What is Familial Hypocalciuric Hypercalcemia?
Familial hypocalciuric hypercalcemia (FHH) is a kind of genetic condition that usually causes a slight increase in calcium levels in the blood. Most people who have it usually don’t experience symptoms and are otherwise in good health. Hypercalcemia, or high calcium levels, is a typical reason for people to be referred to medical professionals, often detected through routine blood tests. How hypercalcemia is diagnosed often relies on how quickly and seriously symptoms appear, along with the level of a hormone called parathyroid hormone (PTH) in the blood.
FHH is caused by changes to a gene that makes a receptor for calcium (CASR), which become less responsive to levels of calcium in the blood. This leads to slightly high levels of calcium and magnesium but lower than normal levels of calcium in urine and phosphate in the blood. PTH levels can also be normal or slightly higher than usual.
FHH is generally harmless and doesn’t come with the severe long-term issues seen with other conditions that cause high calcium levels. One main feature of the condition is that the parathyroid glands, which control calcium levels, become less responsive to calcium and need more calcium in the blood to decrease PTH release. Increased reabsorption of calcium and magnesium by kidneys is another result seen with FHH.
Diagnosing FHH can be difficult because its symptoms can be similar to those of a condition called primary hyperparathyroidism (PHPT). Evaluations typically look at family history, blood and urine tests, and the ratio of calcium clearance to creatinine clearance (Ca/Cr). A ratio of less than 0.01 usually indicates FHH. Genetic testing for changes in the CASR gene might be recommended to confirm diagnosis in cases where it’s unclear.
Even though most with FHH typically don’t show any symptoms, those who do might feel fatigued or weak or experience constipation, excessive urination, increased thirst, or headaches. The risk of fractures doesn’t normally increase with FHH, but there have been occasional reports of bone abnormalities before birth, a condition called chondrocalcinosis (calcium deposits in cartilage), and pancreatitis (inflammation of the pancreas). Treatment usually includes educating patients and reassuring them, with medications like Cinacalcet-HCL or bisphosphonates sometimes used for more serious symptoms, although these are not officially approved treatments for FHH by the FDA.
What Causes Familial Hypocalciuric Hypercalcemia?
The CASR gene plays a critical role in maintaining the right amount of calcium in our blood. It does this by controlling the secretion of a hormone called Parathyroid Hormone (PTH). In most instances, Familial Hypocalciuric Hypercalcemia (FHH) type 1, a condition causing high levels of calcium in the bloodstream, is a result of the CASR gene not functioning correctly. This typically happens due to a change or mutation on one type of the CASR gene located on chromosome 3. People who have this mutation on both types of the CASR gene may experience severe conditions such as high levels of a hormone that controls calcium and phosphate levels in our bodies, weak bones that fracture easily, and failure to grow or develop normally.
Less common cases of FHH, including types 2 and 3, are connected to a mutation found on chromosome 19. Recent studies have found a link between FHH type 2 and a mutation in the GNA11 gene, and FHH type 3 and a mutation in the AP2S1 gene.
In very rare cases, FHH can be caused by the immune system attacking the calcium-sensing receptors. This would lead to decreased activity of the CASR gene. This situation should be considered if a patient has a strong family history of autoimmune disorders and there’s no other known reason for their symptoms.
Risk Factors and Frequency for Familial Hypocalciuric Hypercalcemia
Familial Hypocalciuric Hypercalcemia (FHH) is a rare disease that affects both males and females equally. It’s inherited in a particular way known as “autosomal dominant pattern”. It’s currently estimated that 1 in every 10,000 to 100,000 people have this disease. However, it’s possible that it is more common than we think, because its symptoms are often overlooked. This disease can also be difficult to differentiate from a different disease called Primary Hyperparathyroidism (PHPT).
