Cytochrome P450 side-chain cleavage enzyme (CYP11A1) catalyses the first and rate-limiting step of steroidogenesis. CYP11A1 firstly converts cholesterol into 22R-hydroxycholesterol, which relies on mitochondrial steroidogenic acute regulatory protein (StAR)-mediated cholesterol import. Two further StAR-independent CYP11A1 reactions facilitate pregnenolone biosynthesis. CYP11A1 deficiency is rare and manifests with adrenal insufficiency (AI), and, in 46,XY individuals, with normal male genital development or disorder of sex development (DSD). We describe a 46,XY patient born with hyperpigmentation, micropenis and penoscrotal hypospadias. At birth, biochemical and hormonal findings were normal except for low testosterone concentrations. Development was unremarkable apart from an episode labelled as sepsis (day 15 of life) with documented hyponatraemia and hyperkalaemia. Finally, AI was diagnosed at the age 2.8 yr with raised ACTH and renin, low aldosterone and normal baseline cortisol, not responding to ACTH-stimulation. Ultrasound showed normal-sized adrenals and testicular microlithiasis. Molecular genetic analysis neither showed mutations in the SF1 nor StAR gene. However, two novel CYP11A1 mutations (p.Arg360Trp (g.27921C>T); p.Arg405X (g.28327C>T)) were found. Segregation analysis confirmed compound heterozygosity. Functional in vitro analysis was performed in COS7 cells transiently transfected with wild-type or mutant CYP11A1 cDNA, with or without wild-type StAR cDNA. Transfected cells were incubated with either cholesterol or 22R-hydroxycholesterol. Pregnenolone synthesis was quantified by liquid chromatography/tandem mass spectrometry. The in vitro assays showed that p.Arg360Trp is partially inactivating. Our in silico analysis confirmed these findings and suggest that p.Arg405X completely abolishes CYP11A1 activity. Our data demonstrates that CYP11A1 mutations can differently impact on adrenal and gonadal sterodoidogenesis, which is exemplified by progressive AI during infancy but impaired gonadal function already during prenatal life. The delayed onset of adrenal insufficiency may hinder early diagnosis of CYP11A1 deficiency. Thus, a short synacthen test should be performed in patients with DSD to assess adrenal function and prevent life-threatening adrenal crisis.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: Declaration of Funding: This work was supported by the Marie Curie Intra-European fellowship (IEF-GA-2009-255424, to S.P.); the European Commission (Collaborative Research Project EuroDSD FP7-GA-2008-201444, to W.A.); the Medical Research Council UK (Programme Grant 0900567, to W.A.); and the Wellcome Trust (Clinician Scientist Fellowship GR079865MA, to N.K.)