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Burke E Evans - One of the best experts on this subject based on the ideXlab platform.
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familial Tumoral Calcinosis a forty year follow up on one family
Journal of Bone and Joint Surgery American Volume, 2009Co-Authors: Kelly D Carmichael, James Bynum, Burke E EvansAbstract:Background: Familial Tumoral Calcinosis is a rare autosomal recessive disorder that was first described well in a report on four patients from one family in 1969. The disease leads to periarticular ectopic calcifications. The original report described patients from black, healthy, unrelated parents with sixteen children, seven of whom had the disease. Methods: On the basis of retrospective chart reviews and interviews with surviving family members, we describe the long-term follow-up of this one family, encompassing as long as forty years. Of the sixteen siblings, seven had Tumoral Calcinosis. Results: All seven affected children had hyperphosphatemia. There were two subsequent generations comprising thirteen children and seven grandchildren with no instances of Tumoral Calcinosis. The seven affected patients were followed for as many as forty years and underwent an average of twenty-one operations (range, four to thirty-six operations) for the treatment of calcified lesions. The genetic defect has been identified as the GALNT3 gene, thus leading to the hyperphosphatemic form of the disease. Although two of the patients had died by the time of the present study, the remaining five provided accounts of the disease course, the response to surgery and to medical therapy, and the effect of therapy on their lives. Some members had relatively few lesions and surgical procedures (as few as four), whereas others had an unrelenting course of lesions, recurrences, and surgical procedures (as many as thirty-six, with numerous other procedures). Three patients had multiyear periods with few symptoms—one for seven years, one for twelve years, and one for fifteen years. No effective medical therapy was found to control the lesions, and operations were associated with a high recurrence rate. Conclusions: Familial Tumoral Calcinosis has a varied natural history; some patients have an unrelenting course, while others may experience quiescent periods. The GALNT3 gene is responsible for the hyperphosphatemic form as seen in this family. Molecular testing may be of benefit to members of affected families, and future studies may help to explain the phenotypic variability among affected individuals. No medical or surgical treatment plan seemed to be effective for controlling the lesions in this family.
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familial Tumoral Calcinosis a clinical histopathologic and ultrastructural study with an analysis of its calcifying process and pathogenesis
The American Journal of Surgical Pathology, 1993Co-Authors: Richard E Slavin, Julie Wen, Dhruv Kumar, Burke E EvansAbstract:We describe histopathologic and ultrastructural changes in Tumoral Calcinosis (TC) occurring in seven siblings from a single family. Tumoral Calcinosis appears to be triggered by bleeding followed by aggregation of foamy histiocytes. These in turn are transformed, with participation of collagenolysi
Vicken Topouchian - One of the best experts on this subject based on the ideXlab platform.
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clinical variability of familial Tumoral Calcinosis caused by novel galnt3 mutations
American Journal of Medical Genetics Part A, 2010Co-Authors: Shoji Ichikawa, Anthony M Austin, Andrea H. Sorenson, Leah R. Padgett, Genevieve Baujat, Aksel Seyahi, Anastasia G Garoufali, Erik A Imel, Zagorka Pejin, Vicken TopouchianAbstract:The GALNT3 gene encodes GalNAc-T3, which prevents degradation of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Biallelic mutations in either GALNT3 or FGF23 result in hyperphosphatemic familial Tumoral Calcinosis or its variant, hyperostosis-hyperphosphatemia syndrome. Tumoral Calcinosis is characterized by the presence of ectopic calcifications around major joints, whereas hyperostosis-hyperphosphatemia syndrome is characterized by recurrent long bone lesions with hyperostosis. Here we investigated four patients with hyperphosphatemia and clinical manifestations including Tumoral Calcinosis and/or hyperostosis-hyperphosphatemia syndrome to determine underlying genetic cause and delineate phenotypic heterogeneity of these disorders. Mutational analysis of FGF23 and GALNT3 in these patients revealed novel homozygous mutations in GALNT3. Although the presence of massive calcifications, cortical hyperostosis, or dental anomalies was not shared by all patients, all had persistent hyperphosphatemia, as well as inappropriately normal 1,25-dihyroxyvitamin D [1,25(OH)2D]. Three of the patients also had confirmed low circulating intact FGF23 concentrations. The four novel GALNT3 mutations invariably resulted in hyperphosphatemia due to low intact FGF23, but other clinical manifestations were variable. Therefore, Tumoral Calcinosis and hyperostosis-hyperphosphatemia syndrome represent a continuous spectrum of the same disease caused by increased phosphate levels, rather than two distinct disorders.
