Disorders associated with gastrointestinal polyposis may be classified according to the histological type of the polyps (Hodgson and Murday 1994; see Table 5.2). Adenomatous polyps occur in familial adenomatous polyposis, Turcot syndrome, MUTYH-associated polyposis (Sampson et al. 2009; Vogt et al. 2009), in those with POLE or POLD1 mutations (Palles et al. 2013) and in Lynch syndrome and biallelic MMR mutation carriers and occasionally in Cowden syndrome.
Hamartomatous polyps occur in Peutz–Jeghers syndrome, juvenile polyposis (Hyer et al. 2000; Zhou et al. 2001; Erdman and Barnard 2002), and the hereditary mixed polyposis syndrome (HMPS) (Whitelaw et al. 1997) caused by a single founder GREM1 mutation (Jaeger et al. 2012), Cowden syndrome (Gentry et al. 1978; Eng et al. 2003), Ruvalcaba– Myhre syndrome, McCune–Albright syndrome, and occasionally in Gorlin syndrome. The Cronkhite–Canada syndrome, characterized by hamartomatous (juvenile) polyps throughout the whole intestine and associated with alopecia, onychodystrophy, and abnormal pigmentation of adult onset, is probably not genetic (Daniel et al. 1982) but does predispose to CRC (Zugel et al. 2001).
Table 1 Conditions associated with gastrointestinal polyposis
|1. Adenomatous polyposis|
|FAP (and variants such as Gardner and Turcot)|
|MUTYH-associated polyposis (MAP)|
|CMMRDa (biallelic mismatch repair gene mutations)|
|2. Hamartomatous polyposis|
|Tuberose sclerosis (few, rectal polyps)|
|Hereditary mixed polyposis syndrome DICER1 syndrome (usually few in number)|
|3. Inflammatory polyps|
|Inflammatory bowel disease|
|Neurofibromatosis type 1|
|5. Hyperplastic polyposis (now usually referred to as serrated polyposis)|
aCMMRD – constitutional mismatch repair deficiency
Almost 50 % of cases of juvenile polyposis are due to germline mutations in SMAD4 or BMPR1A, which encode proteins involved in TGF β signaling (Houlston et al. 1998; Howe et al. 2001; Sayed et al. 2002). There is a significant risk of colorectal malignancy in juvenile polyposis and Peutz– Jeghers syndrome. Ganglioneuromatous polyposis may occur in Cowden syndrome, and adenomas and hamartomas may also arise, with malignant potential (Trufant et al. 2011).
Hereditary mixed polyposis syndrome causes an autosomal dominant predisposition to colorectal polyps of varying histological type including sessile, hamartomatous, and adenomatous polyps and early-onset CRC. The locus for the susceptibility gene has been identified as CRAC1 on chromosome 15q in Ashkenazi Jewish families, and the responsible gene, GREM1, has now been identified. Thus far, only one founder mutation (in the AJ population) is known to exist (Jaeger et al. 2012).
Small rectal hamartomatous polyps have recently been described in tuberose sclerosis, but these are thought to be of no clinical significance (Gould et al. 1990). Inflammatory polyps are associated with ulcerative colitis and Crohn’s disease. Gastrointestinal hamartomatous polyps have been noted in those with germ-line DICER1 mutations (Foulkes et al. 2011). Gastrointestinal polyps, predominantly neurofibromas, are found in NF1, possibly in up to 25 % of cases (Hochberg et al. 1974; Cooney and Jewell 2009). A diffuse ganglioneuromatosis of the gastrointestinal tract is described in MEN 2B, with hyperplasia of the ganglion cells, leading to malfunction of the bowel (Fryns and Chrzanowska 1988). Rarely, autosomal dominant inheritance of intestinal neurofibromatosis has been described without other associated manifestations of neurofibromatosis (Heiman et al. 1988).
The juvenile polyps in individuals with McCune–Albright syndrome show some similarities to those seen in PJS, and activating mutations in GNAS have been detected in the polyps. Affected individuals may also have perioral freckling (Zacharin et al. 2011). The Cronkhite–Canada syndrome, characterized by hamartomatous (juvenile) polyps throughout the whole intestine and associated with alopecia, onychodystrophy, and abnormal pigmentation of adult onset, is probably not genetic, but does predispose to CRC (Zugel et al. 2001; Sweetser et al. 2012). Devon polyposis has been described in one family in which multiple inflammatory fibroid polyps were found in the upper gastrointestinal tract in members of three generations of a family from Devon, UK. There did not seem to be an increased risk of cancer in these individuals (Anthony et al. 1984; Allibone et al. 1992).