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Familial hyperaldosteronism type I (GRA)
This rare autosomal dominant condition results from a genetic rearrangement affecting aldosterone production in the adrenal glands. It typically presents with early-onset hypertension that is responsive to steroid treatment and can affect multiple family members across generations.
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Overview
Familial hyperaldosteronism type I, also known as glucocorticoid-remediable aldosteronism (GRA), is a rare inherited form of primary aldosteronism characterised by excessive production of the hormone aldosterone by the adrenal glands. Aldosterone normally regulates sodium and potassium balance in the body, helping to control blood pressure. When produced in excess, it causes the kidneys to retain too much sodium and lose too much potassium, leading to elevated blood pressure and low potassium levels in the blood.
This condition follows an autosomal dominant inheritance pattern, meaning an affected person has a 50% chance of passing the genetic change to each child. The exact prevalence is not well established, though it represents a small proportion of all primary aldosteronism cases. Unlike the more common sporadic forms of hyperaldosteronism, familial hyperaldosteronism type I has a distinctive genetic cause and responds characteristically to specific treatments, making accurate diagnosis clinically important for affected individuals and their families.
Symptoms & clinical features
The hallmark feature of familial hyperaldosteronism type I is high blood pressure that typically begins in childhood or young adulthood, though some individuals may not develop hypertension until later in life. The elevated blood pressure is often moderate to severe and may be difficult to control with standard antihypertensive medications. Many affected individuals have no other obvious symptoms, with hypertension discovered incidentally during routine health checks or family screening.
Some people experience symptoms related to low potassium levels (hypokalaemia), which can include muscle weakness, fatigue, frequent urination, excessive thirst, or muscle cramps. However, potassium levels may be only mildly reduced or even normal in some affected individuals, particularly if dietary potassium intake is adequate. Headaches and other complications of poorly controlled hypertension may develop if the condition remains undiagnosed or inadequately treated over time.
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Affected organs
The primary organs affected are the adrenal glands, two small hormone-producing glands located above the kidneys. In familial hyperaldosteronism type I, a specific region of the adrenal cortex produces excessive aldosterone under the control of adrenocorticotrophic hormone (ACTH), which normally regulates cortisol production rather than aldosterone synthesis.
The cardiovascular system bears the consequences of chronic aldosterone excess, with persistent hypertension potentially leading to left ventricular hypertrophy, increased risk of stroke, and other cardiovascular complications if untreated. The kidneys are also significantly affected, as excessive aldosterone action causes alterations in sodium and potassium handling, potentially leading to kidney damage over time from sustained hypertension.
Risks & severity
The severity of familial hyperaldosteronism type I varies considerably between affected individuals, even within the same family. Some people develop significant hypertension in childhood requiring early intervention, whilst others may have milder blood pressure elevation that is not detected until adulthood. The condition generally responds well to appropriate treatment, and with proper management, most affected individuals can achieve good blood pressure control and maintain normal quality of life.
Untreated or poorly controlled hypertension carries risks of cardiovascular complications including stroke, heart attack, heart failure, and kidney disease. There is some evidence suggesting that individuals with familial hyperaldosteronism type I may have increased risk of cerebral haemorrhage compared to other forms of hypertension, making early diagnosis and treatment particularly important. The long-term outlook is generally favourable with appropriate management and regular monitoring.
Genetic causes
Familial hyperaldosteronism type I results from a specific genetic rearrangement involving CYP11B1 and CYP11B2, which are located very close together on chromosome 8. CYP11B1 normally encodes 11-beta-hydroxylase, an enzyme that catalyses essential steps in cortisol synthesis within the adrenal cortex. CYP11B2 encodes aldosterone synthase, the enzyme responsible for completing aldosterone production.
The condition arises through unequal crossing-over during meiosis, creating a chimeric (hybrid) gene that fuses regulatory elements from CYP11B1 with coding sequences from CYP11B2. This rearrangement places aldosterone synthesis under the control of ACTH, the pituitary hormone that normally regulates cortisol production. Consequently, aldosterone is produced in the zona fasciculata of the adrenal cortex (where cortisol is normally made) rather than in its usual location, the zona glomerulosa, and its production follows the body's cortisol rhythm rather than responding appropriately to the renin-angiotensin system that normally controls aldosterone levels.
- CYP11B1 cytochrome P450 family 11 subfamily B member 1The CYP11B1 gene encodes the 11-beta-hydroxylase enzyme, which plays a vital role in the adrenal glands' production of steroid hormones such as cortisol and corticosterone.
