VARIABLE PHENOTYPE OF FAMILIAL ADENOMATOUS POLYPOSIS IN PEDIGREES WITH 3' MUTATION IN THE APC GENE

Background-Germline mutation in the adenomatous polyposis coli (APC) g ene on chromosome 5 causes familial adenomatous polyposis. ''Attenuate d'' phenotype has been reported with mutation in the 5' end of the gen e (5' to codon 158), but genotype-phenotype relations at the 3' end (3 ' to codon 1596) have not been described fully. Aims-To describe and c ompare colorectal and extracolonic phenotypes in a case series of fami lies with mutation in the 3' end of the APC gene. Methods-Thirty one a t risk or affected members from four families with a mutation in the A PC gene located at codon 1979 or 2644 were evaluated. Results-Variable intrapedigree colorectal phenotype was observed: some members at olde r age had oligopolyposis (fewer University School of than one hundred colorectal adenomas) Medicine whereas other members had classic polypo sis at young age. Colorectal cancer was diagnosed at older mean age (5 0 (7) years) in the four families than in classic FAP pedigrees (39(14 ) years). Extracolonic lesions characteristic of FAP occurred with 3' APC mutations, but variability in intrapedigree and interpedigree extr acolonic phenotype and dissociation of severity of extracolonic manife stations from number of colorectal polyps was noted. Conclusions-Famil ies with 3' mutations of the APC gene exhibit variable intrapedigree p henotype similar to the heterogeneity noted in families with proximal 5' mutations, Genotyping of FAP and oligopolyposis pedigrees can guide appropriate surveillance of the upper and lower gastrointestinal trac t in affected members.