1. Paediatric intestinal cancer and polyposis due to bi-allelic PMS2 mutations: Case series, review and follow-up guidelines
- Author
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Robert M.W. Hofstra, Carli M. J. Tops, Jan H. Kleibeuker, Yvonne J. Vos, Heleen M. van der Klift, Maria J W Olderode-Berends, Rolf H. Sijmons, Rene Scheenstra, Frans Peters, Johanna C. Herkert, Hermine E. Veenstra-Knol, Renee C. Niessen, and Arend Karrenbeld
- Subjects
Proband ,Male ,Cancer Research ,Pathology ,DNA Repair ,Base Pair Mismatch ,Gastroenterology ,PMS2 ,Child ,Mismatch Repair Endonuclease PMS2 ,Adenosine Triphosphatases ,Intestinal Polyposis ,Follow-up recommendations ,WIRELESS CAPSULE ENDOSCOPY ,NONPOLYPOSIS COLORECTAL-CANCER ,GERMLINE MUTATIONS ,Syndrome ,Immunohistochemistry ,Constitutional MMR-deficiency syndrome ,Lynch syndrome ,DNA-Binding Proteins ,Oncology ,Child, Preschool ,HEMATOLOGICAL MALIGNANCY ,Female ,Microsatellite Instability ,Adult ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Adenoma ,EARLY-ONSET ,LYNCH-SYNDROME ,MISMATCH-REPAIR-DEFICIENCY ,Familial adenomatous polyposis ,Frameshift mutation ,Paediatric gastrointestinal cancer ,AU-LAIT SPOTS ,Germline mutation ,Internal medicine ,Intestinal Neoplasms ,medicine ,Humans ,Gastrointestinal cancer ,Germ-Line Mutation ,Family Health ,business.industry ,medicine.disease ,digestive system diseases ,DNA Repair Enzymes ,TURCOT-SYNDROME ,Mutation ,Bi-allelic PMS2 mutation ,business ,Gene Deletion ,Follow-Up Studies ,Microsatellite Repeats - 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.
- Published
- 2011