ESPE Abstracts

Abstract: Steroidogenic factor 1 (SF1)/"nuclear receptor subfamily 5 group A member 1" (NR5A1) is involved in adrenal and gonadal development, steroidogenesis and reproduction. The first patient, published in 1999 presented with a 46,XY difference of sex development (DSD) and adrenal insufficiency. The following year the first female patient with only adrenal insufficiency was described. Since then, heterozygous changes in SF-1/NR5A1 causing 46,XY DSD were found to be very frequent, while adrenal insufficiency is rare. Furthermore, SF1 variants are responsible for premature ovarian failure and ovotesticular DSD, suggesting a pivotal role in the development of both sexes.

Case studies: Patient 1 (*1993) presented with ambiguous genitalia (phallus 1 cm), descended gonads and 46, XY karyotype. No salt wasting crisis. HCG test showed no increase of testosterone. Ultrasound revealed no uterus or vagina. At 3 years of age gonadectomy and clitoroplasty were performed. Histology showed immature seminiferous tubules with normal Sertoli cells. The patient was raised as girl. Vaginoplasty was performed at the age of 16. Psychosocial development was normal with achievement of high degree of education.

Whole Exome Sequencing showed a heterozygote novel variant in NR5A1/SF1 (c.64G>A p.(Gly22Ser)), and is compatible with a de novo event (Minor Allele Frequency, MAF=0).

Patient 2 (*2016) presented with penoscrotal hypospadias (phallus 2.1 cm), at ultrasound the right testis in the scrotum and the left retained in scrotal/inguinal position. No adrenal insufficiency. Karyotype was 46,XY. Urine analysis suggested a testosterone synthesis defect. Testosterone injections at the age of 3, 4 and 5 months resulted in penis growth up to 3 cm. In the first year of life surgical correction of the hypospadias was performed. The patient's sex was assigned male.

Genetic studies showed a de novo heterozygote variant in NR5A1/SF1 (c.250C>T p.Arg84Cys), which has previously been reported to cause 46,XY DSD.

Conclusions: The novel p.Gly22Ser/WT in patient 1 and the c.250C>T p.Arg84Cys/WT in patient 2 are the most likely genetic cause of 46,XY DSD in our patients, given the dominant negative effect of SF1 variants.

These two cases emphasize the different management of two only slightly different phenotypes in patients with NR5A1/SF1 variants. Time of diagnosis (one patient born in 1993 and one in 2016) before and after the change of policy in management of DSD cases with the advent of multidisciplinary teams had probably a stronger influence on decision making for medical and surgical treatment and gender assignment than the phenotype.