46,xy Sex Reversal 6

A number sign (#) is used with this entry because of evidence that this form of 46,XY sex reversal is caused by heterozygous mutation in the MAP3K1 gene (600982) on chromosome 5q11.

For a discussion of genetic heterogeneity of 46,XY sex reversal, see SRXY1 (400044).

Clinical Features

Sternberg et al. (1968) reported 3 cases of 46,XY females, each in a different sibship of a family connected through normal females (proposita, maternal cousin, and maternal aunt).

Espiner et al. (1970) studied a New Zealand kindred of European descent in which 5 phenotypic females from 3 sibships had a normal XY karyotype in all stem lines examined and pure gonadal dysgenesis, with bilateral streak gonads verified at laparotomy. The proband presented at 21 years of age because she was still growing, and had grown 1.9 cm in height over the past 6 months. She had undergone pubertal changes, including some breast development and growth of pubic and axillary hair, between age 14 and 16 years; menarche occurred at age 15 years, with 4 apparently normal menstrual periods, which then ceased. At age 21 years, her physical appearance was eunuchoidal, with sparse pubic and axillary hair; both phenotype and gender role were entirely feminine, and she had normal female external genitalia and normal uterine cervix by palpation. The remainder of the examination was normal, with no neck webbing, cubitus valgus, or other congenital anomaly. Laparotomy revealed a hypoplastic uterus from which apparently normal fallopian tubes extended laterally, with gonadal streaks seen on the posterior aspect of the broad ligaments. Microscopic examination of the fallopian tubes was normal, but multiple sections of the gonadal streaks showed fibrous connective tissue arranged in whorls resembling ovarian stroma. Some vestigial epithelial elements, assumed to be rete tubules, were also seen, but no germ cells could be identified and Leydig cells were sparse. The proband had 2 similarly affected older sisters, who were also evaluated and found to be 46,XY with streak gonads at laparotomy. In addition, she had 2 apparently unaffected older sisters who had borne children: buccal smears from a phenotypic daughter of each of them revealed an XY karyotype, and laparotomy at puberty showed streak gonads in both cases. Espiner et al. (1970) stated that these familial cases, with occurrence over 2 generations, could not be due to loss of male determinants on the Y chromosome (see 400044), but rather, like the cases reported by Sternberg et al. (1968), were consistent with the effects of a single gene located on an autosome or on the X chromosome.

Espiner et al. (1970) emphasized that the affected persons were unusually tall for females. The height of patients with XY gonadal dysgenesis (unusually great for females) is probably explained by androgen production in the streak gonad (Rose et al., 1974). Clitoromegaly is present in some cases.

Le Caignec et al. (2003) described 46,XY gonadal dysgenesis in a large French kindred with various disorders of sexual development, ranging from complete female phenotype without ambiguity of the external genitalia (5 cases) to men with isolated penile or perineal hypospadias (4 cases), including 2 cases with moderate virilization and 1 case with ambiguity of the external genitalia. Histologic examination in 7 subjects yielded findings suggestive of complete gonadal dysgenesis in 1 patient, partial gonadal dysgenesis in 3 patients, and mixed gonadal dysgenesis in 3 patients. Four patients developed gonadal tumors: 2 had gonadoblastoma, 2 had dysgerminoma, and 1 had an immature teratoma, i.e., a dysgerminoma with some areas of gonadoblastoma. None of the affected subjects had other congenital anomalies or dysmorphic features. Previously reported families had implied an X-linked mode of inheritance because of the apparent absence of male-to-male transmission; however, a sex-limited autosomal dominant mode of inheritance affecting only XY individuals could not be ruled out. Analysis of the pedigree reported by Le Caignec et al. (2003) indicated an autosomal dominant mode of inheritance because of male-to-male transmission. Le Caignec et al. (2003) concluded that this family supports the involvement of at least 1 autosomal gene in nonsyndromic 46,XY gonadal dysgenesis.

Mapping

Jawaheer et al. (2003) performed a linkage study in the French family with 46,XY gonadal dysgenesis reported by Le Caignec et al. (2003) and demonstrated by multipoint parametric analysis a lod score of 4.47, assuming sex-limited autosomal dominant inheritance with a penetrance of 0.6, for the pericentromeric region of chromosome 5 at approximately 65 cM (57 Mb) from the end of chromosome 5p. The obligatory carrier females in the kindred showed no abnormality. Jawaheer et al. (2003) concluded that the pattern of inheritance was probably more complicated than simple monogenic diseases, because 3 individuals shared the core haplotype, but did not have obvious clinical abnormalities. They proposed that in 46,XY carriers the mutant gene is highly penetrant but can be modified by a second locus. Among unaffected individuals, the associated phenotypes range from mild hypospadias without impairment of fertility to partial, or even pure, gonadal dysgenesis. In this family, a male affected with hypospadias and chordee had 2 offspring: 1 with perineal hypospadias and chordee and the other with partial gonadal dysgenesis.

Pearlman et al. (2010) performed linkage analysis in the New Zealand family with 46,XY gonadal dysgenesis, originally reported by Espiner et al. (1970), and obtained a maximal lod score of 1.14 at D5S2068. The combined lod score for this family and the French family with 46,XY gonadal dysgenesis, originally reported by Le Caignec et al. (2003), was 4.62 at D5S398; the multipoint lod score was 6.21. Recombination analysis defined a 5-Mb critical interval between D5S1969 and D5S2028.

Molecular Genetics

In the French family with 46,XY gonadal dysgenesis mapping to chromosome 5q, originally reported by Le Caignec et al. (2003), Pearlman et al. (2010) analyzed the MAP3K1 gene and identified a heterozygous splice site mutation that segregated with disease in the family (600982.0001). Sequence analysis of MAP3K1 in the New Zealand family with 46,XY gonadal dysgenesis, originally reported by Espiner et al. (1970), identified a MAP3K1 missense mutation (600982.0002). Screening of the MAP3K1 gene in 11 sporadic cases revealed 2 more missense mutations in 2 patients (600982.0003 and 600982.0004, respectively).

Granados et al. (2017) studied 7 46,XY females with complete or partial gonadal dysgenesis from 4 unrelated families and identified heterozygosity for mutations in the MAP3K1 gene in all affected individuals (see, e.g., 600982.0005 and 600982.0006). All patients underwent gonadectomy, and a premalignant change was found in 1. The authors noted that these 4 families with MAP3K1 mutations represented 28% of their patient population with a diagnosis of complete or partial gonadal dysgenesis.