Rebecca Moon1, John Achermann2, Lin Lin2, Nalin Wickramasuriya1 & Joanna Walker1
Introduction and Case report: Congenital adrenal hyperplasia (CAH) is a heterogenous group of conditions resulting from inborn errors of steroidogenesis, of which over 95% are due to 21-hydroxylase deficiency.
We present a 15-year-old Nepalese female, who was referred to the endocrine clinic for management of CAH. This diagnosis had been at 11 months of age, whilst resident in Hong Kong, when she presented acutely with vomiting and seizures. She had since been treated with fludrocortisone and hydrocortisone. Despite admitting variable compliance with hydrocortisone, she reported menarche at 12 years and regular menstruation. She had no evidence of virilisation or clitoromegaly, and had not had surgery. These findings were not suggestive of classical 21-hydroxylase deficiency. Karyotype was 46,XX. A urinary steroid profile confirmed complete adrenal insufficiency, and magnetic resonance imaging showed normal-sized adrenal glands. DNA analysis revealed a novel homozygous point mutation (G221D) in the steroidogenic acute regulatory protein gene (StAR), suggesting a diagnosis of lipoid CAH (LCAH). The glycine at codon 221 contributes to a hydrophobic cholesterol-interaction domain, which is likely disrupted by replacement with an acidic glutamate.
Discussions and Conclusions: The clinical importance of this case is two-fold. Firstly, the importance of re-evaluating a diagnosis when presented with unusual features is highlighted. StAR controls transfer of cholesterol across the mitochondrial membrane, and impairment results in severely compromised adrenal and testicular steroidogenesis. However StAR-independent ovarian steroidogenesis can result in spontaneous puberty in affected 46,XX subjects. Premature ovarian failure and anovulatory cycles due to ovarian cholesterol deposition are well recognised, however successful pregnancy with fertility support has been recently reported. This emphasises the importance of establishing this diagnosis to allow appropriate fertility counselling.
Secondly, the G221D mutation of StAR has not previously been reported. Functional studies are underway, which could provide additional insight into the molecular mechanisms of LCAH.