Genetic study of patients with dexamethasone-suppressible aldosteronism without the chimeric CYP11B1/CYP11B2 gene

Glucocorticoid-remediable aldosteronism is an inherited disorder caused by a chimeric gene duplication between the CYP11B1 (11 beta -hydroxylase) and CYP11B2 (aldosterone synthase) genes. The disorder is characterized by hype raldosteronism and high levels of 18-hydroxycortisol and 18-oxocortisol, wh ich are under ACTH control. The diagnosis of glucocorticoid-remediable aldo steronism had been traditionally made using the dexamethasone suppression t est; however, recent studies have shown that several patients with primary aldosteronism and a positive dexamethasone suppression test do not have the chimeric CYP11B1/CYP11B2 gene. The aim of this work was to evaluate whethe r other genetic alterations exist in CYP11B genes (gene conversion in the c oding region of CYP11B1 or in the promoter of CYP11B2) that could explain a positive dexamethasone suppression test and to determine another genetic c ause of glucocorticoid-remediable aldosteronism. We also evaluated the role of 18-hydroxycortisol. as a specific biochemical marker of glucocorticoid- remediable aldosteronism. We studied eight patients with idiopathic hyperal dosteronism, a positive dexamethasone suppression test, and a negative gene tic test for the chimeric gene. In all patients we amplified the CYP11B1 ge ne by PCR and sequenced exons 3-9 of CYP11B1 and a specific region (-138 to -284) of CYP11B2 promoter. We also measured the levels of 18-hydroxycortis ol, and we compared the results with those found in four subjects with the chimeric gene. None of eight cases showed abnormalities in exons 3-9 of CYP 11B1, disproving a gene conversion phenomenon. In all patients a fragment o f 393 bp corresponding to a specific region of the promoter of CYP11B2 gene was amplified. The sequence of the fragment did not differ from that of th e wild-type promoter of the CYP11B2 gene. The 18-hydroxycortisol levels in the eight idiopathic hyperaldosteronism patients and four controls with chi meric gene were 3.9 +/- 2.3 and 21.9 +/- 3.5 nmol/liter, respectively (P < 0.01). In summary, we did not find other genetic alterations or high levels of 18-hydroxycortisol that could explain a positive dexamethasone suppress ion test in idiopathic hyperaldosteronism. We suggest that the dexamethason e suppression test could lead to an incorrect diagnosis of glucocorticoid-r emediable aldosteronism.