Publication

Paediatric intestinal cancer and polyposis due to bi-allelic PMS2 mutations: Case series, review and follow-up guidelines

Herkert, J. C., Niessen, R. C., Olderode-Berends, M. J. W., Veenstra-Knol, H. E., Vos, Y. J., van der Klift, H. M., Scheenstra, R., Tops, C. M. J., Karrenbeld, A., Peters, F. T. M., Hofstra, R. M. W., Kleibeuker, J. H. & Sijmons, R. H., May-2011, In : European Journal of Cancer. 47, 7, p. 965-982 18 p.

Research output: Contribution to journalArticleAcademicpeer-review

BACKGROUND: Bi-allelic germline mutations of one of the DNA mismatch repair genes, so far predominantly found in PMS2, cause constitutional MMR-deficiency syndrome. This rare disorder is characterised by paediatric intestinal cancer and other malignancies. We report the clinical, immunohistochemical and genetic characterisation of four families with bi-allelic germline PMS2 mutations. We present an overview of the published gastrointestinal manifestations of CMMR-D syndrome and propose recommendations for gastro-intestinal screening.

METHODS AND RESULTS: The first proband developed a cerebral angiosarcoma at age 2 and two colorectal adenomas at age 7. Genetic testing identified a complete PMS2 gene deletion and a frameshift c.736_741delinsTGTGTGTGAAG (p.Pro246CysfsX3) mutation. In the second family, both the proband and her brother had multiple intestinal adenomas, initially wrongly diagnosed as familial adenomatous polyposis. A splice site c.2174+1G>A, and a missense c.137G>T (p.Ser46Ile) mutation in PMS2 were identified. The third patient was diagnosed with multiple colorectal adenomas at age 11; he developed a high-grade dysplastic colorectal adenocarcinoma at age 21. Two intragenic PMS2 deletions were found. The fourth proband developed a cerebral anaplastic ganglioma at age 9 and a high-grade colerectal dysplastic adenoma at age 10 and carries a homozygous c.2174+1G>A mutation. Tumours of all patients showed microsatellite instability and/or loss of PMS2 expression.

CONCLUSIONS: Our findings show the association between bi-allelic germline PMS2 mutations and severe childhood-onset gastrointestinal manifestations, and support the notion that patients with early-onset gastrointestinal adenomas and cancer should be investigated for CMMR-D syndrome. We recommend yearly follow-up with colonoscopy from age 6 and simultaneous video-capsule small bowel enteroscopy from age 8.

Original languageEnglish
Pages (from-to)965-982
Number of pages18
JournalEuropean Journal of Cancer
Volume47
Issue number7
Publication statusPublished - May-2011

    Keywords

  • Constitutional MMR-deficiency syndrome, Bi-allelic PMS2 mutation, Paediatric gastrointestinal cancer, Follow-up recommendations, NONPOLYPOSIS COLORECTAL-CANCER, MISMATCH-REPAIR-DEFICIENCY, WIRELESS CAPSULE ENDOSCOPY, AU-LAIT SPOTS, LYNCH-SYNDROME, EARLY-ONSET, MICROSATELLITE INSTABILITY, GERMLINE MUTATIONS, TURCOT-SYNDROME, HEMATOLOGICAL MALIGNANCY

ID: 5326135