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In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.

ObjectivesWomen with Turner syndrome (TS) are frequently counselled against pregnancy due to lack of data and unclear aortic dissection risk. However, with advances in fertility therapy, more women with TS are contemplating pregnancy. This study compared rates of adverse cardiovascular (CV) outcomes among: (1) pregnant and non-pregnant women with TS and (2) pregnant women with TS with/without structural heart disease.MethodsRetrospective analysis of pregnant and age-matched non-pregnant controls with TS (2005–2017) across 10 CV centres was done. Data were collected at initial evaluation in pregnancy and outcomes were assessed to 6 months postpartum. Adverse CV events were defined as CV death, aortic dissection/rupture and/or aortic intervention. Non-pregnant age-matched controls were followed over the same time period.ResultsSixty-eight pregnancies were included (60 women, mean age 33 years, 48% primigravid, 49% fertility therapy, 80% structurally normal heart, 25% XO karyotype). Based on American Society of Reproductive Medicine criteria, 10 pregnancies occurred in women stratified to high-risk category. There were no CV events in the pregnant women or in the non-pregnant women with TS. Obstetric events complicated 12 (18%) pregnancies with 9 (13%) attributed to hypertensive disorder of pregnancy. Fetal events included small for gestational age neonates (18%), preterm delivery (15%) and fetal death (3%).ConclusionsThis study helps to refine the approach to pregnancy in women with TS. Among women with TS without structural heart disease, pregnancy does not impose an increased risk of CV outcomes. Among women with TS with structural heart disease, the risk of pregnancy is not as prohibitive as previously described but does require ongoing evaluation.

An international advisory group met at the National Institutes of Health in Bethesda, Maryland in 2017, to discuss a new classification system for the ectodermal dysplasias that would integrate both clinical and molecular information. We propose the following, a working definition of the ectodermal dysplasias building on previous classification systems and incorporating current approaches to diagnosis: ectodermal dysplasias are genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives, including hair, teeth, nails, and certain glands. Genetic variations in genes known to be associated with ectodermal dysplasias that affect only one derivative of the ectoderm (attenuated phenotype) will be grouped as non-syndromic traits of the causative gene (e.g. non-syndromic hypodontia or missing teeth associated with pathogenic variants of EDA “ectodysplasin” ). Information for categorization and cataloging includes the phenotypic features, Online Mendelian Inheritance in Man number, mode of inheritance, genetic alteration, major developmental pathways involved (e.g. EDA, WNT “wingless-type”, TP63 “tumor protein p63”) or the components of complex molecular structures ( e.g. connexins, keratins, cadherins).

High quality information is critical for informed decision-making in pregnancy following a prenatal diagnosis of sex chromosome aneuploidy. The goal of this study was to define the spectrum of outcomes in patients with prenatally diagnosed 45,X/46,XX mosaic Turner syndrome in order to provide a better basis for genetic counseling at the time of intrauterine diagnosis. Phenotype data for twenty-five patients with prenatally diagnosed 45,X/46,XX mosaicism were collected by retrospective chart review and, when possible, semi-structured telephone interview. Existing data from a cohort of 58 patients with postnatally diagnosed 45,X/46,XX mosaicism were used for comparison. Relative to those diagnosed postnatally, prenatal patients were more likely to have normal growth and normal secondary sexual development, less likely to manifest distinctive Turner syndrome features such as nuchal webbing and edema, and had significantly fewer renal defects. These differences underscore the need for a nuanced approach to prenatal counseling in cases of 45,X/46,XX mosaicism.

Chapter 11 covers Porphyrias (Congenital Erythropoietic Porphyria, Erythropoietic Protoporphyria, Hereditary Coproporphyria, Porphyria Cutanea Tarda, and Variegate Porphyria), Mucopolysaccharidoses (Hunter Syndrome), and Other Metabolic Disorders (Acrodermatitis Enteropathica, Alkaptonuria, Biotinidase Deficiency, Familial Cutaneous Amyloidosis, and Prolidase Deficiency). Each condition is discussed in detail, including dermatologic features, associated anomalies, histopathology, basic defect, treatment, mode of inheritance, prenatal diagnosis, and differential diagnosis.

