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

Background: Cytochrome P450c17 (CYP17) has two principal enzyme activities, 17 alpha-hydroxylase and 17,20-lyase, which are required for cortisol and androgen biosynthesis, respectively. Mutations in the gene encoding for CYP17 result in 17 alpha-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. Patient: 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. Methods: 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. Results: 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. Conclusion: This patient is a compound heterozygote for nonsense mutations in the CYP17 gene, which confirms the diagnosis of 17OHD.