Review Paediatric intestinal cancer and polyposis due to bi-allelic PMS2 mutations: Case series, review and follow-up guidelines Johanna C. Herkert a, * , Rene ´e C. Niessen a , Maria J.W. Olderode-Berends a , Hermine E. Veenstra-Knol a , Yvonne J. Vos a , Heleen M. van der Klift b , Rene Scheenstra c , Carli M.J. Tops b , Arend Karrenbeld d , Frans T.M. Peters e , Robert M.W. Hofstra a , Jan H. Kleibeuker e , Rolf H. Sijmons a a Department of Genetics, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands b Department of Clinical Genetics and Human Genetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands c Department of Paediatrics, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands d Department of Pathology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands e Department of Gastroenterology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands ARTICLE INFO Article history: Received 18 October 2010 Accepted 20 January 2011 Available online 4 March 2011 Keywords: Constitutional MMR-deficiency syndrome Bi-allelic PMS2 mutation Paediatric gastrointestinal cancer Follow-up recommendations 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 dis- order 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 fam- ily, 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 ade- nocarcinoma at age 21. Two intragenic PMS2 deletions were found. The fourth proband devel- oped 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. 0959-8049/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejca.2011.01.013 * Corresponding author: Tel.: +31 50 3617100; fax: +31 50 3617230. E-mail address: j.c.herkert@medgen.umcg.nl (J.C. Herkert). EUROPEAN JOURNAL OF CANCER 47 (2011) 965 – 982 available at www.sciencedirect.com journal homepage: www.ejconline.com