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

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.

SUBMITTER: Jha S

PROVIDER: S-EPMC7577747 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Jha Smita S Fratzl-Zelman Nadja N Roschger Paul P Papadakis Georgios Z GZ Cowen Edward W EW Kang Heeseog H Lehky Tanya J TJ Alter Katharine K Deng Zuoming Z Ivovic Aleksandra A Flynn Lauren L Reynolds James C JC Dasgupta Abhijit A Miettinen Markku M Lange Eileen E Katz James J Klaushofer Klaus K Marini Joan C JC Siegel Richard M RM Bhattacharyya Timothy T

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20180914 1

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, ...[more]

PMID: 30138550

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

Publications

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

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