad Z, Phadke SR, Arch E, Glass J, Agarwal AK, Garg A. Homozygous null mutations in ZMPSTE24 in restrictive dermopathy: Evidence of genetic heterogeneity. Clin Genet. 2012;81(2):158–164. Diociaiuti A, D’Amico P, Pisaneschi E, Giancristoforo S, Pappalardo MG, Di Guardo V, Zambruno G, El Hachem M. Teledermatology diagnosis of the first Italian patient affected with restrictive dermopathy due to ZMPSTE24 homozygous mutation. J Eur Acad Dermatol Venereol. 2019;33(3):e139–e140. Kim JY, Kim SH, Ji HY, et al. A case of restrictive dermopathy with novel ZMPSTE24 gene mutation. Pediatr Dev Pathol. 2012;15(5):393–396. Scott JB, Yanes AF, Vivar KL, Yun D, Wagner A, Kruse L, Mancini AJ. Restrictive dermopathy: Three new patients with ZMPSTE24 mutations and a review of the literature. Pediatr Dermatol. 2021;38(6):1535–1540.

Fig. 6.51 

Atypical progeroid syndromes (APSs) APSs have been described in a spectrum ranging from mandibuloacral dysplasia to atypical Werner syndrome. APSs are due to heterozygous, homozygous or compound heterozygous mutations in the LMNA gene other than ZMPSTE24 gene or homozygous BANF1 mutations. The clinical features of patients with atypical progeria include growth retardation and involve the same body systems (bones, body fat, skin and hair) as in classical HGPS, but the course and severity of the symptoms vary.

Mandibuloacral dysplasia (MAD) Synonyms

• Type A: MAD-A • Type B: MAD-B • MADPS (Mandibuloacral dysplasia progeroid syndrome, MADaM)

Fig. 6.52 

Atlas of Genodermatoses

144 • • • •

Bone and joint deformities Short stature Fractures, osteopenia, osteoporosis Metabolic syndrome, such as insulin resistance, glucose intolerance, diabetes mellitus and hypertriglyceridaemia • Vascular complications • Renal disease (renal glomerulosclerosis and severe hypertension in MADPS) • Myopathy has been reported in one case of MAD-B

Course and prognosis

• The course is slowly progressive, hence, reports of the syndrome recognized in adults and paediatric case are scarce • The lifespan of patients extends into the third decade of life or later

Genetics and pathogenesis

• Autosomal recessive • MAD-A: • the disease is caused by homozygosity or compound heterozygosity for different mutations in the LMNA gene • matrix metalloproteinase-9 shows increased levels and activity, influencing bone development, remodelling and homeostasis • MAD-B: • the disease is caused by compound heterozygous or homozygous mutations of the ZMPSTE24 gene • null ZMPSTE24 activity rescued by a heterozygous LMNA null mutation causes a severe, HGPS- like, MAD-B phenotype, whereas partial accumulation of prelamin A with reduced ZMPSTE24 enzyme activity is associated with milder MAD-B phenotypes • MADPS (MADaM): • compound heterozygous or homozygous mutations of the MTX2 gene, involved in transport of proteins into the mitochondrion

Differential diagnosis

• Atypical Hutchinson-Gilford progeria syndrome (AHGPS) • Wiedemann-Rautenstrauch syndrome

Therapy

Lonafarnib treatment also improves the aberrant nuclear phenotypes in MAD-B patient cells with mutations in ZMPSTE24 (P248L or L425P) Therapeutic measures include those aimed at inhibiting bone resorption.

Bibliography Ben Yaou R, Navarro C, Quijano-Roy S, et al. Type B mandibuloacral dysplasia with congenital myopathy due to homozygous ZMPSTE24 missense mutation. Eur J Hum Genet. 2011;19(6):647–654. Cunningham VJ, D’Apice MR, Licata N, Novelli G, Cundy T. Skeletal phenotype of mandibuloacral dysplasia associated with mutations in ZMPSTE24. Bone. 2010;47(3):591–597. Garavelli L, D’Apice MR, Rivieri F, et al. Mandibuloacral dysplasia type A in childhood. Am J Med Genet A. 2009;149A(10):2258–2264. Guglielmi V, D’Adamo M, D’Apice MR, et al. Elbow deformities in a patient with mandibuloacral dysplasia type A. Am J Med Genet A 2010;152A(11):2711–2713.

Jéru I, Nabil A, El-Makkawy G, Lascols O, Vigouroux C, Abdalla E. Two Decades after Mandibuloacral Dysplasia Discovery: Additional Cases and Comprehensive View of Disease Characteristics. Genes (Basel). 2021;12(10):1508. Odinammadu KO, Shilagardi K, Tuminelli K, Judge DP, Gordon LB, Michaelis S. The farnesyl transferase inhibitor (FTI) lonafarnib improves nuclear morphology in ZMPSTE24-deficient fibroblasts from patients with the progeroid disorder MAD-B. Nucleus. 2023;14(1):2288476. Yeter Doğan B, Günay N, Ada Y, Doğan ME. A novel MTX2 gene splice site variant resulting in exon skipping, causing the recently described mandibuloacral dysplasia progeroid syndrome. Am J Med Genet A. 2023 Jan;191(1):173–182.

Nestor-Guillermo progeria syndrome (NGPS) Epidemiology

Three cases have been reported in the literature.

Age of onset

At about 2 years of age.

Cutaneous findings

• Generalized lipoatrophy • Skin is thin, dry, and atrophic, with small light-brown spots over the thorax, scalp and limbs and fine wrinkles over the face • Persistence of scalp hair until the second decade of life • Presence of eyebrows and eyelashes • Marked subcutaneous veins • Dystrophic nails

Extracutaneous findings

• Post-natal growth delay • Aged appearance • Facies with prominent eyes, a convex nasal ridge, a small retrognathic chin and thin lip vermillion • Open cranial sutures • Dental crowding and malocclusion • Clavicular and mandibular hypoplasia • Severe osteolysis with osteoporosis from the second decade of life • Stiff joints • Profound skeletal abnormalities with severe scoliosis • Absence of cardiovascular impairment and metabolic complications in early adulthood

Complications and course

• Patients have a relatively long survival, reaching the third decade of life • Skeletal abnormalities affect quality of life (patients experience pain, dysfunction and disability) and occasionally may result in life-threatening complications, such as pulmonary hypertension

Genetics and pathogenesis

• Autosomal recessive • The disease is caused by homozygous alanine-to-threonine mutation at position 12 (A12T) in the BANF1 gene, which is implicated in nuclear envelope assembly and interacts with lamin A/C • Heterozygous BANF1 mutation carriers have a normal phenotype, indicating that a single copy of normal BANF1 is sufficient to avoid the development of this syndrome

Poikilodermas and Aging Syndromes Differential diagnosis

• HGPS • MAD • Wiedemann-Rautenstrauch syndrome

Follow-up and therapy

Symptomatic treatment and bone forming and antiresorptive agents such as amino bisphosphonates and/or teriparatide, a recombinant human parathyroid hormone, may be a rational approach in the treatment of musculoskeletal abnormalities.

Bibliography Cabanillas R, Cadiñanos J, Villameytide JA, et al. Néstor– Guillermo progeria syndrome: A novel premature aging condition with early onset and chronic development caused by BANF1 mutations. Am J Med Genet A. 2011;155A(11):2617–2625. Fisher HG, Patni N, Scheuerle AE. An additional case of NéstorGuillermo progeria syndrome diagnosed in early childhood. Am J Med Genet A. 2020;182(10):2399–2402. Janssen A, Marcelot A, Breusegem S, Legrand P, Zinn-Justin S, Larrieu D. The BAF A12T mutation disrupts lamin A/C interaction, impairing robust repair of nuclear envelope ruptures in Nestor-Guillermo progeria syndrome cells. Nucleic Acids Res. 2022;50(16):9260–9278.

Mandibular hypoplasia, deafness and progeroid features with concomitant lipodystrophy (MDPL) syndrome

145 Extracutaneous findings • • • • • • • • •

Mandibular hypoplasia Facies with prominent eyes, beaked nose Stiff joints Early onset sensorineural hearing loss Hypogonadism Absent clavicular hypoplasia/acro-osteolyses Osteopenia Insulin resistance Dyslipidaemia

Genetics and pathogenesis

• Autosomal dominant • Almost always a de novo variant in the POLD1 gene, encoding the DNA polymerase δ, conferring proofreading activities of DNA polymerase which, in turn, is involved in DNA replication and in multiple DNA repair mechanisms

Differential diagnosis • HGPS • MAD • NGPS

Follow-up and therapy

Metformin has recently been shown to enhance mitochondrial respiratory activity and is considered as a potential “geroprotector”, due to its ability in increasing proliferation and inhibiting senescence.

Synonyms

Mandibular hypoplasia, Deafness and Progeroid features with concomitant Lipodystrophy syndrome.

Epidemiology

Rare, with a prevalence G; p.I342S and c.1531_1532insT; p.L511Ffs*17) were reported in congenital nuclear cataract combined with hypotrichosis • Biallelic variants in LSS were also reported in alopecia with mental retardation (APMR) syndrome, a rare autosomal recessive condition characterized by hypotrichosis and intellectual disability or developmental delay frequently associated with early-onset epilepsy and other dermatological features

Hypotrichosis simplex of the scalp (HTSS) Age of onset

During the first decade of life.

Cutaneous findings

• Marked hypotrichosis of the scalp, resulting in nearly complete alopecia by the beginning of the third decade of life (Figure 7.1)

APCDD1, SNRPE LSS CDSN, RPL21 U2HR, EPS8L3 KRT71, KRT74, KRT25 LIPH, LPAR6 PADI3, TGM3, TCHH KRT81, KRT83, KRT85 DSG4 HR CDH3

Abbreviations: AD, autosomal dominant; AR, autosomal recessive.

146

Genetics and pathogenesis

Fig. 7.1 

DOI: 10.1201/9781003124351-7

Hair Diseases

147

• Scalp hair is sparse, short and lighter than normal; terminal hair is without signs of inflammation or scarring of the skin • Eyelashes, eyebrows, axillary and pubic hair are not affected and are normal

Genetics and pathogenesis

• Autosomal dominant • CDSN gene coding for corneodesmosin, which is expressed in the inner root sheath of the hair follicles and the cornified layer of the epidermis; it plays an essential role in cellto-cell adhesion • CDSN is also causative of peeling skin syndrome type B • Patients with phenotypes of both conditions caused by nonsense mutation in the CDSN gene have been reported • RPL21 gene, encoding for a ribosomal protein

Differential diagnosis

• Ectodermal dysplasias • Marie-Unna hypotrichosis

Therapy

• Aminoglycoside antibiotics (gentamicin) suppress nonsense mutations by exon skipping. • Three-month cycle with oral minoxidil 0.25 mg/die and growth factors containing caffeine and hyaluronic acid may improve hair growth.

Bibliography Guo D, Zhang Q. A case of LSS-associated congenital nuclear cataract with hypotrichosis and literature review. Am J Med Genet A. 2023;191(9):2398–2401. Hayashi R, Shimomura Y. Update of recent findings in genetic hair disorders. J Dermatol. 2022;49(1):55–67. Kokordelis P, Betz RC. Bi-allelic Mutations in LSS, Encoding Lanosterol Synthase, Cause Autosomal-Recessive Hypotrichosis Simplex. Am J Hum Genet. 2018;103(5):777–785. López-Balboa P, Martos-Cabrera L, Ramírez-Lluch M, et al. Hypotrichosis simplex of the scalp and peeling skin disease, two sides of the same coin. J Eur Acad Dermatol Venereol. 2022;36(10):e789–e790. Ohguchi Y, Nomura T, Suzuki S, et al. Gentamicin-induced readthrough and nonsense-mediated mRNA decay of SERPINB7 nonsense mutant transcripts. J Invest Dermatol. 2018;138(4):836–843. Romano MT, Tafazzoli A, Mattern M, Sivalingam S, et al. Bi-allelic Mutations in LSS, Encoding Lanosterol Synthase, Cause Autosomal-Recessive Hypotrichosis Simplex. Am J Hum Genet. 2018 Nov 1;103(5):777–785. Shimomura Y. Journey toward unravelling the molecular basis of hereditary hair disorders. J Dermatol Sci. 2016;84(3):232–238. Shimomura Y, Agalliu D, Vonica A, et al. APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex. Nature. 2010;464(7291):1043–1047. Besnard T, Sloboda N, Goldenberg A, et al. Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome. Genet Med 2019;21(9):2025–2035. Vastarella M, Martora F, Ocampo-Garza S, Patri A, Battista T, Nappa P, Fabbrocini G, Cantelli M. Treatment of hereditary hypotrichosis simplex of the scalp with oral minoxidil and growth factors. Dermatol Ther. 2022;35(9):e15671. van der Velden JJAJ, van Geel M, Engelhart JJ, Jonkman MF, Steijlen PM. Mutations in the CDSN gene cause peeling skin disease and hypotrichosis simplex of the scalp. J Dermatol. 2020;47(1):3–7.

Fig. 7.2 

Marie-Unna hereditary hypotrichosis Age of onset

At birth or during the first years of life.

Cutaneous findings

• Sparse hair on the scalp and face at birth (Figure 7.2) • Hair loss gradually develops • Progressively, most patients show complete alopecia and sparse androgenetic-like scalp alopecia (Figure 7.3) • Large variations in severity

Genetics and pathogenesis

• Autosomal dominant • U2HR gene on 5′-untranslated region (5′ UTR) of hairless (HR) gene • Increased translation of the main physiological open reading frame of the HR gene that links inhibition of Wnt inhibitor • Loss-of-function mutations of the U2HR gene lead to overexpression of HR protein • Alopecia universalis congenita is caused by homozygous HR (hairless) gene missense mutations • Mutation in EPS8L3 gene, which is involved in the wellestablished pathway of the epidermal growth factor receptor, which is known to transmit extracellular mitogenic signals

Fig. 7.3 

Atlas of Genodermatoses

148 Differential diagnosis

• Ectodermal dysplasias • Hypotrichosis simplex of the scalp • Menkes disease

Bibliography Lee M, Lee G, Chung YJ, Kang MJ, Yu DS, Lee YB. A novel loci of the HR gene in Marie - Unna hereditary hypotrichosis using whole-exome sequencing. Indian J Dermatol Venereol Leprol. 2020;86(3):321–324. Yang J, Liang Y, Zeng K, Huang L, Zheng M. Marie Unna hereditary hypotrichosis: a recurrent c.74C>T mutation in the U2HR gene and literature review. Int J Dermatol. 2014;53(2):206–209. Zhang X, Guo BR, Cai LQ, et al. Exome sequencing identified a missense mutation of EPS8L3 in Marie Unna hereditary hypotrichosis. J Med Genet. 2012;49(12):727–730.

Woolly hair

Fig. 7.5 

Age of onset

At birth or during infancy

Cutaneous findings

• Unruly scalp hair that curls in a spiral but does not form locks and shows a slow twist on its long axis (Figures 7.4 and 7.5)

Fig. 7.6  • Hair is extremely thin, brittle, light coloured, tightly curled and very fragile (Figure 7.6) • Eyebrows and body hair may be affected • Keratosis pilaris atrophicans

Genetics and pathogenesis

Fig. 7.4 

• Autosomal recessive • LIPH gene encodes a membrane-associated phospholipase A1(PA-PLA1) that produces 2-acyl-lysophosphatidic acid (LPA) from phosphatidic acid. Mutations result in loss-of-function of PA-PLA1 • LPAR6 gene, also known as P2RY5, encodes a G-protein-coupled receptor and is a receptor of 2-acyl LPA • C3ORF52 gene, binding with the LIPH gene product and causing altered release of TGF-α, with consequently abnormal hair growth

Hair Diseases

149 Uncombable hair Synonyms

• Pili triangulari et canaliculi • Cheveux incoiffables • Spun-glass hair

Epidemiology

Only about 100 known cases have been reported so far.

Age of onset

From infancy to childhood.

Cutaneous findings

• Dry, coarse, fuzzy, shiny, reddish-blond hairs that stand straight out from the scalp, arranged in different directions and impossible to comb (Figures 7.8–7.10) • These hairs are usually normal in length, quantity and tensile strength and are not fragile • Eyelashes and eyebrows are unaffected • Localized forms have been described • Atopy

Fig. 7.7  • Autosomal dominant • KRT74 gene and KRT71 gene, encoding members of the type II keratin family • KRT25 gene mutations; KRT25 homozygous missense mutation c.712G>T (p.Val238Leu) were identified in two families of Pakistani with autosomal recessive woolly hair • Woolly hair nevus (WHN) is a mosaic disorder characterized by distinct patterns of tightly curled scalp hair (Figures 7.6 and 7.7). WHN may appear concurrently with epidermal nevi (EN) at other sites. WHN represents a mosaic RASopathy due to somatic HRAS p.G12S mutation with phenotype determined by location, either due to distinct epidermal progenitor types or site-specific mesenchymal interactions

Fig. 7.8 

Therapy

Topical minoxidil 2–5% lotion.

Bibliography Akiyama M. Isolated autosomal recessive woolly hair/hypotrichosis: genetics, pathogenesis and therapies. J Eur Acad Dermatol Venereol. 2021;35(9):1788–1796. Gomes TF, Guiote V, Henrique M. Woolly hair nevus: case report and review of literature. Dermatol Online J. 2020;26(1):13030/ qt5nq8f75q. Mizukami Y, Hayashi R, Tsuruta D, Shimomura Y, Sugawara K. Novel splice site mutation in the LIPH gene in a patient with autosomal recessive woolly hair/hypotrichosis: Case report and published work review. J Dermatol. 2018;45(5):613–617. Zernov NV, Skoblov MY, Marakhonov AV, Shimomura Y, Vasilyeva TA, Konovalov FA, Abrukova AV, Zinchenko RA. Autosomal recessive hypotrichosis with woolly hair caused by a mutation in the keratin 25 gene expressed in hair follicles. J Invest Dermatol. 2016 Jun;136(6):1097–1105.

Fig. 7.9 

Atlas of Genodermatoses

150

Fig. 7.11 

Fig. 7.10 

Laboratory findings

• Scanning electron microscopy: individual hair shafts show a longitudinal groove and are triangular in cross section, hence, pili canaliculi et triangulari (~80% of hairs of affected patients) • Histopathologic findings: irregularity in shape of the inner root sheath with premature maturation

Genetics and pathogenesis

• Mutations in the PADI3, TGM3 or TCHH gene: these genes provide instructions for making proteins that help give structure to the hair strand • The proteins produced from the PADI3 and TGM3 genes modify the protein produced from the TCHH gene, known as trichohyalin. The modified trichohyalin can attach to other trichohyalin proteins and to keratin intermediate filaments to create organized cross-links, providing structure to the hair shaft and give it a cylindrical shape • The PADI3 gene is also involved in the pathogenesis of central centrifugal cicatricial alopecia, which is the most common form of scarring alopecia among women of African ancestry

Bibliography Alsabbagh MM. Uncombable hair syndrome and beyond. Acta Dermatovenerol Alp Pannonica Adriat. 2022;31(2):49–64. Drivenes JL, Grimalt R, Betz RC. Ugreelig hår [Uncombable hair]. Tidsskr Nor Laegeforen. 2022;142(10). Norwegian.

Monilethrix

Monilethrix is a rare non-syndromic form of genetic hair disorders characterized by fragile scalp hair shafts.

Cutaneous findings

• Very short, dry, fragile, sparse, matte, brittle and beaded hair (Figure 7.11) • Alopecia of occipital region slowly extending over the entire scalp, and also occurring occasionally in eyelashes, eyebrows and body hair

Fig. 7.12  • Keratosis pilaris as red follicular papules can be associated with abnormal hairs, mainly on the nape and occipital areas (Figures 7.12) • Nails may be brittle

Extracutaneous findings • • • •

Teeth abnormalities Cataracts Syndactyly Oligophrenia

Laboratory findings

• Trichogram shows characteristic beaded appearance of scalp hair shaft: knots and narrowing along the hair shaft similar to pearl necklace. Elliptical knots show a regular periodicity (0.7–1 mm) (Figure 7.13) • Electron microscopy of the hair shaft: narrowing hairs are medullated with cortical and cuticular alterations, with knots of regular periodicity (Figure 7.14)

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Fig. 7.13  Fig. 7.15 

Bibliography Avhad G, Ghuge P. Monilethrix. Int J Trichology. 2013;5(4):224–225. doi: 10.4103/0974-7753.130423. Chabchoub I, Souissi A. Monilethrix. 2022 Jun 21. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. Gómez-Moyano E, Casaño AV, Fernandez Ballesteros MD. Monilethrix. J Pediatr. 2020;224:175.

Atrichia with papular lesions (APL) Epidemiology

This disease is very rare: about 50 pedigrees have been described.

Age of onset Fig. 7.14 

Genetics and pathogenesis

• Autosomal dominant • Mutations in KRT81, KRT83 or KRT85 genes. All these genes encode a type II hair keratin, and are predominantly expressed in the keratinizing zone of the hair shaft cortex. • Autosomal recessive • Mutations in the DSG4 gene, which is expressed in the keratinizing zone of the hair shaft cortex where the expression overlaps with KRT81, KRT83 and KRT85. • DSG4 is also expressed in a dynamic region of the hair bulb, where proliferation and differentiation of the matrix cells actively occur

Differential diagnosis

• Menkes disease • Other hypotrichosis

Therapy

Topical minoxidil 2–5% lotion (Figure 7.15, after several months of treatment)

• First months of life.

Cutaneous findings

• Progressive alopecia leading to complete absence of scalp, axilla and body hair (Figure 7.16) • Lanugo hairs are present at birth in most patients with APL, but such neonatal hairs are usually shed within the first few months of life • At the age of 2 years, patients begin to develop multiple cysts filled with keratin known as follicular papules, which is a unique feature of the disease because catagen follicles are unable to re-enter the anagen phase (Figure 7.17) • Hypochromic streaks on the scalp and milia-like papules on the face • Sparse to absent eyebrows and eyelashes • Lack of secondary axillary, pubic or body hair • Normal sweating and nails

Laboratory findings

• Histopathology of nodules reveals epidermal cysts • Analysis of a scalp biopsy showed rare hair follicles of small size, with cystic lumens and without hair shafts or inflammatory infiltrate

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• The lack of expression of this factor causes disruption of the normal growth cycle of the mature hair follicle resulting in alopecia and development of dermal cysts. • Fifty-one distinct mutations of the HR gene have been described in APL in humans to date

Differential diagnosis

• Familial area celsi (alopecia areata) • Decalvans folliculitis • Ectodermal dysplasias (Clouston syndrome)

Course and prognosis

The disease is rapidly progressive.

Follow-up and therapy

• Cosmetic evaluation • Cosmetic devices • Psychological support

Bibliography

Fig. 7.16 

Ali G, Awan NB, Sadia, Khawaja AW, Foo JN, Khor CC, Chang CH, Chew EG, Kiani FR, Jelani M. Identification of a recurrent nonsense mutation in HR gene responsible for atrichia with papular lesions in two Kashmiri families. J Gene Med. 2020;22(5):e3167. Ibrahim A, Buket Basmanav F, Bohelay G, Lévy A, Betz RC, Caux F. Atrichia with papular lesions: A differential diagnosis of alopecia universalis not to be missed. J Eur Acad Dermatol Venereol. 2021;35(11):e801–e803.

Hereditary hypotrichosis and recurrent skin vesicles Epidemiology Very rare.

Age of onset

First months of life.

Cutaneous findings

• Sparse and fragile hair on the scalp (Figure 7.18) • Absent eyebrows and eyelashes • Vesicles on the scalp and skin of most of the body (Figure 7.19, arrows)

Fig. 7.17 

Genetics and pathogenesis

• Autosomal recessive • Mutations in the human hairless (HR) gene have been identified • This gene encodes a putative zinc finger transcription factor protein that is exclusively expressed in the skin and brain

Fig. 7.18 

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Fig. 7.20 

Cutaneous findings

• Short and sparse hair at birth (Figure 7.20)

Fig. 7.19 

Extracutaneous findings

None.

Laboratory findings

Scalp skin biopsy shows slight follicular plugging, a mild presence of perivascular and periadnexal inflammatory cells and normal hair follicles.

Genetics and pathogenesis

• Autosomal recessive. • The disease is due to homozygous mutations of the DSC3 gene, coding for desmocollin-3

Differential diagnosis

• Localized hypotrichosis • Hypotrichosis simplex of the scalp • Ectodermal dysplasia/skin fragility syndrome

Extracutaneous findings

• Progressive macular degeneration with decreased visual acuity leading to blindness during the first to fourth decade of life

Laboratory findings

• High number of vellus to terminal hair as well as a high number of regressing hair follicles in histopathological • The ocular fundus appearance varies from mild pigmentary changes with diffuse flecks and atrophy to nummular patterns of atrophic and hyperpigmented patches confined to the macula and surrounding areas

Genetics and Pathogenesis

• Autosomal recessive • The disease is due to homozygous deletions of CDH3 gene which encodes P-cadherin, a transmembrane cadherin expressed in hair follicles and retinal pigment epithelium

Bibliography Ayub M, Basit S, Jelani M, et al. A homozygous nonsense mutation in the human desmocollin-3 (DSC3) gene underlies hereditary hypotrichosis and recurrent skin vesicles. Am J Hum Genet. 2009;85(4):515–520.

Syndromic forms of congenital hypotrichosis Hypotrichosis with juvenile macular dystrophy (HJMD) Age of onset

• Hair loss during the first months of life • Progressive macular degeneration in the first or second decade of life

Bibliography Kadhi A, Hamie L, Tamer C, Nemer G, Kurban M. A novel pathogenic CDH3 variant underlying heredity hypotrichosis simplex detected by whole-exome sequencing (WES)—A case report. Cold Spring Harb Mol Case Stud. 2022;8(5):a006225. Sprecher E, Bergman R, Richard G, et al. Hypotrichosis with juvenile macular dystrophy is caused by a mutation in CDH3, encoding P-cadherin. Nat Genet. 2001;29(2):134–136.

Hypotrichosis-lymphedema-telangiectasia syndrome (HLTS)

See Chapter 16.

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154

Congenital hypertrichosis Hypertrichosis is defined as an excessive hair growth compared to the individuals of the same age, race and sex. Congenital hypertrichosis is classified into congenital generalized hypertrichosis and congenital complex syndrome with hypertrichosis.

Congenital generalized hypertrichosis (CGH) Age of onset

Congenital at birth.

Cutaneous findings

• Generalized hypertrichosis lanuginosa, sparing the palms, soles, and mucosae (Figures 7.21–7.23) • Hair is curly and its colour depends upon racial background

Fig. 7.23  • Distribution of body hair may create areas of minor involvement (Figures 7.22 and 7.23) • Clinical presentation may be different within the same family

Extracutaneous findings • • • • •

Fig. 7.21 

Gingival hyperplasia/dental anomalies Mental retardation Deafness Cataracts Skeletal abnormalities

Genetics and pathogenesis

• X-linked recessive (large insertion into the FGF13 gene) • Autosomal recessive (homozygous loss-of-function mutation in the ABCA5 gene) • Autosomal dominant (copy number variation on locus 17q24.2-q24.3) • Aberrant expression of SOX9 transcription factor • Female carriers show hypertrichosis distributed in a checkerboard pattern

Differential diagnosis

• Ambras syndrome • Hormone-dependent hirsutism

Follow-up and therapy

• Search for associated anomalies • Psychological consultation • Lasers for epilation

Bibliography

Fig. 7.22 

Afifi HH, Fukai R, Miyake N, Gamal El Din AA, et al. De Novo 17q24.2q24.3 microdeletion presenting with generalized hypertrichosis terminalis, gingival fibromatous hyperplasia, and distinctive facial features. Am J Med Genet A. 2015;167A(10):2418–2424.

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DeStefano GM, Fantauzzo KA, Petukhova L, et al. Position effect on FGF13 associated with X-linked congenital generalized hypertrichosis. Proc Natl Acad Sci U S A. 2013 May 7;110(19):7790–7795. DeStefano GM, Kurban M, Anyane-Yeboa K, et al. Mutations in the cholesterol transporter gene ABCA5 are associated with excessive hair overgrowth. PLoS Genet. 2014;10(5):e1004333.

Congenital localized hypertrichosis Synonyms

• Hairy elbows • Hairy neck • Hypertrichosis cubiti

Epidemiology

• The condition is uncommon.

Fig. 7.25 

Age of onset

• First years of life.

Cutaneous findings

• In hairy elbows, fine and long hairs are visible within the first years of life on the extensor surface of the arms (Figure 7.24). • Patches of hypertrichosis may be visible on lumbar and sacral areas (Figures 7.25) without any underlying hamartomas or skeletal abnormalities; also, posterior cervical and sternal areas may host patches of isolated long and fine hair. • Lesions are usually single but may be rarely multifocal.

Extracutaneous findings

• Localized hypertrichosis (neck and lumbar region) may be isolated or associated with underlying abnormalities (skeletal and nervous system). • Hairy elbows are associated with short stature in one publication.

Laboratory findings

• There are no specific findings.

Genetics and pathogenesis

• The disease is sporadic and probably autosomal dominant. In hairy elbows, there may be an abnormal distribution during embryogenesis and/or a different maturation of hair follicles due to hormonal stimuli. In other areas, localized hypertrichosis may be considered to be a hamartomatous lesion.

Differential diagnosis

• Neurofibromatosis type 1 (plexiform tumors with hypertrichosis) • Becker nevus

Course and prognosis

• A certain degree of amelioration of the symptoms is described for the hairy elbows condition.

Follow-up and therapy

• Search for associated abnormalities • Laser epilation

Bibliography Buch J, Ranganath P. Approach to inherited hypertrichosis: A brief review. Ind J Dermatol Venereol Leprol. 2021 Jan-Feb;88(1): 11–21. García-Hernández MJ, Ortega-Resinas M, Camacho FM. Primary multifocal localized hypertrichosis. Eur J Dermatol. 2001 JanFeb;11(1):35–37. PMID: 11174135. Saleh D, Yarrarapu SNS, Cook C. Hypertrichosis. 2023 Aug 16. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing.

