{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T16:51:22Z","timestamp":1783529482948,"version":"3.55.0"},"reference-count":63,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T00:00:00Z","timestamp":1662422400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fujian Natural Science Foundation Project","award":["2021J01775"],"award-info":[{"award-number":["2021J01775"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>(1) Introduction: Tourette syndrome (TS) and chronic tic disorder (CTD) are common neurodevelopmental\/-psychiatric disorders. The aetiological factors that contribute to the pathogenesis of TS\/CTD are still poorly understood. The possible risk factors for TS\/CTD are considered to be a combination of genetic, immunological, psychological and environmental factors. A comprehensive systematic review was conducted to assess the association between aetiological factors and TS\/CTD. (2) Methods: Electronic databases, including PubMed, Embase, Web of Science, Wanfang data, and CNKI, were searched to identify the etiological factors of children and adolescents (\u226418 years) with TS\/CTD based on a case-control study. Quality assessments were performed according to the Newcastle-Ottawa scale (NOS). (3) Results: According to sample sizes and NOS values, recent evidence may support that genetic factors (BTBD9 and AADAC), immunological factors (streptococcus and mycoplasma pneumoniae infections), environmental factors (conflict, history of perinatal diseases, and family history of neurological and psychiatric diseases and recurrent respiratory infections) and psychological factors (major life events) are associated with the pathogenesis of TS\/CTD. (4) Conclusions: Some risk factors in different categories may be the etiological factors of TS\/CTD, but there is a lack of studies on the interaction among the factors, which may require more attention in the future.<\/jats:p>","DOI":"10.3390\/brainsci12091202","type":"journal-article","created":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T20:52:51Z","timestamp":1662497571000},"page":"1202","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The Aetiology of Tourette Syndrome and Chronic Tic Disorder in Children and Adolescents: A Comprehensive Systematic Review of Case-Control Studies"],"prefix":"10.3390","volume":"12","author":[{"given":"Jilong","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Fujian Medical University Union Hospital, Fuzhou 350001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengxin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Fujian Medical University Union Hospital, Fuzhou 350001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huifang","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Fujian Medical University Union Hospital, Fuzhou 350001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhui","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Fujian Medical University Union Hospital, Fuzhou 350001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1007\/s00787-021-01842-2","article-title":"European clinical guidelines for Tourette syndrome and other tic disorders\u2014version 2.0. Part I: Assessment","volume":"31","author":"Szejko","year":"2022","journal-title":"Eur. Child Adolesc. Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/B978-0-444-63233-3.00023-3","article-title":"Tourette disorder and other tic disorders","volume":"147","author":"Fernandez","year":"2018","journal-title":"Handb. Clin. Neurol."},{"key":"ref_3","unstructured":"American Psychiatric Association (2018). Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Association. [5th ed.]."},{"key":"ref_4","first-page":"774","article-title":"Current Status, Diagnosis, and Treatment Recommendation for Tic Disorders in China","volume":"11","author":"Liu","year":"2020","journal-title":"Front. Psychiatry"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1016\/j.jclinepi.2009.06.005","article-title":"Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement","volume":"62","author":"Moher","year":"2009","journal-title":"J. Clin. Epidemiol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Page, M.J., McKenzie, J.E., Bossuyt, P.M., Boutron, I., Hoffmann, T.C., Mulrow, C.D., Shamseer, L., Tetzlaff, J.M., Akl, E.A., and Brennan, S.E. (2021). The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. PLoS Med., 18.","DOI":"10.1371\/journal.pmed.1003583"},{"key":"ref_7","unstructured":"American Psychiatric Association (1980). Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Association. [3rd ed.]."},{"key":"ref_8","unstructured":"American Psychiatric Association (1987). Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Association. [3rd ed.]. Revised."},{"key":"ref_9","unstructured":"American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Association. [4th ed.]