Background: 5α-Reductase type 2 deficiency (5ARD) is caused by mutations in the SRD5A2 gene. Inadequate masculinisation in XY individuals results from failure to convert testosterone (T) to dihydrotestosterone (DHT), a potent androgen. A decreased serum T:DHT ratio is frequently taken to identify 5ARD, but requires hCG stimulation for prepubertal patients; findings are not always supported by genotyping. Urine steroid profiling (USP) by GC-MS is established as showing significantly reduced excretion of 5α- compared with 5β-reduced steroid metabolites in 5ARD. We assessed the utility of USP as a definitive diagnostic test for 5ARD by evaluating four 5α/5β-reduced metabolite ratios.
Methods: Retrospective study of 45 male patients selected from our database and ascertained between 1985 & 2011 with a USP consistent with 5ARD and expected clinical picture. Genetic mutations were subsequently confirmed in 21; none tested were negative. Interquartile ranges (IQR) for four age ranges (n) [<6 years (19), 610 (9), 1117 (10) and >17 (7)] were compared with 45 age and sex-matched controls. Twelve parents (obligate heterozygotes) of 5ARD patients (4 with genetic confirmation) were also studied.
Results: Corticosteroid metabolite ratios were markedly lower in the 5ARD group: allo-tertrahydrocorticosterone (α-THB):tetrahydrocorticosterone (THB) and allo-tetrahydrocortisol (5α-THF):tetrahydrocortisol (THF) showed no IQR overlap. The 5α-THF:THF ratio was the best discriminator, giving by far the lowest values and differentiating the majority of carriers from controls and all 5ARD patients from their parent carriers. Androgen metabolite ratios (androsterone:aetiocholanolone and 11β-OH androsterone:11β-OH aetiocholanolone) were lower than in controls but IQRs overlapped for some comparisons in the <10 groups.
Conclusion: Genotyping is currently the definitive diagnostic test; 21 of our 45 patients have a genetic confirmation. We are seeking information on completed analyses for the remainder via an ethically approved questionnaire. We propose that 5α-THB:THB and 5α-THF:THF ratios be used to diagnose 5ARD, with 5α-THF:THF differentiating 5ARD from carriers.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.