Congenital complex syndromes with hypertichosis Ambras syndrome Epidemiology 80% of patients and persist throughout life

Follow-up and therapy

• Oral leukokeratosis does not have a propensity for neoplastic changes • Frequent difficulty in walking and using hands • Treatment is palliative and frequently disappointing: • Nail lesions: surgical treatments (radical excision and curettage) • Skin lesions: lubricants, keratolytic agents, antiseptic dressings, special shoes

Nail-patella syndrome Synonym

Nail-patella-elbow

Epidemiology

The incidence is usually given as 1 per 50.000

Age of onset

At birth, but minor or asymptomatic abnormalities are often difficult to diagnose

Cutaneous findings

• Fingernails involved in a symmetrical fashion (98%) with anonychia, hyponychia, koilonychia and onychorrhexis (Figure 8.11) • Characteristic triangular or V-shaped lunula

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Fig. 8.11 

• Fingernail abnormalities are most severe on the ulnar side of the thumb decreasing to the little finger • Toenails are rarely involved • Palmoplantar hyperhidrosis • Absence of distal dorsal phalangeal skin creases

Extracutaneous findings Bone involvement:

• Hypoplasia of the capitulum and radial heel (90%) • Patella aplasia with recurrent or permanent luxation (90%) (Figures 8.12 and 8.13) • Bilateral posterior iliac horns (30%) • Scapular hypoplasia • Scoliosis • Genu valgum • Hyperextensible joints of the digits

Renal involvement: • • • •

Renal dysplasia (40%) Urethral duplication (25%) Glomerulonephritis Renal failure

Fig. 8.13 

Ocular involvement:

• Heterochromia of the iris, with hyperpigmentation of the papillary margin: Lester’s iris (45%) • Microcornea • Glaucoma

Genetics and pathogenesis

• Autosomal dominant disease • Heterozygous inactivating mutations in the LIM homeodomain transcription factor LMX1B • The LIM-homeodomain protein family plays an essential role in the normal development of dorsal-ventral limb structures, morphogenesis and in the functions of podocytes and the glomerular basal membrane, anterior segment of the eye and some types of neurons • Genotype–phenotype correlations have been demonstrated • Several studies have reported entire deletions of the LMX1B gene in patients with NPS, supporting haploinsufficiency as the major pathogenic mechanism underlying the disease • Heterozygous mutation LMX1B R246Q within the homeodomain in isolated nephropathy • A novel missense mutation (c.709T>C, p.S237P) in the LMX1B gene of a child presenting with nephrotic syndrome and rapid progression to early onset end-stage renal disease was identified

Differential diagnosis

Fig. 8.12 

• Patella hypoplasia/agenesis • Small patella syndrome • Nail patella-like disorder characterized by co-occurrence of joint laxity caused by a loss-of-function mutation in WIF1, a WNT signalling regulator involved in mesoderm segmentation • Rapadilino syndrome: underdevelopment or absence of the bones in the forearms and the thumbs (radial ray malformations); patellae underdevelopment or absent; cleft palate, arch palate, slender nose and dislocated joint. The disease is due to recessive mutations in RECQL4 (see also Chapter 6)

Atlas of Genodermatoses

170 Course and prognosis The disease is lifelong

Follow-up and treatment

• Joint abnormalities and associated pain may limit physical activity and are managed with analgesia, physiotherapy and surgery • Primary open-angle glaucoma is treatable, and all patients with nail-patella syndrome should be screened routinely • Annual screening for kidney disease, including blood pressure measurement and urinalysis, should begin at birth • Treatment with angiotensin-converting enzyme inhibitors is indicated for proteinuria and/or hypertension • Less than 5% of cases result in kidney failure. Patients who have undergone kidney transplantation usually have good results

Bibliography Carinelli S, Blanco OA, Perdomo-Ramirez A, Claverie-Martin F. NailPatella syndrome with early onset end-stage renal disease in a child with a novel heterozygous missense mutation in the LMX1B homeodomain: A case report. Biomed Rep. 2020;13(5):49. Jones MC, Topol SE, Rueda M, Oliveira G, Phillips T, Spencer EG, Torkamani A. Mutation of WIF1: A potential novel cause of a NailPatella-like disorder. Genet Med. 2017;19(10):1179–1183. Konomoto T, Imamura H, Orita M, et al. Clinical and histological findings of autosomal dominant renal-limited disease with LMX1B mutation. Nephrology (Carlton). 2016;21(9):765–73.

Iso-Kikuchi syndrome Synonym

Congenital onychodysplasia of the index finger(s)

Cutaneous findings

• Hypoplastic nail and hypoplasia of the index finger are the hallmarks of the disease (Figures 8.14 and 8.15) • Defects of different degrees may involve other fingers and/ or nails and toes

Fig. 8.15  • The full spectrum of onychodysplasia may be present: irregular lunula, malalignment, micronychia, polyonychia, anonychia, and hemi-onychogryphosis

Extracutaneous findings

• Brachydactyly and short hands • Bone malformations of the finger (Y-shaped bifurcation and hypoplasia of the distal phalanx) • Bilateral inguinal hernia

Laboratory findings

• Plain radiographs showed distal phalangeal bone protuberance with characteristic Y-shaped configuration • Ultrasound is a useful non-invasive tool for supporting diagnosis • Arteriography reveals stenosis in the radial artery or palmar digital artery

Genetics and pathogenesis

• Autosomal dominant transmission pattern but no loci have been identified • Different pathogenic theories have been proposed to explain Iso-Kikuchi syndrome: • Fetal disorders affecting the palmar digital artery with in utero ischemic changes • In utero alterations of the crescent-shaped distal phalanx • Fetal exposure to teratogens, in particular antiepileptic drugs

Follow-up and therapy Cosmetic surgery

Differential diagnosis

• Poland syndrome • Other isolated or complex onychodysplasias

Bibliography

Fig. 8.14 

Peña-López S, Monteagudo B, Álvarez-Devesa L, González-Moure C, Figueroa-Silva O, Vilas-Sueiro A. Iso-Kikuchi-Syndrom mit Y-förmiger Bifurkation der distalen Phalanx der Zeigefinger. J Dtsch Dermatol Ges. 2020;18(10):1173–1174 [German]. Pertusi G, Graziola F, Annali G, et al. Iso–Kikuchi syndrome in an Italian newborn with Y-shaped bifurcation of the index fingers. Eur J Dermatol. 2011;21(3):423–424.

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Leuconychia Age of onset

From birth to childhood.

Cutaneous findings

• Nails may be completely white (leukonychia totalis) or incompletely white (leukonychia partialis, striata or punctata) (Figure 8.16) • The colour may be white, milky or porcelain

• Loss-of-function mutations in CAST gene, encoding calpastatin, cause peeling skin syndrome, leukonychia, acral punctate keratoses, cheilitis and knuckle pads, called PLACK syndrome (see Chapter 3)

Course and prognosis This disease is lifelong

Follow-up and therapy Cosmetics

Extracutaneous findings

It can sometimes unmask severe systemic disorders or congenital conditions Hereditary true leukonychia, has been observed and associated with other syndromes • • • • • • • • • • •

Pilar cysts Pili torti Sebaceous cysts Koilonychia Palmoplantar keratoderma Knuckle pads Dental changes Keratosis pilaris Hypoparathyroidism Cataracts Noonan with multiple lentigines syndrome (LEOPARD syndrome) • Renal calculi

Laboratory findings

The keratohyalin containing cells in the nail plate reflect light, resulting in a white nail that prevents visualization of the underlying nail bed

Genetics and pathogenesis

• Mutation of GJB2, encoding for connexin 26 • Mutations in the gene coding for phospholipase C delta-1 (PLCD1), which regulates nail formation downstream of FOXN1, have been identified as relevant in both hereditary autosomal dominant and recessive leukonychia

Bibliography Iorizzo M, Starace M, Pasch MC. Leukonychia: What Can White Nails Tell Us? Am J Clin Dermatol. 2022;23(2):177–193. Yokoyama R, Hayashi R, Ansai O, Hasegawa A, Shinkuma S, Abe R. Congenital leukonychia caused by a mutation in GJB2. Eur J Dermatol. 2021;31(4):560–562.

Yellow nail syndrome Epidemiology

The estimated prevalence is less than 1/1.000.000 In general, the syndrome is acquired and affects adults over age 50. However, there are case reports of YNS occurring in children and even newborns.

Cutaneous findings

• Xanthonychia (yellow nail coloration) • Discoloration varies from pale yellow to dark green; nails can be opaque or translucent

Extracutaneous findings

• Lymphedema in the bilateral lower extremities • Respiratory tract disease as chronic cough, bronchiectasis, recurrent pneumonia, sinusitis and pulmonary fibrosis, followed by pleural effusion with a lymphocytic predominance

Genetic and pathogenesis

• Few cases of familial and congenital YNS have been reported • Dysfunction of the lymphatic system • Exposure to titanium, specifically titanium dioxide (used in various products such as dental and joint implants, surgical staples and various cosmetics) • Associated with certain malignancies, autoimmune diseases, and immunodeficiency disorders

Course and prognosis

Fig. 8.16 

• It depends on the individual’s symptoms and timing of diagnosis • In some mild cases, the symptoms of YNS can resolve without intervention; unfortunately, many symptoms recur despite treatment and require continuous care • Recurring soft tissue infections (e.g., cellulitis from severe lymphedema), pulmonary infections (pneumonia/empyema), and pulmonary effusions can lead to complications such as antibiotic resistance, pulmonary scarring and protein loss

Atlas of Genodermatoses

172 Bibliography

Bibliography

Cheslock M, Harrington DW. Yellow nail syndrome. 2022 Sep 19. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022. Razi E. Familial yellow nail syndrome. Dermatol Online J. 2006;12(2):15. Vignes S, Baran R. Yellow nail syndrome: A review. Orphanet J Rare Dis. 2017;12(1):42. doi: 10.1186/s13023-017-0594-4. PMID: 28241848; PMCID: PMC5327582.

Caputo R, Cappio F, Rigoni C, et al. Pterygium inversum unguis. Report of 19 cases and review of the literature. Arch Dermatol. 1993;129(10):1307–1309. Oiso N, Narita T, Tsuruta D, Kawara S, Kawada A. Pterygium inversum unguis: Aberrantly regulated keratiniza-tion in the nail isthmus. Clin Exp Dermatol. 2009;34(7):e514–e515.

Congenital malalignment of the great toenail

Witkop syndrome See Chapter 11.

Pterygium inversum unguis Synonym

Familial subungual pterygium of the nails

Age of onset At birth.

Cutaneous findings

• The distal part of the nail bed remains adherent to the ventral surface of the nail plate, eliminating the distal groove (Figure 8.17) • The fingers of both hands are affected symmetrically • Occasional paroxysms of digital pain

Epidemiology

No epidemiological data

Age of onset At birth

Cutaneous findings

• Monolateral or bilateral deviation of the toenail plate (Figure 8.18) • Nails may be thickened and dystrophic (Figure 8.19)

Laboratory findings

There are no specific findings

Laboratory findings

On histological examination, a marked, highly eosinophilic, keratinized substance can be detected attaching the distal and visceral nail plate, including the nail’s distal free edge, with distinct, pale and nucleated corneocytes.

Genetics and pathogenesis

• Autosomal dominant and autosomal recessive inheritance • The suggested cause is a disproportional extension of the nail bed epithelium with dislocation of the hyponychium

Course and prognosis The disease is lifelong

Fig. 8.18 

Fig. 8.17 

Fig. 8.19 

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Genetics and pathogenesis

This disease is autosomal dominant

Differential diagnosis

• Naegeli-Franceschetti syndrome • Rubinstein-Taybi syndrome • Note that dysplastic nails may be seen in chromosomal disorders. Volar placement of nails is associated to del6q16-21 and del4q34

Course and prognosis

• Spontaneous improvement is reported • Ingrown nails or onychogryphosis

Follow-up and therapy

• Surgical treatment for ingrown nails • Cosmetic treatment (artificial nail implantation)

Bibliography Buttars B, Scott SG, Glinka D, Daniel CR, Brodell RT, Braswell MA. Congenital malalignment of the great toenail, the disappearing nail bed, and distal phalanx deviation: A review. Skin Appendage Disord. 2022;8(1):8–12.

DOORS syndrome Acronym for:

Deafness, sensorineural hearing loss, Onychodystrophy, Osteodystrophy, mental Retardation and Seizures

Epidemiology

More than 40 cases have been reported

Cutaneous findings

Misshapen, discoloured, hypoplastic and/or rudimentary nails or even absence of nails

Extracutaneous findings

• Coarse facial features with broad nasal bridge, anteverted nares, everted lower lip and high-arched palate • Triphalangeal thumbs • Hypoplasia of the terminal phalanges, and “decapsalidic” fingerprints (an arch pattern on each finger) • Mental retardation • Seizures with abnormal EEG • Deafness

Genetics and pathogenesis

• Autosomal recessive inheritance • Mutation in the TBC1 domain family member 24 (TBC1D24) gene which may serve as GTP-ase activating proteins, involved in the regulation of membrane trafficking

Bibliography Campeau PM, Kasperaviciute D, Lu JT, et al. The genetic basis of DOORS syndrome: An exome-sequencing study. Lancet Neurol. 2014;13(1):44–58. Danarti R, Rahmayani S, Wirohadidjojo YW, Chen W. Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome: A new case report from Indonesia and review of the literature. Eur J Dermatol. 2020;30(4):404–407.

9

NEUROCUTANEOUS SYNDROMES Neurofibromatosis type 1 (NF1)

Epidemiology

Recently, after about 40 years, new diagnostic criteria have been published (see Table 9.1).

Synonym

NF1 is one of the most frequent genetic diseases involving the skin. Recent data give an estimated prevalence of 1/2.000 to 1/2.500

Age of onset

Lesions of NF1 (in analogy of those of Tuberous Sclerosis, see further in this chapter) have a specific age of onset. Data are summarized in Schemes 9.1 and 9.2 for skin and extracutaneous signs, respectively.

Von Recklinghausen disease

TABLE 9.1: Revised Diagnostic Criteria for Neurofibromatosis Type 1 (NF1) A: The diagnostic criteria for NF1 are met in an individual who does not have a parent diagnosed with NF1 if two or more of the following are present: • Six or more café-au-lait macules over 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in post-pubertal individualsa • Freckling in the axillary or inguinal regiona • Two or more neurofibromas of any type or one plexiform neurofibroma • Optic pathway glioma • Two or more iris Lisch nodules identified by slit lamp examination or two or more choroidal abnormalities (CAs) defined as bright, patchy nodules imaged by optical coherence tomography (OCT)/near-infrared reflectance (NIR) imaging • A distinctive osseous lesion such as sphenoid dysplasia,b anterolateral bowing of the tibia or pseudarthrosis of a long bone • A heterozygous pathogenic NF1 variant with a variant allele fraction of 50% in apparently normal tissue such as white blood cells B: A child of a parent who meets the diagnostic criteria specified in A merits a diagnosis of NF1 if one or more of the criteria in A are present. Notes: a lf only café-au-lait macules and freckling are present, the diagnosis is most likely NF1, but exceptionally the person might have another diagnosis such as Legius syndrome. At least one of the two pigmentary findings (café-au-lait macules or freckling) should be bilateral. b Sphenoid wing dysplasia is not a separate criterion in case of an ipsilateral orbital plexiform neurofibroma.

At birth

1 yr

2 yr

4–5 yr

6–7 yr

8–9 yr

Puberty

Adulthood

CALMs Small CALMS at major folds Anemic nevus Herald patches

Plexiform tumors

Hypochromic macules Soft skin touch Darker base colour of skin Juvenile xanthogranulomas MPNST Neurofibromas Glomus tumors Cherry angiomas

SCHEME 9.1  174

DOI: 10.1201/9781003124351-9

Neurocutaneous Syndromes At birth

1 yr

175 2 yr

4–5 yr

6–7 yr

8–9 yr

Puberty

Adulthood

Choroidal amartomas* Lisch nodules+ Optic pathway gliomas UBOs Dysplasia of long bones Sphenoid dysplasia Elevated head circumference Facies Major vascular malformations (pulmonary artery stenosis, congenital heart defects and renal artery stenosis) Specific neuropsychological pattern Hypermotility, sleep disturbances, autism Seizures Scoliosis, hyperlordosis Precocious puberty Stroke Cancer proneness (brain, mammary, blood) Arterial hypertension *present at birth but non-detectable due to patient’s compliance detected only with MRI

+visible in late childhood, rarely before

Detected usually later

SCHEME 9.2 

Cutaneous findings Pigmentary lesions

• CALMs: typical CALMs are variable colour macules (usually light-brown) with a homogeneous tone and a smooth regular border, often present at birth as a first clinical sign of the disease. In fair-skinned newborns, it may be difficult to appreciate and may darken during childhood and adulthood, before lightening again when elderly. They also vary considerably in size from few millimetres to several centimetres, the size increasing in proportion with growth. • Atypical CALMs are defined by jagged contours and irregular borders. • Although CALMs may be located elsewhere on the skin surface, they are most frequently visible on the torso and lower extremities and they usually appear rarely on the face. The number of CALMs increase with age and is also greatly variable and unrelated to the severity of the disease (Figures 9.1–9.3) • CALMs may present a hypochromic halo, especially visible in the context of a Mongolian spot, leading some authors to claim for a further diagnostic sign that may help in early infancy when other signs are absent. This phenomenon may be due to the time of occurrence of the CALM and the

Fig. 9.1  Mongolian spot, reflecting, in our opinion, different times of occurrence of the two different lesions and maybe to the time of migration of melanoblasts in the dermis. Tyndall phenomenon as in blue nevi and Ota nevi may be also involved in the phenotype. Finally, confirming our hypothesis, not all the CALMs intermingled in a Mongolian spot

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Fig. 9.2 

Fig. 9.4 

Fig. 9.3  develop such hypochromic halo and, furthermore, the halo seems to be almost exclusive of the lower thoracic and lumbar areas • CALMs of minor dimensions (historically known as “freckling”) are visible as small lentiginous-like lesions distributed preferentially on large folds (axillary, inguinal, intergluteal), rarely present at birth but, rather, developing during childhood usually from the age of 3-years onwards (Figures 9.4–9.6) • It is relevant to underline that CALMs and “freckling”, unfortunately currently considered two separate entities, show histological, ultrastructural and molecular identity and, in our opinion, may be considered the same lesions, differentiated only by the site of appearance and the time of occurrence

Fig. 9.5  • A subset of patients (5%) presents a diffuse small lentiginous-like pattern involving the entire skin, intermingled with classical CALMs (Figure 9.7). (See also Chapter 15 for segmental lentiginosis) • Hypopigmented ovalar spots similar to those occurring in Tuberous Sclerosis are noted (10% of patients) (Figure 9.8) • Darker coloured skin compared with healthy family subjects

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Fig. 9.8 

Fig. 9.6 

Fig. 9.9 

Fig. 9.7 

Neurofibromas

• Sessile, more rarely pedunculated, benign nodules ranging from 2–3 mm to maximum 1–2 cm in dimensions, flesh coloured, randomly distributed (Figures 9.9–9.12) • Less frequently, they are soft, subcutaneous and slightly protruding with a cupoliform appearance, easily pressable with palpable borders (“button-hole” neurofibromas, “pseudoatrophic macules”) (Figures 9.6 and 9.13)

Fig. 9.10 

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Fig. 9.13 

Fig. 9.11 

Fig. 9.14 

Fig. 9.12  • Neurofibromas are visible from the prepuberal age and very rarely before 8–9 years of age • Subcutaneous neurofibromas may be larger of size, placed along the course of the peripheral nerves with poorly defined borders and elastic consistency

Plexiform tumours

• Visible at birth as hyperpigmented often hairy lesions (“herald patch”) (see Figure 9.14) growing progressively with age as a large subcutaneous soft tumour showing mosaic distribution (due to loss of heterozygosity, Figure 9.15) with a particular “full-bag” texture, located elsewhere on the skin and potentially reaching huge dimensions, becoming the so-called “tumeurs royales” (Figures 9.16 and 9.17)

Fig. 9.15 

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179

Fig. 9.16 

Fig. 9.18 

Fig. 9.17  • More rarely, they are part of an overgrowth syndrome with underlying soft tissues and bone hypertrophy • On the face, they are more often associated to sphenoidwing anomalies (Figure 9.18)

Vascular lesions

• Anaemic nevus (AN) (occurring in the 20–30% of NF1 patients in scholar age) visible since birth, presenting as a non-obvious, less coloured portion of the skin, mimicking hypopigmented macules, spontaneously visible under emotional or temperature stress or evoked by rubbing the skin, located preferentially on the upper trunk (anterior and posterior areas) and neck and more rarely visible on the face and other districts (Figures 9.19 and 9.20)

Fig. 9.19  • AN may be single or multiple and may appear as a polycyclic confluent lesion of different dimensions (usually less than 5 cm) (Figure 9.21) • Spontaneous regression of AN in adulthood is a matter of fact • Blue-red macules: rare (98th centile) and cranial bone abnormalities (Figure 9.31) • Fibrous dysplasia of the sphenoid wing, highly characteristic of the disease, usually monolateral and almost exclusively associated to a neighbouring plexiform neurofibroma and amblyopia (Figure 9.18) • Lordosis, scoliosis of different degree (Figures 9.32 and 9.33), vertebral bodies and ribs may be dysplastic. Chest wall (sternal) abnormalities

Fig. 9.32 

Fig. 9.33 

Fig. 9.31 

• Long bones dysplasias and pseudoarthrosis (Figures 9.34 and 9.35). Non-ossifying fibromas of the proximal femur and distal tibia • About a third of NF1 patients are shorter than the family background • Anomaly of the second toe has been reported • Mesodermal dysplasia (anomalies of collagen structures) is key to the pathogenesis of many of the NF1-related bone abnormalities

Neurocutaneous Syndromes

183 TABLE 9.2  Neurological Complication Learning difficulties Severe cognitive impairment (IQ 2.0, >3.0 in children) at the level of the sinuses of Valsalva, a predisposition for aortic tear and rupture, mitral valve prolapse with or without regurgitation, tricuspid valve prolapse and enlargement of the proximal pulmonary artery • Ectopia lentis (main feature: 75%), myopia, retinal detachment, glaucoma and early cataract formation • Arachnodactyly (Figures 12.46 and 12.47)

Bibliography LeWitt TM, Paller AS, Bell A, et al. Lipoid proteinosis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021.

Marfan syndrome (MFS) Epidemiology

The estimated frequency of this disease is 1:3.000–1:5.000

Age of onset

• First signs are usually visible during late childhood; full-blown picture after puberty, however early onset is possible • Neonatal Marfan syndrome (nMFS) is the most severe form of the disease with fast progression and poor prognosis

Fig. 12.46 

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Fig. 12.47 

Fig. 12.49 

Differential diagnosis

• EDSs • Shprintzen-Goldberg syndrome (a very rare genetic disorder characterized by craniosynostosis, craniofacial and skeletal abnormalities, marfanoid habitus, cardiac anomalies, neurological abnormalities and intellectual disability) • Loeys-Dietz syndrome (discussed next) • Familial thoracic aortic aneurysms and aortic dissection • Homocystinuria

Course and prognosis Fig. 12.48  • Joint laxity (Figure 12.48) • Pes planus (Figure 12.49) • Scoliosis is common and can be mild or severe and progressive • Pectus carinatum or excavatum • Spontaneous pneumothorax • Dural ectasia • Poor muscular tone

Genetics and pathogenesis

• Autosomal dominant disease with high penetrance, rare case reports have described biallelic FBN1 mutations. • About 25% sporadic cases • Mutations in the gene encoding fibrillin I (FBN1) have been found in 90% affected patients, inducing a lack of the fibrillin responsible for the ocular, cardiovascular and musculoskeletal defects • In less than 10% of patients with typical Marfan phenotype, no mutation in FBN1 is identifiable, likely due to complete allele deletion or altered regulation of the FBN1 gene • Mosaic conditions have been reported • No clear genotype-phenotype correlation exists • In almost all nMFS cases, a de novo FBN1 gene mutation was identified in the “neonatal region” involving exons 24–32

• Aortic root disease, leading to aortic regurgitation, aneurysmal dilatation and dissection, is the primary cause of morbidity and mortality in MFS, in up to 60–80% of patients • The lifespan of untreated patients with the classic MFS was approximately 32 years in 1972 but has markedly increased to 72 years. Beta-blockers, non-invasive aortic imaging, and elective aortic root repair have all contributed to an improvement in survival. Life expectancy is significantly lower in men than in women • Pregnancy can be dangerous, especially if the aortic root exceeds 4 cm. Complications include rapid progression of aortic root enlargement and aortic dissection or rupture during pregnancy, delivery and the post-partum period

Follow-up and therapy

• Periodical echocardiographic evaluations. Prophylactic surgery is recommended when the diameter of the ascending aorta at the level of the aortic sinuses reaches 5 cm in adults or older children, when the rate of increase of the aortic diameter approaches 1 cm per year or when progressive aortic regurgitation occurs • Radiography to detect skeletal abnormalities • Annual ophthalmologic assessment • Medications that reduce haemodynamic stress on the aortic wall, such as losartan or Beta-blockers, are generally initiated at diagnosis or for progressive aortic dilatation • Avoid activities that cause joint injury or pain

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Bibliography Arnaud P, Milleron O, Hanna N, et al. Clinical relevance of genotypephenotype correlations beyond vascular events in a cohort study of 1500 Marfan syndrome patients with FBN1 pathogenic variants. Genet Med. 2021;23(7):1296–1304. Kocyigit D, Griffin BP, Xu B. Medical therapies for Marfan syndrome and other thoracic aortic dilatation in adults: A contemporary review. Am J Cardiovasc Drugs. 2021;21:609–617.

Loeys-Dietz syndrome (LDS) This syndrome is mainly characterized by the triad of hypertelorism, cleft palate/bifid uvula and wide-spread aneurysmal disease with arterial tortuosity.

Age of onset At birth

Cutaneous findings • • • • •

Velvety and translucent skin (Figure 12.50) Easy bruising Widened, dystrophic scars Striae distensae Milia

Extracutaneous findings

• Vascular findings: cerebral, thoracic (aortic root dilation in 95% of patients) and abdominal arterial aneurysms and/or dissections, as well as arterial tortuosity that is often most prominent in head and neck vessels • Skeletal manifestations: pectus excavatum/carinatum, scoliosis, joint laxity, arachnodactyly, and talipes equinovarus, cervical spine malformation and/or instability, osteoarthritis (Figure 12.51) • Craniofacial manifestations: ocular hypertelorism, bid uvula/cleft palate, craniosynostosis (Figure 12.52) • Blue sclerae, myopia • Dural ectasia • Spontaneous pneumothorax • Food allergies, seasonal allergies, asthma/chronic sinusitis, eczema, eosinophilic esophagitis/gastritis

Fig. 12.50 

Fig. 12.51  • Inflammatory bowel disease • A minority of affected individuals have developmental delay, most often associated with craniosynostosis and/or hydrocephalus

Fig. 12.52 

Atlas of Genodermatoses

284 Laboratory findings

Histological analysis of aortic vasculature demonstrates abnormalities in the tunica media and greater collagen deposition.

Genetics and pathogenesis

• Autosomal dominant • LDS can be caused by heterozygous pathogenic variant in TGFBR2 (~55–60% of cases), TGFBR1 (~20–25%), TGFB2 (~5–10%), SMAD3 (~5–10%), SMAD2 (~1–5%), TGFB3 (~1–5%) genes • LDS caused by a heterozygous pathogenic variant in any of the six known genes is a continuum in which affected individuals may have various combinations of clinical features. • Wide intrafamilial phenotypic variability • In LDS TGF-beta pathway is enhanced and subsequently leads to dysregulation in the processes that maintain vascular integrity

Differential diagnosis

• MFS • EDS vascular type • Shprintzen-Goldberg syndrome (craniosynostosis, craniofacial and skeletal abnormalities, marfanoid habitus, cardiac anomalies, neurological abnormalities and intellectual disability) • Arterial tortuosity syndrome (discussed next) • TAAD (thoracic aortic aneurysm and aortic dissection)

Course and prognosis

• The natural history of LDS is characterized by aggressive arterial aneurysms (mean age at death: 26.1 years) • Aortic dissection occurs at smaller aortic diameters than observed in MFS • Life-threatening manifestations include spontaneous rupture of the spleen and bowel, and uterine rupture during pregnancy

Follow-up and therapy

Fig. 12.53 

Extracutaneous findings

• Dysmorphic features: long face, hypertelorism, downslanted palpebral fissures, sagging cheeks, large ears, beaked nose and high-arched palate (Figures 12.53 and 12.54) • Tortuosity and elongation of the large and medium-sized arteries, propensity to aneurysm formation and vascular dissection. • Arterial narrowing, both locally and over longer stretches, may be associated • Hernias, skeletal abnormalities, joints hypermobility and congenital contractures

• Beta-adrenergic blockers or angiotensin receptor blockers (ARBs) are prescribed to reduce haemodynamic stress. • Echocardiography at frequent intervals to monitor the status of the ascending aorta • MRA or CT scan with 3D reconstruction from head to pelvis to identify arterial aneurysms and arterial tortuosity throughout the arterial tree • Aneurysms are amenable to early and aggressive surgical intervention • Contact sports and isometric exercise should be avoided

Bibliography Loeys BL, Dietz HC. Loeys-Dietz syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2023.

Arterial tortuosity syndrome (ATS) Epidemiology

About 100 patients reported in the literature

Cutaneous findings

• Hyperextensible skin and CL

Fig. 12.54 

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285

• Diaphragmatic hernia and infant respiratory distress syndrome (IRDS) are frequently observed • Corneal thinning

Laboratory findings

Skin and vascular biopsies show fragmented elastic fibres and increased collagen deposition.

Genetics and pathogenesis

ATS is caused by mutations in the SLC2A10 gene, encoding the facilitative glucose transporter 10 (GLUT10), an intracellular transporter of dehydroascorbic acid, which contributes to collagen and elastin cross-linking in the endoplasmic reticulum, redox homeostasis in the mitochondria and global and gene-specific methylation/hydroxymethylation affecting epigenetic regulation in the nucleus.

Differential diagnosis • • • •

Vascular EDS MFS LDS ARCL1B

Fig. 12.55 

Course and complications

• Death at a young age was related to respiratory insufficiency and ventricular hypertrophy resulting in global heart failure, myocarditis and ischemic stroke • Severe but rare vascular complications include early and aggressive aortic root aneurysms, neonatal intracranial bleeding and gastric perforation • Mortality rate of up to 12% usually before the age of 5 years

Follow-up and therapy

• The occurrence of early aneurysm formation of the aortic root at a young age warrants initial echocardiographic follow-up at least every 3 months until the age of 5 years, and then at least annually • Aortic root replacement for aortic aneurysms and pulmonary artery reconstruction

Bibliography Beyens A, Albuisson J, Boel A, et al. Arterial tortuosity syndrome: 40 new families and literature review. Genet Med. 2018;20(10):1236–1245.

Stickler syndrome Synonym

Hereditary progressive arthro-ophthalmopathy

Epidemiology

Approximately 1:7.500–1:9.000

Age of onset At birth

Cutaneous findings

• Midfacial underdevelopment (most pronounced in infancy) with anteverted nares, depressed nasal bridge, micrognathia, long philtrum and epicanthus (Figures 12.55)

Extracutaneous findings

• Ocular findings: non-progressive myopia (>3 diopters), cataracts, retinal detachment, vitreous anomaly and

• • • • • • •

vitreoretinal dystrophy. Ocular-only phenotypes exist. Thus, a diagnosis of Stickler syndrome should be considered in an individual with suggestive ocular findings even if no systemic features are present Sensorineural or conductive hearing impairment (40% of cases), that may be progressive Bifid uvula Pierre-Robin sequence (micrognathia, cleft palate and glossoptosis) Spondyloepiphyseal dysplasia and/or early-onset osteoarthritis and joint hypermobility Short stature Scoliosis, kyphosis or platyspondyly and pectus carinatum Mitral valve prolapses

Laboratory findings

Quantitative back-scattered electron imaging revealed reduced bone mass and bone turnover

Genetics and pathogenesis

• Stickler syndrome exhibits genetic heterogeneity, as to date, pathogenic variants in six different genes can cause the condition • These genes are associated with the formation of collagens type II, IX and XI, with limited genotype–phenotype correlation • Stickler syndrome caused by mutations in COL2A1, COL11A1 or COL11A2 is inherited in an autosomal dominant manner, while when it is caused by mutations in COL9A1, COL9A2 or COL9A3, it is inherited in an autosomal recessive manner • Type I (COL2A1) 80–90% of cases: congenital membranous vitreous anomaly, high risk for retinal detachment, normal hearing or mild impairment, cleft palate and precocious mild osteoarthritis. Individuals harbouring pathogenic variants in exon 2 will exhibit an ocularonly phenotype due to alternative splicing of the gene • Type II (COL11A1) 10–20% of cases: More severe hearing loss and congenital vitreous anomalies. Mild osteoarthritis

Atlas of Genodermatoses

286 • Otospondylomegaepiphyseal dysplasia (Type III) (COL11A2): No ocular involvement, early-onset osteoarthritis, Pierre-Robin sequence • Type IV-VI (COL9A1, COL9A2, COL9A3): Moderate/ severe sensorineural hearing loss, moderate/high myopia with vitreoretinopathy, cataracts and epiphyseal dysplasia • Interfamilial variability

Differential diagnosis

• Wagner syndrome (for ocular findings) • Binder syndrome (maxillonasal dysplasia) • Pierre-Robin sequence (micrognathia, cleft palate and glossoptosis)

Follow-up and therapy

• Mandibular advancement procedure to correct malocclusion • Treatment of retinal detachment and prevention of visual complications; correction of refractive errors • Symptomatic treatment for arthropathy

Bibliography Boothe M, Morris R, Robin N, et al. Stickler syndrome: A review of clinical manifestations and the genetics evaluation. J Pers Med. 2020;10(3):105.

