TREASURE YOUR EXCEPTIONS - WHAT WE CAN LEARN FROM AUTOSOMAL-DOMINANT INHERITED FORMS OF HYPERTENSION

Objective: To discuss the relevance of rare monogenic forms of hyperte nsion to the diagnosis, pathogenesis and treatment of essential hypert ension. Study selection: Three monogenic forms of hypertension have be en identified that are inherited as a simple autosomal-dominant trait. The genetic defects and the pathophysiology of two, namely glucocorti coid-remediable aldosteronism and Liddle's syndrome, have been elucida ted in great detail. The third form of monogenic hypertension, which c osegregates with a second phenotype, brachydactyly, is being investiga ted. Results: Glucocorticoid-remediable aldosteronism is caused by the presence of a chimeric gene, which incorporates the regulatory region of the 11-beta-hydroxylase gene and the structural portion of the ald osterone synthase gene. The enzyme aldosterone synthase is not only ex pressed in the zona fasiculata but is also regulated by adrenocorticot rophic hormone in this condition. Liddle's syndrome is caused by mutat ions in the beta subunit of the epithelial sodium channel. The mutatio ns result in inappropriate channel patency and increased distal sodium reabsorption. Both of these forms of inherited hypertension are low-r enin forms of hypertension. Glucocorticoid-remediable aldosteronism re sembles primary aldosteronism, whereas Liddle's syndrome resembles low -renin essential hypertension. An autosomal-dominant genetic form of h ypertension has been described in northeastern Turkey. The hypertensio n cosegregates 100% with brachydactyly. This form resembles essential hypertension, because levels of renin, aldosterone, catecholamines and other regulators are normal. Furthermore, in contrast to glucocortico id-remediable aldosteronism and Liddle's syndrome, the patients are no t salt-sensitive. Conclusions: Mechanisms of mineralcorticoid hyperten sion, renally induced salt-sensitive hypertension, and possibly essent ial hypertension, may be elucidated by studying exceptional families.