Chapter 10 covers Basal Cell Nevus Syndrome, Cowden Syndrome, Cylindromatosis, Dysplastic Nevus Syndrome, Epidermal Nevus, Gardner Syndrome, Giant congenital nevocytic nevus, Hereditary Keratoacanthomas, Hereditary Leiomyomatosis and renal cell cancer, Infantile Myofibromatosis, Multiple Endocrine Neoplasia Types 1, 2A, and 2B/3, Pilomatricoma, Proteus Syndrome, Sebaceous Nevus Syndrome, and Tumoral Calcinosis. Each condition is discussed in detail, including dermatologic features, associated anomalies, histopathology, basic defect, treatment, mode of inheritance, prenatal diagnosis, and differential diagnosis.

Chapter 14 covers Chediak-Higashi Disease, Chronic Granulomatous Disease, Epidermodysplasia Verruciformis, Familial Mucocutaneous Candidiasis, Griscelli Syndrome Types 1, 2, and 3, Job Syndrome, Mucoepithelial Dysplasia, and Wiskott-Aldrich Syndrome. Each condition is discussed in detail, including dermatologic features, associated anomalies, histopathology, basic defect, treatment, mode of inheritance, prenatal diagnosis, and differential diagnosis.

Chapter 9 covers Congenital Erosive and Vesicular Dermatosis, Erythermalgia, Michelin Tire Baby, and Stiff Skin. Each condition is discussed in detail, including dermatologic features, associated anomalies, histopathology, basic defect, treatment, mode of inheritance, prenatal diagnosis, and differential diagnosis.

Chapter 2 covers Ichthyoses (Bullous Congenital Ichthyosiform Erythroderma, Harlequin Ichthyosis, Ichthyosis Bullosa of Siemens, Ichthyosis Hystrix, Ichthyosis Vulgaris, Lamellar Exfoliation of the Newborn, Lamellar Ichthyosis/Nonbullous Congenital Ichthyosiform Erythroderma, Netherton Syndrome, Peeling Skin Syndrome, Restrictive Dermopathy, and X-linked Recessive Ichthyosis), Erythrokeratodermas (Erythrokeratodermia Variabilis ET PROGESSIVA, and Pityriasis Rubra Pilaris), Acrokeratoderma (Acrokeratoelastoidosis, Acrokeratosis Verruciformis (HOPF)), Hereditary Palmoplantar Keratodermas (Hereditary Palmoplantar Keratoderma with Deafness, Hereditary Palmoplantar Keratoderma Epidermolytic Hyperkeratosis, Hereditary Palmoplantar Keratoderma Howel-Evans, Hereditary Palmoplantar Keratoderma Olmsted, Hereditary Palmoplantar Keratoderma Punctate, Hereditary Palmoplantar Keratoderma Striata, Hereditary Palmoplantar Keratoderma Unna-Thost, Hereditary Palmoplantar Keratoderma Vohwinkel, Keratolytic Winter Erythema, Mal de Meleda, Papillon-Lefèvre, Scleroatrophic and Keratotic Dermatosis of the Limbs), Porokeratoses (Porokeratosis of Mibelli), Other Disorders of the Epidermis (Absence of Dermatoglyphics, Acanthosis Nigricans, Darier-White Disease, Hereditary Painful Callosities, Keratosis Follicularis Spinulosa Decalvans, Knuckle Pads, Kyrle/Flegel Disease, Ulerythema Ophryogenes), Syndromic Disorders (CHILD Syndrome, Chondrodysplasia Punctata, Ichthyosis with Hypogonadism, KID Syndrome, Neu-Laxova Syndrome, Neutral Lipid Storage Disease with Ichthyosis, Refsum Disease, Richner-Hanhart Syndrome, Sjögren-Larsson Syndrome), Cohesion (Epidermolysis Bullosa, Epidermolysis Bullosa Simplex Dowling-Meara, Epidermolysis Bullosa Simplex Generalized, Epidermolysis Bullosa Simplex Localized, Epidermolysis Bullosa Junctional Generalized, Epidermolysis Bullosa Junctional Generalized Atrophic Benign, Epidermolysis Bullosa Dystrophica Cockayne-Touraine, Epidermolysis Bullosa Dystrophica, Hallopeau-Siemens, Epidermolysis Bullosa Dystrophica Pretibial, Transient Bullous Dermolysis of the Newborn, Hailey-Hailey Disease). Each condition is discussed in detail, including dermatologic features, associated anomalies, histopathology, basic defect, treatment, mode of inheritance, prenatal diagnosis, and differential diagnosis.

Chapter 13 covers Bloom Syndrome, Hartnup Disorder, Kindler Syndrome, Polymorphous Light Eruption, Rothmund-Thomson Syndrome, and Xeroderma Pigmentosum. Each condition is discussed in detail, including dermatologic features, associated anomalies, histopathology, basic defect, treatment, mode of inheritance, prenatal diagnosis, and differential diagnosis.