Fig. 12.57 

Connective tissue nevi Epidemiology

No epidemiological data are available in the literature

Age of onset

Rarely visible at birth, these nevi may be detected within the first decade of life

Cutaneous findings

• “Pure” connective tissue (collagenic) nevi or hamartomas are represented by firm, yellow or flesh-coloured papules and nodules, which may coalesce into plaques of various dimensions located anywhere on the skin (Figures 12.56 and 12.57). More “mixed” hamartomas may be associated with hypertrichosis (Figure 12.58). Mucinous nevi are described as histologic findings

Fig. 12.58 

Extracutaneous findings

• Usually, connective tissue nevi do not show any associations (except for Buschke-Ollendorff syndrome, discussed next) • Nevus lipomatosus (Figure 12.59) and nevi occurring in tuberous sclerosis in the form of shagreen patches and angiofibrolipomatous nevi (see Figures 9.76 and 9.79) are also included in this category

Laboratory findings

• Histologically, these nevi may be well differentiated, following cellular populations and specific patterns.

Genetics and pathogenesis

• All of these nevi represent clones of undifferentiated cells deriving from post-zygotic mutations, distributed randomly without a specific distribution pattern.

Differential diagnosis Fig. 12.56 

• Epidermal nevi • Leiomyomas

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Fig. 12.59 

Course and prognosis

Fig. 12.60 

• Nevi may enlarge slowly, but are usually steady throughout life.

Follow-up and therapy

• Investigations to exclude internal associations • Rarely, these nevi require surgery

Bibliography Arora H, Falto-Aizpurua L, Cortés-Fernandez A, et al. Connective tissue nevi: A review of the literature. Am J Dermatopathol. 2017;39(5):325–341.

Buschke-Ollendorff syndrome Epidemiology 1-9/100.000

Age of onset

Rarely visible at birth, these nevi may be detected within the first decade of life

Cutaneous findings

• Symmetrically disseminated white or yellowish papules on the trunk and extremities composed of elastic or, less often, collagen fibres

Extracutaneous findings

• Osteopoikilosis (OPK) (Figures 12.60 and 12.61)

Laboratory findings

• X-rays shows multiple localized spotted dense sclerotic areas in the bones, often involving cavernous bones, cortical bones, and joints. The closer to the joint, the denser the lesion • Histopathologic examination of the skin lesions demonstrates a normal papillary dermis with numerous thick interlacing fibres in the dermis between and amongst the collagen bundles. Examination with Verhoeff-van Gieson stain reveals numerous elastic fibres, without signs of fragmentation

Genetics and pathogenesis

• Buschke-Ollendorff syndrome is associated with loss-offunction mutations in the LEMD3 gene. LEMD3 may cause

Fig. 12.61  downregulation of transforming growth factor (TGF-ß) and bone morphogenic protein (BMP) downstream target genes by activating the TGF-ß and BMP signalling pathways, leading to the increase of extracellular products (including the increase of collagen and elastic fibres, and the deposition of mucin) • Germline mutations in the LEMD3 gene have been related to a variable phenotypic spectrum, including isolated OPK, and OPK-associated to melorheostosis

Differential diagnosis

• Connective-tissue nevus needs to be distinguished from familial collagenoma and tuberous sclerosis. OPK should be distinguished from metastatic cancer, osteophyseal dysplasia, and so forth • Epidermal nevi • Leiomyomas

Course and prognosis

• Nevi may enlarge slowly, but are usually steady throughout life • Rarely, these nevi require surgery

Atlas of Genodermatoses

288 Bibliography Hellemans J, Preobrazhenska O, Willaert A, et al. Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. Nat Genet. 2004;36:1213–1218.

Melorheostosis A rare bone dysplasia characterized by OPK, cortical and medullary hyperostosis and sclerosis. At X-ray examination, periosteal hyperostosis is reminiscent of a “dripping candle wax”. • The skeletal lesions are usually acral and can be associated with: Soft tissue hyperplasia and focal subcutaneous fibrosis, ectopic calcification and joint contractures of the neighbouring areas Vascular anomalies such nevoid telangiectasia, lymphatic malformations Epidermal nevus Linear scleroderma-like lesions Linear hypertrichosis Linear hyperpigmentation (Figure 12.62) • Loss-of-function mutations in the LEMD3 gene have been described in families with isolated OPK and in families affected by melorheostosis and bone poikilosis • LEMD3 mutations have been found only in a subset of isolated or syndromic melorheostosis. This may be due to the challenging analysis of a mosaic somatic mutations (i.e., representing only 1–2% of cells) • We can speculate that MR may be a mosaic post-zygotic variant of LEMD3 mutations with type 1 or type 2 mosaicism • The involvement of tissues derived from different embryonic compartments may be explained by a precocious somatic mutation in a multipotent stem cell giving rise to a different tissue • LEMD3 germinal heterozygous mutations are responsible for Buschke-Ollendorff syndrome (previously discussed in chapter)

Elastosis perforans serpiginosa Synonym

Lutz-Miescher disease

Age of onset

From 6 to 20 years

Cutaneous findings

• Skin-coloured or slightly erythematous keratotic papules that are 2–5 mm in diameter and arranged in arcuate or serpiginous configurations and located predominantly on the neck, upper part of the trunk, face and extremities (Figures 12.63 and 12.64). • This phenomenon may be seen in different diseases, namely: • MFS • EDS • Pseudoxanthoma elasticum • Down syndrome • Osteogenesis imperfecta • It can be induced by drugs such as D-penicillamine

Laboratory findings

Histopathologic findings include the presence of narrow epidermal sinus tracts containing elastotic material, cellular debris and keratin

Bibliography Wordsworth P, Chan M. Melorheostosis and osteopoikilosis: A review of clinical features and pathogenesis. Calcif Tissue Int. 2019; 104(5):530–543.

Fig. 12.62 

Fig. 12.63 

Fig. 12.64 

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Genetics and pathogenesis • Unknown

Differential diagnosis • • • •

Kyrle disease Granuloma annulare Annular sarcoidosis Porokeratosis of Mibelli

Course and complications

• Usually persistent, with the development of new lesions • Spontaneous involution reported, leaving atrophic scars

Follow-up and therapy

• Various treatment modalities such as topical treatment with corticosteroids, tazarotene, tretinoin, calcipotriol, intralesional corticosteroid, narrow ultraviolet B radiation, cryotherapy and laser therapy have been reported, with poor response. Sometimes it is self-resolving.

Bibliography Besekar SM, Jogdand SD, Naqvi WM. A systematic review of case reports of a rare dermatological condition: Elastosis perforans serpiginosa. Cureus. 2023;15(6):e40296.

Congenital symmetric circumferential skin creases (CSCSC) Synonyms

• Michelin tire baby syndrome • Circumferential skin creases, Kunze type

Epidemiology

Fig. 12.65 

Differential diagnosis • CL • Lymphoedema

Course

The disease is lifelong; spontaneous improvement of skin lesions is frequent

About 20 cases have been reported in the literature.

Age of onset At birth.

Cutaneous findings

• Numerous, symmetric, ring-like lesions on the limbs and trunk, giving an appearance resembling the Michelin tire company’s famous mascot (Figure 12.65) • Occasional hypertrichosis

Extracutaneous findings

• Facial anomalies, including a deformed ear and nose, upslanted palpebral fissures and cleft palate • Intellectual disability and developmental delays are reported in a few patients • Microcephaly • Short stature • Cardiac and genital anomalies

Laboratory findings

• Histopathologic findings include underlying nevus lipomatosus, smooth muscle hamartomas or abnormal elastic fibres. Normal skin histopathology is also reported

Genetics and pathogenesis

• Pathogenic variants in TUBB and MAPRE2 have been linked to CSCSC, in an autosomal dominant manner

Bibliography Isrie M, Breuss M, Tian G, et al. Mutations in either TUBB or MAPRE2 cause circumferential skin creases kunze type. Am J Hum Genet. 2015;97(6):790–800.

Hyaline fibromatosis syndrome Synonyms

• Fibromatosis hyalinica multiplex • Infantile systemic hyalinosis • Juvenile hyaline fibromatosis

Epidemiology

About 100 cases have been reported worldwide.

Age of onset

Between 3 months and 4 years of age.

Cutaneous findings

• Small fleshy, pearly-white papules on the face and neck • Translucent nodules of gelatinous consistency on the fingers, ears and nose (Figures 12.66 and 12.67) • Large subcutaneous tumours on the scalp, trunk and limbs (Figure 12.68) • All three types of lesions may occur in the same patient • The skin covering the joints is often hyperpigmented

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Fig. 12.69  • Hyperhidrosis • Gingival hypertrophy may be severe. The teeth may be overlapped and misaligned (Figure 12.69)

Extracutaneous findings Fig. 12.66 

• Flexion contractures of the large joints is the first and more constant finding • Myopathy • Short stature • Villous atrophy and intestinal lymphangiectasia

Laboratory findings

• Radiography: osteolytic lesions, osteoporosis, and calcification of soft tissue • Histopathologic features: closely packed, thick bundles of collagen, increased numbers of oval and spindle-shaped fibrocytes and homogeneous eosinophilic material that is periodic acid-Schiff positive and diastase resistant

Genetics and pathogenesis

Fig. 12.67 

• Autosomal recessive disease caused by mutations in ANTXR2 which leads to loss of function of the transmembrane protein anthrax toxin receptor 2 • A defect in ANTXR2 can lead to extravasation of hyaline material (plasma components) through the basement membrane into the perivascular space • Abnormal production and accumulation of glycosaminoglycans and glycoproteins • Defect in collagen synthesis

Differential diagnosis

• Winchester syndrome (peripheral osteolysis, interphalangeal joint erosions, subcutaneous fibrocollagenous nodules, facial dysmorphism) • Farber disease (painful and progressively deformed joints, subcutaneous nodules, and progressive hoarseness)

Course and complications

Fig. 12.68 

• • • •

Susceptibility to superficial infections Dental caries The disease is progressive Motor development could be delayed due to physical deformities

Disorders of Connective Tissue Follow-up and therapy

• Infantile systemic hyalinosis is the more-severe form with onset in the newborn period and high mortality rate. Juvenile hyaline fibromatosis patients tend to have a relatively longer life span up to the fourth decade of life in most cases • Therapy is unsatisfactory. Excision of cutaneous lesions is followed by recurrences • Transient improvement of joint contractures can be obtained with systemic corticosteroids or capsulotomy

Bibliography Cozma C, Hovakimyan M, Iurașcu M-I, et al. Genetic, clinical and biochemical characterization of a large cohort of patients with hyaline fibromatosis syndrome. Orphanet J Rare Dis. 2019;14(1):209.

Cutaneous mastocytosis Synonym

• Familial urticaria pigmentosa.

291 Genetics and pathogenesis

• Autosomal dominant pattern with incomplete penetrance is described • Overproduction of mast cells is caused by gainof-function mutations in the c-kit proto-oncogene (KIT), resulting in constitutive activation of KIT tyrosine kinase • Familial cases are 3–13% in literature

Differential diagnosis

• Systemic mastocytosis • Solid tumours (extracutaneous mastocytoma and mast cell sarcoma)

Follow-up and therapy

• Avoidance of mediator-releasing agents • Symptomatic (antihistaminic drugs) • Imatinib and omalizumab seem to be good options in severe systemic cases • Patients showing D816V mutations seems to be non-sensitive to imatinib therapy

Age of onset

• Infancy or childhood.

Cutaneous findings

• Most frequently consists of lesions of urticaria pigmentosa (~50 families): macules, papules or nodules irregularly scattered on the skin with positive Darier sign (Figure 12.70) • Less frequently consists of lesions of telangiectasia macularis eruptiva perstans (three families)

Laboratory findings

• Histopathologic findings: various degrees of mast cell infiltration • Occasional elevated levels of histamine metabolites in the blood or urine

Bibliography Matito A, Azaña JM, Torrelo A, et al. Cutaneous mastocytosis in adults and children: New classification and prognostic factors. Immunol Allergy Clin North Am. 2018;38(3):351–363.

Dermochondrocorneal dystrophy Synonym

François syndrome.

Epidemiology

Fewer than 15 patients have been reported in the literature.

Age of onset

Childhood or adolescence.

Cutaneous findings

• Firm, white-grey papulonodular lesions symmetrically distributed on the back of the hands and on the face (nose and ears) (Figures 12.71 and 12.72) • Hyperplasia of gingival and palatal mucous membranes (Figure 12.73)

Fig. 12.70 

Fig. 12.71 

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• Multicentric reticulo-histiocytosis • Fibroblastic rheumatism • Juvenile hyaline fibromatosis

Course and prognosis

The disease is slowly progressive.

Follow-up

• Multiple surgical operations by ophthalmologists and dentists to correct gingival hyperplasia and pterygoid • Corneal transplants

Therapy

• Papulonodular lesions may be excised

Bibliography Hidalgo-Bravo A, Acosta-Nieto ML, Normendez-Martinez MI, et al. Dermochondrocorneal dystrophy (Francois syndrome) in a Mexican patient and literature review. Am J Med Genet A. 2016; 170A(2):446–451.

Fig. 12.72 

Fig. 12.73 

Extracutaneous findings

• Osteochondrodystrophy of the bones of the hands and feet: subluxations and tendinous contractures with limitations of movement • Corneal dystrophy: bilateral superficial and central white opacities

Laboratory findings

• Increased urinary excretion of hydroxyproline • Histopathology: strong fibrotic reaction and presence of vacuolized cells (spongiocytes)

Genetics and pathogenesis

• Possible autosomal recessive inheritance pattern but no genes have been associated to this disease • Multitissue proliferation of anomalous fibroblasts with hyperproduction of type III collagen

Differential diagnosis

• Familial histiocytic dermoarthritis

GNAS-related syndromes: Osteoma (osteomatosis) cutis (OC), progressive osseous heteroplasia (POH) and Albright’s hereditary osteodystrophy (AHO) The GNAS-related conditions (GNAS is a stimulatory G protein of adenyl cyclase) are rare autosomal dominant disorders of mesenchymal differentiation. As clearly summarized by Adegbite in 2008, osteoma cutis (OC) defines superficial heterotopic ossification, even if the term superficial seems to be rather aspecific. Conversely, progressive osseous heteroplasia (POH), despite some disagreement, is a widely accepted term in the medical literature and defines deeper heterotropic ossification that is not exclusively cutaneous but also fascial and muscular. Albright’s hereditary osteodystrophy (AHO) with or without hormone resistance and pseudohypoparathyroidism also belong to GNAS-related phenotypes. Overall, mutations of GNAS may create a wide spectrum of clinical presentations, starting from OC as the less-severe presentation to a continuum represented by POH and AHO with or without hormonal resistance (pseudohypoparathyroidism). In our opinion, schematic subdivision may appear confusing to students and colleagues who are not particularly devoted to these topics. As for p63-related syndromes, the rule of one gene (GNAS) with a spectrum of different mutations causing different clinical presentations (pleiotropism) must be accepted.

Epidemiology

Less than 100 cases have been described in the literature; the sex ratio is equal.

Age of onset

Initial lesions may be noted in the first year of life.

Cutaneous findings

• Initial lesions are small, firm red–purplish papules and nodules that are palpable and randomly dispersed (Figure 12.74)

Disorders of Connective Tissue

293

Fig. 12.76  Fig. 12.74  • Plaques may be visible later as a consequence of coalescing subcutaneous lesions, with a red–brownish discoloration (Figures 12.75 and 12.76) • The head and face are usually spared • The phenotype is very variable and there is evidence of different clinical expression within the same family • Type II segmental manifestations have been reported, showing a mosaic form of severe HO along Blaschko’s lines • Multiple angiomas

Extracutaneous findings • Oligohydramnios • Low birthweight • Growth retardation

• Usually, normal intelligence in POH patients • Parathormone and thyroid stimulating hormone (TSH) resistance may be seen The classical phenotype of AHO is characterized by: • • • • •

Round face Obesity Brachydactyly Short stature Motor and speech delay requiring extra help in preschool and first grade • In some cases, hormonal resistance • Notably, AHO phenotypes may rarely show heterotopic ossification

Laboratory findings

• Upon conventional microscopy, mature bone formation is visible on the dermis and subcutaneous fat (OC); later, involvement of the fascia, tendons and even muscle is found (POH) • Radiography reveals heterotopic bone in soft subcutaneous tissues • Thyroid function tests and parathyroid hormone levels are normal, as well as vitamin D levels

Genetics and pathogenesis

Fig. 12.75 

• This group of disorders is due to heterozygous loss-offunction mutations in the GNAS gene • Mutations are detected in about 60% of patients and patients without GNAS mutations are indistinguishable from those with confirmed mutations • Data from the literature strengthen the observation that the same GNAS mutation may present with variable phenotypic expression • Interestingly, the GNAS gene shows imprinting: maternally derived mutations result in AHO with

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294

• •

• • •

pseudohypothyroidism, whereas paternal mutations may give rise to POH or AHO with pseudohypothyroidism. Furthermore, some reports demonstrated that this rule is not always true, highlighting phenotypic heterogeneity and clinical overlap of GNAS-related disorders The GNAS gene is a key regulator of adipose-derived mesenchymal progenitor cells’ commitment to osteoblastic differentiation The underlying cause of POH may be second-hit postzygotic mutations, affecting tissues in patients with inherited heterozygous inactivating Gsα mutations (loss of heterozygosity, LOH) It is also shown using mouse models that Gsα ablation causes heterotopic ossification through activation of hedgehog signalling Epigenetic factors (methylation/demethylation) may also modulate clinical presentation in this group of diseases GNAS is also mutated in McCune-Albright syndrome (see also Chapter 15)

Differential diagnosis

• Fibrodysplasia ossificans progressiva: a rare autosomal dominant genetic condition causing osseus heteroplasia with congenital malformations of the great toes and a preossification inflammatory phase. It is caused by an activating missense mutation of the gene encoding the bone morphogenic protein (BMP) type I receptor ACVR1 • Solitary osteoma cutis (post-traumatic or post-inflammatory) • Epithelioma of Malherbe/desmoid tumours • Scleroderma • Laminopathies (localized)

Course and prognosis

• GNAS-related disorders are age-dependent phenotypes; patients may worsen with age • Smaller lesions merge into larger plaques that may result in extensive ossification and ankylosis of the affected joints, leading to limb-length asymmetries, growth retardation of the limbs and limitation of movement • Ulceration of lesions is possible, with discharge of bony material and infections • Even if pain is the major referred symptom, milder cases are reported • The small number of cases renders long-term prognosis difficult to define

Bibliography Adegbite NS, Xu M, Kaplan FS, Shore EM, Pignolo RJ. Diagnostic and mutational spectrum of progressive osseous heteroplasia (POH) and other forms of GNAS-based heterotopic ossification. Am J Med Genet A. 2008;146A(14):1788–1796. Hou JW. Progressive osseous heteroplasia controlled by intravenous administration of pamidronate. Am J Med Genet A. 2006;140(8): 910–913. Lebrun M, Richard N, Abeguilé G, et al. Progressive osseous heteroplasia: A model for the imprinting effects of GNAS inactivating mutations in humans. J Clin Endocrinol Metab. 2010;95(6): 3028–3038.

Cutis verticis gyrata (CVG) CVG is classified as two forms: primary (subdivided into essential and non-essential cases) and secondary. The primary form of CVG is characterized by essentially normal skin histopathology, while secondary CVG occurs as a response to inflammatory or neoplastic processes that produce pathological changes in the scalp structure. The primary non-essential form can be associated with mental deficiency, cerebral palsy, epilepsy, seizures or ophthalmologic abnormalities (cataracts, strabismus, blindness or retinitis pigmentosa). Primary essential CVG, on the other hand, represents an extremely rare situation in which no other abnormalities are identified. Secondary CVG is more common and is associated with cerebriform intradermal nevi, neurofibromas, acromegaly, myxedema, leukaemia, acanthosis nigricans, paraneoplastic syndromes and cutaneous neurocristic hamartoma.

Epidemiology

1 in 100.000 in the male population and 0.026 in 100.000 in the female population.

Age of onset

At puberty, rarely during childhood.

Cutaneous findings

• The term CVG is used to describe a pattern of deep, redundant, linear skin folds in the scalp (Figure 12.77) • The hypertrophy of these skin folds mimics the brain’s gyri • Usually, these deep lines are anteroposteriorly oriented, but horizontal patterns are described, as well as the presence of hypertrophic skin folds on the forehead

Follow-up and therapy

• Orthopaedic advice is mandatory to plan surgery for smaller lesions and for eventual corrective devices for limb asymmetries and growth retardation • Echotomographic examination may be helpful • Analgesic drugs for pain and discomfort in severe cases • Antibiotics for skin ulcerations • Genetic counselling for families, bearing in mind the imprinting of the GNAS1 gene and the related different diseases • Bisphosphonate therapy was found to improve mobility, normalize the deranged calcium/phosphate metabolism, and decrease the alkaline phosphatase (AlkP) level in some patients who are severely affected • Pamidronate may have an effect on energy expenditure, increased appetite and, thus, energy intake

Fig. 12.77 

Disorders of Connective Tissue Extracutaneous findings • • • • • •

Intellectual disability Seizures Schizophrenia Ocular defects Scoliosis Heart defects (rare)

Laboratory findings

At histological examination, connective tissue may be normal with some degree of adnexal hypertrophy

Genetics and pathogenesis

• The possible role of genetic transmission of CVG in uncertain • The familial occurrence is rare and is often associated with pachydermoperiostosis (see Chapter 4). • A hormonal cause of CVG has been postulated due to the male predominance and post-pubertal onset of this disorder; a personal observation of a patient who developed CVG following hormonal therapy for sex change reinforces this hypothesis

Differential diagnosis

295 Follow-up and therapy

• Exclusion of associated diseases • Surgery in disfiguring cases

Bibliography Nguyen NQ. Cutis verticis gyrata. Dermatol Online J. 2003;9:32. Ramos-e-Silva M, Martins G, Dadalti P, Maceira J. Cutis verticis gyrata secondary to a cerebriform intradermal nevus. Cutis. 2004;73: 254–256. Saha D, Kini UA, Kini H. Cutaneous neurocristic hamartoma presenting as cutis verticis gyrata. Am J Dermatopathol. 2014;36(3):e66–e69. Tucci A, Pezzani L, Scuvera G, Ronzoni L, Scola E, Esposito S, Milani D. Is cutis verticis Gyrata-Intellectual disability syndrome an underdiagnosed condition? A case report and review of 62 cases. Am J Med Genet A. 2017;173(3):638–646.

Atrophoderma of Moulin Is a rare and distinct entity presenting as atrophic and hyperpigmented late-onset linear lesions distributed along Blaschko’s lines (Figures 12.79 and 12.80), mimicking morphea lesions and

• Genetic diseases presenting with CVG: • Pachydermoperiostosis • Acromegaly • Ehlers-Danlos syndrome • CL • Acanthosis nigricans (insulin-resistance syndromes) • Costello syndrome • Noonan syndrome • Sotos syndrome • Turner, Klinefelter, and X-fragile syndrome • Beare-Stevenson syndrome • Inflammatory skin diseases with CVG: • Amyloidosis • Myxoedema • Cutaneous focal mucinosis • Giant melanocytic tumours • Cutaneous neurocristic hamartoma (Figure 12.78)

Course and prognosis

The disease slowly progresses with age.

Fig. 12.79 

Fig. 12.78 

Fig. 12.80 

296 may be unilateral and less frequent with mosaic lesions on both sides of the body, with stable non-progressive course but without remission. Lesions are asymptomatic and more rarely preceded by inflammatory-like lesions. Histology shows inflammatory infiltrate and, in some case, collagen may be, as in our case, denser and more sclerotic, leading to decreased dermal thickness (Figure 12.81). Adnexa are not involved, nor are internal organs.

Fig. 12.81 

Atlas of Genodermatoses Bibliography Zhang LW, Li CH, Fu LX, Zhou PM, Meng HM, Shen X, Nie J, Chen T. Linear atrophoderma of Moulin is due to the decreased dermal thickness. Skin Res Technol. 2022;28(4):646–648.

13

FATTY TISSUE ANOMALIES Launois-Bensaude syndrome Synonyms

• Familial symmetric lipomatosis • Madelung’s disease

Epidemiology 1:25.000

Age of onset

From the third decade of life

Cutaneous findings

• Slowly enlarging and disfiguring asymptomatic lipomas affecting: • Type I: neck (Ia) + shoulder grindle + upper arms (Ib) + chest, abdomen, upper and lower back (Ic) (Figures 13.1 and 13.2) • Type II: hips, bottom and upper legs • Type III: general distribution skipping head, forearms and lower legs • Lesions also may be nodular or create a diffuse hypertrophy of the body fat, giving the appearance of a “body-builder” • Progressive macroglossia is a rare but possible finding

Extracutaneous findings

• Glucose intolerance, diabetes and related peripheral neuropathy • Hyperlipidaemia • Gout and renal acidosis • Alcohol abuse is noted in many of the reported patients

Fig. 13.2 

Genetics and pathogenesis

• Majority of sporadic cases • Few pedigrees described (autosomal dominant? personal observation) • The causative gene is unknown • It is assumed to be a discrete malfunction in fat metabolism resulting from damage to mitochondrial DNA

Differential diagnosis

• Dercum’s disease (Adiposis dolorosa) (Figure 13.3) • Other lipomatoses

Laboratory findings

On conventional microscopy, lipomas appear well circumscribed and non-encapsulated

Fig. 13.1 

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Fig. 13.3  297

Atlas of Genodermatoses

298 • Sebocystomatosis • Myoclonic epilepsy with ragged red fibres (MERFF) syndrome with lipomatosis

Course and prognosis

• Prognosis depends on the severity of related metabolic abnormalities • Cutaneous lesions are slowly progressive

Follow-up and therapy

• Check for metabolic abnormalities • Prevention of alcohol abuse • Surgery when mandatory (with a high level of recurrence)

Bibliography Lemaitre M, Chevalier B, Jannin A, et al. Multiple symmetric and multiple familial lipomatosis. Presse Med. 2021;50(3):104077.

Fig. 13.5 

Congenital generalized lipodystrophy (CGL) Synonyms

• Total lipodystrophy • Seip-Lawrence syndrome • Berardinelli syndrome

Epidemiology

Estimated prevalence 1–9/1.000.000

Age of onset

At birth or during early infancy

Cutaneous findings

• Hypertrichosis (Figure 13.4) • Acanthosis nigricans (Figure 13.5) • Scrotal tongue (Figure 13.6) Fig. 13.6  • Hypotrophy of subcutaneous fat • Curly scalp hair • Hypertrophy of external genitalia (Figure 13.5)

Extracutaneous findings

• Severe insulin-resistant diabetes • Characteristic facies with prominent zygomatic bones, hollowed temples, sunken cheeks and prominent ears • Prominent superficial and scalp veins • Muscular hypertrophy • Prominent abdomen • Hepatomegaly • Intellectual disability • Cardiac, ovarian, skeletal and ocular anomalies

Laboratory findings • • • • •

Persistent hyperglycaemia and severe glycosuria Extremely low serum leptin levels Hyperlipidaemia Abnormal liver function Advanced skeletal age

Genetics and pathogenesis Fig. 13.4 

• Autosomal recessive inheritance • AGPAT2 (CGL1) and BSCL2 (CGL2) are the main causative genes. AGPAT2 (1-acyl-sn-glycerol-3-phosphate

Fatty Tissue Anomalies

•

• • • •

acyltransferase beta) is a key enzyme in the biosynthesis of triglycerides. Study of yeast seipin (encoded by BSCL2) indicates that it is located at the junction of endoplasmic reticulum and lipid droplets called adiposomes. When seipin is absent, irregularly shaped small lipid droplets replace these well-formed adiposomes Two additional rarer forms of total lipodystrophy, CGL3 and CGL4, result from biallelic mutations in CAV1 (caveolin-1) and CAVIN1/PTRF, respectively (cavin-1), which are major components of specialized plasma membrane microdomains called caveolae CGL3 patients typically have serum creatine kinase concentrations between 2.5 and 10 times the upper limit of normal in addition to features resembling classic CGL CGL4 is characterized by distal muscular dystrophy, elevated serum creatine kinase concentration and cardiac conduction anomalies in addition to CGL phenotype Intellectual impairment is more frequent in the BSCL2related form (80%) than in AGPAT2 (10%) In rare patients biallelic pathogenic variants in the genes PPARG or LMNA can cause CGL; heterozygous mutations in the same genes are associated with familial partial lipodystrophy

Differential diagnosis

• Leprechaunism • Cockayne syndrome (see Chapter 6) • Rabson-Mendenhall syndrome (a rare syndrome that belongs to the group of extreme insulin-resistance syndromes)

Course and prognosis

• The disease is slowly progressive • Life-expectancy is greatly reduced, mainly due to diabetes and its complications • Sudden death due to cardiac arrhythmia may occur

Follow-up and therapy

• Control of metabolic alterations • Metreleptin (a human leptin analogue) therapy has been shown to improve metabolic abnormalities, including decreased serum triglyceride levels, increased insulin sensitivity, and reduced hepatic steatosis

Bibliography Van Maldergem L. Berardinelli-seip congenital lipodystrophy. 2003 Sep 8 [updated 2016 Dec 8]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Mirzaa GM, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2023.

Partial lipodystrophy Synonyms

• Familial lipodystrophy of limbs and lower trunk • Kobberling-Dunningan syndrome

Epidemiology 1:100.000

Age of onset

Late childhood or puberty

299

Fig. 13.7 

Cutaneous findings

• Loss of subcutaneous fat restricted to the limbs, buttocks and hips (Figure 13.7) • Regional excess fat accumulation is frequent, varies by subtype and may result in a Cushingoid appearance • Acanthosis nigricans • Xanthomas

Extracutaneous findings • • • •

Prominent musculature and veins Insulin-resistant diabetes mellitus Hyperlipoproteinaemia Cardiomyopathy

Genetics and pathogenesis

• Autosomal dominant disorder mainly caused by missense mutations in the lamin A/C (LMNA) gene encoding nuclear lamina proteins, structural components of the nuclear envelope • Heterozygous mutations of gene coding PPARG, an adipogenic transcription factor, lead to milder forms with severe hypertension and metabolic diseases • Heterozygous mutations in PLIN1, which codes for perilipin, the most abundant protein coating lipid droplets in adipocytes, where it is required for droplet formation and maturation, optimal triglyceride storage and the release of free fatty acids from the droplet, are reported. The pattern of lipodystrophy associated with PLIN1 variants differs from the previously described forms of familial partial lipodystrophy, with a more uniform reduction in all fat depots • Other rarer forms are caused by mutations in CIDEC and LIPE genes (both with autosomal recessive inheritance) and ADRA2A and AKT2 genes (autosomal dominant) • Heterozygous mutation in the CAV1 gene can cause familial partial lipodystrophy-7 (FPLD7)

Differential diagnosis

• Acquired lipodystrophy • Scleroderma

Course and prognosis

The disease is slowly progressive

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Sebocystomatosis

Follow-up and therapy

No treatment is available. Metreleptin therapy in partial lipodystrophy is approved in Europe through compassionate care programs. Patients with lower leptin levels show the most benefits.

Bibliography Brown RJ, Araujo-Vilar D, Cheung PT, et al. The diagnosis and management of lipodystrophy syndromes: A multi-society practice guideline. J Clin Endocrinol Metab. 2016;101(12):4500–4511.

Lipomas, familial multiple lipomatosis and nevus lipomatosus

Synonyms • • • •

Steatocystoma multiplex Eruptive vellus hair cysts Multiple pilosebaceous cyst syndrome Hereditary epidermal polycystic disease

Age of onset Adolescence

Cutaneous findings

• Asymptomatic, multiple (up to hundreds) dome-shaped, smooth papulonodular lesions that are skin-coloured or

Lipomas are by far the most frequent type of soft tissue benign tumour with a prevalence of more than 2:1000. They are easily recognizable as asymptomatic subcutaneous masses, usually well-defined and encapsulated, isolated or multiple and may be part of an autosomal dominant disorder ( familial cutaneous lipomatosis) in which lipomas are diffuse in the entire body surface with predilection for the dorsal areas and the upper limbs. In severe familial cases, lipomatous masses may be located elsewhere in the internal organs, causing symptoms due to the compression of the involved structures. Nevus lipomatosus (NL, also called NL superficialis or NL of Hoffmann-Zurhelle) consists of soft, vegetant, cerebriform and confluent nodules of different size arranged on a segmental pattern, especially located on dorso-lumbar areas and buttocks (Figure 13.8) (see also encephalocraniocutaneous lipomatosis, Chapter 18). Histopathologically, they show hyperplastic and lobulated fatty tissue and may be combined with different degrees of angiomatous (angiolipomas) or connective tissue ( fibrolipomas) proliferation. Similar lesions may be seen in tuberous sclerosis (see Chapter 9).

