Dexamethasone-suppressible hyperaldosteronism (glucocorticoid-remediable aldosteronism) is a rare familial disorder inherited as an autosomal-dominant trait that exhibits the clinical features of hyperaldosteronism outlined previously.45 As a result of an abnormality in the adrenal glands of patients with dexametha-sone-suppressible hyperaldosteronism, ACTH causes a sustained overproduction of aldosterone (Fig. 80-8). This is in contrast to
the usual response of aldosterone secretion to the prolonged administrationof ACTH: after an initial rise, plasma aldosterone levels fall back to baseline values on the second day and show little change during the subsequent days of ACTH treatment (Fig. 80-9). Patients with dexamethasone-suppressible hyperaldosteronism exhibit gene duplication in which there is an unequal crossing over and fusion of the 5′ regulatory region of 11β-hydroxylase with the coding region of aldosterone synthase to form a chimeric gene.46 These chimeric gene formations probably have occurred because of the close proximity of the genes for 11β-hydroxylase and aldosterone synthase on chromosome 8 and their almost identical (95%) nucleotide sequences. These chimeric genes result in expression of aldosterone synthase under the regulatory control of ACTH in adrenal fasciculata cells. This explains why aldosterone is regulated by ACTH in these patients and why ACTH produces a sustained overproduction of aldosterone (see Fig. 80-8) instead of the normal transitory rise with a fall back to baseline values for the remainder of ACTH administration (see Fig. 80-9). The presence of an ACTH-regulated aldosterone synthase in adrenal fasciculata cells also explains why these patients form and excrete in their urine supernormal amounts of 18-hydroxycortisol and 18-oxocortisol47 in addition to aldosterone. The production of aldosterone by fasciculata cells leads to suppression of the production of aldosterone by the zona glomerulosa. Because 18-oxocortisol has mineralocorticoid activity,48 it may represent the mineralocorticoid activity seen in the radioreceptor assay that is not accounted for by summation of known mineralocorticoids.49