Endocrine Abstracts

Introduction: Biallelic loss of function of the 5α-reductase 2 enzyme, with impaired conversion of testosterone to dihydrotestosterone, is associated with undervirilisation in 46 XY DSD. We identified 5 individuals with 5α-reductase 2 deficiency (5ARD), disease varying from mild to severe.

Patients: 1. 2 Turkish siblings, with microphallus and coronal/glanular hypospadias (External masculinisation score (EMS) 8) had 3-day HCG and urine steroid profiles (USP) consistent with 5ARD. They harbour a homozygous variant p.Gly196 Ser, a noted SRD5A2 hotspot, interfering with the enzyme’s NADPH domain.2. A third individual, Bangladeshi, with coronal hypospadias, microphallus (EMS 8) and indicative biochemistry was compound heterozygous for variants p.Arg227Ter (affects enzymatic activity) and p.Ala52Thr (of uncertain significance).3. For one Asian individual with penoscrotal hypospadias, chordee and bilateral undescended testes (EMS 7) investigations were less conclusive. USP ratio of 5A/5B reduced tetrahydrocortisone was not as low as expected with 5ARD, but inferred a mild phenotype/carrier status. He is heterozygous for p.Phe234Leu (affects enzymatic activity); no other cause for his DSD has been identified.4. An infant (Australian/New Zealand ethnicity) had predominatly female typic genitalia, however testes were palpable bilaterally in the labioscrotal folds (EMS 3). USP tetrahydrocortisols, which are used as best markers of 5ARD can appear paradoxically later in the condition and genetic testing has instead been invaluable in early diagnosis for this infant. He is compound heterozygous for p.Gln126Arg and p.His231Arg (associated with reduced enzymatic activity and testosterone affinity respectively). There is generally no genotype-phenotype correlation described, but some variants including p.Gln126Arg, are consistently associated with severe undervirilisation. He has been assigned male sex, with due consideration given to prenatal androgen exposure, scope for virilisation in puberty and preserving fertility. Support in managing the sex difference is important and carefully timed surgery in adulthood, with phalloplasty potentially required. Virilisation in puberty is evident in our patients of age, a phenomenon that can mark 5ARD out from other causes of 46XY DSD.

Conclusion: This small series exemplifies the phenotypic variability of 5ARD and annotation of the natural history with associated genotypes continues to play a role in our understanding of this rare disease.