Constitutional Mismatch Repair Deficiency Syndrome (CMMRD)

Cancer risk with constitutional mismatch repair deficiency syndrome

The exact risk of developing cancer for people with this syndrome is not known. The risk for cancer is expected to be high. CMMRD can cause a variety of cancers. It is hard to predict what type of cancer a child may develop and when that cancer will occur.

Causes of constitutional mismatch repair deficiency syndrome

Genes carry information telling cells in the body how to function. CMMRD is related to changes in the genes MLH1, MSH2, MSH6, or PMS2. It can sometimes be related to a gene called EPCAM, but this is rare.

The MLH1, MSH2, MSH6, and PMS2 genes help repair a type of DNA damage through a process called “mismatch repair” or MMR. It is harder for people with CMMRD to repair the damage that naturally happens in their genes. This can lead to polyps and tumors in young children.

Most people have 2 working copies of each of the MMR genes in their cells. They inherit 1 copy from their mother and 1 copy from their father. A gene change that causes the gene to not work properly is called a mutation.

When someone inherits an MMR gene mutation from their mother and another mutation in the same MMR gene from their father, they have CMMRD. This person has a mutation that affects each of the 2 copies of an MMR gene.

Most children with this syndrome inherit the MMR gene mutations from their parents. Parents of a child with this syndrome have a 25% or 1 in 4 chance each pregnancy of having a child with the same syndrome.

All children of a parent with CMMRD will inherit 1 MMR mutation. Lynch syndrome is a condition where people have 1 MMR gene mutation. The partner of a person with Lynch syndrome might consider genetic testing to see if they also carry an MMR gene mutation. This can help determine risks of having a child with CMMRD.

About Lynch syndrome

A person with 1 working copy and 1 non-working copy of a mismatch repair (MMR) gene has a condition known as hereditary non-polyposis colorectal cancer (Lynch syndrome). When a child has constitutional mismatch repair deficiency, it is likely that both parents have Lynch syndrome.

People with Lynch syndrome are more likely to develop certain types of cancer, such as colon, uterine, ovarian, and small bowel cancer. They develop these most often as adults.

It is important that those with Lynch syndrome have routine health care visits and screenings. It may be best to find a gastroenterologist who knows the condition well.

If you have Lynch syndrome, talk with your primary care provider about suggested cancer screenings:

• Adults should have colonoscopies to look for and remove any polyps and detect colon cancer.
• Women with Lynch syndrome may want to do screenings of their reproductive organs.
• Other cancer screenings depend on the gene involved and the family history.

Diagnosis of constitutional mismatch repair deficiency syndrome

Health history

A health care provider may suspect that your child has CMMRD after studying their medical and family history.

This information helps the health care provider and the genetic counselor know if:

• There are more cancers than normal in your family
• These cancers happened at a younger age than expected
• The cancers are those that are seen with MMR mutations

Health care providers or genetic counselors may recommend genetic testing of the MMR genes if they suspect CMMRD. Learn more about types of genetic testing.

Genetic testing for CMMRD

A blood sample is sent to a genetic testing lab. The lab runs genetic tests that looks for changes in the MLH1, MSH2, MSH6, PMS2, and/or EPCAM genes.

If your child has a gene mutation, the genetic counselor will work with your family to:

• Find out if other family members should consider testing for an MMR mutation
• Help your family understand the increased cancer risk from CMMRD
• Give you information to help with your decisions about prenatal genetic testing

Genetic testing before or during pregnancy

Parents may choose to do prenatal testing to find out if a pregnancy is affected with known MMR mutations. Testing may take place either before pregnancy occurs or during pregnancy.

You should work with a genetic counselor to review the pros and cons of the test. The genetic counselor can also help you prepare for the test results.

Testing before pregnancy is called preimplantation genetic testing (PGT). This special type of genetic testing is done along with in vitro fertilization (IVF). PGT tests embryos for known MMR mutations before a provider places them into the uterus.

Testing during pregnancy can help providers see if a pregnancy is affected with known MMR mutations. A doctor gathers cells from the pregnancy in 1 of 2 ways:

• Chorionic villus sampling (CVS) is done during the first trimester (first 3 months).
• Amniocentesis is done during the second trimester or later (last 6 months).

After tissue collection, the lab checks the sample for MMR mutations. Both tests carry minor risks. Discuss risks with an experienced health care provider or genetic counselor.

Special concerns for genetic testing

Take time to consider the benefits and risks. Speak with a genetic counselor before testing. If you decide to get tested, review the results with the health care provider or genetic counselor so you can understand what they mean.

It is normal to feel sad, anxious, or angry after learning about genetic mutations. Parents who pass on MMR mutations to 1 or more of their children may feel guilty. People with MMR mutations may have trouble getting disability coverage, life insurance, or long-term care insurance in some states.

Read more about genetic discrimination.

Monitoring and follow-up care for constitutional mismatch repair deficiency syndrome

Children with CMMRD are at risk of developing multiple types of cancer during their life. It is important to monitor children’s health and help them adopt healthy habits. They need to have regular physical checkups and screenings. This way, the care team can find cancer early at the most treatable stage.

Cancer screening for those with CMMRD

Discuss tumor screening tests with a health care provider who knows this syndrome well.

Screening tests may include:

• Physical exams 2 times each year
• Gastrointestinal tract screening: including colonoscopy, esophagogastroduodenoscopy (EGD), and video capsule endoscopy (VCE)
• MRI exam of the brain
• Abdominal imaging
• Chest X-rays
• Routine blood tests

It is possible that recommended screenings may change over time as health care providers learn more about CMMRD. People with CMMRD should discuss all screening options with a health care provider who knows this condition well.

Living with constitutional mismatch repair deficiency syndrome

Problems to watch for

Watch closely for signs or symptoms that could signal cancer, such as:

• Unexplained weight loss
• Tiredness
• Fever that does not go away
• Night sweats
• Loss of appetite
• Aches, pains, lumps or swelling that have no clear cause and do not go away
• Headaches, vomiting, or changes in vision or nerve function that do not go away
• Swollen glands
• Trouble breathing
• Blood in the stool
• Pain in the belly

Maintain a healthy lifestyle

Habits that will help you maintain a healthy lifestyle include:

• Eat a healthy diet with lots of fruits and vegetables.
• Get regular exercise.
• Avoid smoking or using tobacco products.
• Avoid secondhand smoke.
• Avoid excess sun exposure and always wear sunscreen, a hat, and protective clothing when out in the sun.
• Avoid radiation exposure when possible.

Constitutional mismatch repair deficiency syndrome care at St. Jude

The St. Jude Cancer Predisposition Program is dedicated to diagnosing and screening children with a genetic predisposition for cancer. Our program offers the best clinical care possible. We engage in cutting-edge research to gain more information about genetic disorders and cancer, and to improve the care and treatment for patients who are affected by these conditions. Learn more about the Division of Cancer Predisposition at St. Jude.

Our genetic counselors, clinicians, genetics nurse practitioners, and research assistants work together to provide patients with:

• A complete health history
• A record of cancer that happened over the past 3 generations (family tree or pedigree) to see how diseases were passed down
• Physical exams to check for genetic disease
• Confidential genetic counseling and testing
• Cancer screenings for those with genetic disease to detect and treat cancer as soon as it occurs
• Recommended cancer treatments and ways to reduce cancer risk
• Genetic testing for immediate (1^st degree) relatives

CMMRD increases your child’s risk for many types of cancer. 

Related clinical trials

If you have questions about the Genetic Predisposition Clinic and care for CMMRD, email our team at GPTeam@stjude.org.

Resources outside St. Jude