{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T10:47:31Z","timestamp":1789728451861,"version":"4.0.1"},"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T00:00:00Z","timestamp":1721174400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Foundation of Scientific Research OLVG"},{"name":"the research fund of the Dutch HME-MO association"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Multiple Osteochondromas (MO) is a rare genetic disorder characterised by the presence of numerous benign bone tumours, known as osteochondromas. Within the spectrum of debilitating symptoms associated with MO, pain is recognized as a major problem. Interestingly, our clinical observations suggest that fatigue is also a significant concern but has merely been touched upon in MO literature. This study aims to (1) assess the level of pain and fatigue in adult patients with MO; (2) compare fatigue in MO to healthy subjects and patients with Rheumatoid Arthritis (RA); (3) identify associated variables for pain and fatigue in patients with MO.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>In this cross-sectional study, 353 adult MO patients completed a survey with validated questionnaires on pain, fatigue and psychosocial factors. Pain and fatigue were assessed with the Numeric Rating Scale (NRS), and fatigue was also measured with the Checklist Individual Strength (CIS). Fatigue (CIS) was compared with reference scores of healthy subjects and patients with RA, using a one-sample t-test. Multiple linear regression models for pain and fatigue were developed using a-priori selected independent variables based on a theoretical framework (ICF-model).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Pain was reported by 87.8% (NRS = 3.19\u00b12.6) and fatigue by 90.4% (NRS = 4.1\u00b12.6) of patients with MO. Fatigue scores for MO (CIS = 84.1\u00b115.3) were significantly higher (p&lt;0.001) compared to reference scores of healthy subjects and patients with RA. The multivariable analysis for pain provided a final regression model with six variables (R<jats:sup>2<\/jats:sup> = 0.445, p&lt;0.001) of which fear avoidance beliefs and fatigue had the strongest association. For the fatigue models NRS (R<jats:sup>2<\/jats:sup> = 0.455, p&lt;0.001) and CIS (R<jats:sup>2<\/jats:sup> = 0.233, p&lt;0.001), the strongest associations were found with anxiety and depression respectively.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>Pain and fatigue are highly prevalent in patients with MO. Fatigue is significantly higher compared to healthy subjects and patients with RA. Several variables associated with pain and fatigue have been identified that could help improve multidisciplinary treatment plans.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0305640","type":"journal-article","created":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T17:32:07Z","timestamp":1721237527000},"page":"e0305640","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Pain and fatigue in adult patients with multiple osteochondromas: The Netherlands"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5464-8636","authenticated-orcid":true,"given":"Ihsane","family":"Amajjar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7866-3045","authenticated-orcid":true,"given":"Kuni","family":"Vergauwen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nienke W.","family":"Willigenburg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. John","family":"Ham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob J. E. 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Results in a single-center cohort of 319 adult patients","author":"HJ Van der Woude","year":"2023","journal-title":"Skeletal Radiol."},{"issue":"1","key":"pone.0305640.ref004","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s00256-019-03268-z","article-title":"Whole-body MRI in assessing malignant transformation in multiple hereditary exostoses and enchondromatosis: audit results and literature review.","volume":"49","author":"AG Jurik","year":"2020","journal-title":"Skeletal Radiol."},{"issue":"7","key":"pone.0305640.ref005","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1302\/0301-620X.86B7.14815","article-title":"Severity of disease and risk of malignant change in hereditary multiple exostoses. A genotype-phenotype study","volume":"86","author":"DE Porter","year":"2004","journal-title":"J Bone Joint Surg Br"},{"issue":"3","key":"pone.0305640.ref006","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1097\/01.bpo.0000150813.18673.ad","article-title":"Hereditary multiple exostosis and pain","volume":"25","author":"S Darilek","year":"2005","journal-title":"J Pediatr Orthop"},{"issue":"11","key":"pone.0305640.ref007","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.2106\/JBJS.K.00406","article-title":"Pain, physical and social functioning, and quality of life in individuals with multiple hereditary exostoses in The Netherlands: a national cohort study.","volume":"94","author":"AL Goud","year":"2012","journal-title":"J Bone Joint Surg Am."