Normophosphatemic Familial Tumoral Calcinosis

Normophosphatemic familial tumoral calcinosis (NFTC) is a rare genetic disorder characterized by the deposition of calcium phosphate crystals in soft tissues of the body, resulting in the formation of painful calcified masses or tumors. NFTC is a subtype of familial tumoral calcinosis (FTC), which is a broader term that refers to a group of genetic disorders that share similar clinical features. The following is a detailed explanation of NFTC, including its definitions, types, causes, symptoms, diagnosis, and treatment.

Definitions:

Normophosphatemic: Refers to the normal levels of phosphate in the blood. In NFTC, the levels of phosphate are usually normal or slightly decreased, unlike other forms of FTC, where high levels of phosphate are present.

Familial: Indicates that the disorder is inherited and passed down through generations of a family.

Tumoral calcinosis: Describes the calcification or hardening of soft tissues due to the deposition of calcium phosphate crystals.

Types:

NFTC is classified into two types based on the genetic mutation responsible for the disorder:

• Type 1: Caused by mutations in the GALNT3 gene, which encodes for an enzyme involved in the modification of proteins. This type of NFTC is inherited in an autosomal recessive pattern, meaning that an affected individual must inherit two copies of the mutated gene, one from each parent.
• Type 2: Caused by mutations in the FGF23 gene, which encodes for a hormone that regulates phosphate and vitamin D metabolism. This type of NFTC is inherited in an autosomal dominant pattern, meaning that an affected individual only needs to inherit one copy of the mutated gene from either parent to develop the disorder.

Causes

There are several known causes of NFTC, including:

