IMPE Abstracts

Nuclear receptor subfamily 5 group A member 1 (NR5A1), is a member of the nuclear receptor family. It plays a crucial role in transcriptional regulation of genes involved in steroidogenesis, gonadal development and reproduction. NR5A1 mutations represent one of the most frequent defects associated with 46,XY gonadal dysgenesis, associated with a wide phenotypic spectrum of DSD. Some patients with mutations in the NR5A1 may have normal testosterone levels at puberty and progress to spontaneous puberty or virilization, which suggests that Leydig cell function is sufficient in these patients at postnatal life. We retrospectively studied a cohort of 23 patients with an identified pathogenic NR5A1variant and described clinical features. The degree of virilization was according to the Sinnecker classification. A family history of DSD was presented in four cases, one of them has a mother that developed ovarian insufficiency at 39 years. None of the patients had symptoms or signs of adrenal insufficiency, and normal basal adrenal function was documented in ten patients. Only one patient had a typical male genitalia (Sinnecker 1), two of them had a Sinnecker 2a, two 2b, six 3a, two 4a and six 4b. Two cases cannot be classified for lack of records. There are 13 cases that were assigned as female at birth, five of them changed to male social sex later. Among the reassigned individuals four had normal testosterone levels and one had undergone bilateral gonadectomy. Twelve of the 19 non orchiectomyzed adult patients presented normal levels of testosterone; seven had a normal basal serum testosterone (279 to 548 ng/dl), five were evaluated in the prepubertal phase, four had a normal of testosterone level after hCG test (280 to 320 ng/dl) and one with normal basal serum testosterone levels during minipuberty (350 ng/dL). Nine from 10 postpubertal patients presented spontaneous puberty but one patient of the hCG test group did not. LH levels in adult patients were elevated in the vast majority (3.9 - 36 U/L) as well as FSH (5.1 - 74 U/L) with further increase during the course of puberty. The identified pathogenic variants in NR5A1 were found at DNA-binding domain, hinge region, ligand-binding domain and splice site and no association with the location and testosterone production was possible. Likewise, the nine patients who had spontaneous puberty had different Sinecker classification. Spontaneous male puberty in severely under virilized patients with NR5A1 variants is frequent for yet unknown mechanisms.