Novel mutation in cytochrome P450c17 causes complete combined 17alpha-hydroxylase/17,20-lyase deficiency

Cytochrome P450c17 (CYP17) has two principal enzyme activities, 17alpha-hydroxylase and 17,20-lyase, which are required for cortisol and androgen biosynthesis, respectively. Mutations in the gene encoding for CYP17 result in 17alpha-hydroxylase deficiency (17OHD), a rare form of congenital adrenal hyperplasia, a disorder characterized by adrenal insufficiency, hypertension, primary amenorrhea and sexual infantilism. We describe a case of complete combined 17OHD caused by mutations in the CYP17 gene.

This study evaluates a 19 year-old Korean female born from a non-consanguineous relationship who presented with primary amenorrhea, hypertension, hyperpigmentation, absent axillary hair and pubic hair, and Tanner I breasts. Laboratory evaluation showed markedly elevated adrenocorticotropin and 11-deoxycorticosterone with suppressed plasma renin, aldosterone, and cortisol, consistent with 17OHD.

Genomic DNA was isolated from peripheral blood leukocytes. The eight exons of the human CYP17 gene were amplified in four segments by polymerase chain reaction. Amplicons were gel-purified and directly sequenced.

The patient was found to be compound heterozygous for mutations in exon 6: a novel mutation R358X (CGA--TGA) and Y329 del/ sub (TAC-->AA). Both alterations introduce premature stop codons prior to the hemebinding cysteine and are predicted to completely inactivate the encoded P450c17 proteins.

This patient is a compound heterozygote for nonsense mutations in the CYP17 gene, which confirms the diagnosis of 17OHD.