Hyperphosphatemic Tumoral Calcinosis Research Articles

A rare case of Hyperphosphatemic Tumoral Calcinosis in a 13 year old Nigerian boy

Tumoral calcinosis is a rare disorder that presents with ectopic calcifications deposited at different periarticular soft tissue regions of the body- mostly hips, elbows and shoulders. It results from a relative deficiency of, or resistance to, the phosphate-regulating hormone - Fibroblast Growth Factor 23 (FGF23), due to gene mutations, causing hyperphosphatemia. We describe this condition in a 13 year old, Nigerian boy who presented with a 7 year history of multiple body swellings of firm to hard consistency. Laboratory investigations showed hyperphosphatemia with normal serum calcium, vitamin D and parathyroid hormone levels. Radiological and histological findings were consistent with tumoral calcinosis. Having had two previous surgeries to remove the lesions, he was now commenced on low phosphate diet and phosphate binders. It is important to differentiate tumoral calcinosis from other causes of pathological calcification using clinical and laboratory findings especially in environments where molecular genetic testing is not readily available.

A rare disease: Familial hyperphosphatemic tumoral calcinosis

Abstract Introduction Tumoral calcinosis (TC) is a rare disease characterized by soft tissue calcification as a result of repetitive trauma and prolonged pressure in periarticular areas of large joints; such as hip, knee, shoulder and elbow. There are three different forms; sporadic, familial and secondary TC due to chronic renal diseases, vitamin D hypervitaminosis. Familial hyperphosphatemic TC, which will be presented in this case, causes by relative deficiency or resistance of FGF-23, which is the critical regulatory hormone in the phosphorus metabolism. Clinical Case A 38-year-old male patient was referred from the nephrology department for hyperphosphatemia. He underwent 14 operations mass lesions, which were painful, progressively enlarging, in the different regions. His first operation at the age of 11 for a lesion in the right knee. Pathologic diagnoses of surgical specimens were reported as tumoral calcinosis. The patient was followed up by different orthopedic clinics from the age of 11, and was operated as new masses appeared. He does not have any complaints other than the pain in the periods when the lesions appear. He has 4 siblings without any known diseases, and his parents were third degree consanguineous. In physical examination, blood pressure was 115/72 mmHg, pulse was 76/min, and temperature was 36.7°C. Her height was 183 cm, and weight was 82 kg, BMI: 24.5 kg/m2. In laboratory tests, serum calcium 10.1 mg/dl, serum phosphate 6,8 mg/dl, parathormone 25 pg/ml, 25-OH Vitamin D 19 ng/ml, creatinine 0.9 mg/dl, alkaline phosphatase 71 U/l, 24-h urinary calcium 129 mg/day and 24-h urinary phosphate 205 mg/day. Bone mineral density at the femoral neck was 1.258 g/cm2, Z score was -1.6, and BMD at the lumbar spine was 1.081 g/cm2, Z score was -0.9. In bone survey, we detected that mild right-facing rotoscoliosis in the thoracolumbar region, increased calcification of the costosternal cartilages, osteophytic tapering in the thoracic region, intracranial calcification in the parietal region, L3-L4 level syndesmophyte, irregularity and adjacent soft tissue calcification at the distal phalanx level of the first toe of the right and left foot (Fig 1). We recommended the patient to avoid trauma and a low phosphorus diet. Maintenance dose vitamin D replacement and phosphorus-binding treatment (calcium-asetate 700 mg 3×2) with meals were started. When phosphate reduction could not be achieved, sevalemer 800 mg 3×3 was added with gradually increasing, phosphorus level dropped to 5.2 mg/dl. Genetic analysis revealed GALNT3 homozygous mutation. Genetic counseling and eye examination were recommended. Conclusion TC should also be considered in patients with a history of multiple surgery due to soft tissue masses, especially in the presence of hyperphosphatemia. In our case, a mutation was detected at a rather late age, and phosphorus-lowering therapy was started at the age of 38 years and genetic counseling should be offered to these patients at an early age.

