ESPE Abstracts

Steroidogenic factor-1 (SF1), encoded by plays a central role in sex development, steroidogenesis, and reproduction in both males and females. NR5A1 mutations have been described in a diverse spectrum of disorders of sex development (DSD). We report on a case of XY Partial Gonadal Dysgenesis with paternal inheritance of a NR5A1 variant. A 17-year-old girl was referred to us due to primary amenorrhea and absence of secondary female sex characteristics. She was born at term to healthy unrelated parents after an uneventful pregnancy with a birth weight of 3085 g and length 51 cm. Her neuromotor development was normal, there were no significant health problems and family history was unremarkable. On physical examination weight was 87.5 Kg and height 184 cm. She had a 3-cm phallus, a female urethra and a vaginal opening; no gonads were palpable, and pubertal stage was B1P3. Karyotype was 46,XY, there were high FSH and LH concentrations, low estradiol, low serum testosterone and no accumulation of testosterone precursors. Müllerian derivatives could not be identified on pelvic ultrasound and pelvic MRI. She was subject to bilateral laparoscopic gonadectomy and pathology revealed bilateral dysgenetic testes. Estrogen replacement therapy for puberty induction was initiated and vaginal dilation will be performed in due time. Sequencing of NR5A1 revealed a heterozygous 17-bp deletion (c.268_285 p.M98Gfs*44) in exon 4. This mutation, which is located in the DNA binding domain of SF1, was inherited from her father. Adrenal function was evaluated in both of them, with normal results. Most NR5A1 mutations in patients with a 46,XY DSD are heterozygous and may be inherited from the mother in a sex-limited dominant manner. However, paternal inheritance has also been reported in a few cases where the father was unaffected or presented a milder phenotype. These findings add further complexity to genetic studies of NR5A1 in DSD and point out to the need to perform sequencing of all family members of a patient with a NR5A1 variant, irrespective of genetic sex and phenotype.