},{"issue":"1","key":"pone.0305640.ref008","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1002\/ajmg.1320550113","article-title":"Natural history study of hereditary multiple exostoses","volume":"55","author":"CL Wicklund","year":"1995","journal-title":"Am J Med Genet"},{"issue":"7","key":"pone.0305640.ref009","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1136\/jmg.38.7.430","article-title":"Genotype-phenotype correlation in hereditary multiple exostoses","volume":"38","author":"C Francannet","year":"2001","journal-title":"J Med Genet"},{"issue":"2","key":"pone.0305640.ref010","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1111\/j.1399-0004.2006.00653.x","article-title":"The genotype-phenotype correlation of hereditary multiple exostoses","volume":"70","author":"C Alvarez","year":"2006","journal-title":"Clin Genet"},{"key":"pone.0305640.ref011","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1097\/BLO.0b013e3181334b51","article-title":"Evaluation of the anatomic burden of patients with hereditary multiple exostoses","volume":"462","author":"CM Alvarez","year":"2007","journal-title":"Clin Orthop Relat Res"},{"issue":"1","key":"pone.0305640.ref012","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1177\/0036933013518150","article-title":"Hereditary multiple exostoses: anatomical distribution and burden of exostoses is dependent upon genotype and gender.","volume":"59","author":"ND Clement","year":"2014","journal-title":"Scott Med J"},{"issue":"1","key":"pone.0305640.ref013","doi-asserted-by":"crossref","first-page":"85","DOI":"10.2353\/jmoldx.2008.070086","article-title":"Mutation screening of EXT1 and EXT2 by denaturing high-performance liquid chromatography, direct sequencing analysis, fluorescence in situ hybridization, and a new multiplex ligation-dependent probe amplification probe set in patients with multiple osteochondromas","volume":"10","author":"I Jennes","year":"2008","journal-title":"J Mol Diagn"},{"issue":"5","key":"pone.0305640.ref014","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1002\/gcc.20429","article-title":"A combined analytical approach reveals novel EXT1\/2 gene mutations in a large cohort of Italian multiple osteochondromas patients","volume":"46","author":"E Signori","year":"2007","journal-title":"Genes Chromosomes Cancer"},{"issue":"2","key":"pone.0305640.ref015","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1097\/BPO.0b013e31823ee31c","article-title":"Health-related quality of life in people with hereditary multiple exostoses","volume":"32","author":"H Chhina","year":"2012","journal-title":"J Pediatr Orthop"},{"key":"pone.0305640.ref016","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.ijotn.2019.02.001","article-title":"Fatigue and pain in children and adults with multiple osteochondromas in Norway, a cross-sectional study.","volume":"34","author":"T Bathen","year":"2019","journal-title":"Int J Orthop Trauma Nurs."},{"key":"pone.0305640.ref017","first-page":"97","article-title":"Pain, Fatigue, and Physical Activity in Osteoarthritis: The Moderating Effects of Pain- and Fatigue-Related Activity Interference","author":"SL Murphy","year":"2016","journal-title":"Arch Phys Med Rehabil"},{"issue":"1","key":"pone.0305640.ref018","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1186\/s12891-022-05162-7","article-title":"The temporal relation between pain and fatigue in individuals receiving treatment for chronic musculoskeletal pain","volume":"23","author":"K Yamada","year":"2022","journal-title":"BMC Musculoskelet Disord"},{"issue":"3","key":"pone.0305640.ref019","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.ejpain.2009.05.010","article-title":"Co-occurrence and associations of pain and fatigue in a community sample of Dutch adults","volume":"14","author":"ST Creavin","year":"2010","journal-title":"Eur J Pain"},{"issue":"7","key":"pone.0305640.ref020","first-page":"1341","article-title":"Is chronic widespread pain a predictor of all-cause morbidity? A 3 year prospective population based study in family practice","volume":"32","author":"UT Kadam","year":"2005","journal-title":"J Rheumatol"},{"issue":"6","key":"pone.0305640.ref021","doi-asserted-by":"crossref","first-page":"e0198975","DOI":"10.1371\/journal.pone.0198975","article-title":"The association of fatigue, pain, depression and anxiety with work and activity impairment in immune mediated inflammatory diseases.","volume":"13","author":"MW Enns","year":"2018","journal-title":"PLoS One."