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Familial Hyperaldosteronism Type II: Description of a Large Kindred and Exclusion of the Aldosterone Synthase (CYP11B2) Gene¹

Unit on Genetics and Endocrinology (D.J.T., C.A.S., S.E.T.), Section on Pediatric Endocrinology (G.P.C.), Developmental Endocrinology Branch, National Institute of Child Health and Human Development; and the Section on Genetic Studies, Laboratory of Skin Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases (J.-P.L.), National Institutes of Health, Bethesda, Maryland 20892; and the Hypertension Unit, Greenslopes Hospital (R.D.G., M.S., P.R.H.), Greenslopes, Brisbane, Queensland 4120, Australia

Address all correspondence and requests for reprints to: Constantine A. Stratakis, M.D., D.Sc., Unit on Genetics and Endocrinology, Building 10, Room 10 N 262, 10 Center Drive, MSC 1862, Bethesda, Maryland 20892-1862. E-mail: stratakc{at}cc1.nichd.nih.gov

Familial hyperaldosteronism type II (FH-II) is characterized by autosomal dominant inheritance and hypersecretion of aldosterone due to adrenocortical hyperplasia or an aldosterone-producing adenoma; unlike FH type I (FH-I), hyperaldosteronism in FH-II is not suppressible by dexamethasone. Of a total of 17 FH-II families with 44 affected members, we studied a large kindred with 7 affected members that was informative for linkage analysis. Family members were screened with the aldosterone/PRA ratio test; patients with aldosterone/PRA ratio greater than 25 underwent fludrocortisone/salt suppression testing for confirmation of autonomous aldosterone secretion. Postural testing, adrenal gland imaging, and adrenal venous sampling were also performed. Individuals affected by FH-II demonstrated lack of suppression of plasma A levels after 4 days of dexamethasone treatment (0.5 mg every 6 h). All patients had negative genetic testing for the defect associated with FH-I, the CYP11B1/CYP11B2 hybrid gene. Genetic linkage was then examined between FH-II and aldosterone synthase (the CYP11B2 gene) on chromosome 8q. A polyadenylase repeat within the 5'-region of the CYP11B2 gene and 9 other markers covering an approximately 80-centimorgan area on chromosome 8q21–8qtel were genotyped and analyzed for linkage. Two-point logarithm of odds scores were negative and ranged from -12.6 for the CYP11B2 polymorphic marker to -0.98 for the D8S527 marker at a recombination distance () of 0. Multipoint logarithm of odds score analysis confirmed the exclusion of the chromosome 8q21–8qtel area as a region harboring the candidate gene for FH-II in this family. We conclude that FH-II shares autosomal dominant inheritance and hyperaldosteronism with FH-I, but, as demonstrated by the large kindred investigated in this report, it is clinically and genetically distinct. Linkage analysis demonstrated that the CYP11B2 gene is not responsible for FH-II in this family; furthermore, chromosome 8q21–8qtel most likely does not harbor the genetic defect in this kindred.

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