{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T22:54:14Z","timestamp":1787612054835,"version":"build-2736575974"},"reference-count":22,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2018,8,23]],"date-time":"2018-08-23T00:00:00Z","timestamp":1534982400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"},{"start":{"date-parts":[[2018,9,14]],"date-time":"2018-09-14T00:00:00Z","timestamp":1536883200000},"content-version":"vor","delay-in-days":22,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["asbmr.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,1,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>\u2003<\/jats:title>\n                  <jats:p>Melorheostosis is a rare hyperostotic disease of the long bones classically characterized by a \u201cdripping candle-wax\u201d 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 \u201cdripping candle-wax\u201d appearance on radiographs (p\u2009=\u20090.01), characteristic vascular lesions on skin overlying affected bone (p\u2009=\u20090.01), and higher prevalence of extraosseous mineralization and joint involvement (p\u2009=\u20090.04 for both). Melorheostotic bone from both MAP2K1-positive and MAP2K1-negative patients showed two zones of distinct morphology\u2014an 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\u2009=\u20090.0012), increased number of osteoblasts (p\u2009=\u20090.012) and osteoclasts (p\u2009=\u20090.04), 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. \u00a9 2018 American Society for Bone and Mineral Research.<\/jats:p>\n                  <jats:p>Abstract<\/jats:p>\n                  <jats:p>Patients with melorheostosis associated with somatic mosaic MAP2K1 mutations (found in affected bone and skin overlying affected bone) were more likely to have cutaneous vascular changes in skin overlying affected bone, classic \u201cdripping candle-wax appearance\u201d on x-rays and increased osteoid on bone histomorphometry. Presence of these characteristics may predict association with MAP2K1 mutations.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.3577","type":"journal-article","created":{"date-parts":[[2018,8,23]],"date-time":"2018-08-23T19:41:55Z","timestamp":1535053315000},"page":"145-156","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Distinct Clinical and Pathological Features of Melorheostosis Associated With Somatic <i>MAP2K1<\/i> Mutations"],"prefix":"10.1093","volume":"34","author":[{"given":"Smita","family":"Jha","sequence":"first","affiliation":[{"name":"Program in Reproductive and Adult EndocrinologyEunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)National Institutes of Health (NIH)BethesdaMDUSA"},{"name":"Clinical and Investigative Orthopedics Surgery UnitNational Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)National Institutes of Health (NIH)BethesdaMDUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadja","family":"Fratzl-Zelman","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Vienna Regional Health Insurance Fund (WGKK)and Allgemeine Unfallversicherungsanstalt (AUVA; the Austrian Workers\u2019 Compensation Board) Trauma Center Meidling1st Medical Department Hanusch HospitalViennaAustria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Roschger","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Vienna Regional Health Insurance Fund (WGKK)and Allgemeine Unfallversicherungsanstalt (AUVA; the Austrian Workers\u2019 Compensation Board) Trauma Center Meidling1st Medical Department Hanusch HospitalViennaAustria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios Z","family":"Papadakis","sequence":"additional","affiliation":[{"name":"National Institute of Dental and Craniofacial Research (NIDCR)National Institutes of Health (NIH)BethesdaMDUSA"},{"name":"Foundation for Research and Technology Hellas (FORTH)Institute of Computer Science (ICS)Computational Bio-Medicine Laboratory (CBML)HeraklionCreteGreece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward W","family":"Cowen","sequence":"additional","affiliation":[{"name":"Dermatology BranchNational Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)National Institutes of Health (NIH)BethesdaMDUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heeseog","family":"Kang","sequence":"additional","affiliation":[{"name":"Section on Heritable Disorders of Bone and Extracellular MatrixNational Institute of Child Health and Human Development (NICHD)National Institutes of Health (NIH)BethesdaMDUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanya J","family":"Lehky","sequence":"additional","affiliation":[{"name":"Electromyography (EMG) SectionNational Institutes of Neurological Disorders and Stroke (NINDS)National Institutes of Health (NIH)BethesdaMDUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharine","family":"Alter","sequence":"additional","affiliation":[{"name":"Functional and Applied Biomechanics SectionRehabilitation Medicine DepartmentNational Institutes of Health (NIH)BethesdaMDUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuoming","family":"Deng","sequence":"additional","affiliation":[{"name":"Biodata Mining and Discovery SectionOffice of Science and TechnologyNational Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)National Institutes of Health (NIH)BethesdaMDUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Ivovic","sequence":"additional","affiliation":[{"name":"Immunoregulation SectionAutoimmunity BranchNational Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)National Institutes of Health (NIH)BethesdaMDUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Flynn","sequence":"additional","affiliation":[{"name":"National Institutes of Neurological Disorders and Stroke (NINDS)National Institutes of Health (NIH)BethesdaMDUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James C","family":"Reynolds","sequence":"additional","affiliation":[{"name":"Nuclear Medicine DivisionRadiology and Imaging SciencesNational Institutes of Health (NIH) Clinical CenterBethesdaMDUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhijit","family":"Dasgupta","sequence":"additional","affiliation":[{"name":"Clinical Trials and Outcomes BranchNational Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)National Institutes of Health (NIH)BethesdaMDUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markku","family":"Miettinen","sequence":"additional","affiliation":[{"name":"Surgical PathologyLaboratory of PathologyNational Cancer Institute (NCI)National Institutes of Health (NIH)BethesdaMDUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eileen","family":"Lange","sequence":"additional","affiliation":[{"name":"Office of the Clinical DirectorNational Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)National Institutes of Health (NIH)BethesdaMDUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Katz","sequence":"additional","affiliation":[{"name":"Office of the Clinical DirectorNational Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)National Institutes of Health (NIH)BethesdaMDUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Klaushofer","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Vienna Regional Health Insurance Fund (WGKK)and Allgemeine Unfallversicherungsanstalt (AUVA; the Austrian Workers\u2019 Compensation Board) Trauma Center Meidling1st Medical Department Hanusch HospitalViennaAustria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joan C","family":"Marini","sequence":"additional","affiliation":[{"name":"Section on Heritable Disorders of Bone and Extracellular MatrixNational Institute of Child Health and Human Development (NICHD)National Institutes of Health (NIH)BethesdaMDUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard M","family":"Siegel","sequence":"additional","affiliation":[{"name":"Immunoregulation SectionAutoimmunity BranchNational Institute of Arthritis and Musculoskeletal and 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