Hyperphosphatemic Tumoral Calcinosis Research Articles

Tumor-induced osteomalacia associated with a maxillofacial tumor producing fibroblast growth factor 23: report of a case and review of the literature

Tumor-induced osteomalacia (TIO) is a rare acquired paraneoplastic disease characterized by renal phosphate wasting and hypophosphatemia. Recently, it was reported that tumors associated with TIO produce fibroblast growth factor (FGF) 23, identified as the last member of the FGF family and of which excessive action causes several hypophosphatemic diseases whereas deficient FGF23 activity results in hyperphosphatemic tumoral calcinosis. In this case, although it was difficult to locate the associated tumor, an abnormal mass in the left maxilla was detected by imaging. The tumor was removed by partial resection of the left maxillary alveolar region. Thereafter, serum level of FGF23 rapidly decreased, hypophosphatemia improved, and the clinical symptoms greatly improved. Histopathologic diagnosis of the tumor was phosphaturic mesenchymal tumor, mixed connective tissue variant. Immunohistochemical findings confirmed that the removed tumor produced FGF23. These results indicate that development of osteomalacia in this patient was related to the maxillary tumor, which overexpressed FGF23.

Defective O-Glycosylation due to a Novel Homozygous S129P Mutation Is Associated with Lack of Fibroblast Growth Factor 23 Secretion and Tumoral Calcinosis

Homozygous mutations in fibroblast growth factor (FGF23) have recently been described as the genetic cause of one form of hyperphosphatemic tumoral calcinosis (HFTC). However, it remained unclear to date how these mutations lead to loss of biologically active FGF23 in the circulation. We here report a novel homozygous mutation, c.385T>C in FGF23 exon 2, which changes codon 129 from serine to proline (S129P) in a previously described individual affected by HFTC. The S129P mutation as well as two known FGF23 mutations, S71G and S129F, were introduced into an expression vector encoding wild-type (wt) human (h) FGF23 to yield [P129]hFGF23, [F129]hFGF23, and [G71]hFGF23; whole lysates, glycoprotein fractions, and conditioned media from HEK293 and COS-7 cells expressing these constructs were subjected to Western blot analysis using affinity-purified goat anti-hFGF23(51-69) and anti-hFGF23(206-222) antibodies. We detected 25- and 32-kDa protein species in total lysates of HEK293 cells expressing wt-hFGF23. The 32-kDa band, representing O-glycosylated hFGF23, was not detectable in the glycoprotein fraction of lysates from HEK293 cells expressing [P129]hFGF23, and in comparison with wt-FGF23 only small amounts of [P129]hFGF23 were secreted into the medium. Similar results were obtained for cells expressing [G71]hFGF23 and [F129]hFGF23. Our data for the first time directly show that FGF23 mutations associated with HFTC impair O-glycosylation in vitro resulting in poor secretion of the mutant hormone thereby explaining the characteristic hyperphosphatemic phenotype of homozygous carriers in vivo.

Fibroblast Growth Factor 23 (FGF23) and Disorders of Phosphate Metabolism

Derangements in serum phosphate level result in rickets/osteomalacia or ectopic calcification indicating that healthy people without these abnormalities maintain serum phosphate within certain ranges. These results indicate that there must be a regulatory mechanism of serum phosphate level. Fibroblast growth factor 23 (FGF23) was identified as the last member of FGF family. FGF23 is produced by bone and reduces serum phosphate level by suppressing phosphate reabsorption in proximal tubules and intestinal phosphate absorption through lowering 1,25-dihydroxyvitamin D level. It has been shown that excess and deficient actions of FGF23 result in hypophosphatemic rickets/osteomalacia and hyperphosphatemic tumoral calcinosis, respectively. These results indicate that FGF23 works as a hormone, and several disorders of phosphate metabolism can be viewed as endocrine diseases. It may become possible to treat patients with abnormal phosphate metabolism by pharmacologically modifying the activity of FGF23.

