In humans, alteration of the tumor suppressor gene, APC, causes adenomatous polyposis coli, a condition causing predisposition to colorectal cancer. The syndrome inconsistently associates characteristic patches of congenital hypertrophy of the retinal pigment epithelium (CHRPE). Ocular examination revealed that patients expressing CHRPE tend to cluster within specific families. The exact APC mutation was identified in 42 unrelated patients. In all cases these mutations were predicted to lead to the synthesis of a truncated protein. The extent of CHRPE was found to be dependent on the position of the mutation along the coding sequence. CHRPE lesions are almost always absent if the mutation occurs before exon 9, but are systematically present if it occurs after this exon. Thus, the range of phenotypic expression observed among affected patients may result in part from different allelic manifestations of APC mutations.