46,xx Sex Reversal 3

A number sign (#) is used with this entry because of evidence that 46,XX male sex reversal can be caused by genomic duplications or deletions in the SOX3 (313430) regulatory region on chromosome Xq26.

Clinical Features

Sutton et al. (2011) studied 3 46,XX SRY (480000)-negative male sex reversal patients. Patient 'A' was a male of European descent who presented at age 30 years for evaluation of infertility, which was confirmed by azoospermia on 2 spermograms. He had no evidence of hypopituitarism or intellectual disability, and had normal-appearing secondary sexual characteristics. Patient 'B' was a 35-year-old of European descent, who had gender dysphoria reported from around 6 years of age, leading to gender reassignment surgery at age 26 years. On examination at age 25 years, external genitalia were noted to be normal male except for small, soft testes, measuring less than 4 ml by orchidometer. Postsurgical histology showed atrophic changes in the testes, with loss of normal spermatogenesis, thickening and hyalinization of the tubular basal lamina, and diminished numbers of interstitial cells. Spermatic cords were histologically normal, as was the penis. Patients A and B both underwent puberty at around 14 years of age. Patient 'C' was a boy of Mexican origin who presented at 19 months of age with failure to thrive and developmental delay; he had microcephaly and a hypoplastic scrotum with retractile testes.

Molecular Genetics

Sutton et al. (2011) screened a cohort of 16 SRY (480000)-negative 46,XX male patients for copy number variation (CNV) and identified rearrangements encompassing or in close proximity to the SOX3 gene in 3 patients. Patient A had tandem microduplications of approximately 123 kb and 85 kb, respectively, with the larger spanning the entire SOX3 gene. There was no evidence for skewed inactivation of the X chromosome. Patient B had a single 343-kb microdeletion immediately upstream of SOX3, suggesting that altered regulation rather than increased dosage of SOX3 is the cause of XX male sex reversal. Patient C, who had a more complex phenotype including microcephaly, developmental delay, and growth retardation, had a large, approximately 6-Mb duplication that encompassed SOX3 and at least 18 additional distally located genes.