Clinical and gene mutation studies on a Chinese pedigree with glucocorticoid-remediable aldosteronism.

OBJECTIVE

To report the clinical characteristics, biochemical profiles, diagnosis and treatment of one Chinese pedigree with glucocorticoid-remediable aldosteronism (GRA) and to study its molecular mechanism.

METHODS

Plasma and urinary aldosterone, cortisol and plasma renin activities were dynamically tested and diagnostic therapy with dexamethasone was undergone in 3 affected subjects. Long-distance PCR as well as DNA sequencing were applied to detect the fusion gene in this pedigree.

RESULTS

In this GRA pedigree, there were 4 affected subjects who had hypertension, hypokalemia and low basic and provoked renin activity. Three patients were given dexamethasone treatment, and had a significant decrease in plasma aldosterone concentrations (PACs) (from 192 +/- 9 ng/L to 87 +/- 7ng/L, P < 0.05) after 5 days. Among them, one patient (II -3) responded quite satisfactorily to the therapy, with serum K(+) rising from baseline value of 2.5 to 2.9, 3.8 and 4.15 mEq/L on the 10th, 28th and 35th days after treatment respectively. Three weeks later, his blood pressure decreased from its original level of 146.3 +/- 1 0.7/94.6 +/- 5.3 mm Hg to 138.3 +/- 3.1/87.3 +/- 6.1 mm Hg (P < 0.05). The other 2 members (III -2 and III -4) showed modest improvement although their PACs decreased significantly. Using long-distance PCR, we found a 3.9 kb band in all 4 affected individuals, which was absent in 5 unaffected members from this pedigree or 8 patients with aldosterone-producing adenoma (APA) or idiopathic hyperaldosteronism (IHA). By DNA sequence analysis, we found that the breakpoint of "unequal crossing-over" is both within intron 2 of the 11beta-hydroxylase gene (CYP11B1) and the aldosterone synthase gene (CYP11B2).

CONCLUSIONS

The excess of mineralocorticoid in patients with GRA can be inhibited by exogenous glucocorticoids. The fusion gene resulting from unequal crossing-over between the 11beta-hydroxylase gene and the aldosterone synthase gene is the pathogenesis of this Chinese GRA pedigree.