A novel form of human mendelian hypertension featuring nonglucocorticoid-remediable aldosteronism

Context: Primary aldosteronism is a leading cause of secondary hypertension (HTN), but the mechanisms underlying the characteristic renin-independent secretion of aldosterone remain unknown in most patients. Objectives: We report a new familial form of aldosteronism in a father and two daughters. All were diagnosed with severe HTN refractory to medical treatment by age 7 yr. We performed a variety of clinical, biochemical, and genetic studies to attempt to clarify the underlying molecular defect. Results: Biochemical studies revealed hyporeninemia, hyperaldosteronism, and very high levels of 18-oxocortisol and 18-hydroxycortisol, steroids that reflect oxidation by both steroid 17-alpha hydroxylase and aldosterone synthase. These enzymes are normally compartmentalized in the adrenal fasciculata and glomerulosa, respectively. Administration of dexamethasone failed to suppress either aldosterone or cortisol secretion; these findings distinguish this clinical syndrome from glucocorticoid-remediable aldosteronism, another autosomal dominant form of HTN, and suggest a global defect in the regulation of adrenal steroid production. Genetic studies excluded mutation at the aldosterone synthase locus, further distinguishing this disorder from glucocorticoid-remediable aldosteronism. Because of unrelenting HTN, all three subjects underwent bilateral adrenalectomy, which in each case corrected the HTN. Adrenal glands showed dramatic enlargement, with paired adrenal weights as high as 82 g. Histology revealed massive hyperplasia and cellular hypertrophy of a single cortical compartment that had features of adrenal fasciculata or a transitional zone, with an atrophic glomerulosa. Conclusion: These findings define a new inherited form of aldosteronism and suggest that identification of the underlying defect will provide insight into normal mechanisms regulating adrenal steroid biosynthesis.