Endocrine Abstracts

JOINT1084

In 46,XY DSD with NR5A1/SF1 variants, genotype-phenotype correlations have failed to be found. SF1 is a nuclear receptor regulates early testis differentiation and the expression of steroidogenic enzymes, the androgen receptor (AR) and AMH. Variants affecting SF1 would be expected to result in gonadal dysgenesis and/or specific defects in androgen synthesis or action and/or in AMH expression, leading to various degrees of undervirilisation. This report describes two cases with 46,XY DSD and variants in NR5A1 and opposite phenotypes, with hormonal and anatomic features that challenge the hypotheses on the potential pathogenic mechanisms. Case 1, assigned male at birth, was referred at 2 years of age, the phallus was 2.5-cm long, with penoscrotal hypospadias, partial labioscrotal fusion and labioscrotal gonads (External Genital Score-EGS: 7/12). Serum hormone levels were: FSH 5 mIU/mL (ref: 0.3-1.7), AMH 338 pmol/l (300-1800), LH 0.8 mIU/mL (0.1-0.3). At 6 years, testosterone post-hCG was 150 ng/dl. Altogether, these results indicated a mild primary hypogonadism. Müllerian remnants were absent in imaging studies. Gonadal histology, showing abnormally branching seminiferous tubules with typical Sertoli and premeiotic germ cells and a normal albuginea, was interpreted as mild testicular dysgenesis. Genetic analysis by NGS identified a heterozygous, missense, likely pathogenic variant NM_004959.5:c.259C>T, NP_004950.2:p.(Arg87Cys) in exon 4, corresponding to the DNA-binding domain (DBD), of NR5A1. Case 2, assigned female, was referred at 11 years of age for clitoromegaly. The phallus length was 3.5 cm, completely separated labia majora, a single urogenital opening and nonpalpable gonads (EGS 3/12). Hormone levels were: FSH 23 mIU/mL (ref for 46,XY: 1.3-6.5), AMH 10 pmol/l (40-400), LH 10 mIU/mL (0.7-5.2), testosterone 272 ng/dl (40-550), indicating mild primary hypogonadism. Surgical exploration showed the existence of abdominal gonads and absence of Müllerian remnants. Gonadal histology, showing normal albuginea, seminiferous tubules with typical Sertoli cells, absence of germ cells and thickened basement membrane, and interstitial tissue with typical Leydig cells, was interpreted as typical testicular tissue with changes associated with cryptorchid position. NGS identified a heterozygous, missense, likely pathogenic variant NM_004959.5:c.1210T>A, NP_004950.2:p.(Tyr404Asn) in exon 7 corresponding to the ligand-binding domain (LBD) of NR5A1. In conclusion, these two cases with very mildly affected testicular function showed normal Müllerian duct regression, as expected, but completely opposite androgen activity. These observations advocate against an effect of the NR5A1 variants on testis differentiation and AMH expression, with potentially different effects on testosterone production and/or AR activity, and highlight the need for further functional explorations.