Nonfamilial hyperphosphatemic tumoral calcinosis with ulnar neuropathy

We present a case of multiple large juxta-articular painless masses involving both the elbows and right hip in a 27-year old south Asian male who presented with ulnar neuropathy and constitutional symptoms. Radiology, blood investigations and biopsy confirmed it to be hyperphosphatemic tumoral calcinosis. Patient was also diagnosed with an extremely rare association, testicular microlithiasis. Complete surgical excision with low phosphate diet resulted in complete neurological recovery and no recurrence at 30 months. Tumoral calcinosis should be considered in the differential diagnosis of a case with multiple, symptomatic juxta-articular masses.

Physiological Regulation and Disorders of Phosphate Metabolism -Pivotal Role of Fibroblast Growth Factor 23-

Fibroblast growth factor (FGF) 23 has been identified as the last member of FGF family. FGF23 reduces serum phosphate level by suppressing proximal tubular phosphate reabsorption and intestinal phosphate absorption. FGF23 is produced by bone and acts on the kidney through a specific receptor system which is composed of Klotho and certain subtypes of FGF receptors. Excess actions of FGF23 cause several hypophosphatemic diseases characterized by impaired renal phosphate reabsorption and rickets/osteomalacia. In contrast, deficient actions of FGF23 result in hyperphosphatemic tumoral calcinosis with enhanced renal phosphate reabsorption. These results indicate that FGF23 works as a hormone to regulate the serum phosphate level.

Vertebral involvement in hyperphosphatemic tumoral calcinosis

Hyperphosphatemic tumoral calcinosis (HTC) is an inherited metabolic disorder characterized by calcified soft tissue masses and hyperphosphatemia. Besides these typical features, a number of less common manifestations have been reported, all of them related to pathologic calcification of various tissues. We have investigated the case of a woman with hyperphosphatemia, recurrent episodes of lumbar pain, and a positive familial history of HTC. A bone scan showed markedly increased uptake in the lower lumbar spine. Magnetic resonance imaging showed pathological changes in L5 compatible with an inflammatory reaction and not suggestive of neoplastic process. There was no evidence of infection, trauma, malignancy, or other disease that could cause the lesion. We treated the patient with analgesics and NSAIDs and the pain remitted over a period of 1 week. In a follow-up magnetic resonance imaging 7 months later, the L5 lesion had disappeared completely. A computed tomography scan analysis with a bone window showed a sclerotic area at the L5 vertebral body. We believe that this patient was affected by the syndrome of HTC and that the inflammatory phenomena found in L5 are a manifestation of this disease.

Dementia associated with hyperphosphatemic tumoral calcinosis

Hyperphosphatemic tumoral calcinosis (HTC) is a rare inherited metabolic disorder manifested by pararticular calcification and hyperphosphatemia, caused by an elevated renal phosphate reabsorption threshold and elevated serum 1,25-dihydroxyvitamin D levels. The disorder usually affects African-American subjects, but has also been described in Caucasians and Hispanics. Vascular calcifications and angioid streaks have been reported to be associated with the disorder; however, dementia has not been previously reported. Our medical center has followed two African-American siblings, with HTC for over 30 years, who have developed dementia at 56 years and 67 years of age. Neither man has been hypertensive, however, magnetic resonance imaging (MRI) scans in both cases revealed multiple periventricular infarcts, suggestive of infarcts caused by vascular calcification in the central nervous system. These two brothers with HTC suggest that periventricular infarcts with dementia may be a long term complication of this disorder.

