Pediatrics

Gastrointestinal Polyps: Familial adenomatous polyposis (FAP)

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Familial Adenomatous Polyposis? What are the typical findings for this disease?

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome with near complete penetrance whereby hundreds to thousands of polyps develop in the colon. Left untreated 90% of patients will develop colon cancer by 40 years of age.

The majority of children and adolescents with FAP have no gastrointestinal symptoms. Occasionally children with FAP can present with rectal bleeding sometimes associated with mucus. When present gastrointestinal symptoms usually develop in the second or third decade of life in patients with FAP.

The pediatric patient may have a range of polyps from zero to thousands. Pediatric patients who present with symptoms most likely have a severe polyposis phenotype. Patients with attenuated FAP (AFAP) develop fewer polyps at later ages and therefore have a more mild polyposis phenotype.

Virtually all patients with FAP will eventually develop adenocarcinoma of the colon or rectum if left untreated. Rarely young patients with FAP can present with extraintestinal tumors associated with FAP. Extracolonic benign tumors include sebaceous cysts, desmoid tumors, and osteomas of the jaw.

Polyp Development

Polyps in classic FAP develop during the first and second decade of life. Polyp development in classic FAP occurs in the rectosigmoid. Polyps less than 2 mm are often difficult to see without dye spray.

Screening for FAP

If genetic testing in a family member with FAP is informative (APC mutation identifed) genetic counselling and genetic testing can be offered to other at risk family members. Most centers offer genotyping beginning at 10 to 12 years of age. Mutation testing permits the identification of gene carriers and avoids unnecessary surveillance in non-carriers.

At least half of children and adolescents evaluated for FAP are identified in the context of a postive family history of FAP. Current clinical screening recommendations for all first-degree relatives of patients with FAP include annual sigmoidscopy beginning at 10 to 12 years of age. Once polyps are identified annual colonoscopy is recommended. Upper endoscopy starting in adulthood.

In kindreds with AFAP screening recommendations are different. In contrast to classic FAP whereby polyps generally develop in the sigmoid colon initially the polyps in AFAP develop initially in the right colon. Consequently a full colonoscopy is required to assess the right colon beginning at 16 to 18 years or onset of symptoms. Annual colonoscopy recommended in AFAP after polyps identified.

Recognition of characteristic bilateral congenital hypertrophy of the retinal pigmented epithelium (CHRPE) on routinue opthalmologic evaluation may raise the suspicion of underlying FAP. However, people without FAP can also be found with CHRPE and not all FAP patients have CHRPE.

What other disease/condition shares some of these symptoms?

The majority of children and adolescents with FAP are asymptomatic although patients can present with rectal bleeding. Generally these patients have a severe phenotype with extensive polyposis. Prior to diagnosis at colonoscopy the clinical picture may be suggestive of inflammatory bowel disease.

The presence of adenomatous polyps in a child or teen must raise the question of an underlying genetic predisposition to colorectal cancer. Adenomatous polyps are also found in MYH associated polyposis (MAP). Very rarely children and adolescents have been reported with polyps and MAP. To date the majority of patients with MYHmutations and polyps are adults. As more prospective phenotypic data is collected evaluating young patients with MYH mutations our understanding of MAP will expand.

Other rare conditions with multiple adenomatous polyps in childhood or young adulthood includes patients with biallelic Lynch mutations. These patients typically have cafe-au-lait macules and are at risk of a novel childhood cancer syndrome associated with bi-allelic DNA mismatch repair (MMR) genes. The distinct syndrome is characterized by brain tumors, leukemias, lymphomsa and early onset colorectal cancer. The families often have no immediate family history of Lynch syndrome related cancers and consanguinity is frequent.

Very rarely colorectal cancer can present with rectal bleeding during adolescence. Any colorectal cancer in a pediatric patient must be considered to have an underlying genetic cause.

What caused this disease to develop at this time?

FAP is an autosomal dominant inherited disease with near complete penetrance. Family history may include early onset colorectal cancer or a history of extensive polyposis possibly in multiple generations. In some patients routine opthalmological evaluation may identify congenital hypertrophy of the retinal pigment epithelium (CHRPE) which raises the question of possible FAP. Patients with more severe mutations may present earlier with rectal bleeding. Physical examination is usually unremarkable. Occasionally sebaceous cysts, or a desmoid tumor can be found on examination. Genotyping is recommended if there is a known mutation in the kindred.

