Ectodermal dysplasias

Abstract

Ectodermal dysplasias are a large group of heritable conditions characterized by congenital defects of one or more ectodermal structures and their appendages: hair (hypotrichosis, partial, or total alopecia), nails (dystrophic, hypertrophic, abnormally keratinized), teeth (enamel defect or absent), and sweat glands (hypoplastic or aplastic). The ectodermal dysplasias, as a rule, are not pure "one-layer diseases." Mesodermal and, rarely, endodermal dysplasias coexist. Embryogenesis exhibits distinct tissue organizational fields and specific interactions among the germ layers that may lead to a wide range of ectodermal dysplasias when genes important for development are mutated or otherwise altered in expression. Of the approximately 200 different ectodermal dysplasias, about 30 have been studied at the molecular level with identification of the causative gene. Freire-Maia and Pinheiro used the clinical aspects for their classification, and Priolo integrated molecular genetic and clinical aspects for her scheme. Those two more historical classification schemes have the difficulty that, when applied strictly, several additional groups of diseases should be integrated within the term "ectodermal dysplasias," e.g. keratodermas with skin or hair alterations or the ichthyoses with associated features. Such consequent classification would lead to an endless list of diseases and would be useless for the practical work. Recent evidence implicates a genetic defect in different pathways orchestrating ectodermal organogenesis. Modern molecular genetics will increasingly elucidate the basic defects of the different syndromes and yield more insight into the regulatory mechanisms of embryology. In this way, a reclassification of ectodermal dysplasias will be possible according to the function of their involved mutated genes. Lamartine recently proposed a helpful classification according to the functions of the genes discovered in different types of ectodermal dysplasias. Accordingly, the present overview categorizes the various ectodermal dysplasias into four major functional subgroups: cell-cell communication and signaling, adhesion, transcription regulation, and development.

Adult mice lacking the p53/p63 target gene Perp are not predisposed to spontaneous tumorigenesis but display features of ectodermal dysplasia syndromes

“…7 The enhanced susceptibility of PerpÀ/À mice to infection also recalls human ectodermal dysplasias, in which patients may develop chronic infections in the ear, nose, and throat. 8 Although rampant infection was a clear cause of death in this subset of PerpÀ/À mice, the source of lethality in animals that did not succumb to infection remains to be determined. No obvious histological abnormalities were identified in other tissues, but we cannot exclude the possibility that subtle functional defects are present in other Perp-expressing tissues such as the heart.…”

“…7 Keratoderma is also a feature of many ectodermal dysplasia syndromes. 8 Many of the mice with features of palmoplantar keratoderma also exhibited inflammation on the soles of the feet -a condition known as pododermatitis (25% of all mice, 36% of those with keratoderma). We did not observe these lesions in age-and background-matched mice, indicating that they are due specifically to Perp loss.…”

“…Finally, affected structures may also include those that rely on epithelialmesenchymal signaling for development, such as the palate or limbs. 1,8 Ectodermal dysplasias fall within the larger class of ectodermal dysplasia syndromes, which include diseases that have certain symptoms in common with ectodermal dysplasia, but are linked to mutations affecting differentiation rather than development. To date, almost 200 ectodermal dysplasia syndromes have been identified, but only a limited number have been linked to mutation of a particular gene.…”

“…To date, almost 200 ectodermal dysplasia syndromes have been identified, but only a limited number have been linked to mutation of a particular gene. Of those syndromes where a causative mutation has been found, mutations in both p63 as well as various desmosomal adhesion proteins have been identified, 8 suggesting the interesting possibility that Perp, as a desmosomal protein and a target of p63, may be mutated in human ectodermal dysplasia syndromes of unknown etiology. Indeed, the characteristics of PerpÀ/À mice resemble those of human ectodermal dysplasia syndromes: keratoderma, especially in the soles of the feet, aberrant nail development, hair abnormalities, dermatitis, and a predisposition to infection, are symptoms typical of these diseases.…”

“…Distinct mutation profiles in p63 have been identified in different ectodermal dysplasia syndromes with overlapping but not identical symptoms, suggesting that subtle alterations in the p63 protein can affect its activity in diverse ways. 8 For example, mutations in the DNA binding domain are most commonly found in EEC syndrome, which affects many ectoderm derivatives and limb development, while mutations in the sterile alpha motif (SAM) domain are associated with AEC/Hay-Wells syndrome, in which patients generally develop many abnormalities in the epithelia but have minimally affected limb formation. A better understanding of specific genes downstream of p63 may ultimately help explain the varying effects of different mutations in this critical transcription factor, by identifying genes that are important for the development and maintenance of different ectoderm-derived tissues.…”