Recognition of 5α-reductase-2 deficiency in an adult female 46XY DSD clinic

Context: The late presentation of steroid 5 alpha-reductase-2 (SRD5A2) deficiency in females is poorly characterised. The ratios of 5 alpha/5 beta-reduced metabolites of adrenal steroids in a urine steroid profile (USP) can give an indication of SRD5A2 deficiency, although the diagnostic cut-off for 5 alpha/5 beta ratios are not clearly defined in genetically confirmed cases. Objective: The aim of this study was to establish the frequency of SRD5A2 deficiency in an adult clinic for disorders of sexual development (DSD) focussing on 46XY partially virilised adult female subjects. We investigated the relationship between USP results and SRD5A2 genetic sequence and determined the cut-off for USP 5 alpha/5 beta-reduced steroid ratios compared with gene sequencing for the identification of SRD5A2 deficiency. Methods: USP and SRD5A2 genetic analyses were performed in 23 adult females, aged 19-57 years, with 46XY DSD and in four males with confirmed SRD5A2 deficiency. 5 alpha-Reductase activity was assessed using the USP ratio of androsterone to aetiocholanolone (A/Ae), 5 alpha-tetrahydrocortisol (5 alpha-THF)/tetrahydrocortisol (THF) and 5 alpha-tetrahydrocorticosterone to tetrahydrocorticosterone (5 alpha-THB/THB). Results: The SRD5A2 gene mutations were found in 10/23 (43%) females and in all four males. Totally, four novel mutations were identified. All mutation-positive subjects had A/Ae and 5 alpha-THB/THB ratios below the lower limit of normal (100% sensitivity) while the sensitivity of 5 alpha-THF/THF ratio was 90%. Conclusion: SRD5A2 deficiency is more prevalent than expected in the adult female 46XY DSD population. The clinical spectrum of this disorder may extend to a more female phenotype than previously considered to include individuals with little or no virilisation.