Fig. 13.9 

Fig. 13.8 

Fig. 13.10 

Fatty Tissue Anomalies variably pigmented (yellow, blue or red–brown), varying in diameter from 1 mm to 20 mm • The cysts commonly involve the face, scalp, arms, trunk and thighs (Figures 13.9–13.12)

301 • The cysts contain an oily, clear or opaque, milky or yellowish, odourless fluid or cheesy solid material • Occasionally, lesions may be localized

Laboratory findings Histopathologic findings:

• Eruptive vellus hair cysts: cystic proliferation lined by squamous epithelium with an evident granular layer and containing keratinous material and vellus hairs • Steatocystoma multiplex: cystic proliferation characterized by stratified squamous epithelium without a granular layer and associated with large sebaceous glands located within the cyst wall

Genetics and pathogenesis

• Autosomal dominant disease • The familial sebocystomatosis is associated with a mutation in the KRT17 gene, encoding a type I keratin expressed in a number of epidermal appendages, such as the nail bed, hair follicles and sebaceous glands • Keratin 17 mutations are also responsible for a subset of pachyonychia congenita with variable hair and tooth anomalies • Multiple pilosebaceous cysts seem to be a nevoid malformation of the pilosebaceous duct junction zone. The resulting cystic tumours may develop with a predominantly follicular differentiation as in eruptive vellus hair cysts, or with differentiation and imitation of the sebaceous duct as in steatocystoma multiplex

Fig. 13.11 

Differential diagnosis • • • • • •

Adnexal tumours Epidermoid cysts Trichilemmal cysts Perforating dermatoses Milia Acne cysts

Course and prognosis

• After eruption, the lesions become stationary; occasional spontaneous resolution occurs through transepidermal elimination • Risk of infections

Follow-up and therapy

• Surgery for cystic lesions • Oral retinoids and antibiotics • Yttrium aluminum garnet and CO2 lasers

Bibliography

Fig. 13.12 

Koprulu M, Naeem M, Nalbant G, Shabbir RMK, Mahmood T, Huma Z, Malik S, Tolun A. KERATIN 17-related recessive atypical pachyonychia congenita with variable hair and tooth anomalies. Eur J Hum Genet. 2022;30(11):1292–1296. Zhang B, Sun L, Fu X, Yu G, Liu H, Zhang F. Mutation analysis of the KRT17 gene in steatocystoma multiplex and a brief literature review. Clin Exp Dermatol. 2020;45(1):132–134. doi: 10.1111/ced.14030. Epub 2019 Sep 17. PMID: 31237972.

14

APLASIA CUTIS Aplasia cutis Epidemiology

0.5–1/10.000 live births

Age of onset At birth

Cutaneous findings (Frieden’s classification, Table 14.1)

• Total (full thickness, ulcerated) (Figure 14.1) or partial (membranous) (Figure 14.2) absence of skin components, frequently focal and single, but may more rarely be multiple (Figure 14.3) • Largely, the preferred site is the scalp (vertex), but all areas may be involved (Figures 14.4 and 14.5) • Lesions are round or oval and usually small (1–4 cm diameter) • Larger and irregular lesions are rare • Often, on the scalp, a collarette of darker and even hair is present around the aplastic lesion (Figure 14.6)

Fig. 14.2 

TABLE 14.1 Type Description 1 2 3 4 5 6 7 8 9

Scalp ACC without multiple anomalies Scalp ACC with associated limb abnormalities Scalp ACC with associated epidermal and organoid nevi ACC overlying embryologic malformations ACC associated with fetus papyraceous or placental infarcts ACC associated with epidermolysis bullosa; not a real type of ACC ACC localized to extremities without blistering ACC caused by specific teratogens ACC associated with malformation syndromes

Fig. 14.3 

Fig. 14.1  302

Fig. 14.4 

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Aplasia Cutis

303

Fig. 14.5 

Fig. 14.7 

Fig. 14.6  • Lesions heal in a few months, leaving atrophic and alopecic scars (Figure 14.7); some cases show hypertrophic or keloidal scars • Large, irregular and deforming scars on the abdomen and trunk are associated with intra-uterine twin death, fetus papyraceus and placental thrombosis (type V aplasia cutis congenita) (Figures 14.8 and 14.9) • A single case of aplasia cutis distributed along Blaschko’s lines is reported • Cutis marmorata telangiectatica congenita is statistically more frequent in patients with aplasia cutis congenita • Epidermal–sebaceous nevus of the head and face can be associated

Fig. 14.8 

Extracutaneous findings

• Skull defects and meningeal exposure are associated with severe ulcerated lesions of aplasia cutis • Vertebral midline closure defects and meningocele • More rarely, severe central nervous system (CNS) malformations are associated • Limb defects (anomalies of the fingers) appear to be genetically heterogeneous and are relatively frequent (10–20%) as distal phalangeal aplasia, ectrodactyly and syndactyly

Laboratory findings

Echotomography (Figure 14.10) is diagnostic, especially for large lesions, which are associated with fetus papyraceus.

Fig. 14.9 

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304

Fig. 14.12 

Differential diagnosis Fig. 14.10 

Fig. 14.11 

Genetics and pathogenesis

• Most cases are sporadic, but dominant (Figure 14.11) and, less frequently, recessive and mosaic forms have been documented. Autosomal-dominant aplasia cutis is due to BMS1 gene defect. The mutated ribosomal GTPase BMS1 interferes with preribosomal RNA processing and led to a reduced cell proliferation rate • Aplasia cutis seems to be related to closure defects during embryo development (midline in the scalp is represented by a camera obturator mechanism, and these defects explain the round or oval shape of aplasia cutis lesions at the vertex) • Trisomy 13 and chromosome 12q abnormality are associated with aplasia cutis • Aplasia cutis maybe due to the teratogenic effects of some drugs taken during pregnancy (e.g., thyreostatics as methimazole, valproic acid, benzodiazepines, heparin, cocaine), intrauterine trauma or determined by herpes virus diseases contracted during gestation

• Adams–Oliver syndrome (see Chapter 16) • Setleis disease (bilateral forceps marks and aplasia cutis) (Figure 14.12) • Scalp-ear-nipples (SEN) syndrome: Congenital aplasia cutis of scalp, lack of nipples or breasts, variable anomalies of digits, ears and nails. It is due to autosomal dominant missense mutations in the potassium-channel gene KCTD1 • Delleman syndrome or oculocerebrocutaneous syndrome and drop-like lateral aplasia cutis (Figure 14.13) • Rapp-Hodgkin syndrome (p63 defect-related ectodermal dysplasia) (see Chapter 11) • Goltz syndrome (see Chapter 11) • In all three forms of epidermolysis bullosa at birth, even large areas of the body (abdomen, arms and legs) may be denuded (formerly known as Bart’s syndrome), owing to the specific defects of each form: this clinical phenotype shouldn’t be considered as an aplasia cutis but it is due to complications related to the genetic defects in EB patients • Johansson–Blizzard syndrome (beak-like nose, mental retardation, aplasia cutis, skin dimples and hair anomalies) • Amniotic rupture sequence

Fig. 14.13 

Aplasia Cutis

305 Follow-up and therapy

• Diagnostic images (echotomography and MRI) are useful to follow the spontaneous healing of full-thickness lesions • Neurologic and orthopaedic advice for CNS lesions and limb defects

Bibliography Freiden IJ. Aplasia cutis congenital: A clinical review and proposal for classification. J Am Acad Dermatol. 1986;14:646–660. Maillet-Declerck M, Vinchon M, Guerreschi P, et al. Aplasia cutis congenita: Review of 29 cases and proposal of a therapeutic strategy. Eur J Pediatr Surg. 2013;23(2):89–93. Marneros AG. Genetics of aplasia cutis reveal novel regulators of skin morphogenesis. J Invest Dermatol. 2015;135(3):666–672. Sathishkumar D, Ogboli M, Moss C. Classification of aplasia cutis congenita: A 25-year review of cases presenting to a tertiary paediatric dermatology department. Clin Exp Dermatol. 2020; 45(8):994–1002.

Fig. 14.14  • Focal facial dermal dysplasia type 4: isolated, single or multiple, pre-auricolar atrophic skin lesions with or without hair collarette, no facial dysmorphism associated (Fig. 14.14)

15

DISORDERS OF PIGMENTATION Scheme 15.1. A schematic illustration of known, crucial steps in neural crest specification and migration, respectively melanosome biogenesis.

Oculocutaneous albinisms

• Rarely, there is the possibility of a heat-related pattern in the secretion of melanin in milder cases, as occurs in Siamese cats

Extracutaneous findings

• The iris may be pink-red or blue-grey in milder cases, and shows translucency on slit lamp examination (Figures 15.1 and 15.2) • Strabismus (Figure 15.2), nystagmus, photophobia and poor vision • Foveal hypoplasia (Figure 15.6) • Even auditory-evoked responses may be abnormal, without hearing impairment

OCA type 1 Synonyms

• Tyrosinase-negative albinism • OCA1 types A and B

Epidemiology

• OCAs in general have an estimated frequency worldwide of 1:17.000 • OCA1 in Europe has a prevalence of 1:40.000, but is very rare among Africans and African-American people

Complications

• Long-term exposure to the sun of lightly pigmented skin can result in coarse, rough, thickened skin (pachydermia) • Rare amelanotic melanomas • Sunburn and squamous and basal cell carcinomas (ultraviolet [UV]-induced) (Figure 15.4)

Age of onset At birth

Cutaneous findings

• Wide spectrum of presentations, depending on genotype– phenotype correlation • From total absence of melanin in skin, hair and eye (the classic albino features, or OCA1 type A) (Figures 15.1–15.4) to milder cases with hair pigmentation and changes after sun exposure with the occurrence of nevi and freckles (OCA1 type B) (Figure 15.5) Neural crest specification and migration WS4A WS4B

Course

• In milder cases, some degree of pigmentation of the skin, hair and eyes is visible during childhood and adolescence • In the same cases, it is common to detect melanocytic nevi, ephelides and lentigines (Figure 15.3) • Nystagmus may ameliorate with age

Stage 1

WS2

EDN3

KITLG

PMEL17

EDNRB

C-KIT

PMEL17

WS: Waardenburg syndrome

HermanskyPudlak

Melanosome biogenesis

MITF

AP1 AP3

MAPK

BLOC1

HPS2 HPS9 BLOC2

WS1 Waardenburg type I

PAX3

WS2A

P MITF

SOX10

BLOC3

WS2E WS4C

HPS5

TYR P DCT TYRP1 MATP

aMSH MC1R

OCA1A,B OCA2 OCA8 OCA3 OCA4

Red hair

Oculocutaneous albinisms

HPS1,4 Stage 2, 3

WS2D SNAI2

Stage 4

? c-SRC P BDCS SH3PXD2B

Borrone-TerHaar syndrome

cActin

MT

Griscelli

GS1

MYOS0A

GS2

RAB27

MLPH

GS3

LYST?

CHS

Chediak-Higashi

SCHEME 15.1  Modified from Van Steensel MA, Semin Cell Dev Biol. 2016 306

DOI: 10.1201/9781003124351-15

Disorders of Pigmentation

307

Fig. 15.3 

Fig. 15.1 

Fig. 15.4 

Fig. 15.2 

Laboratory findings

• On histological examination, skin, and hair-bulb structures are normal • On ultrastructural examination, the first step of the development of cytoplasmic organelles with melanin-related functions is normal

Genetics and pathogenesis

• OCA1 is inherited in a recessive mode and is due to mutations of the TYR gene. There is wide variability in gene mutations, including stop-codon, missense, splicing, frameshift and deletion mutations, which is responsible for the wide variation in phenotypes of these patients

Fig. 15.5 

Atlas of Genodermatoses

308 OCA type 2 Synonym

Tyrosinase-positive albinism

Epidemiology

OCA2 may be the most common albinism in African (1:3.900) and African-American populations (1:10.000); by contrast, in Europe, there is an estimated prevalence of 1:36.000.

Age of onset At birth

Cutaneous findings

• Some amount of pigment is present at birth • Minimal to moderate pigmentation of the hair, skin, and eyes from northern Caucasian to Mediterranean populations • Hair may be fairly blond at birth and the skin may be creamy (Figures 15.7 and 15.8)

Fig. 15.6  • OCA1 type A is caused by null mutations of the TYR gene that produce a completely inactive or an incomplete tyrosinase enzyme polypeptide • OCA1 type B is caused by mutations of the TYR gene that produce a partially active tyrosinase enzyme. Affected individuals may be homozygous for a single hypomorphic mutation, compound heterozygous for two different hypomorphic mutations or compound heterozygous for a hypomorphic and a null or inactivating mutation • A particular missense mutation renders the tyrosinase gene temperature sensitive. Those patients with temperature-sensitive cutaneous albinism develop some degree of pigmentation in the cooler areas of the body after puberty, producing the Siamese cat pattern

Differential diagnosis • • • •

Other OCAs X-linked ocular albinism Hermansky-Pudlak syndrome Chediak-Higashi syndrome

Fig. 15.7 

Follow-up and therapy

• Ocular assessment is mandatory in the follow-up of these patients • Prevention of sunburn and UV-derived complications to avoid skin cancers

Bibliography Li C, Chen Q, Wu J, Ren J, Zhang M, Wang H, Li J, Tang Y. Identification and characterization of two novel noncoding tyrosinase (TYR) gene variants leading to oculocutaneous albinism type 1. J Biol Chem. 2022;298(5):101922. Lin S, Sanchez-Bretaño A, Leslie JS, et al. Evidence that the Ser192Tyr/ Arg402Gln in cis Tyrosinase gene haplotype is a disease-causing allele in oculocutaneous albinism type 1B (OCA1B). NPJ Genom Med. 2022;7(1):2. van Steensel MA. Making the invisible visible. Semin Cell Dev Biol. 2016;52:58–65.

Fig. 15.8 

Disorders of Pigmentation • In African and African-American populations, the hair is yellow and the skin is very clear (Figures 15.9 and 15.10) • Brown OCA, initially identified in Africans and AfricanAmericans with light brown hair and skin, is part of the spectrum of OCA2 • Hair colour may darken with age as well iris pigmentation

309 Extracutaneous findings

• The iris may be blue-grey or sandy in colour with punctate and radial translucency • Retinal pigmentation is fair • Visual impairment is common • Nystagmus • Misrouting of the optic nerve fibre radiations at the chiasm, associated with strabismus, reduced stereoscopic vision and altered visual-evoked potentials

Genetics and pathogenesis

The OCA2 gene, a human homolog of the mouse pink-eye dilution locus, is mutated in these patients; different types of mutation are present, giving rise to different phenotypes. The OCA2 gene product, the pink protein, modulates the processing and trafficking of tyrosinase, acting as an ion transporter and modulator of melanosomal pH, resulting in the abnormal secretion of melanin. This gene is 1 of about 16 different genes that are responsible for the determination of human eye colour. The disease is inherited in a recessive manner.

Differential diagnosis

Fig. 15.9 

• Other OCAs • Hermansky-Pudlak syndrome • Interestingly, diffuse depigmentation can be noted also in Down syndrome and in Prader-Willi-Angelman syndrome complex (due to parent-of-origin deletions of 15q11–13): • Prader-Willi syndrome (deletion in paternally inherited chromosome 15) is characterized by neonatal hypotonia and poor feeding. On the contrary, during infancy they become hyperphagic and obese. They show also short stature and developmental delay • Patients affected by Angelman syndrome (deletion in maternally inherited chromosome 15) show ataxia and severe learning and speech delay

Course

• During the first two decades of life, pigmented nevi and freckles may occur • No tan develops after sun exposure • Possible development of cutaneous neoplasias

Follow-up and therapy

• Ophthalmological assessment is mandatory, as well as preventative measures to ensure avoidance of UV-induced damage • Annual skin examination for the evidence of sun-related skin damage and/or pre-cancerous or cancerous lesions

Bibliography Loftus SK, Lundh L, Watkins-Chow DE, et al. A custom capture sequence approach for oculocutaneous albinism identifies structural variant alleles at the OCA2 locus. Hum Mutat. 2021;42(10):1239–1253.

OCA type 3 Epidemiology Fig. 15.10 

This form of OCA seems to be more frequent in the South African native population (1:8.500) and is very rare in northern European and American populations.

Atlas of Genodermatoses

310 Age of onset At birth

Cutaneous findings

Light-brown skin and hair to reddish-brown skin and red hair (rufus albinism) (Figures 15.11 and 15.12).

Extracutaneous findings

Genetics and pathogenesis

The disease is autosomal recessive and is due to mutations in the TYRP1 gene. The TYRP1 protein, which is one of the melanosomal glycoproteins, has the activity of a catalase (catalase B) that is related to the oxidation process, leading to indolequinones in the eumelanin pathway. The peculiar reddish hue may be due to the uninvolved secretion of phaeomelanins.

Blue-grey iris and nystagmus

Bibliography Patel MH, Dolinska MB, Sergeev YV. Tyrp1 mutant variants associated with OCA3: Computational characterization of protein stability and ligand binding. Int J Mol Sci. 2021;22(19):10203.

OCA type 4, OCA type 5, OCA type 6, OCA type 7 and OCA type 8 A further OCA, named OCA4 (1:85.000 in Japan, but very rare in Europe and North America) shares an indistinguishable clinical pattern compared to that of the other oculocutaneous albinisms and is due to mutations of the SLC45A2 gene (member of the Solute Carrier protein family) previously called MATP (membrane-associated transporter protein gene) and are thought to function in a parallel pathway to the OCA2 gene, regulating the pH of melanosomes as a protein sugar pump and copper binding by tyrosinase gene (Figures 15.13 and 15.14).

OCA5 A further locus has been mapped to the human chromosome 4q24 region which is responsible for OCA5 type in a single Pakistani family. This shows the classic visual symptoms and signs but without an obvious change in the skin pigmentation patterns, with golden coloured hair white skin, photophobia and nystagmus, foveal hypoplasia and impaired visual acuity. Fig. 15.11 

Fig. 15.12 

Fig. 15.13 

Disorders of Pigmentation

311 Bibliography OCA4 Hayashi M, Suzuki T. Oculocutaneous Albinism Type 4. 2005 Nov 17 [updated 2017 Sep 7]. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022. PMID: 20301683. Kruijt CC, Schalij-Delfos NE, de Wit GC, Florijn RJ, van Genderen MM. Evident hypopigmentation without other ocular deficits in Dutch patients with oculocutaneous albinism type 4. Sci Rep. 2021;11(1):11572. OCA5 Kausar T, Bhatti MA, Ali M, Shaikh RS, Ahmed ZM. OCA5, a novel locus for non-syndromic oculocutaneous albinism, maps to chromosome 4q24. Clin Genet. 2013;84(1):91–93.

Fig. 15.14 

OCA6 Few families are described with this subtype of OCA. Mutations of SLC24A5 are responsible for this rare subtype with the following clinical presentation: skin heterogeneous phenotype with lighter hair colour that may darken with age, photophobia, nystagmus, iris transillumination foveal hypoplasia and reduced visual acuity. OCA6 seems to be distributed worldwide and its single nucleotide polymorphism (SNP) may be responsible of the establishment of human pigmentation and racial differences.

OCA7 Leucine rich melanocyte differentiation associated (LRMDA, also known as C10orf11) gene mutations have been found recently in two families. This gene acts via a modulation of melanocyte differentiation and shows a phenotype with predominant eye involvement with severe iris transillumination, nystagmus, reduced vison and chiasm misrouting of the optical trait. Skin presents lighter pigmentation as compared to the unaffected family members.

OCA8 The L-dopachrome tautomerase (DCT) gene, one of the genes responsible of eumelanin production, is involved in the pathogenesis of OCA8, that may show classic OCA phenotype but also only skin or only eye involvement with classical triad of foveal defects, nystagmus and hypovision.

Differential diagnosis Other OCAs

Course

There are no consistent changes throughout life

Follow-up and therapy

• Cutaneous and ophthalmological survey • UV protection

OCA6 Saito T, Okamura K, Kosaki R, Wakamatsu K, et al. Impact of a SLC24A5 variant on the retinal pigment epithelium of a Japanese patient with oculocutaneous albinism type 6. Pigment Cell Melanoma Res. 2022;35(2):212–219. Zhang Y, Zhang Y, Liu T, Bai D, Yang X, Li W, Wei A. Identification of two Chinese oculocutaneous albinism type 6 patients and mutation updates of the SLC24A5 gene. J Dermatol. 2019;46(11):1027–1030. OCA7 Beyers WC, Detry AM, Di Pietro SM. OCA7 is a melanosome membrane protein that defines pigmentation by regulating early stages of melanosome biogenesis. J Biol Chem. 2022;298(12):102669. Federico JR, Krishnamurthy K. Albinism. 2022 Aug 22. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 30085560. OCA8 Garrido G, Fernández A, Montoliu L. HPS11 and OCA8: Two new types of albinism associated with mutations in BLOC1S5 and DCT genes. Pigment Cell Melanoma Res. 2021;34(1):10–12. Ullah MI. Clinical and mutation spectrum of autosomal recessive nonsyndromic oculocutaneous albinism (nsOCA) in Pakistan: A review. Genes (Basel). 2022;13(6):1072.

X-Linked ocular albinism Epidemiology

About 1:60.000 males

Age of onset

At birth or in infancy

Cutaneous findings

• The entire skin is affected only in males, with low- to medium-grade hypopigmented skin • Especially in northern European and North American populations, the diagnosis is sometimes very difficult and is possible only after comparing the colour of the skin of the entire family (Figures 15.15 and 15.16) • Rarely, in female carriers, patchy areas of hypopigmented skin may be visible after sun exposure

Extracutaneous findings

• Severe ocular defects only in male patients • Congenital or early-onset nystagmus and misrouting of optic pathway fibres • Severe refractory defects and reduced binocular visual acuity

Atlas of Genodermatoses

312

Fig. 15.17  Fig. 15.15 

Differential diagnosis

• Other OCAs • The association of pseudo-albinism and deafness (Tietz syndrome) is merely a variant of Waardenburg syndrome (see later in this chapter)

Bibliography Moshiri A, Scholl HP, Canto-Soler MV, Goldberg MF. Morphogenetic model for radial streaking in the fundus of the carrier state of X-linked albinism. JAMA Ophthalmol. 2013;131(5):691–693. Tsang SH, Sharma T. X-linked Ocular Albinism. Adv Exp Med Biol. 2018;1085:49–52.

Cross syndrome Synonyms Fig. 15.16  • Hypoplastic fovea and retinal boundary hypopigmentation • Photophobia and strabismus • Patchy retinal pigmentation in female carriers (Figure 15.17)

Genetics and pathogenesis

• Mutations in the GPR143 gene lead to altered early-phase melanosomal assembly and are directly related to ocular and skin signs • Very rare occurrences of contiguous gene syndromes: association with X-linked ichthyosis, Kallmann’s syndrome, albinism and sensorineural deafness

Course

Skin and hair pigmentation may vary during life and with sun exposure

Follow-up and therapy

• Ophthalmological follow-up is mandatory • UV protection • Annual dermatological consultation

• Cross-McKusick-Breen syndrome • Oculocerebral hypopigmentation syndrome • Preus syndrome

Epidemiology

Less than 20 cases have been reported

Age of onset At birth

Cutaneous findings

• Tyrosinase-positive forms of generalized hypopigmentation • Blond hair with yellow-orange to grey metallic sheen (Figure 15.18) • Ocular albinism

Extracutaneous findings • • • •

Dolichocephaly Growth retardation Congenital sensorineural deafness Nystagmus, corneal, and lens opacity, microphthalmia, myopia and photophobia • Mental deficiency • Spasticity, athetoid movements, hyperreflexia and hyperirritability

Disorders of Pigmentation

313 Patton MA, Baraitser M, Heagerty AHM, Eady RAJ. An oculocerebral hypopigmentation syndrome: A case report with clinical, histochemical, and ultrastructural findings. J Med Genet. 1987;24(2):118–122. Scheinfeld NS. Syndromic albinism: A review of genetics and phenotypes. Dermatol Online J. 2003;9(5):5.

Hermansky-Pudlak syndrome (HPS) Synonym

Albinism with haemorrhagic diathesis

Epidemiology

This disease is rare. In Puerto Rico, there are several families that segregate for HPS, with a prevalence of 1:1.800. A few non-Puerto Rican pedigrees are known, especially in large Jewish or Muslim populations. A total prevalence is estimated at 1:500.000 to 1:1.000.000.

Age of onset At birth

Cutaneous findings

Nine subtypes of HPS exist, each related to nine different genes. They have in common the following signs, with varying severity: Fig. 15.18  • • • • • •

Hypogonadism and cryptorchidism Small, widely spaced teeth Gingival fibromatosis Hypochromic anaemia Urinary tract abnormalities Generalized osteoporosis

Genetics and pathogenesis

• Autosomal recessive inheritance • Candidate gene has been mapped into the interval of 3q27.1–29

Differential diagnosis • • • • •

OCA Hermansky-Pudlak Syndrome Chediak-Higashi syndrome Griscelli syndrome Waardenburg syndrome

• Ethnic-dependent hypopigmentation of the skin and hair (albinism) (Figure 15.19) • Progressive pigmentation recovery • Bruising and ecchymoses • Skin infections • Cutaneous cancers

Extracutaneous findings

• Different degrees of iris colour: red to light brown • Red retinal reflex, photophobia and nystagmus • Haemorrhagic diathesis due to a storage pool platelet defects (menorrhagia and epistaxis) • Severe pulmonary fibrosis and inflammatory bowel disease in HPS type 1 Puerto Rican families, which are absent in HPS type 2 and HPS type 3 (mild hypopigmentation and bleeding) mutation-related subjects • Childhood neutropenia and recurrent upper respiratory infections in some families (HPS type 2)

Course

Malignant tumours of the skin can be a complication

Follow-up and therapy

• Broad-spectrum sunscreen and adequate clothing when outside to prevent UV-induced damage to the skin • The use of sunglasses will reduce the symptoms of light sensitivity, as well as protecting the eyes • Periodic screening for skin cancer

Bibliography Chabchoub E, Cogulu O, Durmaz B, Vermeesch JR, Ozki- nay F, Fryns JP. Oculocerebral hypopigmentation syndrome maps to chromosome 3q27.1q29. Dermatology. 2011;223:306–310. De Oliveira Sobrinho RP, Steiner CE. What syndrome is this? Oculocerebral hypopigmentation syndrome of Preus. Pediatr Dermatol. 2007;24(3):313–315.

Fig. 15.19 

Atlas of Genodermatoses

314

Pigmentary mosaicism (PM)

Laboratory findings

• Melanocytes contain macromelanosomes and are tyrosinase positive • Currently, the sine qua non for the diagnosis of HPS is the absence of dense bodies on the whole amount of the platelets analysed by electron microscopy

Genetics and pathogenesis

• Autosomal recessive • Nine genes (HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3 and BLOC1S6 [PLDN]) have been identified as causative genes for HPS in humans • All of the identified genes related to HPS encode proteins and factors related to the formation of melanosomes, platelet-dense bodies, and lysosomal compartments (cytoplasmic vesicular trafficking), explaining the clinical phenotypes of HPS

Differential diagnosis • • • •

OCA Griscelli disease (see Chapter 7) Chediak-Higashi syndrome (see Chapter 19) Elejalde syndrome (see Chapter 7)

Course and prognosis

The lethal pulmonary fibrosis of HPS is associated with defects in BLOC-3 (HPS type 1 and HPS type 4)

Follow-up and therapy

• Skin examination for the severity of hypopigmentation and, after infancy, for evidence of skin damage and skin cancer • For evaluation of lung fibrosis, pulmonary function tests should be performed in individuals older than age 20 years of age • Corticosteroids and immunosuppressants should be administered cautiously, especially in candidates for lung transplantation, as these drugs can result in a infectious disease • Although it is possible that pirfenidone has a favourable effect, lung transplantation is currently accepted as the only curative treatment

Definition

This term encompasses different patterns of hypopigmented, hyperpigmented or, more rarely, mixed pigmentary lesions of the skin that comprises the old “umbrella” terms “hypomelanosis of Ito” and “linear and whorled nevoid hypermelanosis” that, in our opinion, should be gradually abandoned. These pigmentary disorders are distributed along the migration pathways of keratinocytes and melanocytes during embryogenesis, reflecting mosaic conditions due to post-zygotic mutations (see Chapter 23). Some chimeric (organism composed by two different normal cell lines) PM has been described. PM may be represented by disorders affecting only the skin or they may be part of complex syndromes involving mainly the central nervous system (CNS), eyes, musculoskeletal tissues and dysmorphic facial features (see also further in this chapter).

Synonyms

• Hypomelanosis of Ito • Linear and whorled nevoid hypermelanosis

Epidemiology

• The incidence of PM is frequently overlooked. In our cohort of nearly 8000 hereditary skin disorders patients, PM isolated or syndromic is about 5–6% of consultations, reaching more than 400 patients, among them three-quarters affecting skin only and one-fourth with extracutaneous involvement, showing a slight female predominance • A recent review shows 651 published cases from 1985 to 2017

Age of onset

At birth or after the first sun exposure, more rarely after the first two years of life

Cutaneous findings

• Hypopigmentation along Blaschko lines or, more rarely, with checkerboard or other PM patterns (Figures 15.20–15.23) • Hyperpigmented lesions following the lines of Blaschko and, less frequently, checkerboard or other PM pattern (Figures 15.24 and 15.25) • A combination of lighter and darker skin lesions is visible in less than 10% of patients (see also Cutis tricolor, discussed later in the chapter)

Bibliography Cavounidis A, Pandey S, Capitani M, et al. Hermansky-Pudlak syndrome type 1 causes impaired anti-microbial immunity and inflammation due to dysregulated immunometabolism. Mucosal Immunol. 2022;15(6):1431–1446. Huizing M, Malicdan MCV, Gochuico BR, Gahl WA. HermanskyPudlak Syndrome. 2000 Jul 24 [updated 2021 Mar 18]. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022. PMID: 20301464. Huizing M, Helip-Wooley A, Dorward H, et al. Hermansky–Pudlak syndrome: A model for abnormal vesicle formation and trafficking. Pigment Cell Res. 2003;16:584. Santos Malave G, Izquierdo NJ, Sanchez NP. Dermatologic manifestations in patients with the Hermansky-Pudlak syndrome types 1 and 3. Orphanet J Rare Dis. 2022;17(1):305.

