Steroid 17α-hydroxylase (CYP17A1) exerts two distinct activities that catalyze conversion reactions at key branch points in steroidogenesis. CYP17A1 17α-hydroxylase activity is the key step in cortisol synthesis whereas CYP17A1 17,20 lyase activity generates sex steroid precursors. Inactivating CYP17A1 mutations result in CYP17A1 deficiency (17OHD), a rare form of congenital adrenal hyperplasia that classically presents with combined glucocorticoid and sex steroid deficiency and hypokalaemic hypertension. We have investigated four patients with 17OHD harbouring four novel mutations, which we analyzed in vitro and in silico. Case 1 (46,XY; homozygous p.F53/54del) presented at 12 years with glandular hypospadias, gynaecomastia and cryptorchidism. Endocrine assessment revaled hypergonadotropic hypogonadism, low cortisol at baseline and after ACTH1-24 stimulation, but notably normal blood pressure. Case 2 (46,XX; homozygous p.Y60IfsK88X) presented with severe adrenal insufficiency three weeks after birth. Case 3 (46,XX; p.G111V/p.P409L) presented at the age of 15 years with lack of pubertal development and a history of hypokalaemic hypertension since the age of 2 years. Case 4 (46,XY; p.R347H/p.A398E) was born with ambiguous genitalia but had normal blood pressure and no evidence of glucocorticoid deficiency at the age of 24 years. Urinary steroid profiling with gas chromatography/mass spectrometry established the biochemical diagnosis in all cases. Functional in vitro analysis of CYP17A1 activities in transiently transfected HEK293 cells confirmed p.Y60IfsK88X, p.P409L and p.G111V to severely reduce or abolish CYP17A1 function; p.A398E, p.F53/54del and p.R347H resulted in mild to moderate impairment of enzyme activity. Results of in silico analysis of the identified mutations were consistent with the in vitro findings. In summary, we have identified four novel CYP17A1 mutations and our functional studies confirmed the pathogenicity of these mutations. The clinical presentations ranged from neonatal presentation with severe adrenal insufficiency to delayed pubertal development and normal adrenal function, illustrating the broad phenotypic spectrum in 17OHD.
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 Medical Research Council UK (Research Fellowship G1001964, to J.I,. and Program Grant 0900567, to W.A.), the European Society for Paediatric Endocrinology (Research Fellowship to J.I.), the European Communitys Seventh Framework Program (Collaborative Research Project EuroDSD GA-2008201444, to W.A), and the Wellcome Trust (Clinician Scientist Fellowship GR079865MA, to N.K.).