Spitz_Genodermatoses, 3e

First page 1 Next page Last page

Animated publication

Spitz’s Genodermatoses A Full Color Clinical Guide to Genetic Skin Disorders

THIRD EDITION

Joel L. Spitz, MD Department of Dermatology Columbia University Vagelos College of Physicians and Surgeons New York Presbyterian Hospital New York, New York

Illustrations by Vaune J. Hatch Deep River, Connecticut

Acquisitions Editor: James Sherman Development Editor: Eric McDermott Editorial Coordinator: Anju Radhakrishnan Editorial Assistant: Kristen Kardoley Marketing Manager: Kirsten Watrud Production Project Manager: Bridgett Dougherty Design Coordinator: Joseph Clark Artist/Illustrator: Vaune J. Hatch Manufacturing Coordinator: Lisa Bowling Prepress Vendor: S4Carlisle Publishing Services

Third Edition

All rights reserved. This book is protected by copyright. No part of this book may be reproduced or transmitted in any form or by any means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews. Materials appearing in this book prepared by individuals as part of their official duties as U.S. government employees are not covered by the above-mentioned copyright. To request permission, please contact Wolters Kluwer at Two Commerce Square, 2001 Market Street, Philadelphia, PA 19103, via email at permissions@lww.com, or via our website at shop. lww.com (products and services).

9 8 7 6 5 4 3 2 1

Printed in Mexico

Library of Congress Cataloging-in-Publication Data ISBN-13: 978-1-4511-1651-9 Cataloging-in-Publication data available on request from the Publisher.

This work is provided “as is,” and the publisher disclaims any and all warranties, express or implied, including any warranties as to accuracy, comprehensiveness, or currency of the content of this work.

This work is no substitute for individual patient assessment based upon healthcare professionals’ examination of each patient and consideration of, among other things, age, weight, gender, current or prior medical conditions, medication history, laboratory data and other factors unique to the patient. The publisher does not provide medical advice or guidance and this work is merely a reference tool. Healthcare professionals, and not the publisher, are solely responsible for the use of this work including all medical judgments and for any resulting diagnosis and treatments. Given continuous, rapid advances in medical science and health information, independent professional verification of medical diagnoses, indications, appropriate pharmaceutical selections and dosages, and treatment options should be made and healthcare professionals should consult a variety of sources. When prescribing medication, healthcare professionals are advised to consult the product information sheet (the manufacturer’s package insert) accompanying each drug to verify, among other things, conditions of use, warnings and side effects and identify any changes in dosage schedule or contraindications, particularly if the medication to be administered is new, infrequently used or has a narrow therapeutic range. To the maximum extent permitted under applicable law, no responsibility is assumed by the publisher for any injury and/or damage to persons or property, as a matter of products liability, negligence law or otherwise, or from any reference to or use by any person of this work. shop.lww.com

To Jacqueline—always believing —JOEL L. SPITZ, MD

To former, current, and future medical students, residents, and physicians. —JACKSON GLENN TURBEVILLE, MD

Love to my husband, Kelton … for everything. —VAUNE J. HATCH

For my parents, Wil and Terry Hand. —JENNIFER L. HAND, MD

Acknowledgments

W ow—I can’t believe this third edition has finally gone to print. It’s been a long time coming. It took a perfect storm to make it happen. That storm included finding coauthors for the very first time—being a solo author was no longer in the cards for this busy practitioner and family man. I needed someone that both the audience and I can trust. I found that person in spades with Jennifer Hand— Peds, Derm, and Genetics trained—an ideal triple threat perfectly suited to join me on this Genodermatoses journey. Adding a new great young mind in Jackson Turbeville was icing on the cake. Now that the authorship team was in place I needed to have the perfect editor to see this to fruition. From Lea and Febiger to Williams and Wilkins to Lippincott and now Wolters Kluwer I have had more than a dozen editors in the 27-year history of the book. Seemingly out of nowhere James Sherman heroically arrived on the scene and he imme diately announced, “We will make this happen.” And so it did. Both James and Eric McDermott, our development editor, brought the kind of pro fessionalism and determination that was needed to push us relentlessly to the finish line. A special shout out to my editorial assistant, good friend, and forever enabler of my crazy ideas—Liz Menges—none of this happens without you—thank you. Of course to my home team for always being by my side cheering me on—Jackie, Sophia, Jonah, Ava, Griffin, Scarlett, and Rowan! Lastly, I want to thank our loyal audience who continued to buy the second edition all these years, pushed their programs to include Spitz review in their curriculum, and inspired me and Wolters Kluwer to go for it once again. Joel L. Spitz, MD I would like to express my deepest gratitude for brilliant and forward-thinking mentors in genetics and dermatology. Much of their wisdom enlightens these pages. I also thank dermatology role models and colleagues for their support, especially Drs. Roy Rogers III, Mark Pittelkow, Rokea el-Azhary, and Ilene Rothman. Lastly, to my family, especially my husband Mike and children Jerry, Erin, and Thomas whose unwavering support and belief in this project sustained me, I am profoundly grateful. Jennifer L. Hand, MD, FAAD, FACMG When I first picked up a copy of Genodermatoses as a third-year medical student rotat ing through a dermatology clerkship, little did I realize that several years later I would be helping to complete the third edition. This book allowed me to visualize disease with the whole patient in my mind, and I was thrilled to have the opportunity to update this text for a new generation of medical professionals. I want to thank Jennifer Hand for introducing me to Joel Spitz and for his invitation to contribute to this project. Contributing to the new edition has been both challenging and incredibly rewarding. I am eternally grateful to my mentors throughout my training and career that helped shape me into the physician I am today and have inspired my passion for dermatology including Kimberly Edwards, Charles Phillips, Leila Tolaymat, Jason Sluzevich, James Keeling III, Megha Tollefson, Dawn Marie Davis, Jennifer Hand, and Harper Price. Lastly, I want to express my gratitude for my family—especially my mother and father—and their unwavering support in my endeavors over the years. Jackson Glenn Turbeville, MD

Copyright © 2024 Wolters Kluwer, Inc. Unauthorized reproduction of the content is prohibited. To the generations of physicians that have shared their collective wisdom in these pages, I am profoundly thankful for your contributions to this and previous editions of this book.

