{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T14:13:56Z","timestamp":1769696036262,"version":"3.49.0"},"reference-count":46,"publisher":"Wiley","license":[{"start":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:00:00Z","timestamp":1763683200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Paediatrics Child Health"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Tuberous sclerosis complex (TSC) is a multi\u2010system autosomal dominant condition associated with disease\u2010causing variants in either of the\n                    <jats:italic>TSC1<\/jats:italic>\n                    or\n                    <jats:italic>TSC2 genes<\/jats:italic>\n                    . It can be associated with variable benign tumours (hamartomas) in different organs, most notably the brain, kidneys, skin and heart with different ages of onset. Affected children may have early\u2010onset epilepsy, refractory epilepsy, varying degrees of developmental disability, ranging from normal cognition and learning difficulties to moderate\u2013severe intellectual disability, neurodevelopmental disorders and mental health disorders. Multidisciplinary TSC\u2010specific clinical care is recommended. A precision medicine (mechanistic target of rapamycin (mTOR) inhibitors) aimed at the early treatment of epilepsy and TSC\u2010specific therapy for tumours can reduce the burden of the disease and improve clinical outcomes. We describe a multidisciplinary model of care for TSC, with an emphasis on the early detection and diagnosis of TSC and active surveillance\/management of electrical seizures and clinical seizures. This review article will cover the following: clinical presentation and diagnosis of TSC, its genetic basis, the role of genetic counselling, pre\u2010seizure surveillance of infants and TSC\u2010specific (neurological, neurodevelopmental, renal, dermatological and pulmonary) management guidelines throughout life.\n                  <\/jats:p>","DOI":"10.1111\/jpc.70243","type":"journal-article","created":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T07:07:13Z","timestamp":1763795233000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Diagnosis and Management of Children With Tuberous Sclerosis Complex"],"prefix":"10.1111","author":[{"given":"Celia","family":"Dewell","sequence":"first","affiliation":[{"name":"Tuberous Sclerosis Complex Management Clinic Sydney Children's Hospital  Sydney Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7039-8400","authenticated-orcid":false,"given":"Denise L.","family":"Chan","sequence":"additional","affiliation":[{"name":"Tuberous Sclerosis Complex Management Clinic Sydney Children's Hospital  Sydney Australia"},{"name":"Discipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine and Health UNSW Sydney  Sydney Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vanessa","family":"Sarkozy","sequence":"additional","affiliation":[{"name":"Tuberous Sclerosis Complex Management Clinic Sydney Children's Hospital  Sydney Australia"},{"name":"Discipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine and Health UNSW Sydney  Sydney Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleanor","family":"Farley","sequence":"additional","affiliation":[{"name":"Tuberous Sclerosis Complex Management Clinic Sydney Children's Hospital  Sydney Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacqueline","family":"Russell","sequence":"additional","affiliation":[{"name":"Tuberous Sclerosis Complex Management Clinic Sydney Children's Hospital  Sydney Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Mowat","sequence":"additional","affiliation":[{"name":"Tuberous Sclerosis Complex Management Clinic Sydney Children's Hospital  Sydney Australia"},{"name":"Discipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine and Health UNSW Sydney  Sydney Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sean E.","family":"Kennedy","sequence":"additional","affiliation":[{"name":"Tuberous Sclerosis Complex Management Clinic Sydney Children's Hospital  Sydney Australia"},{"name":"Discipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine and Health UNSW Sydney  Sydney Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1319-7570","authenticated-orcid":false,"given":"Clara W. T.","family":"Chung","sequence":"additional","affiliation":[{"name":"Tuberous Sclerosis Complex Management Clinic Sydney Children's Hospital  Sydney Australia"},{"name":"Discipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine