Phenotypic differences in familial adenomatous polyposis based on APC gene mutation status.

Background: Familial adenomatous polyposis (FAP) is a clinically well defined hereditary disease caused by germline mutations within the adenomatous polyposis coli (APC) gene. Although several techniques are applied in the mutation analysis of FAP kindreds about 20-50% of cases remain unclear, with no APC mutation identified (APC negative).

Aims: To delineate phenotypic differences between APC positive and APC negative patients with respect to colonic and extracolonic disease in order to determine whether additional mechanisms are involved in the pathogenesis of FAP.

Methods: The entire coding region of the APC gene was analysed using single stranded conformation polymorphism and protein truncation tests in 50 Swiss FAP families with a total of 161 affected individuals. Differences in phenotypic manifestation were statistically evaluated by Student's t test, Fisher's exact test, and chi2 test.

Results: Thirty six families (72%) were APC positive. Statistically significant differences between APC positive and APC negative groups were found for the mean age at diagnosis of colonic polyposis (35.2 versus 45.3 years, respectively) and for the occurrence of stomach polyps (14 patients, all APC positive). Additionally, APC negative patients displayed lower polyp numbers at diagnosis and less extracolonic manifestations.

Conclusions: FAP kindreds without detected APC gene mutations present with a notably milder disease phenotype compared with APC positive families, suggesting that different genetic factors might be involved.