},{"issue":"11C","key":"pone.0305640.ref022","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1111\/j.1365-2702.2007.02082.x","article-title":"Persistent severe fatigue in patients with rheumatoid arthritis.","volume":"16","author":"H Repping-Wuts","year":"2007","journal-title":"J Clin Nurs"},{"key":"pone.0305640.ref023","author":"WorldHealthOrganization","year":"2022","journal-title":"Towards a common language for functioning"},{"key":"pone.0305640.ref024","author":"EDC Castor","year":"2019","journal-title":"Castor Electronic Data Capture"},{"issue":"5","key":"pone.0305640.ref025","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/0022-3999(94)90099-X","article-title":"Dimensional assessment of chronic fatigue syndrome.","volume":"38","author":"JH Vercoulen","year":"1994","journal-title":"J Psychosom Res"},{"issue":"Suppl 1","key":"pone.0305640.ref026","first-page":"60","article-title":"Assessment of fatigue among working people: a comparison of six questionnaires.","volume":"1","author":"J De Vries","year":"2003","journal-title":"Occup Environ Med"},{"issue":"1\u20132","key":"pone.0305640.ref027","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.pain.2004.12.010","article-title":"Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4).","volume":"114","author":"D Bouhassira","year":"2005","journal-title":"Pain"},{"issue":"4","key":"pone.0305640.ref028","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1037\/1040-3590.7.4.524","article-title":"The Pain Catastrophizing Scale: Development and validation","volume":"7","author":"MJL Sullivan","year":"1995","journal-title":"Psychological Assessment"},{"issue":"2","key":"pone.0305640.ref029","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/0304-3959(93)90127-B","article-title":"A Fear-Avoidance Beliefs Questionnaire (FABQ) and the role of fear-avoidance beliefs in chronic low back pain and disability.","volume":"52","author":"G Waddell","year":"1993","journal-title":"Pain"},{"issue":"6","key":"pone.0305640.ref030","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1111\/j.1600-0447.1983.tb09716.x","article-title":"The hospital anxiety and depression scale.","volume":"67","author":"AS Zigmond","year":"1983","journal-title":"Acta Psychiatr Scand"},{"issue":"5","key":"pone.0305640.ref031","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1093\/ajcn\/36.5.936","article-title":"A short questionnaire for the measurement of habitual physical activity in epidemiological studies","volume":"36","author":"JA Baecke","year":"1982","journal-title":"Am J Clin Nutr"},{"issue":"7","key":"pone.0305640.ref032","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1093\/rheumatology\/keq043","article-title":"Physical and psychosocial correlates of severe fatigue in rheumatoid arthritis.","volume":"49","author":"D van Hoogmoed","year":"2010","journal-title":"Rheumatology (Oxford)."},{"key":"pone.0305640.ref033","doi-asserted-by":"crossref","first-page":"e77","DOI":"10.1016\/j.wneu.2018.08.229","article-title":"Prediction of Objectively Measured Physical Activity and Self-Reported Disability Following Lumbar Fusion Surgery.","volume":"121","author":"M Jakobsson","year":"2019","journal-title":"World Neurosurg"},{"key":"pone.0305640.ref034","doi-asserted-by":"crossref","first-page":"739764","DOI":"10.3389\/fpsyg.2021.739764","article-title":"A Proposal for a Unifying Set of Definitions of Fatigue.","volume":"12","author":"S Skau","year":"2021","journal-title":"Front Psychol."},{"issue":"1","key":"pone.0305640.ref035","doi-asserted-by":"crossref","first-page":"20977","DOI":"10.1038\/s41598-021-00337-z","article-title":"Fatigue in patients with chronic disease: results from the population-based Lifelines Cohort Study.","volume":"11","author":"YMJ Goertz","year":"2021","journal-title":"Sci Rep."},{"issue":"4","key":"pone.0305640.ref036","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1097\/j.pain.0000000000002104","article-title":"Sex differences in brain modular organization in chronic pain","volume":"162","author":"C Fauchon","year":"2021","journal-title":"Pain"},{"issue":"4","key":"pone.0305640.ref037","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1111\/ppc.12127","article-title":"Correlates of Disability in Asian Patients With Major Depressive Disorder.","volume":"52","author":"K Eurviriyanukul","year":"2016","journal-title":"Perspect Psychiatr Care."},{"issue":"1","key":"pone.0305640.ref038","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1093\/rheumatology\/keab512","article-title":"Correlation between pain severity and levels of anxiety and depression in osteoarthritis patients: a systematic review and meta-analysis","volume":"61","author":"D Fonseca-Rodrigues","year":"2021","journal-title":"Rheumatology"},{"issue":"3","key":"pone.0305640.ref039","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1080\/08964289.2020.1796572","article-title":"Fatigue severity and fatigue sensitivity: relations to anxiety, depression, pain catastrophizing, and pain severity among adults with severe fatigue and chronic low back pain.","volume":"48","author":"K Manning","year":"2022","journal-title":"Behav Med."