Constitutional Mismatch Repair Deficiency – Definition
Constitutional mismatch repair deficiency (CMMRD; OMIM #276300) results from biallelic pathogenic germline variants of mismatch repair genes and is a rare, highly aggressive cancer predisposition syndrome that leads to malignancies in childhood and predisposes to leukemias or lymphomas, brain tumors, Lynch syndrome-associated tumors and other neoplasms. In addition, germline deletions in the EPCAM gene (upstream of the MSH2 gene) can also lead to hypermethylation of the MSH2 promoter and, consequently, to the absence of MSH2, thus triggering CMMRD.
Synonyme:
Constitutional mismatch repair deficiency
Gene:
MSH2, MSH6, MLH1, PMS2 (mismatch repair genes, MMR genes),
TACSTD1 (EPCAM gene)
Gene products:
MSH2, MSH6, MLH1, PMS2 (mismatch repair proteins),
EPCAM
Function:
Correction of incorrectly replicated base pairs and small insertions/deletions in the DNA
Pattern of inheritance:
autosomal recessive
Prevalence:
unknown, the incidence is higher in regions with a high consanguinity rate
Genotype-phenotype correlation:
Not yet fully understood. Biallelic pathogenic germline variants of the MMR genes often show the phenotypic picture of neurofibromatosis type 1, associated with various childhood cancers.
Pathogenic variants in MSH6 and PMS2 are significantly more frequent and lead to a different clinical picture than pathogenic variants in MLH1 and MSH2. The latter lead more frequently to hematologic cancers and the average age at first cancer diagnosis is lower than for carriers of biallelic pathogenic variants in MSH6 or PMS2. Patients with pathogenic variants in MSH6 or PMS2 are particularly prone to Lynch syndrome (LS)-associated cancers and brain tumors and usually develop another cancer after surviving the first one.
Due to the low monoallelic penetrance of PMS2 and MSH6 , affected children often have unaffected parents, even though they are carriers of the defective gene.
Penetrance:
Extremely high; most children do not reach adulthood.
Long-term observations with significantly more patients are required for more precise information.
Constitutional Mismatch Repair Deficiency – Diagnosis
The diagnosis of CMMRD should be considered in cancer patients who have one or more of the following features at the same time:
- Café-au-lait spots and/or other NF1-typical skin changes and/or hypopigmented skin lesions
- Consanguineous parents
- Positive family history of LS-associated tumors
- Second cancer
- Sibling with childhood cancer
Diagnostic protocol of “Care for CMMRD (C4CMMRD)”
The European consortium “Care for CMMRD (C4CMMRD)” has also developed a diagnostic protocol according to which the presence of CMMRD is suspected if 3 or more points are present. If more than one of the following diseases or characteristics is present, the corresponding points must be added together.
Cancer Diseases / Previous Cancer Diseases: One is Mandatory
| LS-associated tumors aged <25 years | 3 pts. |
| Multiple adenomas of the intestine aged <25 years without APC/MUTYH mutation(s) or single adenoma with high-grade dysplasia aged <25 years |
3 pts. |
| Glioma WHO grade III or IV aged <25 years | 2 pts. |
| NHL of the T-line or sPNET | 2 pts. |
| Any cancer at the age of <18 years | 1 pt. |
Abbreviations in the table: LS, Lynch syndrome; NHL, non-Hodgkin’s lymphoma; sPNET, supratentorial primitive neuroectodermal tumor; NF1, neurofibromatosis type 1
Additional Features: Optional
| Clinical signs of NF1 and/or ≥2 hyperpigmented and/or hypopigmented Skin changes Ø >1cm on the patient |
2 pts. |
| Presence of LS in a first- or second-degree relative | 2 pts. |
| Cancer from the LS spectrum* aged <60 years in a first-, second- or third-degree relative | 1 pt. |
| Sibling with cancer from the LS spectrum*, high-grade glioma, sPNET or NHL | 2 pts. |
| Sibling with any type of childhood cancer | 1 pt. |
| Multiple pilomatrixomas on the patient | 2 pts. |
| One pilomatrixoma on the patient | 1 pt. |
| Corpus callosum agenesis or non-therapy-induced cavernoma in the patient | 1 pt. |
| Consanguine parents of the patient | 1 pt. |
| Absence/reduced levels of Ig2/4 and/or IgA | 1 pt. |
*Colorectal carcinoma, endometrial, small intestine, ureter, renal pelvis, bile duct, stomach, bladder carcinoma
Abbreviations in the table: LS, Lynch syndrome; NHL, non-Hodgkin’s lymphoma; sPNET, supratentorial primitive neuroectodermal tumor; NF1, neurofibromatosis type 1
Genetic Diagnostics
Immunohistochemistry of mismatch repair proteins in tumor material, hematological cancers, or healthy individuals with suspected CMMRD from a skin biopsy. The protein that is difficult to stain is the protein that may carry a pathogenic variant.
