A recent cross-sectional study (PP Stanich et al. Clin Gastroenterol Hepatol 2019; 17: 2008-15, editorial 1942-44) identified a high frequency of genetic mutations among adults with at least 10 colonic polyps (cumulative burden of either adenomatous or hamartomatous).
This study had 3789 subjects who underwent multigene panel testing (MGPT) from 2012-16.
- All subjects had at least 14 CRC-associated genes tested: APC, BMPR1A, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, TP53
- A subset had 3 more newly recognized polyposis genes: GREM1, POLD1, and POLE
- A mutation in at least 1 gene was found in 13.7%
- In those with fewer than 20 cumulative adenomas, 7.6% had a disease-associated genetic mutation with the majority (5.3%) being nonpolyposis CRC genes
- Younger patients, 18-29, were more likely to have mutations in any gene. For example, among patients with 10-19 polyps, these younger patients had a mutation in one of these genes in 27.8%; this is more than double the rate in any other age group.
- Hamartomatous polyps, regardless of number, had a very high yield with genetic testing: 40% with 10-19 polyps and 72% with 20-99 polyps.
- There is a referral bias in that the population was derived from a testing laboratory (Ambry)
- In clinical practice, genetic testing frequently results in variants of unknown significance
My take: This study shows that genetic mutations are fairly frequent in patients with cumulative polyp burden of 10 or more, especially in younger age groups. The surprising finding is the high frequency of nonpolyposis CRC genes. Thus, in patients with adenomatous polyposis, testing beyond APC and MUTYH may be needed.
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A recent review article (SP MacFarland et al. JPGN 2019; 69: 273-80) provides clearcut guidelines on polyposis syndromes in pediatric patients.
Table 1 lists the syndrome, the mutated gene (s), and recommended screening (onset & interval). The article and table provide more nuance/guidance but the basic recommendations are noted as follows:
- For Familial Adenomatous Polyposis (FAP), the authors recommend onset of colonoscopy at 10 years and with 1 year intervals. “Colectomy recommended by 20 to 25 years.” EGD is recommended at 18 to 20 years. Thyroid ultrasound is recommended at 18 years. Alpha-fetoprotein levels to check for hepatoblastoma are recommneded every 3-6 months in infancy up to 5 years of age.
- For Juvenile Polyposis Syndrome, EGD and Colonoscopy are recommended at 15 years with interval evaluations at 1-3 years.
- For Peutz-Jeghers syndrome, EGD and Colonoscopy are recommended at 8 to 10 years (along with small bowel evaluation with either MRE or video capsule). Interval followup is recommended every 2-3 years.
Table 2 provides suggestions for familial screening in pediatric polyposis syndromes.
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Management of Familial Adenomatous Polyposis in Children and Adolescents: A Position Paper from the ESPGHAN Polyposis Working Group: Link: JPGN 2019; 68 (3): 442-441
Unlike some working groups, the working group for ESPGAN Polyposis did not equivocate in making clear cut recommendations, especially for recommendations #6a and #6b, for Familial Adenomatous Polyposis (FAP) in children.
- SOME OF THE RECOMMENDATIONS
Recommendation 1: Predictive genetic testing should be offered to at-risk children at the age of 12 to 14 years. Families should receive genetic counselling before and at the time of testing. Children who are symptomatic with rectal bleeding should undergo earlier testing. (weak recommendation, low-quality evidence, consensus agreement 100%)
- Recommendation 3: In those confirmed to have FAP on predictive genetic testing, and those considered at risk where genetic testing is not possible, colonic surveillance should commence age 12 to 14 years. Once adenomas have been identified, intervals between surveillance colonoscopy should be individualized depending on colonic phenotype every 1 to 3 years. Rectal bleeding or mucous discharge should lead to a colonoscopy at any age. (weak recommendation, low-quality evidence, consensus agreement 100%)
- Recommendation 4: Colectomy is necessary to prevent CRC in adulthood. Decision on the timing for colectomy should be determined by polyp burden and characteristics of colonic adenomas in the context of social, personal, and educational factors. IRA or IPAA have their merits and disadvantages and many factors impact on the choice of surgery. The choice should be based on patient phenotype (rectal and colonic burden) and genotype, at the discretion of the surgeon. (weak recommendation, low-quality evidence, consensus agreement 100%)
- Recommendation 5: Despite the presence of gastric polyps in children, and the
later risk of duodenal polyposis and ampullary cancer in adult practice, there is no justification to commence routine UGI surveillance until the age of 25 years.
(weak recommendation, low-quality evidence, consensus agreement 90%)
- Recommendation 6a: Routine screening for HPB [Hepatoblastoma] in patients with FAP is not recommended. In children found to have HPB, there is no evidence that routine genetic testing or endoscopic screening for FAP is required.
(weak recommendation, low-quality evidence, consensus agreement 100%)
- Recommendation 6b: Children with bilateral and multiple CHRPE [congenital hypertrophy of retinal pigment epithelium] lesions should
undergo colonoscopy at age 12 to 14 years. If CHRPE lesions are single or unilateral in the absence of relevant family history, further evaluation should not be required. (weak recommendation, low-quality evidence, consensus agreement 100%)
- Recommendation 6c: The vast majority of desmoids tumours are sporadic; children identified to have a DT have approximately 10% risk of FAP. If the kindred is known to have FAP and the child has a desmoid, it should be presumed the child has FAP. In a child presenting with a DT, testing the DT for a b-catenin /CTNNB1 mutation is recommended. If a b-catenin /CTNNB1 mutation is found, this indicates sporadic desmoid and further investigations for FAP are not required. If b-catenin /CTNNB1 mutation is not found, the patient should be investigated for FAP. (weak recommendation, low-quality evidence, consensus agreement 100%)
- Recommendation 7: There is no role for the use of chemoprevention agents in
children with FAP. (strong recommendation; moderate-quality evidence, 100%
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In their introduction (KP Quinn et al. Clin Gastroenterol Hepatol 2016; 14: 1296-1301), the authors state the following: “Despite the widely held notion that pouchitis is a rare complication in FAP following IPAA, clinical experience at our institution suggests [it]…is underestimated.”
Methods: retrospective cohort study of all FAP patients who underwent IPAA (ileal ouch-anal anastomosis) from 1992-2015 at their institution (Mayo clinic), n=113.
- 25 (22.1%) developed pouchitis with a mean time to pouchitis of 4.1 years.
- Of the 25 who developed pouchitis, 72% had an acute course and 28% had a chronic course.
My take: While pouchitis does occur more commonly in IBD following IPAA, it does occur with FAP more frequently than previously described.
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Here’s a link to abstract: Updated Guidelines on Genetic Testing/Management for Hereditary GI Cancer Syndromes (The American Journal of Gastroenterology 110, 223-262 (February 2015) | doi:10.1038/ajg.2014.435). This ACG guideline specifically discusses genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), Peutz–Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer.
I glanced at the guideline –it is about 40 pages in length. It provides a lot of in-depth information on these infrequent disorders.
Some online resources for similar information: