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Hyperphosphatemic Tumoral Calcinosis
Introduction
Hyperphosphatemic tumoral calcinosis (HTC), also known as hyperphosphatemic familial tumoral calcinosis or familial tumoral calcinosis/hyperostosis hyperphosphatemia syndrome, is a disorder of phosphate regulation.[1] It is a rare disabling disorder manifesting as ectopic calcifications in periarticular regions and thereby causing limitation in joint motions and disability. Besides, inflammatory bony pains are also a peculiar feature of this disorder.[2] Due to the extreme rarity of the disease and lack of clinical trials, the evidence regarding various management options is not robust. The management options include phosphate-lowering therapies, anti-inflammatory medications, and surgical excision of the calcific masses with significantly disabled cases.[3]
Etiology
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Etiology
The cause of HTC is reported to be a functional deficiency of intact fibroblast growth factor 23 (FGF 23), which is a critical hormonal regulator of phosphate metabolism. It is an autosomal recessive disorder with genetic mutations causing a defect in the functioning of FGF23, in either the stage of its production, post-translational processing, or by causing end-organ resistance.[4] Recently a case of HTC has been described highlighting autoimmunity against FGF23 with autoantibodies hampering the end-organ functioning of FGF23.[5]
Epidemiology
HTC is extremely rare, with less than 100 genetically confirmed cases reported in the literature. Though there have been no prevalence studies on HTC, the disorder was previously predominantly reported from Africa and the Middle-East countries; however, later cases were also identified in European people.[6][7]
Pathophysiology
FGF23 Function and Processing
FGF23 is a peptide hormone secreted by mainly osteocytes and osteoblasts.[8] It is the chief regulator of serum phosphate levels. It acts on the proximal renal tubules to inhibit sodium phosphate cotransporters NPT2a and NPT2c, thereby causing phosphaturia.[9] Also, it inhibits 25-hydroxy vitamin D 1-alpha-hydroxylase in the kidney to decrease the levels of the active form of vitamin D- 1,25 dihydroxy vitamin D. Besides, it stimulates 24-alpha-hydroxylase , which increases the levels of 24,25 dihydroxy vitamin D. Decrease in the active form of Vitamin D also decreases the absorption of calcium and phosphate from the intestine, thereby further regulating the levels of serum phosphate.
FGF23 undergoes post-translational processing in the form of O-glycosylation in the Golgi apparatus, done by N-acetylgalactosaminyl transferase-3 enzyme (encoded by GALNT3 gene).[10] The active form of FGF23 then acts on the FGFR1 receptor along with its co-receptor KLOTHO (encoded by the KL gene) in proximal renal tubules.
FGF23 Defect in HTC
The most common form of HTC results from a loss-of-function mutation in the GALNT3 gene, resulting in congenital disorder of O-glycosylation of FGF23 (GALNT3-CDG). The resultant form of FGF23 undergoes degradation by the Furin enzyme into its inactive N-terminal and C-terminal fragments.[4] A mutation in the FGF23 has also been reported, resulting in decreased functional FGF23 levels, causing hyperphosphatemia. In both the types mentioned above of HTC, there is a decrease in the serum levels of intact FGF23 (iFGF23) and an increase in levels of the inactive C-terminal fragments of FGF23. The third type of HTC has been reported to result from a mutation in the KL gene, thereby causing resistance to the actions of FGF23. As a result, the serum iFGF23 levels and the levels of C-terminal fragments are found to be increased.[1] Recently, an autoimmune variety of HTC has been reported in an 8-year-old child, in which autoantibodies against FGF23 resulted in end-organ resistance and an increase in serum iFGF23 levels.[5]
Ultimately, the resultant defect in all types of HTC is a lack of inhibition of the sodium-phosphate cotransporters NPT2a and NPT2c and decreased activity of 25-hydroxy vitamin D 1-alpha-hydroxylase in kidneys. It increases the serum phosphate levels and a high to inappropriately-normal 1,25 dihydroxy vitamin D levels.
History and Physical
Patients with HTC display a spectrum of signs and symptoms. Moreover, there is a significant heterogeneity reported in the clinical profile of patients with similar biochemical reports.
