{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T13:07:43Z","timestamp":1765976863006,"version":"3.41.2"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T00:00:00Z","timestamp":1750982400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Type II DNA topoisomerases (EC5.99.1.3) are enzymes that catalyze topological changes during DNA replication and gene transcription in an ATP-dependent manner. Vertebrates have two isoforms: topoisomerase II<jats:italic>\u03b1<\/jats:italic> and <jats:italic>\u03b2<\/jats:italic>. Type II topoisomerase <jats:italic>\u03b2<\/jats:italic> is encoded by <jats:italic>TOP2B<\/jats:italic>. For <jats:italic>TOP2B<\/jats:italic>, a number of germline pathogenic variants have been identified as causative for human diseases, including Hoffman syndrome, ablepharon-macrostomia syndrome with immunodeficiency, B-cell immunodeficiency, distal limb anomalies, and urogenital malformations syndrome. To date, only 14 patients with the above diseases from seven families have been reported in PubMed. Herein, we describe an additional case of a child who presented with \u201cinfantile epileptic spasms syndrome\u201d (IESS) as the first symptom, B-cell immunodeficiency, dysmorphic facial features, and a pathogenic variant in <jats:italic>TOP2B<\/jats:italic>. The c.1901A\u2009&amp;gt;\u2009G variant in <jats:italic>TOP2B<\/jats:italic> is new to our study, which further enriches the genotype of TOP2B deficiency. Our patient manifested as a typical triad: infantile spasms, hypsarrhythmia on electroencephalogram, and developmental arrest at the age of 7\u2005months. Although epilepsy and neurodevelopmental disorders have been reported in patients with TOP2B deficiency, typical IESS has not been described previously. IESS in our patient further expands the phenotype of <jats:italic>TOP2B<\/jats:italic>. The patient was started on monthly intravenous immunoglobulin replacement therapy after being diagnosed with TOP2B deficiency and since then has not suffered from severe infections. TOP2B deficiency is a group of heterogeneous diseases, which is ultrarare. The results from our study extend the phenotype and genotype spectrum of TOP2B deficiency. <jats:italic>TOP2B<\/jats:italic> may be a causative gene for IESS.<\/jats:p>","DOI":"10.3389\/fped.2025.1542268","type":"journal-article","created":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T05:32:54Z","timestamp":1751002374000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Infantile epileptic spasms syndrome as a new phenotype in TOP2B deficiency caused by a de novo variant: a case report and literature review"],"prefix":"10.3389","volume":"13","author":[{"given":"Guo-qin","family":"Zhu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yao","family":"Yao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling-yun","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Hua","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guo-min","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3375","DOI":"10.3390\/molecules26113375","article-title":"DNA-topology simplification by topoisomerases","volume":"26","author":"Hanke","year":"2021","journal-title":"Molecules"},{"key":"B2","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1146\/annurev.biochem.70.1.369","article-title":"DNA topoisomerases: structure, function, and mechanism","volume":"70","author":"Champoux","year":"2001","journal-title":"Annu Rev Biochem"},{"key":"B3","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1038\/s41580-022-00452-3","article-title":"Human topoisomerases and their roles in genome stability and organization","volume":"23","author":"Pommier","year":"2022","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"113809","DOI":"10.1016\/j.celrep.2024.113809","article-title":"Mapping catalytically engaged TOP2B in neurons reveals the principles of topoisomerase action within the genome","volume":"43","author":"Segev","year":"2024","journal-title":"Cell Rep"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2483","DOI":"10.1042\/BST20200454","article-title":"TOP2B\u2019s contributions to transcription","volume":"49","author":"Austin","year":"2021","journal-title":"Biochem Soc Trans"},{"key":"B6","doi-asserted-by":"publisher","first-page":"2765","DOI":"10.3390\/ijms19092765","article-title":"TOP2B: the first thirty years","volume":"19","author":"Austin","year":"2018","journal-title":"Int J Mol Sci"},{"key":"B7","doi-asserted-by":"publisher","first-page":"982870","DOI":"10.3389\/fimmu.2022.982870","article-title":"Topoisomerase 2\u03b2 and DNA topology during B cell development","volume":"13","author":"Papapietro","year":"2022","journal-title":"Front Immunol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1497","DOI":"10.1182\/blood.2019003299","article-title":"Topoisomerase 2\u03b2 mutation impairs early B-cell development","volume":"135","author":"Papapietro","year":"2020","journal-title":"Blood"},{"key":"B9","doi-asserted-by":"publisher","first-page":"3794","DOI":"10.1016\/j.molcel.2022.09.012","article-title":"Calcineurin dephosphorylates topoisomerase II\u03b2 and regulates the formation of neuronal-activity-induced DNA breaks","volume":"82","author":"Delint-Ramirez","year":"2022","journal-title":"Mol Cell"},{"key":"B10","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.cca.2017.03.022","article-title":"Global developmental delay and intellectual disability associated with a de novo TOP2B mutation","volume":"469","author":"Lam","year":"2017","journal-title":"Clin Chim Acta"},{"key":"B11","doi-asserted-by":"publisher","first-page":"e1145","DOI":"10.1002\/mgg3.1145","article-title":"A de novo TOP2B variant associated with global developmental delay