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The wide clinical expression spectrum presented in two families with NR5A1 mutation

Yanning Song, LijunFan, Xiu Zhao, Xiaoya Ren, Beibei Zhang & Chunxiu Gong*

Context: Patients with NR5A1 mutations present a wide spectrum of phenotype. The gene is frequently associated with 46, XY disorders of sex development (DSD). Objectives: To analyze the clinical expression and NR5A1 mutations in two families with probands presenting 46, XY DSD. Results: Two probands with 46, XY gonadal dysgenesis from two unconsanguineous families showed spontaneous puberty, normal levels of ACTH, cortisol, testosterone, increased FSH and decreased LH/FSH, AMH and INHB. In Family 1, a novel pathogenic variant, p.C33X, was identified in the proband. By determining other members in this family, the variant was found in the proband’s mother, two elder sisters and two nephews. However, no obvious anomaly was presented in the eldest sister with the variant while her two sons showed hypospadias. In Family 2, the proband inherited a reported pathogenic variant, p.M1I from his mother who delivered 4 children by natural pregnancy. The self-reported family puberty and fertility history was negative until we calculated the exact menopause age of mothers at 36 and 41 years of age respectively. Conclusion: The 46, XY DSD patients with NR5A1variants show highly variable phenotypes, from complete female genitalia to ambiguous external genitals/hypospadias. While 46, XX individual may have inconspicuous symptoms. Normal fertility is not a reliable negative family history on this disease. The identified novel pathogenic variant, p.C33X in patient 46, XY DSD and 46, XX primary ovarian insufficiency extends the genotypic and phenotypic spectrum of NR5A1. This study also highlights the critical role of NR5A1 protein in gonadal development and differentiation.