Homozygous PMS2 germline mutations in two families with early-onset haematological malignancy, brain tumours, HNPCC-associated tumours, and signs of neurofibromatosis type 1

Eur J Hum Genet. 2008 Jan;16(1):62-72. doi: 10.1038/sj.ejhg.5201923. Epub 2007 Sep 12.


Heterozygous germline mutations in mismatch repair (MMR) genes MLH1, PMS2, MSH2, and MSH6 cause Lynch syndrome. New studies have indicated that biallelic mutations lead to a distinctive syndrome, childhood cancer syndrome (CCS), with haematological malignancies and tumours of brain and bowel early in childhood, often associated with signs of neurofibromatosis type 1. We provide further evidence for CCS reporting on six children from two consanguineous families carrying homozygous PMS2 germline mutations. In family 1, all four children had the homozygous p.I590Xfs mutation. Two had a glioblastoma at the age of 6 years and one of them had three additional Lynch-syndrome associated tumours at 15. Another sibling suffered from a glioblastoma at age 9, and the fourth sibling had infantile myofibromatosis at 1. In family 2, two of four siblings were homozygous for the p.G271V mutation. One had two colorectal cancers diagnosed at ages 13 and 14, the other had a Non-Hodgkin's lymphoma and a colorectal cancer at ages 10 and 11, respectively. All children with malignancies had multiple café-au-lait spots. After reviewing published cases of biallelic MMR gene mutations, we provide a concise description of CCS, revealing similarities in age distribution with carriers of heterozygous MMR gene mutations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / genetics*
  • Adolescent
  • Age of Onset
  • Brain Neoplasms / genetics*
  • Child
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Consanguinity
  • DNA Mismatch Repair
  • DNA Repair Enzymes / genetics*
  • DNA-Binding Proteins / genetics*
  • Female
  • Germ-Line Mutation*
  • Germany
  • Glioblastoma / genetics
  • Hematologic Neoplasms / genetics*
  • Homozygote
  • Humans
  • Infant
  • Male
  • Mismatch Repair Endonuclease PMS2
  • Neoplastic Syndromes, Hereditary / genetics*
  • Neurofibromatosis 1 / genetics*
  • Pedigree
  • Syndrome
  • Turkey / ethnology


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