{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:28Z","timestamp":1787028448333,"version":"build-2736575974"},"reference-count":82,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,4,28]],"date-time":"2021-04-28T00:00:00Z","timestamp":1619568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Conselleria d'Empresa i Coneixement de la Generalitat de Catalunya","award":["2017SGR1080 373 and 2017SGR1282"],"award-info":[{"award-number":["2017SGR1080 373 and 2017SGR1282"]}]},{"name":"Ministerio de Espa\u00f1a de Econom\u00eda y Competitividad y FEDER","award":["SAF2015-68016-R and PID2019-111254RB-I00"],"award-info":[{"award-number":["SAF2015-68016-R and PID2019-111254RB-I00"]}]},{"name":"la Caixa\u201d Banking Foundation","award":["LCF\/PR\/GN18\/51140001"],"award-info":[{"award-number":["LCF\/PR\/GN18\/51140001"]}]},{"name":"CIBERONC, MCIU\/AEI\/FEDER, UE","award":["RTI2018-094049-B-I00 and SAF2014-55000"],"award-info":[{"award-number":["RTI2018-094049-B-I00 and SAF2014-55000"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Biallelic germline mismatch repair (MMR) gene (MLH1, MSH2, MSH6, and PMS2) mutations are an extremely rare event that causes constitutional mismatch repair deficiency (CMMRD) syndrome. CMMRD is underdiagnosed and often debuts with pediatric malignant brain tumors. A high degree of clinical awareness of the CMMRD phenotype is needed to identify new cases. Immunohistochemical (IHC) assessment of MMR protein expression and analysis of microsatellite instability (MSI) are the first tools with which to initiate the study of this syndrome in solid malignancies. MMR IHC shows a hallmark pattern with absence of staining in both neoplastic and non-neoplastic cells for the biallelic mutated gene. However, MSI often fails in brain malignancies. The aim of this report is to draw attention to the peculiar IHC profile that characterizes CMMRD syndrome and to review the difficulties in reaching an accurate diagnosis by describing the case of two siblings with biallelic MSH6 germline mutations and brain tumors. Given the difficulties involved in early diagnosis of CMMRD we propose the use of the IHC of MMR proteins in all malignant brain tumors diagnosed in individuals younger than 25 years-old to facilitate the diagnosis of CMMRD and to select those neoplasms that will benefit from immunotherapy treatment.<\/jats:p>","DOI":"10.3390\/ijms22094629","type":"journal-article","created":{"date-parts":[[2021,4,28]],"date-time":"2021-04-28T10:41:58Z","timestamp":1619606518000},"page":"4629","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["The Challenge of Diagnosing Constitutional Mismatch Repair Deficiency Syndrome in Brain Malignancies from Young Individuals"],"prefix":"10.3390","volume":"22","author":[{"given":"Cristina","family":"Carrato","sequence":"first","affiliation":[{"name":"Department of Pathology, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Sanz","sequence":"additional","affiliation":[{"name":"Department of Pathology, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Mar\u00eda","family":"Mu\u00f1oz-M\u00e1rmol","sequence":"additional","affiliation":[{"name":"Department of Pathology, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignacio","family":"Blanco","sequence":"additional","affiliation":[{"name":"Program on Clinical Genetics and Genetic Counseling, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Pineda","sequence":"additional","affiliation":[{"name":"Hereditary Cancer Program, ONCOBELL Program, Hospitalet de Llobregat, Catalan Institute of Oncology, Institut d\u2019Investigaci\u00f3 Biom\u00e8dica de Bellvitge (IDIBELL), 08908 L\u2019Hospitaled de Liobregat, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer (CIBERONC), 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3607-7045","authenticated-orcid":false,"given":"Jes\u00fas","family":"Del Valle","sequence":"additional","affiliation":[{"name":"Hereditary Cancer Program, ONCOBELL Program, Hospitalet de Llobregat, Catalan Institute of Oncology, Institut d\u2019Investigaci\u00f3 Biom\u00e8dica de Bellvitge (IDIBELL), 08908 L\u2019Hospitaled de Liobregat, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer (CIBERONC), 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9650-7791","authenticated-orcid":false,"given":"Estela","family":"D\u00e1maso","sequence":"additional","affiliation":[{"name":"Hereditary Cancer Program, ONCOBELL Program, Hospitalet de Llobregat, Catalan Institute of Oncology, Institut d\u2019Investigaci\u00f3 Biom\u00e8dica de Bellvitge (IDIBELL), 08908 L\u2019Hospitaled de Liobregat, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manel","family":"Esteller","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer (CIBERONC), 28040 Madrid, Spain"},{"name":"Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain"},{"name":"Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), 08007 Barcelona, Spain"},{"name":"Instituci\u00f3 Catalana de Recerca i Estudis Avan\u00e7ats (ICREA), 08010 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Musulen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain"},{"name":"Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain"},{"name":"Department of Pathology, Hospital Universitari General de Catalunya-Grupo Quir\u00f3nSalud, 08195 Sant Cugat del Vall\u00e8s, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,28]]},"reference":[{"key":"ref_1","first-page":"290","article-title":"Human MLH1 deficiency predispones to hematological malignancy and neurofibromatosis type 1","volume":"59","author":"Ricciardone","year":"1999","journal-title":"Cancer Res."},{"key":"ref_2","first-page":"294","article-title":"Neurofibromatosis and early onset of cancers in hMLH1-deficient children","volume":"59","author":"Wang","year":"1999","journal-title":"Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1136\/jmedgenet-2014-102284","article-title":"EU-consortium care for CMMRD (C4CMMRD). 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