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Familial hyperaldosteronism type III
This excess aldosterone can lead to severe, early-onset high blood pressure that can be difficult to manage. It typically affects individuals from childhood or young adulthood and is caused by changes in the KCNJ5 gene.
Overview
Familial hyperaldosteronism type III is a rare genetic disorder where the adrenal glands produce an excessive amount of aldosterone [PMID:24623351]. Aldosterone is a hormone that regulates blood pressure and the balance of salts (like sodium and potassium) in the body. When too much aldosterone is produced, it can lead to hypertension (high blood pressure) which may begin at a younger age and can be severe, potentially resisting standard treatments.
This condition is part of a group of disorders known as primary aldosteronism, where the problem originates directly in the adrenal glands, which are small glands located on top of each kidney. Unlike some other forms of primary aldosteronism, FH-III is inherited and typically presents within families.
Symptoms & clinical features
The primary symptom of familial hyperaldosteronism type III is high blood pressure, often presenting in childhood or adolescence. This hypertension can be severe and may be resistant to multiple blood pressure medications [PMID:21297046]. Uncontrolled high blood pressure can lead to various complications affecting organs such as the heart, kidneys, and brain.
Other symptoms that may be observed include low potassium levels in the blood (hypokalaemia), which can cause muscle weakness, fatigue, and heart rhythm abnormalities. Some individuals might experience headaches, blurred vision, or dizziness due to their high blood pressure. The severity of symptoms can vary among affected individuals, even within the same family.
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Affected organs
The adrenal glands are the primary organs affected in familial hyperaldosteronism type III. These glands become overactive, specifically the outer layer (cortex), leading to the excessive production of aldosterone. The adrenal glands are crucial for regulating various bodily functions through hormone production.
Secondary effects of high blood pressure can impact other organs. The cardiovascular system is significantly affected, with an increased risk of heart disease, stroke, and kidney damage if hypertension remains poorly controlled. The kidneys are also directly involved in the regulation of blood pressure and electrolytes, and chronic hypertension can lead to kidney dysfunction.
Risks & severity
Familial hyperaldosteronism type III can lead to severe and early-onset high blood pressure, which may be challenging to manage with conventional treatments. The severity of hypertension can vary, but individuals with FH-III often require aggressive management to prevent long-term complications [PMID:21297046].
Untreated or poorly controlled high blood pressure significantly increases the risk of serious health issues, including heart attacks, strokes, kidney failure, and damage to blood vessels. The age of onset usually ranges from childhood to young adulthood, and lifelong monitoring and management are typically necessary to mitigate these risks. While the exact prevalence is not well established due to its rare nature, it represents a small proportion of all cases of primary aldosteronism.
Genetic causes
Familial hyperaldosteronism type III is caused by pathogenic variants in the KCNJ5 gene. This gene provides instructions for making a protein that forms a potassium channel within the cells of the adrenal glands [PMID:20980590]. Potassium channels are crucial for regulating the electrical activity within cells and controlling the release of hormones.
Pathogenic changes in KCNJ5 can alter the function of this potassium channel, leading to an imbalance in ion flow across the cell membrane. This disruption causes the adrenal gland cells to become overactive and produce too much aldosterone. The resulting excessive aldosterone production is responsible for the elevated blood pressure and other features of the condition.
- KCNJ5 potassium inwardly rectifying channel subfamily J member 5
Inheritance pattern
Familial hyperaldosteronism type III is inherited in an autosomal dominant pattern. This means that a person only needs to inherit one copy of the altered KCNJ5 gene from either parent to develop the condition.
If one parent has FH-III, there is a 50% chance with each pregnancy that their child will inherit the pathogenic gene variant and therefore be affected by the condition. The condition affects males and females equally. Individuals with FH-III may have other affected family members, but new changes in the gene (de novo variants) can also occur, meaning the condition appears in someone with no prior family history.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of familial hyperaldosteronism type III usually begins with the identification of high blood pressure, particularly if it is severe, early-onset, or resistant to treatment. Blood tests to measure aldosterone and renin levels are typically performed, along with checks for low potassium [PMID:24623351]. A high aldosterone-to-renin ratio often indicates primary aldosteronism.
Once primary aldosteronism is suspected, genetic testing for variants in the KCNJ5 gene can confirm a diagnosis of FH-III. Referrals for genetic testing are typically made by specialist clinicians, such as endocrinologists or clinical geneticists, often following an R-code associated with primary aldosteronism through the NHS Genomic Medicine Service. Genetic counselling is also available to discuss the implications of such a diagnosis for the individual and their family.
