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Clinical characteristics and genotype-phenotype correlation analysis in 279 patients with 5α-reductase type 2
Kun Wang1, Bingbing Shi2, Lili Huang1
1Department of Endocrinology and Metabology, Liaocheng People's Hospital, Liaocheng, China.
Objective:
5α-Reductase type 2 deficiency (5α-RD2) is an autosomal recessive differences/disorders of sex development caused by SRD5A2 gene mutations, characterized by impaired testosterone-to-dihydrotestosterone conversion and highly heterogeneous clinical phenotypes. The genotype-phenotype correlation of 5α-RD2 remains incompletely understood, and large-scale multicenter evidence is lacking for clinical management.
Methods:
We systematically searched PubMed, Embase, CNKI, Wanfang, and Chinese Medical Journals databases from inception to December 2025. A total of 279 genetically confirmed patients with 5α-RD2 from 36 countries (64.77% from Asia) were included. Demographic, clinical, biochemical, genetic, and prognostic data were extracted and analyzed using SPSS 25.0.
Results:
Seventy-eight pathogenic SRD5A2 mutations were identified, with missense mutations being the most common (64.10%) and p.R246Q the most prevalent variant. The mutation spectrum showed significant geographic heterogeneity. Consanguinity was strongly associated with homozygous mutations (P < 0.001), and patients with homozygous mutations had significantly more severe undermasculinization than compound heterozygotes (P = 0.011). p.R246Q, p.G203S, and p.R246W were significantly associated with a higher likelihood of hypospadias; p.R227Q was significantly associated with a lower likelihood of cryptorchidism and scrotal abnormalities. Frameshift mutations were associated with impaired pubertal development (P = 0.013). Homozygous carriers were diagnosed significantly later than heterozygotes (P = 0.029), and serum FSH levels positively correlated with phenotypic severity (P = 0.021).
Conclusion:
We verified that the genotype-phenotype correspondence is non-linear and multifactorial, jointly modulated by mutation subtype, residual enzyme activity, endocrine axis status, geographical disparities, consanguinity, and regional medical resource availability. These findings provide more reliable evidence for clinical diagnosis, treatment, and prognosis assessment.