Androgen Insensitivity, Partial

A number sign (#) is used with this entry because partial androgen insensitivity (PAIS) is caused by mutation in the androgen receptor gene (AR; 313700) on chromosome Xq12.

Description

Individuals with androgen insensitivity have a 46,XY karyotype and testes that produce age-appropriate androgen levels but have undermasculinized external genitalia due to defects in androgen action. The phenotype in PAIS varies depending on residual androgen receptor function, ranging from severe undermasculinization presenting as female-like external genitalia to male-appearing genitalia. The typical presentation comprises micropenis, severe hypospadias, and bifid scrotum with or without cryptorchidism (summary by Mongan et al., 2015).

Clinical Features

Reifenstein (1946) reported a family in which 9 of 10 male members over 2 generations exhibited abnormally high follicle-stimulating hormone secretion, hypospadias, sterility, gynecomastia, small testes, absent beard, height of 65 +/- inches, normal sized phallus, normal 17-ketosteroid excretion, late puberty, and normal libido. The syndrome appeared to be transmitted by females. In an article by Nelson and Heller (1947), Reifenstein commented further on this Syrian family.

Peters et al. (1955) described gynecomastia, inguinal testes, and slight hypogonadal traits in 2 half brothers (sons of the same mother) and in a cousin, the son of the mother's sister. One affected male had intercourse and ejaculation.

Boczkowski and Teter (1965) described 3 cases of incomplete testicular feminization among the children of 2 sisters.

Wilson et al. (1974) studied a family with 11 affected males. The phenotype in these varied from minimal changes (microphallus and bifid scrotum) in 2, to almost complete male pseudohermaphroditism (perineoscrotal hypospadias, absent vas deferens and vaginal orifice) in 1. On the basis of this and another reported pedigree, they suggested that the affected members in the kindred reported by Gilbert-Dreyfus et al. (1957), Lubs et al. (1959) and Rosewater et al. (1965) had the same condition as that reported by Reifenstein (1946). Wilson et al. (1974) chose to refer to the condition as type 1 familial incomplete male pseudohermaphroditism (type 2 is autosomal recessive; 264600). From studies of blood levels of testosterone and luteinizing hormone and the rate of production of estrogen and androgen, they concluded that the underlying defect is in androgen action not androgen synthesis. Leonard et al. (1975) described a kindred with 8 affected persons in 4 sibships of 3 generations.

According to Wilson (1976), Morris (1953) first described incomplete testicular feminization and concluded that the complete (AIS; 300068) and incomplete forms never occur in the same family. The incomplete syndrome resembles the complete form in respect to female phenotype, bilateral testes and 46,XY karyotype, but differs by clitoral enlargement from birth and virilization at puberty. The abnormality of the external genitalia is characteristic; fusion of the labioscrotal folds occurs for about half of the dorsal portion. Although the degree of masculinization of the external genitalia is variable, most patients are raised as females. In the family described by Lubs et al. (1959), some spermatogenesis was found. There is partial responsiveness to androgen (Winterborn et al., 1970) in this form of the disorder.

Amrhein et al. (1977) studied 8 patients and concluded that 'partial androgen insensitivity syndrome' is an appropriate designation. Studies of binding of dihydrotestosterone by fibroblasts showed 2 genetic variants (as in the complete androgen insensitivity syndrome, or testicular feminization). One patient had partial deficiency of cytoplasmic DHT-binding; 4 others had normal binding. Keenan et al. (1977) also found 2 male sibs with normal binding. Aiman et al. (1979) presented evidence that androgen insensitivity can cause severe oligospermia or azoospermia. Plasma concentrations and production rates of testosterone were elevated. Specific high-affinity dihydrotestosterone binding capacity of cultured genital skin fibroblasts was low and in the same range as that of incomplete testicular feminization or Reifenstein syndrome.

