Update--steroidogenic factor 1 (SF-1, NR5A1)

Steroidogenic factor 1 (SF1, NR5A1, Ad4BP) is a nuclear receptor and regulator of multiple genes involved in adrenal and gonadal development, steroidogenesis, and the reproductive axis. Complete deletion of Nr5a1 in XY mice results in adrenal and gonadal agenesis, female external genitalia and presence of Müllerian structures. These findings were first reported in the early 1990s. Subsequently, NR5A1 mutations were found in two 46,XY phenotypic females with Müllerian structures and adrenal failure and in one 46,XX female with adrenal failure. More recently, heterozygous NR5A1 mutations have been identified in a substantial proportion of patients with 46,XY disorders of sex development (46,XY DSD) without adrenal insufficiency. Most of these individuals display severe underandrogenization with ambiguous genitalia at birth, partial gonadal dysgenesis, and absence of Müllerian structures or remnants. Some of the patients have a milder phenotype such as hypospadias and cryptorchidism, due to less severe defects in androgen synthesis. Testosterone, inhibin B and AMH are usually low indicating a partial (or sometimes progressive) form of gonadal dysgenesis in most cases. However, normal testosterone production at birth might also be present. The frequency of NR5A1 mutations in otherwise unexplained 46,XY DSD with underandrogenization and partial testicular dysgenesis has been estimated to be about 15%. Furthermore, NR5A1 mutations have now been found in women with familial and sporadic 46,XX primary ovarian insufficiency without adrenal failure. These human phenotypes associated with NR5A1 mutations show that SF-1 is a key factor involved in both human testis and ovarian development, but that human adrenal development seems to be more resistant to the effects of SF-1 haploinsufficiency than gonadal development. Patients with 46,XY DSD and mild underandrogenization due to partial testicular dysgenesis should possibly be assigned to the male sex, as small testes with Leydig, Sertoli and germ cells are present in almost all cases. Additionally, spontaneous virilization in puberty might be possible in patients with NR5A1 mutations. However, fertility options and the risk of testicular malignancy and adrenal insufficiency in adulthood are unknown and need to be investigated in long-term outcome studies.