Chapter 7 covers Cholestasis-Lymphedema Syndrome, Distichiasis and Lymphedema, and Hereditary Lymphedema. Each condition is discussed in detail, including dermatologic features, associated anomalies, histopathology, basic defect, treatment, mode of inheritance, prenatal diagnosis, and differential diagnosis.

Chapter 4 covers Hyperpigmentation (including Carney Complex, Dowling-Degos Disease, Dyskeratosis Congenita, Fanconi Anemia, H Syndrome, Hemochromatosis, Incontinentia Pigmenti, LEOPARD Syndrome, Linear and Whorled Nevoid Hypermelanosis, McCune-Albright Syndrome, Naegeli Syndrome, Neurofibromatosis, Nevus Phakomatosis Pigmentovascularis, Peutz-Jeghers Syndrome, and Universal Melanosis) and Hypopigmentation ( Albinisms, Albinism with Deafness, Hermansky-Pudlak Syndrome, Oculocutaneous Albinism Tyrosinase Negative, Oculocutaneous Albinism Tyrosinase Positive, Yellow Mutant Albinism, Cross Syndrome, Hypomelanosis of Ito, Piebaldism, Premature Canities, Vitiligo, and Waardenburg Syndrome Types 1, 2, 3, and 4). Each condition is discussed in detail, including dermatologic features, associated anomalies, histopathology, basic defect, treatment, mode of inheritance, prenatal diagnosis, and differential diagnosis.

Chapter 8 covers Familial Cold Urticaria, Hereditary Angioedema, Melkersson-Rosenthal Syndrome, Muckle-Wells Syndrome, NOMID/CINCA, and Urticaria Pigmentosa. Each condition is discussed in detail, including dermatologic features, associated anomalies, histopathology, basic defect, treatment, mode of inheritance, prenatal diagnosis, and differential diagnosis.

This book is a readable, reliable guide to the diagnosis and differential of inherited skin disorders to which generalists, paediatricians, dermatologists, and geneticists can refer during an examination. The new edition reflects the most up-to-date understanding of the molecular and genetic bases of heritable skin diseases. Each chapter describes the signs and symptoms of heritable skin diseases and enumerates pertinent associated clinical features and differential diagnoses. Non-dermatological signs are symptoms round out the information on each condition. Where appropriate, descriptions of histopathology at both the light and electron microscopic levels are included. Over 800 full-colour photographs illustrate the concepts discussed in the text. Annotated bibliographies at the end of each section direct readers to more extensive sources, and an updated listing of support groups for patients and their families supplements the resources for medical professionals.

Chapter 6 covers Cerebrotendinous Xanthomatosis, Familial Multiple Lipomatosis, Familial Symmetric Lipomatosis, Fibrodysplasia Ossificans Progressiva, Lipogranulomatosis, Partial Lipodystrophy, and Berardinelli-Seip Syndrome. Each condition is discussed in detail, including dermatologic features, associated anomalies, histopathology, basic defect, treatment, mode of inheritance, prenatal diagnosis, and differential diagnosis.

Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (Hay-Wells syndrome, MIM #106220) is a rare autosomal dominant ectodermal dysplasia syndrome. It is due to mutations in the TP63 gene, known to be a regulatory gene with many downstream gene targets. TP63 is important in the differentiation and proliferation of the epidermis, as well as many other processes including limb and facial development. It is also known that mutations in TP63 lead to skin erosions. These erosions, especially on the scalp, are defining features of AEC syndrome and cause significant morbidity and mortality in these patients. It was this fact that led to the 2003 AEC Skin Erosion Workshop. That conference laid the groundwork for the International Research Symposium for AEC Syndrome held at Texas Children's Hospital in 2006. The conference brought together the largest cohort of individuals with AEC syndrome, along with a multitude of physicians and scientists. The overarching goals were to define the clinical and pathologic findings for improved diagnostic criteria, to obtain tissue samples for further study and to define future research directions. The symposium was successful in accomplishing these aims as detailed in this conference report. Following our report, we also present 11 manuscripts within this special section that outline the collective clinical, pathologic, and mutational data from 18 individuals enrolled in the concurrent Baylor College of Medicine IRB-approved protocol: Characterization of AEC syndrome. These collaborative findings will hopefully provide a stepping-stone to future translational projects of TP63 and TP63-related syndromes.

