Familial 46,XX Ovotesticular Differences in Sex Development Associated With an NR5A1 p.Arg92Trp Variant.
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INTRODUCTION: NR5A1 encodes steroidogenic factor 1 (SF-1), a key regulator of adrenal and gonadal development, steroidogenesis, AMH transcription, and the balance between pro-testicular and pro-ovarian pathways. The recurrent NR5A1 c.274C>T (p.Arg92Trp) variant is associated with SRY-negative 46,XX testicular and ovotesticular differences in sex development (DSD), but intrafamilial expression remains difficult to predict. Case Presentation We report a rare multigenerational familial presentation of SRY-negative 46,XX ovotesticular DSD associated with the heterozygous NR5A1 p.Arg92Trp variant. The proband was noted antenatally to have atypical genital development. Antenatal karyotyping confirmed a 46,XX, SRY-negative result. At birth, the proband had clitoromegaly, posterior labioscrotal fusion, a perineal urethral opening, absent vaginal opening, and palpable labioscrotal gonads. Testosterone, anti mullerian hormone (AMH), and inhibin B were elevated, consistent with functioning testicular tissue, while adrenal investigations were normal. Imaging and laparoscopy showed mixed Müllerian and Wolffian structures, and gonadal histology confirmed ovarian primordial follicles. The family history was notable for DSD in the mother's sister, who had undergone childhood genital surgery and gonadectomy, with histology showing intratubular germ cell neoplasia. She was the first family member found to carry the NR5A1 p.Arg92Trp variant, prompting targeted testing in the proband and her mother, both of whom were positive. The variant was subsequently identified in the maternal grandmother and in the proband's older 46,XX, SRY-negative brother, who was raised male and had typical male external genitalia with bilateral scrotal gonads; the mother's brother tested negative. The mother had previously been treated for a unilateral ovarian germ cell tumour. These findings demonstrate marked intrafamilial variability and highlight the importance of family-history-led genetic testing, tumour-risk assessment, and long-term multidisciplinary follow-up. CONCLUSION: This family captures the striking phenotypic breadth of NR5A1 p.Arg92Trp within a single pedigree and illustrates the role of NR5A1 as a developmental regulator of gonadal fate and AMH-mediated ductal differentiation. It emphasises the need for cautious individualised management, tumour surveillance, long-term follow-up, genetic counselling, and psychological support.