Management & lifestyle
Management of familial hyperaldosteronism type III focuses on controlling blood pressure and addressing the excess aldosterone production. Medical treatment often involves medications that block the effects of aldosterone, such as mineralocorticoid receptor antagonists, or other antihypertensive drugs. Regular monitoring of blood pressure, kidney function, and electrolyte levels is essential.
In some cases, surgical removal of the affected part of the adrenal gland (adrenalectomy) might be considered, particularly if one adrenal gland is significantly overactive. Decisions regarding surgery are made on an individual basis after thorough clinical assessment. Patients can access specialist care through NHS pathways, often involving endocrinologists who specialise in adrenal gland disorders. Genetic counsellors can provide support and information regarding the genetic aspects of the condition and family planning.
UK care pathway
In the UK, individuals suspected of having familial hyperaldosteronism type III would typically be referred to an endocrinologist or a hypertension specialist. If primary aldosteronism is confirmed biochemically, genetic testing may be offered through the NHS Genomic Medicine Service, usually following an R-code for primary aldosteronism. This pathway allows for comprehensive genetic analysis.
Access to clinical geneticists and genetic counsellors is available within the NHS. They provide expert guidance on genetic testing, inheritance patterns, and the implications of a diagnosis for individuals and their families. This support helps ensure informed decisions are made regarding treatment and family planning.
Frequently asked questions
What does 'autosomal dominant' mean for my family?
Autosomal dominant means that if you have familial hyperaldosteronism type III, each of your children has a 50% chance of inheriting the altered gene and therefore developing the condition. It affects males and females equally.
Can FH-III be cured?
Familial hyperaldosteronism type III is a lifelong genetic condition, so there isn't a 'cure' for the underlying genetic change. However, the condition's symptoms, particularly high blood pressure, can be effectively managed with medication and, in some instances, surgery, to prevent complications.
How often do I need to be monitored if I have FH-III?
Individuals with familial hyperaldosteronism type III typically require regular, lifelong monitoring of their blood pressure, kidney function, and electrolyte levels. The exact frequency of monitoring will be determined by your specialist based on your specific condition and treatment plan.
Are there lifestyle changes that can help manage my blood pressure?
While medications are crucial for managing familial hyperaldosteronism type III, adopting a healthy lifestyle, such as a low-sodium diet, regular physical activity, and maintaining a healthy weight, can help support blood pressure control. Always discuss any lifestyle changes with your healthcare team.
Why is genetic testing important for FH-III?
Genetic testing for FH-III can confirm the diagnosis, which is vital for guiding the most effective treatment for high blood pressure. It also provides important information for family members who may be at risk and can help inform family planning decisions through genetic counselling.
References
- Monticone S, Tetti M, Burrello J. Familial hyperaldosteronism type III. Journal of human hypertension. 2017. PMID: 28447626
- Pons Fernández N, Moreno F, Morata J. Familial hyperaldosteronism type III a novel case and review of literature. Reviews in endocrine & metabolic disorders. 2019. PMID: 30569443
- Vaidya A, Hamrahian AH, Auchus RJ. Genetics of primary aldosteronism. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2015. PMID: 25667376
- Meyer KM, Malhotra N, Kwak JS. Relevance of KCNJ5 in Pathologies of Heart Disease. International journal of molecular sciences. 2023. PMID: 37446026
- Tong A, Liu G, Wang F. A Novel Phenotype of Familial Hyperaldosteronism Type III: Concurrence of Aldosteronism and Cushing's Syndrome. The Journal of clinical endocrinology and metabolism. 2016. PMID: 27403928
- Mulatero P. A new form of hereditary primary aldosteronism: familial hyperaldosteronism type III. The Journal of clinical endocrinology and metabolism. 2008. PMID: 18685118
- Mir-Bashiri S, Rakete S, Wei J. Selective Cell Death of Adrenocortical Cells by Pharmacological Activation of Mutant KCNJ5. Hypertension (Dallas, Tex. : 1979). 2026. PMID: 42605674
- Adachi M, Muroya K, Asakura Y. Discordant genotype-phenotype correlation in familial hyperaldosteronism type III with KCNJ5 gene mutation: a patient report and review of the literature. Hormone research in paediatrics. 2014. PMID: 24819081