title: Familial hyperaldosteronism type II: description of a large kindred and exclusion of the aldosterone synthase (CYP11B2) gene.
abstract: 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 (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 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.
authors.affiliation: Unit on Genetics and Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Torpy
authors.forename: R D
authors.initials: RD
authors.lastname: Gordon
authors.forename: J P
authors.initials: JP
authors.lastname: Lin
authors.forename: P R
authors.initials: PR
authors.lastname: Huggard
authors.forename: S E
authors.initials: SE
authors.lastname: Taymans
authors.forename: M
authors.initials: M
authors.lastname: Stowasser
authors.forename: G P
authors.initials: GP
authors.lastname: Chrousos
authors.forename: C A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D000450:Aldosterone / Q000097:blood; D015139:Blotting, Southern; D002874:Chromosome Mapping; D002898:Chromosomes, Human, Pair 8; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics*; D003907:Dexamethasone; D005260:Female; D005838:Genotype; D006801:Humans; D006929:Hyperaldosteronism / Q000201:enzymology / Q000235:genetics*; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011188:Potassium / Q000097:blood; D012083:Renin / Q000097:blood
chemical_list: D000450:Aldosterone; D003907:Dexamethasone; D019405:Cytochrome P-450 CYP11B2; D012083:Renin; D011188:Potassium