FAMILIAL HYPERALDOSTERONISM TYPE-II - DESCRIPTION OF A LARGE KINDRED AND EXCLUSION OF THE ALDOSTERONE SYNTHASE (CYP11B2) GENE

Familial hyperaldosteronism type II (FH-II) is characterized by autoso mal dominant inheritance and hypersecretion of aldosterone due to adre nocortical hyperplasia or an aldosterone-producing adenoma; unlike FH type I (FH-I), hyperaldosteronism in FH-II is not suppressible by dexa methasone. Of a total of 17 FH-II families with 44 affected members, w e studied a large kindred with 7 affected members that was informative for linkage analysis. Family members were screened with the aldostero ne/PRA ratio test; patients with aldosterone/PRA ratio greater than 25 underwent fludrocortisone/salt suppression testing for confirmation o f autonomous aldosterone secretion. Postural testing, adrenal gland im aging, and adrenal venous sampling were also performed. Individuals af fected by FH-II demonstrated lack of suppression of plasma A levels af ter 4 days of dexamethasone treatment (0.5 mg every 6 h). All patients had neg ative genetic testing for the defect associated with FH-I, th e CYP11B1/CYP11B2 hybrid gene. Genetic linkage was then examined betwe en 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 chromo some 8q21-8qtel were genotyped and analyzed for linkage. Two-point log arithm of odds scores were negative and ranged from -12.6 for the CYP1 1B2 polymorphic marker to -0.98 for the D8S527 marker at a recombinati on distance (theta) 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 tha t FH-II shares autosomal dominant inheritance and hyperaldosteronism w ith FH-I, but, as demonstrated by the large kindred investigated in th is report, it is clinically and genetically distinct. Linkage analysis demonstrated that the CYP11B2 gene is not responsible for FH-II in th is family; furthermore, chromosome 8q21-8qtel most likely does not har bor the genetic defect in this kindred.