Hypospadias 1, X-Linked

A number sign (#) is used with this entry because of evidence that X-linked isolated hypospadias-1 (HYSP1) is caused by mutation in the androgen receptor gene (AR; 313700) on chromosome Xq12.

Description

Hypospadias is a common congenital malformation of the penis, affecting approximately 1 in 750 births in Europe. Due to developmental arrest of urethral fusion, the urethral opening is displaced along the ventral side of the penis. The opening can be located glanular, penile, or even more posterior in the scrotum or perineum. Although most children with this condition undergo surgery in their second year of life, serious medical, social, and sexual problems may still exist later in life (summary by van der Zanden et al., 2011). Hypospadias is a feature of several syndromic disorders, including the androgen insensitivity syndrome (300068) and Opitz syndrome (300000).

Genetic Heterogeneity of Hypospadias

See also HYSP2 (300758), caused by mutation in the MAMLD1 gene (300120) on chromosome Xq28; HYSP3 (146450), a familial form which has been mapped to chromosome 7q32.2-q36.1; and HYSP4 (300856), a susceptibility locus mapped to chromosome Xp11.22 and associated with variation in the DGKK gene (300837).

Clinical Features

Batch et al. (1993) reported 2 brothers, born to nonconsanguineous parents, who presented at birth with perineal hypospadias. Both brothers had a 46,XY karyotype, and endocrine investigations were normal in both. Both showed a qualitative defect in androgen binding, suggesting that the androgen receptor was defective.

Inheritance

Quoting a frequency of hypospadias of about 3 per 1,000 male births, Fredell et al. (2002) performed a complex segregation analysis of 2,005 pedigrees in Sweden. The probands were ascertained through the departments of paediatric surgery, plastic surgery, and urology, where boys with hypospadias underwent surgery. In 7% of the ascertained families, 1 or more additional cases of hypospadias were present. Complex segregation analysis showed a heritability of 0.99 and evidence for multifactorial inheritance. The results suggested that hypospadias may be due to monogenic effects in a small proportion of families, but that there is a multifactorial cause for most cases.

Population Genetics

In a case-control study in Alsace, France, Stoll et al. (1990) found 176 cases of hypospadias out of 60,847 male infants, giving a prevalence at birth of 2.89 per 1,000 male newborns. Other malformations were present in about 15% of infants with hypospadias; of those with other malformations, renal and urinary tract malformations were present in 37%. The recurrence risk for brothers was 17%, and the heritability coefficient was calculated to be 56.9%.

Biochemical Features

Dolk (1998) commented on the rise of the prevalence of hypospadias and the concern that 'endocrine-disrupting chemicals' in the environment may be contributing to the increase.

Molecular Genetics

In 2 brothers with perineal hypospadias, Batch et al. (1993) found a qualitative androgen binding defect and a point mutation in the AR gene (313700.0020); they suggested that familial hypospadias is part of the phenotypic spectrum of partial androgen sensitivity.

Sutherland et al. (1996) analyzed penile tissue from several locations in 40 patients who underwent reconstructive surgery for various degrees of hypospadias and found a C-to-T transition in exon 2 of the androgen receptor gene (pro546-to-ser) in only 1 patient (313700.0037). In the child with the mutation, the hypospadias was at the distal penile shaft and not associated with other genitourinary anomalies. Of the 26 patients with adequate information, none had an affected father or brother. Allera et al. (1995) also observed an AR mutation in exon 2 in a case of perineal isolated hypospadias and likewise concluded that AR mutations are rarely the cause of isolated hypospadias.