SNP Shot: Genomic Insights

Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare genetic condition that significantly elevates the risk of children and young adults developing cancer. The most frequent cancers associated with CMMRD syndrome include cancers of the colon and rectum (colorectal cancer), brain tumors, and blood cancers (leukemia or lymphoma).

In most individuals with CMMRD syndrome, cancer develops before the age of 18, typically during late childhood. The age at diagnosis varies based on the type of cancer. Brain cancers, leukemia, and lymphomas tend to be diagnosed earlier than colorectal cancer in those with CMMRD syndrome. It's estimated that 20% to 40% of individuals with CMMRD syndrome who develop cancer will experience a second cancer later in life.

Individuals with CMMRD syndrome may develop multiple non-cancerous growths (adenomas) in the colon, which have a high likelihood of becoming cancerous (malignant) over time. Brain tumors in CMMRD syndrome commonly involve glial cells, resulting in gliomas or glioblastomas. The most common blood cancer seen in CMMRD syndrome is non-Hodgkin lymphoma, which affects white blood cells. Other cancers that can occur in CMMRD syndrome encompass cancers of the small intestine, urinary tract, or the lining of the uterus (endometrial cancer).

Many individuals with CMMRD syndrome exhibit characteristics similar to those found in neurofibromatosis type 1. These include skin pigmentation changes, such as flat patches of skin that are darker than the surrounding area (café-au-lait spots). Some individuals have freckling or areas of skin that are abnormally light (hypopigmented). Rarely, individuals with CMMRD syndrome may develop Lisch nodules, benign growths in the colored part of the eye (iris), which are also seen in neurofibromatosis type 1. Lisch nodules do not impair vision. Consequently, some individuals with CMMRD syndrome are initially misdiagnosed with neurofibromatosis type 1.

Inheritance:

CMMRD syndrome is inherited in an autosomal recessive manner. This means that mutations in both copies of a gene greatly increase the risk of developing cancer. Both parents of a child with CMMRD syndrome carry one copy of the mutated gene. A single mutation in a gene associated with CMMRD syndrome typically results in Lynch syndrome, another cancer predisposition syndrome. Because the parents of an individual with CMMRD syndrome usually carry a single copy of the mutated gene, they may have Lynch syndrome. Lynch syndrome increases the risk of various cancers, especially colorectal cancer, but also cancers of the stomach, small intestine, gallbladder ducts, upper urinary tract, endometrium, brain, and skin. Unlike CMMRD syndrome, Lynch syndrome often leads to cancer development in adulthood. Furthermore, not everyone with Lynch syndrome develops cancer, so a person with CMMRD syndrome may not have a family history of cancer.