CMMRD
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
Inheritance:
- Autosomal recessive
Prevalence:
- 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.
Follow-up:
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) |
Literature:
- 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
- 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