CLINICAL CASE SEMINAR Heterozygous Mutation of Steroidogenic Factor-1 in 46,XY Subjects May Mimic Partial Androgen Insensitivity Syndrome

Context:TheclinicalandbiologicalfeaturesofSertolicellandLeydig 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 genitaliaassociatedwithstrikinglydifferenthormonalphenotypesintwo 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 codingsequenceoftheSF-1andtheandrogenreceptor(AR)geneswas performed. Results: Both 46,XY children had ambiguous genitalia with no Mullerianstructuresandnoadrenalinsufficiency.Theolderchildshowed normal elevation of T (up to 7.6 nmol/liter, 2.2 ng/ml), AMH (504 pmol/liter,70.6ng/ml),inhibinB(245pg/ml),FSH,andLHduringthe first weeks, which led to a presumptive diagnosis of partial androgen insensitivity syndrome. 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 partial androgen insensitivity syndrome and no mutation in the AR gene. (J Clin Endocrinol Metab 92: 2868–2873, 2007)