In 1 of 21 Brazilian patients with 46,XY sex reversal (SRXY1; 400044), Domenice et al. (1998) found a ser18-to-asn (S18N) missense mutation upstream of the 5-prime border of the HMG box of the SRY gene. The variant sequence was also found in DNA obtained from blood and sperm of his father and in blood cells of his normal brother. The S18N mutation was not found in 50 normal males, ruling out the possibility of a common polymorphism. The patient had been evaluated at 4 years of age for ambiguous genitalia, characterized by microphallus, perineal hypospadias, bifid scrotum, and a gonad in the left inguinal region. His basal serum testosterone level was 16 ng/dl rising to 189 ng/dl after hCG stimulation. Histologic study showed a right streak gonad, a left dysgenic testis, and the presence of both wolffian and mullerian ducts. His brother at 18 years of age had normal male external genitalia with complete development of secondary sexual characteristics. The father was a 43-year-old phenotypically normal male.
Canto et al. (2000) performed molecular studies of the SRY gene in 3 patients with an Ullrich-Turner syndrome (see 163950) phenotype and bilateral streaks; 2 were 45,X/46,XY mosaic, and the third had a Y marker chromosome. In 2 of the patients, the authors identified an S18N mutation in the 5-prime non-HMG box region in DNA from blood and both streaks. This mutation was not identified in 5 normal males. Sequencing of the DNA region was normal in the father and older brother of patient 1, demonstrating that in this patient the mutation was de novo. The authors concluded that the previous report of a 46,XY patient with partial gonadal dysgenesis and the same mutation indicates the probable existence of a hotspot in this region of the SRY gene and strengthens the possibility that all gonadal dysgeneses constitute a spectrum of the same disorder. They also pointed out that this single genetic abnormality can result in a wide range of phenotypic expression.
