Pseudovaginal Perineoscrotal Hypospadias

A number sign (#) is used with this entry because pseudovaginal perineoscrotal hypospadias (PPSH) is caused by homozygous or compound heterozygous mutation in the steroid 5-alpha-reductase-2 gene (SRD5A2; 607306) on chromosome 2p23.

Description

Pseudovaginal perineoscrotal hypospadias is a form of male pseudohermaphroditism in which 46,XY males show ambiguous genitalia at birth, including perineal hypospadias and a blind perineal pouch, and develop masculinization at puberty. The name of the disorder stems from the finding of a blind-ending perineal opening resembling a vagina and a severely hypospadiac penis with the urethra opening onto the perineum.

Clinical Features

De Vaal (1955) reported 3 brothers who were thought for a time to be girls. The parents and grandparents on one side were first cousins, and the great-grandparents were also related. Simpson et al. (1971) described a family with 3 affected brothers whose parents were double first cousins. Each of the affected sibs had an XY karyotype and ambiguous genitalia, leading to rearing as females. No breast development or menstruation occurred at puberty, and instead typical masculinization was observed.

Opitz et al. (1972) concluded that the consanguineous family reported by Philip and Trolle (1965) had pseudovaginal perineoscrotal hypoplasia.

PPSH can be difficult to distinguish from the incomplete testicular feminization syndrome (PAIS; 312300), also known as Reifenstein syndrome, especially in the young child. The distinction is obviously important since PPSH is a male-limited autosomal recessive with a recurrence risk of 1 in 8, whereas PAIS is X-linked recessive as is the complete syndrome (AIS; 300068). Wilson et al. (1974) chose to refer to PPSH as type 2 familial incomplete male pseudohermaphroditism, type 1 being Reifenstein syndrome. PPSH resembles the most severe form of type 1 incomplete male pseudohermaphroditism, but differs from it by the lack of breasts and by its autosomal inheritance. Dihydrotestosterone (DHT) formation is defective in this condition. Testosterone and estrogen levels are normal, hence the lack of gynecomastia. Other evidence as well suggests that DHT is important to external virilization.

In a village in the Dominican Republic, Imperato-McGinley et al. (1974) studied 12 families with 22 male pseudohermaphrodites. The affected males were born with ambiguous genitalia and masculinized at puberty without breast development. The testes were normal histologically. The patients had no mullerian structures, complete wolffian differentiation, small phallus, bifid scrotum, urogenital sinus with perineal hypospadias and blind vaginal pouch. At puberty, they showed male habitus with excellent muscular development, voice change, enlargement of phallus and production of semen, but small prostate and scanty beard. Plasma testosterone was normal; plasma 5-alpha-dihydrotestosterone was low. An abnormally small amount of radioactive testosterone was converted to dihydrotestosterone. One woman studied showed the same biochemical defect.

The disorder has been found in blacks, whites, American Indians, and Latin Americans, as well as in families from Malta, Jordan, and Pakistan. Imperato-McGinley et al. (1991) described a cluster of male pseudohermaphrodites in the Simbari Anga linguistic group in the Eastern Highlands of Papua New Guinea. Their studies revealed a phenotypic and biochemical profile similar to that in patients studied in the Dominican Republic, except for a greater abundance of facial and body hair. DHT is responsible for masculinization of the external genitalia of the fetus and for masculinization at puberty. The virilization at puberty in PPSH may be related to the facts that the reductase is not completely absent and that low levels of DHT are found in plasma.

Biochemical Features

Leshin et al. (1978) suggested the existence of two forms of 5-alpha-reductase deficiency. In one form (represented by a family in Dallas and by the Dominican kindred), an abnormal Km for substrate and low activity suggested a structural alteration in the enzyme. In a second form, represented by a Los Angeles family, activity in the biopsy specimen was not detectable, although cultured fibroblasts showed normal activity with normal Km for testosterone. The authors postulated either a structural mutation that was corrected or compensated for in tissue culture or a regulatory mutant. These persons have plasma testosterone levels in the high normal range. Although raised as girls, most change to a male-gender identity at puberty. This indicates that the effects of testosterone on the brain override sociocultural factors. Hydroxylation at the fifth position, converting testosterone to dihydrotestosterone, seems like an insignificant change; however, functionally it produces a marked change because in steric configuration the molecule becomes much flatter and fits its receptor in a way that testosterone cannot (Wilson, 1981). Wilson (1981) studied 14 families; in 11, the enzyme was virtually undetectable. In the other 3, a qualitative abnormality of the enzyme was found.

Inheritance

Chavez et al. (2000) performed DNA analyses in 2 unrelated subjects with SRD5A enzyme deficiency and found differences in the mode of transmission for the disease. Their data showed that in both families the fathers were carriers for a glu197-to-asp mutation (E197D; 607306.0014), whereas the mothers were carriers for a pro212-to-arg mutation (P212R; 607306.0013). While patient 1 was identified as a compound heterozygote for both alterations, patient 2 was found to be homozygous for the paternal mutation. The reduction to homozygosity for the E197D mutation, as confirmed by restriction analysis, supported this view. The authors concluded that their study gives evidence of the first case of SRD5A deficiency resulting from uniparental disomy and reveals an alternate mechanism whereby this enzymatic disorder can be derived from a single parent.

Pathogenesis

Thigpen et al. (1993) provided evidence that the 5-alpha-reductase type 1 enzyme is responsible for the virilization in type 2-deficient subjects during puberty.

Clinical Management

Price et al. (1984) presented evidence that high dose androgen therapy may improve virilization, self-image, and sexual performance in patients with alpha-reductase deficiency who have male-gender behavior and in those patients with Reifenstein syndrome (312100) who have normal amounts of a qualitatively abnormal androgen receptor.

A number of male pseudohermaphrodites have married and expressed a desire to father a child. However, a deficiency in dihydrotestosterone production not only impairs differentiation of male external genitalia but also affects the development and secretory function of the prostate and seminal vesicles. Consequently, affected adults have a rudimentary prostate and underdeveloped seminal vesicles, resulting in a highly viscous semen and an extremely low volume of ejaculate, although sperm counts may be normal. Katz et al. (1997) described the use of intrauterine insemination with sperm from a man with this disorder and a history of infertility. The first pregnancy gave rise to a normal son; the second pregnancy produced fraternal twins. All 3 children were heterozygous for the father's C-to-T mutation in exon 5 of the SRD5A2 gene.

Molecular Genetics

In 2 related men with PPSH from the Simbari Anga linguistic group in the Highlands of Papua New Guinea, Andersson et al. (1991) found deletion of most of the SRD5A2 gene (607306.0001).

In 3 Japanese patients with micropenis, Sasaki et al. (2003) identified homozygous or compound heterozygous mutations in the SRD5A2 gene (see, e.g., 607306.0015-607306.0016).

Exclusion Studies

Jenkins et al. (1992) showed that the enzyme encoded by SRD5A1 (184753) on chromosome 5 is not the site of the defect in classic PPSH; in 16 patients with deficiency of 5-alpha-reductase, no SRD5A1 gene rearrangements were detected; in 5 of these subjects, sequence analysis revealed no mutation in the coding regions of the SRD5A1 gene; linkage studies with a RFLP showed recombination and heterozygosity, which would not occur in an autosomal recessive disease. These findings provided evidence for the existence of 2 steroid 5-alpha-reductase enzymes (see SRD5A2; 607306).