Agenesis of the corpus callosum and gray matter heterotopia in three patients with constitutional mismatch repair deficiency syndrome

Eur J Hum Genet. 2013 Jan;21(1):55-61. doi: 10.1038/ejhg.2012.117. Epub 2012 Jun 13.


Constitutional mismatch repair deficiency (CMMR-D) syndrome is a rare inherited childhood cancer predisposition caused by biallelic germline mutations in one of the four mismatch repair (MMR)-genes, MLH1, MSH2, MSH6 or PMS2. Owing to a wide tumor spectrum, the lack of specific clinical features and the overlap with other cancer predisposing syndromes, diagnosis of CMMR-D is often delayed in pediatric cancer patients. Here, we report of three new CMMR-D patients all of whom developed more than one malignancy. The common finding in these three patients is agenesis of the corpus callosum (ACC). Gray matter heterotopia is present in two patients. One of the 57 previously reported CMMR-D patients with brain tumors (therefore all likely had cerebral imaging) also had ACC. With the present report the prevalence of cerebral malformations is at least 4/60 (6.6%). This number is well above the population birth prevalence of 0.09-0.36 live births with these cerebral malformations, suggesting that ACC and heterotopia are features of CMMR-D. Therefore, the presence of cerebral malformations in pediatric cancer patients should alert to the possible diagnosis of CMMR-D. ACC and gray matter heterotopia are the first congenital malformations described to occur at higher frequency in CMMR-D patients than in the general population. Further systematic evaluations of CMMR-D patients are needed to identify possible other malformations associated with this syndrome.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adenosine Triphosphatases / genetics
  • Agenesis of Corpus Callosum / genetics*
  • Agenesis of Corpus Callosum / pathology
  • Child
  • Child, Preschool
  • Contractile Proteins / genetics
  • DNA Repair Enzymes / genetics
  • DNA Repair-Deficiency Disorders / etiology
  • DNA Repair-Deficiency Disorders / genetics*
  • DNA-Binding Proteins / genetics
  • Female
  • Filamins
  • Glioblastoma / complications*
  • Glioblastoma / diagnosis
  • Glioblastoma / genetics
  • Glioblastoma / therapy
  • Humans
  • Male
  • Malformations of Cortical Development, Group II / genetics
  • Malformations of Cortical Development, Group II / pathology*
  • Microfilament Proteins / genetics
  • Microsatellite Instability
  • Mismatch Repair Endonuclease PMS2
  • MutL Protein Homolog 1
  • Mutation
  • Nuclear Proteins / genetics
  • Parotid Neoplasms / complications*
  • Parotid Neoplasms / diagnosis
  • Parotid Neoplasms / genetics
  • Parotid Neoplasms / therapy
  • Pregnancy
  • Syndrome


  • Adaptor Proteins, Signal Transducing
  • Contractile Proteins
  • DNA-Binding Proteins
  • Filamins
  • MLH1 protein, human
  • Microfilament Proteins
  • Nuclear Proteins
  • Adenosine Triphosphatases
  • PMS2 protein, human
  • Mismatch Repair Endonuclease PMS2
  • MutL Protein Homolog 1
  • DNA Repair Enzymes