{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T07:01:12Z","timestamp":1780124472581,"version":"3.54.0"},"reference-count":20,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Unidade Local de Sa\u00fade de Santo Ant\u00f3nio"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Pediatr"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    HyperCKemia is a frequent laboratory finding in pediatric practice and may reflect a wide spectrum of conditions, ranging from benign transient states to rare primary neuromuscular disorders. The lack of pediatric-specific diagnostic algorithms complicates risk stratification and clinical decision-making. A retrospective cohort study was conducted, including patients under 18\u00a0years of age with hyperCKemia referred to a tertiary reference center between January 2017 and December 2024. Clinical, laboratory, genetic, and histological data were collected. Statistical analyses included univariate testing and logistic regression to identify predictors of primary disease. A total of 119 patients were included (median age 10\u00a0years; 76.5% male). Most were symptomatic at presentation (87.4%), and 80.3% met criteria for rhabdomyolysis. A primary disorder was identified in 25.2% of patients, while 52.1% had secondary causes, predominantly viral myositis, and 22.7% remained undiagnosed. Metabolic myopathies accounted for the majority of primary diagnoses (60.0%), followed by muscular dystrophies (23.3%) and inflammatory myopathies (13.3%). Persistent hyperCKemia and male sex emerged as strong independent predictors of primary disease (\n                    <jats:italic>OR<\/jats:italic>\n                    8.5 and 5.1, respectively). Muscle weakness and exercise intolerance were exclusive to primary disorders. Genetic testing yielded a diagnosis in 26.8% of tested patients, with targeted next-generation sequencing proving particularly valuable.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:italic>Conclusions:<\/jats:italic>\n                    In pediatric hyperCKemia, persistent CK elevation and male sex are key predictors of underlying primary neuromuscular disease. A phenotype-driven, stepwise diagnostic approach incorporating early genetic testing may improve diagnostic yield and optimize resource utilization.\n                    <jats:table-wrap>\n                      <jats:table>\n                        <jats:tbody>\n                          <jats:tr>\n                            <jats:td align=\"left\">\n                              <jats:bold>What is Known:<\/jats:bold>\n                              \u2022\u00a0\n                              <jats:italic>HyperCKemia in children is most frequently secondary to benign conditions such as viral myositis, while primary neuromuscular disorders are less common but clinically significant.<\/jats:italic>\n                              \u2022\u00a0\n                              <jats:italic>Creatine kinase levels lack specificity, and the diagnostic approach increasingly relies on genetic testing.<\/jats:italic>\n                            <\/jats:td>\n                          <\/jats:tr>\n                          <jats:tr>\n                            <jats:td align=\"left\">\n                              <jats:bold>What is New:<\/jats:bold>\n                              \u2022\u00a0\n                              <jats:italic>Persistent hyperCKemia and male sex were identified as independent predictors of primary disease.<\/jats:italic>\n                              \u2022\u00a0\n                              <jats:italic>Most primary disorders occurred in patients with CK over 1000 UI\/L, and higher inter-crisis CK levels were associated with an increased likelihood of underlying disease.<\/jats:italic>\n                            <\/jats:td>\n                          <\/jats:tr>\n                        <\/jats:tbody>\n                      <\/jats:table>\n                    <\/jats:table-wrap>\n                  <\/jats:p>","DOI":"10.1007\/s00431-026-06914-6","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T07:30:45Z","timestamp":1775806245000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pediatric HyperCKemia: a 13-year retrospective study and predictors of neuromuscular disease and metabolic myopathy"],"prefix":"10.1007","volume":"185","author":[{"given":"In\u00eas","family":"Aires Martins","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joana","family":"Baptista de Lima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margarida