and Health UNSW Sydney  Sydney Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"issue":"11","key":"e_1_2_19_2_1","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1136\/adc.2011.211995","article-title":"The Tuberous Sclerosis 2000 Study: Presentation, Initial Assessments and Implications for Diagnosis and Management","volume":"96","author":"Yates J. R. W.","year":"2011","journal-title":"Archives of Disease in Childhood"},{"issue":"1","key":"e_1_2_19_3_1","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/s13023-018-0870-y","article-title":"Incidence of Tuberous Sclerosis and Age at First Diagnosis: New Data and Emerging Trends From a National, Prospective Surveillance Study","volume":"13","author":"Ebrahimi\u2010Fakhari D.","year":"2018","journal-title":"Orphanet Journal of Rare Diseases"},{"issue":"1","key":"e_1_2_19_4_1","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/epi4.12286","article-title":"Epilepsy in Tuberous Sclerosis Complex: Findings From the TOSCA Study","volume":"4","author":"Nabbout R.","year":"2018","journal-title":"Epilepsia Open"},{"key":"e_1_2_19_5_1","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.pediatrneurol.2017.05.014","article-title":"Early Detection of Tuberous Sclerosis Complex: An Opportunity for Improved Neurodevelopmental Outcome","volume":"76","author":"Chung C. 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T.","year":"2017","journal-title":"Pediatric Neurology"},{"key":"e_1_2_19_6_1","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.pediatrneurol.2021.07.011","article-title":"Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations","volume":"123","author":"Northrup H.","year":"2021","journal-title":"Pediatric Neurology"},{"issue":"9","key":"e_1_2_19_7_1","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1016\/S1474-4422(22)00213-7","article-title":"Advances in the Genetics and Neuropathology of Tuberous Sclerosis Complex: Edging Closer to Targeted Therapy","volume":"21","author":"Curatolo P.","year":"2022","journal-title":"Lancet Neurology"},{"issue":"9861","key":"e_1_2_19_8_1","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/S0140-6736(12)61134-9","article-title":"Efficacy and Safety of Everolimus for Subependymal Giant Cell Astrocytomas Associated With Tuberous Sclerosis Complex (EXIST\u20101): A Multicentre, Randomised, Placebo\u2010Controlled Phase 3 Trial","volume":"381","author":"Franz D. N.","year":"2013","journal-title":"Lancet"},{"issue":"9869","key":"e_1_2_19_9_1","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/S0140-6736(12)61767-X","article-title":"Everolimus for Angiomyolipoma Associated With Tuberous Sclerosis Complex or Sporadic Lymphangioleiomyomatosis (EXIST\u20102): A Multicentre, Randomised, Double\u2010Blind, Placebo\u2010Controlled Trial","volume":"381","author":"Bissler J. J.","year":"2013","journal-title":"Lancet"},{"issue":"10056","key":"e_1_2_19_10_1","doi-asserted-by":"crossref","first-page":"2153","DOI":"10.1016\/S0140-6736(16)31419-2","article-title":"Adjunctive Everolimus Therapy for Treatment\u2010Resistant Focal\u2010Onset Seizures Associated With Tuberous Sclerosis (EXIST\u20103): A Phase 3, Randomised, Double\u2010Blind, Placebo\u2010Controlled Study","volume":"388","author":"French J. 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K.","year":"2018","journal-title":"JAMA Dermatology"},{"issue":"21","key":"e_1_2_19_12_1","doi-asserted-by":"crossref","DOI":"10.3390\/jcm13216335","article-title":"Prenatal mTOR Inhibitors in Tuberous Sclerosis Complex: Current Insights and Future Directions","volume":"13","author":"Racioppi G.","year":"2024","journal-title":"Journal of Clinical Medicine"},{"issue":"2","key":"e_1_2_19_13_1","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1002\/ana.25956","article-title":"Prevention of Epilepsy in Infants With Tuberous Sclerosis Complex in the EPISTOP Trial","volume":"89","author":"Kotulska K.","year":"2021","journal-title":"Annals of Neurology"},{"issue":"1","key":"e_1_2_19_14_1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/ana.26778","article-title":"Early Treatment With Vigabatrin Does Not Decrease Focal Seizures or Improve Cognition in Tuberous Sclerosis Complex: The PREVeNT Trial","volume":"95","author":"Bebin E. M.","year":"2023","journal-title":"Annals of Neurology"},{"issue":"1","key":"e_1_2_19_15_1","doi-asserted-by":"crossref","DOI":"10.1186\/s13023-024-03495-1","article-title":"Long\u2010Term