Signs and Symptoms of Familial Hypocalciuric Hypercalcemia
Familial Hypocalciuric Hypercalcemia (FHH) type 1 patients usually don’t show symptoms, or they might have only a few mild ones because of slightly increased calcium levels in their blood. If symptoms do appear, they may include tiredness, weakness, constipation, frequent urination, excessive thirst, or headaches. However, FHH type 3 patients often have more symptoms. Some may even show signs of low phosphate in their blood and softening of the bones.
Even though FHH type 1 doesn’t typically increase the risk of fractures, these patients can still experience them and may also suffer from osteoporosis. Some reports mention cases of abnormal bone development in the womb within the same family and calcification in cartilage. Though some patients have been observed with pancreatitis (inflammation of the pancreas), it’s not yet clear whether FHH type 1 causes this. Lastly, there have been isolated cases of children with FHH type 1 developing a kidney disease that causes high levels of protein in their urine.
Testing for Familial Hypocalciuric Hypercalcemia
Diagnosing Familial Hypocalciuric Hypercalcemia (FHH), a condition causing high levels of calcium in your blood and a low amount of calcium in your urine, may not be easy as it shares similar characteristics with Primary Hyperparathyroidism (PHPT), another disorder that leads to high calcium levels in the blood. Being able to distinguish between the two is crucial for the right treatment plan. A good starting point for diagnosing FHH involves a complete review of your health history and family’s medical history. Pre-existing medical documents showing a history of hypercalcemia, which involves too much calcium in the blood, can also provide useful insights for the diagnosis. FHH is often the cause if you’ve had hypercalcemia before turning 40 and don’t have any symptoms.
Signs hinting at FHH include a lack of usual symptoms related to high calcium levels, slightly increased blood calcium levels with average or slightly high parathyroid hormone (PTH) levels, hypercalcemia in the family’s medical history, or a personal or family history where neck surgery did not help. However, some patients might still have high blood calcium levels backed up with increased PTH.
It’s important to note that a key tool used to distinguish FHH from PHPT is to measure the calcium excreted in a 24-hour urine sample. Low calcium levels (<200 mg/24 hours) in urine despite high levels of calcium in the blood usually indicates FHH. Another key indicator is the ratio of calcium to creatinine (a waste product filtered out of the blood by the kidneys) excreted from the body, with a very low ratio of less than 0.01 usually points to FHH in about 80-90% of cases. However, around 10% of sporadic PHPT may also have a Ca/Cr ratio of less than 0.01. It is also recommended to screen for any genetic mutations in patients with a Ca/Cr clearance ratio less than or equal to 0.020.
It may be harder to diagnose FHH if there is no family history attached, normal PTH levels, or if the Ca/Cr clearance ratio ranges between 0.01 and 0.02. While factors like the age of diagnosis and family history might help in identifying the issue, there could be cases where the genetic mutation causing FHH has newly emerged, making the family history irrelevant to the diagnosis.
It’s also crucial to rule out and correct other causes that might reduce calcium levels in urine before ongoing testing. Factors like a deficiency in Vitamin D, not enough calcium intake, kidney disease, and usage of thiazide diuretics (medications for lowering blood pressure) or lithium can lead to falsely low urinary calcium levels. Comparatively in FHH patients, the levels of magnesium, another mineral in your blood, are often high, while in PHPT, they can be low.
Treatment Options for Familial Hypocalciuric Hypercalcemia
Familial hypocalciuric hypercalcemia (FHH) is generally a harmless condition that usually doesn’t lead to complications. Therefore, the primary care for FHH patients and their affected family members is providing reassurance and education about the disorder. On rare occasions, a patient might exhibit unusual symptoms or complications, and in these few cases, a procedure called sub-total parathyroidectomy might be required.
In more syptom-filled cases, the CASR (Calcium Sensing Receptor) presents a possible treatment target. The CASR can be stimulated using calcimimetic medicines, like Cinacalcet-HCL, which has helped to reduce and occasionally even resolve high calcium levels in children and adults. Bisphosphonates – another type of medication – can also help control high calcium levels. However, since FHH is a long-term condition, these drugs might need to be given repetitively. One important thing to understand is that these medications are not officially approved by the Food and Drug Administration (FDA) for the treatment of FHH. It’s always wise to consult with your doctor for your best treatment options.
