"Constitutional Mismatch Repair Deficiency" – What Is It?
Constitutional mismatch repair deficiency (CMMRD) is a rare genetic, i.e., hereditary, disease. It can lead to various malignant tumors such as brain tumors, intestinal tumors, ovarian tumors, and many others, as well as leukemia, even in childhood. CMMRD is, therefore, a cancer predisposition disease.
How Is "Constitutional Mismatch Repair Deficiency" Diagnosed?
The diagnosis of CMMRD should be considered in cancer patients who have one or more of the following characteristics at the same time:
- Café-au-lait spots and/or other neurofibromatosis 1-typical skin changes and/or less pigmented skin lesions
- Consanguine (blood-related) parents
- Lynch syndrome-associated tumors in the family (colorectal carcinoma, small bowel carcinoma, endometrial/ovarian carcinoma, ureteral/renal pelvis carcinoma)
- Second cancer
- Sibling with childhood cancer
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, i.e., hereditary, disease, a genetic test should be carried out to confirm the diagnosis. This can reveal whether there is a mutation, i.e., a change in the genetic material, in the genes MSH2, MSH6, MLH1, and PMS2 that are relevant for CMMRD. It is also important to know that every gene in our body is present twice, so there are two so-called alleles. Mutations can affect either one of the alleles or both, whereby the latter is referred to as a biallelic mutation. This biallelic mutation is the basis of CMMRD and can also be detected in a genetic test.
With this form of inheritance, the risk of the parents having another sick child is 25%. The probability that another child will carry the mutation but not be ill is 50%. It, therefore, makes sense to genetically test both the parents of an affected child and their siblings.
Further Clinical Features
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 time after diagnosis of the first cancer is 30 months. The diseases described to date in the context of a CMMRD are listed below:
Hematologic 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 carcinoma
- Small intestine carcinomas
- Endometrial/ovarian carcinoma
- Ureteral/renal pelvis carcinoma
Other
- 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. It has been shown so far that those affected develop cancer very early, and the risk of cancer is very high, so most affected children do not reach adulthood. The probability of developing one tumor or another depends on the mutated gene. Mutations in MSH6 and PMS2 are significantly more common and lead to a different clinical picture than mutations in MLH1 and MSH2. The latter leads more frequently to hematologic cancers (leukemias, lymphomas), and the average age at 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 carcinoma, small bowel carcinoma, endometrial/ovarian carcinoma, ureteral/renal pelvis carcinoma) and brain tumors and usually develop another cancer after surviving the first one.
What Is Known About the Development of "Constitutional Mismatch Repair Deficiency"?
In our cells, the DNA, i.e., our genetic information, is copied and “translated” again and again, whereby errors can occur. To ensure that these errors can be corrected, there is the so-called “mismatch repair system”. This system consists of many proteins for which various corresponding 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 produced incorrectly or not at all. As a result, the repair system cannot work correctly, and cancer develops.
CMMRD is a genetic disease. If two mutated genes meet in an individual, this person is homozygous for this mutation, and the disease develops. This form of inheritance is referred to as autosomal recessive inheritance. It is usually the case that the parents carry the mutation but are not affected by the disease, as it only occurs if both alleles are genetically altered. The patient’s siblings can either develop the disease with a probability of 25% each or not carry a mutation on this gene. There is a 50% probability that siblings carry the mutation but are not ill.
Is There Any Form of Treatment Available?
The therapy depends on the disease in question and the existing symptoms. In most cases, it consists of a combination of surgical therapy and chemotherapy. The latter does not cause any greater intolerance in cancer patients with CMMRD than in other cancer patients. However, some substances are not as effective and should not be used. Studies are currently testing the effect of checkpoint inhibitors.
Diagnosis of " Constitutional Mismatch Repair Deficiency" What's Next?
If you have been diagnosed with this cancer predisposition syndrome, it is important to see a specialist. The following section explains whether cancer screening tests or other measures are needed and how they should be carried out. We also give you some valuable tips on what you can do yourself. If you have any questions, please do not hesitate to contact us or your doctor.
Diagnosis of " Constitutional Mismatch Repair Deficiency" What's Next?
If you have been diagnosed with this cancer predisposition syndrome, it is important to see a specialist. The following section explains whether cancer screening tests or other measures are needed and how they should be carried out. We also give you some valuable tips on what you can do yourself. If you have any questions, please do not hesitate to contact us or your doctor.
Medical Measures for Early Detection
Regular examinations of patients with CMMRD aim to detect cancer or its precursors as early as possible so that early treatment can take place. Clinical examinations and various instrumental and laboratory tests 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 examinations of CMMRD patients based on currently available data on cancer in CMMRD and the respective onset of the disease.
Children and Young People
Brain Tumors
- MRI of the head every six months from diagnosis of CMMRD (not to be replaced by whole-body MRI) and in case of clinical suspicion
- Ultrasound through the open fontanel is not an adequate substitute for MRI
Various Tumors
- Whole-body MRI from the age of 6 (or as soon as it can be performed without anesthesia) once a year (cannot replace MRI of the head)
Leukemias
- Complete blood count every 6 months from 1 year
Lymphomas
- Abdominal ultrasound every six months from 1 year (can be alternated with whole-body MRI)
Gastrointestinal Tumors
- Colonoscopy once a year from the age of 6; every six months from the appearance of polyps
- Gastroscopy and video capsule endoscopy once a year from the age of 8
- Precautionary colon removal depends on the number of polyps and their degree of cell changes
Adults (aged 18 and over)
Tumors of the Genital Tract and Urinary Tract
- Gynecological examination with ultrasound, sampling of uterine lining, urine tests once a year from the age of 20
Constitutional Mismatch Repair Deficiency- What You Can Do Yourself
You Should Pay Attention to This
Hematological diseases can manifest through malaise, fatigue, reduced performance, paleness, susceptibility to infections, fever, night sweats, weight loss, bleeding (e.g., nose or gum), or increased bruising.
Neurological abnormalities can be symptoms of a brain tumor. These include headaches, drowsiness and even loss of consciousness, morning vomiting, movement or coordination disorders, and a tendency to fall.
Stool abnormalities and blood in the stool or urine may indicate intestine or urinary system tumors.
If you observe one or more of these signs in your child, you should urgently consult a doctor.
Constitutional mismatch repair deficiency is also being researched in our companion projects Liquid Biopsy and ADDRess, so we encourage patients to sign up for this in addition to the CPS Register.
Further Information
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