and autism spectrum disorder","volume":"8","author":"Hiraide","year":"2020","journal-title":"Mol Genet Genomic Med"},{"key":"B12","doi-asserted-by":"publisher","first-page":"3547","DOI":"10.1007\/s10072-020-04600-5","article-title":"West syndrome: a comprehensive review","volume":"41","author":"Pavone","year":"2020","journal-title":"Neurol Sci"},{"key":"B13","doi-asserted-by":"publisher","first-page":"100893","DOI":"10.1016\/j.spen.2021.100893","article-title":"Definitions and diagnostic criteria for infantile spasms and West syndrome\u2014historical perspectives and practical considerations","volume":"38","author":"Mytinger","year":"2021","journal-title":"Semin Pediatr Neurol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1111\/epi.17841","article-title":"Mechanisms of infantile epileptic spasms syndrome: what have we learned from animal models?","volume":"65","author":"Ng","year":"2024","journal-title":"Epilepsia"},{"key":"B15","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1177\/08830738231151993","article-title":"The epilepsy surgery experience in children with infantile epileptic spasms syndrome at a tertiary care center in Canada","volume":"38","author":"Gettings","year":"2023","journal-title":"J Child Neurol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"984","DOI":"10.1111\/epi.17900","article-title":"Timing the clinical onset of epileptic spasms in infantile epileptic spasms syndrome: a tertiary health center\u2019s experience","volume":"65","author":"Hadjinicolaou","year":"2024","journal-title":"Epilepsia"},{"key":"B17","doi-asserted-by":"publisher","first-page":"266","DOI":"10.3390\/genes15030266","article-title":"Genetic advancements in infantile epileptic spasms syndrome and opportunities for precision medicine","volume":"15","author":"Snyder","year":"2024","journal-title":"Genes (Basel)"},{"key":"B18","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1136\/jmg.38.7.488","article-title":"B cell immunodeficiency, distal limb abnormalities, and urogenital malformations in a three generation family: a novel autosomal dominant syndrome?","volume":"38","author":"Edery","year":"2001","journal-title":"J Med Genet"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/00019605-200101000-00001","article-title":"Humoral immunodeficiency with facial dysmorphology and limb anomalies: a new syndrome","volume":"10","author":"Hoffman","year":"2001","journal-title":"Clin Dysmorphol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1111\/j.1399-0004.2004.00349.x","article-title":"Autosomal dominant B-cell immunodeficiency, distal limb anomalies and urogenital malformations (BILU syndrome)\u2014report of a second family","volume":"66","author":"Tischkowitz","year":"2004","journal-title":"Clin Genet"},{"key":"B21","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1002\/ajmg.a.33678","article-title":"Hoffman syndrome: new patients, new insights","author":"H\u00fcgle","year":"2011","journal-title":"Am J Med Genet A"},{"key":"B22","doi-asserted-by":"publisher","first-page":"3644","DOI":"10.1038\/s41467-019-11570-6","article-title":"Mutations in topoisomerase II\u03b2 result in a B cell immunodeficiency","volume":"10","author":"Broderick","year":"2019","journal-title":"Nat Commun"},{"key":"B23","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1007\/s10875-020-00963-8","article-title":"Inherited TOP2B mutation: possible confirmation of mutational hotspots in the TOPRIM domain","volume":"41","author":"Erd\u0151s","year":"2021","journal-title":"J Clin Immunol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1111\/cge.14341","article-title":"Revisiting TOP2B-related phenotypes: three new cases and literature review","volume":"104","author":"\u00c7epni","year":"2023","journal-title":"Clin Genet"},{"key":"B25","doi-asserted-by":"publisher","first-page":"2008","DOI":"10.1002\/1873-3468.13482","article-title":"Mutations in TOP2B cause autosomal-dominant hereditary hearing loss via inhibition of the PI3K-Akt signalling pathway","volume":"593","author":"Xia","year":"2019","journal-title":"FEBS Lett"},{"year":"","key":"B26"},{"year":"","key":"B27"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1016\/j.str.2022.05.009","article-title":"A comprehensive structural analysis of the ATPase domain of human DNA topoisomerase II beta bound to AMPPNP, ADP, and the bisdioxopiperazine, ICRF193","volume":"30","author":"Ling","year":"2022","journal-title":"Structure"},{"key":"B29","doi-asserted-by":"publisher","first-page":"5416","DOI":"10.1093\/nar\/gkf677","article-title":"Characterisation of the DNA-dependent ATPase activity of human DNA topoisomerase IIbeta: mutation of Ser165 in the ATPase domain reduces the ATPase activity and abolishes the in vivo complementation ability","volume":"30","author":"West","year":"2002","journal-title":"Nucleic Acids Res"},{"key":"B30","doi-asserted-by":"publisher","first-page":"20627","DOI":"10.1038\/s41598-022-24883-2","article-title":"Disease-associated H58Y mutation affects the nuclear dynamics of human DNA topoisomerase II\u03b2","volume":"12","author":"Morotomi-Yano","year":"2022","journal-title":"Sci Rep"}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2025.1542268\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T05:32:55Z","timestamp":1751002375000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2025.1542268\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,27]]},"references-count":30,"alternative-id":["10.3389\/fped.2025.1542268"],"URL":"https:\/\/doi.org\/10.3389\/fped.2025.1542268","relation":{},"ISSN":["2296-2360"],"issn-type":[{"type":"electronic","value":"2296-2360"}],"subject":[],"published":{"date-parts":[[2025,6,27]]},"article-number":"1542268"}}