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attenuated familial adenomatous polyposis

Saturday 1 December 2012

"attenuated FAP" (attenuated familial adenomatous polyposis); AFAP phenotype

The concept that AFAP is invariably characterized by less than 100 adenomas has been disputed following the use of dye-spray during colonoscopy.

Four subjects had a family history consistent with FAP but had less than 20 adenomas on standard colonoscopy.

In each of the subjects, the use of dye-spray highlighted over 1000 adenomas. These were sufficiently large to be recognized and counted within the subsequent colectomy specimen. In a more recent series of genetically proven cases of AFAP, 12 of 24 subjects with a formal polyp count had >100 adenomas, and 7 of these had >500 adenomas.

While true AFAP does exist, these findings raise the possibility that many cases of AFAP are in fact classical FAP in which the majority of adenomas remain relatively small.

The preceding data highlight the importance of obtaining at least an estimate of total polyp numbers.

In surgical specimens, the total polyp number can be counted within the area of a plastic 35 mm slide that is approximately 10 cm2.

If counting is repeated in each region of the bowel and the approximate mucosal area of each region is obtained, then one can calculate the total number of polyps per region and for the entire bowel.

It is suggested that only lesions 2 mm or greater should be counted as polyps. Below that size, minor mucosal irregularities or lymphoid polyps cannot be reliably distinguished from adenomas. Nevertheless, there may be plentiful micro-adenomas @<@2 mm in size.

Index case

The concept of AFAP began with the documentation of a large ‘multiple adenoma family’ characterized by the presence of less than 100 adenomas per subject. The adenomas were mainly proximally located, tended to be flat, and colorectal cancers were relatively late in onset. There was a lack of extra-colorectal features.

This family was originally diagnosed as having Lynch syndrome or hereditary non-polyposis colorectal cancer (HNPCC), and this led to the concept of flat adenomas being characteristic of Lynch syndrome/HNPCC.

Because adenomas in Lynch syndrome are more likely to be proximally located and proximal adenomas are more likely than distal adenomas to be flat, there is probably a weak connection between flat adenomas and both AFAP and Lynch syndrome. However, it is likely that the more definitive connection is between flatness and anatomic (proximal) location.

Linkage to 5q21 and the presence of pathogenic mutations in APC identified the ‘flat adenoma syndrome’ as a form of AFAP and excluded the diagnosis of Lynch syndrome.

In fact it is unusual to find multiple adenomas in subjects with Lynch syndrome. In a series of 22 adenoma-positive patients with a proven germline mutation in a DNA mismatch repair and under strict colonoscopic surveillance, most subjects had only one adenoma, and only three had three adenomas.


The AFAP phenotype is associated with germline mutations in specific regions of the APC gene: 5′ in codons 78–167, 3′ in codons 1581–2843, and in exon 9.