Two Cases of 46,XY Differences of Sex Development Due to Gonadal Dysgenesis Associated With Novel NR5A1 Variants

Differences of sex development (DSDs) are rare conditions with atypical chromosomal, gonadal, or anatomical sex. We describe 2 cases of 46,XY DSD due to complete gonadal dysgenesis, a 16-year-old female and a 45-year-old female, who both presented with primary amenorrhea and hirsutism. The 16-year-old had tall stature and normal-appearing female external genitalia but absent female secondary sex characteristics. Hormonal assessment revealed hypergonadotropic hypogonadism. The uterus appeared normal on transabdominal ultrasound. Testing revealed 46,XY karyotype and SRY+ using fluorescence in situ hybridization (FISH). 46,XY DSD genetic testing found a novel, heterozygous, likely pathogenic NR5A1 variant (NM_004959.5:c.1166_1180del). Low-dose transdermal estradiol was commenced for pubertal induction, planned for gradual uptitration before progestogen introduction. The 45-year-old female had osteoporosis and had been taking the oral contraceptive pill (OCP) long-term for previously misdiagnosed Turner syndrome. She had normal-appearing female external genitalia, tall stature, and no Turner syndrome features. Hormonal assessment was confounded by previous gonadectomy and OCP use. Testing revealed 46,XY karyotype and SRY+ using FISH. 46,XY DSD genetic testing revealed a novel, heterozygous, likely pathogenic variant of NR5A1 (NM_004959.5:c.489del). Hormone therapy was changed to transdermal estradiol/progestogen. These cases highlight 2 novel NR5A1 variants associated with 46,XY DSD.