Explaining differences in the severity of familial adenomatous polyposis and the search for modifier genes

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Abstract
FAP (OMIM 175100) is an autosomal dominant disorder with a population frequency of approximately 1 in 8000 and a penetrance of almost 100%. The disease is typified by florid adenomatous polyposis of the colon and rectum, although a less severe variant, attenuated adenomatous polyposis (AAPC), also exists. Patients typically present with hundreds to thousands of polyps in the colon. The minimum number for a diagnosis of classical FAP is 100. Progression of one or more of these polyps to carcinoma is almost inevitable unless prophylactic colectomy is undertaken. In addition, FAP is characterised by a number of extracolonic manifestations in some individuals: congenital hypertrophy of the retinal pigment epithelium (CHRPE); epidermoid skin cysts and benign craniofacial and long bone tumours (Gardner's syndrome); fibrous tumours (desmoids) classically sited in the retroperitoneum and abdominal wall; and upper gastrointestinal polyposis. Upper gastrointestinal cancers, especially in the duodenum, are a serious problem in some patients who have undergone prophylactic colectomy. Other malignancies which are seen in a relatively small proportion of FAP patients include non-medullary thyroid cancer and hepatoblastoma. Desmoid disease and duodenal cancer account for the major mortality attributable to FAP in patients who have undergone colectomy.