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Clinical variability of familial Tumoral Calcinosis caused by novel GALNT3 mutations.
American journal of medical genetics. Part A, 2010Co-Authors: Shoji Ichikawa, Anthony M Austin, Andrea H. Sorenson, Leah R. Padgett, Genevieve Baujat, Aksel Seyahi, Anastasia G Garoufali, Erik A Imel, Zagorka Pejin, Vicken TopouchianAbstract:The GALNT3 gene encodes GalNAc-T3, which prevents degradation of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Biallelic mutations in either GALNT3 or FGF23 result in hyperphosphatemic familial Tumoral Calcinosis or its variant, hyperostosis-hyperphosphatemia syndrome. Tumoral Calcinosis is characterized by the presence of ectopic calcifications around major joints, whereas hyperostosis-hyperphosphatemia syndrome is characterized by recurrent long bone lesions with hyperostosis. Here we investigated four patients with hyperphosphatemia and clinical manifestations including Tumoral Calcinosis and/or hyperostosis-hyperphosphatemia syndrome to determine underlying genetic cause and delineate phenotypic heterogeneity of these disorders. Mutational analysis of FGF23 and GALNT3 in these patients revealed novel homozygous mutations in GALNT3. Although the presence of massive calcifications, cortical hyperostosis, or dental anomalies was not shared by all patients, all had persistent hyperphosphatemia. Three of the patients also had inappropriately normal 1,25-dihyroxyvitamin D [1,25(OH)(2)D] and confirmed low circulating intact FGF23 concentrations. The four novel GALNT3 mutations invariably resulted in hyperphosphatemia as a result of low intact FGF23, but other clinical manifestations were variable. Therefore, Tumoral Calcinosis and hyperostosis-hyperphosphatemia syndrome represent a continuous spectrum of the same disease caused by increased phosphate levels, rather than two distinct disorders.
Shoji Ichikawa - One of the best experts on this subject based on the ideXlab platform.
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Autoimmune hyperphosphatemic Tumoral Calcinosis in a patient with FGF23 autoantibodies
Journal of Clinical Investigation, 2018Co-Authors: Mary Scott Roberts, Daniela Egli-spichtig, Farzana Perwad, Lori C. Guthrie, Christopher J Romero, Emily G. Farrow, Peter D. Burbelo, Shoji Ichikawa, Michael T CollinsAbstract:Hyperphosphatemic familial Tumoral Calcinosis (HFTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is an autosomal recessive disorder of ectopic calcification due to deficiency of or resistance to intact fibroblast growth factor 23 (iFGF23). Inactivating mutations in FGF23, N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO (KL) have been reported as causing HFTC/HHS. We present what we believe is the first identified case of autoimmune hyperphosphatemic Tumoral Calcinosis in an 8-year-old boy. In addition to the classical clinical and biochemical features of hyperphosphatemic Tumoral Calcinosis, the patient exhibited markedly elevated intact and C-terminal FGF23 levels, suggestive of FGF23 resistance. However, no mutations in FGF23, KL, or FGF receptor 1 (FGFR1) were identified. He subsequently developed type 1 diabetes mellitus, which raised the possibility of an autoimmune cause for hyperphosphatemic Tumoral Calcinosis. Luciferase immunoprecipitation systems revealed markedly elevated FGF23 autoantibodies without detectable FGFR1 or Klotho autoantibodies. Using an in vitro FGF23 functional assay, we found that the FGF23 autoantibodies in the patient’s plasma blocked downstream signaling via the MAPK/ERK signaling pathway in a dose-dependent manner. Thus, this report describes the first case, to our knowledge, of autoimmune hyperphosphatemic Tumoral Calcinosis with pathogenic autoantibodies targeting FGF23. Identification of this pathophysiology extends the etiologic spectrum of hyperphosphatemic Tumoral Calcinosis and suggests that immunomodulatory therapy may be an effective treatment.