Tumoral Calcinosis
The most common presentation in such patients is painful calcified masses, particularly in peri-articular regions exposed to repetitive trauma/pressure.[11] The symptoms usually begin in the first two decades of life. However, HTC has also been reported in a 64-year-old individual after undergoing total knee arthroplasty.[12] The calcified swellings may grow and become very large to cause severe limitations in joint movements, thereby causing significant disability. The most common location for such swellings in the lateral aspect of the hips along with the abductor's muscles; the other reported areas include elbows, shoulders, hands, knees, and feet. The deposits are made up of hydroxyapatite crystals and calcium carbonate.[11][13]
Such calcifications have also been found incidentally in small and large vessels, including carotids, coronary, iliac, and aorta.[14][15] Peripheral vessel disease has been reported with decreased peripheral pulses and cold extremity, ultimately requiring amputation.[16] Besides, some visceral structures have also been involved in calcification, including the small intestine, tongue, and dura mater. Other areas where these deposits have been reported include kidneys causing nephrocalcinosis and testicular microdeposits.[1][11][17]
Hyperostosis and Inflammatory Symptoms
Many patients present with recurring bony pains, particularly involving tibia bones, but also reported in ulna, radius, and metacarpals. On examination, localized tenderness, redness, increased local temperature are noted, mimicking features of osteomyelitis.[2] Also, non-specific inflammatory symptoms such as joint pains, fever, anemia have been described with raised inflammatory markers like erythrocyte sedimentation rate and C-reactive protein. The cause of raised inflammatory markers is engulfed by macrophages of the hydroxyapatite crystals from calcified deposits, which secrete inflammatory cytokines.[11]
Dental Involvement
Teeth are involved very commonly in HTC. The various dental defects reported include pulp chamber obliteration, pulp stones, shortening of roots with bulbous enlargement in the middle, and enamel changes. Besides, a peculiar thistle shape of roots has been described. Also, the roots have often been found curved, a process called dilaceration. These dental changes are most commonly seen in premolar teeth.[18] The importance of dental involvement lies in its early recognition by dentists, as often these are the first reported manifestations of HTC before the development of tumoral calcinosis. Thus, appropriate evaluative, preventive, and treatment measures can be initiated once these changes are identified.
Eye Involvement
In HTC, calcific deposits have been described in eyelids, conjunctiva, and cornea. Such deposits may cause eye discomfort and itching. Calcification has also been reported in the elastin-rich membrane between the retina and choroid.[1][19][20]
Evaluation
The diagnosis of HTC can be established based on the peculiar clinical symptoms of tumoral calcinosis and the pattern of blood investigation reports. The findings in various blood tests include:
- Elevated serum phosphate levels
- Normal serum calcium levels
- Elevated to inappropriately normal serum 1, 25 dihydroxy Vitamin D levels
- Inappropriately increased tubular reabsorption of phosphorus
- Low-normal serum parathyroid levels
- Normal kidney function
- Elevated serum levels of C-terminal fragments of FGF23 (assessed by ELISA immunoassay)
When the clinical and laboratory investigations do not confirm the diagnosis in a suspected patient, genetic testing for FGF23, GALNT3, or KL gene may be helpful.
Plain Radiography
X-ray of the affected part demonstrates a heterogenous calcified mass in HTC.[11] In cases with hyperostosis, the X-ray features include dense periosteal reaction, patchy sclerosis in the medullary cavity, and hypermineralized cortex.[17] Dental radiographs show the changes of short and bulbous roots, pulp stones, and obliteration of pulp chambers.[18]
CT Scan
To characterize the anatomical features of the calcified masses, especially before surgical excision, a CT scan may be done. However, the risk-benefit ratio must be adequately assessed given the exposure to a high amount of harmful radiation.
Treatment / Management
As there is a lack of good-quality clinical trials in HTC, given the rarity of the disorder, the treatment options are mainly based on previous observational studies, case series, and case reports. As such, the medical management for HTC continues to evolve as newly published evidence becomes available. The medical therapies chiefly focus on lowering serum phosphate levels and decreasing the levels of inflammatory markers. However, the ideal therapy for the heritable form of HTC would be gene-replacement therapy for the defective gene. Until the time becomes available, research should also focus on hormone replacement therapy with iFGF23 to regulate serum phosphate levels.