."},{"key":"ref_10","unstructured":"American Psychiatric Association (2000). Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Association. [4th ed.]. Revised."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1007\/s10654-010-9491-z","article-title":"Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses","volume":"25","author":"Stang","year":"2010","journal-title":"Eur. J. Epidemiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1111\/iej.13538","article-title":"The association between apical periodontitis and adverse pregnancy outcomes: A systematic review","volume":"54","author":"Jakovljevic","year":"2021","journal-title":"Int. Endod. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.jpsychires.2008.01.014","article-title":"Dopaminergic receptor D5 mRNA expression is increased in circulating lymphocytes of Tourette syndrome patients","volume":"43","author":"Ferrari","year":"2008","journal-title":"J. Psychiatr. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1097\/YPG.0b013e32835862b1","article-title":"Analysis of the BTBD9 and HTR2C variants in Chinese Han patients with Tourette syndrome","volume":"22","author":"Guo","year":"2012","journal-title":"Psychiatr. Genet."},{"key":"ref_15","first-page":"10","article-title":"Association between Tourette syndrome curative effects and the dopamine transporter gene","volume":"44","author":"He","year":"2011","journal-title":"Chin. J. Psychiatry"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"654","DOI":"10.4103\/0366-6999.151665","article-title":"Association between Tourette Syndrome and the Dopamine D3 Receptor Gene Rs6280","volume":"128","author":"He","year":"2015","journal-title":"Chin. Med. J."},{"key":"ref_17","first-page":"568","article-title":"The executive function in Han Chinese children with Tourette\u2019s syndrome and it\u2019s association with polymorphism of DRD4 VNTR","volume":"24","author":"Ji","year":"2010","journal-title":"Chin. Ment. Health J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1002\/ajmg.b.32103","article-title":"Gene expression changes in peripheral blood from Chinese Han patients with Tourette syndrome","volume":"159B","author":"Lei","year":"2012","journal-title":"Am. J. Med. Genet. Part B Neuropsychiatr. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.jpsychires.2008.03.012","article-title":"Age-related gene expression in Tourette syndrome","volume":"43","author":"Lit","year":"2009","journal-title":"J. Psychiatr. Res."},{"key":"ref_20","first-page":"60","article-title":"Study on the dopamine beta-hydroxylase gene Taq I digestion polymorphism and Tourette syndrome: A case-control study","volume":"9","author":"Liu","year":"2009","journal-title":"Chin. J. Contemp. Neurol. Neurosurg."},{"key":"ref_21","first-page":"357","article-title":"Association between the polymorphism in the promoter region of dopamine D4 receptor gene and chronic tic disorder","volume":"8","author":"Lu","year":"2006","journal-title":"Chin. J. Contemp. Pediatr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"608355","DOI":"10.3389\/fnmol.2020.608355","article-title":"Enrichment and Correlation Analysis of Serum miRNAs in Comorbidity Between Arnold-Chiari and Tourette Syndrome Contribute to Clarify Their Molecular Bases","volume":"13","author":"Mirabella","year":"2021","journal-title":"Front. Mol. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s13041-015-0133-y","article-title":"Circulating miRNAs profiles in Tourette syndrome: Molecular data and clinical implications","volume":"8","author":"Rizzo","year":"2015","journal-title":"Mol. Brain"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1002\/ajmg.b.31140","article-title":"Exon expression and alternatively spliced genes in Tourette syndrome","volume":"156","author":"Tian","year":"2011","journal-title":"Am. J. Med. Genet. Part B Neuropsychiatr. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.neulet.2017.12.034","article-title":"Association of the AADAC gene and Tourette syndrome in a Han Chinese cohort","volume":"666","author":"Yuan","year":"2018","journal-title":"Neurosci. Lett."},{"key":"ref_26","first-page":"349","article-title":"Association between Mycoplasma pneumoniae infection and children with Tourette syndrome","volume":"32","author":"Chang","year":"2006","journal-title":"Chin. J. Nerv. Ment. Dis."},{"key":"ref_27","first-page":"207","article-title":"Increased expression of autoantibody protein and soluble IL-6 receptor in serum of patients with Tourette\u2019s syndrome patients","volume":"9","author":"Cheng","year":"2009","journal-title":"J. Neurosci. Ment. Health"},{"key":"ref_28","first-page":"63","article-title":"Study on the relationship between Tourette syndrome and the changes of ASO","volume":"25","author":"Dong","year":"2009","journal-title":"J. Chifeng Univ. (Nat. Sci. Ed.)"