Daniela Ramírez Pertuz, Pediatric Endocrinologist: No financial relationships to disclose
Indroduction: NR5A1 gene mutations encoding Steroidogenic Factor-1 cause highly variable genital phenotypes in patients with 46,XY differences of sex development (DSD). We present two 46,XY individuals carrying heterozygous NR5A1 variants, one with partial and the other with complete gonadal dysgenesis. Both cases were diagnosed late, the patient with partial gonadal dysgenesis having been assigned female at birth and later developing gender dysphoria.
Case 1: A 46,XY patient with primary amenorrhea, absent breast development, and female external genitalia. Laboratory evaluation showed hypergonadotropic hypogonadism with elevated LH and FSH, markedly low estradiol, AMH, and testosterone levels. Pelvic MRI revealed rudimentary uterus without visible ovaries. Laparoscopy identified gonadal structures. Genetic testing confirmed heterozygous pathogenic variant in NR5A1. Low-dose conjugated estrogen therapy was initiated. Adrenal function was preserved.
Case 2: a 46 XY patient born with undervirilized external genitalia and assigned female during infancy. At puberty, progressive virilization was noted, including a 6-cm phallic structure, partially fused labioscrotal folds, single proximal urogenital opening, and right inguinal and left palpable gonad. At age 13, she underwent right orchiopexy with bilateral testicular biopsy and vaginoscopy, with no malignancy detected. Genetic testing identified a likely pathogenic variant in NR5A1. No adrenal insufficiency was detected during follow-up. Gender dysphoria developed during puberty and follow-up included psychiatric support. New biopsy and hormonal management were deferred until adulthood.
Conclusion: Heterozygous NR5A1 variants result in a wide phenotypic spectrum in 46,XY DSD, ranging from complete testicular dysgenesis with Müllerian structures to partial dysgenesis with atypical genitalia, proximal hypospadias with cryptorchidism or micropenis. In complete dysgenesis with female sex assignment, prophylactic gonadectomy is recommended due to germ cell tumor risk. In partial dysgenesis, significant pubertal virilization may occur; therefore, careful sex assignment and avoidance of irreversible procedures during infancy are recommended.
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