Contributors

Jean Bolognia, MD Professor of Dermatology Yale University School of Medicine New Haven, Connecticut Anna L. Bruckner, MD, MSCS

Sharon Glick, MD Chairman Department of Dermatology SUNY Downstate Health Sciences University Brooklyn, New York

Jennifer L. Hand, MD, FAAD, FACMG Clinical Associate Professor of Pediatrics Jacobs School of Medicine and Biomedical Sciences State University of New York at Buffalo Medical Director of Pediatric Dermatology Oishei Children’s Hospital Buffalo, New York Chief of Service, Dermatology Kaleida Health Buffalo, New York Kurt Hirschhorn † , MD Chairman Emeritus Department of Pediatrics Mount Sinai School of Medicine New York, New York Francisco Jimenez, MD Associate Professor Clínica Mediteknia and Universidad Fernando Pessoa Canarias Gran Canaria, Spain Kim Keppler-Noreuil, MD Professor of Pediatrics Department of Pediatrics School of Medicine and Public Health University of Wisconsin Madison, Wisconsin Bernice Krafchik † , MD Department of Pediatrics and Medicine (Dermatology) University of Toronto Head, Division of Dermatology The Hospital for Sick Children Toronto, Ontario, Canada Mazen Kurban, MD Tenured Professor Departments of Dermatology, and Biochemistry and Molecular Genetics Research Director, Department of Dermatology American University of Beirut Medical Center Beirut, Lebanon

Professor of Dermatology and Pediatrics University of Colorado School of Medicine Section Head, Pediatric Dermatology Children’s Hospital Colorado Aurora, Colorado David R. Deyle, MD, PhD

Associate Professor Clinical Genomics Mayo Clinic

Rochester, Minnesota Lisa A. Drage, MD Consultant Department of Dermatology Mayo Clinic Rochester, Minnesota Lawrence Eichenfield, MD Professor of Dermatology and Pediatrics Chief, Pediatric and Adolescent Dermatology

University of California, San Diego Rady Children’s Hospital, San Diego San Diego, California D. Gareth R. Evans, MD, FRCP Consultant and Professor Department of Genomic Medicine University of Manchester Manchester, United Kingdom

Philip Fleckman † , MD Division of Dermatology University of Washington Medical Center Seattle, Washington Ilona J. Frieden, MD Professor Department of Dermatology and Pediatrics School of Medicine University of California, San Francisco San Francisco, California

† Published posthumously

Diana H. Lee, MD, PhD Associate Professor of Clinical Dermatology and Pediatrics Israel Englander Department of Dermatology Weill Cornell Medicine

Amy S. Paller, MD Walter J. Hamlin Professor and Chair Department of Dermatology The Feinberg School of Medicine of Northwestern University Chicago, Illinois Mark Pittelkow, MD Professor Departments of Dermatology, and Biochemistry and Molecular Biology Mayo Clinic Arizona Scottsdale, Arizona Gabrielle Richard, MD, FACMG Medical Director GeneDx Gaithersburg, Maryland William Rizzo, MD Professor Department of Pediatrics University of Nebraska Medical Center Omaha, Nebraska Jillian F. Rork, MD Clinical Assistant Professor of Dermatology and Pediatrics Department of Dermatology and Pediatrics Dartmouth Hitchcock Medical Center Manchester, New Hampshire Claire Shovlin, PhD, FRCP Professor of Practice (Clinical and Molecular Medicine) National Heart and Lung Institute Imperial College London London, United Kingdom Dawn Siegel, MD Clinical Professor Department of Dermatology, and by courtesy, Pediatrics Stanford University School of Medicine Palo Alto, California Robert Silverman, MD Clinical Associate Professor Department of Pediatrics MedStar Georgetown University Hospital Washington, District of Columbia

New York, New York Harvey Levy, MD Senior Physician in Medicine/Genetics

Department of Medicine Boston Children’s Hospital Boston, Massachusetts Moise Levy, MD Professor Department of Pediatric Medicine (Dermatology) Dell Medical School

University of Texas at Austin Dell Children’s Medical School Austin, Texas Marilyn G. Liang, MD Associate Professor Department of Dermatology Boston Children’s Hospital

Boston, Massachusetts Anne W. Lucky, MD Adjunct Professor of Dermatology and Pediatrics Department of Dermatology Cincinnati Children’s Hospital University of Cincinnati College of Medicine Cincinnati, Ohio Leonard Milstone, MD Professor Emeritus Department of Dermatology Yale Medical School New Haven, Connecticut Andreea Nissenkorn, MD Director Pediatric Neurology Unit Wolfson Medical Center and Tel Aviv University Tel Aviv, Israel Seth Orlow, MD, PhD Professor of Cell Biology and of Pediatrics Weinberg Professor of Pediatric Dermatology The Ronald O. Perelman Department of Dermatology New York University Grossman School of Medicine New York, New York

vii

Eli Sprecher, MD, PhD Professor and Chair, Division of Dermatology Deputy Director General for R&D and Innovation Tel Aviv Sourasky Medical Center Tel Aviv, Israel Jeffrey Sugarman, MD, PhD Professor of Dermatology University of California, San Francisco San Francisco, California C. Gail Summers, MD Professor Emerita Department of Ophthalmology and Visual Neurosciences

