46,xy Sex Reversal 2

A number sign (#) is used with this entry because of evidence that dosage-sensitive sex reversal is due to duplication of the DAX1 gene (NR0B1; 300473) on chromosome Xp21.3-p21.2.

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

Clinical Features

The existence of an X-specific gene involved in human sex determination was first postulated by German et al. (1978), on the basis of a family with an apparent X-linked mode of inheritance of 46,XY gonadal dysgenesis. A number of families with X-linked recessive (or sex-limited autosomal dominant) transmission of the disorder were reported thereafter (reviewed by Fechner et al., 1993).

Bardoni et al. (1994) studied 4 patients with 46,XY sex reversal, who were raised as girls due to their having either ambiguous or female external genitalia. Histologic examination of the internal genitalia was performed in 3 of the patients and confirmed partial gonadal dysgenesis. The authors noted that the patients exhibited a complex phenotype, including mental retardation and multiple minor malformation, but clinical details were not provided in that report.

Smyk et al. (2007) reported a 21-year-old 46,XY female who presented with primary amenorrhea, a small immature uterus, and gonadal dysgenesis without adrenal insufficiency, in whom they identified a submicroscopic 257-kb deletion with a distal breakpoint 11.3 kb upstream of the NR0B1 gene. The deletion was also present in the patient's mother, who had a history of ovarian cysts, but was not found in 1,184 controls. The authors suggested that loss of regulatory sequences may have resulted in position effect upregulation of NR0B1 expression.

Molecular Genetics

Bardoni et al. (1994) studied 8 patients with duplications at chromosome Xp21, including 4 who had 46,XY sex reversal and 4 who were 46,XY phenotypic males. Breakpoint analysis identified an approximately 20-Mb region on Xp21.2-p22.1 that was duplicated only in the 46,XY females. Further analysis involving 1 additional 46,XY sex-reversed patient with a submicroscopic duplication on Xp defined a 160-kb critical region adjacent to the congenital adrenal hypoplasia locus (AHC; 300200) that was exclusively duplicated in the patients with male-to-female sex reversal; the authors designated the locus DSS for 'dosage sensitive sex reversal' (see 300473.0014). Identification of males deleted for DSS suggested that the locus is not required for testis differentiation. Bardoni et al. (1994) proposed that DSS has a role in ovarian development and/or functions as a link between ovary and testis formation.

Animal Model

Swain et al. (1998) created a transgenic mouse model for studying events in mammalian sex differentiation. The data showed that Dax1 functions as an anti-testis gene by acting antagonistically to Sry. This suggested that dosage-sensitive sex reversal can be caused by duplication of the DAX1 gene in humans.