Fig. 15.20 

Disorders of Pigmentation

315

Fig. 15.21 

Fig. 15.24 

Fig. 15.22 

Fig. 15.25 

Fig. 15.23 

• PM may be visible in all body areas, including hair (Figure 15.26). Hyperpigmented skin may have a large hue of colour ranging from sand to dark brown, usually with well-defined borders. Hypopigmented lesions may also have different degree of hypopigmentation (Figures 15.27 and 15.28). Sometimes classical mosaic patterns are not obvious to recognize (Figure 15.29) and in many patients, especially within the first year of life, it is challenging or impossible to determine whether the light or the dark skin areas could be pathological

Atlas of Genodermatoses

316

Fig. 15.26 

Fig. 15.28 

Fig. 15.27 

Extracutaneous findings

• Occurrence of extracutaneous manifestations range from 20% (our cases) to 45% (literature) and roughly present in the same quote both in hypo- and hyperpigmented mosaicism • More frequent associations are: mental retardation, developmental delay with intellectual impairment, autism spectrum, seizures, with or without brain lesions detected by electroencephalogram (EEG) or neuroimaging, with wide spectrum of severity • Dysmorphic facial features, skeletal deformities. Heart and kidney defects are less frequently reported

Genetics and pathogenesis

• Mosaic condition (at least two different cell lines present in an organism), even if some PM due to true chimeras has been described as well as familiar cases up to three generations

Fig. 15.29  • In recent years, several new well-characterized and very rare syndromes has been described with PM and extracutaneous involvement and are extensively discussed in this chapter • Studying large cohort of patients with PM, with or without systemic manifestations from the cytological point of view (peripheral blood lymphocytes, lesional skin

Disorders of Pigmentation

•

•

• •

fibroblasts and, less successfully, keratinocytes and melanocytes), clearly showed the relevance of cytogenetic approach to these patients, demonstrating abnormalities in about 40% of patients. In a large cohort of 263 patients, 111 abnormal cytogenetic analysis was found. Cytogenetic (chromosomal) abnormalities are more frequent in PM with extracutaneous involvement Mosaic chromosomal abnormalities are largely more frequent than other different chromosomal structural or numerical (i.e., diploids/triploids) disorders. They are distributed in the following chromosomes: 2, 3, 4, 5, 7, 8, 9, 10, 12, 13, 14, 15, 18, 20, 22 and sexual chromosomes, making genotype–phenotype correlations difficult to define In example, full trisomy 13 is associated with haemangiomas and other vascular mosaicism in about 50% of patients and mosaic trisomy 13 may be associated with “phylloid PM”, other aspecific PM and skin redundancy In summary, chromosomal abnormalities are largely the more frequent cause of PM Finally, lyonization phenomenon may lead to PM (epigenetic mosaicism) (see also Chapter 23)

317 Saida K, Chong PF, Yamaguchi A, et al. Monogenic causes of pigmentary mosaicism. Hum Genet. 2022;141(11):1771–1784. Schaffer JV. Pigmentary mosaicism. Clin Dermatol. 2022;40(4): 322–338.

SYNDROMIC PIGMENTARY MOSAICISM TFE3-related Pigmentary Mosaicism Age of onset

At birth or shortly thereafter

Epidemiology

Unknown prevalence Twenty described cases, female-to-male ratio of 12:5.

Cutaneous findings

• Hypochromic PM, almost exclusively distributed along Blaschko’s lines (70%) • Facial hypertrichosis (50%) • Loose and wrinkled skin in a minority of patients • Nail clubbing may be present

Extracutaneous findings

Laboratory findings

To recognize and characterize the pathogenesis of PM, isolated or syndromic, is mandatory to perform firstly cytogenetic examinations and, when possible, “deep” next-generation sequencing (NGS) of the affected tissue (skin) and blood that are allowed to detect even 1% of mutated cells

Differential diagnosis

• Incontinentia pigmenti (late phases) • Epidermal nevi (onset phases) • Lichen striatus (late phases)

Course and prognosis

PM are relatively stable during life, but fading of the lesions and repigmentation of hypochromic PM is referred

Follow-up and therapy

• Neurological assessment is mandatory in syndromic PM as well as neuroimaging. Specific therapy for seizures. • Multidisciplinary approach may be useful with paediatricians, ophthalmologists and orthopaedics • No specific therapy exists for isolated hypo- and hyperpigmented mosaicism • We strongly recommend investigating these patients with cytological analysis, micro-array, exome and deep NGS to restrict the even high percentage of patients without cytogenetic/molecular diagnosis

Bibliography Chamli A, Litaiem N. Hypomelanosis of Ito. 2023 Jun 20. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2023 Jan–. PMID: 30855856. Martinez-Falero BS, Koutalopoulou A, Douglas AGL, Kharbanda M, Collinson MN, Lotery A, Lotery H. Pigmentary anomaly caused by mosaic 3q22.2q29 duplication. Clin Exp Dermatol. 2022 Dec;47(12):2342–2345.

• • • • • •

• • • • •

Delayed psychomotor development is a constant feature Truncal hypotonia, ataxia Epilepsy, autism spectrum Congenital hearing loss Ophthalmological anomalies (50%) strabismus, retinal degeneration, impaired vision, iris depigmented macules Facial dysmorphism: flat-coarse face, flat nasal bridge, hypertelorism with “almond-shaped eyes”, short nose with anteverted nares, full and erythematous cheeks, thick lips, abnormal earlobe Skeletal anomalies (>50): scoliosis, hyperlordosis, clubfeet, hip dislocation Recurrent infections of upper respiratory trait (25%) Congenital heart defects are reported More rarely anogenital abnormalities Late onset obesity

Laboratory findings

Magnetic resonance imaging (MRI) abnormalities in one-third of patients

Genetics and pathogenesis

• X-linked recessive transmission (in a large series of 17 patients, 12 females and 5 males) • TFE3 gene missense mutations in exon 3 and 4 • TFE3 belongs to the microphthalmia transcription family (MITF) with TFEB and TFEC (mammalian basic helix-loop zipper transcription factors) and plays a crucial function in the regulation of embryonic stem cells and cellular homeostasis and transcription of target genes, especially involved in lysosomal formation leading to the embryonic stem cell renewal, via the signalling and modulation of mTOR complex 1. Moreover, TFE3 mutations are well known to cause a subset or renal cell carcinoma • Mosaic distribution of PM reflects epigenetic mosaicism in females or “hypomorphic” mosaic mutations in survived males (see also IP and FDH in Chapter 11) • TFE3 mutations may account for a proportion of Ito patients

Atlas of Genodermatoses

318 Differential Diagnosis

• Other syndromic PM subset • Metabolic diseases

Bibliography

Bibliography

Gerber CB, Fliedner A, Bartsch O, et al. Further characterization of Borjeson-Forssman-Lehmann syndrome in females due to de novo variants in PHF6. Clin Genet. 2022;102(3):182–190. Garcia-Melendo C, Roé E, Rodríguez-Santiago B, Amat-Samaranch V, Cubiró X, Puig L, Boronat S. A case report of PHF6 mosaicism: Beyond the classic Börjeson-Forssman-Lehmann syndrome. Pediatr Dermatol. 2021;38(4):919–925.

Lehalle D, Vabres P, Sorlin A, et al. De novo mutations in the X-linked TFE3 gene cause intellectual disability with pigmentary mosaicism and storage disorder-like features. J Med Genet. 2020;57(12):808–819.

RHOA-related pigmentary mosaicism

Follow-up and therapy

Neuropsychological and ophthalmological survey

Borjeson-Forssman-Lehmann syndrome Epidemiology

64 patients reported, 1:1.000.000 prevalence

Age of onset

At birth, but fully developed after 2 years of life

Cutaneous findings

• Hyperpigmentation especially in females (70%) more common linear hyperpigmented streaks along Blaschko’s lines but also large hyperpigmented areas without specific pattern or diffuse hyperpigmentation • Sparse hair both in males and females • Hirsutism (20% of females)

Extracutaneous findings

• Typical facial features: coarse face, large ears, deep-set eyes, anomalies of eyebrows, narrow eyelid, short nose with broad nasal tip and large mouth (differences between males and females) • Intellectual disability, party behaviour, epilepsy • Developmental delay, low stature • Dental anomalies • Abnormalities of fingers and toes • Truncal obesity • Endocrinological abnormalities (growth hormone) • Hypogonadism and abnormal genitalia, gynecomastia • Sporadically attempt of visceral organs (kidneys)

Genetics and pathogenesis

• X-linked recessive with highly skewed inactivation in females, carrier females may be oligo-asymptomatic • PHF6 gene mutations: “plant homeodomain like finger” with two zinc-finger domains involved in transcriptional regulation, localized in the nucleolus • The exact mechanism underlying hyperpigmentation is unclear • PHF6 is related also to haematological malignancies • Prenatal diagnosis is available in families at risk

Laboratory findings None specific

Differential diagnosis

• Coffin-Siris syndrome • Prader-Willi syndrome • Klinefelter syndrome

Follow-up and therapy

• Endocrinological survey • Echotomography to detect visceral abnormalities

Epidemiology

Five patients reported in the literature

Age of onset At birth

Cutaneous findings (panel 15.1)

• Linear hypopigmentation • Hypotrichosis along Blaschko’s lines

Extracutaneous findings

• Facies: microstomia, malar hypoplasia, downslanted palpebral fissures and broad nasal bridge • Oligodontia, microdontia, conical teeth, abnormal enamel • Brachydactyly-syndactyly, broad first toe • Microphthalmia, strabismus, myopia • Diffuse cystic leukoencephalopathy and enlargement of lateral ventricles at the MRI without signs of neurological abnormalities or intellectual deficiency

Genetics and pathogenesis

• Post-zygotic inactivating mutations of RHOA gene, encoding a Ras-related Rho GTPase detected in skin derived DNA samples and absent in blood DNA samples (mutant allele fractions from 1.9% to 33%) • This GTPase is known to regulate cell-cycle progression, morphogenesis and axonal guidance • Moreover, its function is related to chemotaxis and plays a central role in signal transduction and, via the regulation of stress fibres and focal adhesion formation, in the dynamics of cytoskeleton leading to microtubule disorganization • The RHOA gene is part of the “core essentialome”, a group of genes that is essential for cell life • Lethal mutations surviving only by mosaicism, with negative selection of mutant cells

Laboratory findings

MRI is mandatory to reveal brain malformations

Differential diagnosis

Other syndromic hypopigmented mosaicisms

Follow-up and therapy

• Odontoiatric and ophthalmological treatments • Plastic and maxillo-facial surgery for the facial asymmetries

Bibliography Vabres P, Sorlin A, Kholmanskikh SS, Demeer B, et al. Postzygotic inactivating mutations of RHOA cause a mosaic neuroectodermal syndrome. Nat Genet. 2019;51(10):1438–1441.

Disorders of Pigmentation

319

Panel 15.1  Reprinted with permission from Vabres P et al, Nat Genet, 2019

TUBB3-related pigmentary mosaicism Recently, we observed a patient suffering from neurological symptoms (seizures, low IQ, autism spectrum) with signs of developmental abnormalities of the cortex at the neuroimaging associated with a typical pigmentary mosaicism along Blaschko’s lines, especially visible along arms and legs (Figure 15.30). Deep NGS sequencing revealed a mutation in TUBB3 gene. This gene encodes for a class III tubulin, essential for the development of neuronal migration and guidance. We hypothesize that the same disturbances in the formation of microtubule and vesicle trafficking may explain the abnormal melanocytes migration and the pigmentary mosaicism of this patient. Interestingly, a further case of missense TUBB3 mutation with abnormal brain structures showed autonomic disturbances, leading to a monolateral hypohidrosis.

Bibliography Fukumura S, Kato M, Kawamura K, Tsuzuki A, Tsutsumi H. A Mutation in the Tubulin-Encoding TUBB3 Gene Causes Complex Cortical Malformations and Unilateral Hypohidrosis. Child Neurol Open. 2016 Sep 1;3:2329048X16665758.

Fig. 15.30 

Atlas of Genodermatoses

320

Other rare phenotypes: • SOS1 gene related pigmentary mosaicism is described in one case (see also chapter 9) • USP9X gene cause in females a complex syndrome named USP9X-female syndrome that is characterized by mental retardation of different degrees and may show pigmentary mosaicism

Familial progressive hyper-hypopigmentation Synonyms

KITGL gene-related pigmentary mosaicism

Epidemiology

No clear incidence or prevalence More than 50 cases reported.

Age of onset At birth

Cutaneous findings

• Progressive, diffuse, patches or reticular hyperpigmented lesions with or without “confetti-like” hypopigmented spots, lentigines and café-au-lait macules (cafe-noir macules…) (Figures 15.31 and 15.32) • Hyperpigmented lesions may vary in dimensions through age from 0.2 cm to several centimetres (Figure 15.33) • Palms and soles may be interested • Congenital linear and mottled hyperpigmentation suggesting mosaicism has been reported in a single patient with KITGL de novo post-zygotic mutation • Vitiligo in one family • Oral mucosa is rarely involved

Fig. 15.32 

Extracutaneous findings

Growth retardation, intellectual disability and seizures are reported in the literature in a minority of cases.

Fig. 15.33 

Genetics and pathogenesis

Fig. 15.31 

• Mutations in KITGL gene, which encodes for the C-Kit ligand, are responsible for FPHH phenotypes • KITGL gene is involved also in Waardenburg syndrome (see further in this chapter) and in Isolated autosomal dominant non-syndromic deafness • Autosomal dominant inheritance with reduced penetrance • Missense mutations with a downstream gain of function effect • After KITGL binding, KIT dimerizes and play a pivotal role in the homeostasis and maintenance of the melanocytes in human skin; these changes affect migration of melanoblasts, melanosome transfer and melanin synthesis, leading to the phenotype of hyper and hypopigmentation

Disorders of Pigmentation • Several families with a FPHH phenotype do not harbour KITGL mutations on exome sequencing, suggesting locus heterogeneity • A single de novo post-zygotic mutation on KITGL is reported, expanding the spectrum of non-lethal genes causing mosaic and constitutive diseases

Laboratory findings None specific

Differential diagnosis

• Dyschromatosis symmetrica hereditaria (Dohi) • Kitamura disease • Poikilodermas

Follow-up and therapy

• Photoprotection • Examination for potential associated malignancies

Bibliography Wang J, Li W, Zhou N, et al. Identification of a novel mutation in the KITLG gene in a Chinese family with familial progressive hyperand hypopigmentation. BMC Med Genomics. 2021;14(1):12.

Terminal osseous dysplasia with pigmentary defects Synonyms

• Terminal osseous dysplasia • Digitocutaneous dysplasia

Epidemiology

About 25 reported cases so far

Age of onset

At birth or within the first year of life

Cutaneous findings • • • •

Atrophic, hyperpigmented “punched-out” lesions on the face Digital fibromas on hands and feet Accessory gingival frenulum Prominent vermillion border of the lower lip

Extracutaneous findings

• Facies: frontal bossing, hypertelorism, telecanthus, epicanthal folds, broad nasal root • Multiple, firm, non-tender erythematous nodules on fingers and toes • Brachydactyly and clinodactyly • Conical teeth, dental fissures due to enamel defects • Rarely cardiac, urogenital defects • Intellectual impairment (?) • Wide phenotypical variability also in the same family

321 Laboratory findings

• Histopathology of hyperpigmented lesions lead to an anetodermal state • Histology of nodules is identical of that found in isolated digital fibromas

Follow-up and therapy

• Heart, abdomen and brain imaging to detect associated malformation • Full skeletal X rays to delineate osseous developmental defects • Digital nodules may disappear spontaneously, but surgery is sometimes required when a substantial functional limitation appears

Differential diagnosis

• Anetodermas • Goltz syndrome • Delleman and Setleis syndrome

Bibliography Gontijo JRV, Dos Santos WF, Gontijo B, Happle R. Terminal osseous dysplasia presenting with intracytoplasmic inclusion bodies in digital fibromas. Pediatr Dermatol. 2018;35(6):e353–e356.

mTOR-related syndromic pigmentary mosaicism Synonyms None

Epidemiology

Twenty cases described

Age of onset

At birth, even in some cases pigmentary mosaicism may be patent after the first sun exposure.

Cutaneous findings

• Hypopigmented Blaschko-linear streaks (Figure 15.34) • Hyperpigmented Blaschko-linear streaks • Combined hypo-hyperpigmentary mosaicism as in “cutis tricolor” (Figure 15.35) • Less frequently “flag-like” hypopigmented lesion • Café-au-lait spots • Scalp heterochromia

Genetics and pathogenesis

• Inherited as an X-linked dominant trait, lethal in males • Mutations in FLNA gene, encoding Filamin A, involved in organogenesis, signalling pathways and cytoskeleton formation. FLNA mutations are responsible for other syndromes, among other, OFD1-2 syndromes (see page 393) and several other cardiac and intestinal malformations syndromes

Fig. 15.34 

Atlas of Genodermatoses

322

• Seizures • Hypotonia, joint laxity • Segmental overgrowth (Figures 15.36a and 15.36b)

Laboratory findings

• NGS sequences with high-performance techniques of affected tissues and blood are highly recommended to define the molecular defects • Wide spectrum of cerebral anomalies by MRI • Abnormalities of EEG • Histology shows decreased number of melanocytes and melanocytes activity (reduced melanosomes)

Genetics and pathogenesis

Fig. 15.35  • Woolly/curly hair in minority of patients • Mosaic distribution of lesions may not be obviously recognizable in some case • Skin signs and overgrowth may be present without CNS involvement

Extracutaneous findings

• Focal cortical dysplasia, megalencephaly, hemimegaloencephaly, polymicrogyria, aqueductal stenosis, hydrocephalus, focal grey matter heterotopia, papilledema, hypomyelination • Head circumference >90 percentile • Peculiar facies with: low-set ears, frontal bossing, depressed nasal bridge, hypertelorism, cranial anomalies due to megalencephaly/hemimegaloencephaly • Large spectrum of intellectual impairment, from mild retardation to non-verbal-non-ambulatory status

• Germline and mosaic mTOR mutations • mTOR gain-of-function mutations are directly related to cellular hypertrophy and proliferation and may act via melanocyte inducing transcription factor (MITF) in the pathogenesis of the pigmentary lesions as occurs in tuberous sclerosis due to TSC1 and TSC2 genes that are modulators of mTOR gene and cascade • Similarly, mTOR is strictly related to the cascade of AKTPIK3CA, thus, explaining the overgrowth of brain and other tissues in these patients

Differential diagnosis

• Pigmentary mosaicism, non-syndromic • Other syndromic pigmentary mosaicism

Course and prognosis

Wide spectrum of progression of the disease due to the variant allelic fraction (VAF) in the brain tissues.

Follow-up and therapy

• Targeted therapy with mTOR inhibitors may have a role in the future for these patients • Neurological follow-up • Physiatric therapies

    Fig. 15.36 

Disorders of Pigmentation

323

Bibliography Carmignac V, Mignot C, Blanchard E, et al. Clinical spectrum of MTORrelated hypomelanosis of Ito with neurodevelopmental abnormalities. Genet Med. 2021;23(8):1484–1491. Handoko M, Emrick LT, Rosenfeld JA, et al. Undiagnosed Diseases Network, Lee BH, Bacino CA, Chao HT. Recurrent mosaic MTOR c.5930C > T (p.Thr1977Ile) variant causing megalencephaly, asymmetric polymicrogyria, and cutaneous pigmentary mosaicism: Case report and review of the literature. Am J Med Genet A. 2019;179(3):475–479. Itoh K, Pooh R, Shimokawa O, Fushiki S. Somatic mosaicism of the PI3KAKT-MTOR pathway is associated with hemimegalencephaly in fetal brains. Neuropathology. 2023;43(2):190–196.

Piebaldism Synonym

Partial albinism

Epidemiology

The incidence is estimated to be less than 1:20.000

Age of onset At birth

Cutaneous findings

• Totally depigmented skin patches, especially in midfrontal areas (diamond patches) (Figure 15.37) and the chin, chest, abdomen, arms and legs (symmetrical distribution) (Figure 15.38) • Islet of repigmentation within the white patches, with different colour hues (Figure 15.39)

Fig. 15.37 

Fig. 15.38  • Cafe-au-lait macules are absent in piebaldism • White forelock and the involvement of the eyebrows and eyelashes (Figure 15.40) • In some patients, striking contiguous depigmentation is visible across lower limbs

Extracutaneous findings

Rare associations include the following: • Hirschsprung’s disease or aganglionic megacolon • Anaemia

Fig. 15.39 

Atlas of Genodermatoses

324 Differential diagnosis

• Vitiligo • Waardenburg syndrome • The group of the following three diseases called dyschromatosis universalis hereditaria, familial progressive hyperpigmentation and (sic!) familial progressive hyper- and hypopigmentation, show progressive diffuse darkening of the skin, together with hyper- and hypopigmented congenital patches that may increase in number and size with age, located passim on the skin and less frequently mucosae with or without café-au-lait macules. They are allelic diseases due to mutations in a receptor for c-Kit called KITLG that is an important modulator of skin pigmentation (previously discussed in the chapter).

Fig. 15.40 

Laboratory findings

• Abnormal melanocyte cytoplasmic pattern • Decreased Langerhans cells

Genetics and pathogenesis

• The disease is autosomal dominant (Figure 15.41), as in this family with an isolated forelock. Proto-oncogene c-Kit mutations are responsible for the disease, enabling the normal development and migration of melanocytes during embryogenesis • Heterozygous deletion of SNAI2 also causes human piebaldism, whereas a homozygous deletion of this gene causes human Waardenburg syndrome type 2 • SNAI2 gene (or SNUG) is a zinc-finger transcription factor gene that mediates the SCF/c-kit signalling pathway, involved in a piebaldism-related phenotype • The contiguous pattern of distribution of depigmentation across the lower limbs in a subset of patient may be explained by the recent theory of mesodermal melanocyte migration. A subset of melanocyte precursors develops within the mesoderm very early in embryogenesis and noteworthy before the formation of limb buds, migrating centrifugally from midline structures in a bilateral pattern, explaining this peculiar phenotype.

Course and prognosis

Depigmented skin lesions may undergo slight modification in life.

Follow-up and therapy

• A combination of dermabrasion and grafting of pigmented skin onto depigmented areas, with or without phototherapy, may be worthwhile in selected patients • Depigmented areas may be treated with thin split-thickness grafts and minigrafting or with in vitro-cultured epidermis and suction epidermal grafting with additional minigrafting

Bibliography Alexeev V, Igoucheva O, Yoon K. Simultaneous targeted alteration of the tyrosinase and c-kit genes by singlestranded oligonucletides. Gene Ther. 2002;9:1667–1675. Funkhouser CH, Kinsler VA, Frieden IJ. Striking contiguous depigmentation across the lower limbs in piebaldism and its implications for understanding melanocytic migration and development. Pediatr Dermatol. 2019;36(4):511–513. Goh BK, Chua XM, Chong KL, de Mil M, van Geel NA. Simplified cellular grafting for treatment of vitiligo and piebaldism: The “6-well plate” technique. Dermatol Surg. 2010;36(2):203–207. Kinsler VA, Larue L. The patterns of birthmarks suggest a novel population of melanocyte precursors arising around the time of gastrulation. Pigment Cell Melanoma Res. 2018;31(1):95–109. Thomas I, Kihiczak GG, Fox MD, Janniger CK, Schwartz RA. Piebaldism: An update. Int J Dermatol. 2004;43(10):716–719. Yang YJ, Zhao R, He XY et al. SNAI2 mutation causes human piebaldism. Am J Med Genet A. 2014;164A(3):855–857.

Waardenburg syndrome Synonyms

• Klein-Waardenburg syndrome • Shah-Waardenburg syndrome

Epidemiology

Its prevalence is estimated to be 1:42.000.

Age of onset At birth

Cutaneous findings

Fig. 15.41 

• White forelock and white patches randomly distributed on the scalp (Figure 15.42) • Premature generalized canities • Patches of white skin on frontal areas • Synophrys

Disorders of Pigmentation

325

Fig. 15.44 

Fig. 15.42 

Extracutaneous findings

• Iris heterochromia • Dystopia canthorum and displacement of the lower lacrimal duct origin (Figure 15.43) • Broad nasal root (Figures 15.42 and 15.43) • Cleft lip and palate with scrotal tongue (Figure 15.44) • Temporal bone abnormalities • Uni- or bilateral hearing loss (Figure 15.45) • Hirschsprung malformation of the gut

Fig. 15.45 

Laboratory findings

• No melanocytes visible in the affected skin • Where present, melanocytes show abnormal melanosomes

Genetics and pathogenesis

• Clinical and genetic heterogeneities are markers of Waardenburg syndrome • It is often described as an autosomal dominant inherited disorder, but we now know that Waardenburg syndrome is clinically and genetically heterogeneous and that not all forms are dominantly inherited • Six genes are involved in its pathogenesis: PAX3 (encoding the paired box 3 transcription factor), MITF (encoding the microphthalmia-associated transcription factor), SOX10 (encoding the Sry bOX10 transcription factor), SNAI2 (encoding snail homolog 2), EDN3 (encoding endothelin 3) and EDNRB (encoding endothelin receptor type B) • These defects may be involved in the migration defects of the melanocytes and neural cells during embryogenesis

Differential diagnosis Fig. 15.43 

• Piebaldism • Vitiligo

Atlas of Genodermatoses

326 • • • •

Isolated white forelock Syndromic hypopigmentary mosaicism Isolated nevus depigmentosus Mowat-Wilson syndrome: widespread patchy hypopigmented areas, Hirschsprung’s disease, severe mental retardation and microcephaly, hypospadias, strikingly upturned earlobes and feeding difficulties. This disease is related to a mutation in the zinc finger homeobox B gene • Tietz syndrome: congenital profound deafness and generalized hypopigmentation (snow white at birth; patients gradually gain some pigmentation and have fair skin and blonde to white hair as adults with white eyebrows and eyelashes). Autosomal dominant inheritance with full penetrance due to MITF mutations. This disorder is to be considered allelic to Waardenburg syndrome and not as a separate entity

Course and prognosis

• Progressive severe intestinal symptoms occur in the developing megacolon of patients

Fig. 15.46 

Follow-up and therapy

• Gastroenterological consultations for management of Hirschsprung’s disease • Survey for hearing loss

Bibliography Lee CY, Lo MY, Chen YM, et al. Identification of nine novel variants across PAX3, SOX10, EDNRB, and MITF genes in Waardenburg syndrome with next-generation sequencing. Mol Genet Genomic Med. 2022;10(12):e2082. Milunsky JM. Waardenburg Syndrome Type I. 2001 Jul 30 [updated 2022 Oct 20]. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022. PMID: 20301703. Pingault V, Ente D, Dastot-Le Moal F, Goossens M, Marlin S, Bondurand N. Review and update of mutations causing Waardenburg syndrome. Hum Mutat. 2010;31(4):391–406. Smith SD, Kelley PM, Kenyon JB, Hoover D. Tietz syndrome (hypopigmentation/deafness) caused by mutation of MITF. J Med Genet. 2000;37(6):446–448. Zhang H, Chen H, Luo H et al. Functional analysis of Waardenburg syndrome-associated PAX3 and SOX10 mutations: Report of a dominant-negative SOX10 mutation in Waardenburg syndrome type II. Hum Genet. 2012;131(3):491–503.

Fig. 15.47 

McCune-Albright syndrome Synonym

Polyostotic fibrous dysplasia with café-au-lait macules

Epidemiology

This disease is rare. About 200 cases have been reported in the literature.

Age of onset

At birth or developing progressively during infancy

Cutaneous findings

• Usually large café-au-lait macules with somewhat dark and different homogeneous pigmentation and irregular borders (Figures 15.46–15.48)

Fig. 15.48 

Disorders of Pigmentation

327 Laboratory findings

• Radiography clearly shows the long-bone polycystic changes and hyperostotic changes in the maxillofacial region • Blood tests for hormonal abnormalities

Genetics and pathogenesis

Fig. 15.49  • Cutaneous lesions are usually monolateral and distributed in a mosaic pattern (Figure 15.49) • The trunk and arms are the preferred sites; the head and face are less frequently involved • More rarely oral mucosa pigmentation, soft-tissue myxomas and epidermal nevi • Cutaneous lesions are not invariably present

Extracutaneous findings

• Pseudocystic long-bone fibrous dysplasia (hockey stick deformities) with loss of trabeculae that are replaced by fibrous stroma, often homolaterally to the cutaneous lesions • Fibrous dysplasia lesions are distributed in a mosaic pattern, usually at the proximal femur and skull base, but lesions may be detected in any skeletal sites • Facial hyperostotic lesions of the maxillae, jaws and skull base, often resulting in facial asymmetry in a third of patients (Figure 15.50) • Precocious puberty and ovarian cysts in females with normal fertility (20–25% of patients) • Other endocrinopathies (hyperthyroidism [20% of patients] and hyperprolactinemia) • Growth hormone excess • Neonatal hypercortisolism and phosphate renal wasting

• In survivors, the condition exists as mosaicism, (postzygotic mutations of an autosomal dominant lethal gene), confirmed by molecular analysis in 1991 by Weinstein; this paper was the first demonstration of genetic mosaicism causing a mosaic phenotype • The few familiar cases are due to misdiagnosis (i.e., neurofibromatosis type 1) or may be due to a paradominant inheritance as occurs in Becker’s nevus and proteus syndrome • The related gene is called GNAS and encodes the alphasubunit of the stimulatory G protein that is coupled to two other (p–y) subunits, forming a signal-transducing protein mediating several hormonal processes (i.e., parathormone) via the activation of adenylate cyclase and the synthesis of cyclic adenosine monophosphate. Mutations of GNAS have been found in various percentages of cells in the lesions of involved tissue (mosaic pattern) • GNAS is also mutated in progressive osseous heteroplasia of the skin and isolated fibrous dysplasia (see also Chapter 12)

Differential diagnosis

• Neurofibromatosis type 1 • Isolated osseous fibrous dysplasia

Course and prognosis

• The signs are steady • Fractures, which are often multiple and recurrent, of the involved bones (60–70% of patients) • Malignant transformation of bone cystic fibrous lesions in fewer than 5% of patients • Breast cancer reported in a minority of patients • Rarely, mental retardation (secondary to skull development?)

Follow-up and therapy

• Osseous lesions may require surgery and/or pain-relieving drugs • Thyroid metabolism abnormalities require the usual pharmacological or surgical approach

Bibliography

Fig. 15.50 

Baszko-Błaszyk D, Slynko J, Liebert W, Sosnowski P, Sowiński J, Waśko R. Difficulties in diagnosis and treatment of acromegaly in a patient with a McCune–Albright syndrome. A case report and a review of literature. Neuro Endocrinol Lett. 2010;31(5):594–596. Holbrook L, Brady R. McCune Albright Syndrome. 2022 Jul 12. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 30725777. Narumi S, Matsuo K, Ishii T, Tanahashi Y, Hasegawa T. Quantitative and sensitive detection of GNAS mutations causing McCune– Albright syndrome with next generation sequencing. PLoS One. 2013;8(3):e60525. Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCune– Albright syndrome. N Engl J Med. 1991;325(24):1688–1695.

Atlas of Genodermatoses

328

MELAS syndrome Synonyms

Mitochondrial myopathy, encephalopathy lactic acidosis and stroke-like episodes

Cutaneous findings

Linear hyperpigmented nevi (Figures 15.51 and 15.52) are frequently a marker of the disease together with hair abnormalities. These two latter signs may be visible in about 10% of patients with mitochondrial DNA- associated diseases. In mitochondrial diseases, four signs are common, unfortunately without any phenotype–genotype correlation:

Clinicians should consider a mitochondrial disease when facing an unexplained association of symptoms or when seemingly unrelated organs are involved.

Melanocytic nevi and related syndromes Classic melanocytic nevi

• These nevi are very common and well-known skin lesions that may present at birth or be manifest after sun exposure during the entire life • They sometimes show a peculiar distribution reflecting mosaicism, as shown in Figures 15.53–15.55

• Alopecia and hair shaft abnormalities (hair are brittle and thick, with a large diameter) • Hypertrichosis, especially on the back • Mottled or reticulated hyperpigmentation, often preceded by erythematous rashes in photoexposed areas (photosensitivity?) • Hypopigmentation is also reported • Acrocyanosis Skin signs may be the presenting symptom of genetic diseases related to mutations of mitochondrial DNA or appear at any age during their course.