Kishore Vellody, MD Medical Director Down Syndrome Center of Western Pennsylvania Children’s Hospital of Pittsburg

Pittsburg, Pennsylvania David Whiting † , MD

Clinical Professor of Dermatology and Pediatrics University of Texas Southwestern Medical Center Medical Director, Baylor Hair Research and Treatment Center Dallas, Texas Judith Willner, MD Associate Professor (Retired)

University of Minnesota Minneapolis, Minnesota

Department of Genomics and Genetics Mount Sinai Icahn School of Medicine New York, New York

Jackson Glenn Turbeville, MD Assistant Professor of Dermatology Department of Dermatology School of Medicine and Public Health University of Wisconsin–Madison Madison, Wisconsin

Juoni Uitto † , MD, PhD Professor and Chairman

Department of Dermatology and Cutaneous Biology Professor of Biochemistry and Molecular Pharmacology Director, Jefferson Institute of Molecular Medicine Program Director, Jefferson Dermatology Residency Training Program Thomas Jefferson University, Jefferson Medical College Philadelphia, Pennsylvania

† Published posthumously

viii

Introduction

I t is a pleasure to introduce the newest edition of “ Genodermatoses ,” a textbook that takes a complex group of disorders and highlights important disease features while provid ing numerous illustrations. The enduring popularity of “The Spitz Textbook” among trainees emphasizes the power of artistic drawings, as well as photographs, to illustrate important disease components. The availability of advanced technology, both whole ex ome sequencing and whole genome sequencing, to elucidate the underlying basis for genetic disorders has revolutionized our ability to diagnose subtypes of genodermatoses. In many cases, this information is important for prenatal diagnosis, offering prognostic clues and, in some cases, suggesting new therapeutic directions. However, our recogni tion of clinical patterns that indicate disease will never be replaced and remain paramount to classification by group of genodermatoses (eg, ichthyosis, epidermolysis bullosa, ecto dermal dysplasia), leading to management decisions and choice of the appropriate panel for testing early in life to define the underlying cause. It is reassuring and important that despite stunning advances in molecular genetics, physical examination continues to be the cornerstone of genetic diagnosis for all clinicians. Each chapter in this book describes a group of disorders that are associated with a specific biologic abnormality of the skin. For example, Chapter 2 focuses on disorders of pigmentation, each caused by disruption of melanin biogenesis or function. Chapter by chapter, these groups of disorders provide a view of essential components of skin biology and how dysfunction through genetic variants and alterations in resultant proteins leads to disease. Given the complexity and multicell composition of skin, these altered proteins may impact dermal connective tissue (as in Ehlers-Danlos syndrome), skin repair after UV damage (as in xeroderma pigmentosum), regulation of cell proliferation or survival (as in tumor syndromes), the lipid or protein epidermal barrier (as in the ichthyoses), adherence of epidermis to dermis (as in epidermolysis bullosa), and many other functions. Taken to gether, the various genetic disorders of skin tell a story of how skin cells work in a coordi nated manner to maintain skin integrity and function. As in prior editions of Spitz’s Genodermatoses, gene names are included in each dis order description. It is now common to seek the genetic basis of skin disorders, especially since available tests to discover underlying gene variants have become both simpler tech nically and less costly. Not only is the genetic basis for these diseases appearing in most reports, but increasingly disease names are being altered to include the variant gene itself, as for the upcoming reclassification of ichthyoses and palmoplantar keratodermas. As a result, gene names included in this text are written in italics to distinguish gene, allele, and RNA names from the names of protein products. Most genetic disorders described in this book are rare. The now multiple authors of Genodermatoses have included pearls from their own experience, as well as from the input of patients and support groups. As such, readers will find a wealth of information that is both accurate and valuable. In addition to the concise information imparted in the text, readers are encouraged to learn more about the various genodermatoses from their pa tients and through participating in the many advocacy groups that provide educational and social networking support to patients and families whose lives are impacted by ge netic skin disease.

Amy S. Paller, MD November 2023

Contents

Acknowledgments................................................. v Contributors ............................................................vi Introduction ............................................................ix

Griscelli Syndrome .......................................................... 68 Piebaldism.......................................................................... 70 Waardenburg Syndrome .............................................. 72 Pigmentary Mosaicism .................................................. 74 Incontinentia Pigmenti.................................................. 76 Noonan Syndrome With Multiple Lentigenes (Formerly LEOPARD syndrome).................................. 80 Carney Complex............................................................... 82 McCune-Albright Syndrome ....................................... 84 Neurofibromatosis Type 1............................................ 86 Neurofibromatosis Type 2............................................ 90 Tuberous Sclerosis ..........................................................92 CHAPTER 3 Disorders of Vascularization Clinical Pearls by Ilona J. Frieden, MD (IF), Kim Keppler Noreuil, MD (KK-N), Andreea Nissenkorn, MD (AN), and Claire Shovlin, PhD, FRCP (CS) Sturge-Weber Syndrome (SWS) ...............................104 Klippel-Trenaunay Syndrome ...................................108 Cobb Syndrome .............................................................112 Proteus Syndrome.........................................................114 Beckwith-Wiedemann Syndrome............................118 PIK3CA -Related Overgrowth Spectrum (PROS)......122 Von Hippel-Lindau Syndrome ..................................126 Ataxia-Telangiectasia ...................................................130 Hereditary Hemorrhagic Telangiectasia (HHT) Syndrome.............................................................134 Cutis Marmorata Telangiectatica Congenita.......138 Maffucci Syndrome.......................................................140 Blue Rubber Bleb Nevus Syndrome........................142 Kasabach-Merritt Phenomenon (KMP) ..................144 Multifocal Infantile Hemangiomas ± Extracutaneous Disease ..............................................146 PHACE Syndrome ..........................................................148 CHAPTER 4 Disorders of Connective Tissue Clinical Pearls by David R. Deyle, MD, PhD (DD), Juoni Uitto, MD, PhD (JU), Ilona J. Frieden, MD (IF), Jennifer L. Hand, MD (JH), and Marilyn G. Liang, MD (MG). Ehlers-Danlos Syndrome ............................................158 Marfan Syndrome..........................................................164 Cutis Laxa .........................................................................166 Pseudoxanthoma Elasticum......................................170 Osteogenesis Imperfecta............................................174 Buschke-Ollendorff Syndrome .................................176

