ESPE Abstracts

Introduction-Purpose: In addition to chromosomal abnormalities, a number of genes have been implicated as causes of Disorders of Sexual Development (DSD). The NR5A1 (SF-1) gene expresses a transcription factor that plays a role in steroidogenesis by controlling multiple stages of adrenal and gonadal development, and its mutations have been reported in cases of DSD.

Case presentation: A 15^2/12-year-old teenager was admitted to the Children's ICU of the University Hospital of Patras, Greece, due to acute encephalitis. On physical examination labia majora and minora, open vaginal opening, and a 4.8cm phallus (stretched length) in the anatomical position of the clitoris, were identified. In addition, the patient presented with hirsutism with intense hair growth on the chest, abdomen, thighs and cheeks, breast development was Tanner stage I, and pubic hair was Tanner V. Medical history revealed primary amenorrhea. Extensive hormonal investigations demonstrated: LH: 8.2 mIU/ml, FSH: 24.8 mIU/ml, E2 (estradiol): 36.67 pg/ml, Testosterone: 118.1 ng/dl, SHBG: 25.9 nmol/l, Δ4-Androstenedione: 2.6ng/ml, DHEA-SO4: 141.4 μg/dl, 17-OH-Progesterone: 0.7ng/ml, Progesterone: <0.05ng/ml, Cortisol: 16.61 µg/dl, ACTH: 18.9 pg/ml, Renin: 28.4 µU/ml, Aldosterone: 60.2 pg/ml, AMH: 0.37 ng/ml, INH-B: 6 pg/ml, β-hCG: < 2.30 IU/ml, CEA: 1.19 ng/ml, αFP: < 2 ng/ml, Prolactin: 22.3 ng /ml, TSH (mIU/L): 2.59, FT4: 1.30 ng/dl, Anti-TPO: 12.1 mIU/L, anti-TG: 10.6 mIU/L. On ultrasound of the lower abdomen, a 3.31x0.85 cm lesion was identified posterior to the bladder, indicating residual duct of Muller. MRI scan of the lower abdomen revealed oval formations with limited diffusion and magnetic signals primarily compatible with testicular parenchyma in the anatomical location of the inguinal ducts bilaterally. The karyotype revealed a 46,XY individual and whole exome sequencing (WES) revealed the presence of the heterozygous splice site variant of the NR5A1 gene (NM_004959.5), c.990G>C, p.Glu330Asp, which on further genetic testing of the parents was proven to be de novo. Based on the ACGM criteria, the mutation is classified as Pathogenic. According to psychiatric assessment, the patient self-identifies as female. A gonadectomy and laparoscopic exploration of possible residual Mullerian ducts were performed, and hormone replacement therapy with estrogens was initiated.

Conclusions: We describe a very rare case of male pseudomaphroditism (46.XY DSD) in an adolescent phenotypically female patient carrying the novel de novo p.Glu330Asp variant of the NR5A1 gene. We also highlight the delay in diagnosis of ambiguous external genitalia.