Fig. 15.53 

Fig. 15.51 

Fig. 15.52 

Fig. 15.54 

Disorders of Pigmentation

Fig. 15.55  • Dysplastic nevi are also described as following the checkerboard pattern of mosaicism and, obviously, it must be noted that they may evolve into neoplastic proliferations • In many cases, these nevi represent a polygenic nonMendelian trait due to the loss of heterozygosity in the many genes involved in the pathogenesis of melanoma

Giant melanocytic nevi (see Chapter 23)

• Kinsler et al., provided evidence that multiple congenital melanocytic nevi (CMN) and neurocutaneous melanosis are caused by post-zygotic mutation in codon 61 of NRAS gene (Figures 15.56 and 15.57) • Other genes are also involved in the pathogenesis, such as BRAF, GNAQ and MAP2K1

Fig. 15.56 

329

Fig. 15.57  • Different colours of nevi depend on the underlying mutated gene (NRAS gene: melanocytes are distributed more superficial, hence, the nevus will be darker; BRAF gene: melanocytes are located deeper in the skin, therefore, the colour will be light brown) • Neurocutanous melanosis is a rare, congenital syndrome characterized by the association of (1) CMN of the skin with overlying hypertrichosis, presenting as (a) large (LCMN) (Figure 15.58) or giant and/or multiple (MCMN) melanocytic lesions (or both; sometimes associated with smaller “satellite” nevi) or (b) as proliferative melanocytic nodules; and (2) melanocytosis (with infiltration) of the brain parenchyma and/or leptomeninges. CMN of the skin and leptomeningeal/nervous system infiltration are usually benign and, more rarely, may progress to melanoma or non-malignant melanosis of the brain. Approximately 12% of individuals with LCMN will develop NCM: wide extension and/or dorsal axial distribution of LCMN increases the risk of NCM. Neurological manifestations

Fig. 15.58 

Atlas of Genodermatoses

330 can appear acutely in infancy, or more frequently later in childhood or adult life, and include signs/symptoms of intracranial hypertension, seizures/epilepsy, cranial nerve palsies, motor/sensory deficits, cognitive/behavioural abnormalities, sleep cycle anomalies and eventually neurological deterioration. NMC patients may be symptomatic or asymptomatic, with or without evidence of the typical nervous system changes at MRI

Speckled lentiginous nevus (SLN; nevus spilus)

In the current literature, a division into papular and macular subtypes has been proposed:

Papular SLN:

• Randomly distributed, multiple pigmentary lesions that are raised and palpable, sometimes innumerable, immersed in a light brown café-au-lait-like background (Figures 15.59 and 15.60) with a checkerboard pattern • Papular SLN may be associated with hyperhidrosis, dysesthesias and ipsilateral muscular defects, configuring the syndromic form • These neurologic defects are also visible in phakomatosis pigmentokeratotica (papular SLN, epidermal nevi and associated neurologic defects and malformations are discussed in Chapter 10) • So far, HRAS mutations have only been identified in nonsyndromic papular SLN and papular SLN within phakomatosis pigmentokeratotica • An evolution toward spitzoid lesions and the occurrence of melanoma is possible

Fig. 15.60 

Macular SLN:

• These nevi maintain the same light-brown colour background, but the interspersed melanocytic nevi are flat, more homogeneously distributed and monomorphous (Figure 15.61) • They show a peculiar lentigo pattern (melanocyte nests at the dermoepidermal junction) upon histological examination • Macular SLN may be associated with superficial capillary malformation, defining one of the subtypes of phakomatosis pigmentovascularis (see Chapter 16)

Fig. 15.61 

Bibliography

Fig. 15.59 

Frings VG, Goebeler M, Kneitz H. Dermpath & clinic: In situ melanoma arising within a speckled lentiginous nevus. Eur J Dermatol. 2018;28(6):857–859. Greywal T, Matiz C. Speckled lentiginous nevus: A rare presentation associated with motor neuropathy and muscular atrophy in a child. Pediatr Dermatol. 2018;35(3):e161–e162. Torchia D, Happle R. Papular nevus spilus syndrome: Old and new aspects of a mosaic RASopathy. Eur J Dermatol. 2019;29(1):2–5.

Disorders of Pigmentation

331

Segmental lentiginosis Synonyms • • • •

Lentiginous nevus Partial unilateral lentiginosis Agminated lentigines Lentiginous mosaicism

Epidemiology

Considered to be rare, but we think that this phenotype is underestimated.

Age of onset

• Rarely at birth • Usually within school age after UV exposure

Cutaneous findings

• Lentigines (pinpoint to small, pigmented macules) in a mosaic pattern (checkerboard) especially located in the upper part of the body (Figures 15.62–15.65) with or without intermingled café-au-lait macules (Figure 15.66)

Fig. 15.64 

Fig. 15.62 

Fig. 15.65 

Fig. 15.63 

• True melanocytic nevi may be scattered in association with segmental lentiginosis (Figure 15.67) • Association with SLN with a histological lentigo pattern (Figures 15.68 and 15.69, same patient) • Association with classic neurofibromatosis type 1 or twinspots with segmental neurofibromatosis type 1 (Figures 15.70 and 15.71)

Atlas of Genodermatoses

332

Fig. 15.66 

Fig. 15.68 

Fig. 15.67 

Extracutaneous findings

• There is occasional osseous and CNS involvement, configuring a segmental lentiginosis–neurocutaneous syndrome • Some reports of Lisch nodules in these patients

Genetics and pathogenesis

• Sporadic cases and rare paradominant inheritance • The distinction between true lentiginous mosaicism and mosaic forms of neurofibromatosis type 1 is still to be explained and elucidated by molecular analysis

Fig. 15.69 

• Many authors, including ourselves, consider mosaic lentiginosis as part of the NF1 phenotype • Note that diffuse non-syndromic lentiginosis is possible (Figures 15.72 and 15.73).

Differential diagnosis

• Neurofibromatosis type 1 • SLN • Syndromic lentiginoses (Carney’s complex, Noonan with multiple lentigines [LEOPARD syndrome] and PeutzJeghers syndrome)

Disorders of Pigmentation

333

Fig. 15.70 

Fig. 15.72 

Fig. 15.71 

Course and prognosis

The disease is modified directly by UV exposure

Follow-up and therapy • • • •

Detection of associated abnormalities Epidiascopy UV protection Alexandrite Q-switched laser

Fig. 15.73 

Atlas of Genodermatoses

334 Bibliography Lee WS, Yoo MS, Ahn SK, Won JH. Partial unilateral lentiginosis associated with segmental neurofibromatosis. J Dermatol. 1995;22: 958–959. Marchesi L, Naldi L, Di Landro A et al. Segmental lentiginosis with “jentigo” histologic pattern. Am J Dermatopathol. 1992;14:323–327. Pretel M, Irarrazaval I, Aguado L, Lera JM, Navedo M, Giménez de Azcárate A. Partial unilateral lentiginosis treated with alexandrite Q-switched laser: Case report and review of the literature. J Cosmet Laser Ther. 2013;15(4):207–209.

OTA nevus Epidemiology

Central Americans and Asian native populations are preferentially involved. Ota nevi are less frequently reported in Caucasians. Slight female predominance.

Age of onset

Lesions may be visible at birth but often they are visible during infancy or at puberty.

Fig. 15.75 

Cutaneous findings

• Typical bluish or matte greenish lesions usually with nonhomogeneous pattern are preferentially distributed in a checkerboard pattern along the two upper quadrants on the face (frontal, parietal, palpebral and zygomatic areas) with indistinct, irregular or even polycyclic borders (Figure 15.74). More rarely, the external ear is involved • This nevus shows progressive changes of colour and size during infancy, childhood and adolescence (Figure 15.75, same patient years later)

Extracutaneous findings

• Sclera and conjunctiva are characteristically involved with blue-green-blackish discolouration (Figure 15.76) • Rarely, oral and nasal mucosae may be involved as well as upper digestive and respiratory tracts (Figure 15.77)

Laboratory findings

Fig. 15.76 

Fig. 15.74 

Fig. 15.77 

Upon histological examination, dendritic melanocytes are found to be intermingled between fibroblasts in the lower dermis, significantly overlapping with blue nevus pattern.

Disorders of Pigmentation

335

Genetics and pathogenesis

• Post-zygotic mutations of GNAQ gene are found in a minority of cases (10%) • Note that mutations of the GNAQ gene are found in a majority of blue nevi (>80%), Sturge-Weber and port-wine stain capillary malformations (see also Chapter 16)

Differential diagnosis • • • •

Melanocytic nevi, blue nevi SLN (early phases) Epidermal-sebaceous nevus (early phases) Blue sclerae are present also in connective tissue disorders (see Chapter 12)

Course and prognosis

• The occurrence of uveal, dural, cutaneous and CNS melanomas in patients with nevus of Ota is rare but significant (1:400 compared to 1:13.000 of the normal population) • CNS melanocytoma • Recent studies confirm that recurrent mutations in GNAQ (R183) are found in these melanomas as well as a second step mutations of other genes, namely, GNA11, PMS1, TP53, SF3B1, monosomy chr3 and BAP1 mutations as a factor in the pathogenesis of these neoplasms

Fig. 15.78 

Follow-up and therapy • • • •

Ophthalmological consultations Laser therapy Prevention of risk of melanomas Targeted therapies of melanomas arising in these patients is related to genetic studies of mutated genes involved in the pathogenesis

Bibliography Abdolrahimzadeh S, Pugi DM, Manni P, Iodice CM, Di Tizio F, Persechino F, Scuderi G. An update on ophthalmological perspectives in oculodermal melanocytosis (Nevus of Ota). Graefes Arch Clin Exp Ophthalmol. 2023;261(2):291–301. Agarwal P, Patel BC. Nevus Of Ota and Ito. 2022 Jul 12. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. Yamada-Kanazawa S, Jinnin M, Fukushima S. Nevus of Ota on the auricle successfully treated with Q-switched ruby laser. Drug Discov Ther. 2022 Nov 20;16(5):254–255.

Dermal melanocytosis (DM) Synonyms

• Mongolian spots • Mongolian blue spots

Epidemiology

Reported as 70–95% in African and Asian neonates, 10–15% in Caucasian.

• • • • •

media like skin, shorter wavelengths (blue colour) are more reflected compared to long wavelength (red tinges) leading to the “bluish” colour visible in the areas of skin with DM, like in older tattoos They may involve unusual sites (acral), be of very large dimensions (“extensive dermal melanocytosis”), have darker colour and more definite borders Type 1 Mosaic distribution (unilateral, half body, congenital unilateral dermal melanocytosis) may occur as well as superimposed type II mosaicism Presence of typical or atypical café-au-lait macules outside the DM or intermingled Vascular birthmarks (Phakomatosis Pigmento-vascularis, see Chapter 16) Moreover, they may persist throughout life

Extracutaneous findings

Atypical DM presentations may be associated with: • Co-localized cleft lip, ocular melanocytosis and melanomas, vascular birthmarks as in phakomatosis pigmentovascularis • Lysosomal storage diseases: Hurler’s syndrome (X-linked mucopolysaccharidosis type 1): hepatosplenomegaly, skeletal deformities, deafness, mental retardation and corneal opacities, GM1 gangliosidosis, Niemann-Pick disease, mucopolysaccharidosis type II and IV.

Laboratory findings

At birth or during the first weeks of life

Histology shows spindle-shaped cells that contain pigment located between collagen fibres deep within the dermis.

Cutaneous findings

Genetic and pathogenesis

Age of onset

• Usually flat and blue-brownish-coloured lesions, located in lumbar, sacral and gluteal areas, with typical indistinct borders and self-solving during the first years of life (Figure 15.78). The different bluish hues in DM are due to the “Tindall-effect”, meaning that in disomogeneous

• Mutations in the GNAQ gene have been found in DNA derived from skin in extensive DM (but not in blood samples), extending the phenotypic spectrum of human GNAQ mutations surviving only by mosaicism from SturgeWeber syndrome (vascular only), through phakomatosis

Atlas of Genodermatoses

336 pigmentovascularis (vascular and pigmentary) and finally to extensive DM (pigmentary only). Furthermore, somatic GNAQ mutations are frequently associated to blue nevi and uveal melanoma • Somatic GNA11 mutations have also been found in patients with extensive DM • These mutations may affect the distribution of melanoblasts and melanocytes during embryogenesis and may affect the final steps of migration from the dermis to epidermis • Of note, extensive DM may be a diagnostic clue in patients with constitutional mismatch repair deficiency syndrome (see Chapter 22)

Differential diagnosis • • • • • •

Blue nevi Nevus of Ota Capillary malformations Phakomatosis pigmentovascularis Child abuse A recently described autosomal recessive disorder causing diffuse hyperpigmentation with focal worsening due to the ABCD4 gene affecting an ATPase function and the intracellular processing of Vitamin B12

Fig. 15.79 

Follow-up and therapy

• In extensive and persisting DM, a multidisciplinary observation is mandatory to exclude metabolic syndromes • Ophthalmological examination for face localization • Otolaryngologist examination when cleft-lip is present • No specific therapy • Q-switched alexandrite laser for cosmetic purposes in persisting lesions

Bibliography Chua RF, Pico J. Dermal Melanocytosis. 2022 Aug 1. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. Mishra S, Pai P, Uttarilli A, Girisha KM. Mongolian spots in GM1 gangliosidosis: a pictorial report. Clin Dysmorphol. 2021;30(1):6–9. Prasad T, Tully J. Late onset congenital dermal melanocytosis ‘Mongolian blue spots’ confused as child abuse: Are there more lessons to be learnt? J Paediatr Child Health. 2017;53(9):908–911. Rayala BZ, Morrell DS. Common skin conditions in children: Neonatal skin lesions. FP Essent. 2017;453:11–17.

Cutis tricolor Epidemiology

More than 20 cases reported

Age of onset

At birth or during infancy

Cutaneous Findings

• Presenting as a purely cutaneous manifestation consisting of: a. a combination of usually paired hypo- and hyperpigmented lesions roughly arranged in “safety-belt” “sashlike” pattern with a background of normal pigmented skin, especially visible on the back (Figure 15.79) and b. multiple disseminated small-to-medium-sized hypoand hyperpigmented skin macules, called cutis tricolor “parvimaculata” (Figure 15.80)

Fig. 15.80 

• Both subtypes may be visible as an isolated cutaneous trait or be part of a complex multiorgan syndrome • Bushy eyebrows • Associated with cutis marmorata telangiectatica congenita and phakomatosis pigmentovascularis

Extracutaneous Findings In syndromic forms:

• Characteristic facies with downslanting and hypertelorism, low-set ears, prognathism • Dolichocephaly and abnormal sella turcica, long-bone dysplasias (tibial bowing), vertebral anomalies, scoliosis • Hypoplasia of corpus callosum, EEG anomalies, seizures • Mental retardation and behavioural disturbances

Disorders of Pigmentation

337

Laboratory findings

Abnormalities of MRI and EEG

Genetics and pathogenesis

• Some authors report cutis tricolor in association with Ring Chromosome 15 • Up to now, specific gene mutations are not reported • Cutis Tricolor may be considered a further example of “allelic Twin-spotting” • The earlier the mutation during embryogenesis the wider the involvement of the skin, CNS and bones • By contrast, later mutational post-zygotic events may generate only skin involvement • A familial case is reported leading to consider a paradominant inheritance

Differential Diagnosis

• Other non-syndromic or syndromic pigmentary mosaicism • Phakomatosis pigmentokeratotica and pigmentovascularis • Ataxia-telangiectasia (see also Chapter 19), Fanconi anaemia (see Figure 19.41) and mismatch repair syndrome may show similar mixed pigmentary lesions

Fig. 15.81 

Course and Prognosis

In severe syndromic cases, lifespan may be reduced.

Follow-up and therapy

• Neuroimaging, neurological and psychiatric follow-up for seizures and behavioural abnormalities • Orthopaedic devices for long-bone dysplasia and scoliosis

Bibliography Ribeiro Dias Barroso C, Silveira Gomes L, Abrantes Silvestre V, Yamada Utagawa C. Cutis tricolor parvimaculata in ring chromosome 15 syndrome: A case report. Pediatr Dermatol. 2018;35(3): e204–e205. Ruggieri M, Polizzi A, Schepis C, et al. Cutis tricolor: a literature review and report of five new cases. Quant Imaging Med Surg. 2016;6(5):525–534. Tekin B, Yucelten AD, Bayri Y. A novel association of an uncommon pigmentation pattern: coexistence of cutis tricolor with intracranial teratoma and holoprosencephaly. Dermatol Online J. 2014;20(10):13030/qt2jq3s5x6.

Dyschromatosis symmetrica hereditaria Synonym

Acropigmentation symmetrica of Dohi

Epidemiology

This disease is rare, with few families reported in the Japanese literature and some sporadic cases in other ethnic groups.

Age of onset

During childhood

Cutaneous findings

• Presence of hypo- and hyperpigmented macules on the dorsal aspects of the hands and feet (Figures 15.81 and 15.82) • Hair and body hair may be hypo/hyperpigmented

Extracutaneous findings Dental anomalies

Fig. 15.82 

Laboratory findings

Histologically, melanin pigment in patients has been described as increased in the basal cells of hyperpigmented macules, and the number of melanocytes is decreased in the macules with hypopigmentation.

Genetics and pathogenesis

• The disease is autosomal dominant • Heterozygous mutations of adenosine deaminase acting on the RNA1 gene (ADAR1) or double-stranded RNA-specific adenosine deaminase (DSRAD) have been described to be the causes of dyschromatosis symmetrica hereditaria • The human ADAR1 protein is known to have two isoforms (p150 and p110) due to the use of alternative promoters. Mutations that lead to DSH result in a non-functional p150 protein in the patients carrying these mutations, while these had no effect on the expression of p110. Thus, haploinsufficiency of p150 is the genetic mechanism underlying dyschromatosis symmetrica hereditaria

Atlas of Genodermatoses

338 Differential diagnosis • • • •

Kitamura disease Vitiligo Post-lesional pigmentations (e.g., burns, sunburns, etc.) Dyschromatosis Universalis Hereditaria (ABCB6 and SASH-1 genes, Figure 15.83) • KITGL-related pigmentary mosaicism (previously mentioned in this chapter)

Fig. 15.83 

Course and prognosis

The disease is slowly progressive without complications.

Follow-up and therapy Photoprotection

Bibliography Suganuma M, Kono M, Yamanaka M, Akiyama M. Pathogenesis of a variant in the 5′ untranslated region of ADAR1 in dyschromatosis symmetrica hereditaria. Pigment Cell Melanoma Res. 2020;33(4):591–600. Wang C, Xia S, Cui Z, Liu X, Qian K, Li Q, Zong X. Analysis of ADAR gene variant in a Chinese pedigree affected with dyschromatosis symmetrica hereditaria. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2022;39(2):202–204. Chinese.

16

VASCULAR DISORDERS Attempts to classify vascular disorders result in a long story. We tried to adhere to the last classification (ISSVA, 2018), centred on the involved vessels, but conversely, the large use of eponyms and the frequent overlap (clinical, anatomic and functional) render this effort often misleading and confusing, with the result that a logical and useful classification is still unavailable.

Fast-flow malformations RASA 1-related phenotypes (Isolated) cutaneous arteriovenous malformations (AVMs)

• Almost localized bright erythematous to purple-coloured lesions, usually present at birth • The most common location is the head and neck (60–70%) (Figure 16.1), but they may be visible at any site on the body (Figure 16.2) • They may become more evident in adolescence and adulthood and never disappear • Lesions are warmer than the surrounding skin and you may feel pulses and thrills upon touching the AVM • Frequently, an epicentric feeding vessel may be visible • With age, draining veins may become prominent • Ulcerations and bleeding may occur as major complications • AVMs may affect soft subcutaneous tissues and bones neighbouring the skin lesions and may result in partial overgrowth (see syndromic forms, discussed next) • Doppler ultrasonography and magnetic resonance angiography are used for follow-up • Arterial embolization and surgery may be required in severe cases

Fig. 16.1 

DOI: 10.1201/9781003124351-16

Fig. 16.2 

Syndromic arteriovenous malformations (AVMs) (Parkes-Weber syndrome)

We must stress that this eponym is particularly confusing. We love Professor Weber’s discoveries in late 1800s, but the “Weber” name is currently associated with “Sturge-Weber syndrome” and with the “Klippel-Trénaunay” eponym, creating confusion in the non-expert reader in this difficult chapter of vascular disorders. We hope that in the future, eponyms will be avoided when they cause visible overlap and discomfort. • Under this eponym are grouped capillary, arteriovenous and lymphatic malformations (even though this complex derivation of lesions is overtly in contradiction regarding the definition of fast-flow anomalies) plus limb overgrowth • Capillary malformations may cover the whole involved extremity or may be patchy (Figure 16.3) • Usually, the lower extremities are involved (75% of patients); less frequently, lesions are on the arms or the buttocks and trunk (Figure 16.4) • Skin lesions are usually pink or red and are usually homogeneous, but may be telangiectatic or reticular and become darker with age • Vascular malformations may be warmer than the neighbouring skin, with or without bruit, due to numerous arteriovenous fistulae (shunts) • Soft tissues and bone overgrowth may create asymmetry with discrepancies in length and diameter of the involved limb (Figures 16.3, 16.5 and 16.6) • Parkes-Weber syndrome is due to a mutation in the RASA-1 gene in two-thirds of patients • Wyburn-Mason, Brégeat and Bonnet-Dechaume syn­ dromes depict the same cutaneous lesions, but with cen­ trofacial localization, eye and central nervous system (CNS) involvement 339

Atlas of Genodermatoses

340

Fig. 16.3 

Fig. 16.5 

Fig. 16.4  • As for the isolated form, syndromic variants may undergo severe complications (bleeding and ruptures) • Doppler echotomography and magnetic resonance angiography are used for diagnosis and management • Selective arterial embolization and vascular–neurovascular surgery may be required

Fig. 16.6 

Vascular Disorders

341 Bibliography

Flores Daboub JA, Grimmer JF, Frigerio A, et al. Parkes Weber syndrome associated with two somatic pathogenic variants in RASA1. Cold Spring Harb Mol Case Stud. 2020;6(4):a005256. Revencu N, Boon LM, Mulliken JB, et al. Parkes–Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations. Hum Mutat. 2008;29(7):959–965. Ziyeh S, Spreer J, Rössler J, et al. Parkes Weber or Klippel–Trénaunay syndrome? Non-invasive diagnosis with MR projection angiography. Eur Radiol. 2004;14(11):2025–2029.

Capillary malformation arteriovenous malformations (CM-AVMs)

• Multiple (2 to 50) vascular skin lesions present at birth, but increasing in number with age, with an estimated prevalence of 1:100.000. • Size ranges from few millimetres to several centimetres wide in the major axis and the lesions are located elsewhere on the skin (Figure 16.7), presenting increased flow on Doppler examination • Round to oval and with irregular shapes and borders • Pink, red to brown in colour, homogeneous or finely telangiectatic (Figures 16.8 and 16.9)

Fig. 16.9 

Fig. 16.7 

Fig. 16.10 

Fig. 16.8 

• At least half of such lesions are surrounded by a pale hypoemic halos (Figure 16.10) • We observed several patients with a phenotype represented by pinpoint vascular lesions surrounded by a clear anaemic halo, diffuse or in a mosaic distribution over the arms (Figures 16.11 and 16.12) • Mucosae are less frequently involved • More than a third of patients have fast-flow vascular malformations, namely, arteriovenous shunts and/or aneurisms that may be located on the extremities (Figure 16.13), face and neck, or may be intracranial (i.e., vein of Galen aneurisms), intraspinal or vertebral • Visceral localizations are exceptional

Atlas of Genodermatoses

342

Fig. 16.11 

• To avoid major complications (aneurism rupture and intracranial haemorrhages), it is mandatory to study all affected patients with Doppler echotomography and magnetic resonance angiography • In severe cases, neurosurgery is used for intracranial localizations • CM-AVM is a dominant disorder due to mutations of the RASA-1 gene with large internal intrafamilial clinical heterogeneity; furthermore, as with other RASopathies, a somatic multihit hypothesis could lead to a total loss of RASA 1 expression and to a large spectrum of phenotypic presentations. In other words, typical skin lesions of CM-AVM originate by a second somatic mutation in the RASA1 gene with loss of heterozygosity. Of note, each vascular lesion shows a different mutation, as occurs in caféau-lait macules of NF1 (Figure 16.14) • A subset of CM-AVM (cited also as CM/AVM2) patients harbour mutations in EPHB4 (Ephrin Type-B receptor 4) gene (Figure 16.15) • EPHB4-released protein is involved in endothelial cell adhesion and migration, and plays a central role in heart morphogenesis, angiogenesis and blood vessels remodelling and permeability • Patients suffering from lymphatic abnormalities have been demonstrated by Burrows in 2013 to be part of the phenotypic spectrum of RASA-1 mutations, confirming the data obtained in mice; in these patients, it is recommended to use the investigational technique of near-infrared fluorescence lymphatic imaging to detect anomalies of lymphatic vessel development. • Finally, patients carrying Endoglin 1 mutations (the gene related to haemorrhagic teleangectasia) may show cutaneous lesions superimposable to that of CM-AVM (Figure 16.16)

Fig. 16.12 

Fig. 16.13 

Fig. 16.14 

Vascular Disorders

343 Revencu N, Boon LM, Mendola A, et al. RASA1 mutations and associated phenotypes in 68 families with capillary malformation– arteriovenous malformation. Hum Mutat. 2013;34(12):1632–1641. Revencu N, Fastre E, Ravoet M, et al. RASA1 mosaic mutations in pati­ ents with capillary malformation-arteriovenous malformation. J Med Genet. 2020;57(1):48–52. Valdivielso-Ramos M, Martin-Santiago A, Azaña JM, et al. Capillary malformation-arteriovenous malformation syndrome: A multicentre study. Clin Exp Dermatol. 2021;46(2):300–305. Wooderchak-Donahue WL, Akay G, Whitehead K, et al. Phenotype of CM-AVM2 caused by variants in EPHB4: How much overlap with hereditary hemorrhagic telangiectasia (HHT)? Genet Med. 2019;21(9):2007–2014.

Slow-flow malformations Venous malformations

• Single (>90%) or, less frequently, diffuse skin lesions composed by ectatic, enlarged venous channels, located on the dermis or subcutaneous soft tissues, sometimes with a checkerboard pattern, clearly visible as bluish irregular masses of vessels, located elsewhere on the body, with some degree of local overgrowth (Figures 16.17 and 16.18) • While they may have a small size, they may be more extensive (i.e., a whole limb)

Fig. 16.15 

Fig. 16.16 

Bibliography Amyere M, Revencu N, Helaers R, et al. Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation-arteriovenous malformation (CM-AVM2) deregulating RASMAPK signaling. Circulation. 2017;136(11):1037–1048. El Hajjam M, Mekki A, Palmyre A, et al. RASA1 phenotype overlaps with hereditary haemorrhagic telangiectasia: Two case reports. J Med Genet. 2021;58(9):645–647.

Fig. 16.17 

Atlas of Genodermatoses

344

Fig. 16.18  • In some cases, venous malformations are clearly mixed with lymphatic abnormalities (Figure 16.19) • Thrombosis and calcifications, ulcerations and phleboliths are frequently observed and must be cured promptly to avoid major complications (disseminated intravascular coagulation)

Fig. 16.20  • Vascular surgery is mandatory in severe cases (Figure 16.20) • Somatic mutations in the TIE2 gene, coding for a receptor of venous endothelial cells, is present in the majority of venous malformations and also for blue rubber bleb syndrome • There is some description of the TIE2 gene mutations inherited in a dominant pattern in families with a disorder called familial, multiple, cutaneous and mucosal venous malformations • PIK3CA gene mutations may be also responsible for venous malformation with or without overgrowth • Isolated and complex arteriovenous malformation and arteriovenous fistulae (“sporadic vascular malformations”) are caused also by four genes of the RAS/MAPK pathway, namely, KRAS, NRAS (low-flow) and in MAP2K1 and BRAF (fast-flow) gene somatic mutations with a variant allelic fraction from 3% to 25% in affected tissues (Figure 16.18) • Of note, BRAF, HRAS and KRAS mutations also cause a subset of pyogenic granulomas (Figure 16.21) and cherry angiomas • These genetic data are relevant to the targeted therapy with RAS/MAPK inhibitor trials • These lesions may be with or without overgrowth and underlying anatomical structures may be involved

Capillary malformations

Fig. 16.19 

• This definition encompasses lesions of different origin and seems to be as ambiguous as it is diffuse and widely accepted in medical literature • This group of disorders also comprises the more frequent vascular abnormalities seen in humans, namely, nuchal (70–80%), glabellar (25–30%) and eyelids (40–50%) pinkish patches known often with the nickname of stork-bites or angel’s kiss. These lesions usually disappear within the first to second year of life, with the exception of nuchal lesions

Vascular Disorders

345

Fig. 16.21 

GNAQ-GNA11-related disorders Isolated port-wine stains (nevus flammeus)

Fig. 16.23 

• This cutaneous capillary malformation occurs in about 3 of 1.000 newborns • Usually located on the face and neck, rarely with mucosal involvement (Figure 16.22) with a clear checkerboard mosaic distribution (Figures 16.23 and 16.24) but they are frequently visible at any body site (Figure 16.25), and they may be either unilateral or bilateral

Fig. 16.24 

Fig. 16.22 

• These lesions are red-purplish in colour and may be homogeneous (Figure 16.24) or display a more reticular pattern (Figures 16.23 and 16.25) • Dermal derivates (vessels comprised) follow a flag-likequadrant migration pattern and this distribution is typical of these vascular lesions. There is no scientific demonstration that vessels should follow peripheral nerve structures during embryonic development; by contrast, somatic mutations (post-zygotic, mosaicism) of the GNAQ/GNA11/ GNA14 genes are demonstrated for isolated and syndromic port-wine stains. Finally, we can consider that, on the face, there are three areas (placodes, quadrants) as illustrated in Figures 16.23 and 16.26 (see also Figure 16.27). Scheme 16.1

Atlas of Genodermatoses

346

Fig. 16.27 

Fig. 16.25 

SCHEME 16.1 

Cutaneous findings Fig. 16.26 

Sturge-Weber syndrome Epidemiology

This neurocutaneous disease occurs in 1:20.000 to 1:50.000 live births.

Age of onset At birth

• This syndrome is defined by a port-wine stain that is mainly located in the upper quadrant of the face, unilateral or bilateral, and associated with mucosal, eye and CNS (leptomeningeal) capillary malformations, leading to ophthalmologic and neurologic symptoms (Figures 16.26 and 16.27) • Patients may have multifocal capillary malformation (Figure 16.26) that clinically show homogeneous or a reticular pattern • Soft-tissue and bone tissue overgrowth is frequent and may be of different degrees of severity, as well as facial asymmetry (Figure 16.28)

Vascular Disorders

Fig. 16.28 

Extracutaneous findings

• Eye abnormalities include vascular choroidal malformations, glaucoma, retinal detachment and blindness • Neurological symptoms are represented by early-onset epilepsy, hemiparesis, hemiplegia and delayed development, due to CNS abnormal development and growth • Early onset hypertension

Laboratory findings

Angio-magnetic resonance imaging (MRI), computed tomography (CT)-scan, and positron emission tomography (PET) are useful for monitoring cerebral lesions.

Follow-up and therapy

Medical treatment for seizures and laser treatment for ocular and skin lesions are used in these patients; less frequently, neurosurgery is recommended to treat more complicated intracranial anomalies.

Genetics and pathogenesis

• Specific somatic mosaic activating mutation in the GNAQ gene (pArg183gln) in affected skin and brain tissues has been shown to be responsible for this syndrome, as well as for non-syndromic port-wine stain-capillary malformation • GNAQ encodes Gaq, one of the q class of G-protein a-subunits that modulates signals between G-protein-coupled receptors and their effectors • The specific pArg183gln results in a reduction of GTPase activity, leading to increased signalling activity (the MAPK pathway with increased cell proliferation and reduced apoptosis) and may also be mediated through endothelin, a further G-protein-coupled receptor. Endothelin has an important role both in early melanogenesis and in vasculogenesis, and may play a relevant role in vascular malformations for both Sturge-Weber and non-syndromic capillary malformations • Also, GNA11 gene mutations are responsible for a subset of Sturge-Weber patients with a less homogeneous, reticulate

347 appearance of the vascular lesions, hypo-overgrowth and mild neurological symptoms • It is noteworthy that mosaic activating GNAQ mutations also underlie blue nevi and nevus of Ota (see Chapter 15) and may also be responsible for phakomatosis pigmentovascularis (association of vascular and pigmentation mosaic lesions) in analogy to RAS mutations occurring in phakomatosis pigmentokeratotica (association of a keratinocytic nevus and a speckled lentiginous nevus): the mutation occurs early in embryonic development and a progenitor mutated cell gives birth to both vascular and melanocyte abnormal lines, creating this peculiar phenotype • Shirley (2013) hypothesizes that only the weaker effects of somatic GNAQ mutation specific of Sturge-Weber syndrome is compatible with abnormal, but non-lethal, development of the skin and cerebrovascular system. The time in which the mutation occurs during embryonic development and the cell type involved may mediate the severity of the disease in each patient • More recently, a further subset of Sturge-Weber-like presentation was linked to somatic missense mutations in GNB2 gene mutations encoding a beta-chain of the same G-protein of GNAQ signalling pathway. GNB2 acts also via the yes-associated protein (YAP, an activator of “hippo” pathway) and not only via the MAPK pathway, leading to a potential new pathogenesis for this disorder and a consideration for the next targeted therapy

Bibliography Davies OMT, Ng AT, Tran J, et al. Early-onset hypertension associated with extensive cutaneous capillary malformations harboring postzygotic variants in GNAQ and GNA11. Pediatr Dermatol. 2022;39(6):914–919. Fjær R, Marciniak K, Sundnes O, et al. A novel somatic mutation in GNB2 provides new insights to the pathogenesis of Sturge-Weber syndrome. Hum Mol Genet. 2021;30(21):1919–1931. Lee BB, Antignani PL, Baraldini V, et al. ISVI-IUA consensus document diagnostic guidelines of vascular anomalies: Vascular malformations and hemangiomas. Int Angiol. 2015;34(4):333–374. Epub 2014 Oct 6. Schaffer JV. JAAD game changers∗: Forehead location and large segmental pattern of facial port-wine stains predict risk of Sturge-Weber syndrome. J Am Acad Dermatol. 2023 May;88(5):1223. Shirley MD, Tang H, Gallion CJ, et al. Sturge–Weber syndrome and portwine stains caused by somatic mutation in GNAQ. N Engl J Med. 2013;368(21):1971–1979.

