Clinical Spectrum, Surgical Management, and Outcomes of NR5A1-Related 46,XY Differences of Sex Development: A...

Background and Objectives: NR5A1-related 46,XY differences of sex development (DSD) represent a heterogeneous group of conditions characterized by variable degrees of undervirilization, gonadal dysgenesis, and endocrine dysfunction. Mutations in the NR5A1 gene affect critical pathways of gonadal development and steroidogenesis, leading to complex diagnostic and management challenges. This narrative review aims to summarize the clinical spectrum, diagnostic algorithms, surgical management, and outcome data of pediatric NR5A1-related 46,XY DSD. Materials and Methods: A comprehensive search of PubMed, Scopus, and Web of Science databases was conducted, using terms related to NR5A1 mutations, ambiguous genitalia, gonadal dysgenesis, tumor risk, and surgical management. A total of 26 studies were initially identified, of which 16 met the inclusion criteria for pediatric patients (≤18 years) with confirmed 46,XY karyotype, NR5A1 mutation, and available clinical or surgical data. Results: NR5A1 mutations are associated with phenotypes ranging from complete female external genitalia to apparently normal males with later infertility. While Sertoli cell function during fetal life is often preserved, Leydig cell dysfunction leads to incomplete masculinization. Spontaneous virilization during puberty has been reported. Management of gonadal dysgenesis remains controversial: while streak-like intra-abdominal gonads carry high germ cell tumor risk, warranting early gonadectomy, well-formed testes may be preserved under strict surveillance. Conclusions: NR5A1-related 46,XY DSD requires individualized, multidisciplinary management integrating genetic, endocrine, surgical, and psychosocial expertise. Gonadectomy decisions should be risk-stratified and, when possible, delayed to allow patients to participate in decision-making. Early psychological support and lifelong follow-up are essential to optimize physical and psychosocial outcomes.