Constitutional Mismatch Repair Deficiency
Expert Opinion

Diagnostic criteria:

  • Detection of bi-allelic mutation in one of the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6 or PMS2)
  • Suspicion of CMMRD: score >3 points (see Table 1)

Table 1: Criteria for CMMRD testing in cancer patients

Malignancies/premalignancies: one is mandatory; if more than one is present in the patient, add the points
Carcinoma from the LS spectrum* at age <25 years 3 points
Multiple bowel adenomas at age <25 years and absence of APC/MUTYH mutation(s) or a single high-grade dysplasia adenoma at age <25 years 3 points
WHO grade III or IV glioma at age <25 years 2 points
NHL of T-cell lineage or sPNET at age <18 years 2 points
Any malignancy at age <18 years 1 point
Additional features: optional; if more than one of the following is present, add the points
Clinical sign of NF1 and/or ≥2 hyperpigmented and/or hypopigmented skin alterations Ø>1 cm in the patient 2 points
Diagnosis of LS in a first-degree or second-degree relative 2 points
Carcinoma from LS spectrum* before the age of 60 in first-degree, second-degree, and third-degree relative 1 point
A sibling with carcinoma from the LS spectrum*, high-grade glioma, sPNET or NHL 1 point
A sibling with any type of childhood malignancy 1 point
Multiple pilomatricomas in the patient 1 point
One pilomatricoma in the patient 1 point
Agenesis of the corpus callosum or non-therapy-induced cavernoma in the patient 1 point
Consanguineous parents 1 point
Deficiency/reduced levels of IgG2/4 and/or IgA 1 point

*  Colorectal, endometrial, small bowel, ureter, renal pelvis, biliary tract, stomach, bladder carcinoma

CMMRD, constitutional mismatch repair deficiency; LS, Lynch syndrome; NHL, non-Hodgkin’s lymphomas; sPNET, supratentorial primitive neuroectodermal tumours


  • Autosomal recessive


  • rare

Clinical features:

  • Very high risk of developing brain tumor usually <10 years
  • Very high risk of digestive tract tumor (high risk of tumor in the colorectal carcinoma of the tract but also duodenal carcinoma) usually between 10 and 30 years
  • high risk of developing a hematologic malignancy (esp. Non-Hodgkin lymphoma and leukemia) usually <10 years
  • increased risk of Lynch syndrome associated tumors such as endometrial carcinoma and urinary tract tumors in young adulthood
  • Skin characteristics:
    • café au lait maculae (CALM) which often have irregular edges and may have different intensities of pigmentation and thus can be distinguished from the the cafe-au-lait macules of Neurofibromatosis Type 1
    • Hypopigmentations, axillary freckling, neurofibromas and Lisch nodules are also described

Other characteristics (rare)

  • Agenesis of the corpus callosum (ACC) and grey matter heterotopias
  • Immunodeficiency: IgA-deficiency, IgG2/4-deficiency
  • lupus erythematosus
  • Multiple pilomatricomas
  • Multiple cavernomas
  • Increased risk of multiple tumors (synchronous and metachronous)

Genetic basis:
Homozygote or compound heterozygote mutation in one of the DNA mismatch repair (MMR) genes: MLH1, MSH2 (also EPCAM deletions), MSH6 and PMS2.

Frequent cause is mutation in PMS2, ~50%

Indication for referral to Clinical Genetics for counseling and DNA diagnostics:
See table 1

DNA Diagnostics:
In patients suspected of CMMRD based on the above-mentioned criteria:

  • immunohistochemistry (IHC) of the MMR proteins in tumor material and normal tissue
  • Depending on the IHC outcome, sequencing of the MMR genes. In very strong clinical suspicion (eg, (atypical) café-au-lait maculae in child with cancer typical of CMMRD), sequencing of the MMR genes in patients with normal immunohistochemistry results, starting with PMS2
  • In case of hematological malignancy where lHC is not possibly, then IHC on the other available solid tissue or skin biopsy, or directly perform MMR gene analysis, starting with PMS2
  • MSI analysis is a low-sensitivity test for CMMRD especially for brain tumors
  • If mutations are known: pre-symptomatic DNA testing after counseling by a clinical geneticist with support from a psychosocial worker

Periodic examination:
See table 2.
In research settings and after discussing the advantages and disadvantages thoroughly.

Policy and follow-up of the mutation carriers in a multi-disciplinary setting (pediatric oncologist, pediatric gastroenterologist, clinical geneticists)

Table 2: Surveillance protocol for patients with CMMR-D proposed by the European consortium

Type of cancer Lower age limit Procedure/interval
brain tumours from age 2 yrs MRI, 1x/6-12 months
small bowel cancer from age 10 yrs VCE, Upper GI endoscopy1; 1x/yr
colorectal cancer from age 8 yrs Ileo-Colonoscopy; 1x/yr;


NHL/other lymphoma from age 1 yr Clinical examination 1x/6 months;

Optional: abdominal US 1x/6 months

Leukaemia from age 1 yr Blood count 1x/6 months
Lynch syndrome-associated cancers from age 20 yrs Gynaecologic examination, Transvaginal US, Pipelle curettage (1x/yr),

urine cytology, dipstick (1x/yr)



  1. Wimmer K, Kratz CP, Vasen HF et al. Diagnostic criteria for constitutional mismatch repair de ciency syndrome: suggestions of the European consortium ‘care for CMMRD’ (C4CMMRD). J Med Genet 2014; 51: 355-65
  2. Vasen HF, Ghorbanoghli Z, Bourdeaut F et al. Guidelines for surveillance of individuals with constitutional mismatch repair- de ciency proposed by the European Consortium ‘Care for CMMR-D’ (C4CMMR-D). J Med Genet 2014; 51: 283-93