},{"key":"ref_29","first-page":"337","article-title":"Determination of T-cell subpopulations, ASO, IL-6, and IL-8 in children with Tourette\u2019s syndrome","volume":"40","author":"Ji","year":"2005","journal-title":"J. Zhengzhou Univ. (Med. Sci.)"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1177\/08830738060210091001","article-title":"Increased Antistreptococcal Antibody Titers and Anti\u2014Basal Ganglia Antibodies in Patients with Tourette Syndrome: Controlled Cross-Sectional Study","volume":"21","author":"Rizzo","year":"2006","journal-title":"J. Child Neurol."},{"key":"ref_31","first-page":"48","article-title":"Association between Mycoplasma pneumoniae infection and children with Tourette syndrome","volume":"4","author":"Yang","year":"2010","journal-title":"Chin. J. Mod. Drug Appl."},{"key":"ref_32","first-page":"303","article-title":"Association of Tourette syndrome and obsessive-compulsive disorder with allergic diseases in children and adolescents: A preliminary study","volume":"18","author":"Yuce","year":"2014","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_33","first-page":"177","article-title":"Analysis of risk factors of children with Tourette Syndrome","volume":"13","author":"Zhao","year":"2017","journal-title":"Chin. J. Obstet. Gynecol. Pediatr. (Electron. Ed.)"},{"key":"ref_34","first-page":"3943","article-title":"Behavior problems and family environment of children with Tourette syndrome","volume":"28","author":"Gu","year":"2013","journal-title":"Matern. Child Health Care China"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1111\/j.1651-2227.2005.tb01837.x","article-title":"Tourette syndrome and other tic disorders in a total population of children: Clinical assessment and background","volume":"94","author":"Khalifa","year":"2005","journal-title":"Acta Paediatr."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.ntt.2003.07.018","article-title":"A comparison of the effects of parental risk markers on pre- and perinatal variables in multiple patient cohorts with fetal alcohol syndrome, autism, Tourette syndrome, and sudden infant death syndrome: An enviromic analysis","volume":"25","author":"Klug","year":"2003","journal-title":"Neurotoxicol. Teratol."},{"key":"ref_37","first-page":"2698","article-title":"Analysis of risk factors of children with Tourette Syndrome","volume":"31","author":"Li","year":"2010","journal-title":"Guangdong Med. J."},{"key":"ref_38","first-page":"595","article-title":"Family environment and rearing styles of parents of children with Tourette syndrome and obsessive compulsive disorder","volume":"21","author":"Liu","year":"2007","journal-title":"Chin. Ment. Health J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1007\/s00702-007-0014-3","article-title":"Is onset of Tourette syndrome influenced by life events?","volume":"115","author":"Horesh","year":"2008","journal-title":"J. Neural Transm."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1007\/s00787-010-0115-7","article-title":"Severe psychosocial stress and heavy cigarette smoking during pregnancy: An examination of the pre- and perinatal risk factors associated with ADHD and Tourette syndrome","volume":"19","author":"Motlagh","year":"2010","journal-title":"Eur. Child Adolesc. Psychiatry"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.psychres.2017.11.016","article-title":"Major and minor life events, personality and psychopathology in children with Tourette syndrome","volume":"260","author":"Horesh","year":"2018","journal-title":"Psychiatry Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1016\/j.psyneuen.2008.03.014","article-title":"Examining cortisol rhythmicity and responsivity to stress in children with Tourette syndrome","volume":"33","author":"Corbett","year":"2008","journal-title":"Psychoneuroendocrinology"},{"key":"ref_43","first-page":"73","article-title":"Testosterone and DHEA-S levels with chronic tic disorder in children","volume":"9","author":"Erbay","year":"2016","journal-title":"J. Obs.-Compuls. Relat. Disord."},{"key":"ref_44","first-page":"182","article-title":"Changes in plasma prolactin levels in children with Tourette syndrome","volume":"6","author":"Liu","year":"1998","journal-title":"J. Brain Nerv. Dis."},{"key":"ref_45","first-page":"211","article-title":"Analysis on the family environment of children with Tourette syndrome","volume":"25","author":"Liu","year":"2008","journal-title":"J. Clin. Res."