What is Hyperphosphatemic Tumoral Calcinosis?
Hyperphosphatemic tumoral calcinosis (HTC), also known as hyperphosphatemic familial tumoral calcinosis or familial tumoral calcinosis/hyperostosis hyperphosphatemia syndrome, is a disease that affects how your body controls phosphates. It’s an uncommon disorder that results in abnormal calcification, or hardening, around the joints. This can limit joint movement and cause disability. In addition, this illness often causes specific types of bone pain.
Because this disease is so rare and there aren’t many clinical trials on it, we don’t have a lot of definitive information about different treatment options. However, possibilities include medication to reduce phosphate levels in the body, anti-inflammatory drugs to reduce swelling and pain, and in severe cases, surgery to remove the hardened areas.
What Causes Hyperphosphatemic Tumoral Calcinosis?
The cause of HTC (Hyperphosphatemic Tumoral Calcinosis) is thought to be a problem with the production or functioning of a hormone called fibroblast growth factor 23 (FGF23). This hormone plays a crucial role in managing phosphate levels in the body. HTC is a condition that you inherit from your parents, which means it’s caused by specific gene mutations. These mutations can make the FGF23 hormone work improperly, either during its production, in the process after it’s made, or by making the body resistant to it.
Recently, there have been cases of HTC where the body’s immune system attacks FGF23. This is called autoimmunity. When this happens, the body produces autoantibodies that interfere with how FGF23 works, disrupting phosphate levels in the body.
Risk Factors and Frequency for Hyperphosphatemic Tumoral Calcinosis
HTC is an exceptionally rare condition, with fewer than 100 cases that have been confirmed through genetic testing reported in medical literature. While it was initially more often reported in people from Africa and the Middle-East, HTC cases have also been discovered in Europeans.
Signs and Symptoms of Hyperphosphatemic Tumoral Calcinosis
HTC, or Hyperostosis, can result in a range of symptoms. HTC patients often display varied signs and vary significantly from each other in spite of having similar lab results.
The most frequent symptom in HTC patients is painful, calcified lumps near the joints that experience repetitive stress or pressure. These symptoms usually start in early life but can occur at any age, as shown by a case in a 64-year-old individual. These lumps can grow and cause significant discomfort, restricting joint movement and can often lead to disability. Typically, these lumps appear on the hips but are also reported on elbows, shoulders, hands, knees, and feet. These lumps consist of hydroxyapatite crystals and calcium carbonate.
Oddly enough, these calcifications sometimes show up in small and large blood vessels, like the carotids, coronary, iliac, and aorta, and were found accidentally. The disease can affect peripheral vessels, causing reduced pulse and coldness in the limbs, leading to amputation in severe cases. Other parts of the body, like the small intestine, tongue, dura mater, kidneys (causing nephrocalcinosis), and testicles, can also be affected by calcification.
Other symptoms include recurring bone pains, especially in the tibia. The inflamed area can sometimes mimic the symptoms of osteomyelitis, displaying localized pain, redness, and raised temperature. Along with these, non-specific inflammatory symptoms like joint pains, fever, anemia, and raised erythrocyte sedimentation rate and C-reactive protein might occur due to inflammation caused by the engulfment of hydroxyapatite crystals by macrophages.
Interestingly, teeth can also be affected by HTC, leading to various dental defects. These can range from pulp chamber obliteration, pulp stones, and root shortening with middle enlargement, to enamel changes and a particular thistle shape in roots. Often the change in tooth roots is the first reported symptom of HTC, emphasizing the importance of dentists in early detection of the disease.
Lastly, calcific deposits in HTC can also be found in parts of the eye, including the eyelids, conjunctiva, and the cornea. These deposits may result in discomfort and itching in the eyes. There are also reported cases of calcification in the retina and choroid membrane.
Testing for Hyperphosphatemic Tumoral Calcinosis
Tumoral calcinosis, or HTC, can sometimes be identified just by looking at its unique symptoms. However, usually, blood tests are needed to confirm the diagnosis.
These blood tests often show:
- High levels of phosphate in the blood
- Normal levels of calcium in the blood
- High or normally high levels of vitamin D in the blood
- An unusually high amount of phosphorus being reabsorbed by the kidney tubes
- Parathyroid hormone levels on the low side of normal
- Normal kidney function
- High levels of C-terminal fragments of FGF23, a protein that helps regulate phosphate levels in the body (this is assessed by a test called an ELISA immunoassay)
If these tests don’t confirm HTC, but your doctor still suspects it, you might get a genetic test to check for specific genes that are linked to tumoral calcinosis.
The next steps often involve imaging tests. An X-ray of the affected area can show a mixed, calcified mass characteristic of HTC. If your bones are also affected, X-rays might show a dense reaction on the outer layer of the bone, patchy hardening inside the bone marrow, and an exceptionally hard cortex, or outer layer of the bone. Dental X-rays can reveal shorter, bulbous roots, small calcified masses known as pulp stones, and empty, or “obliterated,” pulp chambers in your teeth.
A CT scan, which uses X-rays to create detailed pictures of your body, could also be used to give a clearer picture of the calcified masses before any surgery. However, because CT scans involve exposure to potentially harmful radiation, your doctor will need to weigh up the benefits against the risks.
