Recommended panel testing at Breda Genetics for this condition (also including the chimeric gene analysis):

Summary
Familial hyperaldosteronism is a group of inherited conditions in which the adrenal glands produce excess of the hormone called aldosterone. Aldosterone helps control the amount of salt retained by the kidneys. When aldosterone is in excess, more salt than normal is retained by the kidneys. This causes high blood pressure (hypertension) by increasing the body’s fluid levels.
Detailed clinical description
Hypertension in familial hyperaldosteronism may develop at any age, sometimes even in childhood. If untreated, hypertension increases the risk of heart attacks, strokes, and kidney failure. Based on differences in clinical features and genetic causes, familial hyperaldosteronism is categorized into four types:
- Familial hyperaldosteronism type I (HALD1): it is also known as glucocorticoid-remediable aldosteronism (GRA) as it can be treated with glucocorticoids. In familial hyperaldosteronism type I, hypertension ranges from mild to severe and generally appears from childhood to early adulthood.
- Familial hyperaldosteronism type II (HALD2): it does not improve with glucocorticoids and hypertension usually appears in early to middle adulthood.
- Familial hyperaldosteronism type III (HALD3): in most individuals with this type, the adrenal glands are enlarged. Hypertension starts in childhood and is rarely treatable, leading to early damage in heart and kidneys.
- Hyperaldosteronism, familial, type IV (HALD4): in this form hypertension onset is in childhood (before 10 years of age), with no apparent adrenal mass or hyperplasia at the time of presentation.
Familial hyperaldosteronism is inherited in an autosomal dominant pattern.
As hyperaldosteronism is mainly characterized by excessive secretion of aldosterone, there is a consequent increase in potassium and hydrogen ion excretion and sodium reabsorption. Clinical features include:
- Hypertension, which may lead to cardiac problems (frequently characterized by left ventricular hypertrophy and diastolic dysfunction), as well as neurologic, retinal, and renal problems.
- Metabolic alkalosis.
- Hypokalemia – which may cause fatigue, headaches, muscle weakness, cramping, and palpitations.
- Polyuria and polydipsia from hypokalemia-induced nephrogenic diabetes insipidus.
- Altered insulin and leptin secretion.
- Cardiovascular fibrosis, directly related to aldosterone hypersecretion.
Prevalence
The prevalence of familial hyperaldosteronism is unknown. Familial hyperaldosteronism type II appears to be the most common form. All types of familial hyperaldosteronism combined account altogether for fewer than 1 out of 10 cases of hyperaldosteronism, since most cases of hyperaldosteronism are not genetic.
Molecular Genetics
The four forms of familial hyperaldosteronism described above are caused by genetic mutations in known (HALD1, HALD3, HALD4) and unknown (HALD2) genes:
- HALD1 or glucocorticoid-remediable aldosteronism (GRA) is caused by the chimeric gene CYP11B1/CYP11B2 caused by an anti-Lepore-type gene fusion. The CYP11B1 gene provides instructions for making 11-beta-hydroxylase, which helps produce corticosterone and cortisol. The CYP11B2 gene provides instructions for making aldosterone synthase, which helps produce aldosterone. When these two genes are abnormally fused together, too much aldosterone synthase is produced. This overproduction causes the adrenal glands to secrete aldosterone in excess.
- HALD2 is caused by mutations in the CLCN2 gene which encodes a voltage-gated chloride channel with high expression in the adrenal glomerulosa.
- HALD3 is caused by mutations in the KCNJ5 gene. This gene provides instructions for making the potassium channel. Mutations in this gene result in the production of less selective potassium channels, allowing other ions to pass as well. The abnormal ion flow leads to increased aldosterone production.
- HALD4 is caused by mutation in the CACNA1H gene.
Differential diagnosis
It is of primary importance to distinguish between primary and secondary hyperaldosteronism (caused e.g. by aldosterone producing adenoma or drugs). The genetic differential diagnosis include other disorders of genetic origin such as:
- Congenital adrenal hyperplasia, due to 11-beta-hydroxylase deficiency (CYP11B1 gene mutations), of which diagnosis should be considered in patients with features of hyperandrogenism and hypertension of the mineralocorticoid-excess type.
- Glucocorticoid resistance (NR3C1 gene mutations), which is characterized by hypoglycemia, hypertension, and metabolic alkalosis. Hypertension, early-onset, autosomal dominant, with exacerbation in pregnancy (NR3C2 gene gain-of- function mutations). The Ser810Leu (S810L) mutation is a gain-of-function mutation which results in early onset hypertension in men and gestational hypertension in women. Patients respond to amiloride administration. Apparent mineralocorticoid excess (HSD11B2 gene mutations), which is form of low-renin hypertension associated with metabolic alkalosis, hypernatremia, and hypokalemia, but low aldosterone.
- Liddle syndrome, (SCNN1B or SCNN1G gene mutations), in which patients may present with hypertension and hypokalemia early in life.
- There is also a condition called primary aldosteronism, seizures, and neurologic abnormalities (CACNA1D gene mutations). This syndrome is characterized by hypertension, hypokalemia, plus other features such as generalized seizures, cerebral palsy, spasticity, intellectual disability, and developmental delay.
Genetic Testing
Given the genetic heterogeneity, it is highly recommended to proceed to a multigene panel, possibly based on whole exome or whole genome sequencing, integrating gene sequencing with a targeted molecular approach for the detection of the chimeric gene CYP11B1/CYP11B2.
Recommended panel testing at Breda Genetics for this condition (also including the chimeric gene analysis):
References:
Familial hyperaldosteronism. Stowasser M, Gordon RD. J Steroid Biochem Mol Biol. 2001 Sep;78(3):215-29. PMID: 11595502
New genetic insights in familial hyperaldosteronism. Jackson RV, Lafferty A, Torpy DJ, Stratakis C. Ann N Y Acad Sci. 2002 Sep;970:77-88. PMID: 12381543
Familial hyperaldosteronism type II: description of a large kindred and exclusion of the aldosterone synthase (CYP11B2) gene. Torpy DJ1, Gordon RD, Lin JP, Huggard PR, Taymans SE, Stowasser M, Chrousos GP, Stratakis CA. J Clin Endocrinol Metab. 1998 Sep;83(9):3214-8. PMID: 9745430
CLCN2 chloride channel mutations in familial hyperaldosteronism type II. Scholl UI, Stölting G, Schewe J, Thiel A, Tan H, Nelson-Williams C, Vichot AA, Jin SC, Loring E, Untiet V, Yoo T, Choi J, Xu S, Wu A, Kirchner M, Mertins P, Rump LC, Onder AM, Gamble C, McKenney D, Lash RW, Jones DP, Chune G, Gagliardi P, Choi M, Gordon R, Stowasser M, Fahlke C, Lifton RP. Nat Genet. 2018 Mar;50(3):349-354. PMID: 29403011
A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism. Fernandes-Rosa FL, Daniil G, Orozco IJ, Göppner C, El Zein R, Jain V, Boulkroun S, Jeunemaitre X, Amar L, Lefebvre H, Schwarzmayr T, Strom TM, Jentsch TJ, Zennaro MC. Nat Genet. 2018 Mar;50(3):355-361. PMID: 29403012