CHAPTER 1 Disorders of Keratinization

Clinical Pearls by Philip Fleckman, MD (PF), Jennifer L. Hand, MD (JH), Francisco Jimenez, MD (FJ), Mazen Kurban, MD (MK), Leonard Milstone, MD (LM), William Rizzo, MD (WR), Amy S. Paller, MD (AP), Gabrielle Richard, MD (GR), Eli Sprecher, MD (ES), and Jeffrey Sugarman, MD, PhD (JS) Ichthyosis Vulgaris .............................................................2 Recessive X-Linked Ichthyosis .......................................4 Epidermolytic Ichthyosis (EI) and Superficial Epidermolytic Ichthyosis (SEI)........................................6 Autosomal Recessive Congenital Ichthyosis (ARCI): Lamellar Ichthyosis ........................................... 10 Congenital Ichthyosiform Erythroderma................ 14 Harlequin Ichthyosis....................................................... 16 Sjögren-Larsson Syndrome.......................................... 18 Refsum Syndrome ........................................................... 20 Conradi-Hünermann Syndrome ................................22 CHILD Syndrome .............................................................24 Netherton Syndrome ..................................................... 26 Erythrokeratodermia Variabilis................................... 28 KID Syndrome ................................................................... 30 Diffuse Palmoplantar Keratoderma .......................... 32 Howel-Evans Syndrome ................................................ 34 Vohwinkel Syndrome..................................................... 36 Mal de Meleda .................................................................. 38 Papillon-Lefèvre Syndrome ......................................... 40 Richner-Hanhart Syndrome......................................... 42 Darier Disease ................................................................... 44 Epidermal Nevus Syndrome (ENS) ............................ 46 CHAPTER 2 Disorders of Pigmentation Clinical Pearls by C. Gail Summers, MD (GS), Diana H. Lee, MD (DL), Seth Orlow, MD, PhD (SO), Jean Bolognia, MD (JB), Sharon Glick, MD (SG), Dawn Siegel, MD (DS), Robert Silverman, MD (RS), Jennifer L. Hand, MD (JH), Amy S. Paller, MD (AP), and D. Gareth R. Evans, MD (GE). Oculocutaneous Albinism Type 1.............................. 58 Oculocutaneous Albinism Type 2.............................. 60 Hermansky-Pudlak Syndrome .................................... 62 Chédiak-Higashi Syndrome ......................................... 66

CHAPTER 8 Disorders With Photosensitivity Clinical Pearls by Lawrence Eichenfield, MD (LE), Kurt Hirschhorn, MD (KH), Harvey Levy, MD (HL), Moise Levy, MD (ML), and Mark Pittelkow, MD (MP) Bloom Syndrome...........................................................262 Rothmund-Thomson Syndrome..............................266 Cockayne Syndrome.....................................................270 Trichothiodystrophy.....................................................274 Xeroderma Pigmentosum..........................................278 Hartnup Disease.............................................................282 CHAPTER 9 Disorders With Immunodeficiency Clinical Pearls by Moise Levy, MD (ML) Wiskott-Aldrich Syndrome.........................................288 Chronic Granulomatous Disease..............................290 Hyper-Immunoglobulin E Syndrome.....................294 Severe Combined Immunodeficiency....................296 Hereditary Angioedema..............................................300 CHAPTER 10 Bernice Krafchik, MD (BK), Joel Spitz, MD (JS), Kurt Hirschhorn, MD (KH), Judith Willner, MD (JW), Jackson Glenn Turbeville, MD (JT), and Jennifer L. Hand, MD (JH) Menkes Syndrome.........................................................306 Björnstad Syndrome.....................................................308 Argininosuccinic Aciduria...........................................310 Monilethrix.......................................................................312 Uncombable Hair Syndrome.....................................314 Hypohidrotic Ectodermal Dysplasia........................316 Hidrotic Ectodermal Dysplasia..................................320 Ectrodactyly-Ectodermal Dysplasia-Cleft Syndrome. ........................................................................322 Ankyloblepharon-Ectodermal Dysplasia-Cleft Lip/Palate (AEC) Syndrome.........324 Pachyonychia Congenita............................................328 Nail-Patella Syndrome..................................................332 Disorders of Hair and Nails Clinical Pearls by David Whiting, MD (DW),

