Heterozygous mutations in one of the DNA mismatch repair genes cause hereditary 
nonpolyposis colorectal cancer (MIM114500). Turcot syndrome (MIM276300) has been 
described as the association of central nervous system malignant tumors and 
familial colorectal cancer and has been reported to be both a dominant and 
recessive disorder. Homozygous and compound heterozygous mutations in APC, MLH1, 
MSH2, and PMS2 genes have been reported in five families. Here we describe a 
nonconsanguineous Pakistani family, including a son with lymphoma and colorectal 
cancer diagnosed at ages 5 and 8, respectively, and an 8-year-old daughter with 
glioblastoma multiforme. Both children had features of neurofibromatosis type 1 
including atypical café au lait spots and axillary freckling without a family 
history consistent with neurofibromatosis type 1, familial adenomatous 
polyposis, or hereditary nonpolyposis colorectal cancer. Mutational analysis was 
done for MLH1, MSH2, and MSH6 using denaturing high-performance liquid 
chromatography and sequencing of a blood sample from the daughter. A novel 
homozygous single base insertion mutation was identified (3634insT) resulting in 
a premature stop at codon 1,223 in exon 7 of the MSH6 gene. Both parents were 
found to be heterozygous for the 3634insT mutation. Microsatellite instability 
testing showed instability in the glioblastoma sample. We report here the first 
identification of a homozygous mutation in MSH6 in a family with childhood-onset 
brain tumor, lymphoma, colorectal cancer, and neurofibromatosis type 1 
phenotype. Our findings support a role for MSH6 in Turcot syndrome and are 
consistent with an autosomal recessive mode of inheritance.