Phenotypic and Genotypic Characterization and Treatment of a Cohort With Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome

Mary Scott Ramnitz, Pravitt Gourh, Raphaela Goldbach-Mansky, Felasfa Wodajo, Shoji Ichikawa, Michael Econs, Kenneth White, Alfredo Molinolo, Marcus Y. Chen, Theo Heller, Jaydira Del Rivero, Patricia Seo-Mayer, Bita Arabshahi, Malaka B. Jackson, Sarah Hatab, Edward McCarthy, Lori C. Guthrie, Beth A. Brillante, Rachel I. Gafni, Michael T. Collins

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Familial tumoral calcinosis (FTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is a rare disorder caused by mutations in the genes encoding fibroblast growth factor-23 (FGF23), N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO. The result is functional deficiency of, or resistance to, intact FGF23 (iFGF23), causing hyperphosphatemia, increased renal tubular reabsorption of phosphorus (TRP), elevated or inappropriately normal 1,25-dihydroxyvitamin D3 (1,25D), ectopic calcifications, and/or diaphyseal hyperostosis. Eight subjects with FTC/HHS were studied and treated. Clinical manifestations varied, even within families, ranging from asymptomatic to large, disabling calcifications. All subjects had hyperphosphatemia, increased TRP, and elevated or inappropriately normal 1,25D. C-terminal FGF23 was markedly elevated whereas iFGF23 was comparatively low, consistent with increased FGF23 cleavage. Radiographs ranged from diaphyseal hyperostosis to massive calcification. Two subjects with severe calcifications also had overwhelming systemic inflammation and elevated C-reactive protein (CRP). GALNT3 mutations were identified in seven subjects; no causative mutation was found in the eighth. Biopsies from four subjects showed ectopic calcification and chronic inflammation, with areas of heterotopic ossification observed in one subject. Treatment with low phosphate diet, phosphate binders, and phosphaturia-inducing therapies was prescribed with variable response. One subject experienced complete resolution of a calcific mass after 13 months of medical treatment. In the two subjects with systemic inflammation, interleukin-1 (IL-1) antagonists significantly decreased CRP levels with resolution of calcinosis cutis and perilesional inflammation in one subject and improvement of overall well-being in both subjects. This cohort expands the phenotype and genotype of FTC/HHS and demonstrates the range of clinical manifestations despite similar biochemical profiles and genetic mutations. Overwhelming systemic inflammation has not been described previously in FTC/HHS; the response to IL-1 antagonists suggests that anti-inflammatory drugs may be useful adjuvants. In addition, this is the first description of heterotopic ossification reported in FTC/HHS, possibly mediated by the adjacent inflammation.

Original languageEnglish (US)
Pages (from-to)1845-1854
Number of pages10
JournalJournal of Bone and Mineral Research
Volume31
Issue number10
DOIs
StatePublished - Oct 1 2016

Fingerprint

Calcinosis
Inflammation
Camurati-Engelmann Syndrome
N-Acetylgalactosaminyltransferases
Hyperphosphatemia
Heterotopic Ossification
Mutation
Calcitriol
Interleukin-1
C-Reactive Protein
Phosphorus
Phosphates
Familial Hypophosphatemia
Hyperostosis-hyperphosphatemia syndrome
Molecular Biology
Anti-Inflammatory Agents
Genotype
Diet
Phenotype
Biopsy

Keywords

  • FAMILIAL TUMORAL CALCINOSIS
  • FIBROBLAST GROWTH FACTOR 23
  • HYPEROSTOSIS-HYPERPHOSPHATEMIA SYNDROME
  • HYPERPHOSPHATEMIA

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

Phenotypic and Genotypic Characterization and Treatment of a Cohort With Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome. / Ramnitz, Mary Scott; Gourh, Pravitt; Goldbach-Mansky, Raphaela; Wodajo, Felasfa; Ichikawa, Shoji; Econs, Michael; White, Kenneth; Molinolo, Alfredo; Chen, Marcus Y.; Heller, Theo; Del Rivero, Jaydira; Seo-Mayer, Patricia; Arabshahi, Bita; Jackson, Malaka B.; Hatab, Sarah; McCarthy, Edward; Guthrie, Lori C.; Brillante, Beth A.; Gafni, Rachel I.; Collins, Michael T.

In: Journal of Bone and Mineral Research, Vol. 31, No. 10, 01.10.2016, p. 1845-1854.