Abstract #1183932: Management Challenge in Hyperphosphatemic Tumoral Calcinosis

Tumoral calcinosis (TC) is a rare metabolic disorder causing abnormal calcium salt deposition in different peri-articular soft tissue regions. The most common site is lateral hips. TC can be primary normo-phosphatemic or primary hyperphosphatemic. It can be secondary also, seen commonly in chronic renal failure. We describe a case report of 14 years old girl who presented with primary hyperphosphatemic tumoral calcinosis with recurrent swellings even after surgery and medical therapy. A 14-year-old girl presented to us with recurrent soft tissue mass and persistent hyperphosphtemia associated with pain and decreased movements. She was operated twice for this soft tissue. Her medical record stated that patient had undergone 6 surgeries till date for these periarticular swellings at multiple sites (right elbow, left hip, right hip and left knee) but it recurs after 3-4 months of surgery and progressively enlarges in size. Physical examination revealed firm tender 9 X 4 cm oval shaped swelling in the left greater trochanteric area with restriction in abduction, internal rotation and rotator movements at hip joint and 4 X 4 cm circular hard, non-sessile mass over medial aspect of left knee joint with slight difficulty in complete flexion of knee. Biochemical work up showed hyperphosphatemia with normal serum calcium and low iPTH levels, low serum 25 hydroxyvitamin-D and slightly high 1,25 vitamin D with calculated TmP/GfR of 5.7 mg/dl. C-terminal FGF23 level was grossly elevated to 1200 RU/ml. Histological evaluation of previously surgically excised soft tissue mass revealed fibrocollagenous stroma with clusters of crystalline and amorphous calcium enclosed by band of histiocytes and lymphocytes compatible with findings seen in tumoral calcinosis. Presently the patient is maintaining the near normal phosphate level with oral phosphate restricted diet and multiple phosphate binder and acetazolamide. Hyperphosphatemic Tumoral calcinosis is a disorder of dysregulated phosphate metabolism characterized by hyperphosphatemia and deposition of calcium salts in soft tissue regions of the body usually in the periarticular sites. FGF23 is a 251-amino acid peptide secreted by osteoblasts, osteocytes and erythroid precursor cells of the bone marrow that plays a critical role in phosphate regulation. In the proximal tubule of the kidney, FGF23 binds to the FGF receptor 1 (FGFR1) and its co-receptor KLOTHO, downregulating expression of the sodium-phosphate cotransporters NPT2a and NPT2c, which leads to phosphaturia. Additionally, FGF23 inhibits 1-alpha-hydroxylase and stimulates 25-vitamin D-24 hydroxylase, resulting in decreased 1,25-(OH)2-vitamin D (1,25D), the active form of vitamin D. Recently an entitity named autoimmune hyperphosphataemic tumoral calcinosis has been reported in which pathogenetic autoantibodies mediate FGF23 resistance.Treatment is to lower serum phosphorus by blocking dietary phosphate absorption and increasing renal phosphate excretion. Surgery is usually reserved for patients with significant pain or restricted movements of joint.

Phosphate-Sensing.

The blood level of phosphate is tightly regulated in a narrow range. Hyperphosphatemia and hypophosphatemia both lead to the development of diseases, such as hyperphosphatemic tumoral calcinosis and rickets/osteomalacia, respectively. Although several humoral factors have been known to affect blood phosphate levels, fibroblast growth factor 23 (FGF23) is the principal hormone involved in the regulation of blood phosphate. This hormone is produced by bone, particularly by osteocytes and osteoblasts, and has the effect of lowering the blood level of phosphate in the renal proximal tubules. Therefore, some phosphate-sensing mechanism should exist, at least in the bone. However, the mechanisms through which bone senses changes in the blood level of phosphate, and through which the bone regulates FGF23 production remain to be fully elucidated. Our recent findings demonstrate that high extracellular phosphate phosphorylates FGF receptor 1c (FGFR1c). Its downstream extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling pathway regulates the expression of several transcription factors and the GALNT3 gene, which encodes GalNAc-T3, which plays a role in the regulation of posttranslational modification of FGF23 protein, which in turn enhances FGF23 production. The FGFR1c-GALNT3 gene axis is considered to be the most important mechanism for regulating the production of FGF23 in bone in the response to a high phosphate diet. Thus-in the regulation of FGF23 production and blood phosphate levels-FGFR1c may be considered to function as a phosphate-sensing molecule. A feedback mechanism, in which FGFR1c and FGF23 are involved, is present in blood phosphate regulation. In addition, other reports indicate that PiT1 and PiT2 (type III sodium-phosphate cotransporters), and calcium-sensing receptor are also involved in the phosphate-sensing mechanism. In the present chapter, we summarize new insights on phosphate-sensing mechanisms.

