Familial Adenomatous Polyposis (FAP)

Inherited as an autosomal dominant pattern with offspring having a 50% risk of inheriting a gene mutation (APC).

FAP Is most commonly caused by pathogenic germline variants in the adenomatous polyposis coll (APC) gene.
Carries a lifetime risk of colorectal cancer of 100% if left untreated.
Attenuated FAP is a form of the disease with lower severity, delayed onset of polyps, fewer polyps 0-100, and lower risk of colorectal cancer of 70%.  
It is characterized by progressive development of hundreds to thousands of adenomatous polyps in the lower G.I. tract, mainly in the colon and rectum.
Upper gastrointestinal tract polyposis develops in the duodenum in more than 80% of patients with FAP, and duodenal or periampullary cancer occurs in 5-12% of these patients.

Makes up 1-2% of hereditary type colorectal cancers.

 Up to 30% of cases of FAP  are due to de novo APC Mutations.
Incidence is one in 10,000, consistent in all populations.
It presents most often in early adolescence with gastrointestinal symptoms that are non-specific.

Mutations in APC gene located on chromosome 5q21-q22.

Related to the inheritance of a single copy of the mutated adenomatous polyposis coli, a tumor suppressor gene.

Caused by germline mutations in the adenomatous polyposis coli (APC ) gene.

A somatic mutation in the wild-type APC allele leads to the development of dysplastic aberrant crypt foci which causes small adenoma.

Clinical features that warrant genetic studies for FAP include: the family or personal history of early onset colorectal cancer and extra intestinal features including congenital hypertrophy of the retinal pigmental epithelium, osteomas, and desmoid tumors.

Inactivation of both alleles of the adenomatous polyposis coli (APC) gene are among the earliest events in the transition to a malignant process.

The APC tumor suppressor gene proteins is the negative regulator of the Wnt/beta-cats in in signaling pathway and plays a significant role in the maintenance of intestinal epithelial homeostasis.
Inactivation of the APC gene leads to stimulation of this pathway, resulting in acquiring beta-dateline the ability to translocate into the cell nucleus and stimulate proliferation leading to polyp formation.
Microbes that participate in the dysregulation of the W t/beta-catelin signaling pathway contribute to the initiation of cancerogenesis.
Testing for APC gene should be considered when there are more than 20 adenomas in the colon or rectum over the lifetime of a patient, a known diagnosis of FAP in the family, and more than 10 adenomas evident on a single colonoscopy.

Mutations in the activation of K-ras occurs early in the process of malignant transformation.

Loss of heterozygosity in chromosome 18q, which causes loss of tumor suppressor genes DCC, DPC4,and MADR2, initiates changes of the adenoma to a malignant transformation.

Gene end product plays a role in the Wnt/Beta-catenin signaling pahway. Affected individuals develop more than 100 polyps.

Colonic polyps typically appear in early teens.

Familial adenomatous polyposis-affects one in 10,000 people.

Average age of diagnosis is 39 years.

If left untreated colon cancer will develop when patients are in their forties.

Patients commonly have gastroduodenal polyps and can have duodenal and periampullary cancers.

Patients with FAP have more than a 100 fold lifetime risk of developing duodenal cancer.

Patients may have hundreds to thousands of adenomatous polyps in the colorectum and nearly 100% lifetime risk of colorectal cancer.

Ampullary and duodenal malignancies are the second leading cancer related causes of death.

Extracolonic manifestations include: fundic gland polyps, duodenal adenomas, epidermoid cysts, desmoid tumors, osteomas, retina pigment hyperplasia, and thyroid cancer.

Duodenal polyps identified in approximately 95% of FAP patients.

Presently, duodenal and desmoid tumors are the most common causes in the FAP population.

Patients a great risk for duodenal neoplasia, with duodenal adenomas eventually forming in more than 50% of patients and duodenal adenocarcinoma occurring in up to 12%.

Treatment for 6 months with the COX-2 inhibitor sulindac combined with tyrosine kinase inhibitor erlotinib alert terminated reduces duodenal polyp burden and polyp number.

4-38% of patients develop desmoid tumors.

100% lifetime risk of developing colorectal cancer.

First degree relatives of patients with familial adenomatous polyposis should undergo colonoscopy beginning at age 12.

If the syndrome is diagnosed at age 12 colectomy is recommended to prevent colon cancer.

Prophylactic colectomy usually needed once diffuse polyposis is documented.

Prophylactic colectomy has become the standard of care, once the extent of polyposis is beyond endoscopic control and abrogates the risk of colorectal cancer.

A total colectomy is the preferred procedure but in some cases a subtotal colectomy is reasonable.

If a subtotal colectomy is performed endoscopic surveillance of the residual rectum should be performed at 6 month intervals.

Among patients who have undergone an initial colectomy and iliorectal anastomosis, protectomy  with ileal pouch-anal anastomoses  resection is performed in up to 30% of patients because of progressive polyposis or Cancer.
Colectomy and proctocolectomy are associated with complications including: diarrhea, fecal incontinence, adverse sexual function, fertility and health related quality-of-life.
In the majority of patients with FAP, management of duodenal adenomas is necessary as Mesenteric desmoid tumors may also develop in these patients.

Lifelong surveillance for cancers in extracolonic sites is indicated with upper gastrointestinal gastroscopy every 1-3 years with ampulla biopsy, even if it appears normal.

Annual thyroid examinations are recommended.

Screening for childhood hepatoblastomas with ultrasound exams of the liver, and alpha fetoprotein tests should be considered.

Attenuated FAP refers to a less aggressive process with 90% without an identifiable APC mutationans have fewer than 100 polyps.

Colonoscopy is effective in reducing risk of colorectal cancer in patients with FAP until the polyp burden increases beyond endoscopic control.
Colonoscopy should begin by age 10-12 years and repeated annually.
Colonoscopy for attenuated FAP can be stored in the late teens in repeat everyone-two years.

Following a colectomy, duodenal adenocarcinoma is the leading cause of cancer death in these patients.

Prevention of duodenal adenocarcinomas by endoscopic surveillance with polyp resection, duodenectomy, Whipple surgical procedure and ampullectomy are still suboptimal choices.

Among patients with FAP the use of sulindac and erlotinib compared with placebo results in lower duodenal polyp burden after six months.

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