DEFINITIVE EVIDENCE FOR AN AUTOSOMAL RECESSIVE FORM OF HYPOHIDROTIC ECTODERMAL DYSPLASIA CLINICALLY INDISTINGUISHABLE FROM THE MORE COMMON X-LINKED DISORDER

A crucial issue in genetic counseling is the recognition of nonallelic genetic heterogeneity. Hypohidrotic (anhidrotic) ectodermal dysplasia (HED), a genetic disorder characterized by defective development of h air, teeth, and eccrine sweat glands, is usually inherited as an X-lin ked recessive trait mapped to the X-linked ectodermal dysplasia locus, EDA, at Xq12-q13.1. The existence of an autosomal recessive form of t he disorder had been proposed but subsequently had been challenged by the hypothesis that the phenotype of severely affected daughters born to unaffected mothers in these rare families may be due to marked skew ing of X inactivation. Five families with possible autosomal recessive HED have been identified, on the basis of the presence of severely af fected females and unaffected parents in single sibships and in highly consanguineous families with multiple affected family members. The di sorder was excluded from the EDA locus by the lack of its cosegregatio n with polymorphic markers flanking the EDA locus in three of five fam ilies. No mutations of the EDA gene were detected by SSCP analysis in the two families not excluded by haplotype analysis. The appearance of affected males and females in autosomal recessive HED was clinically indistinguishable from that seen in males with X-linked HED. The findi ngs of equally affected males and females in single sibships, as well as the presence of consanguinity, support an autosomal recessive mode of inheritance. The fact that phenotypically identical types of HED ca n be caused by mutations at both X-linked and autosomal loci is analog ous to the situation in the mouse, where indistinguishable phenotypes are produced by mutations at both X-linked (Tabby) and autosomal loci (crinkled and downless).