Tumoral calcinosis lesions can become very large and frequently require surgical resection due to pain, deformity and limitation of joint movements. Surgery may be curative, but unfortunately, these lesions typically recur [64
] due to persistence of the underlying metabolic defect.
Medical treatment for tumoral calcinosis is based on limited clinical evidence. Due to the rarity of hFTC, controlled trials are lacking and all available treatment information is based on case reports or case series. Assessment of treatment options is complicated by the extreme variability between subjects in terms of the severity of biochemical abnormality and the number and size of TC lesions. Furthermore, the measure of effect varies between reports, including increasing renal phosphate excretion, decreasing serum phosphate concentration and resolution or reduction in size of TC lesions. From the patient's perspective, the most important outcome is probably resolution of TC lesions, as these can be both painful and disabling.
However, in both healthy adults and patients with chronic kidney disease, serum phosphate concentrations are associated with cardiovascular disease and mortality, even within the normal phosphate range [67
]. Furthermore, vascular calcifications are reported in patients with FTC [25
]. Consequently, even without disabling effects of TC lesions, aggressive management of the biochemical profile may be important for patients with hFTC.
Most hFTC treatment regimens involve altering the abnormal biochemical profile to counteract the consequences of insufficient FGF23 action, allowing gradual resolution of the lesions. Thus treatment is targeted at decreasing the intestinal absorption of phosphate, using both dietary phosphate restriction and oral phosphate binding agents, and decreasing tubular reabsorption of phosphate. The FGF23 knockout mouse develops vascular calcifications and is biochemically similar to humans with hFTC. In these mice, while restricting dietary phosphate does decrease serum phosphate and vascular calcifications, vitamin D restriction did not alter these parameters. However, these mice have a shortened lifespan, and although not applicable to human treatment, vitamin D restriction did prolong survival [70
Phosphate restriction is challenging because phosphate is ubiquitous in the western diet, and is generally very well absorbed. Detailed nutritional education is necessary, and may require dietary restriction as low as 400 mg daily [71
]. Classically, dietary phosphate deprivation is combined with aluminum and magnesium based phosphate binders often using high doses. Although several case reports have demonstrated successful decrease in serum phosphate concentrations [71
] and regression of hFTC lesions [71
] with a low phosphate diet combined with phosphate binders (mostly aluminum hydroxide), the results have been inconsistent. However, in many cases these measures have still failed to resolve hFTC lesions, and the response in terms of serum phosphate is highly variable [64
]. Although hypercalcemia is not typical in TC, calcium based phosphate binders are likely to increase the absorbed calcium and may increase the calcium-phosphorus product which could adversely affect hFTC lesions. Treatment with newer phosphate binders, such as sevalemer has also been reported, with similarly mixed results [35
]. However, phosphate binders can be combined with therapies to increase renal phosphate excretion to augment the effect on phosphate balance.
Acetazolamide is a carbonic anhydrase inhibitor that has phosphaturic effect [73
], which is independent of PTH as emphasized by both experiments in thyroparathyroidectomized animals [81
] and hypoparathyroid or pseudohypoparathyroid humans [82
]. This effect has also been demonstrated in hFTC patients [73
]. After a single dose of acetazolamide, there is a mild decrease in serum phosphate coinciding with increased urinary phosphate excretion [73
]. Long term treatment with acetazolamide combined with sevalemer as a phosphate binding agent has resulted in resolution of a very large hFTC lesion [35
], and another case reported lack of recurrence after excision during treatment with acetazolamide [64
]. In contrast, other investigators have noted no lesional improvements after acetazolamide [78
Calcitonin also increases phosphaturia independently of PTH. Calcitonin was demonstrated to increase fractional excretion of phosphate and decrease serum phosphate in hFTC patients [83
]. However the published response of TC lesions to this treatment is limited. In one patient the TC lesion did not progress during treatment [83
], but in two other patients, there was an apparent increase in size of the TC lesions [85
In fact, data from XLH (a disorder biochemically opposite to hFTC) suggest that calcitonin might actually be harmful as a treatment of TC. At least two studies have demonstrated that administering calcitonin increases serum 1,25D concentration and increases serum phosphate in XLH patients [86
]. Furthermore, in one study after infusion of calcitonin, the serum FGF23 concentrations were decreased [87
]. These effects on FGF23 and 1,25D would be the opposite of the desired goals for biochemical management of TC. However, although short term calcitonin did increase serum 1,25D in one TC patient [83
], the authors noted lack of new lesions during long term treatment.
Other treatments have been tried based on analogy to ectopic calcifications occurring in the setting of inflammatory disorders. Although case reports suggest a possible benefit of bisphosphonates on other forms of calcinosis [88
], limited reports suggest no benefit for FTC lesions [91
]. Other reports have noted lack of benefit with methotrexate or steroids [64
]. Since these treatments did not address the primary biochemical problem, it is not surprising that they were ineffective.
From a pathophysiologic sense the ideal treatment for FTC due to GALNT3
mutations would address the deficiency of FGF23, either by administering FGF23 itself or an agonist. Certainly in animal models, administration of FGF23 increases renal phosphate excretion, and lowers serum phosphate [45
]. Thus the ability to treat with FGF23 could prevent or eliminate the tumoral calcinosis lesions in subjects with GALNT3
mutations through effects on the biochemical profile. Delivery of αKL protein is unlikely to be an effective treatment for these mutations, as αKL expression is already up-regulated in the Galnt3
-null mouse [39
] and αKL's role in renal phosphate regulation is largely dependent on the presence of active FGF23.
Conversely, since αKL is necessary for FGF23 action at the renal tubule, FGF23 would likely be an ineffective therapy for FTC due to αKlotho mutations. Although parathyroid hormone decreases renal phosphate reabsorption, PTH also stimulates 1,25D production and increases serum calcium concentrations; thus, despite its phosphaturic effect, the increases in 1,25D and in calcium-phosphate product would likely be harmful rather than beneficial in hFTC.