Molecular Pathway-Based Classification of Ectodermal Dysplasias: First Five-Yearly Update.

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.

Ectodermal dysplasias: Classification and organization by phenotype, genotype and molecular pathway.

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 (EDs) that would integrate both clinical and molecular information. We propose the following, a working definition of the EDs building on previous classification systems and incorporating current approaches to diagnosis: EDs 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 EDs 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).

Ectodermal dysplasias: clinical and molecular review.

Ectodermal dysplasias (EDs) as defined by Freire-Maia [Freire-Maia (1971); Hum Hered 21: 309-312; Freire-Maia (1977); Acta Genet Med Gemellol 26: 121-131] are congenital disorders characterized by alterations in two or more ectodermal structures, at least one of these involving alterations in hair, teeth, nails, or sweat glands. Suggestions for a new definition and, consequently, for a new classification of EDs have being proposed lately, mainly with the purpose of connecting clinical knowledge with recent discoveries of gene mutations responsible for about 30% of EDs. The aim of this review was to update the clinical classification of EDs with recent molecular (64 genes and 3 chromosome regions) and clinical data, mainly of EDs of the A group (N = 186), in order to contribute information for the evaluation of the ED definition proposed by Freire-Maia. Our conclusion is that the combination of both procedures-clinical and molecular-only brings advantages for a deeper knowledge of EDs. First, it allows a rapid diagnosis that may become even more precise whenever DNA exams are available. Secondly, the comprehension of the biological mechanisms that cause EDs is needed for the design of efficient prevention and treatment approaches.

X-linked hypohidrotic ectodermal dysplasia mutations in Brazilian families.

X-linked hypohidrotic ectodermal dysplasia (XLHED) is characterized by severe hypohidrosis, hypotrichosis, and hypodontia. The gene responsible for this pleiotropic syndrome (ED1) consists of 12 exons, 8 of them coding for a transmembrane protein (ectodysplasin-A; EDA-A) involved in the developmental process of epithelial-mesenchymal interaction. ED1 mutations that cause alterations in this protein lead to the XLHED phenotype. The major objective of the present study was to detect ED1 mutations in four Brazilian families with the XLHED phenotype and to compare them to the more than 60 different mutations already reported. DNA of the EDA-A coding exons was amplified by PCR, and single strand conformation analysis (SSCA) of the electrophoretic bands was carried out in polyacrylamide gel stained with silver nitrate. Two of these four families showed altered DNA band patterns. Subsequent DNA sequencing of the two mutated exons showed: (1) a 36 nucleotide deletion at exon 5 responsible for the loss of four Gly-X-Y repeats of the collagen subdomain of EDA-A; (2) a guanine deletion at exon 6 (966 or 967 sites) that alters EDA-A after amino acid 241 and leads to a premature ending at amino acid 279. This mutation at exon 6 seems not to have been reported previously and determines a truncated EDA-A without a part of its extracellular domain that contains the whole TNF homologue subdomain. These two DNA mutations are compatible with the XLHED phenotype. In the other two families the PCR-SSCA methodology was unable to detect any mutation responsible for the XLHED phenotype.