Cobb syndrome Synonym

Cutaneomeningeal angiomatosis

Epidemiology

The disease is very rare, with not more than 50 cases published.

Age of onset At birth

Cutaneous findings

• Port-wine stains, cutaneous and subcutaneous vascular malformations overlying spinal defects almost totally located in the lumbar region (Figures 16.29 and 16.30) • Rarely port-wine stains in other areas

Atlas of Genodermatoses

348 Laboratory findings

• Echotomography of lumbar areas may detect closure defects at birth • Angio-MRI provides a tool for both prognosis and therapy

Genetics and pathogenesis

In a single report of Cobb syndrome, a KRAS somatic mosaic mutation was detected

Differential diagnosis

• Other syndromic vascular anomalies • Spina bifida complex • Non-syndromic port-wine stains of lumbar areas

Course and prognosis

The course of the disease is directly related to the severity of vascular spinal defects.

Follow-up and therapy

Neurosurgery when requested

Bibliography Fig. 16.29 

Dilmé-Carreras E, Iglesias-Sancho M, Márquez-Balbás G, Sola-Ortigosa J, Umbert-Millet P. Cobb syndrome: Case report and review of the literature. Dermatology. 2010;221(2):110–112. Edwards EA, Phelps AS, Cooke D, Frieden IJ, Zapala MA, Fullerton HJ, Shimano KA. Monitoring arteriovenous malformation response to genotype-targeted therapy. Pediatrics. 2020;146(3):e20193206. Palanca Arias D, Rius Gordillo N, García Fructuoso G, Candela Cantó S, Sola Martínez T, Palomeque Rico A. Cobb syndrome or cutaneomeningospinal angiomatosis. An Pediatr (Barc). 2010;73(2): 109–111. Rodesch G, Hurth M, Alvarez H, et al. Classification of spinal cord arteriovenous shunts: Proposal for a reappraisal—The Bicetre experience with 155 consecutive patients treated between 1981 and 1999. Neurosurgery. 2002;51:374–379; discussion 379–80.

Other syndromes with prominent vascular signs von Hippel-Lindau syndrome Synonym

Haemangioblastoma of retina and cerebellum

Epidemiology 1:36.000 births

Age of onset At birth

Cutaneous findings Fig. 16.30 

Extracutaneous findings • • • • •

Vertebral and paravertebral haemangiomas Intraspinal epidural malformations and angiomatosis Intramedullary haemangiomas Meningeal angiomatosis Hemiplegia or paraplegia due to vascular malformation defects

• Port-wine stains of the face, occipital and cervical regions occur in 5–20% of patients • Café-au-lait spots

Extracutaneous findings • • • •

Cerebellar and/or spinal haemangioblastomas Retinal angiomas in a large percentage of patients Less frequently, vascular malformations in internal organs Pheochromocytoma and renal polycystic disease and carcinomas, as well as pancreatic neuroendocrine tumour

Vascular Disorders

349 tumor suppressor protein: Mechanism of the disease and implications for drug development. Proteins. 2013;81(2):349–363. Mikhail MI, Singh AK. Von Hippel Lindau Syndrome. 2022 Feb 2. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. Tong D, Zhang Y, Jiang J, Bi G. Identification of a VHL gene mutation in atypical Von Hippel-Lindau syndrome: Genotype-phenotype correlation and gene therapy perspective. Cancer Cell Int. 2021; 21(1):685.

Anemic nevus Synonyms

• Nevus anaemicus • Hypoemic nevus

Epidemiology

This is an underestimated condition

Age of onset

At birth or in early childhood

Cutaneous findings Fig. 16.31 

Laboratory findings

Angio-MRI is used to detect the severity of cerebellar and retinal lesions (Figure 16.31).

Genetics and pathogenesis

• The disease is inherited as an autosomal dominant trait and is due to mutations on the VHL gene, which may be responsible for the associated neoplasms • Dysfunction of the VHL protein causes accumulation and activation of hypoxia inducible factor (HIF), which can be demonstrated in the earliest stages of tumorigenesis and is followed by expression of VEGF, erythropoietin, nitric oxide synthase and glucose transporter 1 in VHL-deficient tumour cells

• Pale, sharply bordered and well-defined patches, sometimes surrounded by smaller satellite spots (Figure 16.32, where peripheral erythema is due to rubbing) • Visible in allelic twin-spots together with port-wine stains (“nevus vascularis mixtus” NVM) (Figure 16.33) • NVM may be visible in association with cutis marmorata telangiectatica congenita • Part of a subtype of phakomatosis pigmentovascularis (nevus anaemicus and melanocytic nevus) • It is a relevant clinical sign in Neurofibromatosis type 1 (see Chapter 9)

Extracutaneous findings

• Nevus anaemicus and allelic dydymosis can be isolated or syndromic, with overgrowth/hypogrowth • Neurological involvement, rarely large-vein thrombosis, hypertension and renal anomalies

Differential diagnosis

Non-syndromic intracranial vascular malformations.

Course and prognosis

• Rarely, the basic lesions may lead to epilepsy and progressive mental retardation • High risk for vascular intracranial ruptures

Follow-up and therapy

• Angio-MRI • Neurosurgical approach when applicable

Bibliography Charlesworth M, Verbeke CS, Falk GA, Walsh M, Smith AM, MorrisStiff G. Pancreatic lesions in von Hippel–Lindau disease? A systematic review and meta-synthesis of the literature. J Gastrointest Surg. 2012;16(7):1422–1428. Frantzen C, Links TP, Giles RH. Von Hippel–Lindau disease. In Pagon RA, Bird TD, Dolan CR et al., editors. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993. Limaverde-Sousa G, Barreto Ede A, Ferreira CG, Casalida-Rocha JC. Simulation of the mutation F76del on the von Hippel–Lindau

Fig. 16.32 

Atlas of Genodermatoses

350

Bibliography Ahkami RN, Schwartz RA. Nevus anemicus. Dermatology. 1999;198(4):327–329. Daniel RH, Hubler WR Jr, Wolf JE Jr, Holer WR. Nevus anemicus: Donordominant defect. Arch Dermatol. 1977;113:53–56. Tadini G, Brena M, Pezzani L, Gelmetti C, Santagada F, Boldrini MP. Anemic nevus in neurofibromatosis type 1. Dermatology. 2013;226(2):115–118. Tadini G, Brena M. Anemic nevus is a new diagnostic criterion for neurofibromatosis type 1. G Ital Dermatol Venereol. 2017;152(5): 548–549.

Angioma serpiginosum (AS) Epidemiology

Rare disease. Female/male ratio 9:1

Age of onset

At birth or within the first decade of life Fig. 16.33 

Genetics and pathogenesis

• GNAQ and GNA11 gene mutations • Owing to the high frequency of anaemic nevus in NF1 and the fact that NF1 and RASA-1 are part of the RAS–MAPK pathway, which is involved in the pathogenesis of vascular malformations, we can speculate that anaemic nevus in NF1 patients may originate from a somatic mutation in one of these genes • If nevus anaemicus and NVM are caused by an abnormal response to catecholamines or to a real anatomical hypo/ overgrowth of capillary vessels is still to be determined

Cutaneous findings

• Vascular reddish, non-blanchable under pressure macules and papules, grouped in linear, serpiginous or figurate pattern, sometimes on erythematous skin (Figures 16.34 and 16.35)

Differential diagnosis

• Hypopigmented nevus • Vitiligo

Course and prognosis

There are no modifications with age

Follow-up and therapy

Camouflage can be applied if necessary

Fig. 16.35 

Fig. 16.34 

Vascular Disorders

351

Fig. 16.36  • Lesions are mainly asymmetric distributed along Blaschko lines, even if sometimes the mosaic pattern is not obvious (Figure 16.36) • Dermoscopic evaluation reveals well-demarcated red lagoons (Figure 16.37)

Extracutaneous manifestations

• Retinal involvement (retinal vein occlusion) • Neurological abnormalities and psychological distress

Genetics and pathogenesis

• AS usually occurs sporadically, although rare familial cases with autosomal dominant and X-linked dominant inheritance have been reported (Figure 16.38) • Mosaic type I distribution, but also diffuse unpatterned mosaicism (Figure 16.35)

Fig. 16.38 

Course and prognosis

Telangiectases may worsen with age and during pregnancy.

Follow-up and therapy

Therapeutic options include pulsed-dye laser (PDL) and potassium titanyl phosphate (KTP) laser therapy.

Bibliography Anjaneyan G, Kaliyadan F. Angioma Serpiginosum. 2022 Jul 18. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. Diociaiuti A, Cutrone M, Rotunno R, De Vito R, Neri I, Pisaneschi E, El Hachem M. Angioma serpiginosum: A case report and review of the literature. Ital J Pediatr. 2019;45(1):53. Duman N, Ersoy-Evans S. Angioma serpiginosum: Report of two cases suggesting type 1 mosaicism and proposal of adding it to the list of mosaic skin conditions. Int J Dermatol. 2015;54(3):e88–e89.

Cutis marmorata telangiectatica congenita Synonym

Congenital livedo reticularis

Epidemiology

No data available. Fig. 16.37 

Age of onset At birth

Atlas of Genodermatoses

352 Cutaneous findings

• Reticulated, marble-like appearance of the skin due to abnormal venous and capillary distribution of skin-associated vessels, generalized or in mosaic arrangement (Figures 16.39–16.41) • Overlying cutaneous atrophy with ulcerations and loss of substance (Figures 16.42 and 16.43)

Fig. 16.41 

Fig. 16.39 

Fig. 16.42  • Lesions may be more subtle, and the pattern of vascular lesions may give a designed tissue appearance to the entire skin (Figures 16.44 and 16.45) • Vascular lesions may be generalized or unilateral or segmental with a port-wine stains association (Figure 16.46) • Secondary hypo- and hyperpigmented residual figurate lesions may be visible

Extracutaneous findings

Fig. 16.40 

• Asymmetry, particularly of the limbs, syndactyly, stenosis tendinitis, hip dysplasia, clubfoot and cleft palate • Craniofacial abnormalities may lead to micrognathia and triangle-shaped facies • Glaucoma • Involvement of internal organs vasculature i.e., brain vessels

Vascular Disorders

Fig. 16.43 

353

Fig. 16.45 

Fig. 16.44 

Laboratory findings

• There are no specific alterations in routine haematological examination • CT scan can easily detect CNS-associated signs

Genetics and pathogenesis

• Mosaic post-zygotic mutations of GNA11 gene in some patients • GNA11 mutations are absent in a subset of patients showing or genetic heterogeneity or the very low percentage of GNA11 mutations in the affected tissue that remain under the threshold of resolution of the current diagnostic ultradeep next generation sequences

Differential diagnosis

• Aplasia cutis congenita • Adams-Oliver syndrome • Normal reactive livedo reticularis in newborns and in infancy

Fig. 16.46 

Course and prognosis

• Localized necrosis overlying the vascular reticulum (Figures 16.42 and 16.43) • Loss of substance with hypoatrophy in the related leg or area involved • Rarely, hemiatrophy of the face

Atlas of Genodermatoses

354 Follow-up and therapy

• Head circumference should be measured to rule out more serious conditions • Evaluation of asymmetry and overgrowth

Bibliography Levy R, Lam JM. Cutis marmorata telangiectatica congenita: A mimicker of a common disorder. CMAJ. 2011;183(4):E249–E251. Martínez-Glez V, Romanelli V, Mori MA, et al. Macrocephaly – capillary malformation: Analysis of 13 patients and review of the diagnostic criteria. Am J Med Genet A. 2010;152A(12):3101–3106. Schuart C, Bassi A, Kapp F, et al. Cutis marmorata telangiectatica congenita being caused by postzygotic GNA11 mutations. Eur J Med Genet. 2022;65(5):104472. Shareef S, Alves JL, Horowitz D. Cutis Marmorata Telangiectatica Congenita. 2022 Mar 9. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–.

Microcephaly–capillary malformation Epidemiology

Very rare condition (80%). The presence of recalcitrant, widespread cutaneous viral infections (Figure 19.18), asthma and, in particular, food and environmental allergies, as well as the absence of coarse facies, favours the clinical diagnosis of DOCK8 deficiency • Elevated IgE levels and associated atopic dermatitis-like recalcitrant rashes are described in Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome, a further rare PID disorder caused by FOXP3 mutations that lead to the abnormal development of regulatory T cells. Cutaneous manifestations of IPEX syndrome may include viral and bacterial infections, psoriasis-like lesions, nail dystrophy and autoimmune symptoms as area Celsi and chronic urticaria

Differential diagnosis

• Severe forms of atopic dermatitis • Wiskott-Aldrich syndrome

Course and prognosis

In cases of prompt diagnosis and treatment, the disease may have a chronic course, but death may occur early owing to deep infections.

Fig. 19.17 

Fig. 19.18 

Follow-up and therapy

• Patients must be closely followed for infections and association with malignancies • Antibiotics • Intravenous human immunoglobulins • Cimetidine or ranitidine to induce an improvement in recurrent infections • Incision and drainage of abscesses • Bone marrow transplantation does not correct the syndrome

Atlas of Genodermatoses

426 Bibliography Minegishi Y. Hyper-IgE syndrome, 2021 update. Allergol Int. 2021 Oct; 70(4):407–414. Tangye SG, Gray PE, Pillay BA, Yap JY, Figgett WA, Reeves J, Kummerfeld SK, Stoddard J, Uzel G, Jing H, Su HC, Campbell DE, Sullivan A, Burnett L, Peake J, Ma CS. Hyper-IgE Syndrome due to an Elusive Novel Intronic Homozygous Variant in DOCK8. J Clin Immunol. 2022 Jan;42(1):119–129. Tsilifis C, Freeman AF, Gennery AR. STAT3 Hyper-IgE Syndrome-an Update and Unanswered Questions. J Clin Immunol. 2021 Jul; 41(5):864–880.

Hereditary Angioedema Synonym

C1q esterase inhibitor deficiency

Epidemiology

The estimated frequency is 1:50.000 persons.

Age of onset

Usually within the first decade

Cutaneous findings

• Recurrent swelling of the mucosae and skin, especially the lips, face and hands (Figure 19.19) • Episodes heal spontaneously in hours or days • Erythema marginatum in a minority of patients (which may herald the oedema)

Extracutaneous findings

• Autoimmune disorders such as lupus erythematosus and glomerulonephritis are reported • Severe involvement of oral mucosa and the upper respiratory tract is common • Gastrointestinal symptoms (diarrhoea and colic pain)

Laboratory findings

• Low levels of C4 and C1 esterase inhibitors that are present but dysfunctional and unable to inhibit target proteases • Analysis of C1q can help differentiate between HAE and acquired angioedema caused by C1-inhibitor (INH) deficiency • Skin biopsies give aspecific results • There are three types of HAE: type 1 HAE is most common, occurring in ~85% of patients and characterized by decreased production of C1-INH, resulting in reduced functional

activity to 5–30% of normal. In type 2, which occurs in 15% of cases, C1-INH is detectable in normal or elevated quantities but is dysfunctional. Finally, type 3, which is rare and almost exclusively occurs in women, is oestrogen dependent and associated with normal CI-INH and C4 levels

Genetics and pathogenesis

• Autosomal dominant disease • Mutations in the C1q esterase inhibitor gene (SERPING1)

Differential diagnosis

• Common urticaria • Autoimmune skin diseases • Common hypersensitivity and allergic episodes

Course and prognosis

• The disease persists throughout life • Episodes may be caused by emotional and thermal stress or intercurrent diseases • Severe episodes characterized by laryngeal involvement may be life threatening if not promptly cured

Follow-up and therapy

• Prompt rescue for severe laryngeal episodes • Detection of affected relatives • Various treatment options for acute attacks and prophylaxis of HAE are authorized and available on the market, including plasma-derived and recombinant C1 inhibitors, the kallikrein inhibitor ecallantide and the bradykinin B2 receptor antagonist icatibant • Lanadelumab, a fully human monoclonal antibody that selectively inhibits active plasma kallikrein, is used in preventing hereditary angioedema attacks

Bibliography Banerji A, Riedl MA, Bernstein JA, Cicardi M, Longhurst HJ, Zuraw BL, Busse PJ, Anderson J, Magerl M, Martinez-Saguer I, DavisLorton M, Zanichelli A, Li HH, Craig T, Jacobs J, Johnston DT, Shapiro R, Yang WH, Lumry WR, Manning ME, Schwartz LB, Shennak M, Soteres D, Zaragoza-Urdaz RH, Gierer S, Smith AM, Tachdjian R, Wedner HJ, Hebert J, Rehman SM, Staubach P, Schranz J, Baptista J, Nothaft W, Maurer M; HELP Investigators. Effect of Lanadelumab Compared With Placebo on Prevention of Hereditary Angioedema Attacks: A Randomized Clinical Trial. JAMA. 2018 Nov 27;320(20):2108–2121. Sarkar A, Nwagwu C, Craig T. Hereditary Angioedema: A Disease Often Misdiagnosed and Mistreated. Prim Care. 2023 Jun;50(2):295–303. Sinnathamby ES, Issa PP, Roberts L, Norwood H, Malone K, Vemulapalli H, Ahmadzadeh S, Cornett EM, Shekoohi S, Kaye AD. Hereditary Angioedema: Diagnosis, Clinical Implications, and Pathophy­ siology. Adv Ther. 2023 Mar;40(3):814–827.

Omenn syndrome-severe combined immunodeficiencies Synonyms

Omenn syndrome is an umbrella term of the clinical presentation of many immunodeficiency syndromes that develop Omenn-like features that are clinically indistinguishable one from each other: Fig. 19.19 

• SCID • Familial reticuloendotheliosis with eosinophilia

Immunodeficiency Disorders

427

Epidemiology 38°C) with severe asthenia, acute abdominal pain and large-joint arthritis lasting for less than a week • Polyserositis and chest pain • Skin involvement is variable and often absent

Autoinflammatory Diseases

443

• Erysipela-like, cellulitis-like lesions are reported in 7–40% of patients, normally located on the lower limbs • Secondary amyloidosis • Autosomal recessive missense mutations in the MEFV gene, leading to an abnormal production and modulation of IL-1β (see also Chapter 5)

Mevalonate kinase deficiency with elevated immunoglobulin D and periodic fever syndrome

• This disease is rare; no epidemiological data are available • Onset is usually in early childhood and, in the majority of cases, with a benign evolution during adulthood • Recurrent high fever flares, often triggered by different stimuli (i.e., immunizations), lasting 3–7 days and relapsing every 4–6 weeks • Bilateral cervical lymphadenopathy • Abdominal pain, diarrhoea and vomiting • Polyarthralgia • Papular, urticarial, nodular and purpuric rashes in more than 80% of patients • Less frequently, aphthous-like ulcers (Figure 20.17) • High immunoglobulin D serum levels, often with hyperimmunoglobulin A • Autosomal recessive mevalonate kinase gene mutations

TNF1-associated periodic syndrome (TRAPS)

• Incidence in Germany estimated as 5.6 per 106 person/years • First manifestations during childhood or adolescence • Recurrent fever episodes with mean a 2-week length, but frequently lasting many weeks, although in a few genetically confirmed reported patients, fever was absent • Associated acute abdominal pain (often misdiagnosed and surgically treated) • Myalgia, fasciitis and arthralgia • Migratory pain with overlying, aspecific, tender erythematous skin rash (Figure 20.18) • Recurrent conjunctivitis with periorbital oedema • Headache, aseptic meningitis, optic neuritis and behavioural alterations • 25% of patients develop secondary amyloidosis

Fig. 20.17 

Fig. 20.18 

PFAPA syndrome

• Periodic Fever, APhthous stomatitis, cervical Adenitis • Onset from 1 to 5 years of age • Episodic fevers, recurrent every few weeks, starting abruptly and lasting from 3 to 7 days • Aphthous stomatitis, pharyngitis • Cervical adenitis • Joint pain, abdominal pain, headache, vomiting and diarrhoea • Familial cases are reported but no mutations found so far • Susceptibility loci (IL12, IL10, STAT4) link PFAPA, recurrent aphthous stomatitis and Behcet disease

Cryopyrinopathies

This definition encompasses a continuum of three previously separated entities: a. Familial cold autoinflammatory syndrome (CINCA) b. Muckle-Wells syndrome c. Neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurological, cutaneous, and articular syndrome • Autosomal dominant diseases due to gain-of-function mutations in the NLRP3 gene, encoding the protein cryopyrin, a component of a complex that modulate IL-1β (NLRP3 — inflammasome) • Somatic mosaicism of the NLRP3 gene has been demonstrated with milder severity • Onset is variable from shortly after birth to childhood • Recurrent flares of fever with different pattern, from cold-exacerbated brief-duration episodes of low-grade fever to continuous low-grade fever with exacerbations • Urticarial rash starting as an aspecific maculo-papular migratory exanthema evolving into wheels with a particular non-pruritic, burning-stinging sensation (Figure 20.19) • Conjunctivitis • Articular involvement • Sensorineural hearing loss

Atlas of Genodermatoses

444

• Exanthema reminiscent of an erythematous autosomal recessive congenital ichthyosis in some patients • Maculopapular rashes, aspecific, erythema nodosum • Chronic arthritis in 100% of patients, boggy synovitis • Ocular involvement in 85% of patients with chronic and persistent uveitis, cataracts and glaucoma • Untreated patients may show progressive blindness

DIRA-DITRA spectrum syndromes

• Deficiency of IL-1 receptor antagonist (DIRA) syndrome is a very rare autosomal recessive disorder caused by loss-offunction mutations in the IL1RN gene, which encodes the IL-1 receptor antagonist; the mutated receptor antagonist loses competitive ability, resulting in IL-1 overactivity • Deficiency of the interleukin 36 receptor antagonist (DITRA) is caused by mutations in the IL-36 receptor antagonist

Fig. 20.19  • Neurological involvement (headache, aseptic meningitis, nausea, and vomiting; rarely, seizures and strokes) • Secondary amyloidosis may develop in a minority of patients • Interestingly, at the histological examination, a dermal polymorphonuclear dense infiltrate is visible, which is different from the eosinophilic-lymphocytic infiltrate of classical urticaria • Therapy is based on IL-β inhibitor, anakinra

Schnitzler syndrome

• Late onset (13–30 years) and late diagnosed (5 years) recurrent febrile rash, joint and bone pain, fatigue, enlarged lymph nodes, leukocytosis • Monoclonal IgM component and systemic inflammatory activation • The urticaria-like rash is present in all patients with flat or pomphoid lesions, lasting 1 day and moderate itching, with variable time of recurrence with a neutrophilic infiltrate without vasculitis upon histological examination and IgM deposition along the dermal-epidermal junction • Angio-oedema and dyspnoea are rare, as well as hearing loss • Amyloidosis in late stages • The overall prognosis is related to the risk of evolution toward lymphoproliferative disorders that occurs in >20% of patients (lymphomas, IgM myelomas, Waldenstrom disease) • In one patient, a mutation in the NLRP3 gene was unsurprisingly demonstrated, given the striking clinic and pathogenetic similarities between Schnitzler syndrome and the group of cryopyrinopathies • Therapy, in analogy with the cryopyrinopathies, is based on the use of IL1-inhibitor anakinra and IL-6 inhibitors • JAK inhibitors and colchicine may be considered as other choices of treatment

DIRA

• Early onset of pustular rash that may be sparse or in crops or merge into a generalized pattern reminiscent of pustular psoriasis (Figure 20.20) • Onychomadesis • Stomatitis • Painful multifocal osteomyelitis and periostitis with joint swelling • Fever is usually absent • Conjunctivitis

DITRA

• Same pustular-psoriasis-like involvement • High-grade fever flares

without

bone

Majeed syndrome • • • •

Recessive loss-of-function mutations in the LPIN2 gene Neonatal onset of recurrent multifocal aseptic osteomyelitis Dyserythropoietic anaemia Pustular neutrophilic dermatitis and psoriasis-like plaques are possible

PAPA-PASH-PAPASH-AA-SAPHO spectrum syndromes

Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) Pyoderma gangrenosum, acne and hidradenitis suppurativa (PASH)

Blau syndrome

• Also called paediatric granulomatous arthritis or, in the past, early-onset sarcoidosis • This disease is very rare and no epidemiological data are available • Autosomal dominant gain-of-function mutations in the NOD2/CARD15 gene

rashes

Fig. 20.20 

Autoinflammatory Diseases

445

Pyogenic arthritis, pyoderma gangrenosum, acne and hidradenitis suppurativa (PAPASH) Aseptic abscesses (AA) Severe inflammation associated with synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) • These five acronyms account for a unique disease with autosomal dominant transmission caused by different kinds of mutations of the PSTPIP1 gene • The PSTPIP1 protein binds and modulates pyrin, a structure that is exclusively expressed on neutrophils and functions as an inhibitor of the inflammatory process. In these syndromes, the mutated PSTPIP1 protein increased its capacity to bind pyrin, resulting in higher recruitment of the caspase-1 enzyme and an overproduction of IL-1 via the proteolytic cleavage of pro-IL-1 • Early onset of pyogenic sterile arthritis is normally the first sign • Severe nodulo-cystic acne (Figures 20.21 and 20.22) • Pyoderma gangrenosum (Figure 20.23) • Hidradenitis suppurativa (Figure 20.24) • These symptoms may be present alone or in different combinations

Fig. 20.22 

Syndromic hidradenitis suppurativa (HS)

• Recent advances demonstrated the involvement of autoinflammatory genes, including NOD2 (nucleotide-binding oligomerization domain-containing protein 2), NLRC4 (NLR family CARD domain containing 4), WDR1 (WD repeat domain 1), MPO (myeloperoxidase) and OTULIN (OTU deubiquitinase with linear linkage specificity), as well as GJB2 (gap junction protein beta 2), a key gene of keratinization pathway, in a cohort of syndromic HS patients, corroborating the polygenic autoinflammatory nature of HS syndromic forms

Fig. 20.23 

Fig. 20.21 

Fig. 20.24 

Atlas of Genodermatoses

446 • NLRC4 is one of the best correlated with triggering formation of the inflammasome; after interaction with NAIP (NLR family of apoptosis inhibitory protein) and its activation, NLRC4-NAIP forms the inflammasome. NLCR4-dependent inflammasome activates caspase 1, with proinflammatory cytokines release, and the pyroptosis inducer Gasdermin D. Gain-of-function mutations in NLCR4 gene have been related to inflammasomopathies as well as to joint and gut inflammation in the context of syndromic HS, in particular in PAPASH and PASH/SAPHO overlapping syndrome • WDR1 is a protein coding gene involved in several processes such as cytokinesis, chemotactic cell migration and establishment of cell polarity during follicular epithelium development. Mutations in this gene are associated to autoinflammatory diseases, macrothrombocytopaenia and neutrophilia and genetic changes in WDR1 contributes to the pyrin inflammasome formation, triggering autoinflammatory diseases driven by IL-18. A novel potential causal variant in this gene has been found in a PASH/SAPHO overlapping patient with severe and refractory HS • OTULIN is known to participate and regulate NFkBdependent inflammatory signalling and immune response, and the MPO gene has been demonstrated to be a local mediator of tissue damage and, thus, involved in the resulting inflammation in different inflammatory disorders • The GJB2 gene encodes a member of the gap junction protein family, gap junction beta 2, more commonly known as connexin 26 (Cx26) (see Chapter 11). CX26 is also responsive to the NFkB transcription factor, which plays a crucial role in inflammation and immunity, as well as in cell proliferation and differentiation. A GJB2 pathogenic variant has been found in a PASH patient with gut inflammation • Pathogenic variants in NCSTN and PSENEN genes have been reported not only in HS familial cases but also in syndromic forms of this disease. Recently novel NCSTN frameshift mutations have been reported in a PAPASH and PASH/SAPHO patient with joint inflammation

Early-onset inflammatory bowel disease

• Autosomal recessive mutations in the IL-10 and IL-10 receptor genes • Onset of intestinal symptoms within the third month of age • Severe bloody diarrhoea • Recurrent folliculitis episodes in two-thirds of patients • Recurrent episodes of fever • Failure to thrive

CARD14 gene-related diseases • Autosomal dominant gain-of-function mutations of the CARD14 gene • Some of these mutations are NF-kB activating (regulation of inflammatory response) • Plaque psoriasis or severe generalized pustular psoriasis • CARD14 mutations also cause familial pityriasis rubra pilaris (Figure 20.25) (see also Chapter 5) • Skin biopsies show a classical pattern of these three wellknown dermatological entities

Fig. 20.25 

APLAID syndrome Synonyms

Autoinflammation and Phospholipase C-gamma2-associated Antibody deficiency and Immune Dysregulation

Epidemiology

The disease is very rare, fewer than 10 patients reported

Age of onset Neonatal

Cutaneous findings

• Eruption of sterile pustules on erythematous acral sites, merging and evolving in crusting lesions (perforating neutrophilic and granulomatous dermatitis of the newborn) • Scaly infiltrated plaques • Acral haemorrhagic blisters • Granulomatous lesions, cellulitis • Cutis laxa • Cold-induced urticaria (PLAID)

Extracutaneous findings • • • • • • • •

Immunodeficiency, recurrent infections Enterocolitis Eye inflammation, conjunctivitis Interstitial pneumonia Arthralgia Sensorineural deafness Allergic diseases CNS vasculitis and infarcts

Laboratory findings

Histological examination of skin biopsies shows dense histiocytic and granulomatous infiltrate, heavy neutrophils aggregates and leukocytoclastic vasculitis.

Genetics and Pathogenesis

• The disease is caused by missense mutations in the PLCG2 gene, which encodes for a cytoplasmic signalling enzyme with pivotal role in many immune and inflammatory pathways, i.e., calcium dependent activation of cryopyrin cascade • APLAID syndrome is caused by “hypermorphic” gain of function mutations

Autoinflammatory Diseases

447

• PLAID syndrome is allelic disorder due to in-frame gain-of-function deletions of the same gene with similar phenotype • Overlapping is frequent and patients with the same heterozygous missense variant c.77C>T may have both cutaneous phenotypes associated with recurrent fevers, conjunctivitis, lymphadenopathies, headaches, myalgia, abdominal pain and pulmonary infections

Differential diagnosis

• Other cryopyrinopathies • Other autoinflammatory syndromes

NLRC4-related autoinflammatory disorder Epidemiology

Fewer than 10 cases described

Age of onset

During infancy

Cutaneous findings

• Periodic urticarial rash • Nodular lesions, acral and painful • Relevant clinical heterogeneity

Fig. 20.26 

Extracutaneous findings • • • •

Recurrent febrile episodes Enterocolitis, splenomegaly Joint swelling and arthralgia Eye inflammatory disorders

Genetics and pathogenesis

• Gain-of-function mutation in NRLC4 gene. This gene is a further component of inflammasomes (see also cryopyrinopathies) • Elevated IL18

Differential diagnosis

Other autoinflammatory diseases

Therapy

Anakinra has been tested in some patients with different results.