Research output: Contribution to journalArticle

Ramnitz, MS, Gourh, P, Goldbach-Mansky, R, Wodajo, F, Ichikawa, S, Econs, M, White, K, Molinolo, A, Chen, MY, Heller, T, Del Rivero, J, Seo-Mayer, P, Arabshahi, B, Jackson, MB, Hatab, S, McCarthy, E, Guthrie, LC, Brillante, BA, Gafni, RI & Collins, MT 2016, 'Phenotypic and Genotypic Characterization and Treatment of a Cohort With Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome', Journal of Bone and Mineral Research, vol. 31, no. 10, pp. 1845-1854. https://doi.org/10.1002/jbmr.2870
Ramnitz, Mary Scott ; Gourh, Pravitt ; Goldbach-Mansky, Raphaela ; Wodajo, Felasfa ; Ichikawa, Shoji ; Econs, Michael ; White, Kenneth ; Molinolo, Alfredo ; Chen, Marcus Y. ; Heller, Theo ; Del Rivero, Jaydira ; Seo-Mayer, Patricia ; Arabshahi, Bita ; Jackson, Malaka B. ; Hatab, Sarah ; McCarthy, Edward ; Guthrie, Lori C. ; Brillante, Beth A. ; Gafni, Rachel I. ; Collins, Michael T. / Phenotypic and Genotypic Characterization and Treatment of a Cohort With Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome. In: Journal of Bone and Mineral Research. 2016 ; Vol. 31, No. 10. pp. 1845-1854.
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AU - Gourh, Pravitt

AU - Goldbach-Mansky, Raphaela

AU - Wodajo, Felasfa

AU - Ichikawa, Shoji

AU - Econs, Michael

AU - White, Kenneth

AU - Molinolo, Alfredo

AU - Chen, Marcus Y.

AU - Heller, Theo

AU - Del Rivero, Jaydira

AU - Seo-Mayer, Patricia

AU - Arabshahi, Bita

AU - Jackson, Malaka B.

AU - Hatab, Sarah

AU - McCarthy, Edward

AU - Guthrie, Lori C.

AU - Brillante, Beth A.

AU - Gafni, Rachel I.

AU - Collins, Michael T.

PY - 2016/10/1

Y1 - 2016/10/1

N2 - Familial tumoral calcinosis (FTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is a rare disorder caused by mutations in the genes encoding fibroblast growth factor-23 (FGF23), N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO. The result is functional deficiency of, or resistance to, intact FGF23 (iFGF23), causing hyperphosphatemia, increased renal tubular reabsorption of phosphorus (TRP), elevated or inappropriately normal 1,25-dihydroxyvitamin D3 (1,25D), ectopic calcifications, and/or diaphyseal hyperostosis. Eight subjects with FTC/HHS were studied and treated. Clinical manifestations varied, even within families, ranging from asymptomatic to large, disabling calcifications. All subjects had hyperphosphatemia, increased TRP, and elevated or inappropriately normal 1,25D. C-terminal FGF23 was markedly elevated whereas iFGF23 was comparatively low, consistent with increased FGF23 cleavage. Radiographs ranged from diaphyseal hyperostosis to massive calcification. Two subjects with severe calcifications also had overwhelming systemic inflammation and elevated C-reactive protein (CRP). GALNT3 mutations were identified in seven subjects; no causative mutation was found in the eighth. Biopsies from four subjects showed ectopic calcification and chronic inflammation, with areas of heterotopic ossification observed in one subject. Treatment with low phosphate diet, phosphate binders, and phosphaturia-inducing therapies was prescribed with variable response. One subject experienced complete resolution of a calcific mass after 13 months of medical treatment. In the two subjects with systemic inflammation, interleukin-1 (IL-1) antagonists significantly decreased CRP levels with resolution of calcinosis cutis and perilesional inflammation in one subject and improvement of overall well-being in both subjects. This cohort expands the phenotype and genotype of FTC/HHS and demonstrates the range of clinical manifestations despite similar biochemical profiles and genetic mutations. Overwhelming systemic inflammation has not been described previously in FTC/HHS; the response to IL-1 antagonists suggests that anti-inflammatory drugs may be useful adjuvants. In addition, this is the first description of heterotopic ossification reported in FTC/HHS, possibly mediated by the adjacent inflammation.

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KW - FAMILIAL TUMORAL CALCINOSIS

KW - FIBROBLAST GROWTH FACTOR 23

KW - HYPEROSTOSIS-HYPERPHOSPHATEMIA SYNDROME

KW - HYPERPHOSPHATEMIA

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