Inheritance pattern
Familial hyperaldosteronism type I is inherited in an autosomal dominant pattern, meaning only one copy of the chimeric gene is needed to cause the condition. Each child of an affected parent has a 50% chance of inheriting the genetic rearrangement and developing the condition. The condition affects males and females equally.
Because the genetic change can be passed through families, diagnosis in one person has important implications for blood relatives. First-degree relatives (parents, siblings, and children) of affected individuals have an increased likelihood of carrying the same genetic rearrangement and may benefit from screening, even if they currently have normal blood pressure. Genetic counselling can help families understand inheritance patterns and make informed decisions about testing.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of familial hyperaldosteronism type I typically begins with biochemical testing showing elevated aldosterone levels alongside suppressed renin activity, the hallmark of primary aldosteronism. Potassium levels may be low but can be normal. A key diagnostic feature is that aldosterone levels suppress appropriately when the patient is given dexamethasone, a synthetic glucocorticoid that suppresses ACTH production - this response distinguishes type I from other forms of familial hyperaldosteronism.
Genetic testing can confirm the diagnosis by detecting the characteristic CYP11B1/CYP11B2 chimeric gene. Within the NHS Genomic Medicine Service, testing may be accessed through clinical genetics services following referral from endocrinology or nephrology specialists. A positive family history of early-onset hypertension strengthens clinical suspicion. Accurate diagnosis is important because it guides specific treatment and identifies at-risk family members who may benefit from screening.
Management & lifestyle
The mainstay of treatment for familial hyperaldosteronism type I is low-dose glucocorticoid therapy, typically using dexamethasone or prednisolone. These medications suppress ACTH production from the pituitary gland, which in turn reduces the abnormal aldosterone synthesis driven by ACTH in this condition. Many affected individuals achieve good blood pressure control and normalisation of potassium levels with glucocorticoid treatment alone, though some may require additional standard antihypertensive medications.
Regular monitoring through endocrinology services is important to ensure appropriate glucocorticoid dosing - enough to control aldosterone excess whilst avoiding the side effects of excessive steroid exposure. Blood pressure monitoring, potassium level checks, and periodic assessment of cardiovascular health form part of ongoing care. Dietary measures such as moderating sodium intake may provide additional benefit. Genetic counselling is recommended for affected individuals and their families to discuss inheritance patterns, testing options for relatives, and reproductive considerations. Treatment decisions should always be made in consultation with specialist endocrinology teams familiar with this rare condition.
UK care pathway
Within the NHS, individuals with suspected familial hyperaldosteronism type I are typically managed through specialist endocrinology services, often with input from clinical genetics when a hereditary basis is confirmed or suspected. Referral to the NHS Genomic Medicine Service for genetic testing may be arranged when the clinical presentation and biochemical findings suggest this diagnosis. Genetic counsellors can provide support in understanding test results, inheritance implications, and options for family screening.
Long-term care involves regular specialist review to monitor blood pressure control, adjust medications as needed, and screen for potential complications. Family members identified as at-risk may be offered cascade screening to detect the condition early, potentially before significant hypertension develops. The multidisciplinary approach ensures comprehensive management addressing both the endocrine abnormality and its cardiovascular consequences.
Frequently asked questions
Will my children inherit familial hyperaldosteronism type I?
Each of your children has a 50% chance of inheriting the genetic change that causes this condition. However, inheriting the gene rearrangement does not guarantee when or how severely symptoms will develop, as there is variability in how the condition manifests between individuals.
Can familial hyperaldosteronism type I be cured?
There is no cure that removes the underlying genetic cause, but the condition can usually be very effectively managed with appropriate medication. Many affected individuals achieve excellent blood pressure control with low-dose glucocorticoid treatment, allowing them to lead normal, healthy lives.
How is familial hyperaldosteronism type I different from ordinary high blood pressure?
Unlike essential hypertension, this condition has a specific genetic cause resulting in hormonal excess that drives blood pressure elevation. It typically appears earlier in life, may run in families, and responds characteristically to glucocorticoid treatment that would not be used for ordinary hypertension.
Should my siblings be tested even if they have normal blood pressure?
Discuss this with your clinical team and a genetic counsellor. Because the condition can develop at different ages, relatives who currently have normal blood pressure might still carry the genetic change and could develop symptoms later, making early detection potentially beneficial.