Familial Hyperphosphatemic Tumoral Calcinosis A Report From Saudi Arabia

The clinical details and radiologic and histopathologic findings of lesions from three male siblings and their female cousin with hyperphosphatemic tumoral calcinosis are presented. The three siblings were children of consanguineous parents. The patients were aged 5, 17, 19, and 20 years; however, they first presented when they were 3.5, 8, 4, and 5 years of age, respectively; resulting in a disease duration ranging from 1.5 to 15 years. All are alive with persistent disease. The eldest patient has an alpha-thalassemia trait. Sites of lesions included the periarticular soft tissues of gluteal region, the shoulder, elbow, interscapular area, axilla, and popliteal fossa. A calcified soft tissue mass was seen radiologically at all sites affected. Histologically, locules of calcified debris surrounded by multinucleated osteoclast-type giant cells and foamy histiocytes characterized all lesions. The cells showed cytoplasmic vacuoles that stained positively both with anti-alpha-1-antichymotrypsin and anti-alpha-1-antitrypsin. Ultrastructurally hydroxyapatite deposits were demonstrable in these cytoplasmic vacuoles. All patients had normocalcemia and hyperphosphatemia. A low normal blood level of 25-hydroxycholecalciferol was noted in the youngest patient. Surgical excision was unsuccessful as the lesions recurred and progressed. Medical therapy may only slow the progression of the disease process.

Hyperphosphataemic tumoral calcinosis in Bedouin Arabs — Clinical and radiological features

In the first report of Bedouin Arabs with tumoral calcinosis, three Saudi Arabian male siblings and their female first cousin with the condition are described. In tumoral calcinosis the majority of cases are familial. These patients had associated hyperphosphataemia with normal renal function. The characteristic appearance of periarticular soft tissue calcified masses was present. Two of the cases developed calcific myelitis of long bones--a recognized complication of the disease. Two have widespread arterial calcification, which has not previously been described. Two cases have other unusual features; one has a calcified mass which has destroyed the blade of the scapula, whilst another developed a large tumoral mass on the posterior aspect of the knee.

Successful treatment of hyperphosphatemic tumoral calcinosis with long-term acetazolamide

Successful treatment of hyperphosphatemic tumoral calcinosis with long-term acetazolamide

Tumoral calcinosis: seasonal biochemical studies and chemical studies of eyelid lesion.

We recently described (Arch Ophthalmol 1988; 106:725-6) the presence of unique calcific lesions in the eyelids of a young woman with a history of hyperphosphatemic tumoral calcinosis. Here we document that no immediate family members showed similar lesions and that none was hyperphosphatemic. Dental roentgenography revealed characteristic abnormalities in the patient that confirmed the clinical diagnosis of tumoral calcinosis. Seasonal biochemical studies demonstrated persistently increased concentrations of phosphorus and 1,25-dihydroxyvitamin D in her serum. A calcific eyelid excrescence removed from the patient, studied by x-ray diffraction, was found to consist of crystals of hydroxyapatite. Microprobe analysis indicated the major elements in the deposit to be Ca, P, S, and Cl, just as in the periarticular deposits found in tumoral calcinosis. The Ca concentration in the patient's tear fluid, measured by atomic absorption spectrometry, was within the range found in tears of healthy volunteers. Phosphorus was undetectable (less than 30 mumol/L) in tears of the patient and the volunteers. These findings suggest that the eyelid lesions represent a new manifestation of the pathological process that produces the characteristic periarticular calcific masses of tumoral calcinosis.

Hyperphosphatemic tumoral calcinosis: association with elevation of serum 1,25-dihydroxycholecalciferol concentrations.

Seven siblings with hyperphosphatemic tumoral calcinosis were studied using metabolic measures. Serum phosphorus and 1, 25-dihydroxycholecalciferol concentrations were significantly increased and serum parathyroid hormone and 25-hydroxycholecalciferol concentrations were significantly decreased in these subjects. Metabolic balance studies done in three of the siblings showed positive calcium and phosphorus balances, reflected by increased gastrointestinal absorption and decreased renal excretion. These data suggest that a hereditary abnormality of vitamin D metabolism may be present in patients with hyperphosphatemic tumoral calcinosis. Failure of the normal feedback mechanism regulating the 25-hydroxy-1-alpha-hydroxylase enzyme is suggested as the major cause. Although this defect could lead to many of the metabolic abnormalities seen in these patients, the overall contribution of altered vitamin D metabolism to the pathogenesis of tumoral calcinosis is not fully understood.