Endocrine Abstracts

Introduction: Steroidogenic factor-1 (SF-1) is encoded by the NR5A1 gene on chromosome nine and is a nuclear receptor involved in adrenal and gonadal development and differentiation. There is wide phenotypic variation in individuals with NR5A1 mutations, but little is known about the natural course of patients during puberty. This study reports the case of a phenotypical female who showed profound virilisation at puberty due to a mutation in the NR5A1 gene.

Case Report: A 14-year-old girl presented with facial and axillary hair, absent breast development and amenorrhoea. There was no history of ambiguous genitalia, but genital examination was refused. Her karyotype was found to be 46XY, with a high testosterone level (22.6 nmol/l) and raised testosterone:dihydrotestosterone ratio (14:1). A urine steroid profile was normal. Pelvic imaging showed inguinal gonads but no uterus. Examination under anaesthesia revealed extensive virilisation, with 6 cm clitoromegaly.

Genetic sequencing found no mutation in the androgen receptor gene, 17 HSD3 or SRD5A2 genes. Subsequent analysis of the NR5A1 gene revealed a heterozygous mutation within exon 5, resulting in a ‘stop’ codon, which was determined to be the pathogenic mutation.

After intensive psychological counselling the patient stated her desire for a female gender identity, and proceeded to laparoscopic gonadectomy, clitoral reduction, and oestrogen therapy.

Conclusion: This case highlights a rare presentation of NR5A1 gene mutations, in a patient with no genital ambiguity prior to puberty. The human SF1 protein, encoded by the NR5A1 gene, is one of the main regulators of enzymes involved in adrenal and gonadal steroidogenesis. It is expressed in undifferentiated gonads and there is wide phenotypic variation in XY patients with NR5A1 gene mutations. This case is a previously unreported presentation of this mutation, and highlights the variable presentation of SF1 protein mutations.