Hyperphosphatemic Tumoral Calcinosis: Pathogenesis, Clinical Presentation, and Challenges in Management.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare and disabling disorder of fibroblast growth factor 23 (FGF23) deficiency or resistance. The disorder is manifest by hyperphosphatemia, inappropriately increased tubular reabsorption of phosphate and 1,25-dihydroxy-Vitamin D, and ectopic calcifications. HFTC has been associated with autosomal recessive pathogenic variants in: (1) the gene encoding FGF23; (2) GALNT3, which encodes a protein responsible for FGF23 glycosylation; and (3) KL, the gene encoding KLOTHO, a critical co-receptor for FGF23 signaling. An acquired autoimmune form of hyperphosphatemic tumoral calcinosis has also been reported. Periarticular tumoral calcinosis is the primary cause of disability in HFTC, leading to pain, reduced range-of-motion, and impaired physical function. Inflammatory disease is also prominent, including diaphysitis with cortical hyperostosis. Multiple treatment strategies have attempted to manage blood phosphate, reduce pain and inflammation, and address calcifications and their complications. Unfortunately, efficacy data are limited to case reports and small cohorts, and no clearly effective therapies have been identified. The purpose of this review is to provide a background on pathogenesis and clinical presentation in HFTC, discuss current approaches to clinical management, and outline critical areas of need for future research.

Successful use of oral acetazolamide in symptomatic subcutaneous calcifications in hyperphosphatemic tumoral calcinosis

Successful use of oral acetazolamide in symptomatic subcutaneous calcifications in hyperphosphatemic tumoral calcinosis

FGF23 and Bone and Mineral Metabolism.

FGF23 is a phosphotropic hormone produced by the bone. FGF23 works by binding to the FGF receptor-Klotho complex. Klotho is expressed in several limited tissues including the kidney and parathyroid glands. This tissue-restricted expression of Klotho is believed to determine the target organs of FGF23. FGF23 reduces serum phosphate by suppressing the expression of type 2a and 2c sodium-phosphate cotransporters in renal proximal tubules. FGF23 also decreases 1,25-dihydroxyvitamin D levels by regulating the expression of vitamin D-metabolizing enzymes, which results in reduced intestinal phosphate absorption. Excessive actions of FGF23 cause several types of hypophosphatemic rickets/osteomalacia characterized by impaired mineralization of bone matrix. In contrast, deficient actions of FGF23 result in hyperphosphatemic tumoral calcinosis with high 1,25-dihydroxyvitamin D levels. These results indicate that FGF23 is a physiological regulator of phosphate and vitamin D metabolism and indispensable for the maintenance of serum phosphate levels.

