Abstract 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 (NM₀04959. 5: c. 1166₁180del). 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 (NM₀04959. 5: c. 489del). Hormone therapy was changed to transdermal estradiol/progestogen. These cases highlight 2 novel NR5A1 variants associated with 46, XY DSD.
Gialouris et al. (Tue,) studied this question.