A number sign (#) is used with this entry because of evidence that familial hyperaldosteronism type II (HALD2) is caused by heterozygous mutation in the CLCN2 gene (600570) on chromosome 3q27.

For a general phenotypic description and a discussion of genetic heterogeneity of familial hyperaldosteronism, see HALD1 (103900).

Familial hyperaldosteronism type II (HALD2) is an autosomal dominant disorder characterized by hypertension due to increased aldosterone, often with hypokalemia. Patients usually present before age 20 years, although some may present in infancy. The disorder shows incomplete penetrance and variable expressivity; some patients may have normal blood pressure but have an increased aldosterone:renin ratio (ARR) on laboratory testing. Spironolactone is an effective treatment (summary by Scholl et al., 2018).

For a general phenotypic description and a discussion of genetic heterogeneity of familial hyperaldosteronism, see HALD1 (103900).

Stowasser et al. (1992) reported a family (family 3) with familial hyperaldosteronism. Affected individuals had hypertension and hypokalemia. Adrenal venous sampling was consistent with bilateral production of aldosterone; none had adenomas. Scholl et al. (2018) provided a follow-up of the family reported by Stowasser et al. (1992). There were 7 affected individuals, 6 of whom were found to have hypertension between 16 and 24 years of age. Most had increased serum aldosterone and an increased aldosterone/renin ratio (ARR) with a positive confirmatory fludrocortisone suppression test and non-lateralizing aldosterone production. Severe patients had hypokalemia. Hypertension and hypokalemia responded to treatment with spironolactone. One mutation carrier had normal blood pressure but an increased aldosterone/renin ratio, whereas another mutation carrier was normotensive with a normal aldosterone/renin ratio. These findings indicated incomplete penetrance and variable expressivity. Scholl et al. (2018) also identified 9 patients from 7 additional families with similar features. The age at onset ranged from childhood to young adulthood. One patient presented in infancy, but hypertension resolved by 2 years of age. Scholl et al. (2018) noted that the phenotype was similar to HALD4 (617027).

Fernandes-Rosa et al. (2018) reported a 9-year-old girl with HALD2 who presented with hypertension, hypokalemia, elevated serum aldosterone, and suppressed plasma renin activity. Abdominal imaging showed no adrenal abnormalities. She responded well to treatment with spironolactone and amlodipine.

The transmission pattern of HALD2 in the family reported by Stowasser et al. (1992) and Scholl et al. (2018) was consistent with autosomal dominant inheritance with incomplete penetrance.

In affected members of 8 unrelated families with HALD2, Scholl et al. (2018) identified 5 different heterozygous missense mutations in the CLCN2 gene (600570.0010-600570.0014). The mutation in the first family (family 3, originally reported by Stowasser et al., 1992) was found by exome sequencing and confirmed by Sanger sequencing. The variant segregated with the disorder in the family, although there was evidence of incomplete penetrance and variable disease expressivity. Subsequent CLCN2 mutations in the other families were found by screening the CLCN2 gene in 80 patients with a similar phenotype. In 2 patients, the CLCN2 mutation occurred de novo. One mutation (R172Q; 600570.0010) was found in 4 unrelated families, and haplotype analysis suggested independent occurrence of the mutation. In vitro functional expression studies in human HEK293 and H295R human adrenocortical cancer cells showed that all mutants shifted the activation curve of the channel to more positive voltages with higher open probabilities at the glomerulosa resting potential. All except 1 mutant (S865R; 600570.0012) modified the common gate by increasing the minimum open probability and accelerating activation, resulting in significantly larger chloride efflux compared to wildtype. The S865R variant, which likely has a regulatory function, slowed down deactivation of the gates, with a similar overall effect of increasing chloride flux. The mutations increased expression of CYP11B2 (124080) and its upstream regulator NR4A2 (601828), which increased aldosterone production. Current clamp recordings showed that the R172Q significantly amplified the depolarization of H295R-derived cells compared to wildtype. The findings demonstrated a role of anion channels in glomerulosa membrane potential determination and aldosterone production, and further showed that CLCN2 mutations can increase excitatory anion efflux by modifying the voltage dependence of channel opening, resulting in a gain of function.

In a girl with HALD2, Fernandes-Rosa et al. (2018) identified a de novo heterozygous missense mutation in the CLCN2 gene (G24D; 600570.0015). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The patient was 1 of 12 patients with early-onset hypertension and hyperaldosteronism who underwent whole-exome sequencing. Expression of the mutant protein in Xenopus oocytes dramatically increased current amplitudes compared to wildtype due to a change in the voltage-dependent gating of CLCN2. Expression of the mutation into human adrenocortical cells resulted in increased expression of aldosterone synthase (CYP11B2) and increased aldosterone production, as well as robust chloride currents that lacked strong voltage dependence. Cells expressing the mutation also had increased aldosterone production after stimulation with angiotensin II compared to cells with wildtype CLCN2. Knockdown of CLCN2 in human adrenocortical cells using shRNA abolished chloride currents and decreased aldosterone production. Sequencing of exon 2 of the CLCN2 gene in 100 patients with bilateral adrenal hyperplasia identified 2 rare heterozygous variants (R66Q and P48R) in 2 patients diagnosed with hypertension at 29 and 19 years, respectively, during pregnancy. However, both variants failed to significantly change CLCN2 currents in Xenopus oocytes. The findings suggested that gain-of-function CLCN2 mutations increase chloride conductance in zona glomerulosa cells, resulting in depolarization and a subsequent increase in opening of voltage-gated calcium channels that trigger autonomous aldosterone production by increasing intracellular calcium concentrations.

Torpy et al. (1998) reported linkage analysis on one of 17 families known to them with familial hyperaldosteronism type II. All affected individuals had negative testing for the CYP11B1/CYP11B2 hybrid gene (202010.0002), known to be responsible for familial hyperaldosteronism type I. Linkage analysis also excluded CYP11B2 (124080) on chromosome 8q21 as a candidate for familial hyperaldosteronism type II.

Lafferty et al. (2000) reported further linkage analysis on the extended kindred originally reported by Torpy et al. (1998). They found linkage between familial hyperaldosteronism type 2 and markers within cytogenetic band 7p22, with a 2-point lod score of 3.26 for markers at loci D7S511 and D7S517 (theta = 0.0) and a multipoint lod score of 3.5 between markers at loci D7S2521 and GATA24F03.