46,xy Sex Reversal 9

A number sign (#) is used with this entry because of evidence that 46,XY sex reversal-9 (SRXY9) is caused by heterozygous mutation in the ZFPM2 gene (603693) on chromosome 8q23.

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

Clinical Features

Bashamboo et al. (2014) reported a 3-generation French family in which the 46,XY proband was noted at birth to have a 5-mm genital tubercle and striated genital folds, with no palpable gonads and no response to hCG (see 118860) stimulation. A uterus was present, measuring 14 mm by 3.5 mm. At 2 years of age, gonadectomy revealed complete gonadal dysgenesis, with bilateral streak gonads consisting of wavy ovarian-like stroma without tubules or germ cells. The patient also had bilateral clinodactyly of the fifth finger. A maternal great uncle was described as being undervirilized and did not marry or have children. Bashamboo et al. (2014) also reported a consanguineous Moroccan family in which the parents were second cousins and the 46,XY proband was born with ambiguous external genitalia. There was a single perineal opening at the base of the genital bud and striated genital folds, with hypertrophic labia majora and fused labia minora. The right gonad was in the genital fold with hydrocele, and the left gonad was in the inguinal canal. Genitography at 2 months of age indicated a vaginal cavity opening in the lower part of the urethra without a uterus. Gonadectomy at 16 months revealed a testis-like structure with bilateral vas deferens; histology was consistent with partial gonadal dysgenesis and showed rare Sertoli cells, absence of germ cells, an interstitium consisting of rare wavy stroma-like cells, and an atrophic rete testis. Leydig cells and mullerian structures were not seen. At 16.5 years of age, the proband had major language, reading, and learning difficulties, and was diagnosed with autism spectrum disorder. Brain MRI showed subtentorial ventricular dilation, with no signs of hydrocephalus and normal olfactory bulbs. Both probands were raised as girls. Neither family reported a history of cardiac anomalies.

Molecular Genetics

In the probands from 2 unrelated families with 46,XY sex reversal, Bashamboo et al. (2014) performed exome sequencing and identified missense mutations in the ZFPM2 gene (603693). The proband from a French family was heterozygous for an S402R substitution (603693.0009), which was confirmed by direct sequencing. This mutation was present in the unaffected mother and maternal grandmother, but was not found in 400 ancestry-matched control alleles. The proband from a consanguineous Moroccan family was heterozygous for a de novo R260Q substitution (603693.0010) and homozygous for an M544I missense variant (603693.0007). The latter mutation had been previously identified in an Italian patient with tetralogy of Fallot (see 187500), in whom gonadal anomalies were not reported. The mutations were confirmed by Sanger sequencing, and the unaffected second-cousin Moroccan parents were each heterozygous for the M544I mutation but did not carry the R260Q variant; neither mutation was found in 400 normospermic Moroccan controls. Exome sequencing in the probands revealed no mutations in other genes known to be involved in 46,XY disorders of sex development or in testis development. Functional studies suggested that the failure of testis development in the French and Moroccan patients could be explained by the impaired ability of the mutant ZFPM2 proteins to interact with GATA4 (600576), a regulator of early testis development.