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Liddle’s Syndrome: Prospective Genetic Screening and Suppressed Aldosterone Secretion in an Extended Kindred¹

Endocrine Research Laboratory, Department of Medicine, St. Luke’s Medical Center, Medical College of Wisconsin (J.W.F., H.R.), Milwaukee, Wisconsin 53215; Howard Hughes Medical Institute, Departments of Medicine and Genetics, Boyer Center for Molecular Medicine, Yale University School of Medicine (J.H.H., R.P.L.), New Haven, Connecticut 06510

Address all correspondence and requests for reprints to: James W. Findling, M.D., Department of Medicine, St. Luke’s Health Science Office Building, 2901 West KK River Parkway, Suite 503, Milwaukee, Wisconsin 53215.

Liddle’s syndrome is an autosomal dominant form of hypertension that resembles primary hyperaldosteronism, is characterized by the early onset of hypertension with hypokalemia and suppression of both PRA and aldosterone, and is caused by mutations in the carboxyl-terminus of the ß- or -subunits of the renal epithelial sodium channel. We describe a kindred (K176) whose distinguishing clinical features were mild hypertension and decreased aldosterone secretion. The index case was a 16-yr-old girl with intermittent mild hypertension and hypokalemia and subnormal PRA, aldosterone, 18-hydroxycorticosterone, and deoxycortisol levels, but normal cortisol/cortisone metabolite ratio and cortisol half-life. A frameshift mutation in the carboxyl-terminus of the ß-subunit of the epithelial sodium channel was identified in the index case, establishing the diagnosis of Liddle’s syndrome. Sixteen at-risk relatives of the index case were tested. Seven new subjects were heterozygous for the mutation found in the index case, and two deceased obligate carriers were identified. All genetically affected adult subjects had a history of mild hypertension, and four had a history of hypokalemia. Basal and postcosyntropin plasma aldosterone and urinary aldosterone levels were significantly suppressed in those positive for the mutation. The family demonstrates variability in the severity of hypertension and hypokalemia in this disease, raising the possibility that this disease may be underdiagnosed among patients with essential hypertension.

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