1. Genetic mutations: As mentioned above, mutations in the FGF23, GALNT3, and KL genes are the primary cause of NFTC. These mutations disrupt the normal regulation of phosphate metabolism and lead to the deposition of calcium phosphate in the soft tissues of the body.
2. Age: NFTC typically develops in childhood or adolescence, but can also develop in adulthood.
3. Gender: NFTC affects both males and females equally.
4. Family history: NFTC is an inherited disorder, so individuals with a family history of the condition are at an increased risk of developing it themselves.
5. Ethnicity: NFTC has been reported in individuals from a variety of ethnic backgrounds, but appears to be more common in individuals of African and Middle Eastern descent.
6. Diet: A diet high in phosphorus can exacerbate the symptoms of NFTC, as it can increase the deposition of calcium phosphate in the soft tissues of the body.
7. Kidney function: The kidneys play an important role in regulating phosphate metabolism, so individuals with kidney disease may be at an increased risk of developing NFTC.
8. Hormonal imbalances: Hormones such as parathyroid hormone, vitamin D, and calcitonin play important roles in regulating phosphate metabolism, so imbalances in these hormones may contribute to the development of NFTC.
9. Medications: Certain medications, such as phosphate-binding antacids, can interfere with phosphate metabolism and contribute to the development of NFTC.
10. Liver disease: The liver plays a role in the regulation of phosphate metabolism, so individuals with liver disease may be at an increased risk of developing NFTC.
11. Malabsorption disorders: Disorders that affect the absorption of nutrients in the intestine, such as celiac disease or inflammatory bowel disease, can contribute to the development of NFTC.
12. Alkaline phosphatase deficiency: Alkaline phosphatase is an enzyme that is involved in the metabolism of phosphate. Deficiencies in this enzyme can lead to the deposition of calcium phosphate in the soft tissues of the body.
13. Abnormalities in bone metabolism: Disorders that affect bone metabolism, such as osteoporosis or Paget’s disease, can contribute to the development of NFTC.
14. Immune system dysfunction: Some researchers believe that abnormalities in the immune system may contribute to the development of NFTC, although the exact mechanisms are not well understood.
15. Abnormalities in vitamin D metabolism: Vitamin D is important for the regulation of phosphate metabolism, so abnormalities in vitamin D metabolism may contribute to the development of NFTC.
16. Abnormalities in calcium metabolism: Calcium and phosphate metabolism are closely linked, so abnormalities in calcium metabolism may contribute to the development of NFTC.
17. Abnormalities in magnesium metabolism: Magnesium is also involved in the regulation of phosphate
18. Mutations in the GALNT3 gene: The GALNT3 gene provides instructions for making an enzyme called N-acetylgalactosaminyltransferase 3, which is involved in the modification of proteins. Mutations in this gene can cause abnormal protein modification and lead to the deposition of calcium phosphate in the tissues.
19. Mutations in the FGF23 gene: The FGF23 gene provides instructions for making a hormone called fibroblast growth factor 23, which helps regulate the levels of phosphate in the body. Mutations in this gene can cause an increase in FGF23 levels, which can lead to low phosphate levels and the deposition of calcium phosphate in the tissues.
20. Mutations in the KL gene: The KL gene provides instructions for making a protein called klotho, which is involved in the regulation of phosphate and calcium metabolism. Mutations in this gene can cause a decrease in klotho levels, which can lead to an imbalance in phosphate and calcium levels and the deposition of calcium phosphate in the tissues.
21. Mutations in the GALNT14 gene: The GALNT14 gene provides instructions for making an enzyme called N-acetylgalactosaminyltransferase 14, which is involved in the modification of proteins. Mutations in this gene can cause abnormal protein modification and lead to the deposition of calcium phosphate in the tissues.
22. Mutations in the SAMD9L gene: The SAMD9L gene provides instructions for making a protein that is involved in the regulation of cell growth and division. Mutations in this gene can lead to abnormal cell growth and the deposition of calcium phosphate in the tissues.
23. Mutations in the ABCC6 gene: The ABCC6 gene provides instructions for making a protein that is involved in the transport of molecules across cell membranes. Mutations in this gene can lead to the deposition of calcium phosphate in the tissues.
24. Mutations in the ENPP1 gene: The ENPP1 gene provides instructions for making a protein that is involved in the regulation of phosphate metabolism. Mutations in this gene can lead to an imbalance in phosphate and calcium levels and the deposition of calcium phosphate in the tissues.
25. Mutations in the CD73 gene: The CD73 gene provides instructions for making an enzyme called ecto-5′-nucleotidase, which is involved in the regulation of phosphate metabolism. Mutations in this gene can lead to an imbalance in phosphate and calcium levels and the deposition of calcium phosphate in the tissues.
26. Mutations in the NT5E gene: The NT5E gene provides instructions for making an enzyme called ecto-5′-nucleotidase, which is involved in the regulation of phosphate metabolism. Mutations in this gene can lead to an imbalance in phosphate and calcium levels and the deposition of calcium phosphate in the tissues.
27. Mutations in the TMEM16E gene: The TMEM16E gene provides instructions for making a protein that is involved in the regulation of phosphate metabolism. Mutations in this gene can lead to an imbalance in phosphate and calcium levels and the deposition of calcium phosphate in the tissues.
28. Mutations in the SLC20A2 gene: The SLC20A2 gene provides instructions for making a protein

Symptoms

The symptoms of NFTC can vary depending on the severity of the disease and the location and size of the calcified tumors. Here is a list of common symptoms of NFTC:

1. Soft tissue masses: The most common symptom of NFTC is the formation of calcified masses or tumors in the soft tissues of the body. These masses can be painful, and may cause stiffness or limited mobility in affected areas.
2. Skin lesions: NFTC can cause small, white or yellowish bumps or nodules to form on the skin, especially in areas that are exposed to pressure or trauma.
3. Joint pain: NFTC can cause joint pain and stiffness, especially in the hips and knees.
4. Muscle weakness: NFTC can cause weakness in the muscles of the arms and legs, making it difficult to lift or carry heavy objects.
5. Tooth pain: NFTC can cause tooth pain and sensitivity, as well as dental abnormalities such as enamel hypoplasia or delayed tooth eruption.
6. Fatigue: NFTC can cause fatigue and lethargy, which may be due to the effects of the calcified masses on the body’s metabolism.
7. Hyperpigmentation: NFTC can cause areas of skin to become darker or more pigmented than surrounding skin.
8. Abdominal pain: NFTC can cause abdominal pain and discomfort, especially if the calcified masses affect the digestive tract or other abdominal organs.
9. Vomiting: NFTC can cause nausea and vomiting, especially if the calcified masses affect the digestive tract or other abdominal organs.
10. Constipation: NFTC can cause constipation, especially if the calcified masses affect the digestive tract or other abdominal organs.
11. Diarrhea: NFTC can cause diarrhea, especially if the calcified masses affect the digestive tract or other abdominal organs.
12. Frequent urination: NFTC can cause increased urination, especially if the calcified masses affect the kidneys or bladder.
13. Bone pain: NFTC can cause bone pain and deformities, especially if the calcified masses affect the bones of the arms or legs.
14. Short stature: NFTC can cause growth retardation and short stature in affected individuals, especially if the calcified masses affect the growth plates of the bones.
15. Osteoporosis: NFTC can cause osteoporosis or thinning of the bones, especially if the calcified masses affect the bones of the spine or hips.
16. Hearing loss: NFTC can cause hearing loss or deafness, especially if the calcified masses affect the bones of the middle ear.
17. Vision loss: NFTC can cause vision loss or blindness, especially if the calcified masses affect the eyes or optic nerves.
18. Headaches: NFTC can cause headaches or migraines, especially if the calcified masses affect the brain or surrounding tissues.
19. Seizures: NFTC can cause seizures or convulsions, especially if the calcified masses affect the brain or surrounding tissues.
20. Intellectual disability: NFTC can cause intellectual disability or developmental delays, especially if the calcified masses affect the brain or surrounding tissues.

