Predominant Sertoli cell deficiency in a 46,XY disorders of sex development patient with a new NR5A1/SF-1 mutation transmitted by his unaffected father

Objective: To further investigate the molecular mechanism by which NR5A1/SF-1 mutation led to gonadal dysgenesis with predominant Sertoli cell defect.

Design: Genetic and functional mutation study.

Setting: University hospital.

Patient(s): Genetic analysis of an XY newborn with hypospadias and micropenis. Puberty developed spontaneously with a rise in T levels and normal LH contrasting with high FSH and low inhibin B concentrations, revealing a Sertoli cell defect.

Intervention(s): None.

Main outcome measure(s): NR5A1/SF-1 gene molecular analysis.

Result(s): Genetic analysis identified a new NR5A1/SF-1 mutation, c.842G>C (p.Arg281Pro). In vitro functional studies showed that the p.Arg281Pro mutant mainly altered Sertoli cell function, as observed in vivo with a high FSH level and low inhibin B concentration contrasting with normal LH concentration. The mutation was found in the father's DNA at a low copy number through direct sequencing and high-resolution melting assay, suggesting mosaicism.

Conclusion(s): We describe a new heterozygous NR5A1/SF-1 mutation that mainly altered Sertoli cell function. However, this 46,XY disorders of sex development (DSD) boy had no Müllerian derivatives, suggesting normal Sertoli cell function during fetal life. During puberty, Sertoli cell deficiency became more apparent. This is the first report of a progressive and predominant Sertoli cell defect in an XY patient with testicular dysgenesis owing to NR5A1/SF-1 mutation.