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In 2021, the CNS World Health Organization (WHO) classification drastically changed the diagnosis of the other CNS embryonal tumors including new histo-molecular tumor types. Here, we report a pediatric case of a novel tumor type among the other CNS embryonal tumors classified within the methylation class \u201cCNS Embryonal Tumor with <jats:italic>BRD4\u2013LEUTX<\/jats:italic> Fusion\u201d. The patient was a 4-year girl with no previous history of disease. For a few weeks, she suffered from headaches, vomiting and mild fever associated with increasing asthenia and loss of weight leading to a global deterioration of health. MRI brain examination revealed a large, grossly well-circumscribed tumoral mass lesion located in the left parietal lobe, contralateral hydrocephalus and midline shift. Microscopic examination showed a highly cellular tumor with a polymorphic aspect. The majority of the tumor harbored neuroectodermal features composed of small cells with scant cytoplasm and hyperchromatic nuclei associated with small \u201cmedulloblastoma-like\u201d cells characterized by syncytial arrangement and focally a streaming pattern. Tumor cells were diffusely positive for Synaptophysin, CD56, INI1 and SMARCA4 associated with negativity for GFAP, OLIG-2, EMA, BCOR, LIN28A and MIC-2. Additional IHC features included p53 protein expression in more than 10% of the tumor\u2019s cells and very interestingly, loss of H3K27me3 expression. The Heidelberg DNA-methylation classifier classified this case as \u201cCNS Embryonal Tumor with BRD4:LEUTX Fusion\u201d. RNA-sequencing analyses confirmed the <jats:italic>BRD4 (exon 13)\u2013LEUTX (exon 2)<\/jats:italic> fusion with no other molecular alterations found by DNA sequencing. Our case report confirmed that a new subgroup of CNS embryonal tumor with high aggressive potential, loss of H3K27me3 protein expression, <jats:italic>BRDA4\u2013LEUTX<\/jats:italic> fusion, named \u201cEmbryonal CNS tumor with <jats:italic>BRD4\u2013LEUTX<\/jats:italic> fusion\u201d<jats:italic>,<\/jats:italic> has to be considered into the new CNS WHO classification.<\/jats:p>","DOI":"10.1186\/s40478-023-01549-2","type":"journal-article","created":{"date-parts":[[2023,3,26]],"date-time":"2023-03-26T20:54:54Z","timestamp":1679864094000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Clinicopathological and molecular characterization of a case classified by DNA\u2011methylation profiling as \u201cCNS embryonal tumor with BRD4\u2013LEUTX fusion\u201d"],"prefix":"10.1186","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5663-8180","authenticated-orcid":false,"given":"Laetitia","family":"Lebrun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sacha","family":"Allard-Demoustiez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Gilis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claude","family":"Van Campenhout","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marine","family":"Rodesch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celine","family":"Roman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierluigi","family":"Cal\u00f2","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Lolli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"David","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Fricx","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"De Witte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabienne","family":"Escande","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claude-Alain","family":"Maurage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Salmon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,3,18]]},"reference":[{"key":"1549_CR1","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1111\/his.14217","volume":"78","author":"S Alexandrescu","year":"2021","unstructured":"Alexandrescu S, Meredith DM, Lidov HG, Alaggio R, Novello M, Ligon KL, Vargas SO (2021) Loss of histone H3 trimethylation on lysine 27 and nuclear expression of transducin-like enhancer 1 in primary intracranial sarcoma, DICER1-mutant. 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The ethical committee thus waived the requirement for written informed consent from the participants.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"46"}}