Biallelic Mismatch Repair Deficiency (BMMRD) is a hereditary cancer predisposition syndrome that has a unique morphological phenotype and tumor spectrum. It is important to distinguish BMMRD from other familial cancers since they share some clinical characteristics which often results in misdiagnosis and inappropriate management. Distinction between the two is critical.
Initially the term Turcot syndrome referred to familial appearance of gastrointestinal polyposis and carcinomas in association with malignant brain tumors. Further understanding of the clinical phenotype as well as the molecular alterations which cause these syndromes resulted in two distinct entities known today as the Brain Tumor Polyposis Syndrome (BTPS) type 1 and 2. Currently, BTPS1 is termed Lynch syndrome and is a result of a germline heterozygous mutations in one of the mismatch repair genes. BPTS2 is currently termed Familial Adenomatous Polyposis (FAP) syndrome and is associated with a different set of cancers.
Individuals harboring heterozygous mutations in one of the four mismatch repair genes (MLH1, MSH2, MSH6 or PMS2) will have Lynch syndrome.
Lynch syndrome is an autosomal dominant condition characterized by an increased risk of colon cancer, as well as cancers of the endometrium, ovary, stomach, small intestine, hepatobiliary tract and urinary tract. Diagnosis of Lynch syndrome is made based on family history, using the Amsterdam criteria: at least 3 family members (one of whom is a first-degree relative of the other two) with Lynch syndrome-related cancers, two successive affected generations and at least one of the cancers diagnosed before age 50 years.
Biallelic mutations (homozygous) in any of the mismatch repair genes results in a very different and aggressive cancer predisposition syndrome named Constitutional Mismatch Repair Deficiency Syndrome (CMMRD) or Biallelic Mismatch Repair Deficiency Syndrome (BMMRD).
The more severe BMMRD phenotype presents with cancer during childhood and is characterized by gastrointestinal tumours, brain tumours and haematological malignancies. These children may have cafe´-au-lait (CAL) macula and other findings that mimic Neurofibromatosis-1 (NF-1). The characteristic features of cafe´-au-lait macules observed in BMMRD allow differentiating those from classic CALs: BMRRD associated CALs frequently contain areas of hypopigmentation within the hyper-pigmented macules and the borders of the skin lesions are more diffuse and irregular. Number of skin lesions is variable, ranging from only one or two focal areas to more diffuse areas of skin pigmentation and they are usually present from early childhood.
Other features of NF-1, such as axillary freckling, Lisch nodules and plexiform neurofibromas, are also reported in BMMRD, but are rare and only a small subset of these meet established NF-1 diagnostic criteria.
BMMRD families may lack the impressive family history of gastrointestinal malignancies and therefore do not meet the Amsterdam criteria.
Importantly, consanguinity is present in more than a half of the affected families.
Indications to advance to genetic testing for BMMRD include a child from a consanguineous family presenting with a malignant brain tumour, haematological malignancy or early-onset gastrointestinal (GI) cancer.
Adults can present with uterine or GI cancer and cafe´-au-lait macules without any family history suggestive of a familial predisposition syndrome. Less specific but important is evidence of cafe´-au-lait macules in a highly consanguineous family even without a malignancy.
BMMRD results in extremely high rates of malignant cancers before age 18. The most frequent are brain tumors followed by hematopoietic malignancies (usually T-cell lymphomas) and gastrointestinal cancers. Most individuals will be affected by cancer before they reach adulthood.
In humans, germline mutations are reported in MLH1, MSH2, MSH6 and PMS2. These mismatch repair genes are critical in repairing single base pair mismatches and misalignments. Upon loss of one of these genes (which don´t seem to be functionally redundant), high mutation rates are observed including in cancers which are described as “hypermutator phenotype.”
BMMRD is inherited in an autosomal recessive fashion and is found mostly in consanguineous families.
BMMRD individuals may actually have NF1 which is thought to be caused by “secondary” early or germline mutations in the NF1 gene as a part of the hypermutator phenotype
High grade gliomas are the most common type of tumor observed in children with BMMRD in the first 2 decades of life. Some are presenting with low-grade gliomas, but these tend to transform to high grade tumors (secondary glioblastoma), which are otherwise rare in children. Medulloblastoma and PNET have also been reported. These malignant brain tumors have specific morphological abnormalities mimicking giant cell glioblastoma or pleomorphic astrocytoma. Immunostaining is usually negative for the corresponding mutated gene.
All major types of leukemias and lymphomas have been reported in BMMRD patients. The most common are non-Hodgkin lymphoma with T-cell lymphoma being predominant. T-cell acute lymphoblastic leukemias are also relatively common as a part of T-cell malignancies. B-cell lymphomas and leukemias are also observed, but are less common. Myelogenous leukemias are infrequent in children with BMMRD and account to 10% of these cancers. The incidence of hematological malignancies in adults with BMMRD is unknown.
Adenomatous polyps have been identified in the small intestine and large bowel as well as in the stomach of BMMRD patients. The number of polyps is extremely variable ranging from less than five to > 50. Polyposis is observed in young children.
The colorectal cancer is the initial cancer diagnosed in up to two-thirds of patients with BMMRD. The mean age at first diagnosis in the published series is 16.4 years (range 5–28 years) with more than half classified as paediatric onset colorectal cancer.
Both duodenal and jejunal carcinomas also can occur even in young children.
Individual cases of hepatic adenoma, ureteric, renal, bladder cancers have been reported in young BMMRD patients.