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J Clin Invest. 2018 Dec 3;128(12):5368-5373. doi: 10.1172/JCI122004. Epub 2018 Oct 29.

Autoimmune hyperphosphatemic tumoral calcinosis in a patient with FGF23 autoantibodies.

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Skeletal Disorders and Mineral Homeostasis Section, and.
Dental Clinical Research Core, National Institute of Dental and Craniofacial Research (NIDCR), NIH, Bethesda, Maryland, USA.
Department of Pediatrics, Division of Nephrology, UCSF School of Medicine, San Francisco, California, USA.
Department of Pediatric Endocrinology and Diabetes, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, Missouri, USA.
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.


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.


Autoimmune diseases; Bone Biology; Bone disease; Endocrinology

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