Disorders of sex development (DSDs) encompass a spectrum of congenital conditions characterized by atypical development of chromosomal, gonadal, or anatomical sex. Among these, ambiguous genitalia in neonates is a rare but significant clinical presentation, with an estimated prevalence of approximately 1 in 4500 live births. Despite advancements in diagnostic modalities, including hormonal assays, karyotyping, and molecular genetic analyses, a definitive diagnosis is achieved in fewer than 50% of cases among individuals with 46,XY DSD karyotype, underscoring the complexity of these conditions. Results from a recent large series reported that a definitive diagnosis was reached in up to 60% of individuals with 46,XY DSD karotype, using a combination of clinical, hormonal, and molecular genetic testing.

Deficiency of 5α-reductase type 2 (5α-RD2), caused by mutations in the SRD5A2 gene, is a notable cause of 46,XY DSD and results in impaired conversion of testosterone to dihydrotestosterone (DHT). DHT is crucial for the masculinization of the external genitalia during embryogenesis. Individuals with 5α-RD2 deficiency exhibit a broad phenotypic spectrum, ranging from predominantly female-appearing external genitalia to varying degrees of undervirilization, including isolated micropenis or severe hypospadias with undescended testes. During puberty, increased testosterone levels and increased peripheral conversion of testosterone to DHT may lead to partial virilization, including deepening of the voice, increased muscle mass, and phallic growth; however, the extent of these changes can vary significantly among individuals.

The diagnosis of 5α-RD2 deficiency involves a combination of clinical evaluation, hormonal profiling (including elevated testosterone to DHT ratios, and molecular genetic testing to identify pathogenic variants of the SRD5A2 gene. Early and accurate diagnosis is essential for informed decision-making regarding sex assignment, potential surgical interventions, and long-term management strategies. This educational activity aims to provide healthcare professionals with a comprehensive understanding of the pathophysiology, clinical manifestations, diagnostic approaches, and management considerations for 5α-RD2 deficiency, emphasizing the importance of an interdisciplinary approach to care.