History of the Disease

As mentioned before, FAP is a hereditary autosomal dominant disease and the responsible gene is the APC gene, a quite large gene located on chromosome 5q21, of which there are more than 1400 described mutations [3, 4]. The APC mutation is inherited as a germline mutation from the affected parent, but adenomas start their uncontrolled growth only when the second allele has mutated or is inactivated. The coded APC protein plays a critical role in the difficult balance between healthy and diseased cells, since it is responsible for tumour suppression, cellular proliferation, regular differentiation, migration and apop-tosis [5].

This multifactorial regulation produces many extremely different clinical features and the main difficulty lies in relating a peculiar disease to a multifactorial genetic disease. Most likely, before the APC gene was identified, many syndromes were known: Turcot's syndrome (FAP, neoplasia of central nervous system); Gardner's syndrome (intestinal polyps, multiple osteomata, cysts, desmoid tumours, gastro-duodenal polyps, mesenteric fibromatosis, lymphoid hyperplasia of the distal ileum, ileal adenomas and dental abnormalities); Cronkite-Canada syndrome (gastrointestinal polyps, skin hyperpigmentation, nail dystrophy and alopecia) and attenuated FAP (<100 intestinal polyps, primarily located in the right colon) [6,7], which now simply reflect different locations of mutations along the gene.

A recent study in the UK examined 614 families recorded in six regional registries regarding polypo-sis and identified 111 family clusters as having neither the dominant transmission nor evidence of APC mutation. Molecular genetic tests showed the presence of a biallelic mutation in the MYH gene [8] in 25 families.

The MYH gene is responsible for base excision repair mechanisms and its mutations have been shown to produce an autosomal recessive trait expressed by multiple colorectal adenomas and related high risk of colorectal cancer [9,10]. Now we know that FAP can be transmitted not only as an autosomal dominant disease but also as an autosomal recessive trait, a situation that requires a change in how the physicians regard FAP, in genetic counselling, testing and surveillance.

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