title: Rhabdomyosarcoma in patients with constitutional mismatch-repair-deficiency syndrome.
abstract: BACKGROUND
  Biallelic germline mutations in the mismatch repair genes MLH1, MSH2, MSH6 or PMS2 cause a recessive childhood cancer syndrome characterised by early-onset malignancies and signs reminiscent of neurofibromatosis type 1 (NF1). Alluding to the underlying genetic defect, we refer to this syndrome as constitutional mismatch repair-deficiency (CMMR-D) syndrome. The tumour spectrum of CMMR-D syndrome includes haematological neoplasias, brain tumours and Lynch syndrome-associated tumours. Other tumours, such as neuroblastoma, Wilm tumour, ovarian neuroectodermal tumour or infantile myofibromatosis, have so far been found only in individual cases.
  
  
  RESULTS
  We analysed two consanguineous families that had members with suspected CMMR-D syndrome who developed rhabdomyosarcoma among other neoplasias. In the first family, we identified a pathogenic PMS2 mutation for which the affected patient was homozygous. In family 2, immunohistochemistry analysis showed isolated loss of PMS2 expression in all tumours in the affected patients, including rhabdomyosarcoma itself and the surrounding normal tissue. Together with the family history and microsatellite instability observed in one tumour this strongly suggests an underlying PMS2 alteration in family 2 also.
  
  
  CONCLUSIONS
  Together, these two new cases show that rhabdomyosarcoma and possibly other embryonic tumours, such as neuroblastoma and Wilm tumour, belong to the tumour spectrum of CMMR-D syndrome. Given the clinical overlap of CMMR-D syndrome with NF1, we suggest careful examination of the family history in patients with embryonic tumours and signs of NF1 as well as analysis of the tumours for loss of one of the mismatch repair genes and microsatellite instability. Subsequent mutation analysis will lead to a definitive diagnosis of the underlying disorder.
authors.affiliation: Division of Clinical Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University Innsbruck, Schoepfstr. 41, 6020 Innsbruck, Austria.
authors.forename: C P
authors.initials: CP
authors.lastname: Kratz
authors.forename: S
authors.initials: S
authors.lastname: Holter
authors.forename: J
authors.initials: J
authors.lastname: Etzler
authors.forename: M
authors.initials: M
authors.lastname: Lauten
authors.forename: A
authors.initials: A
authors.lastname: Pollett
authors.forename: C M
authors.initials: CM
authors.lastname: Niemeyer
authors.forename: S
authors.initials: S
authors.lastname: Gallinger
authors.forename: K
authors.initials: K
authors.lastname: Wimmer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D002648:Child; D053843:DNA Mismatch Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D049914:DNA Repair-Deficiency Disorders / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010375:Pedigree; D012208:Rhabdomyosarcoma / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013577:Syndrome; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes