Distinct Clinical and Pathological Features of Melorheostosis Associated With Somatic MAP2K1 Mutations

J Bone Miner Res. 2019 Jan;34(1):145-156. doi: 10.1002/jbmr.3577. Epub 2018 Sep 14.


Melorheostosis is a rare hyperostotic disease of the long bones classically characterized by a "dripping candle-wax" radiographic appearance. We recently described somatic activating mutations in MAP2K1 as a cause of melorheostosis. Here, we report distinguishing characteristics of patients with MAP2K1-positive melorheostosis. Fifteen unrelated patients with radiographic appearance of melorheostosis underwent paired biopsies of affected and unaffected bone for whole-exome sequencing, histology, and cell culture. Eight patients with mutations in MAP2K1 in affected bone were compared to the seven MAP2K1-negative patients to identify distinguishing characteristics. Patients with MAP2K1-positive melorheostosis had a distinct phenotype with classic "dripping candle-wax" appearance on radiographs (p = 0.01), characteristic vascular lesions on skin overlying affected bone (p = 0.01), and higher prevalence of extraosseous mineralization and joint involvement (p = 0.04 for both). Melorheostotic bone from both MAP2K1-positive and MAP2K1-negative patients showed two zones of distinct morphology-an outer segment of parallel layers of primary lamellar bone and a deeper zone of intensely remodeled highly porous osteonal-like bone. Affected bone from MAP2K1-positive patients showed excessive osteoid (p = 0.0012), increased number of osteoblasts (p = 0.012) and osteoclasts (p = 0.04), and increased vascularity on histology in comparison to paired unaffected bone which was not seen in affected bone in most MAP2K1-negative patients. The identification of a distinct phenotype of patients with MAP2K1-positive melorheostosis demonstrates clinical and genetic heterogeneity among patients with the disease. Further studies are needed to better understand the underlying pathophysiology and associated skin findings. © 2018 American Society for Bone and Mineral Research.

Trial registration: ClinicalTrials.gov NCT02504879.


Publication types

  • Clinical Trial
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Bone and Bones* / enzymology
  • Bone and Bones* / pathology
  • Female
  • Humans
  • MAP Kinase Kinase 1 / genetics
  • MAP Kinase Kinase 1 / metabolism
  • Male
  • Melorheostosis* / enzymology
  • Melorheostosis* / genetics
  • Melorheostosis* / pathology
  • Middle Aged
  • Mutation*
  • Osteoblasts* / enzymology
  • Osteoblasts* / pathology
  • Skin* / enzymology
  • Skin* / pathology
  • Whole Exome Sequencing


  • MAP Kinase Kinase 1
  • MAP2K1 protein, human

Associated data

  • ClinicalTrials.gov/NCT02504879