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Distinct Clinical and Pathological Features of Melorheostosis Associated With Somatic MAP2K1 Mutations
Author(s) -
Jha Smita,
FratzlZelman Nadja,
Roschger Paul,
Papadakis Georgios Z,
Cowen Edward W,
Kang Heeseog,
Lehky Tanya J,
Alter Katharine,
Deng Zuoming,
Ivovic Aleksandra,
Flynn Lauren,
Reynolds James C,
Dasgupta Abhijit,
Miettinen Markku,
Lange Eileen,
Katz James,
Klaushofer Klaus,
Marini Joan C,
Siegel Richard M,
Bhattacharyya Timothy
Publication year - 2019
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.3577
Subject(s) - osteoid , pathology , vascularity , medicine , pathological , histology , hyperostosis , phenotype , osteosclerosis , anatomy , biology , genetics , gene
ABSTRACT 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.