Introduction
Disorders of Sexual Development (DSD) comprise a heterogeneous group of conditions characterized by discordance among chromosomal sex, gonadal development, and genital sex. Among individuals with a 46,XY karyotype, current molecular testing enables the identification of genetic etiology in approximately 60% of cases. Pathological variants in the NR5A1 gene, encoding steroidogenic factor 1 (SF1), account for 10–15% of these cases. SF1 plays a pivotal role in the steroidogenic axis, acting as a transcription factor that regulates the expression of key genes, including SRY and SOX9. During early male development, SF1 is expressed in the bipotential gonad, facilitating processes such as regression of the paramesonephric ducts, differentiation of testicular tissue, and biosynthesis of testosterone. The clinical expression of variants in NR5A1 are associated with a broad phenotypic spectrum, ranging from 46,XY DSD with or without adrenal insufficiency to adult male infertility or premature ovarian failure in 46,XX females. This report presents a family with a pathogenic mutation in NR5A1, highlighting the significant variability in clinical presentation and the challenges in diagnosis and management.

Case Presentation
A full-term newborn presenting with ambiguous genitalia was referred for genetic evaluation. This baby was the first child of a healthy, non-consanguineous 19-year-old mother and 18-year-old father. The family history was notable for a maternal aunt (30 years old) with primary amenorrhea and a maternal cousin who was phenotypically female with ambiguous genitalia at birth. Additionally, the mother had two brothers, aged 26 and 15 years, with no reported genital ambiguity or developmental abnormalities, and a healthy 12-year-old sister who had not yet shown signs of secondary sexual development. The pregnancy was unmonitored, with no prenatal care or ultrasound studies performed. Ambiguous genitalia were identified at birth. The physical examination of the neonate revealed a 2 cm phallus, incomplete fusion of hyperpigmented and rugated labioscrotal folds, and a visible vaginal opening. No palpable gonads were detected in the scrotal region. The infant's height and weight were appropriate for age. The patient’s maternal aunt underwent a detailed evaluation. Her weight, height, and head circumference were normal for age. She displayed an android body habitus with male-pattern fat distribution, absence of breast development, clitoromegaly, major labia with a vaginal opening, and bilateral inguinal masses.

Diagnostic Workup
Pelvic ultrasonography revealed bilateral testes located within the inguinal canals. Genetic analysis was performed using next-generation sequencing (NGS) of a DSD-focused gene panel. Both individuals were found to have a 46,XY karyotype and a pathogenic variant in the NR5A1 gene (c.107T>C). This mutation is consistent with the clinical presentations observed in both the neonate and the maternal aunt.

 

Treatment and Management
Neither the aunt nor the newborn had a history of adrenal crises or other signs of adrenal insufficiency, their hormonal blood test reported within normal values. Long-term follow-up will focus on monitoring adrenal function to prevent potential adrenal crises, as well as regular imaging and eventual gonadal biopsy to evaluate for gonadal dysgenesis and reduce the risk of malignancy.

Discussion
Accurate diagnosis in DSD cases is essential for appropriate management and long-term monitoring. In this family, the identification of a pathogenic NR5A1 variant has provided a molecular explanation for the clinical findings, enabling tailored care plans for both affected individuals.

Conclusion
This case underscores the importance of integrating clinical, familial, and molecular data to provide a comprehensive understanding of the variability in DSD presentations and their underlying genetic basis.