Hyperostosis-hyperphosphatemia syndrome: a congenital disorder of O-glycosylation associated with augmented processing of fibroblast growth factor 23

J Bone Miner Res. 2007 Feb;22(2):235-42. doi: 10.1359/jbmr.061105.


Two hyperphosphatemic patients with mutations in GALNT3 showed low intact FGF23 levels with marked increase of processed C-terminal fragments. FGF23 protein has three O-linked glycans and FGF23 with incomplete glycosylation is susceptible to processing. Silencing GALNT3 resulted in enhanced processing of FGF23. Decreased function of FGF23 by enhanced processing is the cause of hyperphosphatemia in patients with GALNT3 mutation.

Introduction: Hyperostosis-hyperphosphatemia syndrome (HHS) is an autosomal recessive entity manifesting as severe hyperphosphatemia associated with episodic bone pain and radiological findings of cortical hyperostosis and periosteal reaction. Persistent hyperphosphatemia is not counterbalanced by PTH or 1,25-dihydroxyvitamin D, posing a mirror image of hypophosphatemic states attributed to increased fibroblast growth factor (FGF)23 activity.

Materials and methods: We describe two children with HHS who were found to be homozygous for a mutation in GALNT3 encoding a peptide involved in mucin-type O-glycosylation (ppGaNTase-T3). FGF23 levels were evaluated by two ELISAs and Western blotting. FGF23 protein was analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Effect of silencing GALNT3 was evaluated using siRNA in cells transfected with expression vector for FGF23.

Results: Both patients had low levels of the full-length FGF23 with markedly augmented amounts of the inactive fragments. Biologically active FGF23 has three O-linked glycans. FGF23 with only one or two O-linked glycans is processed into inactive fragments. Decreasing the expression of the GALNT3 gene by RNA interference resulted in enhanced processing of FGF23.

Conclusions: The primary defect in HHS is impairment of glycosylation of FGF23 resulting from mutations in GALNT3 and leading to augmented processing of FGF23. These changes in FGF23 abolish its phosphaturic effect and lead to severe persistent hyperphosphatemia. This study provides the pathogenetic mechanism of the first mucin-type O-glycosylation defect identified.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Blotting, Western
  • Enzyme-Linked Immunosorbent Assay
  • Fibroblast Growth Factors / chemistry
  • Fibroblast Growth Factors / metabolism*
  • Glycosylation
  • Humans
  • Hyperostosis / congenital
  • Hyperostosis / genetics
  • Hyperostosis / metabolism*
  • Molecular Sequence Data
  • N-Acetylgalactosaminyltransferases / genetics
  • Neoplasm Proteins / genetics
  • Peptide Mapping
  • Phosphates / blood*
  • RNA, Small Interfering
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Syndrome


  • Neoplasm Proteins
  • Phosphates
  • RNA, Small Interfering
  • Fibroblast Growth Factors
  • fibroblast growth factor 23
  • N-Acetylgalactosaminyltransferases
  • polypeptide N-acetylgalactosaminyltransferase