A medical genetics clinic is a unique and complex environment in which care requires a combination of medical knowledge, social intelligence, and emotional sensitivity. We offer a few pearls from our medical genetics clinic that we hope will help the pediatric or general dermatologist when caring for patients with known or suspected genetic disorders. This paper addresses five main topics: When is it more than just atopic dermatitis? How should the clinician approach blistering in the newborn period? What is mosaicism? When is genetic testing useful? Where can clinician, patients, and families turn for available resources?

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine.

This article contains the author's views on genetic counseling in cases concerning the epidermolysis bullosa syndromes. The provision of genetic counseling entails absolutes such as diagnosis, natural history, treatment, mode of inheritance, recurrence risks/prenatal diagnosis and referral. The genetic counselor needs to be informed and informative and answer all the needs of the patients and their families reliably both at the initial consultation and subsequently as needed over the course of the patient's life.

Variable expression and penetrance of dominantly inherited disorders present problems in diagnosis and counseling. The variation in clinical findings within a family with an autosomal dominant skeletal dysplasia is presented. In some members only shortened metacarpals were found, as seen in classic Brachydactyly E. Others presented with more severe and generalized skeletal involvement, such as is found in some of the spondyloepiphyseal dysplasias. This family may represent the true spectrum of Brachydactyly E; they may be affected with a specific spondyloepiphyseal dysplasia; or they may represent a new syndrome. The authors favor the first possibility and feel that this family serves to emphasize the importance of examining all affected members in a kindred with an autosomal dominant disease.

Holt-Oram syndrome is an autosomal dominant disorder with variable expression. From a review of published pedigree data and of a family reported here, we have found that penetrance is 100 % if appropriate studies, including wrist radiographs, are performed. There does not appear to be a significant maternal effect on the severity of expression in affected offspring.

Recommendations for laboratories to report incidental findings from genomic tests have stimulated interest in such results. In order to investigate the criteria and processes for assigning the pathogenicity of specific variants and to estimate the frequency of such incidental findings in patients of European and African ancestry, we classified potentially actionable pathogenic single-nucleotide variants (SNVs) in all 4300 European- and 2203 African-ancestry participants sequenced by the NHLBI Exome Sequencing Project (ESP). We considered 112 gene-disease pairs selected by an expert panel as associated with medically actionable genetic disorders that may be undiagnosed in adults. The resulting classifications were compared to classifications from other clinical and research genetic testing laboratories, as well as with in silico pathogenicity scores. Among European-ancestry participants, 30 of 4300 (0.7%) had a pathogenic SNV and six (0.1%) had a disruptive variant that was expected to be pathogenic, whereas 52 (1.2%) had likely pathogenic SNVs. For African-ancestry participants, six of 2203 (0.3%) had a pathogenic SNV and six (0.3%) had an expected pathogenic disruptive variant, whereas 13 (0.6%) had likely pathogenic SNVs. Genomic Evolutionary Rate Profiling mammalian conservation score and the Combined Annotation Dependent Depletion summary score of conservation, substitution, regulation, and other evidence were compared across pathogenicity assignments and appear to have utility in variant classification. This work provides a refined estimate of the burden of adult onset, medically actionable incidental findings expected from exome sequencing, highlights challenges in variant classification, and demonstrates the need for a better curated variant interpretation knowledge base.

Penttinen syndrome is a distinctive disorder characterized by a prematurely aged appearance with lipoatrophy, epidermal and dermal atrophy along with hypertrophic lesions that resemble scars, thin hair, proptosis, underdeveloped cheekbones, and marked acro-osteolysis. All individuals have been simplex cases. Exome sequencing of an affected individual identified a de novo c.1994T>C p.Va1665Ala variant in PDGFRB, which encodes the platelet-derived growth factor receptor P. Three additional unrelated individuals with this condition were shown to have the identical variant in PDGFRB. Distinct mutations in PDGFRB have been shown to cause infantile myofibromatosis, idiopathic basal ganglia calcification, and an overgrowth disorder with dysmorphic facies and psychosis, none of which overlaps with the clinical findings in Penttinen syndrome. We evaluated the functional consequence of this causative variant on the PDGFRB signaling pathway by transfecting mutant and wild-type cDNA into HeLa cells, and transfection showed ligand-independent constitutive signaling through STAT3 and PLCy. Penttinen syndrome is a clinically distinct genetic condition caused by a PDGFRB gain-of-function mutation that is associated with a specific and unusual perturbation of receptor function.

