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

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

Author information

1
Clinical and Investigative Orthopedics Surgery Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.
2
Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA.
3
Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Vienna Regional Health Insurance Fund (WGKK), and Allgemeine Unfallversicherungsanstalt (AUVA; the Austrian Workers' Compensation Board) Trauma Center Meidling, 1st Medical Department Hanusch Hospital, Vienna, Austria.
4
Foundation for Research and Technology Hellas (FORTH), Institute of Computer Science (ICS), Computational Bio-Medicine Laboratory (CBML), Heraklion, Crete, Greece.
5
National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD, USA.
6
Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.
7
Section on Heritable Disorders of Bone and Extracellular Matrix, National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA.
8
Electromyography (EMG) Section, National Institutes of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD, USA.
9
Functional and Applied Biomechanics Section, Rehabilitation Medicine Department, National Institutes of Health (NIH), Bethesda, MD, USA.
10
Biodata Mining and Discovery Section, Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.
11
Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.
12
National Institutes of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD, USA.
13
Nuclear Medicine Division, Radiology and Imaging Sciences, National Institutes of Health (NIH) Clinical Center, Bethesda, MD, USA.
14
Clinical Trials and Outcomes Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.
15
Surgical Pathology, Laboratory of Pathology, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA.
16
Office of the Clinical Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.

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.

KEYWORDS:

BONE AND SKIN BIOPSIES; DRIPPING CANDLE-WAX; HISTOLOGY; HYPEROSTOSIS

PMID:
30138550
DOI:
10.1002/jbmr.3577

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