Congenital hyperreninemic hypoaldosteronism unlinked to the aldosterone synthase (CYP11B2) gene

Isolated hyperreninemic hypoaldosteronism presenting in infancy is usually caused by mutations in the CYP11B2 gene encoding aldosterone synthase. We s tudied five patients in four unrelated kindreds with hyperreninemic hypoald osteronism, in whom we were unable to find such mutations. All presented in infancy with failure to thrive, hyponatremia, hyperkalemia, markedly eleva ted plasma renin activity, and low or inappropriately normal aldosterone le vels. All had normal cortisol levels and no signs or symptoms of congenital adrenal hyperplasia. All responded to fludrocortisone treatment. There wer e no mutations detected in exons or splice junctions of CYP11B2. Linkage of the disorder to CYP11B2 was studied in two unrelated consanguineous patien ts and in an affected sib pair. The consanguineous patients were each heter ozygous for at least one of three polymorphic microsatellite markers near C YP11B2, excluding linkage to CYP11B2. However, linkage of the, disease to C YP11B2 could not be excluded in the affected sib pair. Genes involved in th e regulation of aldosterone biosynthesis, including those encoding angioten sinogen, angiotensin-converting enzyme, and the AT1 angiotensin II receptor were similarly excluded from linkage. These results demonstrate the existe nce of an inherited form of hyperreninemic hypoaldosteronism distinct from aldosterone synthase deficiency. The affected gene(s) remain to, be determi ned.