Paiva","family":"Coelho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anabela","family":"Bandeira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esmeralda","family":"Martins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joana","family":"Correia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"issue":"6","key":"6914_CR1","doi-asserted-by":"publisher","first-page":"1541","DOI":"10.1007\/s10067-016-3242-9","volume":"35","author":"D Leverenz","year":"2016","unstructured":"Leverenz D, Zaha O, Crofford LJ, Chung CP (2016) Causes of creatine kinase levels greater than 1000 IU\/L in patients referred to rheumatology. Clin Rheumatol 35(6):1541\u20131547. https:\/\/doi.org\/10.1007\/s10067-016-3242-9","journal-title":"Clin Rheumatol"},{"issue":"6","key":"6914_CR2","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1177\/0883073818758455","volume":"33","author":"F Al-Ghamdi","year":"2018","unstructured":"Al-Ghamdi F, Darras BT, Ghosh PS (2018) Spectrum of neuromuscular disorders with hyperCKemia from a tertiary care pediatric neuromuscular center. J Child Neurol 33(6):389\u2013396. https:\/\/doi.org\/10.1177\/0883073818758455","journal-title":"J Child Neurol"},{"key":"6914_CR3","doi-asserted-by":"publisher","first-page":"E72","DOI":"10.1055\/s-0043-124361","volume":"02","author":"RA Kley","year":"2018","unstructured":"Kley RA, Schmidt-Wilcke T, Vorgerd M (2018) Differential diagnosis of hyperCKemia. Neurol Int Open 02:E72-83. https:\/\/doi.org\/10.1055\/s-0043-124361","journal-title":"Neurol Int Open"},{"key":"6914_CR4","unstructured":"Silvestri NJ, Wolfe GI (2019) Practical Neurology [Internet]. Bryn Mawr Communications; [cited 2025 Jan 22]. HyperCKemia. Available from: https:\/\/practicalneurology.com\/articles\/2019-aug-july\/hyperckemia\/pdf.\u00a0Access 12 Apr 2025"},{"issue":"1","key":"6914_CR5","first-page":"58","volume":"15","author":"PA Torres","year":"2015","unstructured":"Torres PA, Helmstetter JA, Kaye AM, Kaye AD (2015) Rhabdomyolysis: Pathogenesis, Diagnosis, and Treatment. Ochsner J 15(1):58\u201369","journal-title":"Ochsner J"},{"issue":"1","key":"6914_CR6","doi-asserted-by":"publisher","DOI":"10.1136\/tsaco-2021-000836","volume":"7","author":"L Kodadek","year":"2022","unstructured":"Kodadek L, Carmichael ISP, Seshadri A, Pathak A, Hoth J, Appelbaum R et al (2022) Rhabdomyolysis: an American Association for the Surgery of Trauma Critical Care Committee Clinical Consensus Document. Trauma Surg Acute Care Open 7(1):e000836. https:\/\/doi.org\/10.1136\/tsaco-2021-000836","journal-title":"Trauma Surg Acute Care Open"},{"issue":"4","key":"6914_CR7","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1007\/s00415-019-09185-4","volume":"267","author":"K Stahl","year":"2020","unstructured":"Stahl K, Rastelli E, Schoser B (2020) A systematic review on the definition of rhabdomyolysis. J Neurol 267(4):877\u2013882. https:\/\/doi.org\/10.1007\/s00415-019-09185-4","journal-title":"J Neurol"},{"issue":"2","key":"6914_CR8","doi-asserted-by":"publisher","first-page":"e70493","DOI":"10.1111\/ene.70493","volume":"33","author":"T Kyriakides","year":"2026","unstructured":"Kyriakides T, Aleksovska K, Angelini C, Argov Z, Claeys KG, de Visser M et al (2026) EFNS guidelines on the diagnostic approach to pauci- or asymptomatic hyperCKemia. EAN 2024 Guideline on the Diagnostic Approach to Oligo\/Asymptomatic HyperCKemia. Eur J Neurol. 33(2):e70493. https:\/\/doi.org\/10.1111\/ene.70493","journal-title":"Eur J Neurol."},{"issue":"1\u20132","key":"6914_CR9","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1177\/08830738221147808","volume":"38","author":"D Pasca","year":"2023","unstructured":"Pasca D, Ginsberg M (2023) Causes of hyperCKemia in children: a retrospective cohort study. J Child Neurol 38(1\u20132):25\u201330. https:\/\/doi.org\/10.1177\/08830738221147808","journal-title":"J Child Neurol"},{"issue":"1","key":"6914_CR10","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12781","volume":"48","author":"H de Calbiac","year":"2025","unstructured":"de Calbiac H, Imbard A, de Lonlay P (2025) Cellular mechanisms of acute rhabdomyolysis in inherited metabolic diseases. J Inherit Metab Dis 48(1):e12781. https:\/\/doi.org\/10.1002\/jimd.12781","journal-title":"J Inherit Metab Dis"},{"issue":"1","key":"6914_CR11","doi-asserted-by":"publisher","first-page":"37","DOI":"10.3949\/ccjm.83a.14120","volume":"83","author":"S Moghadam-Kia","year":"2016","unstructured":"Moghadam-Kia S, Oddis CV, Aggarwal R (2016) Approach to asymptomatic creatine kinase elevation. Cleve Clin J Med 83(1):37\u201342. https:\/\/doi.org\/10.3949\/ccjm.83a.14120","journal-title":"Cleve Clin J Med"},{"issue":"1","key":"6914_CR12","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.12791","volume":"13","author":"S Shaikh","year":"2021","unstructured":"Shaikh S, Gonzalez-Zapata A, Mujeeb A, Rauf