What is Constitutional Mismatch Repair Deficiency?

Constitutional Mismatch Repair Deficiency (CMMRD) is a rare genetic, i.e. hereditary disease. Already in childhood it can lead to various malignant tumors such as brain tumors, intestinal tumors or ovarian tumors and many others, but also to leukemia. CMMRD is therefore a predisposing cancer disease.

How is Constitutional mismatch repair deficiency diagnosed?

Diagnosis of CMMRD should be considered in cancer patients with one or more of the following characteristics simultaneously:

  • Café-au-lait spots and/or other neurofibromatosis 1-typical skin changes and/or low-pigmented skin lesions

  • Consanguine (blood-related) parents

  • Lynch syndrome-associated Tumors in the family (colorectal carcinoma, small intestine carcinoma, endometrial/ovarian carcinoma, ureter/renal pelvic carcinoma)

  • Second cancer disease

  • Sibling with cancer in childhood

The European consortium “Care for CMMRD (C4CMMRD)” has also developed a comprehensive diagnostic protocol that includes brain tumors, lymphomas, skin tumors and immunological factors.

As this is a genetic disease, a genetic examination should be carried out to confirm the diagnosis. It can be found out whether there is a mutation in the genes MSH2, MSH6, MLH1 and PMS2 relevant for CMMRD, i.e. a change in the genetic material. In addition, it is important to know that each gene is present twice in our body, so there are two so-called alleles. Mutations can affect either one of the alleles or both, the latter being referred to as a biallelic mutation. This biallelic mutation is the basis of CMMRD and can also be detected in a genetic examination.

With this form of inheritance, the risk that parents get another sick child is 25%. The probability that another child carrying the mutation, but not sick, is 50%. It therefore makes sense to genetically examine both the parents of an affected child and its siblings.

Further Clinical Features

CMMRD is characterised by the early onset of cancer in children or young adults, with an average age of 7.5 years for the first cancer. The average survival time after diagnosis of the first cancer is 30 months. The following is a list of the diseases described so far in the context of a CMMRD:

Hematological Cancers (average age at first diagnosis 6.6 years)

  • Non-Hodgkin’s lymphoma, especially T-lymphoblastic NHL, and other lymphomas

  • Acute lymphoblastic leukemia (ALL), especially T-cell ALL

  • Acute myeloid leukemia (AML)

  • Atypical chronic myeloid leukemia

  • Acute 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 cancer

  • Small intestine cancers

  • Endometrial/ovarian cancer

  • Ureteral/renal pelvic cancer


  • Sarcomas (osteosarcoma, rhabdomyosarcoma)

  • Neuroblastoma

  • Wilms’ Tumor

  • Infantile myofibromatosis

  • Breast cancer

  • Primitive neuroectodermal tumor of the ovary

What is the risk of cancer?

Exact figures are not yet available. So far, it has been shown that those affected develop cancer very early and that the cancer risk is very high, so that most affected children do not reach adulthood. The probability of developing one or the other tumor depends on the mutated gene. Mutations in MSH6 and PMS2 are significantly more frequent and lead to a different clinical picture than mutations in MLH1 and MSH2. The latter lead more frequently to hematological cancers (leukemias, lymphomas) and the average age at the first cancer diagnosis is lower than in carriers of biallelic mutations in MSH6 or PMS2. Patients with mutations in MSH6 or PMS2 are particularly prone to lynch syndrome (LS)-associated cancers (colorectal cancer, small intestine cancer, endometrium/ovarian cancer, ureter/renal pelvic cancer) as well as brain tumors and usually develop another after surviving first cancer.

What causes Constitutional mismatch repair deficiency?

In our cells the DNA, i.e. our genetic information, is repeatedly copied and “translated”, whereby errors can occur. So that these errors can be corrected, there is the so-called “Mismatch Repair System”, a repair system. This system consists of many different proteins for which different genes code. The genes relevant for CMMRD are MSH2, MSH6, MLH1 and PMS2. If there is a mutation, i.e. a change in one of these genes, the corresponding protein is also produced incorrectly or not at all. As a result, the repair system cannot function correctly and cancer develops.

CMMRD is a genetic disease. If two mutated genes meet in an individual, this person is homozygous with regard to this change and the disease manifests itself. This form of inheritance is referred to as autosomal recessive inheritance. As a rule, the parents are not affected by the disease because it only occurs if both alleles are genetically modified. Siblings of the patient can either fall ill with a probability of 25% or carry no mutation on this gene. With a probability of 50%, siblings are carriers of mutations, but not ill.

Is there a treatment?

The therapy depends on the disease in question and on the existing symptoms. In most cases, it consists of a combination of surgical therapy and chemotherapy. The latter does not cause more intolerance in cancer patients with CMMRD than in other cancer patients. However, some substances are not as effective and should therefore not be used. The effect of checkpoint inhibitors is currently being examined in studies.

Surveillance Recommendations for the Early Detection of Cancer

Surveillance Recommendations

The aim of regular examinations of patients with CMMRD is to detect cancers or their precursors as early as possible so that early treatment can take place. The clinical examination as well as various instruments and laboratory chemical examinations play an important role.

The European Consortium “Care for CMMRD (C4CMMRD)” and the “International Biallelic Mismatch Repair Deficiency Consortium” (BMMRD) have developed a protocol for early detection tests of CMMRD patients based on currently available data on cancer in CMMRD and the onset of the disease.

Children and Adolescents

Brain Tumors

  • MRI of the head from diagnosis CMMRD every 6 months (not to be replaced by whole-body MRI) and in case of clinical suspicion

  • Ultrasound through the open fontanelle is not an adequate substitute for MRT

Various Tumors

  • Whole-body MRI from 6 years of age (or as soon as possible without anesthesia) once a year (cannot replace MRI of the head)


  • Complete blood count from 1 year every 6 months


  • Ultrasound of the abdomen from 1 year on every 6 months (can be done alternately with whole-body MRI)

Gastrointestinal Tumors

  • Colonoscopy once a year from the age of 6; every 6 months from the appearance of polyps

  • Gastroscopy and video capsule endoscopy from 8 years of age once a year

  • Preventive colon removal depending on the number of polyps and their degree of cell changes


Tumors of the Genital Tract and Urinary Tract

  • Ultrasound of the abdomen from 1 year on every 6 months (can be done alternately with whole-body MRI)

Self-Care and Support

What should I pay special attention to?

Hematological diseases can manifest themselves through discomfort, fatigue, reduced performance, paleness, susceptibility to infection, fever, night sweats, weight loss, bleeding (e.g. bleeding from the nose or gums) or increased bruising.

Neurological abnormalities can be symptoms of a brain tumor. These include headaches, drowsiness, consciousness disorders, morning vomiting, movement or coordination disorders and a tendency to fall.

Stool abnormalities as well as blood in the stool or urine can indicate tumors of the intestine or urinary system.

If you observe one or more of these signs in your child, you should urgently consult a doctor.

Support Groups and Additional Information