Familial adenomatous polyposis (FAP) is an autosomal dominant form of
intestinal polyposis and
colorectal cancer caused by germ-line mutations in the
adenomatous polyposis coli (APC) gene. The term
Gardner's syndrome is used to describe extracolonic manifestations, such as
osteomas, skin
cysts, congenital
hypertrophy of the
retinal pigmented epithelium (CHRPE), and
desmoid tumours (
aggressive fibromatosis), that are especially prominent in families with FAP. We postulate that a ciliary dysfunction is the underlying pathogenetic mechanism of extraintestinal manifestations in patients with FAP. This postulation is based on the presence of common clinical manifestations (ie,
cysts,
retinal abnormalities, and
fibrosis) in
Gardner's syndrome and cilia-related disorders. Additionally, both APC and the cilia have degradation of
beta-catenin as the common downstream target in the Wnt-signalling pathway. Mutations in APC causing
Gardner's syndrome are clustered in a region encoding a series of
amino-acid repeats responsible for the binding to
beta-catenin. Proofs of principle that
beta-catenin could be the key mediator of the ciliary disorder also rely in the findings that overexpression of
beta-catenin induces
polycystic kidney disease, and CHRPE phenotypes in animal models. Other candidates for the common link between
Gardner's syndrome and cilia-related disorders are the APC-
binding proteins: end-
binding protein 1 (EB1) and
kinesin-family-member 3a (KIF3a), both of which are ciliary
proteins involved in intraflagellar transport. Finally, pathogenetic similarities between some
ciliopathies and extraintestinal tumours in FAP suggest a cilia defect. Understanding extracolonic manifestations in the context of FAP as a ciliary disorder might add new therapeutic options for patients with
Gardner's syndrome.