Constitutional mismatch repair deficiency syndrome

Updated April 12, 2025

What's new

Added 2024 ERN GENTURIS guidelines for the diagnosis and management of constitutional mismatch repair deficiency syndrome .

Background

Overview

Definition

CMMRD syndrome is a rare, autosomal recessive genetic disorder caused by biallelic mutations in one of the MMR genes associated with a high and lifelong risk of cancer, particularly in children and young adults.

Pathophysiology

CMMRD is caused by homozygous or compound heterozygous pathogenic germline variants in one of four MMR genes (MLH1, MSH2, MSH6, and PMS2), while mono-allelic MMR gene variants result in autosomal dominant Lynch syndrome. These genes are crucial for correcting DNA replication errors, and their deficiency leads to widespread genomic instability, a key factor in the development of malignancies associated with CMMRD.

Risk factors

Risk factors include a family history of Lynch syndrome or childhood malignancy.

Disease course

Patients with CMMRD are predisposed to a variety of malignancies, including brain tumors, digestive tract tumors, and hematological malignancies. Additionally, CMMRD is associated with non-neoplastic manifestations, including café-au-lait maculas, other hypo- and hyperpigmented skin patches, and multiple brain developmental venous anomalies.

Guidelines

Key sources

The following summarized guidelines for the evaluation and management of constitutional mismatch repair deficiency syndrome are prepared by our editorial team based on guidelines from the European Reference Network on GENetic TUmour RIsk Syndromes (ERN GENTURIS 2024).

Screening and diagnosis

Indications for testing: as per ERN GENTURIS 2024 guidelines, offer CMMRD testing in all patients with cancer achieving a minimum of 3 scoring points according to the revised C4CMMRD indication criteria.

Show 5 more

Revised European Consortium Care for Constitutional Mismatch Repair Deficiency (C4CMMRD) Indication Criteria

Calculator

When to use

Pre-malignancies or malignancies in the patient

Carcinoma of the Lynch syndrome spectrum and/or a high-grade dysplastic adenoma of the digestive tract at age < 25 years

Multiple colorectal adenomas at age < 25 years and no genetic diagnosis/explanation upon testing for polyposis syndromes

T-cell lymphoblastic lymphoma at age < 18 years

World Health Organization grade III or IV glioma at age < 25 years

Any other malignancy at age < 18 years

Hypo-/hyperpigmentations in the patient (optional)

Clinical sign of neurofibromatosis type 1 and/or ≥ 4 hyperpigmented and/or hypopigmented skin alterations with a diameter > 1 cm

2 or 3 hyperpigmented and/or hypopigmented skin alterations with a diameter > 1 cm

Pilomatrixomas in the patient (optional)

Multiple pilomatrixomas

One pilomatrixoma

Additional features in the patient (optional)

Agenesis of the corpus callosum

Non-therapy-induced cavernoma

Multiple developmental venous anomalies cerebral venous angiomas) in separate regions of the brain

Pediatric systemic lupus erythematosus

Deficiency/reduced levels of immunoglobulin G 2/4 and/or immunoglobulin A

Additional features in the family (optional)

Consanguineous parents

Diagnosis of Lynch syndrome in a first-degree or second-degree relative

Carcinoma from Lynch syndrome spectrum before the age of 60 years in a first-degree, second-degree, and/or third-degree relative

A sibling with a pre-malignancy or malignancy assigned 2 or 3 C4CMMRD scoring points any of the first four conditions in the first secton above)

A sibling with any type of childhood malignancy

Calculation

Please enter all the required inputs.

The Revised European Consortium Care for Constitutional Mismatch Repair Deficiency (C4CMMRD) Indication Criteria is a clinical calculator used in the field of oncology, specifically for pediatric patients. This scoring system is designed to identify patients who are likely to have Constitutional Mismatch Repair Deficiency (CMMRD), a rare autosomal recessive disorder that predisposes individuals to a variety of cancers at a young age. The C4CMMRD Indication Criteria is used to determine the need for genetic testing for CMMRD in children and adolescents who present with certain types of cancers, or who have a family history of these cancers. The criteria include factors such as the type and number of cancers, age at diagnosis, presence of certain clinical features, and family history of cancer or CMMRD. The clinical utility of this calculator is to aid in the early identification of CMMRD, allowing for appropriate genetic counseling, surveillance for additional cancers, and potentially life-saving interventions. There are no specific exclusion criteria for the use of the C4CMMRD Indication Criteria, but it is primarily intended for use in pediatric and adolescent patients. It may not be as useful or accurate in adults or in individuals without a family history of cancer or CMMRD.

Create free account

Medical management

General principles: as per ERN GENTURIS 2024 guidelines, offer a curative treatment approach in patients with CMMRD diagnosed with cancer.

Show 6 more

Create free account

Nonpharmacologic interventions

Psychological support

As per ERN GENTURIS 2024 guidelines:

Offer psychological support to patients and their families throughout the evaluation process before diagnosing CMMRD, as well as during treatment and surveillance.

Offer age-adapted education about CMMRD to patients and their families.

Create free account

Patient education

General counseling

As per ERN GENTURIS 2024 guidelines:

Educate patients with CMMRD and/or their parents about the tumor risks associated with CMMRD.

Educate patients with CMMRD and/or their parents about symptoms related to the main tumors, particularly dyspnea and superior vena cava syndrome for mediastinal lymphomas, symptoms associated with pancytopenia for leukemia, neurological symptoms for brain tumors, and bleeding for colorectal tumors.

Create free account

Follow-up and surveillance

Surveillance for malignancy, general principles: as per ERN GENTURIS 2024 guidelines, discuss the pros and cons with patients with CMMRD and/or their parents to make a joint decision regarding participation in a surveillance program.

Show 5 more

Create free account

Quality improvement

Requirements for laboratories

As per ERN GENTURIS 2024 guidelines:

Ensure the laboratory performing genetic CMMRD testing offers transcript analysis of all four MMR genes and apply assays circumventing potential diagnostic pitfalls resulting from the high homology of PMS2 and its pseudogene PMS2CL, either through partnership with a different laboratory or within their own laboratory.

Ensure the laboratory performing genetic CMMRD testing of an index patient with or without a (pre-)malignancy has one or more validated ancillary assays available, either through partnership with a different laboratory or within their own laboratory, to definitively confirm or refute the diagnosis of CMMRD if genetic testing yields an inconclusive result.

Create free account