},{"key":"ref_46","first-page":"1267","article-title":"Association of Intronic Variants of the BTBD9 Gene with Tourette Syndrome","volume":"66","author":"Xiong","year":"2009","journal-title":"Arch. Neurol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3984","DOI":"10.1093\/hmg\/dds221","article-title":"Motor restlessness, sleep disturbances, thermal sensory alterations and elevated serum iron levels in Btbd9 mutant mice","volume":"21","author":"DeAndrade","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"0277-19.2019","DOI":"10.1523\/ENEURO.0277-19.2019","article-title":"The Role of BTBD9 in Striatum and Restless Legs Syndrome","volume":"6","author":"Lyu","year":"2019","journal-title":"Eneuro"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"803","DOI":"10.3389\/fneur.2020.00803","article-title":"Association of Genetic Variation in the 3\u2032UTR of LHX6, IMMP2L, and AADAC with Tourette Syndrome","volume":"11","author":"Pagliaroli","year":"2020","journal-title":"Front. Neurol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.biopsych.2015.08.027","article-title":"Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort","volume":"79","author":"Bertelsen","year":"2016","journal-title":"Biol. Psychiatry"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/nature05453","article-title":"Genome-wide atlas of gene expression in the adult mouse brain","volume":"445","author":"Lein","year":"2007","journal-title":"Nature"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1212\/WNL.0000000000007467","article-title":"Comprehensive systematic review summary: Treatment of tics in people with Tourette syndrome and chronic tic disorders","volume":"92","author":"Pringsheim","year":"2019","journal-title":"Neurology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1002\/hup.2498","article-title":"Aripiprazole for Tourette\u2019s syndrome: A systematic review and meta-analysis","volume":"31","author":"Zheng","year":"2016","journal-title":"Hum. Psychopharmacol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1002\/mds.27457","article-title":"Ecopipam, a D1 receptor antagonist, for treatment of Tourette syndrome in children: A randomized, placebo-controlled crossover study","volume":"33","author":"Gilbert","year":"2018","journal-title":"Mov. Disord."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1055\/s-0034-1382020","article-title":"Gilles de la Tourette Syndrome Caused by Mycoplasma pneumoniae Successfully Treated with Macrolides","volume":"226","author":"Schuhfried","year":"2014","journal-title":"Klin. P\u00e4diatrie"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.psychres.2004.04.009","article-title":"Mycoplasma pneumoniae infection and Tourette\u2019s syndrome","volume":"129","author":"Riedel","year":"2004","journal-title":"Psychiatry Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3187","DOI":"10.1111\/ene.14983","article-title":"Immunity and Gilles de la Tourette syndrome: A systematic review and meta-analysis of evidence for immune implications in Tourette syndrome","volume":"28","author":"Lamothe","year":"2021","journal-title":"Eur. J. Neurol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Chao, T.-K., Hu, J., and Pringsheim, T. (2014). Prenatal risk factors for Tourette Syndrome: A systematic review. BMC Pregnancy Childbirth, 14.","DOI":"10.1186\/1471-2393-14-53"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/j.beth.2019.10.004","article-title":"Development and Open Trial of a Psychosocial Intervention for Young Children with Chronic Tics: The CBIT-JR Study","volume":"51","author":"Bennett","year":"2020","journal-title":"Behav. Ther."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1177\/0145445514522056","article-title":"The Modulating Role of Stress in the Onset and Course of Tourette\u2019s Syndrome: A Review","volume":"38","author":"Buse","year":"2014","journal-title":"Behav. Modif."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.jrp.2012.05.005","article-title":"Does personality moderate reaction and adaptation to major life events? Evidence from the British Household Panel Survey","volume":"46","author":"Yap","year":"2012","journal-title":"J. Res. Pers."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.jpsychires.2021.07.051","article-title":"Role of psychotherapy strategy for the management of patients with Tourette syndrome\u2014A Bayesian network meta-analysis","volume":"143","author":"Liang","year":"2021","journal-title":"J. Psychiatr. Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1007\/s00787-021-01845-z","article-title":"European clinical guidelines for Tourette syndrome and other tic disorders-version 2.0. Part II: Psychological interventions","volume":"31","author":"Jakubovski","year":"2022","journal-title":"Eur. Child Adolesc. Psychiatry"}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/12\/9\/1202\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:24:34Z","timestamp":1760142274000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/12\/9\/1202"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,6]]},"references-count":63,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["brainsci12091202"],"URL":"https:\/\/doi.org\/10.3390\/brainsci12091202","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,6]]}}}