Treatment Options for Hyperphosphatemic Tumoral Calcinosis
Hyperostosis-hyperphosphatemia syndrome (HTC) is a rare condition, and because of this, treatments are largely based on previously reported patient cases and observational studies, rather than clinical trials. The treatment strategies for HTC continue to evolve as new research data emerges. The main goal of treatment is to reduce the level of phosphate in the blood and to decrease inflammation. Ideally, future treatments would provide a genetic cure by replacing the faulty gene causing HTC. In the meantime, research continues into the use of a hormone called iFGF23, which can regulate phosphate levels in the blood.
Medications currently used to lower phosphate levels include sevelamer, lanthanum, aluminum hydroxide, acetazolamide, probenecid, nicotinamide, and niacinamide. For best results, some of these drugs, which bind to dietary phosphate and limit its absorption in the intestines, should be taken with meals. Other drugs such as acetazolamide and probenecid work by increasing how much phosphate is excreted in the urine. Additionally, drugs like nicotinamide and niacinamide work by decreasing the absorption of phosphorus in the kidneys and intestines. But, it’s important to note that results from these phosphate-lowering medications can vary widely between patients.
For patients with bone overgrowth and signs of inflammation, non-steroidal anti-inflammatory drugs (commonly known as NSAIDs) are typically used. Moreover, some patients have shown promising outcomes with therapies that block IL-1, a molecule involved in inflammation, including anakinra and canakinumab. There are also reports of successful treatment of some symptoms, such as diminished eyesight due to bleeding from abnormal blood vessels in the retina, with the use of ranibizumab, an antibody therapy. Topically applied sodium thiosulphate has been reported to reduce the size of calcium deposits in some instances.
Less common treatments include certain medications like bisphosphonates, calcitonin, and calcium-channel blockers, as well as dialysis, a procedure generally used for kidney patients to correct certain metabolic abnormalities. Surgery might be required in more severe cases where calcium deposits cause significant joint movement restriction and disability. However, the growths often reoccur, so repeated surgeries might be needed.
What else can Hyperphosphatemic Tumoral Calcinosis be?
When doctors diagnose patients’ conditions, they often have to rule out illnesses with similar symptoms. For this particular condition, some of the potential misdiagnoses could include:
- Normophosphatemic tumoral calcinosis (an overgrowth of calcium)
- Porphyria cutanea tarda (a type of skin disease)
- Calcinosis cutis (calcium deposits in the skin)
- Pseudohypoparathyroidism (a condition that affects calcium and phosphorus levels)
- Chronic renal failure (slow loss of kidney function)
- Fibrodysplasia ossificans progressiva (a disorder where soft tissues gradually turn into bone)
- Osteomyelitis (infection and inflammation of the bone)
What to expect with Hyperphosphatemic Tumoral Calcinosis
The outlook for patients with HTC, or Hyperphosphatemic Tumoral Calcinosis, can be unpredictable because there’s no definitive cure. Existing treatment options are aimed at lowering serum phosphate levels, which are too high in patients with this condition, and managing symptoms.
However, it’s important to note that symptoms can vary widely among individuals. Some patients may have severe symptoms, while others may show only mild or moderate ones, even if their genetic and biochemical makeup is similar.
Tumoral calcinosis, which refers to hard calcium deposits that form in the tissues, grows slowly in most patients, but many find significant relief from their symptoms through medical therapy.
Possible Complications When Diagnosed with Hyperphosphatemic Tumoral Calcinosis
The hard lumps under the skin associated with this condition may break down the skin over time, causing a white substance to leak out. This substance contains a component of bone called hydroxyapatite. In such cases, doctors need to remove these hard masses surgically to prevent any subsequent infections. There is also an increased risk of heart conditions among these patients due to hardening of blood vessels in the heart and heightened inflammatory markers. Both these factors may lead to decreased blood flow to the heart. However, more in-depth evaluations and extended follow-up studies are required to understand how these risk factors affect the patients practically. Notably, two cases have reported a sudden loss of vision in the patients of this condition. This was due to internal bleeding under the retinal surface in one patient and complications of neurological dysfunction and stroke in another patient. Moreover, if blood vessels in the limbs are hardened due to the condition, it may result in loss of pulse, coldness in the limbs, and potentially may require the need to amputate the limb.
Key Points:
- Hard lumps under the skin may break the surface and leak a white substance.
- Surgical removal of these lumps may be necessary to avoid further infections.
- There is an increased risk of heart disease due to hardening of heart vessels and increased inflammatory markers.
- More in-depth studies are required to understand these risk factors.
- There have been reported cases of sudden vision loss due to internal bleeding under the retinal surface and stroke.
- If the condition hardens blood vessels in limbs, it can lead to loss of pulse, extreme cold in the limbs, and even the need to amputate the limb.
Preventing Hyperphosphatemic Tumoral Calcinosis
Individuals diagnosed with HTC, or hyperglycemia-induced tumoral calcinosis, should steer clear from taking supplements containing calcium and vitamin D. The reason is that calcium supplements can cause the growth of tumoral calcinosis lesions, which are hardened lumps under the skin, when they combine with phosphates in the body. Furthermore, these individuals typically already have high or unusually normal levels of vitamin D in the body. Moreover, they should also avoid foods rich in calcium and phosphorus to reduce the risk of worsening their condition.