Focal Dermal Hypoplasia............................................178 Lipoid Proteinosis..........................................................180 Progeria............................................................................. 182 Werner Syndrome..........................................................184 Aplasia Cutis Congenita...............................................186 CHAPTER 5 Disorders With Malignant Potential Clinical Pearls by Lawrence Eichenfield, MD (LE), and Jennifer L. Hand, MD (JH) Basal Cell Nevus Syndrome........................................196 Lynch Syndrome, Muir-Torre Variant......................200 Dyskeratosis Congenita...............................................202 Gardner Syndrome........................................................206 Peutz-Jeghers Syndrome............................................208 Cowden Syndrome........................................................210 Multiple Endocrine Neoplasia Type IIB..................212 Birt-Hogg-Dube Syndrome........................................214 CHAPTER 6 Epidermolysis Bullosa Clinical Pearls by Anne W. Lucky, MD (AL) and Anna L. Bruckner, MD (AB) Epidermolysis Bullosa Simplex..................................222 Junctional Epidermolysis Bullosa.............................226 Dystrophic Epidermolysis Bullosa............................230 Kindler Epidermolysis Bullosa...................................234 CHAPTER 7 Disorders of Porphyrin Metabolism Clinical Pearls by Jennifer Hand, MD (JH) and Lisa A. Drage, MD (LD) Porphyria Cutanea Tarda............................................240 Variegate Porphyria......................................................244 Acute Intermittent Porphyria....................................246 Hereditary Coproporphyria........................................248 Erythropoietic Protoporphyria..................................250 Congenital Erythropoietic Porphyria......................254 Hepatoerythropoietic Porphyria..............................256

CHAPTER 11 Disorders of Metabolism Clinical Pearls by Kurt Hirschhorn, MD (KH),

CHAPTER 13 Disorders With Short Stature Clinical Pearls by Kurt Hirschhorn, MD (KH) Judith Willner, MD (JW), and Jennifer L. Hand, MD (JH) Cornelia de Lange Syndrome....................................396 Rubinstein-Taybi Syndrome......................................398 Russell-Silver Syndrome..............................................400 Familial Dysautonomia................................................402 Figure Credits......................................................407 Index....................................................................... 411

Judith Willner, MD (JW), and Jennifer L. Hand, MD (JH) Alkaptonuria....................................................................340 Fabry Disease...................................................................342 Gaucher Disease.............................................................346 Niemann-Pick Disease..................................................350 Mucopolysaccharidoses..............................................354 Multiple Carboxylase Deficiency..............................358 Phenylketonuria.............................................................360 Wilson Disease................................................................362 Acrodermatitis Enteropathica...................................364 Hemochromatosis.........................................................366 Homocystinuria..............................................................368 Hyperlipoproteinemias................................................370 CHAPTER 12 Disorders With Abnormal Chromosome Number Kishore Vellody, MD (KV), and Jennifer L. Hand, MD (JH) Down Syndrome............................................................380 Turner Syndrome...........................................................384 Noonan Syndrome........................................................388 Klinefelter Syndrome....................................................390 Clinical Pearls by Kurt Hirschhorn, MD (KH), Judith Willner, MD (JW), Jillian F. Rork, MD (JR),

xii

5 CHAPTER

DISORDERS WITH MALIGNANT POTENTIAL

CLINICAL PEARLS

Lawrence Eichenfield, MD (LE), and Jennifer L. Hand, MD (JH)

195

Basal Cell Nevus Syndrome

Synonym(s)

Nevoid basal cell carcinoma (BCC) syndrome Gorlin syndrome, Gorlin-Goltz syndrome

Inheritance

Autosomal dominant (AD) PTCH1 gene on 9q22.32 (50%-85%) PTCH2 gene on 1p34.1 SUFU gene on 10q24.32 (5%)

Prenatal Diagnosis

DNA analysis if mutation known in family

Incidence

~1:60,000; M = F

Age at Presentation

Birth (macrocephaly, skeletal anomalies) or childhood (jaw cysts, BCC)

Pathogenesis

Tumor suppressor gene, PTCH1 , encodes “Patched 1,” a transmembrane receptor in the hedgehog (Hh) signaling pathway that controls cell fate, patterning, and growth during development; PTCH1 decreases cell proliferation by inhibiting Smoothened (Smo); disrup tions in PTCH1 allow accelerated tumor growth characteristic of basal cell nevus syndrome (BCNS) SUFU encodes “suppressor of fused,” which downregulates Hh/Smo signaling by Gli transcription factors; mutations cause constitutive Gli activation, followed by sustained transcription and cell growth Skin BCCs—multiple, quiescent, whitish to skin-colored to dark-colored, dome-shaped “nevi”/papules on the face, neck, trunk; some transform to active BCC (growth, erythema, crusting, bleeding) Palmoplantar pits—“punched-out” or “pin-prick” 2-mm pits, occasionally infected; rarely develop into BCCs; Milium, epidermoid cysts Musculoskeletal Macrocephaly; jaw cysts (odontogenic keratocysts)—painless cysts that disrupt tooth roots, cause tooth loss, potential jaw fracture, usually before age 30; rare—lining with malignant potential (ameloblastoma) Frontal bossing or broad nasal root, bifid ribs, wedge-shaped vertebrae, downsloping shoulders, kyphoscoliosis; cleft lip/palate; polydactyly Central nervous system Calcification of falx cerebri (90% by age 20 years), agenesis of corpus callosum Cognitive deficit, meningiomas; medulloblastoma ( SUFU , 33% risk) Eyes Hypertelorism, unilateral or bilateral congenital blindness, cataracts, colobomas, strabismus Genitourinary Ovarian fibromas, fibrosarcoma, undescended testes Cardiac Fibromas in the first year

Key Features

Differential Diagnosis

Bazex syndrome Unilateral linear nevoid BCCs

Melanocytic nevi Rombo syndrome Xeroderma pigmentosum (XP) (p. 278)

Skin biopsy; head circumference Skeletal x-ray of the skull, maxilla, mandible, ribs, vertebrae (only if clinical criteria fail— radiation risk) Molecular genetic testing

196

Basal Cell Nevus Syndrome (continued)

