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Familial hypocalciuric hypercalcaemia type 2
FHH2 is a generally benign condition where the body's calcium regulation is altered due to a genetic change, leading to mild hypercalcaemia from birth. It typically affects individuals throughout their lives but often requires no specific treatment as severe symptoms are uncommon.
Overview
Familial hypocalciuric hypercalcaemia type 2 (FHH2) is a rare inherited disorder primarily affecting how the body manages calcium. Individuals with FHH2 typically have slightly higher than normal calcium levels in their blood, a condition known as hypercalcaemia, which is present from birth or early childhood [PMID:19363717]. A key feature that helps distinguish FHH2 from other causes of hypercalcaemia is the unusually low amount of calcium excreted in the urine, despite elevated blood calcium levels. This characteristic gave the condition its name, 'hypocalciuric' referring to low urinary calcium.
Unlike some other forms of hypercalcaemia, FHH2 is generally considered a benign condition. Most individuals with FHH2 do not experience significant symptoms and often live normal lives without needing treatment. However, it is important to distinguish FHH2 from primary hyperparathyroidism, which requires different management strategies. The discovery of FHH2 often occurs incidentally during routine blood tests.
Symptoms & clinical features
For most individuals, FHH2 does not cause obvious symptoms and is often discovered by chance when blood tests are performed for unrelated reasons. When symptoms do occur, they are typically mild and non-specific, such as fatigue or thirst. Unlike more severe forms of hypercalcaemia, FHH2 usually does not lead to complications commonly associated with high calcium, such as kidney stones or bone problems.
Occasionally, very high calcium levels or other co-existing factors might lead to more noticeable symptoms. However, these instances are rare in FHH2. The lifelong, mild elevation in blood calcium levels often means the body adapts, further reducing the likelihood of significant clinical issues.
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Affected organs
FHH2 primarily affects the parathyroid glands and the kidneys, which are the main organs involved in regulating the body's calcium balance. The parathyroid glands, located in the neck, produce parathyroid hormone (PTH) which helps control calcium levels. In FHH2, the calcium-sensing receptor, a protein that detects calcium levels, does not function typically, making the parathyroid glands less sensitive to calcium [PMID:30138977]. This leads them to release more PTH than would be expected for the given calcium level, contributing to the elevated calcium.
The kidneys are also affected because they play a crucial role in filtering and reabsorbing calcium. The altered function of the calcium-sensing receptor in the kidneys results in increased reabsorption of calcium, leading to the characteristic low urinary calcium excretion. Despite these alterations, the function of these organs generally remains normal, preserving overall health.
Risks & severity
Familial hypocalciuric hypercalcaemia type 2 is generally a benign condition with a low risk of severe complications. The elevated blood calcium levels often do not reach a threshold where they cause significant health issues. The condition is lifelong, meaning individuals will have higher-than-normal calcium levels throughout their lives, typically starting from birth.
The severity of FHH2 is usually mild, and most individuals remain asymptomatic. In rare cases, very high calcium levels might occur, but this is less common than in other forms of hypercalcaemia. It is important for medical professionals to differentiate FHH2 from conditions like primary hyperparathyroidism, which may require surgery. The accurate diagnosis of FHH2 helps to avoid unnecessary medical interventions like parathyroidectomy (surgical removal of parathyroid glands), which would not resolve the underlying genetic issue in FHH2.
Genetic causes
FHH2 is caused by genetic changes (pathogenic variants) in the GNA11 gene [PMID:19363717]. The GNA11 gene provides instructions for making a protein called G protein subunit alpha 11. This protein is part of a complex signalling pathway that helps cells respond to external signals, including the detection of calcium levels.
Specifically, the GNA11 protein works in conjunction with the calcium-sensing receptor (CaSR), which is crucial for maintaining calcium balance in the body [PMID:30138977]. The CaSR is found on the surface of cells in the parathyroid glands and kidneys. When blood calcium levels are high, the CaSR typically signals the parathyroid glands to reduce parathyroid hormone release and the kidneys to excrete more calcium. Pathogenic variants in GNA11 disrupt this signalling pathway, making the parathyroid glands and kidneys less sensitive to calcium. This altered sensitivity leads to the characteristic features of FHH2: persistently high blood calcium and low urinary calcium excretion.
