Constitutional mismatch repair deficiency syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare disorder that greatly increases the risk of developing different types of cancer throughout a person's lifetime. Affected individuals often develop their first cancer in childhood. The cancers that most commonly occur in people with CMMRD are cancers of the colon and rectum (collectively referred to as colorectal cancer), blood (leukemia or lymphoma), and brain.

Approximately 50 percent of people with CMMRD will develop cancer by age 10, and 90 percent will develop cancer by age 18. Brain cancers, leukemias, and lymphomas tend to occur at a younger age than colorectal cancer in affected individuals. Nearly all people with CMMRD will develop a second cancer if they survive the first cancer.

People with CMMRD often develop multiple abnormal growths (polyps) on the lining of the colon. If these polyps are not removed, they may become cancerous over time.

Brain cancers in people with CMMRD are often high-grade gliomas or glioblastomas, which are tumors that are made up of cells called glial cells.

The most common blood cancers in people with CMMRD are non-Hodgkin lymphomas, such as lymphoblastic lymphoma. These cancers primarily affect white blood cells known as T cells.

Other cancers that can occur in people who have CMMRD include cancers of the small intestine, urinary tract, or lining of the uterus. Cancers of the connective tissue and bone (sarcomas) may also develop.

Some affected individuals have patches of skin that are unusually light in color (hypopigmented). Many people with CMMRD develop features similar to those seen in people with a condition called neurofibromatosis type 1. These features include changes in skin coloring (pigmentation), which are characterized by multiple flat patches on the skin that are darker than the surrounding area (café-au-lait spots). Because of these shared features, CMMRD is sometimes initially misdiagnosed as neurofibromatosis type 1.

Many people with CMMRD also develop a noncancerous (benign) feature called developmental venous anomaly, which is a rearrangement of the small veins in the brain. This feature can only be seen with medical imaging.

Due to the young age at which people with CMMRD develop cancer, the lifespan of affected individuals is typically shortened, with many people surviving only into adolescence or early adulthood.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Genetic changes that cause disease or increase the risk of disease are sometimes called mutations or pathogenic variants. Pathogenic variants in the PMS2 gene cause more than 50 percent of cases of CMMRD, while pathogenic variants in the MSH6 gene cause approximately 20 percent of cases. Pathogenic variants in the MLH1 and MSH2 genes are responsible for the remaining cases of CMMRD. These four genes are involved in repairing errors that occur when DNA is copied in preparation for cell division, a process called DNA replication. Because these genes work together to fix DNA errors, they are known as mismatch repair (MMR) genes.

The pathogenic variants that cause CMMRD reduce the amount of functional MMR protein. A shortage of any of the MMR proteins impairs the cell's ability to fix the errors that naturally occur during DNA replication. These errors can then accumulate and disrupt other genes that are involved in important cellular processes such as cell growth and cell division (proliferation). Uncontrolled cell growth leads to cancer.

Particular pathogenic variants in MMR genes cause a form of CMMRD called attenuated CMMRD. One such pathogenic variant in the PMS2 gene is found in the Nunavik population of Quebec, Canada. People with attenuated CMMRD typically develop cancer later in life, often in adulthood.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

CMMRD is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a pathogenic variant to cause the disorder.

The parents of an individual with CMMRD typically have a pathogenic variant in one copy of a gene associated with CMMRD in each of their cells. These parents have a cancer predisposition syndrome called Lynch syndrome. Lynch syndrome increases the risk of many types of cancer, particularly colorectal cancer, but also cancers of the stomach, small intestine, gallbladder ducts, upper urinary tract, ovaries, endometrium, brain, and skin. Unlike CMMRD, individuals with Lynch syndrome develop these cancers in adulthood. People with CMMRD may not have a history of cancer in their family, as some people with a pathogenic variant in only one copy of an MMR gene do not develop cancer.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

CMMRD is a rare disorder. Only a few hundred affected individuals have been reported in the medical literature. The incidence of CMMRD is estimated to be about 1 in 1,000,000 newborns. The incidence is likely higher among people whose parents are related to one another.

Which doctor should you see?

The suggested department for discussing Constitutional mismatch repair deficiency syndrome is Neurology, with a neurologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which nervous-system findings help explain the symptoms?
• Would an assessment of walking, communication or daily function be helpful?
• Are rehabilitation or other specialist services relevant?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Constitutional mismatch repair deficiency syndrome. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.