PT  - JOURNAL ARTICLE
AU  - Aronson, Melyssa
AU  - Colas, Chrystelle
AU  - Shuen, Andrew
AU  - Hampel, Heather
AU  - Foulkes, William D
AU  - Baris Feldman, Hagit
AU  - Goldberg, Yael
AU  - Muleris, Martine
AU  - Wolfe Schneider, Kami
AU  - McGee, Rose B
AU  - Jasperson, Kory
AU  - Rangaswami, Arun
AU  - Brugieres, Laurence
AU  - Tabori, Uri
TI  - Diagnostic criteria for constitutional mismatch repair deficiency (CMMRD): recommendations from the international consensus working group
AID  - 10.1136/jmedgenet-2020-107627
DP  - 2022 Apr 01
TA  - Journal of Medical Genetics
PG  - 318--327
VI  - 59
IP  - 4
4099  - http://jmg.bmj.com/content/59/4/318.short
4100  - http://jmg.bmj.com/content/59/4/318.full
SO  - J Med Genet2022 Apr 01; 59
AB  - Background Constitutional mismatch repair deficiency syndrome (CMMRD) is the most aggressive cancer predisposition syndrome associated with multiorgan cancers, often presenting in childhood. There is variability in age and presentation of cancers and benign manifestations mimicking neurofibromatosis type 1. Genetic testing may not be informative and is complicated by pseudogenes associated with the most commonly associated gene, PMS2. To date, no diagnostic criteria exist. Since surveillance and immune-based therapies are available, establishing a CMMRD diagnosis is key to improve survival.Methods In order to establish a robust diagnostic path, a multidisciplinary international working group, with representation from the two largest consortia (International Replication Repair Deficiency (IRRD) consortium and European Consortium Care for CMMRD (C4CMMRD)), was formed to establish diagnostic criteria based on expertise, literature review and consensus.Results The working group established seven diagnostic criteria for the diagnosis of CMMRD, including four definitive criteria (strong evidence) and three likely diagnostic criteria (moderate evidence). All criteria warrant CMMRD surveillance. The criteria incorporate germline mismatch repair results, ancillary tests and clinical manifestation to determine a diagnosis. Hallmark cancers for CMMRD were defined by the working group after extensive literature review and consultation with the IRRD and C4CMMRD consortia.Conclusions This position paper summarises the evidence and rationale to provide specific guidelines for CMMRD diagnosis, which necessitates appropriate surveillance and treatment.All data relevant to the study are included in the article or uploaded as supplementary information.