Background: Steroidogenic factor (SF1, NR5A2) regulates multiple genes known to be involved in gonadal development, adrenal development, steroidogenesis, and gonadotroph development. Heterozygous mutations in the NR5A1 gene have been described in association with mild to severe gonadal dysgenesis with or without adrenal failure. Homozygous mutations are rare and have also been described in association with gonadal dysgenesis with or without adrenal failure.
Case vignette: We report a 18-year-old patient of normal female phenotype with absent breast development and primary amenorrhea. Stage of puberty was Tanner B1, PH 3. There was no axillary hair. Serum concentrations were low for estradiol, low for testosterone, low for AMH, and low for Inhibin B. These findings suggested gonadal dysgenesis. Unexpectedly LH and FSH were within the normal range. In addition, endocrine evaluation showed low adrenal androgens, whereas ACTH testing revealed normal cortisol response. Karyotyping revealed 46, XY. Pelvic ultrasound showed no mullerian structures and no gonads. Genetic examination was performed and revealed a novel homozygous mutation in the NR5A1 gene (c.1048C>T; p.Arg350Trp). This mutation has an allele frequency of <0.0001 according to ExAC and gnomAD and has, to our knowledge, not been described in the literature. Prediction programs for a possible pathogenicity SIFT and PolyPhen classify this mutation as deleterious and probably damaging. Both parents are heterozygous for this mutation and phenotypically normal and healthy.
Conclusions: Homozygous SF 1 mutation can be responsible for sex reversal with normogonadotropic hypogonadism and low adrenal androgens.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology