Endocrine Abstracts

Steroidogenic factor 1 (SF-1/NR5A1) is a regulator of steroid hormone biosynthesis and sex development. It was first identified in a 46,XY newborn with complete sex reversal and primary adrenal insufficiency. Most 46,XY patients carrying heterozygote NR5A1 mutations manifest with a disorder of sexual development (DSD) phenotype, although an adrenal only phenotype has also been described in one 46,XX patient. Mutations in NR5A1 may be found in up to 9% of 46,XY subjects with mild to severe DSD. Testes histology is characteristic for fat accumulation and degeneration over time similar to findings observed in patients with lipoid congenital adrenal hyperplasia (due to StAR mutations). Female relatives with heterozygote NR5A1 mutations show primary ovarian insufficiency (POI) at puberty. Ovarian biopsy in one reported female showed extensive fibrosis with no evidence of follicles. However, in 46,XX subjects with sporadic, non-syndromic POI, heterozygote NR5A1 mutations are only found in 1.4–8%. DSD due to heterozygote NR5A1 mutations has also been reported in offsprings of parents who were fertile but were carriers of same NR5A1 mutations. Overall, patient studies show that NR5A1 mutations present with a very broad phenotype, especially in 46,XY. Testis and ovary can be affected to different degrees. Recent findings from mice models establish a role for SF-1 in early gonadal development (sex determination) and gonadal (both testis and ovary) differentiation. In addition, SF-1 is an important transcription factor for steroid biosynthesis. However, the broad phenotypic variability associated with NR5A1 mutations remains a conundrum. Internal (e.g. mutations in other genes) as well as external (e.g. environmental) modulators may be considered but have not been found yet.