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Familial hyperaldosteronism type II
Disease definition
A heritable form of primary aldosteronism (PA) characterized by hypertension of varying severity, non-glucocorticoid remediable hyperaldosteronism, variable hypokalemia, low plasma renin activity (PRA) and increased aldosterone-to-renin ratio.
ORPHA:404
Classification level: DisorderSummary
Epidemiology
PA is the most common form of secondary hypertension and is found in up to 10% of hypertensive patients. However, familial forms are rare and represent 6-7% of adult PA cases. Familial hyperaldosteronism type II (FH-II) is considered the most common form of familial hyperaldosteronism and it is estimated at around 6% of all PA cases.
Clinical description
The clinical and biochemical presentation of FH-II is indistinguishable from sporadic PA, although early onset PA may be observed. Hypertension of varying severity, even within members of the same family, is noted in most patients and occurs at different ages. Fatigue, and muscle weakness are reported. Complications due to hypertension and aldosterone excess (including sodium retention and hypokalemia) may occur. Patients with PA are at increased risk of cardiovascular events, such as coronary artery disease, stroke, non-fatal myocardial infarction, atrial fibrillation and heart failure.
Etiology
FH-II is due to heterozygous gain-of-function mutations in the CLCN2 gene (3q27.1) coding for the CLC-2 chloride channel. Mutations are located in different domains of the ClC-2 channel and affect channel function to different degrees, explaining phenotypic heterogeneity. The mutations result in constitutive channel activation, membrane depolarization of the zona glomerulosa cells of the adrenal cortex, opening of voltage-gated calcium channels, and activation of the calcium signaling pathway that triggers aldosterone biosynthesis.
Diagnostic methods
FH-II is diagnosed when PA is confirmed in two or more family members and other familial forms are excluded. Patients show a non-specific variable aldosterone response to upright posture or AngII infusion. Early onset PA may be observed associated with specific CLCN2 mutations.
Differential diagnosis
FH-II is clinically and biochemically indistinguishable from sporadic PA, although in some cases, CLCN2 mutations are associated with early onset PA. Differential diagnosis also includes the other forms of FH (FH-I, FH-III and FH-IV).
Genetic counseling
FH-II is transmitted in an autosomal dominant mode with variable penetrance. Genetic counselling should be offered to affected individuals informing them that there is a 50% risk of transmitting the pathogenic variant at each pregnancy.
Management and treatment
FH-II does not respond to glucocorticoid treatment and no specific treatment has been identified for carriers of CLCN2 mutations. Treatment consists of medical therapy with mineralocorticoid receptor antagonists, associated to additional antihypertensive medication if required.
Prognosis
With treatment prognosis is good.
Detailed information
Professionals
- Summary information
- Greek (2014, pdf)
- Clinical practice guidelines
- Français (2016)
- English (2016)
Additional information