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

• Published in: European journal of cancer (1990) 2011-05, Vol.47 (7), p.965-982
• Main Authors: Herkert, Johanna C, Niessen, Renée C, Olderode-Berends, Maria J.W, Veenstra-Knol, Hermine E, Vos, Yvonne J, van der Klift, Heleen M, Scheenstra, Rene, Tops, Carli M.J, Karrenbeld, Arend, Peters, Frans T.M, Hofstra, Robert M.W, Kleibeuker, Jan H, Sijmons, Rolf H
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphatases - genetics; Adult; Base Pair Mismatch; Bi-allelic PMS2 mutation; Biological and medical sciences; Child; Child, Preschool; Constitutional MMR-deficiency syndrome; DNA Repair; DNA Repair Enzymes - genetics; DNA-Binding Proteins - genetics; Family Health; Female; Follow-up recommendations; Follow-Up Studies; Gene Deletion; Germ-Line Mutation; Hematology, Oncology and Palliative Medicine; Humans; Immunohistochemistry - methods; Intestinal Neoplasms - genetics; Intestinal Polyposis - genetics; Male; Medical sciences; Microsatellite Instability; Microsatellite Repeats; Mismatch Repair Endonuclease PMS2; Mutation; Paediatric gastrointestinal cancer; Pharmacology. Drug treatments; Syndrome; Tumors
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2011.01.013

Abstract 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.