What else can Familial Hypocalciuric Hypercalcemia be?
Familial hypocalciuric hypercalcemia, or FHH, needs to be distinguished from other sources of parathyroid-dependent hypercalcemia, particularly Primary hyperparathyroidism (PHPT). Both of these conditions can cause high calcium levels in the blood, along with either normal or high levels of parathyroid hormone, the hormone that controls the calcium level. However, PHPT usually results in more extreme elevations. It’s also associated with an increase in calcium in the urine, low blood phosphorus, and low magnesium levels. If PHPT isn’t treated, it can lead to problems like constipation, dehydration, kidney stones, chronic kidney disease, and osteoporosis with fractures.
It can also be tricky to separate FHH from other causes of low calcium in the urine, even though not all of these other causes result in high blood calcium. Conditions like poor calcium intake and low levels of vitamin D can lead to low calcium in the urine and a compensatory increase in parathyroid hormone. Thiazide diuretics, which decrease the amount of calcium excreted in the urine, may cause mild hypercalcemia. This might reveal underlying FHH or mild PHPT; however, in normal individuals, parathyroid hormone levels will be lower than expected.
Chronic kidney disease is another situation that can be confusing. It can result in high levels of parathyroid hormone and calcium, and low levels of calcium in the urine. This happens if tertiary hyperparathyroidism develops or if high levels of calcium occur as a result of treating secondary hyperparathyroidism.
What to expect with Familial Hypocalciuric Hypercalcemia
Most of the time, FHH (Familial Hypocalciuric Hypercalcemia) is not severe and has a good outcome, without any long-term negative effects usually seen in other conditions that cause high calcium levels in the blood.
Possible Complications When Diagnosed with Familial Hypocalciuric Hypercalcemia
: In very rare instances, FHH, caused by two copies of a mutated gene, can show up as a serious condition called neonatal hyperparathyroidism. Usually, this occurs within the first six months of a baby’s life and is more similar to severe PTH-mediated hypercalcemia than FHH. This condition causes extremely high levels of calcium in the body, leading to effects like dehydration due to excessive urination, muscle weakness, failing to adequately grow and develop, and bone damage that could further lead to fractures. There have even been reports of abnormal changes in an unborn baby’s bones in certain families.
Adults can also sometimes face complications due to very high calcium levels (usually when their levels are severely elevated with serum calcium levels being more than 12 mg/dL). Some complications that have been recorded include fractures, chondrocalcinosis (a condition that involves the buildup of calcium inside joints), kidney stones, irregular heart rhythms, and in some extreme cases, inflammation of the pancreas.
Common complications:
- Dehydration due to excessive urination
- Muscle weakness
- Failure to adequately grow and develop
- Bone damage leading to fractures
- Abnormalities in unborn baby’s bones
- Fractures in adults
- Chondrocalcinosis
- Kidney stones
- Irregular heart rhythms
- Inflammation of the pancreas
Preventing Familial Hypocalciuric Hypercalcemia
Familial Hypocalciuric Hypercalcemia (FHH) is a rare condition passed down through families, which causes high calcium levels in the blood. There’s a specific receptor in our bodies that detects calcium levels and needs higher than normal calcium levels to activate the parathyroid glands. These glands release a hormone, also called parathyroid, that helps maintain normal calcium levels.
Generally, FHH is harmless and is not linked with the ordinary signs or problems we usually see when there’s too much calcium in the body for a long time. But, in rare cases, high calcium levels can lead to complications, especially when newborns or babies are affected. In such cases, a medical intervention or an operation to remove the parathyroid glands might be required.
Given that FHH is passed down in families, other family members may also be affected. So, doctors normally suggest that blood relatives also undergo a check-up when a patient is diagnosed with FHH. Both patients and their families should be made aware of abnormal calcium levels and their implications, while also ruling out other, more common reasons for high calcium levels.