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The most common CMMRD-associated malignancies are brain tumors; an accurate diagnosis is challenging when a malignant brain tumor is the only tumor at presentation. We describe two cases of glioblastoma as the initial CMMRD malignancy and discuss current diagnostic and therapeutic challenges.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Case presentation<\/jats:title>\n                <jats:p>Two children with brain tumors without remarkable family history had biallelic pathogenic germline variants in <jats:italic>PMS2<\/jats:italic>. Patient 1: A 6-year-old girl presented biallelic <jats:italic>PMS2<\/jats:italic> germline pathogenic variants. Glioblastomas at the left frontal lobe and right temporal lobe were resistant to immune-checkpoint inhibitor, temozolomide, and bevacizumab. Patient 2: A 10-year-old boy presented biallelic <jats:italic>PMS2<\/jats:italic> germline variants. His glioblastoma with primitive neuroectodermal tumor-like features responded to chemoradiotherapy, but he developed advanced colon cancer and acute lymphocytic leukemia. In both patients, only a monoallelic <jats:italic>PMS2<\/jats:italic> germline variant was detected by conventional gene tests. PMS2 immunohistochemistry showed lack of staining at both the tumors and normal tissue as vascular endothelial cells. Further gene tests revealed large genomic deletion including the entire <jats:italic>PMS2<\/jats:italic> gene, confirming biallelic <jats:italic>PMS2<\/jats:italic> germline variants.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Conventional multi-gene panel tests are insufficient for detecting large deletions of MMR genes, resulting in misdiagnoses of CMMRD as Lynch syndrome. <jats:italic>PMS2<\/jats:italic> variants have low cancer penetrance; family histories may thus be absent. Long-range gene analyses or immunohistochemical staining of MMR proteins in normal tissue should be considered for pediatric brain tumors with a single allele MMR variant when CMMRD is suspected.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12920-022-01403-9","type":"journal-article","created":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T13:03:33Z","timestamp":1673874213000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Diagnostic and therapeutic challenges of glioblastoma as an initial malignancy of constitutional mismatch repair deficiency (CMMRD): two case reports and a literature review"],"prefix":"10.1186","volume":"16","author":[{"given":"Shumpei","family":"Onishi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fumiyuki","family":"Yamasaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuya","family":"Kuraoka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akira","family":"Taguchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Takayasu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiwamu","family":"Akagi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0462-6177","authenticated-orcid":false,"given":"Takao","family":"Hinoi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,1,16]]},"reference":[{"key":"1403_CR1","doi-asserted-by":"publisher","first-page":"319","DOI":"10.3340\/jkns.2018.0031","volume":"61","author":"O Michaeli","year":"2018","unstructured":"Michaeli O, Tabori U. 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