Constitutional Mismatch Repair Deficiency, the Most Aggressive Cancer Predisposition Syndrome - Clinical Presentation, Surveillance, and Management

Sep 23, 2026

Constitutional mismatch repair deficiency (CMMRD) is a rare, highly aggressive autosomal recessive cancer predisposition syndrome caused by biallelic germline mutations in mismatch repair genes. Early-onset malignancies across multiple organs are driven by hypermutation and microsatellite instability, producing a high tumor mutation burden and enabling responsiveness to immune checkpoint inhibitors targeting PD-1/PD-L1. Advances in genetic and molecular diagnostics allow earlier identification, supporting comprehensive, multidisciplinary surveillance and individualized management to improve outcomes and quality of life.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages11

Reading Time28 min

AccessFree to download

Overview of Constitutional Mismatch Repair Deficiency (CMMRD) Syndrome

Role of DNA replication fidelity and mismatch repair

Genetic cause and tumor biology (TMB/MSI)

Clinical relevance to immune checkpoint inhibitor therapy

Review Article J Korean Neurosurg Soc 68 (3) : 294-304, 2025 [https://doi.org/10.3340/jkns.2025.0024](https://doi.org/10.3340/jkns.2025.0024) pISSN 2005-3711 eISSN 1598-7876 Constitutional Mismatch Repair Deficiency, the Most Aggressive Cancer Predisposition Syndrome: Clinical Presentation, Surveillance, and Management Eungu Kang,1 Jin Kyung Suh,2 Sang-Dae Kim3 Department of Pediatrics,1 Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea Department of Pediatrics, 2 Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Department of Neurosurgery, 3 Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea Constitutional mismatch repair deficiency (CMMRD) is a rare and highly aggressive cancer predisposition syndrome caused by biallelic germline mutations in mismatch repair genes. This condition is characterized by early-onset malignancies across multiple organ systems, including central nervous system tumors, hematological cancers, and gastrointestinal malignancies. CMMRD-associated tumors exhibit hypermutation and microsatellite instability, resulting in a high tumor mutation burden and rendering these malignancies responsive to immune checkpoint inhibitors (ICIs). ICIs targeting programmed cell death protein-1 and programmed cell death ligand 1 have demonstrated remarkable efficacy, particularly in hypermutated tumors, providing durable responses and improving survival outcomes. Advances in genetic and molecular diagnostics have enhanced the ability to identify CMMRD early, allowing for the implementation of comprehensive surveillance programs and improved management strategies. A multidisciplinary and individualized approach is essential for managing CMMRD patients. This review underscores the importance of early diagnosis, surveillance, and emerging therapeutic approaches to improve outcomes and quality of life for individuals and families affected by this devastating syndrome. KeyWords : Neoplastic syndromes · Hereditary · DNA mismatch repair · Brain neoplasms. OVERVIEW OF CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY (CMMRD) SYNDROME DNA polymerase enzymes facilitate DNA replication during the S-phase of the cell cycle, a process that, despite its remarkable efficiency, is inherently prone to errors35). During replication, two primary types of errors can occur : single-nucleotide variations, resulting from incorrect base incorporation, and insertions or deletions (indels), often caused by polymerase slippage. This slippage is particularly frequent in repetitive genomic segments known as microsatellites8,31). Replication fidelity, which is essential for maintaining genomic stability and preventing mutations that contribute to cancer and other genetic disorders, is governed by several mechanisms (Fig. 1). These in- • Received : January 21, 2025 • Revised : April 15, 2025 •Accepted : April 20, 2025 •Address for correspondence : Sang-Dae Kim Division of Brain Tumor and Pediatric Neurosurgery, Department of Neurosurgery, Korea University Ansan Hospital, 123 Jeokgeum-ro, Danwon-gu, Ansan 15355, Korea Tel : +82-31-412-5053, Fax : +82-31-412-5054, [E-mail : neuron19@korea.ac.kr](E-mail : neuron19@korea.ac.kr), ORCID : [https://orcid.org/0000-0002-1519-9687](https://orcid.org/0000-0002-1519-9687) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ([http://creativecommons.org/licenses/by-nc/4.0](http://creativecommons.org/licenses/by-nc/4.0)) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 294 Copyright © 2025 The Korean Neurosurgical Society CMMRD | Kang E, et al. POLE DNA polymerase proofreading PMS2 MLH1 MSH6 MSH2 POLD1 Mismatch repair system correcting point mutations/single nucleotide variants (SNVs), and small insertion-deletion Fig. 1. Poly

FAQs

What causes constitutional mismatch repair deficiency (CMMRD)?

CMMRD is caused by biallelic germline mutations in mismatch repair genes (MLH1, MSH2, MSH6, or PMS2), leading to loss of mismatch repair function and genomic instability.

How do CMMRD tumors develop hypermutation and microsatellite instability?

Defective mismatch repair fails to correct base-base mismatches and small insertion-deletion loops during replication, especially in microsatellite regions, resulting in high tumor mutation burden and microsatellite instability.

Why are immune checkpoint inhibitors (ICIs) effective in some CMMRD patients?

Hypermutated mismatch repair–deficient tumors generate immunogenic neoantigens, making them responsive to ICIs targeting PD-1 and PD-L1 and potentially providing durable clinical benefit.

Sep 23, 2026

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