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clinical variability of familial Tumoral Calcinosis caused by novel galnt3 mutations
American Journal of Medical Genetics Part A, 2010Co-Authors: Shoji Ichikawa, Anthony M Austin, Andrea H. Sorenson, Leah R. Padgett, Genevieve Baujat, Aksel Seyahi, Anastasia G Garoufali, Erik A Imel, Zagorka Pejin, Vicken TopouchianAbstract:The GALNT3 gene encodes GalNAc-T3, which prevents degradation of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Biallelic mutations in either GALNT3 or FGF23 result in hyperphosphatemic familial Tumoral Calcinosis or its variant, hyperostosis-hyperphosphatemia syndrome. Tumoral Calcinosis is characterized by the presence of ectopic calcifications around major joints, whereas hyperostosis-hyperphosphatemia syndrome is characterized by recurrent long bone lesions with hyperostosis. Here we investigated four patients with hyperphosphatemia and clinical manifestations including Tumoral Calcinosis and/or hyperostosis-hyperphosphatemia syndrome to determine underlying genetic cause and delineate phenotypic heterogeneity of these disorders. Mutational analysis of FGF23 and GALNT3 in these patients revealed novel homozygous mutations in GALNT3. Although the presence of massive calcifications, cortical hyperostosis, or dental anomalies was not shared by all patients, all had persistent hyperphosphatemia, as well as inappropriately normal 1,25-dihyroxyvitamin D [1,25(OH)2D]. Three of the patients also had confirmed low circulating intact FGF23 concentrations. The four novel GALNT3 mutations invariably resulted in hyperphosphatemia due to low intact FGF23, but other clinical manifestations were variable. Therefore, Tumoral Calcinosis and hyperostosis-hyperphosphatemia syndrome represent a continuous spectrum of the same disease caused by increased phosphate levels, rather than two distinct disorders.
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Clinical variability of familial Tumoral Calcinosis caused by novel GALNT3 mutations.
American journal of medical genetics. Part A, 2010Co-Authors: Shoji Ichikawa, Anthony M Austin, Andrea H. Sorenson, Leah R. Padgett, Genevieve Baujat, Aksel Seyahi, Anastasia G Garoufali, Erik A Imel, Zagorka Pejin, Vicken TopouchianAbstract:The GALNT3 gene encodes GalNAc-T3, which prevents degradation of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Biallelic mutations in either GALNT3 or FGF23 result in hyperphosphatemic familial Tumoral Calcinosis or its variant, hyperostosis-hyperphosphatemia syndrome. Tumoral Calcinosis is characterized by the presence of ectopic calcifications around major joints, whereas hyperostosis-hyperphosphatemia syndrome is characterized by recurrent long bone lesions with hyperostosis. Here we investigated four patients with hyperphosphatemia and clinical manifestations including Tumoral Calcinosis and/or hyperostosis-hyperphosphatemia syndrome to determine underlying genetic cause and delineate phenotypic heterogeneity of these disorders. Mutational analysis of FGF23 and GALNT3 in these patients revealed novel homozygous mutations in GALNT3. Although the presence of massive calcifications, cortical hyperostosis, or dental anomalies was not shared by all patients, all had persistent hyperphosphatemia. Three of the patients also had inappropriately normal 1,25-dihyroxyvitamin D [1,25(OH)(2)D] and confirmed low circulating intact FGF23 concentrations. The four novel GALNT3 mutations invariably resulted in hyperphosphatemia as a result of low intact FGF23, but other clinical manifestations were variable. Therefore, Tumoral Calcinosis and hyperostosis-hyperphosphatemia syndrome represent a continuous spectrum of the same disease caused by increased phosphate levels, rather than two distinct disorders.
