46,xy Sex Reversal 3

A number sign (#) is used with this entry because this form of 46,XY sex reversal is caused by heterozygous mutation in the NR5A1 gene (184757) on chromosome 9q33.

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

Nomenclature

As a result of discussions at the International Consensus Conference on Intersex, Lee et al. (2006) proposed the term 'disorder(s) of sex development' (DSD) to replace the previously used terms 'pseudohermaphroditism,' 'intersex,' and 'sex reversal.'

Clinical Features

Achermann et al. (1999) described a phenotypically female patient who presented with primary adrenal failure in the first 2 weeks of life. Her karyotype was XY, and a presumptive diagnosis of congenital lipoid adrenal hyperplasia (201710) was made. At age 10 years, her hormonal status was examined further before the induction of puberty. Pituitary gonadotropins responded to gonadotropin-releasing hormone (152760) stimulation, but there was no testosterone response after stimulation with human chorionic gonadotropin (see 118860). Notably, normal mullerian structures were found at laparotomy, and streak-like gonads containing poorly differentiated tubules and connective tissue were removed. The patient had complete gonadal dysgenesis, including normal female external genitalia and retention of the uterus. This contrasts with disorders of steroid biosynthesis, in which no uterus is present. Transdermal 17-beta-estradiol gel induced normal breast development. Her uterus grew and regular menstruation occurred after the introduction of cyclical progestogen.

Inheritance

Blecher and Erickson (2007) reviewed knowledge of sexual development and proposed a new paradigm, namely, that sexual dimorphism precedes gonadal development, in a so-called 'pregonadal stage.' Noting that absence of testicular hormones does not produce a normal female phenotype, they stated that contrary to the classic paradigm, female development does not occur by default. Blecher and Erickson (2007) suggested that proximate gonad-determining genes are probably on the autosomes, with indirect and complex interactions between these and the primary factors on sex chromosomes.

Molecular Genetics

In a patient with 46,XY complete gonadal dysgenesis, Achermann et al. (1999) identified heterozygosity for a 2-bp mutation in exon 3 of the SF1 (NR5A1) gene (184757.0001), which encodes part of the DNA-binding domain. The finding provided evidence that SF1 regulates the regression of mullerian structures in humans, either through direct actions on AMH (600957) or secondary to an abnormality of Sertoli cell development or function.

Lin et al. (2006) studied the prevalence of DAX1 (300473) and SF1 mutations in 117 children and adults with primary adrenal failure of unknown etiology (i.e., not caused by congenital adrenal hyperplasia, adrenoleukodystrophy, or autoimmune disease). SF1 mutations causing adrenal failure were found in only 2 patients with 46,XY gonadal dysgenesis. Lin et al. (2006) concluded that SF1 mutations causing adrenal failure in humans are rare and are more likely to be associated with significant underandrogenization and gonadal dysfunction in 46,XY individuals.

Lin et al. (2007) analyzed the NR5A1 gene in 30 patients with 46,XY disorders of sex development and identified heterozygous missense mutations in 4 patients (184757.0007-184757.0010, respectively). Three of the mutations showed loss of function in adrenal, Leydig, and Sertoli cells lines, but an L437Q ligand-binding domain mutant identified in 1 of the patients (184757.0010) retained partial activity in these cell systems, consistent with the milder clinical phenotype of that patient (hypospadias, male gender assignment).

Kohler et al. (2008) analyzed the NR5A1 gene in 27 German 46,XY patients with severe underandrogenization without adrenal insufficiency and identified heterozygous mutations in 5 (18.5%) patients; the authors concluded that NR5A1 mutations are a relatively frequent cause of 46,XY disorders of sex development.

Lourenco et al. (2009) sequenced the NR5A1 gene in 4 families with histories of both 46,XY gonadal dysgenesis and 46,XX primary ovarian insufficiency and in 25 subjects with sporadic ovarian insufficiency. They identified mutations in patients with premature ovarian failure (POF7; 612964) as well as in patients with 46,XY disorders (see 184757.0011-184757.0016). None of the affected subjects had clinical signs of adrenal insufficiency.

By microarray analysis in a mother with premature ovarian failure and her 46,XY son with partial gonadal dysgenesis, Harrison et al. (2013) identified heterozygosity for a 0.232-Mb microdeletion of chromosome band 9q33.3, involving NR5A1 and 4 other genes. There was no family history of disorders of sex development or POF, and the mutation appeared to have arisen de novo in the mother. The authors stated that this was the first NR5A1 microdeletion transmitted in a pedigree with both SRXY and POF, and the first report of an NR5A1 copy number variation (CNV) associated with POF. To assess the frequency of NR5A1 CNVs in DSD states, Harrison et al. (2013) used MPLA to screen 11 patients with 46,XY DSD phenotypes, 21 patients with proximal hypospadias with or without cryptorchidism, and 35 patients with POF, but did not identify any more NR5A1 CNVs.

Animal Model

To examine the role of the Ftzf1 in intact mice, Luo et al. (1994) used targeted disruption of the Ftzf1 gene. Despite normal survival in utero, all Ftzf1-null animals died by postnatal day 8; these animals lacked adrenal glands and gonads and were severely deficient in corticosterone, supporting adrenocortical insufficiency as the probable cause of death. Male and female Ftzf1-null mice had female internal genitalia, despite complete gonadal agenesis. These studies established that the Ftzf1 gene is essential for sexual differentiation and formation of the primary steroidogenic tissues. Normal male sex differentiation requires that Sertoli cells in the embryonic testes produce mullerian-inhibiting substance (AMH; 600957), a TGF-beta-like hormone that causes mullerian duct regression.