952ec18990a630818e861b8418d3e584 ijms-22-04629.pdf 71691d3054b7ef0a91daf2c896359431238d3bae ijms-22-04629.pdf 60dd2b57500832fb60063f5198f5a75f6a5f4e9bfcc85f543fbd278ae88c2b8c ijms-22-04629.pdf Title: The Challenge of Diagnosing Constitutional Mismatch Repair Deficiency Syndrome in Brain Malignancies from Young Individuals Subject: 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. Keywords: constitutional mismatch repair deficiency syndrome; MMR gene expression; immunohistochemistry; MSH6 gene Author: Cristina Carrato, Carolina Sanz, Ana María Muñoz-Mármol, Ignacio Blanco, Marta Pineda, Jesús Del Valle, Estela Dámaso, Manel Esteller and Eva Musulen Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Apr 28 10:08:52 2021 CEST ModDate: Wed Apr 28 10:13:32 2021 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 20 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1966403 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- YFNERV+VnURWPalladioL Type 1 Custom yes yes no 10 0 JJTJXH+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 INBUWY+URWPalladioL-Bold Type 1 Custom yes yes no 20 0 ONHVOZ+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 JGBJTI+VnURWPalladioL-Bold Type 1 Custom yes yes no 28 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 36 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 39 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 61 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 65 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 69 0 NUZJWF+CMSY10 Type 1 Builtin yes yes no 81 0 QVIYXW+URWPalladioL-BoldItal Type 1 Custom yes yes no 88 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 100 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 104 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 108 0 ABCDEE+Palatino Linotype CID TrueType Identity-H yes yes yes 112 0 RHFKGB+EURM10 Type 1 Builtin yes yes no 124 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 132 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 136 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 140 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 153 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 157 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 161 0 ABCDEE+Palatino Linotype CID TrueType Identity-H yes yes yes 165 0 NUUXUW+VnURWPalladioL-Italic Type 1 Custom yes yes no 201 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-06-28 02:30:07 CEST RepresentationInformation: ijms-22-04629.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-01-24 19:13:09 CET Size: 1966403 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 520 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Cases Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Immunohistochemical Analysis of MMR Proteins Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: MSI Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Germline Mutation Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Somatic Mutational Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Brain Tumors in CMMRD Syndrome Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Material and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Children: Item: Title: Immunohistochemical Analysis of MMR Proteins Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: MSI Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Germline MSH6 Mutational Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Targeted Next Generation Sequencing Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Info: Title: The Challenge of Diagnosing Constitutional Mismatch Repair Deficiency Syndrome in Brain Malignancies from Young Individuals Author: Cristina Carrato, Carolina Sanz, Ana María Muñoz-Mármol, Ignacio Blanco, Marta Pineda, Jesús Del Valle, Estela Dámaso, Manel Esteller and Eva Musulen Subject: 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. 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Annotation: Subtype: Link Rect: 447, 445, 484, 456 Annotation: Subtype: Link Rect: 491, 445, 527, 456 Annotation: Subtype: Link Rect: 271, 410, 308, 421 Annotation: Subtype: Link Rect: 118, 377, 155, 387 Annotation: Subtype: Link Rect: 161, 377, 197, 387 Annotation: Subtype: Link Rect: 364, 341, 401, 352 Annotation: Subtype: Link Rect: 408, 341, 444, 352 Annotation: Subtype: Link Rect: 459, 307, 497, 318 Annotation: Subtype: Link Rect: 175, 284, 212, 295 Annotation: Subtype: Link Rect: 59, 250, 97, 260 Annotation: Subtype: Link Rect: 340, 215, 378, 226 Annotation: Subtype: Link Rect: 368, 180, 406, 191 Annotation: Subtype: Link Rect: 412, 180, 448, 191 Annotation: Subtype: Link Rect: 172, 146, 210, 157 Annotation: Subtype: Link Rect: 216, 146, 252, 157 Checksum: 31a9e9f2 Type: CRC32 Checksum: 952ec18990a630818e861b8418d3e584 Type: MD5 Checksum: 71691d3054b7ef0a91daf2c896359431238d3bae Type: SHA-1