Clinical and molecular characteristics of constitutional mismatch repair deficiency syndrome: a case series of five children and appraisal of diagnostic guidelines

Sep 22, 2026

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DNA mismatch repair (MMR) preserves genome integrity by correcting single-base mismatches and insertion-deletion loops created during replication. Germline heterozygous alterations in MMR genes (MSH2, MSH6, MLH1, PMS2) underlie autosomal dominant Lynch syndrome, typically presenting with colonic or endometrial cancers. Constitutional mismatch repair deficiency (CMMRD) results from biallelic germline changes and usually causes cancer in the first decade. A five-child series describes early cancers, including colonic adenocarcinoma, T-lymphoblastic lymphoma, and high-grade glioma, with assessment of diagnostic guidelines.

LanguageEnglish

CategoryHealthcare

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Pages6

Reading Time15 min

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Abstract

Introduction

Materials and methods

Vazzano Goldstone et al. Diagnostic Pathology (2026) 21:17 [https://doi.org/10.1186/s13000-026-01759-x](https://doi.org/10.1186/s13000-026-01759-x) Diagnostic Pathology REVIEW Open Access Clinical and molecular characteristics of constitutional mismatch repair deficiency syndrome: a case series of five children and appraisal of diagnostic guidelines Jennifer Vazzano Goldstone2, Suzanna J. Logan 1, Benjamin J. Wilkins3, Suzanne P. MacFarland4, Miriam Conces1,2, Daniel R. Boué 1,2, Christopher R. Pierson 1,2,5, Samir Kahwash1,2, Kathleen M. Schieffer2,6, Catherine E. Cottrell2,6, Susan Colace7, Kristin Zajo7 and Archana Shenoy1,2,8* Abstract DNA mismatch repair (MMR) is critical for maintaining genome integrity through correction of single-base mismatches and insertion-deletion loops arising from DNA replication. Heterozygous germline alteration of MMR genes (MSH2, MSH6, MLH1, PMS2) cause autosomal dominant Lynch syndrome (LS), most commonly manifesting as colonic or endometrial cancers, although brain, ovarian, and other organ systems may be involved. Neoplasia in LS usually arises after the age of 30 years. Constitutional mismatch repair deficiency (CMMRD) is inherited in an autosomal recessive manner due to biallelic germline alteration in one of the four MMR genes. Individuals with CMMRD typically develop cancer in the first decade of life, although some may present during the second decade. We present a series of five children who developed cancer prior to the age of 20 years (range: 2–12 years) with malignancies including colonic adenocarcinoma (N = 1), T-lymphoblastic lymphoma (N = 3), and high-grade glioma (N = 4) . Two patients with MSH6 alterations developed a constellation of three primary tumors: high-grade glioma, T-lymphoblastic lymphoma, and colonic neoplasia including colonic adenocarcinoma in one patient and a tubular adenoma in the other. *Correspondence: Archana Shenoy [Archana.Shenoy@cchmc.org](Archana.Shenoy@cchmc.org) 1Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, OH, USA 2Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, USA 3Department of Pathology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA 4Division of Oncology, Department of Pediatrics, Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 5Department of Biomedical Education and Anatomy, The Ohio State University College of Medicine, Columbus, OH, USA 6The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, USA 7Department of Hematology & Oncology, Nationwide Children’s Hospital, Columbus, OH, USA 8Division of Pathology, Cincinnati Children’s Hospital, OHCincinnati, United States © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/licenses/by-nc-nd/4.0/](vecommons.org/licenses/by-nc-nd/4.0/.)[.](vecommons.org/licenses/by-nc-nd/4.0/.) Va

FAQs

What genetic changes define constitutional mismatch repair deficiency (CMMRD)?

CMMRD is inherited autosomal recessively due to biallelic germline alterations in one of four MMR genes: MSH2, MSH6, MLH1, or PMS2.

How does CMMRD typically present compared with Lynch syndrome (LS)?

CMMRD usually leads to cancer in the first decade of life, whereas LS most commonly manifests as colonic or endometrial cancers after about age 30.

What cancers were observed in the five children described in the case series?

The series included colonic adenocarcinoma (N=1), T-lymphoblastic lymphoma (N=3), and high-grade glioma (N=4), including a patient set with three primary tumors among those with MSH6 alterations.

Sep 22, 2026

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