ESPE Abstracts

Background: Steroidogenic factor-1 (SF1) is a nuclear receptor transcription factor that plays a crucial role in regulating the adrenal, gonadal, splenic development, steroidogenesis and reproduction.

Objective: To describe a Chinese 46,XY female with sex reversal, primary adrenal insufficiency and congenital splenic dysplasia harboring a novel de novo heterozygous deletion in NR5A1 gene.

Methods & Patients: Mutational analysis of NR5A1 gene.

Patient and Results: A 6-week-old phenotypic female infant of non-consanguineous Chinese parents presented with salt-wasting type of primary adrenal insufficiency early in two days of life. On physical examination, slightly increased skin pigmentation was noted, normal female external genitalia without clitoromegaly or palpable gonads were observed. Hormonal evaluation revealed slightly elevated testosterone (0.94 ng/mL), high level of androstenedione (19.1 nmol/L), and normal level of DHEAs, P and 17(OH)P. Karyotype was 46,XY. SRY was present. At age 5m, hormonal evaluation revealed increased FSH(67.54 mIU/mL) and LH(4.41 mIU/mL), and there was no testosterone response(0.21→0.22 ng/mL) after stimulation with human chorionic gonadotropin. Pelvic ultrasound showed an underdeveloped uterus(0.27ml) and absence of gonads. At age 10.5m, MRI revealed asplenia and adrenal dysplasia. Laparoscopy uncovered the atrophic spleen and normal mulerrian structures and ovarian-like gonads. Splenectomy was performed with the pathological findings of markedly spleen atrophy. A heterozygous deletion of 143 bps (c.616_758del, p.Gln206Lysfs*133) de novo novel mutation was found to NR5A1 exon 4 by sequence analysis. At age 3y5m, histopathology revealed dysplastic ovaries without any follicles on gonadal biopsy. At age 12y, estrogen replacement was initiated. Considering the risk of gonadal tumor due to the slightly increased β-HCG level(5.93-7.8 IU/L) paralleling with elevated LH 33.4IU/L, laparoscopy was performed again and gonadectomy revealed tiny ovaries-like gonads which consisted of a small amount of fallopian tube tissue and fibrous adipose tissue. The patient has never experienced salt loss crisis or severe infection but obesity and metabolic disorder.

Conclusion: We identified a de novo novel heterozygous deletion mutation of NR5A1 gene causing 46, XY female with persistent Mullerian duct(Complete gonadal dysplasia, 46,XY sex reversal type 3), salt-wasting primary adrenal insufficiency (congenital adrenal dysplasia), congenital splenic dysplasia (splenic atrophy), obesity, with no occurrence of gonadal tumors during 13 years follow-up.