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

Annette F Baas, Michael Gabbett, Milan Rimac, Minttu Kansikas, Martine Raphael, Rutger Aj Nievelstein, Wayne Nicholls, Johan Offerhaus, Danielle Bodmer, Annekatrin Wernstedt, Birgit Krabichler, Ulrich Strasser, Minna Nyström, Johannes Zschocke, Stephen P Robertson, Mieke M van Haelst, Katharina Wimmer

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37 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)55-61
Number of pages7
JournalEuropean journal of human genetics
Issue number1
Publication statusPublished - Jan 2013


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

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