Diagnosis

NFTC can be diagnosed through a combination of clinical examination, imaging studies, and genetic testing. Here is a list of diagnosis and tests that are commonly used to diagnose NFTC:

1. Medical history: A detailed medical history can provide important clues about the onset and progression of symptoms, family history, and any previous diagnoses or treatments.
2. Physical examination: A physical examination can help identify the presence of nodules or tumors in soft tissues, particularly around joints.
3. X-rays: X-rays can show the presence of calcifications or nodules in soft tissues, particularly around joints.
4. Ultrasound: Ultrasound can help identify the location and size of nodules or tumors in soft tissues.
5. Computed tomography (CT) scan: CT scan can provide a detailed view of the location, size, and extent of calcifications or nodules in soft tissues.
6. Magnetic resonance imaging (MRI): MRI can provide a detailed view of the location, size, and extent of calcifications or nodules in soft tissues.
7. Biopsy: A biopsy involves taking a small sample of tissue from a nodule or tumor and examining it under a microscope to determine if it is calcified and to rule out other conditions.
8. Blood tests: Blood tests can help evaluate the levels of calcium, phosphate, parathyroid hormone, and vitamin D in the body, which can provide clues about the underlying cause of calcifications.
9. Urine tests: Urine tests can help evaluate the levels of calcium and phosphate in the body, which can provide clues about the underlying cause of calcifications.
10. Genetic testing: Genetic testing can identify mutations in genes associated with NFTC, which can confirm the diagnosis and help identify other family members who may be at risk.
11. Bone scan: A bone scan can help identify the extent of bone involvement in NFTC.
12. Joint aspiration: Joint aspiration involves removing fluid from a joint to evaluate the presence of calcium phosphate crystals, which can confirm the diagnosis of NFTC.
13. Electrocardiogram (ECG): ECG can help identify any cardiac involvement in NFTC, particularly if there is hyperphosphatemia.
14. Renal ultrasound: Renal ultrasound can help identify any renal involvement in NFTC, particularly if there is hyperphosphatemia.
15. Abdominal ultrasound: Abdominal ultrasound can help identify any hepatic involvement in NFTC, particularly if there is hyperphosphatemia.
16. Dual-energy X-ray absorptiometry (DEXA) scan: DEXA scan can help identify any osteoporosis or osteopenia associated with NFTC.
17. 24-hour urine calcium and phosphate measurement: 24-hour urine calcium and phosphate measurement can help evaluate the levels of calcium and phosphate in the body and provide clues about the underlying cause of calcifications.
18. Bone mineral density test: Bone mineral density test can help identify any osteoporosis or osteopenia associated with NFTC.
19. Serum fibroblast growth factor 23 (FGF23) measurement: Serum FGF23 measurement can help evaluate the levels of FGF23, which is involved in the regulation of phosphate metabolism, and provide clues about the underlying cause
20. Genetic testing: Genetic testing may be used to confirm the diagnosis and identify the specific mutation in the FGF23 gene.
21. Family screening: Family screening may be recommended to identify other family members who may be at risk of developing NFTC.
22. Hormone testing: Hormone testing may be used to evaluate the function of the endocrine glands and assess the risk of hormonal imbalances.
23. Liver function tests: Liver function tests may be used to evaluate liver health and assess the risk of liver calcifications
24. Parathyroid hormone (PTH) levels: PTH levels may be elevated in NFTC due to secondary hyperparathyroidism caused by hypocalcemia.
25. Vitamin D levels: Vitamin D levels may be measured to assess its role in calcium and phosphate metabolism.
26. Alkaline phosphatase (ALP) levels: ALP levels may be elevated in NFTC due to increased bone turnover and mineralization.

