Constitutional Mismatch Repair Deficiency
Constitutional Mismatch Repair Deficiency (CMMRD, OMIM #276300, ORPHA 252202) is an extremely rare genetic condition (1 in 1,000,000 new-borns) that causes an increased risk for a broad tumour spectrum including brain tumours, haematological malignancies and colorectal cancers, already in children and young adults. The cancer risk in CMMRD is one of the highest among childhood cancer syndromes (>90% at age 20), with a mean age at first tumour of 7.5 years. Individuals with CMMRD usually present also with non-malignant manifestations including café-au-lait macules (CALM), developmental venous anomalies, pilomatrixomas, agenesis of the corpus callosum, and others.
Early diagnosis of CMMRD is pivotal for appropriate treatment and cancer surveillance of the patients and for timely genetic counselling of the entire family. To improve the diagnosis of CMMRD, the European consortium care for CMMRD (C4CMMRD) developed a scoring system, according to which any cancer patient reaching a minimum of three points by the scoring points assigned to the tumours(s) -with or without scoring points for additional non-malignant features in the patient and/or their family- should be suspected of having CMMRD.
CMMRD is caused by pathogenic germline variants affecting both alleles of one of the DNA MMR genes MLH1, MSH2, MSH6, and PMS2. In over 50% of cases the PMS2 is affected, whereas MSH2 and MLH1 biallelic pathogenic variants account only for a small proportion of cases. Conversely, monoallelic alterations in the latter genes are the most common cause of Lynch syndrome (OMIM # 120435), an autosomal dominant cancer syndrome mainly characterized by an increased risk to develop colorectal and endometrial cancer in adulthood.
A genetic diagnosis of CMMRD is often hampered by the identification of variants of unknown significance and by the difficulties in PMS2 sequencing due to the high sequence homology between this gene and its pseudogene PMS2CL. Several ancillary assays, mainly testing for constitutional microsatellite instability in non-neoplastic tissue, which is a hallmark feature of CMMRD, have recently been developed. They allow to come to a definite diagnosis in patients with inconclusive genetic results.
One of the major roles of the MMR genes is to correct mismatches introduced in the newly synthesized strand during DNA replication. Hence, cells with MMR deficiency, have an accelerated mutation rate which may lead to tumour development. CMMRD-associated tumours are frequently hyper- or even ultra-mutated with tumour mutational burdens over 10 somatic mutations/Mb, which is very uncommon in childhood cancers.
CMMRD is an autosomal recessive disorder: individuals who inherit for one of the MMR genes from each parent an altered copy (i.e., a copy with a pathogenic variant), have two altered copies of this gene and cannot produce the functional MMR protein and are, hence, affected by the disorder.
The diagnosis CMMRD in a child has implications for the entire family: siblings are at risk of also having CMMRD or being monoallelic carrier of a MMR gene pathogenic variant, and parents who are usually obligatory monoallelic carriers, which need adjusted Lynch syndrome surveillance.
Prenatal and preimplantation genetic diagnoses of CMMRD are possible if causative pathogenic variants have been identified in the parents (different legal/ethical perspectives could exist).
Individuals with CMMRD need an intensive surveillance program for early tumour detection. The current surveillance protocols include clinical examination every 6 months from the time of diagnosis, brain MRI every 6-12 months from at least the age of two years, annual ileocolonoscopy from age six years, annual esophagogastroduodenoscopy/video capsule from age 10, and other annual procedures that account for the increased risk of gynaecological and urinary tract cancers. The benefits of such surveillance protocols should be carefully analysed and discussed in each family.
More information regarding Constitutional Mismatch Repair Deficiency can be found on:
Orphanet: Constitutional mismatch repair deficiency syndrome
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A list of healthcare providers with expertise in Thematic Group 4: Other rare - predominantly malignant - genturis can be found here.
A non-exhaustive list of patient associations for genetic tumour risk syndromes in EU member states can be found here.