Management

Referral to dentist/oral surgeon; echocardiography in the first year Referral to dermatologist—surgical excision, electrodesiccation and curettage with/ without general anesthesia, topical 5-fluorouracil, imiquimod, photodynamic therapy; fre quent cutaneous examinations Oral vismodegib, sonidegib; Smo inhibitors considered for advanced BCCs; oral retinoids, nicotinamide—suppression of new BCCs Avoid radiotherapy/x-rays—induces new BCCs Sun avoidance, broad-spectrum sunscreen, protective clothing Referral to orthopedist, neurologist, ophthalmologist, gynecologist, neuropsychologist

Prognosis

Normal life span if BCCs treated early on and no other malignancies develop; close surveil lance with physician throughout life; disfiguring scars may create psychosocial problems

CLINICAL PEARLS

The syndrome is caused by gene defects that regulate growth and differentiation; mu tations in the PTCH gene impair the PTCH protein inhibition of Smo, a transmembrane protein. Smo active signaling contributes to tumor formation . . . Clues to the diagnosis in early life include a family history, larger head size, and broad nasal root . . . Cleft lip and palate may be associated . . . BCCs may begin in early childhood and are often small, banal-appearing monomorphic, brown, smooth dome-shaped papules, very acrochordon like and not looking like typical adult BCCs at all . . . Learning difficulties are common . . . A pediatric dentist should be part of the care team . . . Photoprotection is important and should include sun-protective garments, hats, and broad-spectrum sunscreens . . . X-rays, except with definite medical indication, should be avoided . . . Consider topical imiquimod as a treatment option . . . LE, JH

197

Basal Cell Nevus Syndrome (continued)

5.1. Pigmented facial basal cell carcinomas with postsurgi cal scars and glabellar graft (4).

Copyright © 2024 Wolters Kluwer, Inc. Unauthorized reproduction of the content is prohibited. 5.2. Multiple tan-brown basal cell carcinomas on patient’s back (4). 5.3. Large jaw cysts in maxilla and mandible (4).

198

Skin

Associated Findings

Calcified falx cerebri Medulloblastoma

Frontal bossing Hypertelorism

Basal cell carcinomas

Odontogenic cysts

Bifid ribs

Kyphoscoliosis Vertebral fusion

Ovarian fibroma

Palmar pits

199

Lynch syndrome, Muir-Torre variant

Synonym(s)

Muir-Torre syndrome hereditary nonpolyposis colon cancer (HNPCC), Muir-Torre variant Torre syndrome; Torre-Muir syndrome AD; MSH1 and MSH2 genes on 3p22.2 and 2p21-p16.3, respectively; less commonly MSH6 , PMS2, or EPCAM

Inheritance

Prenatal Diagnosis

DNA analysis

Incidence

Lynch syndrome: 1:270; incidence of Muir-Torre subvariant unknown

Age of Presentation

Fifth to sixth decades of life (internal malignancies usually precede cutaneous lesions)

Pathogenesis

Muir-Torre syndrome refers to a Lynch syndrome variant in individuals with characteristic sebaceous adenomas, epitheliomas, carcinomas, and/or keratoacanthomas of the skin and with characteristic Lynch syndrome internal malignancy. MSH1 , MSH2 , MSH6 , PMS2 , and EPCAM encode mismatch repair genes; MSH2 and MSH6 or MSH3 form a dimer com plex that locates DNA mismatch replication errors; MLH1, complexed with PMS2 ,then binds and removes the error and places a corrected replication product; disrupted DNA mismatch repair genes produce phenotype MSH2 : higher risk of Muir-Torre variant, sebaceous neoplasms; MLH1 : highest colorectal cancer risk Biallelic mutations in MLH1 , MSH2 , MSH2 , or PMS2 result in severe childhood cancer syndrome, Constitutional Mismatch Repair deficiency ( CMMRD ) with café-au-lait macules similar to neurofibromatosis type I Skin Multiple sebaceous tumors: adenomas (most common), carcinomas, hyperplasias, epitheliomas, BCC with sebaceous differentiation Keratoacanthomas Neoplasms Adenocarcinoma of the colon (most common), other gastrointestinal tract, endometrial, genitourinary tract, lung, breast, brain, prostate, and hematologic malignancies described Skin biopsy with immunohistochemical staining for loss of MLH1, MSH2, MSH6, and PMH2 followed by confirmatory molecular testing for germline mutation Endoscopy/gastrointestinal x-ray Close follow-up screening for internal malignancy according to published guidelines for those with confirmed germline mutation; prophylactic hysterectomy after childbearing Referral to dermatologist Referral to gastroenterologist Cowden syndrome (p. 210) Gardner syndrome (p. 206)

Genotype/Phenotype Correlation

Key Features

Differential Diagnosis

Laboratory Data

Management

Prognosis

May have normal life span with close surveillance and early detection of malignancy

Almost any sebaceous adenoma or carcinoma warrants immunohistochemical staining for loss of MSH2, MSH6, and MLH1 on skin biopsy . . . A germline mutation in tissue other than lesional skin is needed to confirm the diagnosis of Lynch syndrome or Muir-Torre variant . . . Sebaceous hyperplasia and sebaceous epitheliomas arising within nevus sebaceous of Ja dassohn are not part of the syndrome . . . The associated visceral malignancies may be indo lent, and detection can lead to prolonged survival . . . The National Comprehensive Cancer Network (NCCN) provides annual surveillance guidelines . . . Both hereditary nonpolyposis colorectal cancer and the Muir-Torre variant are caused by a heritable DNA mismatch repair defect . . . Mutations in the MSH2 gene located on 2p are commonly implicated . . . JH