Treatment

Treatments for Normophosphatemic familial tumoral calcinosis.

1. Surgical excision: The surgical removal of the tumors is the most effective treatment for NFTC. However, the procedure is complex and carries a high risk of recurrence.
2. Medical management: Several medications have been used to manage the symptoms of NFTC, including calcium channel blockers, bisphosphonates, and corticosteroids. These drugs can help reduce pain and prevent the formation of new tumors.
3. Low phosphate diet: A low phosphate diet can help reduce the levels of phosphate in the body and prevent the formation of new tumors. Foods high in phosphate such as dairy products, red meat, and processed foods should be avoided.
4. High-calcium diet: A diet high in calcium can help prevent the absorption of excess phosphate and reduce the risk of tumor formation. Foods high in calcium such as leafy greens, fortified cereals, and dairy products should be included in the diet.
5. Vitamin D supplementation: Vitamin D is essential for the absorption of calcium in the body. Supplementation with vitamin D can help prevent the formation of new tumors by regulating the levels of calcium and phosphate in the body.
6. Phosphate binders: Phosphate binders such as calcium carbonate and sevelamer can be used to reduce the absorption of phosphate in the gut and prevent the formation of new tumors.
7. Sodium thiosulfate: Sodium thiosulfate is a medication that can be used to dissolve calcium deposits in the soft tissues of the body. It can help reduce the size of the tumors and improve symptoms.
8. Magnesium supplementation: Magnesium is an essential mineral that plays a role in bone health and the regulation of calcium levels in the body. Supplementation with magnesium can help prevent the formation of new tumors.
9. Topical treatments: Topical treatments such as calcipotriol and betamethasone can be applied to the skin to reduce inflammation and pain associated with the tumors.
10. Tumor necrosis factor-alpha (TNF-α) inhibitors: TNF-α inhibitors are a class of medications that can help reduce inflammation in the body. These medications have been shown to be effective in reducing calcinosis in some NFTC patients.
11. Colchicine: Colchicine is an anti-inflammatory medication that can help reduce inflammation and swelling associated with calcinosis. It works by inhibiting the activity of white blood cells, which can contribute to inflammation.
12. Sodium thiosulfate: Sodium thiosulfate is a medication that can help dissolve calcium deposits in soft tissues. It is typically administered intravenously and may require frequent dosing.
13. Extracorporeal shock wave lithotripsy (ESWL): ESWL is a non-invasive procedure that uses shock waves to break up calcified masses in soft tissues. This treatment can be effective in reducing the size and frequency of calcified masses, but may require multiple treatments.
14. Laser therapy: Laser therapy can be used to reduce the size of the tumors and improve symptoms. The procedure involves the use of a laser to heat and break down the calcium deposits.
15. Radiation therapy: Radiation therapy can be used to reduce the size of the tumors and improve symptoms. The procedure involves the use of high-energy radiation to kill the cells in the tumor.
16. Cryotherapy: Cryotherapy involves the use of extreme cold to freeze and destroy the tumor cells. The procedure can be effective in reducing the size of the tumors and improving symptoms.
17. Ultraviolet light therapy: Ultraviolet light therapy can be used to reduce the size of the tumors and improve symptoms. The procedure involves the use of a special type of light that penetrates the skin and breaks down the calcium deposits.
18. Acupuncture: Acupuncture can be used to relieve pain associated with the tumors. The procedure involves the insertion of thin needles into specific points on the body.
19. Herbal remedies: Several herbal remedies such as turmeric, ginger, and boswellia can be used to reduce inflammation and pain associated with the tumors.

References