Genetic abnormalities in 13 of 14 families with concurrent primary brain tumors and multiple colorectal adenomas (Turcot’s syndrome) are reported from the Johns Hopkins University School of Medicine and other centers. Germ-line adenomatous poyposis coli (APC) mutations were present in 10 families. The predominant brain tumor in the families with APC was medulloblastoma, present in 11 of 14 patients (79%). The relative risk of cerebellar medulloblastoma in patients with familial APC was 92 times that in the general population. In the group from birth to 29 years, the risk of brain tumor was increased by a factor of 23. The brain tumor presented after the diagnosis of polyposis in 4 patients and before polyposis was detected in 6. The brain tumor was the cause of death in 7 of the 8 patients who died. Patients with glioblastoma multiforme and colorectal tumors, identified in 4 families, including the original family studied by Turcot, had DNA replication errors characteristic of hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome. Two families with HNPCC had germline mutations in nucleotide mismatch-repair genes. Patients with Turcot’s syndrome can be classified by genetic tests for APC gene mutations and for mutant DNA mismatch-repair genes in peripheral blood lymphocytes, and by evaluating tumor DNA for errors of replication. 
COMMENT. These molecular genetic studies can distinguish the phenotypic characteristics of two types of Turcot’s syndrome, those in whom brain tumor is associated with familial APC and those with HNPCC. Medulloblastoma represents a pleiotropic manifestation of the germ-line APC mutation. Glioblastoma mutiforme, cafe-au-lait spots and colorectal carcinoma in childhood may be associated with HNPCC. Glioblastoma in patients with colorectal cancer has a more favorable prognosis and longer survival than usual. Familial clustering occurs in families with APC, 40% of families having two members with brain tumors. Tumor DNA testing for the incidence of mutations in APC genes in sporadic cases of medulloblastoma would be of interest.