Griffin and Wilson (1980) gave a definitive review of androgen resistance. They pointed out that receptor deficiency may express itself simply as infertile men. In a family study of the Reifenstein syndrome, some men were noted to be infertile but otherwise phenotypically normal. They had the same degree of androgen resistance, as manifested by the plasma levels of testosterone and luteinizing hormone, and the same degree of receptor deficiency in cultured skin fibroblasts as did the more severely affected relatives (Wilson et al., 1974).

Aiman and Griffin (1981) found that 8 of 18 phenotypically normal men with idiopathic azoospermia had an androgen receptor Bmax of less than 12 fmol DHT per mg protein. All cases of azoospermia of known cause (Klinefelter syndrome, vasectomy, undescended testes, etc.) had DHT Bmax values in excess of 12 fmol. The mean value for the product of plasma testosterone and plasma luteinizing hormone was 86.7 in patients with binding less than 12 fmol/mg and 195.2 in the subjects with binding more than 12, but the variance was so great that this index alone could not be used for suspecting the diagnosis. Aiman and Griffin (1982) ascertained the frequency of this situation by studying 28 unrelated phenotypically normal men with idiopathic azoospermia or oligospermia. They concluded that 40% or more of these cases may have androgen resistance as the cause and that there may be no functional defect in the pituitary-testicular axis as reflected by abnormal serum concentrations of testosterone or LH.

Boehmer et al. (2001) analyzed the genotype-phenotype relationship in AIS and the occurrence of possible causes of phenotypic variation in families with multiple affected cases. Of 49 index cases with possible AIS identified, 59% had affected relatives. A total of 17 families were studied, 7 families with CAIS (18 patients), 9 families with PAIS (24 patients), and 1 family with female prepubertal phenotypes (2 patients). No phenotypic variation was observed in families with CAIS. However, phenotypic variation was observed in 1 of 3 families with PAIS resulting in different sex of rearing and differences in requirement of reconstructive surgery. Intrafamilial phenotypic variation was observed for mutations R846H (313700.0040) and M771I (313700.0039). Patients with a functional complete defective AR had some pubic hair, Tanner stage P2, and vestigial wolffian duct derivatives despite absence of AR expression. Vaginal length was functional in most but not all CAIS patients. Boehmer et al. (2001) concluded that while phenotypic variation was absent in families with CAIS, distinct phenotypic variation was observed relatively frequent in families with partial AIS.

Molecular Genetics

In 2 unrelated families, Klocker et al. (1992) demonstrated that Reifenstein syndrome was due to a mutation in the AR gene (313700.0011). The 5 patients in the 2 families presented with perineoscrotal hypospadias and undescended testes. After puberty they showed small testes, no palpable prostate, micropenis, azoospermia, and gynecomastia.

In brothers with penoscrotal hypospadias who developed infiltrating ductal cancers of the breast at ages 75 and 55 years, respectively, Wooster et al. (1992) identified a mutation in the AR gene (313700.0016).

History

Miller (1961) considered 'feminizing labial testes' of the type described by Lubs et al. (1959) to be a separate form of male pseudohermaphroditism. However, Wilson et al. (1984) described well-studied cases that indicated that the Lubs syndrome (Lubs et al., 1959), like classic testicular feminization, is due to mutation in the androgen receptor. The patients were first cousins; their mothers were sisters.

In the family described by Rosewater et al. (1965), gynecomastia with hypogonadism occurred in 4 males of 3 sibships in 2 generations connected through females in a pattern consistent with X-linked or autosomal dominant inheritance. None of those affected had hypospadias. Wilson et al. (1974) suggested that the disorder described by Rosewater et al. (1965) was the mildest expression of what they termed incomplete male pseudohermaphroditism, type 1. On the other hand, Gwinup (1974) rebutted by pointing out that this interpretation is made unlikely by the low levels of luteinizing hormones, by decreased Leydig cells on testicular biopsy, and by rapid masculinization when testosterone was administered. Follow-up showed maintenance of masculinization with injections of 200 mg testosterone cypionate monthly.

In the family studied by Bowen et al. (1965) and later by Wilson et al. (1974), Ott et al. (1975) excluded close linkage with Xg and with 3 autosomal loci, P, K and MNS.