CMMRD – risk management

Constitutional mismatch repair deficiency (CMMRD) is an autosomal recessive cancer predisposition syndrome caused by biallelic pathogenic variants in one of the four mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) or biallelic deletion in EPCAM affecting MSH2 function.

This risk management guideline has been developed for individuals who have NOT been diagnosed with a relevant cancer/tumour.

The care of affected individuals should be individualised based on their clinical situation, and the monitoring they need as part of their treatment and post-treatment follow up.

The risk management of an individual with a pathogenic variant in two or more genes that confer a predisposition to cancer should also be individualised.

• Unaffected known biallelic MMR-gene pathogenic variant carrier.

Exclusion criteria

• A biallelic MMR-gene pathogenic variant carrier already diagnosed with a relevant cancer/tumour.
• A monoallelic MMR-gene pathogenic variant carrier - refer to MMR genes (Lynch syndrome) - risk management.

*As only small numbers of biallelic pathogenic variant carriers have been reported, these risk figures are subject to multiple biases, including ascertainment and reporting bias
**Source: Australian Institute of Health and Welfare (AIHW) 2020 Cancer Data in Australia; Canberra: AIHW. <https://www.aihw.gov.au/reports/cancer/cancer-data-in-australia/>. (2016 data)
^#Source: NSW Cancer Registry. Annual NSW cancer incidence and mortality data set, 2015.

There is currently no international consensus on screening. Comprehensive surveillance protocols have been proposed by several expert groups but none have been systematically studied.^rrrr

Surveillance should be considered on an individualised basis and ideally should be coordinated through a multidisciplinary service with expertise in CMMRD. Enrolment in clinical trials evaluating screening protocols should be discussed.

The choice of risk management strategy should take into account current age, other health issues and residual cancer risk.

*Gadolinium contrast, used in some MRI protocols, accumulates in the dentate nucleus and globus pallidus. The likelihood of this occurring increases with repeated dosing. Although there is no clear evidence of harm associated with this finding, longer term prospective studies are needed.
*The impact of lifestyle on cancer risk should be discussed e.g. exercise regularly, maintain a healthy weight, have a healthy diet, limit alcohol intake, do not smoke and avoid excessive sun exposure.

There are limited data on the effectiveness of cancer screening in biallelic MMR-gene pathogenic variant carriers. Published recommendations represent expert opinion and are mostly extrapolated from cancer screening studies in other groups at increased risk of specific cancers.

Colorectal adenoma

Colorectal adenomas are common (estimated lifetime penetrance >90%) with more than 50% of reported CMMRD cases having adenoma detected before age 10 years.^r Multiple colorectal adenomas have been diagnosed in a child aged 6 years.^r There is in vitro evidence that CMMRD-related adenoma show faster progression from benign to malignant than equivalent lesions in heterozygotes (i.e. Lynch syndrome). Consider increasing colonoscopy to 6 monthly if adenoma are detected.

Colorectal cancer

One of the most commonly reported cancers is colorectal carcinoma (CRC), with approximately 50% of reported CRC diagnosed under age 16 years.^rr Colonoscopy is of proven benefit in a number of inherited colorectal polyposis syndromes and it is reasonable to assume at least some benefit in CMMRD. There is no published data on the long term benefits of preventative colectomy in CMMRD.

Small bowel cancer

A recent report from the International BMMRD Consortium detailed the outcome of video capsule endoscopy (VCE) for small bowel surveillance in 17 patients with CMMRD (total of 38 procedures).^r Three patients had small bowel neoplasia detected by VCE (2 with adenoma with high grade dysplasia at 16 and 13 years, 1 with jejunal adenocarcinoma at 15 years). However 4 patients with negative VCE were subsequently diagnosed with duodenal neoplasia (false negatives).

Haematological malignancy

Some experts recommend 6 monthly FBE with differential from age 12 months. There is no evidence that this leads to earlier detection of haematological malignancy, reduced mortality or improved survival.  

Brain tumours

Brain tumours have similar penetrance to CRC, but with a younger median age at diagnosis (9 years). There are multiple reports of brain tumours in children under age 5 years.^rrrr

Both parents and all offspring are at 100% risk of inheriting one of the two identified MMR-gene pathogenic variants, and are at risk of developing Lynch syndrome.

Siblings (brothers/sisters) are at 25% risk of having inherited both pathogenic variants and having CMMRD, and are at up to 50% risk of having inherited one pathogenic variant and are at risk of developing Lynch syndrome.

Genetic relatives should be referred to a clinical genetics service or familial cancer centre to discuss genetic testing. 

Centre for Genetics Education NSW Health
Genetic Alliance Australia
European Consortium Care for CMMR-D (C4CMMRD)
International Biallelic Mismatch Repair Consortium (IBMMRC)

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Bibliography

Bakry, D., M. Aronson, C. Durno, et al. 2014. "Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: report from the constitutional mismatch repair deficiency consortium." Eur J Cancer 50(5):987-996.

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BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) is a devastating cancer predisposition syndrome for which data regarding clinical manifestations, molecular screening tools and management are limited. METHODS: We established an international CMMRD consortium and collected comprehensive clinical and genetic data. Molecular diagnosis of tumour and germline biospecimens was performed. A surveillance protocol was developed and implemented. RESULTS: Overall, 22/23 (96%) of children with CMMRD developed 40 different tumours. While childhood CMMRD related tumours were observed in all families, Lynch related tumours in adults were observed in only 2/14 families (p=0.0007). All children with CMMRD had cafe-au-lait spots and 11/14 came from consanguineous families. Brain tumours were the most common cancers reported (48%) followed by gastrointestinal (32%) and haematological malignancies (15%). Importantly, 12 (30%) of these were low grade and resectable cancers. Tumour immunohistochemistry was 100% sensitive and specific in diagnosing mismatch repair (MMR) deficiency of the corresponding gene while microsatellite instability was neither sensitive nor specific as a diagnostic tool (p<0.0001). Furthermore, screening of normal tissue by immunohistochemistry correlated with genetic confirmation of CMMRD. The surveillance protocol detected 39 lesions which included asymptomatic malignant gliomas and gastrointestinal carcinomas. All tumours were amenable to complete resection and all patients undergoing surveillance are alive. DISCUSSION: CMMRD is a highly penetrant syndrome where family history of cancer may not be contributory. Screening tumours and normal tissues using immunohistochemistry for abnormal expression of MMR gene products may help in diagnosis and early implementation of surveillance for these children.

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