Clinical characterization and analysis of the SRD5A2 gene in 16 Chinese patients with 5α-reductase type 2 deficiency: a single-center retrospective study

BACKGROUND: 5α-reductase type 2 deficiency(5α-RD2) is a rare autosomal recessive disorder primarily caused by variants in the SRD5A2 gene. This condition is characterized by a spectrum of undervirilization in 46, XY individuals, ranging from ambiguous genitalia to predominantly male external genitalia with minimal undervirilization. Early diagnosis and effective management of 5α-reductase type 2 deficiency patients are major challenges for healthcare providers. The mutational analysis of SRD5A2 gene is regarded as the gold standard for the diagnosis of the disease. This study aimed to summarize our center's experience with patients diagnosed with 5α-reductase type 2 deficiency due to variations in the SRD5A2 gene and the associated clinical manifestations to enhance clinicians' awareness of this condition. METHODS: We conducted a retrospective single-center study by reviewing the medical records of patients diagnosed with 5α-reductase type 2 deficiency after genetic testing between April 2018 and July 2025. RESULTS: All 16 patients presented with ambiguous genitalia at birth and received diagnoses between the ages of 3 months and 11 years and 3 months. Of these patients, ten exhibited micropenis accompanied by hypospadias, six displayed an isolated micropenis, and six had either bilateral or unilateral cryptorchidism. Additionally, six patients had an underdeveloped scrotum. All affected individuals had a 46, XY karyotype and tested positive for the SRY gene, with two patients initially raised as female. The testosterone/dihydrotestosterone (T/DHT) ratios after human chorionic gonadotropin (hCG) stimulation ranged from 1.5- to 38.6-fold above the baseline values. This study identified ten distinct pathogenic variants of the SRD5A2 gene, including nine previously reported variants p.Gln6Ter, p.Gly66Arg, p.(Tyr128Cys), p.Asn193Ser, p.Gly196Ser, p.Gly203Ser, p.Phe219Serfs*60, p.Arg227Gln, and p.Arg246Gln and one novel variant p.(Cys119Arg), which expands the spectrum of known SRD5A2 variants. CONCLUSION: This study provides insights into genotype-phenotype correlations in a cohort of 16 Chinese patients diagnosed with 5α-reductase type 2 deficiency and summarized the enzymatic activity of the identified genetic variants. Identifying variants associated with 5α-reductase type 2 deficiency will facilitate genetic counseling for at-risk families and enable prenatal diagnosis, thus empowering parents to make informed decisions and allowing healthcare providers to tailor treatment strategies effectively.