[Clinical and genetic features of pedigrees with NR5A1 related disorders of sex development].

Objective: To summarize the clinical characteristics of children with disorders of sex development (DSD) carrying NR5A1 gene variations and their families. Methods: A case-series study was conducted. Clinical data were collected and analyzed for of 17 pediatric DSD cases with NR5A1 gene variants and their families at Beijing Children's Hospital, Capital Medical University from January 2010 to December 2024. Results: The age at initial diagnosis of the 17 children was 4.7 (1.2, 10.7) years. The sex assigned at initial presentation was male in 9 cases and female in 8. All children had testicular gonadal tissue, with no residual Müllerian or ovotesticular structures observed. None exhibited adrenal insufficiency. The external masculinization score (EMS) was 3.0 (0, 4.0).Among the 17 probands, 10 cases had maternally inherited variations. Associated maternal phenotypes included 5 premature ovarian failure, 4 irregular menstruation, and a single case with no reported phenotype. Premature ovarian failure was also reported in 3 maternal grandmother. Seven probands had paternally inherited variants. Associated paternal phenotypes included 3 oligospermia and asthenospermia, 3 DSD phenotype, and 1 father with no reported phenotype. Of the 6 patients who had entered puberty, 4 exhibited significantly elevated basal follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, with a more pronounced increase in FSH, alongside decreased levels of anti-Müllerian hormone (AMH) and inhibin B. Among the 10 prepubertal children, 8 underwent human chorionic gonadotropin (hCG) stimulation tests, 6 of these patients showed a good testosterone response to hCG stimulation, while 2 demonstrated a poor response (cases 6, 12). Genetic testing identified a total of 17 distinct variants, comprising 9 missense, 3 nonsense, 1 synonymous, 3 in-frame deletions or insertions, and 1 start codon variant. Among these, 9 had been previously reported, while 8 were novel. Of the 8 children initially assigned female sex, 5 underwent reassignment to male. No cases involved reassignment from male to female. Conclusions: The clinical spectrum of phenotypes associated with NR5A1-retated DSD is broad. Fertility is possible for individuals carrying these variants, regardless of their personal phenotypic expression. Notably, children reared females may later undergo gender reassignment to male.