VEXAS syndrome Synonym

Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic syndrome

Epidemiology

300 cases described

Age of onset Fifth decade

Cutaneous findings

Skin lesions are present in 80% of patients: • Neutrophilic dermatosis, urticaria • Vasculitis, erythema nodosum (Figures 20.26 and 20.27) • Papular eruptions, aphthous lesions

Fig. 20.27 

Extracutaneous findings • • • • • • • • •

Non-infectious recurrent fever (>60%) Weight loss (>50%) Lung and pleural involvement (50%) Ocular symptoms: uveitis scleritis periorbital oedema (40%) Relapsing chondritis (>30%) Venous thrombosis (>30%) Lymph nodes enlargement (>30%) Arthralgias (>25%) Peripheral nervous system (15%)

Atlas of Genodermatoses

448 • Gastrointestinal involvement: pain, diarrhoea, subocclusion (>10%) • Haematological: myelodysplastic syndrome and progressive bone marrow failure • Predisposition to haematologic malignancies (myeloma)

Laboratory Findings

Cytoplasmic vacuoles in myeloid and erythroid precursors in all patients examined

Genetics and Pathogenesis

• Somatic mutations in UBA1 gene coding for the major E1 enzyme of cellular ubiquitination. This gene is located on the X chromosome and almost all patients are males. The few women affected suffered from X-monosomy • Mutations are restricted to bone marrow progenitor cell lineages • Ubiquitination is a process devoted to the regulation and balance of protein homeostasis-degradation in eukaryotes and is relevant also for DNA repair and cell differentiation

Differential diagnosis

• Other autoinflammatory syndromes • Cutaneous vasculitis

Course and prognosis

• Is variable and is related to the severity of bone marrow failure • VEXAS syndrome is associated with high morbidity and mortality

Treatment

• Glucocorticoids, Azacytidine • JAK inhibitors • All therapies have a relative impact on symptoms and course

Familial keratosis lichenoides chronica Recently, a new group of diseases called “autoinflammatory keratinization diseases” has been proposed, comprising well-known disorders as DITRA, CARD14-mediated pustular psoriasis, pytiriasis rubra pylaris, KLICK syndrome, porokeratoses (that are part of specific chapters in this Atlas) and familial keratosis lichenoides chronica (KLC). KLC is due to gain-of-function mutations in the NLRP1 gene (remember also that mutations of NLRP3 gene are responsible for cryopyrinopathies, see above in this chapter), encoding for the homonymous inflammatory sensor protein, especially produced by keratinocytes, explaining both the generalized autoinflammation and skin signs: • Multiple small papules with confluent linear-reticular aspects on extremities and trunk (Figure 20.28). Patients may have follicular hyperkeratosis, palmoplantar keratoderma and nail dystrophy • Lichenoid interface infiltrate with necrosis of keratinocytes is visible upon histological examination of skin biopsies • Polyarthritis is referred • Anakinra, as IL1 receptor antagonist, is expected to be useful to treat KLC

Fig. 20.28 

Bibliography Chu CQ. Schnitzler syndrome and Schnitzler-like syndromes. Chin Med J (Engl). 2022;135(10):1190–1202. Deuitch N, Cudrici C, Ombrello A, Aksentijevich I. TNF ReceptorAssociated Periodic Fever Syndrome. 2022 Nov 10. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022. Hernández-Rodríguez J, Mensa-Vilaró A, Aróstegui JI. Paradigm shift in monogenic autoinflammatory diseases and systemic vasculitis: The VEXAS syndrome. Med Clin (Barc). 2022;159(10):489–496. English, Spanish. Kawakami A, Yushiro E, Tomohiro K, Koh-Ichiro Y, Kiyoshi M. Autoinflammatory disease: Clinical perspectives and therapeutic strategies. Inflamm Regen. 2022;42(1):37. Lazea C, Damian L, Vulturar R, Lazar C. PFAPA syndrome: Clinical, laboratory and therapeutic features in a single-centre cohort. Int J Gen Med. 2022;15:6871–6880. Li Y, Yu M, Lu M. Pathophysiology, clinical manifestations and current management of IL-1 mediated monogenic systemic autoinflammatory diseases, a literature review. Pediatr Rheumatol Online J. 2022;20(1):90. Maitrepierre F, Marzano AV, Lipsker D. A Unified concept of acne in the PAPA spectrum disorders. Dermatology. 2021;237(5):827–834. Mao L, Dhar A, Meng G, Fuss I, Montgomery-Recht K, Yang Z, Xu Q, Kitani A, Strober W. Blau syndrome NOD2 mutations result in loss of NOD2 cross-regulatory function. Front Immunol. 2022;13:988862. Marzano AV, Genovese G, Moltrasio C, et al. Whole-exome sequencing in 10 unrelated patients with syndromic hidradenitis suppurativa: A preliminary step for a genotype-phenotype correlation. Dermatology. 2022;238(5):860–869. Mendonça LO, Toledo-Barros MAM, et al. In-vitro NLRP3 functional test assists the diagnosis of cryopyrin-associated periodic syndrome (CAPS) patients: A Brazilian cooperation. Clin Immunol. 2022;245:109159. Monfort JB, Deshayes S, Dusser P, et al. JIR cohort investigators, Hentgen V, Georgin-Lavialle S. Cutaneous manifestations of monogenic auto-inflammatory diseases: An international cohort study

Autoinflammatory Diseases from the Juvenile inflammatory rheumatism cohort. J Am Acad Dermatol. 2022;87(6):1391–1394. Peña-Rosado A, Riera-Martí N, Expósito-Serrano V, Romaní J. Autoinflammatory keratinitzation diseases (AIKDs. Actas Dermosifiliogr (Engl Ed). 2021:S0001-7310(21)00208-8. English, Spanish. Volker-Touw CM, de Koning HD, Giltay JC, et al. Erythematous nodes, urticarial rash and arthralgias in a large pedigree with NLRC4related autoinflammatory disease, expansion of the phenotype. Br J Dermatol. 2017;176(1):244–248.

449 Welzel T, Oefelein L, Holzer U, Müller A, Menden B, Haack TB, Groβ M, Kuemmerle-Deschner JB. Variant in the PLCG2 gene may cause a phenotypic overlap of APLAID/PLAID: Case series and literature review. J Clin Med. 2022;11(15):4369.

EGFR-related autoinflammatory syndrome See Chapter 3.

21

OVERGROWTH SYNDROMES PIK3CA-related syndromes (PROS) (scheme 21.1)

Megalencephaly-capillary malformation (M-CM) Synonyms

Based on the International Society for the Study of Vascular Anomalies (ISSVA) 2018 updated classification, PROS group lesions with heterogeneous segmental overgrowth phenotypes — with or without cutaneous involvement — due to somatic PIK3CA activating mutations are the following: • • • • • • • • •

Fibroadipose hyperplasia or overgrowth (FAO) Hemihyperplasia multiple lipomatosis (HHML) Macrodactyly Fibroadipose infiltrating lipomatosis/Facial infiltrative lipomatosis Dysplastic megalencephaly (DMEG) Megalencephaly-capillary malformation (MCAP or M-CM) Congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal (CLOVES) syndrome Capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry and partial/ generalized overgrowth (CLAPO) syndrome Klippel-Trénaunay syndrome

This syndrome was previously known under the names: • Macrocephaly-cutis marmorata telangiectatica congenita • Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP)

Epidemiology

More than 200 patients have been reported without sex predominance. Prevalence 5 in a lifetime, or a BCC before age of 30)

Fig. 22.3 

Fig. 22.4  Fig. 22.1 

Fig. 22.2  460

Fig. 22.5 

DOI: 10.1201/9781003124351-22

Genodermatoses Related to Malignancy

461 Laboratory findings

Histopathologic findings: typical aspect of BCC or, rarely, of infundibulocystic BCC

Genetics and pathogenesis

Fig. 22.6 

• Autosomal dominant inheritance • The principal causative gene, PTCH, is a tumour suppressor gene. More recently, nonsense and missense variants and multiexon deletion of SUFU were identified in three families with classic BCCS. SUFU-related BCCS is associated with a high risk for medulloblastoma of up to 33% and a high meningioma risk post-radiation. The risk for medulloblastoma in PTCH1-related BCCS is less than 2% • Some authors report mosaic forms of “non-syndromic hereditary multiple basal cell carcinomas” • This entity is a part of the “mosaic hedgehog spectrum” comprising Follicular basaloid hamartomas and Curry-Jones syndrome (characterized by severe gastrointestinal involvement) that are all caused by somatic SMO gene mutations

Differential diagnosis

• Bazex-Dupré-Christol syndrome • Other cancer-related genodermatoses

Course and prognosis

• BCC may increase in number and become aggressive after puberty • Odontogenic cysts occur frequently before BCC and may easily recur after removal. A rare malignant transformation of a keratocyst called ameloblastoma has been reported • Medulloblastoma may occasionally be the first manifestation

Follow-up and therapy

Fig. 22.7  • Palmar and plantar pits in 65–80% of patients (Figure 22.6) • Occasional acrochordons (Figure 22.7)

Extracutaneous findings

• Odontogenic cysts of the jaw in about 80% of patients beginning in the second decade of life: multiple, often symptomatic, causing marked tooth displacement • Calcification of the falx cerebri in about 85% of patients • Childhood medulloblastoma (5%) • Macrocephaly (80%), frontal bossing (65%) • Musculoskeletal abnormalities: fused or bifid ribs (50%), spina bifida occulta of cervical/thoracic vertebrae (60%), kyphoscoliosis (30%), scapular deformity (30%), cleft palate (5%) and pre/post-axial polydactyly (4%) • Eye anomalies (10–25%): cataract, developmental defects, pigmentary changes of the retinal epithelium • Ovarian or cardiac fibroma • Mesenteric or pleural cysts • Hypertelorism • Posterior platicephaly

• Awareness of the risk of medulloblastoma in the first years of life may justify developmental assessment and physical examination every 6 months • Annual head magnetic resonance imaging (MRI) scans until age 8 years in SUFU-related NBCCS affected children • Avoid sun exposure and radiotherapy • BCCs: topical 5-fluorouracil or imiquimod cream, surgical excision, electrodessication, CO2 laser, photodynamic therapy and oral retinoids • Odontogenic cysts: surgical excision

Bibliography Evans DG, Farndon PA. Nevoid Basal Cell Carcinoma Syndrome. 2002 Jun 20 [updated 2018 Mar 29]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022.

Bazex-Dupré-Christol syndrome Synonyms

• Bazex syndrome • Acrokeratosis paraneoplastica • Follicular atrophoderma and BCC

Epidemiology

About 20 families have been reported in the literature.

Age of onset At birth

Atlas of Genodermatoses

462 Cutaneous findings

• Follicular atrophoderma most frequently localized on the dorsa of the hands and feet, on the face and on the extensor surfaces of the elbows and knees (Figure 22.8) • “Spiny” hyperkeratosis (Figure 22.9) • BCC (~50%) mostly localized on the face • Hypotrichosis with pili torti and trichorrhexis nodosa • Milia on the face (“ulerythema ophryogenes”) and upper trunk (Figure 22.10)

• Facial hyperpigmentation • Nail dystrophy • Rarely, hypohidrosis is reported

Extracutaneous findings

• 60% of the associated neoplasms were squamous cell carcinomas of the head, neck and lungs. Less commonly associated carcinomas are poorly differentiated carcinomas (16%), adenocarcinomas of the prostate, lung, oesophagus, stomach and colon (8%) and small-cell carcinomas of the lung • Neuropsychiatric disorders • Scrotal tongue

Laboratory findings

• Histopathologic findings: follicular atrophoderma; depression in the epidermis with clusters of basaloid cells in the superficial dermis; nevoid basal cell proliferations • Microscopic examination of the hair shows rudimentary hair shafts and pili torti

Genetics and pathogenesis

• X-linked dominant inheritance • Caused by mutations in the ARCT1 gene, resulting in an aberrant activation of the Hedgehog signalling pathway

Differential diagnosis Fig. 22.8 

• Ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome • BCCS • Rombo syndrome • Chondrodysplasia punctata • Isolated atrophodermas (Moulin) • Oley syndrome (congenital hypotrichosis — milia with spontaneous regression during adolescence) is merely a variant of Bazex-Dupré-Christol syndrome

Course and prognosis

• Follicular atrophoderma at birth or in early infancy • Hypotrichosis at birth and steady throughout life • BCC starting in the second and third decades of life

Follow-up and therapy Fig. 22.9 

• • • •

Cancer screening Topical retinoids and imiquimod Oral retinoids Surgical, cryosurgical and CO2 laser treatments

Bibliography Schierbeck J, Vestergaard T, Bygum A. Skin cancer associated genodermatoses: A literature review. Acta Derm Venereol. 2019; 99(4):360–369.

Rombo syndrome Epidemiology

Three families have been reported.

Age of onset

From 6 to 7 years of age

Cutaneous findings Fig. 22.10 

• Pearly, milia-like papules (adulthood) and atrophoderma vermiculatum (childhood) on the face (especially the upper

Genodermatoses Related to Malignancy

463 Genetics and pathogenesis

• The disease is autosomal dominant. Etiopathogenesis remains elusive • The propensity to form BCC in sun-exposed areas, together with the acrocyanosis, strongly supports the hypothesis of a further syndrome with an impaired DNA repair cascade

Differential diagnosis • • • • •

Xeroderma pigmentosum Kindler syndrome Cyanosis and soft-skin syndrome Bazex-Dupré-Christol syndrome Cowden syndrome (CS)

Course and prognosis

Fig. 22.11  part) and more scattered on the neck and trunk, giving the skin a “grainy” appearance (Figures 22.11 and 22.12) • Cyanosis of the lips, hands and feet • Defective or completely missing eyelashes and eyebrows in adulthood • Tendency to form BCC (third and fourth decades)

Laboratory findings

Biopsies reveal irregularly distributed and atrophic hair follicles with keratotic plugging and, in the upper dermis, milia are visible, as well as small, dilated vessels. Elastic fibres are thin and irregularly distributed

• Gradually, the skin become coarse with age and BCC become visible at around 30 years of age • Cyanosis remains located to acral regions, without any detectable vascular abnormalities in large vessels • Telangiectases are visible in older patients

Follow-up and therapy

• Periodic dermatological evaluation to prevent the formation of BCC • Surgery for cutaneous neoplasms • Protection from ultraviolet radiation

Bibliography Schierbeck J, Vestergaard T, Bygum A. Skin cancer associated genodermatoses: A literature review. Acta Derm Venereol. 2019;99(4):360–369. doi: 10.2340/00015555-3123

Constitutional mismatch repair deficiency syndromes Mismatch repair deficiency syndrome Synonyms

• CMMR-D syndrome • Biallelic mismatch repair disorder (BMRD)

Epidemiology

1:1.000.000. More than 150 patients reported; in our opinion this disorder is underdiagnosed.

Age of onset

• Usually, skin signs, when visible, precede internal malignancies in infancy or early childhood • Biallelic mutations, in contrast to monoallelic variations (Lynch syndrome), develop malignancies early in infancy

Cutaneous findings

Fig. 22.12 

• Pigmentary changes are mainly atypical café-au-lait macules, with ragged-coast of Maine borders, located elsewhere on the skin surface (less frequently at the major folds) and usually multiple (Figure 22.13) • Hypochromic macules (20% of patients) • Extensive atypical dermal melanocytosis (Mongolian spots) (see also Chapter 15) • Multiple pilomatricomas (Figure 22.14) • Pigmentary changes and pilomatricomas may be present in the same patient

Atlas of Genodermatoses

464

• Due the early onset of malignancies, about half of patients die at a mean age of 12 years (range: 2–25 years) • When patients survive their first primary cancer, there is a high likelihood of developing a second primary cancer

Laboratory findings

Loss of mismatch repair (MMR) protein expression in normal and tumour tissues

Genetics and pathogenesis

Fig. 22.13 

• The disease is autosomal recessive with a very high rate (two-thirds) of consanguinity • Biallelic, homozygous or compound heterozygous mutations in the PMS2 (50%) and MLH1, MSH2 and MSH6 genes • Monoallelic heterozygous mutations in the same four genes cause Lynch syndrome, which is the common cause of hereditary colon cancer • Notably, there is some evidence that NF1 and CTNNB1 (β-catenin 1) genes in patients with CMMR-D are “target genes” and may have higher risk of somatic mutations, causing the pigmentary changes, pilomatricomas and other NF1-like changes in these families • Patients fulfilling NF1-diagnostic criteria which are negative for NF1/SPRED1 mutations must be investigated for CMMR-D-associated genes • MLH1 and MSH2 mutations are not viable in a homozygous state, whereas this may be less likely the case for PMS2 mutations

Follow-up and therapy

Fig. 22.14 

Extracutaneous findings

• Early-onset (first or second decade) malignancies in all organs • More frequently colorectal cancer • CNS involvement (gliomas, agenesia of corpus callosum, grey matter heterotopia, UBOs) • Rhabdomyosarcomas • Leukaemia and lymphomas • Immunoglobulin G (IgG) deficiency • In a small subset of CMMR-D patients are reported: plexiform tumours, Lisch nodules, tibial or sphenoidal malformations, similar to NF1

Course and prognosis

• More than 50% of patients develop malignant brain tumours, 40% develop digestive tract tumours and 30% develop haematological malignancies, all during childhood. The most frequent CMMR-D cancers are brain gliomas (diagnosed at an average age of 9.5 years), nonHodgkin’s lymphomas (diagnosed at 5 years) and colorectal cancers (diagnosed at 16 years)

• Brain MRI is recommended at diagnosis and every 6 months thereafter • Colorectal polyps have been reported in CMMR-D patients as early as 6 years of age, so surveillance is generally initiated at this age. Once polyps are identified, colonoscopy is performed every 6 months. Upper gastrointestinal endoscopy is performed at the same time as colonoscopy • Repeated blood counts and abdominal ultrasounds every 6 months • Heterozygous parents should undergo periodic screening via colonoscopy

Differential diagnosis

• Other cancer-prone genodermatoses • Neurofibromatosis type 1 • Isolated familial multiple pilomatricomas

Bibliography Abedalthagafi M. Constitutional mismatch repair-deficiency: Current problems and emerging therapeutic strategies. Oncotarget. 2018;9(83):35458–35469

Muir-Torre syndrome

Muir-Torre syndrome has been accepted to be a subset of Lynch syndrome type II (hereditary non-polyposis colon cancer [HNPCC])

Synonym

Torre syndrome

Epidemiology 90%).

Genetics and pathogenesis

• Autosomal dominant • The disease is due to missense mutations in RHBDF2, which encodes the inactive rhomboid protease RHBDF2 (also known as iRhom2). The altered RHBDF2 represents a gain-of-function allele that results in sustained epidermal growth factor receptor signalling within the cells

Fig. 22.36 

Differential diagnosis

• It is very difficult to discriminate the PPKs of Howel-Evans syndrome from many other non-syndromic PPKs • The late onset and the predominant plantar involvement may be useful for detecting carriers before the occurrence of dysphagia and neoplastic stenosis

Course and prognosis

• Oesophageal neoplasms occur almost invariably in the affected subjects within the fourth to fifth decades of life

Follow-up and therapy

• Any PPKs of unclear diagnosis must be assessed for even minimal signs of dysphagia • Usual keratolytic agents for PPKs

Fig. 22.37 

Atlas of Genodermatoses

472 Follow-up and therapy

• Dermatological examination once every 2 years as part of the surveillance program to monitor for transformation of cutaneous leiomyomas to leiomyosarcoma • Annual gynaecological examinations from the age of 15 years, counselling regarding the risk of hysterectomy and family planning at the age of 18 years • Annual contrast-enhanced MRI of the kidneys from the age of 10 years • Analgesics for the control of pain • Long-term therapy with calcium channel blockers (up to 3 years) leads to the almost total suppression of pain • Selective surgical excision of skin lesions is frequently followed by relapses

Bibliography Chayed Z, Kristensen LK, Ousager LB, Rønlund K, Bygum A, et al. Hereditary leiomyomatosis and renal cell carcinoma: A case series and literature review. Orphanet J Rare Dis. 2021;16(1):34.

Multiple endocrine neoplasia (MEN) syndrome type 2B Fig. 22.38 

Extracutaneous findings

• Multiple uterine leiomyomata • Renal cell carcinoma • Pheochromocytomas (rare)

Laboratory findings

• Histopathologic findings: dermal tumour composed of interlacing smooth muscle fibres with interspersed collagen bundles • Cutaneous leiomyomas are typically described in three different types: piloleiomyomas, which originate from arrector pili muscles around the hair follicles; angioleiomyomas, which originate from the smooth muscles of blood vessels; and genital leiomyomas, which originate from the tunica dartos of the genital skin and mammary muscles of the nipples

Synonyms

Mucosal neuroma syndrome

Epidemiology

More than 150 cases are described, but it is probably underdiagnosed.

Cutaneous findings

• Enlarged, swollen and often nodular lips (Figures 22.39 and 22.40) • Multiple plexiform neuromata in the oral mucosa (lips and internal cheeks) and tongue

Genetics and pathogenesis

• Autosomal dominant inheritance with poor penetrance • Associated with heterozygous germline mutations in fumarate hydratase gene (FH), a tumour suppressor gene. Biallelic mutations in FH lead to the development of fumarate hydratase deficiency, characterized by neurologic dysfunction and a significantly shortened lifespan

Differential diagnosis • • • •

Neurofibromas Eccrine spiradenoma Granular cell tumour Shagreen patches in Tuberous Sclerosis

Course and prognosis

• There are consecutive outbreaks and then stabilization of skin lesions • Renal cell carcinoma tends to be aggressive and metastasize early

Fig. 22.39 

Genodermatoses Related to Malignancy

Fig. 22.40  • Hyperpigmentation of the entire skin is reported; rarely, perioral lentiginosis • Occasionally, hypertrichosis, and synophrys

Extracutaneous findings

• Long face, with hypertelorism, synophrys, broad nose, enlarged lips, and occasional tarsal hypertrophy (Figure 22.40) • Asthenic-marfanoid habitus with muscular hypotrophy, kyphoscoliosis/lordosis and joint laxity • Medullary carcinoma of the thyroid (“C” cells, MTC) (100%), with possible cutaneous metastasis (Figure 22.41) • Pheochromocytoma (50%), often multiple and bilateral • Diffuse ganglioneuromatosis of the gastrointestinal tract (40%) • Ocular findings: thickened eyelid margins and multiple small plexiform/nodular subconjunctival neuromas. White, medullated corneal nerve fibres are visible under slit-lamp examination (>50%)

Laboratory findings

• Pheochromocytoma is suspected when biochemical screening reveals elevated excretion of catecholamines and catecholamine metabolites • MTC is suspected in the presence of an elevated plasma calcitonin concentration

Genetics and pathogenesis

• The disease is inherited in an autosomal dominant fashion with high penetrance and variable expression. Half of patients are sporadic cases • RET proto-oncogene germline-activating mutations are causative for MEN 2B (95% are in the “hot-spot” of the

473

Fig. 22.41  p.Met918Thr substitution and others are p.Ala883Phe). These mutations cause hyperplasia and neoplasia of cells derived from the neural crest and the related findings of MEN 2B

Differential diagnosis

• MEN 2A (with cutaneous amyloidosis) is an allelic disorder caused by RET oncogene mutations • Neurofibromatosis • CS • Marfan syndrome • Hirschsprung disease • Melkersson-Rosenthal syndrome • Multiple systematized neuromata of the skin and mucosa

Course and prognosis

Individuals with MEN 2B who do not undergo thyroidectomy before 1 year of age are likely to develop metastatic MTC at an early age. Prior to intervention with early prophylactic thyroidectomy, the median age of death in individuals with MEN 2B was 25 years.

Follow-up and therapy

• Preventive ablation is mandatory in known familial cases • Surgery for pheochromocytoma • Medical therapy for pheochromocytoma-related symptoms

Bibliography Eng C. Multiple Endocrine Neoplasia Type 2. 1999 Sep 27 [Updated 2019 Aug 15]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2021

Atlas of Genodermatoses

474

Carney complex Synonyms

• Nevi, Atrial myxoma, Myxomatous neurofibromata and Ephelides (NAME) • Lentigines, Atrial myxoma, Myxoid tumours and Blue nevi (LAMB)

Epidemiology

About 750 cases have been reported in the literature.

Age of onset

Early childhood to adolescence

Cutaneous findings

• Macules (bluish to brown ephelides), especially on the face, neck and lips • Intermingled blue nevi • Brownish discoloration of major folds (Figures 22.42 and 22.43) • Cutaneous myxoma (Figure 22.44) • Pigmentation of conjunctiva • Café-au-lait spots or other birthmarks

Fig. 22.44 

Extracutaneous findings

• Endocrine manifestations: • Cushing syndrome due to primary pigmented adrenocortical disease • Pituitary tumours typically involve the growth hormone-producing cells and cause acromegaly • Thyroid nodules often benign • Gonadal tumours • Non-endocrine manifestations • Cardiac myxoma • Melanotic schwannoma • Osteochondromyxoma

Genetics and pathogenesis

• Heterozygous mutations of the PRKAR1A gene, coding for protein kinase A, have been identified in ∼70% of the Carney complex cases reported worldwide • PRKAR1A is a key component of the cyclic adenosine monophosphate signalling pathway, which has been implicated in endocrine tumorigenesis and could, at least partly, function as a tumour suppressor gene • A second locus has been identified on chromosome 2p16

Fig. 22.42 

Differential diagnosis • • • •

Noonan with multiple lentigines syndrome (LEOPARD) Xeroderma pigmentosum Lentiginoses Peutz-Jeghers syndrome

Course and prognosis

• Breast cancer can occur • Strokes can develop from cardiac emboli due to atrial myxomas

Follow-up and therapy

• Prevention of strokes • Surgery for atrial and intracardiac myxoma when necessary • Plastic surgery for skin myxomata

Bibliography Fig. 22.43 

Vindhyal MR, Elshimy G, Elhomsy G. Carney Complex. 2021 Jul 17. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–.

Genodermatoses Related to Malignancy

475

Birt-Hogg-Dubé syndrome Synonym

Multiple fibrofolliculomas, trichodiscomas and acrochordons

Epidemiology

More than 400 cases reported in the literature

Age of onset

In early adulthood

Cutaneous findings

• Perifollicular fibromas, acrochordons and trichodiscomas on the face, neck and trunk (Figures 22.45–22.47). • Other skin lesions that may be associated include lipomas, angiolipomas, mucous fibromas, angiofibromas, cutaneous collagenomas and epidermal cysts

Extracutaneous findings

• Lung cysts leading to repeated pneumothorax • Increased risk of renal cancer • Other cancers: parotid, thyroid, colon cancer in a few pedigrees

Genetics and pathogenesis

• The disease is due to heterozygous pathogenic variants in an oncogene suppressor gene called folliculin (FLCN).

Fig. 22.47  Mutations cause a loss of proliferation control and susceptibility to hyperproliferation and neoplastic transformation • Recent studies have shown that folliculin interacts with the protein FINP1 and its homolog, FINP2, which, in turn, interact with the AMPK, negatively regulating the mammalian target of rapamycin, which is key for cell proliferation and tumour growth. Thus, a mutation in folliculin prevents this negative regulation, stimulating cell proliferation and uncontrolled growth

Differential diagnosis

• PTEN-opathies • Muir-Torre syndrome • Gardner syndrome

Course and prognosis

The cutaneous lesions progressively increase in number and size. Surgical and laser treatment can lead to temporary improvement of folliculomas, but lesions often recur.

Follow-up and therapy

Once diagnosed, patients must be investigated for kidney and colon disease.

Bibliography

Fig. 22.45 

Sattler EC, Steinlein OK. Birt-Hogg-Dubé Syndrome. 2006 Feb 27 [updated 2020 Jan 30]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Mirzaa GM, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022.

Cyld cutaneous syndrome Synonyms

• Brooke-Spiegler syndrome • Multiple trichoepitheliomas cylindromas

(MFTs)

and

multiple

Age of onset

• Late childhood (milia) to second decade of life (tumours)

Cutaneous findings

Fig. 22.46 

• Within a given family, some members may have cylindromas mainly located on the scalp and trunk (Figures 22.48 and 22.49), whereas others may have trichoepitheliomas (Figures 22.50 and 22.51) mainly located on the face, or both

Atlas of Genodermatoses

476

Fig. 22.48  Fig. 22.50 

Fig. 22.49  • Spiradenomas • Milia and follicular cysts

Extracutaneous findings

• Pulmonary cylindromas (rare) • Tumours of the salivary glands

Laboratory findings

• Histopathologic findings include the co-occurrence of typical lesions of cylindromas, trichoepitheliomas and, rarely, spiradenomas

Genetics and pathogenesis

• Autosomal dominant inheritance • Causative gene is CYLD, a tumour-suppressor gene on chromosome 16q12-q13 • Sporadic trichoepitheliomas have been mapped to PTCH (the same gene mutated in nevoid BCCS)

Differential diagnosis • Tuberous sclerosis • PTEN-opathies • Gardner syndrome

Fig. 22.51 

Course and prognosis

• Lesions may become multiple, disfiguring and of huge dimensions • Although the tumours are usually benign, malignant transformation is recognized

Follow-up and therapy

• Surgical excision • CO2 laser • Recurrences are frequent

Bibliography Dubois A, Rajan N. CYLD Cutaneous Syndrome. 2020 Apr 16. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Mirzaa GM, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022.

Genodermatoses Related to Malignancy

Bloom syndrome Synonym

• Congenital telangiectatic erythema • Bloom-Torre-Machacek syndrome

Epidemiology

Fewer than 300 cases have been reported.

Age of onset

During the first or second summer of life

Cutaneous findings

• Sun-sensitive erythematous telangiectatic patches on the face distributed in a butterfly configuration, resembling lupus erythematosus (main feature) (Figure 22.52) • Occasional erythematous lesions on the forearms and dorsa of the hands • Patchy areas of hyperpigmentation and hypopigmentation on the trunk and extremities (in about 50%) • Blistering and crusting of the lips • Conjunctivitis and loss of eyelashes • Café-au-lait macules

Extracutaneous findings

• Prenatal-onset growth deficiency affecting height, weight and head circumference that persists into infancy, childhood and adulthood • Narrow face, with underdeveloped malar and mandibular prominences and retrognathia or micrognathia. A paucity of subcutaneous fat may cause the nose and/or ears to appear prominent • Characteristic high-pitched voice • Immunodeficiency • Diabetes mellitus

Laboratory findings

• Chromosomal studies show a high frequency of sister chromatid exchanges and quadriradial configurations in cultured lymphocytes • Increased sensitivity to ultraviolet light • Immunoglobulin deficiency of at least one class: IgG, IgM, or IgA

477 Genetics and pathogenesis

• Autosomal recessive disease caused by a germline mutation of the BLM gene • Chromosomal instability is manifest by an increase in the frequency of chromosome breakage and somatic recombination, which, when associated with immunologic deficiency, is a predisposing factor for developing cancer

Differential diagnosis • • • • • • •

Ataxia-telangiectasia syndrome Rothmund-Thomson syndrome Cockayne syndrome Dyskeratosis congenita Xeroderma pigmentosum Kindler syndrome Porphyrias

Course and prognosis

• Predisposition to early-onset cancer (a quarter of patients): leukaemia, lymphoid tumours and carcinomas • The hypersensitivity to both DNA-damaging chemicals and ionizing radiation ordinarily necessitates modification of standard cancer treatment regimens • Increased occurrence of respiratory and gastrointestinal infections • The intensity of facial erythema and of sun sensitivity diminishes with age, but there is an incidence of early death from cancers or infections (mean lifespan is 18 years)

Follow-up and therapy

• Continuous screening of these patients for increased occurrence of malignancies and severe infections is mandatory • Cover exposed skin with clothing, sunscreen application

Bibliography Flanagan M, Cunniff CM. Bloom Syndrome. 2006 Mar 22 [updated 2019 Feb 14]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022.

Epidermodysplasia verruciformis (EV) EV is a genetic dermatologic condition in which patients show a decreased immunologic ability to defend against and eradicate certain types of human papillomavirus (HPV), leading to persistent infection and increased lifetime risk of development of cutaneous dysplasia and malignancy.

Synonym

Lewandowsky-Lutz disease

Epidemiology