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a homozygous missense mutation in human klotho causes severe Tumoral Calcinosis
Journal of Clinical Investigation, 2007Co-Authors: Shoji Ichikawa, Andrea H. Sorenson, Kenneth E. White, Erik A Imel, Mary Kreiter, Donald S Mackenzie, Regina Goetz, Moosa Mohammadi, Michael J EconsAbstract:Familial Tumoral Calcinosis is characterized by ectopic calcifications and hyperphosphatemia due to inactivating mutations in FGF23 or UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3). Herein we report a homozygous missense mutation (H193R) in the KLOTHO (KL) gene of a 13-year-old girl who presented with severe Tumoral Calcinosis with dural and carotid artery calcifications. This patient exhibited defects in mineral ion homeostasis with marked hyperphosphatemia and hypercalcemia as well as elevated serum levels of parathyroid hormone and FGF23. Mapping of H193R mutation onto the crystal structure of myrosinase, a plant homolog of KL, revealed that this histidine residue was at the base of the deep catalytic cleft and mutation of this histidine to arginine should destabilize the putative glycosidase domain (KL1) of KL, thereby attenuating production of membrane-bound and secreted KL. Indeed, compared with wild-type KL, expression and secretion of H193R KL were markedly reduced in vitro, resulting in diminished ability of FGF23 to signal via its cognate FGF receptors. Taken together, our findings provide what we believe to be the first evidence that loss-of-function mutations in human KL impair FGF23 bioactivity, underscoring the essential role of KL in FGF23-mediated phosphate and vitamin D homeostasis in humans.
Erik A Imel - One of the best experts on this subject based on the ideXlab platform.
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hyperphosphatemic familial Tumoral Calcinosis fgf23 galnt3 and αklotho
Best Practice & Research: Clinical Rheumatology, 2011Co-Authors: Emily G. Farrow, Erik A Imel, Kenneth E. WhiteAbstract:Familial Tumoral Calcinosis (TC) is a rare disorder distinguished by the development of ectopic and vascular calcified masses that occur in settings of hyperphosphatemia (hFTC) and normophosphatemia (nFTC). Serum phosphorus concentrations are relatively tightly controlled by interconnected endocrine activity at the level of the intestine, kidney, and skeleton. Discovering the molecular causes for heritable forms of hFTC has shed new light on the regulation of serum phosphate balance. This review will focus upon the genetic basis and clinical approaches for hFTC, due to genes that are related to the phosphaturic hormone fibroblast growth factor-23 ( FGF23 ). These include FGF23 itself, an FGF23-glycosylating enzyme ( GALNT3 ), and the FGF23 co-receptor α-Klotho (α KL ). Our understanding of the molecular basis of hFTC will, in the short term, aid in understanding normal phosphate balance, and in the future, provide potential insight into the design of novel therapeutic strategies for both rare and common disorders of phosphate metabolism.
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clinical variability of familial Tumoral Calcinosis caused by novel galnt3 mutations
American Journal of Medical Genetics Part A, 2010Co-Authors: Shoji Ichikawa, Anthony M Austin, Andrea H. Sorenson, Leah R. Padgett, Genevieve Baujat, Aksel Seyahi, Anastasia G Garoufali, Erik A Imel, Zagorka Pejin, Vicken TopouchianAbstract:The GALNT3 gene encodes GalNAc-T3, which prevents degradation of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Biallelic mutations in either GALNT3 or FGF23 result in hyperphosphatemic familial Tumoral Calcinosis or its variant, hyperostosis-hyperphosphatemia syndrome. Tumoral Calcinosis is characterized by the presence of ectopic calcifications around major joints, whereas hyperostosis-hyperphosphatemia syndrome is characterized by recurrent long bone lesions with hyperostosis. Here we investigated four patients with hyperphosphatemia and clinical manifestations including Tumoral Calcinosis and/or hyperostosis-hyperphosphatemia syndrome to determine underlying genetic cause and delineate phenotypic heterogeneity of these disorders. Mutational analysis of FGF23 and GALNT3 in these patients revealed novel homozygous mutations in GALNT3. Although the presence of massive calcifications, cortical hyperostosis, or dental anomalies was not shared by all patients, all had persistent hyperphosphatemia, as well as inappropriately normal 1,25-dihyroxyvitamin D [1,25(OH)2D]. Three of the patients also had confirmed low circulating intact FGF23 concentrations. The four novel GALNT3 mutations invariably resulted in hyperphosphatemia due to low intact FGF23, but other clinical manifestations were variable. Therefore, Tumoral Calcinosis and hyperostosis-hyperphosphatemia syndrome represent a continuous spectrum of the same disease caused by increased phosphate levels, rather than two distinct disorders.
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Clinical variability of familial Tumoral Calcinosis caused by novel GALNT3 mutations.
