Context: The clinical and biological features of Sertoli cell and Leydig cell dysfunction are usually investigated when characterizing disorders of sex development in 46,XY individuals: This allows gonadal dysgenesis, a defective development of the gonad, to be distinguished from defects restricted to androgen synthesis or sensitivity. In humans, mutations in steroidogenic factor-1 (SF-1), one of the critical factors involved in testis development, have been reported to cause gonadal dysgenesis with or without adrenal failure in 46,XY individuals.

Objective: We report a SF-1 mutation that caused ambiguous genitalia associated with strikingly different hormonal phenotypes in two affected 46,XY children from the same family.

Methods: Hormonal evaluation included testosterone (T), anti-Mullerian hormone (AMH), inhibin B, FSH, and LH measurements during the first weeks of life, a period when physiological activation of the gonadotropin-gonadal system occurs. Direct DNA sequencing of the coding sequence of the SF-1 and the androgen receptor (AR) genes was performed.

Results: Both 46,XY children had ambiguous genitalia with no Mullerian structures, and no adrenal insufficiency. The older child showed normal elevation of T (up to 7.6 nmol/L, 2.2 ng/mL), AMH (504 pmol/L, 70.6 ng/mL), inhibin B (245 pg/mL), FSH and LH during the first weeks, which led to a presumptive diagnosis of partial androgen insensitivity syndrome (PAIS). The AR sequence was, however, normal. In the second child, T, AMH, and inhibin B were low, suggesting gonadal dysgenesis. In both children and their mother, a c.536delC frameshift mutation in the SF-1 gene was found. This mutation terminates translation at position 295, removing the ligand binding domain and the activation function 2 (AF-2) domain, a critical domain for SF-1 transactivating activity.

Conclusions: The usual markers of testis dysgenesis may be normal in 46,XY individuals with SF-1 mutation. Screening for SF-1 mutation should be performed in subjects with apparent PAIS and no mutation in the AR gene.