Turner syndrome is a chromosomal disorder due to an absent or abnormal X chromosome. The two most typical features are short stature and gonadal dysgenesis. There is a wide range of other phenotypic features, many of which are thought secondary to lymphedema during embryogenesis. Reviewed are common sequelae of lymphatic obstruction, as well as common tooth and skin findings.

We describe a family with woolly hair and ulerythema ophryogenes spanning four generations. Both woolly hair and ulerythema ophryogenes have been associated with Noonan syndrome and cardiofaciocutaneous syndrome (CFC), two disorders with considerable phenotypic overlap. This family did not exhibit any of the other findings characteristic of either Noonan syndrome or CFC, similar to a previously described pedigree with hereditary woolly hair. Woolly hair elicits a broad differential diagnosis, including woolly hair nevus and several genodermatoses. Our report reviews the evaluation of woolly hair and discusses the conditions associated with this physical finding.

Areas of blanched skin in children may be seen as an independent finding or in association with vascular birthmarks. We performed a retrospective chart review to identify and describe infants with areas of ventral midline blanching in the presence of segmental infantile hemangiomas. We identified nine full-term infants with partial or full segmental hemangiomas and areas of midline ventral blanching. Additional ventral wall defects were seen in five patients. Six had cardiac anomalies and six had intracranial anomalies. Five were diagnosed with definite PHACE (posterior fossa, hemangioma, arterial, cardiac, and eye abnormalities) syndrome and three had possible PHACE syndrome. Eight were complicated by ulceration. Treatment varied according to the case. Ventral blanching, even in the absence of overt midline defects, can be seen in infants with segmental hemangiomas at risk for PHACE syndrome. We hypothesize that midline blanching may represent a minor manifestation of a developmental ventral defect.

Purpose of reviewThis article reviews the disorders of patterned dyspigmentation and discusses the pathogenesis of the pigmentary changes.Recent findingsA range of cytogenetic abnormalities has been detected in patterned pigmentary disease. This molecular heterogeneity correlates with the wide spect

Malignant melanoma is rare in childhood and has never been reported to cause pancytopenia due to bone marrow metastases in a child. We report a 3-year-old boy with a large congenital melanocytic nevus who presented with bone pain and pancytopenia due to diffuse bone and bone marrow infiltration with metastatic melanoma without an identifiable primary site. Despite treatment with imatinib mesylate there was no response and the patient died with progressive disease. This case illustrates an unusual presentation of bone marrow failure secondary to malignant melanoma in a young child with symptomatic metastatic marrow infiltration, a rarely reported site of melanoma involvement in adults or children.

We studied a new series of 21 individuals mosaic for a ring X chromosome [r(X)]. Of nine individuals with mental retardation, only one had a r(X) that lacked XIST (X-inactive-specific transcript) and was not subject to X inactivation, which would explain the abnormal phenotype; the remaining eight cases had XIST on their r(X). The majority of cases (five of seven) with mental retardation had an apparently early replicating r(X); but the androgen receptor gene (AR) was methylated on one allele in five of six informative cases, including two cases with an early replicating r(X). These conflicting results on two indicators of X inactivation suggest a potential dissociation between late replication and DNA methylation in these r(X) chromosomes, which may fail to become completely silenced. Of the twelve subjects who were not mentally retarded, all had XIST present on their r(X) and most (8/10) showed a late replicating r(X), together with AR methylation in all five informative cases, indicating r(X) inactivation. Thus, the unusual phenotypic features and mental retardation associated with the presence of a r(X) cannot be explained solely on the basis of presence or absence of XIST. The r(X) in cases with mental retardation were consistently smaller than those in individuals with normal intelligence, perhaps indicating inability for small rings to undergo structural changes associated with complete X inactivation or lethality in cases with a large non-inactivated r(X). Of the Turner syndrome features present in the r(X) cases, only edema was present in a lesser frequency than in 45,X individuals. Our cases generally had a less severe phenotype than those previously reported, suggesting that reported incidences of abnormalities may be influenced by ascertainment bias, with mental retardation potentially unrelated to the presence of the r(X) in some cases.