The medications currently prescribed for phosphate reduction include sevelamer, lanthanum, aluminum hydroxide, acetazolamide, probenecid, nicotinamide, and niacinamide.[1][11][17][21][22] Dietary phosphate reduction is also recommended, though it is difficult to achieve given phosphorus in almost every food item.[23] Sevelamer, lanthanum, and aluminum hydroxide are phosphate-binding agents that decrease dietary phosphates' intestinal absorption, and hence should be ideally taken with every meal. Acetazolamide, a carbonic anhydrase inhibitor, causes proximal renal tubular acidosis and increases urinary phosphate excretion; it also contributes to increasing the solubility of calcium phosphate salts found in tumoral calcinosis by lowering the blood pH.[22][24] Probenecid is a uricosuric drug that helps in HTC by increasing urinary phosphate excretion.[1][11][17] (B3)
On the other hand, nicotinamide and niacinamide contribute by inhibiting the sodium-phosphate cotransporters in the proximal renal tubules of kidneys and intestines, thereby decreasing the urinary and intestinal absorption of phosphorus.[25][26] However, the results with all these phosphate-lowering drugs have not been consistent, with some reports demonstrating good results while others are not showing appreciable outcomes.(B3)
Patients with hyperostosis and inflammatory signs and symptoms require non-steroidal anti-inflammatory drugs (NSAIDs). There have been reports of the use of short-term steroids also for such conditions.[1] Also, anti-IL1 therapies, including anakinra (IL-1 receptor blocker) and canakinumab (anti-IL1 beta antibody), have been described in anecdotal reports, with promising results.[27] Also, intravitreal use of ranibizumab (monoclonal antibody against vascular endothelial growth factor) has been described with good results in a 56-year-old woman with decreased visual acuity due to subretinal hemorrhage secondary to retinal angioid streaks.[28] Moreover, topical sodium thiosulphate has also been reported to decrease the size of calcific lesions.[29][30] Some other drugs rarely used with limited efficacy in patients with HTC include bisphosphonates, calcitonin, and calcium-channel blockers. Besides, hemodialysis and peritoneal dialysis have also been described to correct metabolic abnormalities in HTC.[31](B3)
Surgical excision of the calcific masses needs to be done in severe cases, with the swellings causing significant limitation of joint movements and disability. However, often these surgeries have to be repeated when regrowth of the swellings occurs.[11][32]
Differential Diagnosis
Some of the differentials in these patients include normophosphatemic tumoral calcinosis, porphyria cutanea tarda, calcinosis cutis, pseudohypoparathyroidism, chronic renal failure, fibrodysplasia ossificans progressive, and osteomyelitis.
Prognosis
The prognosis remains guarded in patients with HTC due to the lack of availability of a permanent cure. All the treatment options currently available focus on decreasing serum phosphate levels and symptomatic management. However, the presentation is quite variable in these patients, with some of them having very disabling symptoms while others not so symptomatic, though having a similar genetic and biochemical profile. Also, the growth of the tumoral calcinosis lesions is prolonged in most patients with significant remission of the symptoms with medical therapy.
Complications
The calcific masses may ulcerate the skin resulting in a discharge of white material containing liquid hydroxyapatite. Such patients need surgical excision of the lesions to prevent secondary infections.[11] Also, there is an increased potential risk of cardiac events due to coronary vessel calcification and increased inflammatory markers, both of which are risk factors for ischemic cardiac disease. However, detailed evaluation and long-term follow-up research need to be done on the practical implications of these risk factors. Moreover, sudden vision loss has been described in two patients of HTC due to subretinal hemorrhage in a retinal angioid streak in one patient and associated with neurologic dysfunction and stroke in another patient.[28][33] Furthermore, peripheral vascular disease due to calcification can lead to loss of peripheral pulses and cold extremities and may necessitate amputation of the limb.[16]
Deterrence and Patient Education
Patients with HTC should avoid taking calcium and vitamin D supplements, as calcium supplements can enhance the formation of tumoral calcinosis lesions after combining with phosphates, and vitamin D levels are already high/inappropriately normal. Also, such patients should avoid consuming diets high in calcium and phosphorus.
Enhancing Healthcare Team Outcomes
Once the diagnosis of HTC is established, dietician advice should be sought to formulate a diet low in calcium and phosphorus. Also, the management requires interprofessional teamwork comprising an endocrinologist, general physician, general surgeon, and orthopedic surgeon. Moreover, a complete dental evaluation is required, not only for the patient but also for the siblings, for early identification of the disease. An eye check also needs to be done to rule out ocular involvement in HTC. Also, a vascular surgeon should be consulted to screen for peripheral vascular disease. A thorough cardiac workup is also essential to screen for cardiac risk factors. [Level 5] Moreover, a physical therapist should also be consulted to provide adequate joint physiotherapy to decrease limitations in joint movements.
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