1. ¹Department of Surgical Research, Dresden University of Technology, Dresden, Germany
2. ²Institute of Medical Genetics, Charité Hospital, Humboldt University Berlin, Berlin, Germany
3. ³Institute of Human Genetics, University of Bonn, Bonn, Germany
4. ⁴Department of Pediatric Haematology and Oncology, University Childres Hospital, Saarland University Homburg, Homburg, Germany
5. ⁵Institute of Clinical Genetics, Dresden University of Technology, Dresden, Germany
6. ⁶Department of Paediatric Oncology/Haematology, Charité Hospital, Humboldt University Berlin, Berlin, Germany
7. ⁷Institute of Human Genetics, Saarland University Homburg, Homburg, Germany
8. ⁸Structural and Computational Biology Unit, EMBL Heidelberg, Heidelberg, Germany
9. ⁹Institute of Pathology, Charité Hospital, Humboldt University Berlin, Berlin, Germany
10. ¹⁰Institute of Pathology, University of Bonn, Bonn, Germany

Correspondence: Dr S Krüger, Institute of Clinical Genetics, Dresden University of Technology, Fetscherstrae 74, D-01307 Dresden, Germany. Tel: +49 351/458 4277; Fax: +49 351/458 4316; E-mail: Stefan.Krueger@tu-dresden.de

Received 24 April 2007; Revised 6 July 2007; Accepted 16 August 2007; Published online 12 September 2007.

Abstract

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.