- GNA11 G protein subunit alpha 11
Inheritance pattern
Familial hypocalciuric hypercalcaemia type 2 is inherited in an autosomal dominant pattern. This means that only one altered copy of the GNA11 gene in each cell is enough to cause the condition. An individual with FHH2 has a 50% chance of passing on the altered gene to each of their children, regardless of the child's sex.
FHH2 affects males and females equally. In some cases, FHH2 can arise from a new (de novo) genetic change in an individual with no family history of the condition, though this is less common. Family members of an affected individual may be offered genetic counselling to understand the inheritance pattern and discuss testing options.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosing FHH2 typically begins with blood tests showing persistently elevated calcium levels. Further blood and urine tests are then performed to measure parathyroid hormone (PTH) levels and assess how much calcium is being excreted in the urine. A key indicator for FHH2 is a low urinary calcium-to-creatinine clearance ratio, especially in the context of elevated blood calcium and typically normal or slightly elevated PTH levels.
Genetic testing is the definitive method to confirm a diagnosis of FHH2 by identifying a pathogenic variant in the GNA11 gene. Genetic testing for FHH2 (R-code R106 Hypercalcaemia) is available through the NHS Genomic Medicine Service. Referrals for genetic testing and counselling are usually made by endocrinologists or clinical geneticists, particularly when there is a family history of hypercalcaemia or when other causes of elevated calcium have been ruled out.
Management & lifestyle
Most individuals with FHH2 do not require specific medical treatment because the condition is generally benign and asymptomatic. The primary management strategy involves careful monitoring of blood calcium levels over time. Regular follow-up appointments with a healthcare professional, often an endocrinologist, are recommended to ensure calcium levels remain stable and to monitor for any atypical developments.
It is crucial to avoid unnecessary interventions, such as parathyroidectomy, which is a common treatment for primary hyperparathyroidism but would not resolve FHH2. Genetic counselling is an important part of managing FHH2, providing individuals and families with information about the condition, its inheritance, and implications for relatives. Lifestyle adjustments are generally not required, though maintaining adequate hydration is often advised for overall health.
UK care pathway
In the UK, individuals suspected of having FHH2 typically enter the NHS Genomic Medicine Service pathway following a referral from their GP or a specialist. Initial investigations usually involve blood and urine tests by an endocrinologist. If FHH2 is suspected, a referral to a clinical geneticist or a specialist endocrinologist within an NHS Genomic Medicine Centre may be made for genetic counselling and testing. Genetic testing for hypercalcaemia, including FHH2, is available under NHS R-code R106. Genetic counsellors offer support and information to affected individuals and their families, helping them understand the condition and its implications.
Frequently asked questions
Will FHH2 affect my life expectancy?
FHH2 is generally considered a benign condition. It is not typically associated with reduced life expectancy, and most individuals live normal lives without significant health problems from the condition.
Do I need to change my diet or lifestyle if I have FHH2?
Generally, no specific dietary or lifestyle changes are required for FHH2. It's always a good idea to maintain a balanced diet and stay well-hydrated, but these are general health recommendations rather than specific treatments for FHH2.
Can FHH2 be passed on to my children?
Yes, FHH2 is inherited in an autosomal dominant pattern. This means if you have FHH2, each of your children has a 50% chance of inheriting the genetic change and developing the condition. Genetic counselling can provide more personalised information.
What is the difference between FHH2 and primary hyperparathyroidism?
Both conditions cause elevated blood calcium. However, FHH2 is a genetic condition causing lifelong mild hypercalcaemia with low urinary calcium excretion, usually without severe symptoms. Primary hyperparathyroidism is typically due to an overactive parathyroid gland and often has higher urinary calcium excretion, potentially leading to complications that may require surgery. Genetic testing helps differentiate them.
Why is genetic testing important for FHH2?
Genetic testing is crucial to confirm the diagnosis of FHH2, differentiating it from other causes of hypercalcaemia such as primary hyperparathyroidism. An accurate diagnosis ensures you avoid unnecessary treatments (like parathyroid surgery) and helps family members understand their risks and options.