Genotype–phenotype correlation in boys with X‐linked hypohidrotic ectodermal dysplasia

Abstract

X-linked hypohidrotic ectodermal dysplasia (XLHED), the most frequent form of ectodermal dysplasia, is a genetic disorder of ectoderm development characterized by malformation of multiple ectodermal structures such as skin, hair, sweat and sebaceous glands, and teeth. The disease is caused by a broad spectrum of mutations in the gene EDA. Although XLHED symptoms show inter-familial and intra-familial variability, genotype-phenotype correlation has been demonstrated with respect to sweat gland function. In this study, we investigated to which extent the EDA genotype correlates with the severity of XLHED-related skin and hair signs. Nineteen male children with XLHED (age range 3-14 years) and seven controls (aged 6-14 years) were examined by confocal microscopy of the skin, quantification of pilocarpine-induced sweating, semi-quantitative evaluation of full facial photographs with respect to XLHED-related skin issues, and phototrichogram analysis. All eight boys with known hypomorphic EDA mutations were able to produce at least some sweat and showed less severe cutaneous signs of XLHED than the anhidrotic XLHED patients (e.g., perioral and periorbital eczema or hyperpigmentation, regional hyperkeratosis, characteristic wrinkles under the eyes). As expected, individuals with XLHED had significantly less and thinner hair than healthy controls. However, there were also significant differences in hair number, diameter, and other hair characteristics between the group with hypomorphic EDA mutations and the anhidrotic patients. In summary, this study indicated a remarkable genotype-phenotype correlation of skin and hair findings in prepubescent males with XLHED.

Mutational spectrum in 101 patients with hypohidrotic ectodermal dysplasia and breakpoint mapping in independent cases of rare genomic rearrangements

“…Although HED patients often have a quite similar appearance, deviations in the degree of severity are observed. Some genotype-phenotype correlations have been evident with respect to the number and function of sweat glands, 41 cutaneous signs and certain hair findings, 25 and also to the number of teeth. 36 Nevertheless, intrafamilial differences exist, which may be because of additional genetic factors, as already reported for the variant rs3827760 of EDA1R that seems to attenuate HED-related symptoms.…”

“…23,24 Previous investigations of potential genotype-phenotype correlations revealed intra-and interfamilial variabilities, not solely explicable by the patients' mutations. 25 The single-nucleotide polymorphism (SNP) rs3827760 (c.1109T4C; p.Val370Ala) in EDA1R, a gain-of-function allele with a high frequency in the East Asian and Native American population, has been associated with increased hair thickness and shovel-shaped incisors 26,27 and was found to attenuate the severity of X-linked HED-related symptoms in a family of Asian origin. 28 The SNP rs1385699 (c.170G4A; p.Arg57Lys) in EDA2R with a high frequency in the European population (~70%), in contrast, has been associated with androgenetic alopecia.…”

The Gene Network Underlying Hypodontia

“…The number and position of missing teeth are not affected by the mutation type and site in EDA (Yin et al 2012;Jones et al 2013). However, hair number and diameter, other hair characteristics, and sweat gland function show significant differences between patients with hypomorphic EDA mutations and anhidrotic patients (Burger et al 2014).…”

Estudio clínico y molecular en un escolar con displasia ectodérmica hipohidrótica ligada al X

“…Posteriormente, se evidencian alteraciones dentales graves, en la piel, oculares, que pueden condicionar, incluso, trastornos psicosociales. 6 Los pacientes hemicigóticos afectados con DEHLX presentan la mayoría o todos los hallazgos clínicos típicos descritos. Por su parte, las portadoras heterocigotas manifiestan una forma de leve a moderada.…”

“…Igualmente, existieron diferencias significativas en el número, diámetro y otras características del pelo entre el grupo con mutaciones hipomórficas y los pacientes con anhidrosis. 6 El análisis estructural de la mutación presente en el paciente y la madre estudiada produce desestabilización de la estructura monomérica simple y puede invalidar de forma irreversible la propiedad de unión de la ectodisplasina-A. Como ya se hizo referencia, este gen presenta un amplio espectro de mutaciones y la descrita en este caso se encuentra en el dominio similiar a TNF, el cual ha sido documentado en otros estudios.…”