Epidermolysis bullosa simplex are dominant disorders of skin fragility characterized by intraepidermal blistering upon mild mechanical trauma. Skin fragility is caused by expression of either an abnormal keratin 5 or an abnormal keratin 14 protein, which compromises the structure and function of the keratin cytoskeleton of basal cells. We report an epidermolysis bullosa simplex patient with a novel single base substitution (A--T1414) that changes the lysine residue at amino acid 472 to a non-sense codon (K472X). This change predicts the synthesis of a truncated keratin 5, missing 119 amino acids, including the entire tail domain and the highly conserved KLLEGE motif at the carboxy terminus of the 2B domain of the central rod. Expression of an altered keratin 5, of predicted mass and pI for the product of the K472X allele, was documented by one- and two-dimensional western blots of protein extracts from patient skin. Ultrastructural analysis of the patient's nonhyperkeratotic skin was remarkable for basal keratinocytes with dense and irregular keratin filaments proximal to the basement membrane. Keratinocytes, transfected with a cDNA carrying the A--T1414 non-sense mutation, overexpressed a truncated keratin 5, and showed a disorganized and collapsed keratin filament cytoskeleton. This is the second epidermolysis bullosa simplex patient reported with a premature termination mutation in the KLLEGE motif. The remarkable occurrence of severe palmar--plantar hyperkeratosis in both patients suggests that the keratin 5 tail domain may have unrecognized, but important, normal functions in palmar-plantar tissues.

The field of pediatric dermatology continues to be enriched by the insights offered through molecular genetics. For some genetic skin disorders, including neurofibromatosis, tuberous sclerosis complex, and several forms of epidermolysis bullosa, genetic research has resulted in an evolving understanding of the relationship between genotype and phenotype, with the ability to predict some of the features of these disorders on the basis of the genetic defect. However, widespread use of molecular genetics for diagnostic testing of these disorders has not been possible because of genetic heterogeneity, limited availability, and reduced sensitivity. The appropriate use of genetic services is emphasized in this, the molecular era.

Neurofibromatosis type 1 patients with a submicroscopic deletion spanning the NF1 tumor suppressor gene are remarkable for an early age at onset of cutaneous neurofibromas, suggesting the deletion of an additional locus that potentiates neurofibromagenesis. Construction of a 3.5 Mb BAC/PAC/YAC contig at chromosome 17q11.2 and analysis of somatic cell hybrids from microdeletion patients showed that 14 of 17 cases had deletions of 1.5 Mb in length. The deletions encompassed the entire 350 kb NF1 gene, three additional genes, one pseudogene and 16 expressed sequence tags (ESTs). In these cases, both proximal and distal breakpoints mapped at chromosomal regions of high identity, termed NF1REPs. These REPs, or clusters of paralogous loci, are 15-100 kb and harbor at least four ESTs and an expressed SH3GL pseudogene. The remaining three patients had at least one breakpoint outside an NF1REP element; one had a smaller deletion thereby narrowing the critical region harboring the putative locus that exacerbates neurofibroma development to 1 Mb. These data show that the likely mechanism of NF1 microdeletion is homologous recombination between NF1REPs on sister chromatids. NF1 microdeletion is the first REP-mediated rearrangement identified that results in loss of a tumor suppressor gene. Therefore, in addition to the germline rearrangements reported here, NF1REP-mediated somatic recombination could be an important mechanism for the loss of heterozygosity at NF1 in tumors of NF1 patients.

SummaryTurner syndrome is the complex human phenotype associated with complete or partial monosomy X. Principle features of Turner syndrome include short stature, ovarian failure, and a variety of other anatomic and physiological abnormalities, such as webbed neck, lymphedema, cardiovascular and renal anomalies, hypertension, and autoimmune thyroid disease. We studied 28 apparently nonmosaic subjects with partial deletions of Xp, in order to map loci responsible for various components of the Turner syndrome phenotype. Subjects were carefully evaluated for the presence or absence of Turner syndrome features, and their deletions were mapped by FISH with a panel of Xp markers. Using a statistical method to examine genotype/phenotype correlations, we mapped one or more Turner syndrome traits to a critical region in Xp11.2-p22.1. These traits included short stature, ovarian failure, high-arched palate, and autoimmune thyroid disease. The results are useful for genetic counseling of individuals with partial monosomy X. Study of additional subjects should refine the localization of Turner syndrome loci and provide a rational basis for exploration of candidate genes.