A, Thekkemuriyil D (2021) Asymptomatic hyperCKemia: a diagnostic trap. Cureus 13(1):e12791. https:\/\/doi.org\/10.7759\/cureus.12791","journal-title":"Cureus"},{"issue":"5","key":"6914_CR13","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000352","volume":"5","author":"A Rubegni","year":"2019","unstructured":"Rubegni A, Malandrini A, Dosi C, Astrea G, Baldacci J, Battisti C et al (2019) Next-generation sequencing approach to hyperCKemia. Neurol Genet 5(5):e352. https:\/\/doi.org\/10.1212\/NXG.0000000000000352","journal-title":"Neurol Genet"},{"issue":"3","key":"6914_CR14","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1017\/cjn.2017.286","volume":"45","author":"L Wu","year":"2018","unstructured":"Wu L, Brady L, Shoffner J, Tarnopolsky MA (2018) Next-Generation sequencing to diagnose muscular dystrophy, rhabdomyolysis, and hyperCKemia. Can J Neurol Sci 45(3):262\u2013268. https:\/\/doi.org\/10.1017\/cjn.2017.286","journal-title":"Can J Neurol Sci"},{"issue":"5","key":"6914_CR15","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1542\/pir.2021-005438","volume":"44","author":"S Menon","year":"2023","unstructured":"Menon S, Symons JM, Selewski DT (2023) Acute Kidney Injury. Pediatr Rev 44(5):265\u2013279. https:\/\/doi.org\/10.1542\/pir.2021-005438","journal-title":"Pediatr Rev"},{"issue":"5","key":"6914_CR16","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5):405\u2013424. https:\/\/doi.org\/10.1038\/gim.2015.30","journal-title":"Genet Med"},{"issue":"10","key":"6914_CR17","doi-asserted-by":"publisher","first-page":"1585","DOI":"10.1212\/01.wnl.0000216144.69630.6e","volume":"66","author":"C Fernandez","year":"2006","unstructured":"Fernandez C, de Paula AM, Figarella-Branger D, Krahn M, Giorgi R, Chabrol B et al (2006) Diagnostic evaluation of clinically normal subjects with chronic hyperCKemia. Neurology 66(10):1585\u20131587. https:\/\/doi.org\/10.1212\/01.wnl.0000216144.69630.6e","journal-title":"Neurology"},{"issue":"12","key":"6914_CR18","doi-asserted-by":"publisher","DOI":"10.3390\/children11121462","volume":"11","author":"C Monteiro","year":"2024","unstructured":"Monteiro C, Garrido C, Pereira \u00c2, Dias A, Costa M, Magalh\u00e3es C et al (2024) Multicentric study on the diagnostic of neuromuscular diseases in children with high creatinine phosphokinase levels. Children 11(12):1462. https:\/\/doi.org\/10.3390\/children11121462","journal-title":"Children"},{"issue":"1","key":"6914_CR19","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1212\/WNL.0000000000002800","volume":"87","author":"M Savarese","year":"2016","unstructured":"Savarese M, Di Fruscio G, Torella A, Fiorillo C, Magri F, Fanin M et al (2016) The genetic basis of undiagnosed muscular dystrophies and myopathies: results from 504 patients. Neurology 87(1):71\u201376. https:\/\/doi.org\/10.1212\/WNL.0000000000002800","journal-title":"Neurology"},{"issue":"9","key":"6914_CR20","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1016\/j.nmd.2022.07.401","volume":"32","author":"WK Wong","year":"2022","unstructured":"Wong WK, Bryen SJ, Bournazos A, Yasa J, Lemckert F, Bommireddipall S et al (2022) A genetic basis is identified in 74% cases of paediatric hyperCKaemia without weakness presenting to a tertiary paediatric neuromuscular centre. Neuromuscul Disord 32(9):707\u2013717. https:\/\/doi.org\/10.1016\/j.nmd.2022.07.401","journal-title":"Neuromuscul Disord"}],"container-title":["European Journal of Pediatrics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00431-026-06914-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00431-026-06914-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00431-026-06914-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T06:02:32Z","timestamp":1780120952000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00431-026-06914-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,10]]},"references-count":20,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["6914"],"URL":"https:\/\/doi.org\/10.1007\/s00431-026-06914-6","relation":{},"ISSN":["1432-1076"],"issn-type":[{"value":"1432-1076","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,10]]},"assertion":[{"value":"11 January 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 March 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 March 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 April 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was approved by our institutional Ethics Committee (Santo Ant\u00f3nio\u2019s Ethics Committee\u2014Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar; REF. 2024.176 (154-CAC\/143-CE). All data were anonymized in accordance with the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"250"}}