Notable intrafamilial phenotypic variability in a kindred with familial adenomatous polyposis and an APC mutation in exon 9

Background-The phenotypic spectrum of familial adenomatous polyposis (FAP) varies from the classic appearance of hundreds of adenomatous colonic polyps in the young adult and early onset colorectal cancer, to the occurrence of sparse adenomas in the older adult, "attenuated" FAP, due to mutations at the 5' or 3' ends of the APC gene. Aims-To investigate marked intrafamilial phenotypic variation occurring in a family with an APC gene mutation in exon 9. Patients-An extended kindred of 22 people of whom 16 had colorectal neoplasia and/or were APC mutation carriers. Results-Phenotypic manifestation varied from classic FAP to a complete lack of clinical or endoscopic, or bioptic disease in five people in three different generations. This occurred in four of them over two generations, in spite of having a confirmed 11 bp insertion causing a frame shift and stop codon (363) in exon 9 of the APC gene. Conclusions-At present, it is assumed that in this family there is alternative splicing of the APC gene, and/or unidentified modifying genetic factors. The family illustrates the importance of genetic testing in evaluating carrier status and not just clinical examination. This clinical observation also highlights the dilemma in recognising the possible contribution of low penetrance germline APC mutations to what has been considered "sporadic" colorectal neoplasia.