SEX REVERSAL, XY, WITH OR WITHOUT ADRENAL FAILURE
46,XY GONADAL DYSGENESIS, COMPLETE OR PARTIAL, WITH OR WITHOUT ADRENAL FAILURE
46,XY SEX REVERSAL, PARTIAL OR COMPLETE, NR5A1-RELATED
DISORDER OF SEX DEVELOPMENT, 46,XY
SRXY3
A disorder of sex development (DSD) is a 'congenital condition in which development of chromosomal, gonadal, or anatomic sex is atypical.' 46,XY DSD is a disorder of gonadal (testicular) development, which may be complete or partial (Lee et ... A disorder of sex development (DSD) is a 'congenital condition in which development of chromosomal, gonadal, or anatomic sex is atypical.' 46,XY DSD is a disorder of gonadal (testicular) development, which may be complete or partial (Lee et al., 2006). The complete form includes streak gonads, normal mullerian structures, and normal female external genitalia. The partial form includes ambiguous external genitalia and partial development of mullerian and wolffian structures (Berkovitz et al., 1991).
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. ... 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.
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 ... 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.