TY - JOUR
T1 - Agenesis of the corpus callosum and gray matter heterotopia in three patients with constitutional mismatch repair deficiency syndrome
AU - Baas, Annette F
AU - Gabbett, Michael
AU - Rimac, Milan
AU - Kansikas, Minttu
AU - Raphael, Martine
AU - Nievelstein, Rutger Aj
AU - Nicholls, Wayne
AU - Offerhaus, Johan
AU - Bodmer, Danielle
AU - Wernstedt, Annekatrin
AU - Krabichler, Birgit
AU - Strasser, Ulrich
AU - Nyström, Minna
AU - Zschocke, Johannes
AU - Robertson, Stephen P
AU - van Haelst, Mieke M
AU - Wimmer, Katharina
PY - 2013/1
Y1 - 2013/1
N2 - 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.
AB - 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.
KW - Adaptor Proteins, Signal Transducing/genetics
KW - Adenosine Triphosphatases/genetics
KW - Agenesis of Corpus Callosum/genetics
KW - Child
KW - Child, Preschool
KW - Contractile Proteins/genetics
KW - DNA Repair Enzymes/genetics
KW - DNA Repair-Deficiency Disorders/etiology
KW - DNA-Binding Proteins/genetics
KW - Female
KW - Filamins
KW - Glioblastoma/complications
KW - Humans
KW - Male
KW - Malformations of Cortical Development, Group II/genetics
KW - Microfilament Proteins/genetics
KW - Microsatellite Instability
KW - Mismatch Repair Endonuclease PMS2
KW - MutL Protein Homolog 1
KW - Mutation
KW - Nuclear Proteins/genetics
KW - Parotid Neoplasms/complications
KW - Pregnancy
KW - Syndrome
U2 - 10.1038/ejhg.2012.117
DO - 10.1038/ejhg.2012.117
M3 - Article
C2 - 22692065
VL - 21
SP - 55
EP - 61
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
SN - 1018-4813
IS - 1
ER -