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

Eur J Cancer. 2011 May;47(7):965-82. doi: 10.1016/j.ejca.2011.01.013. Epub 2011 Mar 4.


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.

Publication types

  • Case Reports
  • Review

MeSH terms

  • Adenosine Triphosphatases / genetics*
  • Adult
  • Base Pair Mismatch
  • Child
  • Child, Preschool
  • DNA Repair
  • DNA Repair Enzymes / genetics*
  • DNA-Binding Proteins / genetics*
  • Family Health
  • Female
  • Follow-Up Studies
  • Gene Deletion
  • Germ-Line Mutation
  • Humans
  • Immunohistochemistry / methods
  • Intestinal Neoplasms / genetics*
  • Intestinal Polyposis / genetics*
  • Male
  • Microsatellite Instability
  • Microsatellite Repeats
  • Mismatch Repair Endonuclease PMS2
  • Mutation*
  • Syndrome


  • DNA-Binding Proteins
  • Adenosine Triphosphatases
  • PMS2 protein, human
  • Mismatch Repair Endonuclease PMS2
  • DNA Repair Enzymes