Genetics

The adenomatous polyposis coli (APC) gene is located on chromosome 5 and is a tumor suppressor gene. Most mutations are small deletions or insertions that result in the production of a truncated APC protein. In FAP a germline mutation inactivates one of the two APC alleles that underlie the predisposition to adenoma formation. Over 730 germline APC mutations have been identified. Approximately 25% of FAP patients without a family history of the disease appear to have "new mutations".

Much research has evaluated genotype-phenotype correlations in FAP. Mutations at codons 1309 account for a more severe colonic polyposis phenotype and earlier onset of colorectal cancer. Mutations more commonly associated with desmoid tumor formation in FAP tend to have a less severe polyposis phenotype. Genotype-phenotype correlation is not absolute. Within kindreds there is phenotypic variation suggesting that factors apart from genotype affects ultimate disease expression.

It is a challenge when APC mutations are identified which are unclassified genetic variants or variants of unknown significance.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Diagnosis requires colonoscopy with polypectomy and/or biopsy of polyps. Histologic review of polyps by the pathologist will confirm the presence of adenomatous polyps although it can be difficult to determine the degree of dysplasia. By definition any adenomatous polyp has "low grade dysplasia".

FAP is characterized by hundreds to thousands of adenomatous polyps in the colon and rectum. Attenuated FAP (AFAP) is a less severe phenotype with fewer polyps developing initially in the right colon. If AFAP is suspected a colonoscopy is required to assess the right colon as polyp burden in the rectum/sigmoid can be absent or minimal.

Would imaging studies be helpful? If so, which ones?

Currently colonic endoscopic evaluation and polypectomy and or biopsy of polyps is recommended. Upper endoscopy starting in adulthood with frequency of surveillance based on endoscopic findings. MRE and capsule endoscopy to evaluate the small bowel is currently under investigation. Extremity masses can be evaluated by MRI to assess for desmoid.

If you are able to confirm that the patient has Familial Adenomatous Polyposis, what treatment should be initiated?

Education of the patient and family about the condition, it's therapy, its associated long-term implications and the need for chronic follow-up is critical. Genetic counseling and psychosocial support is also crucial.

Referral to a gastroenterologist to determine if annual colonoscopy with polypectomy is an option.

Referral to a surgeon for consideration of possible colectomy if the patient has a severe phenotype with a large polyp burden. The timing of colectomy is a difficult judgement and is based on the severity of the polyposis phenotype.

Cyclooxygenase-2 inhibitors have shown some promise in managing the polyp burden in adults with FAP, but little data on this is available in pediatric patients. A controlled trial of cyclooxygenase-2 inhibitor therapy in pediatric is currently underway.

Management options

Colectomy is the only effective treatment to prevent colorectal cancer. In patients with high grade dysplasia or hundreds of polyps, colectomy is recommended.

In patients with a mild polyposis phenotype and family history of desmoid tumor, most experts advocate delaying colectomy as intraabdominal surgery increases the risk of desmoid development. In these patients, annual colonoscopy and polypectomy can delay colectomy.

Surgical options include subtotal colectomy with ileorectal anastomosis, or restorative proctocolectomy with ileo-anal anastomosis (pouch procedure). Patients with ileorectal anastomosis require ongoing surveillance of the rectum as the rectum is at risk of cancer. The surgical decision is best left with surgeons with experience in managing patients with FAP.

What are the possible outcomes of Familial Adenomatous Polyposis?

Endoscopic surveillance and prophylactic colectomy in FAP have reduced mortality from colorectal cancer and improved survival. Consequently research now is focusing on surveillance strategies to prevent duodenal cancer in FAP. Upper endoscopy is recommended starting in adulthood. Fundic gland polyps are reported in 20% to 84% of adult patients.

What causes this disease and how frequent is it?

Frequency of FAP in the general population is 1:13 528. Presence of FAP in colorectal cancer incident cases 0.07%.

What is the evidence?

Jasperson, KW, Tuohy, TM, Neklason, DW, Burt, RW. "Hereditary and familial colon cancer". Gastroenterology.. vol. 138. 2010. pp. 2044-2058.

(Excellent background reference.)

Durno, CA, Wong, J, Berk, T, Alingary, N, Cohen, Z, Esplen, MJ. "Quality of life and functional outcome for individuals who underwent very early colectomy for familial adenomatous polyposis". Dis Colon Rectum.. vol. 55. 2012. pp. 436-443.

(Pediatric focus.)

Mireskandari, S, Sangster, J, Meiser, B. "Psychosocial impact of familial adenomatous polyposis on young adults: a qualitative study". J Genet Counsel.. vol. 18. 2009. pp. 409-417.

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