Neuropsychologic Outcome of Pre\u2010Emptive mTOR Inhibitor Treatment in Children With Tuberous Sclerosis Complex (TSC) Under 4 Months of Age (PROTECT), a Two\u2010Arm, Randomized, Observer\u2010Blind, Controlled Phase IIb National Multicentre Clinical Trial","volume":"20","author":"Driedger J. H.","year":"2025","journal-title":"Orphanet Journal of Rare Diseases"},{"issue":"3","key":"e_1_2_19_16_1","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1002\/ajmg.c.31651","article-title":"Genetics, Genomics, and Genotype\u2010Phenotype Correlations of TSC: Insights for Clinical Practice","volume":"178","author":"Peron A.","year":"2018","journal-title":"American Journal of Medical Genetics. Part C, Seminars in Medical Genetics"},{"issue":"10","key":"e_1_2_19_17_1","doi-asserted-by":"crossref","DOI":"10.1002\/mgg3.70017","article-title":"Deep Sequencing and Phenotyping in an Australian Tuberous Sclerosis Complex \u201cno Mutations Identified\u201d Cohort","volume":"12","author":"Chung C. W. T.","year":"2024","journal-title":"Molecular Genetics & Genomic Medicine"},{"issue":"11","key":"e_1_2_19_18_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1005637","article-title":"Mosaic and Intronic Mutations in TSC1\/TSC2 Explain the Majority of TSC Patients With no Mutation Identified by Conventional Testing","volume":"11","author":"Tyburczy M. E.","year":"2015","journal-title":"PLoS Genetics"},{"issue":"1","key":"e_1_2_19_19_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s12881-015-0155-4","article-title":"Targeted Next Generation Sequencing Reveals Previously Unidentified TSC1 and TSC2 Mutations","volume":"16","author":"Nellist M.","year":"2015","journal-title":"BMC Medical Genetics"},{"issue":"9","key":"e_1_2_19_20_1","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1038\/s41436-020-0823-4","article-title":"TSC2 Pathogenic Variants Are Predictive of Severe Clinical Manifestations in TSC Infants: Results of the EPISTOP Study","volume":"22","author":"Og\u00f3rek B.","year":"2020","journal-title":"Genetics in Medicine"},{"issue":"23","key":"e_1_2_19_21_1","doi-asserted-by":"crossref","DOI":"10.3390\/jcm10235495","article-title":"Risk Factors Associated With Refractory Epilepsy in Patients With Tuberous Sclerosis Complex: A Systematic Review","volume":"10","author":"Miszewska D.","year":"2021","journal-title":"Journal of Clinical Medicine"},{"issue":"3","key":"e_1_2_19_22_1","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1093\/hmg\/ddq491","article-title":"Tsc2 Gene Inactivation Causes a More Severe Epilepsy Phenotype Than Tsc1 Inactivation in a Mouse Model of Tuberous Sclerosis Complex","volume":"20","author":"Zeng L. H.","year":"2011","journal-title":"Human Molecular Genetics"},{"issue":"11","key":"e_1_2_19_23_1","doi-asserted-by":"crossref","first-page":"2321","DOI":"10.1017\/S0033291715000264","article-title":"Intellectual Abilities in Tuberous Sclerosis Complex: Risk Factors and Correlates From the Tuberous Sclerosis 2000 Study","volume":"45","author":"Bolton P. 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A.","year":"2018","journal-title":"European Journal of Paediatric Neurology"},{"issue":"3","key":"e_1_2_19_29_1","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.trre.2014.03.002","article-title":"Strategies for the Management of Adverse Events Associated With mTOR Inhibitors","volume":"28","author":"Kaplan B.","year":"2014","journal-title":"Transplantation Reviews"},{"issue":"1","key":"e_1_2_19_30_1","doi-asserted-by":"crossref","DOI":"10.1186\/s13023-016-0553-5","article-title":"TuberOus SClerosis Registry to Increase Disease Awareness (TOSCA) \u2010 Baseline Data on 2093 Patients","volume":"12","author":"Kingswood J. C.","year":"2017","journal-title":"Orphanet Journal of Rare Diseases"},{"issue":"3","key":"e_1_2_19_31_1","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1515\/revneuro-2017-0027","article-title":"The Natural History of Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex: A Review","volume":"29","author":"Chan D. 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M.","year":"2025","journal-title":"Expert Review of Neurotherapeutics"},{"issue":"1","key":"e_1_2_19_34_1","doi-asserted-by":"crossref","DOI":"10.1186\/s13023-018-0901-8","article-title":"TSC\u2010Associated Neuropsychiatric Disorders (TAND): Findings From the TOSCA Natural History Study","volume":"13","author":"Vries P. 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