One peripheral blood screening method is the gMSI test. This test is offered in special laboratories (e.g., Prof. Wimmer in Innsbruck) and is suitable for rapid screening for defects in MSH2, MLH1, and PMS2. MSH6 defects escape this method, but screening methods are also being developed here.
The diagnosis should be verified by a mutation analysis of the four MMR genes. This allows both homozygous and heterozygous carriers of the pathogenic variant to be identified.
Differential Diagnoses
- Lynch syndrome
- Neurofibromatosis type 1
Clinical Presentation
CMMRD is characterized by the early onset of cancer in childhood or young adulthood, with the average age at first cancer being 7.5 years. The average survival after diagnosis of the first cancer is 30 months.
Hematologic Cancers
(average age at first diagnosis 6.6 years)
- NHL, especially T-lymphoblastic NHL and other lymphomas
- Acute lymphoblastic leukemia (ALL), especially T-cell ALL
- Acute myeloid leukemia (AML)
- Atypical chronic myeloid leukemia
Brain Tumors
(average age at first diagnosis 10.3 years)
- Glioblastoma and other astrocytic tumors
- Supratentorial primitive neuroectodermal tumor
- Medulloblastoma
Lynch Syndrome-Associated Cancers
- Colorectal carcinoma
- Small bowel carcinoma
- Endometrial/ovarian carcinoma
- Ureteral/renal pelvis carcinoma
Other
- Sarcomas (osteosarcoma, rhabdomyosarcoma)
- Neuroblastoma
- Wilms tumor
- Infantile myofibromatosis
- Breast carcinoma
- Primitive neuroectodermal tumor of the ovary
Special Features of Treatment
To date, there is no standardized procedure for treating CMMRD patients. In contrast to other syndromes with defective DNA repair, no increased cytotoxicity has been observed in CMMRD due to radio- or chemotherapy. However, the existing resistance to therapy when using cytostatic drugs such as mercaptopurine and temozolomide, which use an adequate mismatch repair system to exert their effect, should be noted. Alkylating substances or anthracyclines, on the other hand, have no limited efficacy and can be considered for the treatment of patients with CMMRD.
Furthermore, significant effects have been achieved in individual cases in the treatment of recurrent glioblastomas using immune checkpoint inhibitors.
Consulting
Parents of affected children should be offered genetic counseling, with a recurrence risk of 25% if both parents are tested heterozygous. In addition, genetic testing and the associated genetic counseling of all family members should be reconsidered.
Diagnosis of Constitutional Mismatch Repair Deficiency- What's Next?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Diagnosis of Constitutional Mismatch Repair Deficiency - What's Next?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Recommendations for Early Detection in Your Patients
The goal of care for patients with CMMRD is to detect cancer or its precursors as early as possible to allow for early therapeutic intervention.
According to the latest AACR guidelines, the following screening tests are recommended for patients with constitutional mismatch repair deficiency:
In general
- Detailes clinical examination at each presentation for imaging
Brain Tumors
- Cranial MRI every 6 months after diagnosis of CMMRD (not to be replaced by whole-body MRI) and on clinical suspicion
- First MRI with contrast, then without contrast if findings are normal
- Whole-body MRI is not an adequate substitute for cranial MRI
Various Tumors
- Whole-body MRI once a year from the age of 6 (cannot replace head MRI)
Lymphomas and embryonal tumours
- Abdominal ultrasound every 6 months from diagnosis
Leukemias
- Blood tests are not an integral part of early cancer detection in an unremarkable clinical picture
- A complete blood count and LDH every 3-4 months may be considered
Gastrointestinal Tumors
- Colonoscopy, oesophagogastroduodenoscopy and capsule endoscopy every year from the age of 6
- Preventive colectomy is currently under discussion and must be decided on an individual basis
Tumors of the Genital Tract and Urinary Tract
- Gynaecological examination, transvaginal sonography, endometrial biopsy (pipet method), urine cytology, urine sticks once a year from the age of 20 (see LS guidelines)
Tumours of the skin
- Skin examination from diagnosis yearly