Hyperphosphataemic tumoral calcinosis

Hyperphosphataemic tumoral calcinosis

A Novel Mutation in FGF23 Causing Severe Manifestation of Hyperphosphataemic Familial Tumoral Calcinosis

We present a 16-year girl, second issue of a consanguineous couple presented with painless symmetrical bony swellings around hips for 3 years. She lost 25 kg weight due to profound anorexia in the first year of illness and developed secondary amenorrhea. Last 7 months she had repeated generalized tonic clonic seizure due to hypocalcaemia. The bony swellings were located in both gluteal regions and were 30x35 cm2, hard and non tender. Mobility of hip joints were restricted. Except for severe wasting as a part of generalized cachexia other systemic examination was unremarkable. Investigations revealed anaemia (Hb-E trait), low albumin, low corrected calcium (during convulsions) otherwise normal, persistently high phosphate & vitamin-D level, normal iPTH & alkaline phosphatase (ALP), low serum ascorbic acid, normal ESR & CRP. X-ray & CT scan of pelvis showed large calcified mass in periarticular soft tissues. Biopsy confirmed presence of dystrophic calcification. Diagnosis of tumoral calcinosis was based on biochemical parameters, imaging and biopsy findings. A homozygous novel mutation in FGF homology domain: B-21 mutated from G to A at 232 in exon 2. As a result glutamic acid is replaced by lysine. Phosphate restricted diet and phosphate lowering agent improved biochemical paramaters. Surgical excision has been withheld. Contemporary manifestation of hFTC and Hb E trait; two disease of autosomal recessive inheritance in an individual makes it extremely rare. High index of suspicion is needed for early diagnosis and treatment.

A challenging case of hyperphosphatemic tumoral calcinosis

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

Autoimmune hyperphosphatemic tumoral calcinosis

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

[FGF23 and skeletal metabolism].

FGF23 is an endocrine FGF produced by osteocytes, which increases excretion of phosphate and suppresses the production of 1,25 (OH) 2D. Excessive action of FGF23 causes various forms of hypophosphatemic rickets/osteomalacia, while the loss of function of FGF23 results in the condition called familial hyperphosphatemic tumoral calcinosis. 1,25 (OH) 2D stimulates the production of FGF23, and the interaction between FGF23 and 1,25 (OH) 2D plays a central role in mineral homeostasis. In addition to the its roles in mineral homeostasis, recent studies have suggested the direct action of FGF23 on osteoblasts and chondrocytes.

Differential response of idiopathic sporadic tumoral calcinosis to bisphosphonates.

Context:Tumoral calcinosis is a disorder of phosphate metabolism characterized by ectopic calcification around major joints. Surgery is the current treatment of choice, but a suboptimal choice in recurrent and multicentric lesions.Aims:To evaluate the efficacy of bisphosphonates for the management of tumoral calcinosis on optimized medical treatment.Settings and Design:The study was done in the endocrine department of a tertiary care hospital in South India. We prospectively studied two patients with recurrent tumoral calcinosis who had failed therapy with phosphate lowering measures.Materials and Methods:After informed consent, we treated both patients with standard age adjusted doses of bisphosphonates for 18 months. The response was assessed by X ray and whole body 99mTc-methylene diphosphonate bone scan at the beginning of therapy and at the end of 1 year. We also estimated serum phosphate levels and urinary phosphate to document serial changes.Results:Two patients (aged 19 and 5 years) with recurrent idiopathic hyperphosphatemic tumoral calcinosis, following surgery were studied. Both patients had failed therapy with conventional medical management − low phosphate diet and phosphate binders. They had restriction of joint mobility. Both were given standard doses of oral alendronate and parenteral pamidronate respectively for more than a year, along with phosphate lowering measures. At the end of 1 year, one of the patients had more than 95% and 90% reduction in the size of the lesions in right and left shoulder joints respectively with total improvement in range of motion. In contrast, the other patient (5-year-old) had shown no improvement, despite continuing to maintain normophosphatemia following treatment.Conclusions:Bisphosphonate therapy in tumoral calcinosis is associated with lesion resolution and may be used as a viable alternative to surgery, especially in cases with multicentric recurrence or treatment failure to other drugs.

