Hypospadias 3, Autosomal

For a phenotypic description and a discussion of genetic heterogeneity of hypospadias, see 300633.

Clinical Features

Hypospadias is a common malformation in which the urethra opens on the ventral side of the penis. It is considered a complex disorder with both genetic and environmental factors involved in the pathogenesis (summary by Thai et al., 2008).

Inheritance

Lowry and Kliman (1976) suggested, on the basis of 2 kindreds, that an autosomal dominant form may account for a small number of hypospadias cases. Cote et al. (1979) described 4 males with hypospadias of the midshaft of the penis in 3 generations, with 1 male-to-male transmission and transmission through a female. Page (1979) also suggested autosomal dominant inheritance for some cases.

An autosomal recessive form of hypospadias was suggested by the reports of Frydman et al. (1985) and Tsur et al. (1987). Frydman et al. (1985) found uncomplicated hypospadias in 8 males in a large consanguineous Bedouin family. Virilization and fertility were normal in the 1 affected person who was postpubertal. Dominantly inherited hypertelorism with diastema segregated independently in this kindred. Tsur et al. (1987) described 4 affected males in a consanguineous Muslim family in Israel.

Mapping

Thai et al. (2008) performed genomewide linkage analysis of a 3-generation family of Finnish origin in which 7 individuals had isolated hypospadias inherited in an autosomal dominant pattern. A maximum parametric lod score of 2.71 was found at marker D7S640 on chromosome 7q32.2-q36.1 (nonparametric lod score of 5.01). Haplotype analysis identified an 18.2-Mb (25-cM) region between markers D7S2519 and D7S2442. Mutation analysis excluded pathogenic mutations in the AKR1D1 (604741) and PTN (162095) genes.