American journal of medical genetics. Part A, 2010Co-Authors: Shoji Ichikawa, Anthony M Austin, Andrea H. Sorenson, Leah R. Padgett, Genevieve Baujat, Aksel Seyahi, Anastasia G Garoufali, Erik A Imel, Zagorka Pejin, Vicken TopouchianAbstract:The GALNT3 gene encodes GalNAc-T3, which prevents degradation of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Biallelic mutations in either GALNT3 or FGF23 result in hyperphosphatemic familial Tumoral Calcinosis or its variant, hyperostosis-hyperphosphatemia syndrome. Tumoral Calcinosis is characterized by the presence of ectopic calcifications around major joints, whereas hyperostosis-hyperphosphatemia syndrome is characterized by recurrent long bone lesions with hyperostosis. Here we investigated four patients with hyperphosphatemia and clinical manifestations including Tumoral Calcinosis and/or hyperostosis-hyperphosphatemia syndrome to determine underlying genetic cause and delineate phenotypic heterogeneity of these disorders. Mutational analysis of FGF23 and GALNT3 in these patients revealed novel homozygous mutations in GALNT3. Although the presence of massive calcifications, cortical hyperostosis, or dental anomalies was not shared by all patients, all had persistent hyperphosphatemia. Three of the patients also had inappropriately normal 1,25-dihyroxyvitamin D [1,25(OH)(2)D] and confirmed low circulating intact FGF23 concentrations. The four novel GALNT3 mutations invariably resulted in hyperphosphatemia as a result of low intact FGF23, but other clinical manifestations were variable. Therefore, Tumoral Calcinosis and hyperostosis-hyperphosphatemia syndrome represent a continuous spectrum of the same disease caused by increased phosphate levels, rather than two distinct disorders.
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a homozygous missense mutation in human klotho causes severe Tumoral Calcinosis
Journal of Clinical Investigation, 2007Co-Authors: Shoji Ichikawa, Andrea H. Sorenson, Kenneth E. White, Erik A Imel, Mary Kreiter, Donald S Mackenzie, Regina Goetz, Moosa Mohammadi, Michael J EconsAbstract:Familial Tumoral Calcinosis is characterized by ectopic calcifications and hyperphosphatemia due to inactivating mutations in FGF23 or UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3). Herein we report a homozygous missense mutation (H193R) in the KLOTHO (KL) gene of a 13-year-old girl who presented with severe Tumoral Calcinosis with dural and carotid artery calcifications. This patient exhibited defects in mineral ion homeostasis with marked hyperphosphatemia and hypercalcemia as well as elevated serum levels of parathyroid hormone and FGF23. Mapping of H193R mutation onto the crystal structure of myrosinase, a plant homolog of KL, revealed that this histidine residue was at the base of the deep catalytic cleft and mutation of this histidine to arginine should destabilize the putative glycosidase domain (KL1) of KL, thereby attenuating production of membrane-bound and secreted KL. Indeed, compared with wild-type KL, expression and secretion of H193R KL were markedly reduced in vitro, resulting in diminished ability of FGF23 to signal via its cognate FGF receptors. Taken together, our findings provide what we believe to be the first evidence that loss-of-function mutations in human KL impair FGF23 bioactivity, underscoring the essential role of KL in FGF23-mediated phosphate and vitamin D homeostasis in humans.
Esra Kılıç - One of the best experts on this subject based on the ideXlab platform.
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Novel mutations in GALNT3 causing hyperphosphatemic familial Tumoral Calcinosis
Journal of Bone and Mineral Metabolism, 2011Co-Authors: Alan Yancovitch, Margareta Indelman, Peter Galloway, Margo Whiteford, Dov Hershkovitz, Esra KılıçAbstract:Hyperphosphatemic familial Tumoral Calcinosis (HFTC) is known to be caused by mutations in at least three genes: FGF23, GALNT3 and KL. Two families with two affected members suffering from HFTC were scrutinized for mutations in these candidate genes. We identified in both families homozygous missense mutations affecting highly conserved amino acids in GALNT3. One of the mutations is a novel mutation, whereas the second mutation was reported before in a compound heterozygous state. Our data expand the spectrum of known mutations in GALNT3 and contribute to a better understanding of the phenotypic manifestations of mutations in this gene.