},{"issue":"36","key":"pone.0305640.ref040","doi-asserted-by":"crossref","first-page":"12950","DOI":"10.1073\/pnas.0408576102","article-title":"The subjective experience of pain: where expectations become reality","volume":"102","author":"T Koyama","year":"2005","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"pone.0305640.ref041","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.neulet.2012.03.039","article-title":"How expectations shape pain","volume":"520","author":"LY Atlas","year":"2012","journal-title":"Neurosci Lett"},{"issue":"5","key":"pone.0305640.ref042","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1097\/j.pain.0000000000000859","article-title":"Does expecting more pain make it more intense? Factors associated with the first week pain trajectories after breast cancer surgery","volume":"158","author":"RM Sipila","year":"2017","journal-title":"Pain"},{"issue":"7","key":"pone.0305640.ref043","doi-asserted-by":"crossref","first-page":"1472","DOI":"10.1097\/j.pain.0000000000000542","article-title":"Depression in patients with chronic pain attending a specialised pain treatment centre: prevalence and impact on health care costs","volume":"157","author":"L Rayner","year":"2016","journal-title":"Pain"},{"issue":"6","key":"pone.0305640.ref044","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1007\/s40273-021-01029-2","article-title":"Economic Burden of Treatment-Resistant Depression among Adults with Chronic Non-Cancer Pain Conditions and Major Depressive Disorder in the US","volume":"39","author":"D Shah","year":"2021","journal-title":"Pharmacoeconomics"},{"issue":"6","key":"pone.0305640.ref045","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/S2213-8587(17)30098-0","article-title":"Web-based cognitive behavioural therapy blended with face-to-face sessions for chronic fatigue in type 1 diabetes: a multicentre randomised controlled trial","volume":"5","author":"J Menting","year":"2017","journal-title":"Lancet Diabetes Endocrinol"},{"key":"pone.0305640.ref046","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.ijnurstu.2018.03.008","article-title":"The evidence base for psychological interventions for rheumatoid arthritis: A systematic review of reviews.","volume":"82","author":"L Prothero","year":"2018","journal-title":"Int J Nurs Stud"},{"issue":"6","key":"pone.0305640.ref047","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1016\/j.jpainsymman.2019.12.358","article-title":"A Qualitative Metasynthesis of the Experience of Fatigue Across Five Chronic Conditions.","volume":"59","author":"RB Jaime-Lara","year":"2020","journal-title":"J Pain Symptom Manage"},{"issue":"6","key":"pone.0305640.ref048","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1097\/j.pain.0000000000001194","article-title":"Tired of pain or painfully tired? A reciprocal relationship between chronic pain and fatigue","volume":"159","author":"B Lenaert","year":"2018","journal-title":"Pain"},{"issue":"6","key":"pone.0305640.ref049","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1002\/acr.21932","article-title":"Association between fatigue and pain in rheumatoid arthritis: does pain precede fatigue or does fatigue precede pain?","volume":"65","author":"SA van Dartel","year":"2013","journal-title":"Arthritis Care Res (Hoboken)."},{"issue":"1","key":"pone.0305640.ref050","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1002\/msc.1141","article-title":"Long-Term Outcomes of Multidisciplinary Rehabilitation for Chronic Musculoskeletal Pain.","volume":"15","author":"G Volker","year":"2017","journal-title":"Musculoskeletal Care"},{"issue":"1","key":"pone.0305640.ref051","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1186\/s13104-022-06211-z","article-title":"Systematic description of an interdisciplinary multimodal pain treatment programme for patients with chronic musculoskeletal pain, using the TIDieR checklist.","volume":"15","author":"L Breugelmans","year":"2022","journal-title":"BMC Res Notes."}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0305640","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T17:32:39Z","timestamp":1721237559000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0305640"}},"subtitle":[],"editor":[{"given":"Deema","family":"Jaber","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,7,17]]},"references-count":51,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,7,17]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0305640","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,17]]}}}