CLINICAL PEARLS

200

Skin

Associated Findings

Sebaceous carcinoma

Sebaceous epithelioma Sebaceous hyperplasia Sebaceous adenoma

Keratoacanthoma

Colonic polyposis Colonic cancer, Often right-sided

5.4. Multiple sebaceous adenomas on patient’s forehead (80).

5.5. Sebaceous carcinoma of lower eyelid (81).

201

Dyskeratosis Congenita

Synonym

Zinsser-Engman-Cole syndrome

Inheritance

X-linked recessive (about 25%): DKC1 gene on Xq28 AD: TINF2 (about 15%) on 14q12, TERC (5%-10%) on 3q26.2 and others AD or AR patterns: TERT (1%-7%) gene on 5p15.33 and others

Prenatal Diagnosis

DNA analysis

Incidence

Over 800-1,000 cases known; M:F = 3:1

Age at Presentation

First decade of life (cutaneous, nail, mucosal changes)

Pathogenesis

Group of disorders that impair telomere maintenance, shorten telomere length; telomere preservation requires DNA repeats added to chromosome ends by telomerase using a template (hTR); DKC1 encodes dyskerin that binds hTR (encoded by TERC ); mutations impair RNA nucleolar function and RNA telomerase activity with subsequent problems in cell proliferation in blood and epithelium; TINF2 encodes a critical protein component of shelterin, a protein complex that protects telomeres; TERT encodes hTERT, another major component of telomerase that joins with hTR; all dyskeratosis congenita mutations dis rupt telomerase extension of telomere ends creating disordered cell division, leading to bone marrow failure and cancer predisposition Skin Reticulated, lacy gray-brown hyperpigmentation on the neck, face, trunk, and upper thighs; atrophy, hypopigmentation, and telangiectasias within pigmentation; SCC, especially head and neck Palmoplantar hyperkeratosis, hyperhidrosis, friction bullae, acrocyanosis; loss of dermatoglyphics Hair Thinning alopecia on scalp, eyebrows, and eyelashes Nails Dystrophic with longitudinal ridges, pterygium; atrophic, or absent Mouth Premalignant leukoplakia of the tongue, buccal mucosa, and pharynx; dental caries with early loss of teeth, enlarged tooth pulp chambers (taurodontism) Mucous membranes Premalignant leukoplakia of any mucosal surface; anogenital cancer; urethral stenosis Hematologic Fanconi type pancytopenia with secondary infection, hemorrhage, bone marrow failure Eyes Blepharitis, conjunctivitis, lacrimal duct obstruction with epiphora, ectropion; sparse lashes, trichiasis Pulmonary Pulmonary fibrosis X-linked ( DKC1 ), AD ( TINF2 ) tend to be more severe than other types

Genotype/Phenotype Correlation

Key Features

Differential Diagnosis

Fanconi syndrome Pachyonychia congenita (p. 328) Rothmund-Thomson syndrome (p. 266) Chronic graft-vs-host disease

202

Dyskeratosis Congenita (continued)

Laboratory Data

Skin, mucosal biopsy Complete blood count (CBC); telomere length; bone marrow biopsy; pulmonary function test DNA analysis Referral to hematologist/oncologist—hematopoietic stem cell transplantation, transfu sions, oral retinoids Referral to dermatologist, otolaryngologist, gastroenterologist, ophthalmologist Counsel against excessive sun exposure, smoking

Management

Prognosis

Death usually in 20s-30s secondary to bone marrow failure, pulmonary disease, malig nancy (usually SCC), gastrointestinal hemorrhage, or opportunistic infection

CLINICAL PEARLS

Dyskeratosis congenita is caused by inherited defects in the telomerase complex . . . AD dyskeratosis congenita is associated with mutations in the RNA component of telomerase, hTERC , whereas X-linked dyskeratosis congenita is caused by mutations in the gene encod ing dyskerin, a protein implicated in both telomerase function and ribosomal RNA process ing . . . X-linked dyskeratosis congenita is clearly the most common . . . X-linked recessive and AR cases have a high incidence of nail dystrophy, skin changes, and leukoplakia, with earlier presentation (median is ~15 years) . . . AD cases are usually milder and may present later (median age at diagnosis, 28 years) . . . Telomere length is an important diagnostic test . . . Bone marrow dysfunction can be the first manifestation . . . Mucosal surfaces should be followed carefully with liberal biopsies of any worrisome changes . . . Hematopoietic stem cell transplantation is the standard treatment of bone marrow complications; nonmyeloab lative conditioning regimens may be more successful. LE, JH

203

Dyskeratosis Congenita (continued)

5.6. Poikilodermatous changes in the axilla extending on to the arm (3).

5.7. Dystrophic and absent nails (3).

204

Skin

Associated Findings

Alopecia

Mild cognitive deficit

Blepharitis Conjunctivitis

Premalignant leukoplakia

Reticulated grey/brown hyperpigmentation Telangiectasias Atrophy Hypopigmentation

Hyperhidrosis

Pancytopenia

Palmoplantar keratoderma Friction bullae

Atrophic nail plates Pterygium

205

Gardner Syndrome

Synonyms

Familial adenomatous polyposis (FAP)—Gardner variant; adenomatous polyposis coli (APC) –associated polyposis—Gardner variant

