Familial hyperaldosteronism type II : Description of a large kindred and exclusion of the aldosterone synthase (CYP11B2) gene

• Published in: The journal of clinical endocrinology and metabolism 1998-09, Vol.83 (9), p.3214-3218
• Main Authors: TORPY, D. J, GORDON, R. D, JING PING LIN, HUGGARD, P. R, TAYMANS, S. E, STOWASSER, M, CHROUSOS, G. P, STRATAKIS, C. A
• Format: Article
• Language: English
• Subjects: Adrenals. Adrenal axis. Renin-angiotensin system (diseases); Aldosterone - blood; Biological and medical sciences; Blotting, Southern; Chromosome Mapping; Chromosomes, Human, Pair 8; Cytochrome P-450 CYP11B2 - genetics; Dexamethasone; Endocrinopathies; Female; Genotype; Humans; Hyperaldosteronism - enzymology; Hyperaldosteronism - genetics; Lod Score; Male; Medical sciences; Middle Aged; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Pedigree; Polymerase Chain Reaction; Potassium - blood; Renin - blood
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.83.9.3214

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.