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Congenital Hyperreninemic Hypoaldosteronism Unlinked to the Aldosterone Synthase (CYP11B2) Gene

Division of Pediatric Endocrinology (K.M.K.-W., G.M.T., P.C.W.), University of Texas Southwestern Medical Center, Dallas, Texas 75390-9063; Section of Pediatric Endocrinology (D.S.), All Children’s Hospital, St. Petersburg, Florida 33701; (D.P.) Clearwater, Florida 33761; Department of Pediatrics (K.L.J.), University of California at San Diego, La Jolla, California 92093-6933; and Division of Endocrinology (L.K.), Texas Children’s Hospital, Houston, Texas 77030

Address all correspondence and requests for reprints to: Perrin C. White, M.D., Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9063. E-mail: perrin.white{at}utsouthwestern.edu

Abstract

Isolated hyperreninemic hypoaldosteronism presenting in infancy is usually caused by mutations in the CYP11B2 gene encoding aldosterone synthase. We studied five patients in four unrelated kindreds with hyperreninemic hypoaldosteronism, in whom we were unable to find such mutations. All presented in infancy with failure to thrive, hyponatremia, hyperkalemia, markedly elevated plasma renin activity, and low or inappropriately normal aldosterone levels. All had normal cortisol levels and no signs or symptoms of congenital adrenal hyperplasia. All responded to fludrocortisone treatment. There were no mutations detected in exons or splice junctions of CYP11B2. Linkage of the disorder to CYP11B2 was studied in two unrelated consanguineous patients and in an affected sib pair. The consanguineous patients were each heterozygous for at least one of three polymorphic microsatellite markers near CYP11B2, excluding linkage to CYP11B2. However, linkage of the disease to CYP11B2 could not be excluded in the affected sib pair. Genes involved in the regulation of aldosterone biosynthesis, including those encoding angiotensinogen, angiotensin-converting enzyme, and the AT1 angiotensin II receptor were similarly excluded from linkage. These results demonstrate the existence of an inherited form of hyperreninemic hypoaldosteronism distinct from aldosterone synthase deficiency. The affected gene(s) remain to be determined.

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