Inheritance

AS; APC gene on 5q22.2

Prenatal Diagnosis

DNA analysis

Incidence

FAP: 1:7,000-30,000; M = F; incidence of Gardner variant unknown

Age at Presentation

Infancy to early childhood (bone, skin lesions); second to fourth decades (gastrointestinal lesions) APC encodes APC protein, a tumor suppressor that regulates the Wnt signaling pathway; APC associates with B-catenin, an adherens junction protein controlling cell growth and early embryonic axis formation; disruption promotes tumor formation; FAP with skin find ings is referred to as Gardner syndrome Skin Epidermoid cysts—increased on head and neck; may have unusual location, e.g. toe, scalp, shin Fibromas, pilomatrixomas, lipomas Musculoskeletal Osteomas—maxilla, mandible, other skull bones; small, multiple Gastrointestinal Polyposis with high predisposition to malignant adenocarcinoma; most common in colon/rectum Desmoid tumors—postabdominal surgery; uteral or intestinal obstruction Eyes Congenital hypertrophy of retinal pigment epithelium (CHRPE)—congenital marker for diagnosis Teeth Odontomas, supernumerary teeth Endocrine Adrenal adenomas Neoplasm Increased frequency of duodenal/periampullary, thyroid, pancreatic, hepatoblastoma, and gastric malignancies

Pathogenesis

Key Features

Differential Diagnosis

Epidermoid cysts Familial polyposis coli Turcot syndrome

Laboratory Data

Colonoscopy/biopsy of polyp Endoscopy Radiologic evaluation of the upper and lower gastrointestinal tract Skull films/skeletal survey DNA analysis

Management

Referral to gastroenterologist—semiannual evaluation of gastrointestinal tract, high-fiber diet Referral to surgeon—prophylactic colectomy Referral to ophthalmologist, dentist, endocrinologist Referral to dermatologist—excision of cysts Examination of family members

Prognosis

If total colectomy performed early, before metastases, then normal life span

Gardner variant of FAP is caused by mutations in the ( APC ) gene . . . CHRPE is very useful marker for the disease . . . Ongoing surveillance colonscopy is advised beginning at ages 10 15 years, and total colectomy may be needed . . . When a patient presents with multiple epi dermoid cysts, it should prompt eliciting a family history of polyps and/or colonic cancer . . . Gastroenterology, general surgery, oral surgery, radiology, ophthalmology, endocrinology, genetics, and neurology are all appropriate specialties to assist with care. LE, JH

CLINICAL PEARLS

206

Skin

Associated Findings

Epidermoid cysts

Congenital hypertrophy of retinal pigment epithelium (CHRPE)

Odontomas Supernumerary teeth Osteomas

Hamartomatous polyps Adenocarcinoma Desmoid tumors

5.11. Fundoscopic exam demonstrates congenital hypertrophy of retinal pigment epithelium (85).

5.9. Multiple epidermoid cysts of the face (83).

5.10. Gross surgical specimen demonstrating multi ple polyps of the colon (84).

207

Peutz-Jeghers Syndrome

Synonym

Periorificial lentiginosis

Inheritance

AD; serine/threonine kinase 11 ( STK11 ) gene on 19p13 Spontaneous mutation (~10%-20%)

Prenatal Diagnosis

DNA analysis

Incidence

1:8,000-1:200,000; M = F

Age at Presentation

Birth to first few years of life (pigmented macules); first to third decades of life (polyps)

Pathogenesis

STK11 , a tumor suppressor gene, encodes a kinase that catalyzes addition of serine and threonine regulating adenosine monophosphate (AMP)-activated proteins that affect cell polarity, metabolism, and apoptosis; mutations disrupt regulated cell growth and apopto sis, leading to tumor formation Skin Pigmented macules—0.2-7 mm, brown to black in color, variation in shape on periori ficial skin, lips, buccal mucosa, digits, nails, palms, soles, any mucosal surface; all except buccal mucosal lesions may fade with time Gastrointestinal Hamartomatous polyps—small intestine > large intestine, secondary abdominal pain, gastrointestinal bleeding, anemia, intussusception, obstruction; adenocarcinoma may develop within polyps Neoplasm Increased frequency of colorectal carcinoma, followed by breast, stomach, small bowel, and pancreas. Others include lung, sertoli cell tumors, cervical, and ovarian

Key Features

Differential Diagnosis

LEOPARD syndrome (p. 80) Carney complex (p. 82) Laugier-Hunziker syndrome Cronkhite-Canada syndrome Addison disease Gardner syndrome (p. 206)

Laboratory Data

Bowel x-rays, gastroscopy/colonoscopy screening every 1-2 years, polyp biopsy Stool guaiac Mammography Referral to gastroenterologist/surgeon—removal of symptomatic polyps and those > 1.5 cm via endoscopic perioperative panpolypectomy; screening every 3 years if asymp tomatic; cancer surveillance according to published guidelines Referral to obstetrician/gynecologist—regular pelvic/breast examinations/screening Referral to dermatologist—laser surgery

Management

Prognosis

Normal life span if malignancy detected early

The disorder is caused by mutations in the serine/threonine kinase STK11 gene . . . The pigmented macules on the lips are very amenable to treatment with ruby or Alexandrite lasers . . . We coordinate laser treatment with endoscopy, utilizing the sedation/anesthesia to make the laser “painless” . . . Endoscopy should be routine, with removal of polyps to min imize bowel wall invasion . . . For history buffs, Keller et al. ( Familial Cancer 2002;1:181-185) reviewed the history of Peutz-Jeghers syndrome, including biographic information about Jan Peutz and Harold Jeghers. LE

CLINICAL PEARLS

208

Page 2 Page 3 Page 4 Page 5 Page 6 Page 7 Page 8 Page 9 Page 10 Page 11 Page 12 Page 13 Page 14 Page 15 Page 16 Page 17 Page 18 Page 19 Page 20 Page 21 Page 22 Page 23 Page 24 Page 25 Page 26 Page 27 Page 28 Page 29 Page 30 Page 31 Page 32 Page 33 Page 34 Page 35 Page 36 Page 37

Made with FlippingBook - professional solution for displaying marketing and sales documents online