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To keep pace with the rapid advancements in molecular genetics and rare diseases research, we have updated the list of ectodermal dysplasias based on the latest classification approach that was adopted in 2017 by an international panel of experts. For this purpose, we searched the databases PubMed and OMIM for the term “ectodermal dysplasia”, referring mainly to changes in the last 5 years. We also tried to obtain information about those diseases on which the last scientific report appeared more than 15 years ago by contacting the authors of the most recent publication. A group of experts, composed of researchers who attended the 8th International Conference on Ectodermal Dysplasias and additional members of the previous classification panel, reviewed the proposed amendments and agreed on a final table listing all 49 currently known ectodermal dysplasias for which the molecular genetic basis has been clarified, including 15 new entities. A newly reported ectodermal dysplasia, linked to the gene LRP6, is described here in more detail. These ectodermal dysplasias, in the strict sense, should be distinguished from syndromes with features of ectodermal dysplasia that are related to genes extraneous to the currently known pathways involved in ectodermal development. The latter group consists of 34 syndromes which had been placed on the previous list of ectodermal dysplasias, but most if not all of them could actually be classified elsewhere. This update should streamline the classification of ectodermal dysplasias, provide guidance to the correct diagnosis of rare disease entities, and facilitate the identification of individuals who could benefit from novel treatment options.

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.

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.

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.

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.