Steroidogenic factor-1 (SF-1, also known as Ad4BP) is an orphan nuclear receptor that regulates the transcription of an array of genes involved in reproduction, steroidogenesis and male sexual differentiation (for example, Amh, Ahch, Cyp11a, Star and those encoding steroid hydroxylases, gonadotropins and aromatase 1). Disruption in mice of the gene encoding Sf-1, Ftzf1, causes failure of adrenal and gonadal development, XY sex reversal, persistence of Müllerian structures in males and abnormalities of the hypothalamus and pituitary gonadotropes 1, 2.

Here we report a human FTZF1 mutation in a phenotypically female patient who presented with primary adrenal failure in the first two weeks of life (cortisol, 1.2 μg/dl (normal range 5-25 μg/dl); aldosterone, 5.0 ng/dl (6-105 ng/dl); adrenocorticotropin, 1,665 pg/ml (10-80 pg/ml)). Her karyotype was XY, and a presumptive diagnosis of congenital lipoid adrenal hyperplasia was made. At ten years, her hormonal status was examined further before the induction of puberty. Pituitary gonadotropins responded to gonadotropin-releasing hormone stimulation (luteinizing hormone 1.2→ 8.6 mIU/ml; follicle-stimulating hormone 17.8→ 38.0 mIU/ml), but there was no testosterone response after stimulation with human chorionic gonadotropin. Notably, normal Müllerian structures were found at laparotomy and streak-like gonads (1.5 cm× 0.4 cm× 0.2 cm) containing poorly differentiated tubules and connective tissue were removed (Fig. 1a). Transdermal 17β-estradiol gel induced normal breast development. Her uterus grew and regular menstruation occurred after the introduction of cyclical progestogen.