46,xy Sex Reversal 5

A number sign (#) is used with this entry because of evidence that 46,XY sex reversal-5 (SRXY5) is caused by compound heterozygous mutation in the CBX2 gene (602770) on chromosome 17q25. One such patient has been reported.

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

Clinical Features

Biason-Lauber et al. (2009) reported a child who, despite prenatally determined 46,XY karyotype, presented at birth as a phenotypically normal female. The karyotype was confirmed antenatally. She had low testosterone at 2 years of age that failed to increase after stimulation with chorionic gonadotropin (CG; 118860). Laparoscopy performed at 4.5 years to evaluate and potentially remove the gonads showed 2 ovaries of normal appearance. Histology revealed normal ovarian tissues with primordial follicles. Vaginoscopy showed normal vagina and cervix. The child was too young at the time of the report to investigate pubertal development or fertility.

Molecular Genetics

In a patient with 46,XY karyotype and normal female phenotype, Biason-Lauber et al. (2009) excluded mutations in the SRY (480000) and SOX9 (608160) genes. Sequencing of the CBX2 gene showed 2 missense mutations, pro98 to leu (602770.0001) and arg443 to pro (602770.0002). These mutations were not identified in 160 unrelated individuals.

Norling et al. (2013) analyzed the CBX2 gene in 47 patients with different forms of 46,XY or 46,XX gonadal disorders of sex development (DSD), including 12 cases with 46,XY complete gonadal dysgenesis, 1 with 46,XY ovotesticular DSD, 19 with 46,XX complete gonadal dysgenesis, and 1 46,XX patient with 1 streak gonad and 1 normal functioning ovary, as well as 14 cases with 46,XX premature ovarian failure (see 311360). Norling et al. (2013) did not find any pathogenic mutations or copy number variation, and they concluded that CBX2 is not a common cause of gonadal DSD.

Animal Model

Katoh-Fukui et al. (1998) disrupted the M33 gene in mice by inserting a poly(A) targeting vector into its fifth exon. More than half of the resultant homozygous mutant mice died before weaning, and survivors showed male-to-female sex reversal. Formation of genital ridges was retarded in both XX and XY homozygous mutant embryos. Biason-Lauber et al. (2009) noted that apart from sterility, 50 to 75% of M33-knockout Sry-positive mice were phenotypically perfect females.