Autoimmune hyperphosphatemic tumoral calcinosis in a patient with FGF23 autoantibodies

Mary Scott Roberts, Peter D. Burbelo, Daniela Egli-Spichtig, Farzana Perwad, Christopher J. Romero, Shoji Ichikawa, Emily Farrow, Michael Econs, Lori C. Guthrie, Michael T. Collins, Rachel I. Gafni

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5368-5373
Number of pages6
JournalJournal of Clinical Investigation
Volume128
Issue number12
DOIs
StatePublished - Dec 3 2018

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Calcinosis
Autoantibodies
Fibroblast Growth Factor 1
Fibroblast Growth Factor Receptors
N-Acetylgalactosaminyltransferases
Mutation
Immunomodulation
MAP Kinase Signaling System
Luciferases
Type 1 Diabetes Mellitus
Immunoprecipitation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Roberts, M. S., Burbelo, P. D., Egli-Spichtig, D., Perwad, F., Romero, C. J., Ichikawa, S., ... Gafni, R. I. (2018). Autoimmune hyperphosphatemic tumoral calcinosis in a patient with FGF23 autoantibodies. Journal of Clinical Investigation, 128(12), 5368-5373. https://doi.org/10.1172/JCI122004

Autoimmune hyperphosphatemic tumoral calcinosis in a patient with FGF23 autoantibodies. / Roberts, Mary Scott; Burbelo, Peter D.; Egli-Spichtig, Daniela; Perwad, Farzana; Romero, Christopher J.; Ichikawa, Shoji; Farrow, Emily; Econs, Michael; Guthrie, Lori C.; Collins, Michael T.; Gafni, Rachel I.

In: Journal of Clinical Investigation, Vol. 128, No. 12, 03.12.2018, p. 5368-5373.

Research output: Contribution to journalArticle

Roberts, MS, Burbelo, PD, Egli-Spichtig, D, Perwad, F, Romero, CJ, Ichikawa, S, Farrow, E, Econs, M, Guthrie, LC, Collins, MT & Gafni, RI 2018, 'Autoimmune hyperphosphatemic tumoral calcinosis in a patient with FGF23 autoantibodies', Journal of Clinical Investigation, vol. 128, no. 12, pp. 5368-5373. https://doi.org/10.1172/JCI122004
Roberts MS, Burbelo PD, Egli-Spichtig D, Perwad F, Romero CJ, Ichikawa S et al. Autoimmune hyperphosphatemic tumoral calcinosis in a patient with FGF23 autoantibodies. Journal of Clinical Investigation. 2018 Dec 3;128(12):5368-5373. https://doi.org/10.1172/JCI122004
Roberts, Mary Scott ; Burbelo, Peter D. ; Egli-Spichtig, Daniela ; Perwad, Farzana ; Romero, Christopher J. ; Ichikawa, Shoji ; Farrow, Emily ; Econs, Michael ; Guthrie, Lori C. ; Collins, Michael T. ; Gafni, Rachel I. / Autoimmune hyperphosphatemic tumoral calcinosis in a patient with FGF23 autoantibodies. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 12. pp. 5368-5373.
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AU - Ichikawa, Shoji

AU - Farrow, Emily

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