Cowden's syndrome (CS) is an autosomal dominant disorder associated with an increased risk of developing benign and malignant tumors in a variety of tissues, including the skin, thyroid, breast and brain. Women with CS are felt to have an increased risk of developing breast cancer, and virtually all women with CS develop bilateral fibrocystic disease of the breast. Recently, a series of germline mutations have been identified from CS families in a gene known as PTEN/MMAC1/TEP1. In this study, we used heteroduplex analysis and direct sequencing analysis and identified three novel germline mutations in the PTEN/MMAC1/TEP1 coding sequence from unrelated individuals with CS. We report a de novo transition (T--C) at nucleotide 335 in exon 5. This missense mutation resulted in a leucine to proline (CTA to CCA) change at codon 112. We also describe a novel splice site mutation (801+2T--G) in intron 7 that caused exon skipping in PTEN/MMAC1/TEP1 mRNA. The third mutation we report is a missense mutation, consisting of a transition (T--C) at nucleotide 202 in exon 3, resulting in a tyrosine to histidine (TAC to CAC) change at codon 68. Finally, we also detected a rare polymorphism in exon 7 of the PTEN/MMAC1/TEP1 coding sequence. These data confirm the observation that mutations of the PTEN/MMAC1/TEP1 coding sequence are responsible for at least some cases of CS, and further define the spectrum of mutations in this autosomal dominant disorder.

Two brothers demonstrated a severe variant of trichothiodystrophy. Both had brittle hair, developmental delay with severe failure to thrive, recurrent infections, cataracts, and angioendotheliomas of the liver at autopsy. The elder died at 12 weeks, the younger at 6 months. The younger had the typical appearance of banded hair on polarizing microscopy and a low cystine content measured by ion exchange chromatography. The history, clinical findings, and basic defects of trichothiodystrophy are discussed.

The KRT5 and KRT14 genes encode the proteins keratin 5 and 14, respectively, which are the primary structural components of the 10-nm intermediate filaments of the mitotic epidermal basal cells. A single mutation in either gene can disrupt the keratin intermediate filament cytoskeleton, resulting in the skin fragility and blistering that is characteristic of the group of inherited disorders known as epidermolysis bullosa simplex. We have established a mutation detection system that facilitates KRT5 gene analysis from leukocyte genomic DNA, obviating the need for a skin sample or keratinocyte culture for cDNA synthesis. KRT5 intronic regions that flanked each exon were sequenced and sets of facing intronic primers were designed for specific amplification of each of the nine KRT5 exons. Direct sequencing of KRT5-amplified exons identified three novel missense mutations. One mutation recurred in two unrelated patients with sporadic EBS. This glutamate to lysine substitution (E477K), located in the highly conserved KLLEGE motif at the end of the central rod domain, is the third recurrent mutation identified in dominant epidermolysis bullosa simplex disease. The corresponding glutamate in keratin 2e was previously reported to be frequently mutated in ichthyosis bullosa of Siemens, suggesting that this highly conserved residue may be a potential mutational hot spot in other type II keratins or nonkeratin intermediate filament proteins.

Junctional epidermolysis bullosa (JEB) is a heterogeneous group of rare inherited skin disorders in which defects in cell adhesion components cause incomplete formation of hemidesmosomes. We have immunohistochemically examined the skin from ten JEB patients (JEB gravis, n = 4; JEB mitis, n = 3; JEB plus pyloric atresia [JEB/PA], n = 3) using monoclonal antibodies specific for the integrin adhesion receptors alpha 3 beta 1 and alpha 6 beta 4, and for the alpha 3, beta 3, and gamma 2 subunits of the basement membrane ligand, laminin 5. Consistent with our previous reports, only the JEB gravis patients without associated pyloric atresia expressed reduced or absent epitopes for laminin-5 subunits in their epidermal basement membrane. In contrast, all three JEB/PA cases showed abnormalities in integrin alpha 6 beta 4, but not in laminin 5, expression in their basal epidermal cells. Integrin beta 4 subunit was undetectable in the biopsied epidermis of these JEB/PA individuals using five different monoclonal antibodies that recognize both intra- and extracellular epitopes. The absence of the beta 4 subunit in the epidermis of JEB/PA specimens was confirmed by Western blot analysis of tissue extracts. Epidermal expression of the integrin alpha 6 subunit was variable in the JEB/PA patients. Abnormal integrin alpha 6 beta 4 expression may define the subset of JEB cases with pyloric atresia. These results strongly implicate a functional role for alpha 6 beta 4 in the formation of complete hemidesmosomes and in stable adhesion of basal keratinocytes to the basement membrane in vivo.

Chapter 12 covers Cockayne Syndrome, De Barsy Syndrome, Hallermann-Streiff Syndrome, Hutchinson-Gilford Progeria, and Werner Syndrome. Each condition is discussed in detail, including dermatologic features, associated anomalies, histopathology, basic defect, treatment, mode of inheritance, prenatal diagnosis, and differential diagnosis.