Multiple bilateral symmetrical recurrent hyperphosphatemic tumoral calcinosis in a young adolescent girl: A rare entity

Tumoral calcinosis is an uncommon disease characterized by periarticular soft-tissue hyperplasia and calcification. Large joint such as hip, shoulder and elbow are most commonly involved. This entity usually manifest in adolescent females as slowly growing, painless, mobile soft-tissue tumor like mass around the large joint that may interfere with joint function when large. A familial predisposition has been reported. Exact cause is not known, but there is deposition of calcium phosphate with normal calcium and elevated phosphorus levels. Here, we report a case of 15-year-old female presented with symmetrical, recurrent swellings on various joints with milk like fluid extrusion and scar mark of previous excision.

[Significance of FGF23 measurement].

Excess and deficient actions of FGF23 cause hypophosphatemic rickets/osteomalacia and hyperphosphatemic tumoral calcinosis, respectively. There are two kinds of assays for FGF23. Full-length assay detects only full-length FGF23 with biological activity. In contrast, C-terminal assay measures both full-length FGF23 and processed C-terminal fragment of FGF23. FGF23 measurement is useful for the diagnosis and follow-up of patients with FGF23-related hypophosphatemic diseases. In addition, full-length assay can be used for the differential diagnosis of hypophosphatemic diseases. Furthermore, many epidemiological studies indicated the association between FGF23 levels and several adverse events including higher mortality, cardiovascular diseases and progression of CKD especially in patients with CKD. Therefore, it is possible that FGF23 can be a new marker in the risk assessment of patients with CKD.

A Phex mutation in a murine model of X-linked hypophosphatemia alters phosphate responsiveness of bone cells

Mutations in the PHEX gene cause X-linked hypophosphatemia (XLH). Hypophosphatemia in XLH results from increased circulating levels of a phosphaturic hormone, fibroblast growth factor 23 (FGF23), which inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D (calcitriol) synthesis. The current standard therapy for XLH--high-dose phosphate and calcitriol--further increases FGF23 concentrations, suggesting that patients with XLH may have an altered response to extracellular phosphate. To test for the presence of abnormal phosphate responsiveness, we compared serum biochemistries and femoral Fgf23 mRNA expression between wild-type mice, murine models of XLH (Phex(K496X)) and hyperphosphatemic tumoral calcinosis (Galnt3(-/-)), and Galnt3/Phex double-mutant mice. Phex mutant mice had not only increased Fgf23 expression but also reduced proteolytic cleavage of intact Fgf23 protein, resulting in markedly elevated intact Fgf23 levels and consequent hypophosphatemia. In contrast, despite markedly increased Fgf23 expression, Galnt3 knockout mice had significantly high proteolytic cleavage of Fgf23 protein, leading to low intact Fgf23 concentrations and hyperphosphatemia. Galnt3/Phex double-mutant mice had an intermediate biochemical phenotype between wild-type and Phex mutant mice, including slightly elevated intact Fgf23 concentrations with milder hypophosphatemia. Despite the hypophosphatemia, double-mutant mice attempted to reduce serum phosphate back to the level of Phex mutant mice by upregulating Fgf23 expression as much as 24-fold higher than Phex mutant mice. These data suggest that Phex mutations alter the responsiveness of bone cells to extracellular phosphate concentrations and may create a lower set point for "normal" phosphate levels.

Fibroblast growth factor 23 as a phosphotropic hormone and beyond

Fibroblast growth factor 23 (FGF23) is produced by bone and reduces serum phosphate by inhibiting proximal tubular phosphate reabsorption and intestinal phosphate absorption. Excess actions of FGF23 cause several kinds of hypophosphatemic rickets/osteomalacia while deficient actions of FGF23 result in hyperphosphatemic tumoral calcinosis. In addition, FGF23 has been shown to prevent the development of hyperphosphatemia during the progression of chronic kidney disease-mineral and bone disorder. Epidemiological studies have indicated that high FGF23 levels are associated with unfavorable events including higher mortality, cardiovascular events, progression of CKD and fracture; however, these associations are not observed unequivocally and it is not evident why they are present. While FGF23 has been shown to be a hormone that regulates phosphate metabolism, it remains to be established whether FGF23 has roles other than regulating mineral homeostasis.

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.