Endocrine Abstracts

CYP17A1 is a key enzyme of human steroidogenesis, which is unique in that it catalyses two reactions, 17-hydroxylase activity converting pregnenolone and progesterone to 17-hydroxypregnenolone (17Preg) and 17-hydroxy-progesterone, respectively, and 17,20 lyase activity, responsible for the conversion of 17Preg to dehydroepiandrosterone the crucial precursor of human sex steroid biosynthesis. 17-hydroxylase deficiency, a variant of congenital adrenal hyperplasia, results in glucocorticoid deficiency and accumulation of the mineralocorticoid precursor corticosterone that can also bind the glucocorticoid receptor, clinically manifesting with hypertension and mild glucocorticoid deficiency. Strikingly, loss of 17,20 lyase activity results in sex steroid deficiency, presenting with undervirilisation, i.e. disordered sexual differentiation in boys (46, XY DSD), and lack of pubertal development in affected girls. Here we analysed the genotype and biochemical phenotype in a patient with 17-hydroxylase deficiency caused by a novel, homozygous CYP17A1 mutation. The baby presented in the early neonatal period with signs of severe adrenal insufficiency, raising the suspicion of generalised adrenal insufficiency e.g. due to SF-1, DAX-1 or CYP11A1 mutations. However, gas chromatography/mass spectrometry (GC/MS) analysis of the urinary steroid metabolite pattern revealed predominantly excretion of pregnenolone metabolites. Cortisol metabolites were only detectable in the form of very low concentrations of tetrahydrocorticosterone (THE) whilst corticosterone metabolites, mainly present as tetrahydro-11-deoxycorticosterone (THA), were higher than cortisol metabolites, but not increased as usually expected in 17-hydroxylase deficiency. No C19 steroids, i.e. androgen precursor steroids, were detected. Taken together these results suggest a combined and complete of CYP17A1 activities. Sequencing analysis of the coding region of the CYP17A1 gene by PCR amplification and direct sequencing identified a homozygous A duplication in exon 1 (g.177dupA; c.177dupA; Y60I fs K88X), resulting in a frameshift at codon 60 with a subsequent premature stop codon at codon 88, i.e. N-terminal of the heme-binding sequence of the 508 aa CYP17A1 protein. This very early truncation of the CYP17 protein explains the near total loss of activity with residual corticosterone secretion not sufficient to compensate for the loss of glucocortcoid synthesis in the early neonatal period. These findings further highlight the value of urinary steroid excretion analysis by GC/MS in the differential diagnosis of neonatal adrenal insufficiency.