Chapter 5 covers Collagen disorders (Ainhum, Amniotic Bands, Buschke-Ollendorff Syndrome, Dermatosparaxis), Ehlers-Danlos Syndromes (Ehlers-Danlos Types I, II, and III, Ehlers-Danlos Type IV, Ehlers-Danlos Type VI, Ehlers-Danlos Type VIII, and Reactive Perforating Collagenosis), Elastin (Costello Syndrome, Cutis Laxa, and Pseudoxanthoma Elasticum), Vascular disorders (Ataxia Telangiectasia, Cutis Marmorata Telangiectatica Congenita, Fabry Syndrome, Familial Flame Nevi, Hereditary Glomus Tumors, Hereditary Hemorrhagic Telangiectasia, Klippel-Trenaunay-Weber Syndrome, Maffucci Syndrome, and Sturge-Weber Syndrome, and Multiple Cutaneous and Mucosal Venous Malformations), Mixed disorders (Aplasia Cutis Congenita, Focal Dermal Hypoplasia, Tuberous Sclerosis Complex), and other Disorders of the Dermis (Albright Hereditary Osteodystrophy, Cutis Verticis Gyrata, Familial Dysautonomia, François Syndrome, Hyaline Fibromatosis Syndrome, Lipoid Proteinosis, and Multiple Pterygia). Each condition is discussed in detail, including dermatologic features, associated anomalies, histopathology, basic defect, treatment, mode of inheritance, prenatal diagnosis, and differential diagnosis.

Familial Cold Urticaria – Hereditary Angioedema – Melkersson-Rosenthal Syndrome – Muckle-Wells Syndrome – NOMID/CINCA – Urticaria Pigmentosa

Cholestasis-Lymphedema Syndrome – Distichiasis and Lymphedema – Hereditary Lymphedema

Congenital Erosive and Vesicular Dermatosis – Erythermalgia – Michelin Tire Baby – Stiff Skin

Ichthyoses – Bullous Congenital Ichthyosiform Erythroderma – Continual Peeling Skin – Harlequin Fetus – Ichthyosis Bullosa of Siemens – Ichthyosis Hystrix – Ichthyosis Vulgaris – Lamellar Exfoliation of the Newborn – Lamellar Ichthyosis/Nonbullous Congenital Ichthyosiform Erythroderma – Netherton Syndrome – Restrictive Dermopathy – X-linked Recessive Ichthyosis – Erythrokeratodermas – Erythrokeratodermia Variabilis – Pityriasis Rubra Pilaris – Progressive Symmetric Erythrokeratoderma – Acrokeratoderma – Acrokeratoelastoidosis – Acrokeratosis Verruciformis (HOPF) – Hereditary Palmoplantar Keratodermas – Hereditary Palmoplantar Keratoderma with Deafness – Hereditary Palmoplantar Keratoderma Epidermolytic Hyperkeratosis – Hereditary Palmoplantar Keratoderma Howel-Evans – Hereditary Palmoplantar Keratoderma Olmsted – Hereditary Palmoplantar Keratoderma Punctate – Hereditary Palmoplantar Keratoderma Striata – Hereditary Palmoplantar Keratoderma Unna-Thost – Hereditary Palmoplantar Keratoderma Vohwinkel – Keratolytic Winter Erythema – Mal de Meleda – Papillon-Lefèvre – Scleroatrophic and Keratotic Dermatosis of the Limbs – Porokeratoses – Porokeratosis of Mibelli – Other Disorders of the Epidermis – Absence of Dermatoglyphics – Acanthosis Nigricans – Darier-White Disease – Hereditary Painful Callosities – Keratosis Follicularis Spinulosa Decalvans – Knuckle Pads – Kyrle/Flegel Disease – Ulerythema Ophryogenes – Syndromic Disorders – CHILD Syndrome – Chondrodysplasia Punctata – Ichthyosis with Hypogonadism – KID Syndrome – Neu-Laxova Syndrome – Neutral Lipid Storage Disease with Ichthyosis – Refsum Disease – Richner-Hanhart Syndrome – Sjögren-Larsson Syndrome – Cohesion – Epidermolysis Bullosa – Epidermolysis Bullosa Simplex Dowling-Meara – Epidermolysis Bullosa Simplex Generalized – Epidermolysis Bullosa Simplex Localized – Epidermolysis Bullosa Junctional Generalized – Epidermolysis Bullosa Junctional Generalized Atrophic Benign – Epidermolysis Bullosa Dystrophica Cockayne-Touraine – Epidermolysis Bullosa Dystrophica, Hallopeau-Siemens – Epidermolysis Bullosa Dystrophica Pretibial – Transient Bullous Dermolysis of the Newborn – Hailey-Hailey Disease