eMedicine Specialties > Gastroenterology > Systemic Disease

Familial Adenomatous Polyposis

Author: Mohammad Wehbi, MD, Assistant Professor of Medicine, Associate Program Director, Department of Gastroenterology, Atlanta Veterans Affairs Medical Center, Emory University School of Medicine
Coauthor(s): Nicole M Griglione, MD, Staff Physician, Department of Medicine, Emory University School of Medicine; Vincent W Yang, MD, PhD, R Bruce Logue Professor, Director, Division of Digestive Diseases, Department of Medicine, Professor of Hematology and Oncology, Winship Cancer Institute, Emory University School of Medicine; Kamil Obideen, MD, Assistant Professor of Medicine, Division of Digestive Diseases, Emory University School of Medicine; Consulting Staff, Division of Gastrointestinal Endoscopy, Atlanta Veterans Affairs Medical Center; Jae W Nam, MD, Fellow in Gastroenterology, Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine; Consulting Staff, Department of Critical Care, Decatur Hospital; John M Carethers, MD, Professor of Medicine, Chief, Division of Gastroenterology, Department of Medicine, University of California at San Diego
Contributor Information and Disclosures

Updated: Dec 7, 2009

Introduction

Background

Familial adenomatous polyposis (FAP) is the most common adenomatous polyposis syndrome. It is an autosomal dominant inherited disorder characterized by the early onset of hundreds to thousands of adenomatous polyps throughout the colon. If left untreated, all patients with this syndrome develop colon cancer by age 35-40 years. In addition, an increased risk exists for the development of other malignancies. (See image below and Image 1.)

Syndromes with a germline mutation in the APC gene include FAP, Gardner syndrome, some families with Turcot syndrome, and attenuated adenomatous polyposis coli (AAPC). Gardner syndrome is characterized by colonic polyposis typical of FAP, along with osteomas (bony growth most commonly on the skull and the mandible), dental abnormalities, and soft tissue tumors. Turcot syndrome is characterized by colonic polyposis typical of FAP, along with central nervous system tumors (medulloblastoma). AAPC is characterized by fewer colonic polyps (average number of polyps, 30-35) as compared to classic FAP. The polyps also tend to develop at a later age (average age, 36 y), and they tend to involve the proximal colonic area.

In considering the spectrum of polyposis syndromes, patients with multiple adenomatous polyps most likely have FAP (or one of its variants), AAPC, or MYH-associated polyposis (MAP). If a patient with a suspected polyposis syndrome undergoes genetic testing and does not have an APC gene mutation, MYH gene testing should be performed to assess for MAP, as 10-20% of patients who do not have an APC gene mutation have biallelic MYH gene mutations.¹

The phenotype of MAP is often indistinguishable from FAP or AAPC, with patients having usually 10-100 polyps but sometimes more than 100. The age of onset of MAP is usually in patients older than 45 years, and patients often present symptomatically, with colorectal carcinoma commonly found at the time of diagnosis. This is in part because there is usually no family history given the autosomal recessive inheritance pattern of MAP. Duodenal polyps can be found in up to one fifth of patients.² There is no increased risk of other types of cancers associated with this syndrome.

Pathophysiology

The APC gene is a tumor suppressor gene that is located on band 5q21. Its function is not completely understood but has been shown to play a part in metaphase chromosome alignment.³ Normal APC protein promotes apoptosis in colonic cells. Its most important function may be to sequester the growth stimulatory effects of b-catenin, a protein that transcriptionally activates growth-associated genes in conjunction with tissue-coding factors. Mutations of the APC gene result in a truncated/nonfunctional protein.

The resultant loss of APC function prevents apoptosis and allows b-catenin to accumulate intracellularly and to stimulate cell growth with the consequent development of adenomas. As the clonal expansion of cells that lack APC function occurs, their rapid growth increases the possibility for other growth-advantageous genetic events to occur. This causes alterations in the expression of a variety of genes, thereby affecting the proliferation, differentiation, migration, and apoptosis of cells.

Ultimately, enough genetic events happen that allow the adenomatous polyps to become malignant in patients with FAP. This process is similar to that which occurs in sporadic adenomas. As a result, APC is considered the gatekeeper of colonic neoplasia. Its mutation/inactivation is the initial step in the development of colorectal cancer in patients with FAP.

Germline (ie, inherited) mutations of the APC gene, as is the case with FAP, result in cells containing 1 mutated copy and 1 normal copy of the gene. Patients inherit one mutated APC allele from an affected parent, and adenomas develop as the second allele from the unaffected parent becomes mutated or lost. Consequently, every colonic epithelial cell in patients with FAP has 1 mutated APC allele. Inactivation of the remaining normal copy of the APC gene, by deletion or mutation, completely removes the tumor suppressive function of APC, thus initiating the growth of adenomatous polyps. Inactivation of the second APC allele occurs frequently in the colon, resulting in the development of numerous adenomas.

Frequency

United States

Estimates vary from 1 case in 6,850 persons to 1 case in 31,250 persons.

International

The frequency is constant worldwide.

Mortality/Morbidity

• The principal cause of mortality is colorectal cancer, which develops in all patients unless they are treated. The mean age at which colorectal cancer develops in patients with classic FAP is 39 years. Patients with adenomatous polyposis itself often are asymptomatic.
• The second reported lethal complication of FAP is diffuse mesenteric fibromatosis and is referred to as a desmoid tumor. It involves intra-abdominal organs and vessels, causing gastrointestinal obstruction and constriction of veins, arteries, and ureters. Desmoid tumors are reported in 4-32% of patients. Even after the appropriate surgical treatment of FAP, 20% of patients may develop desmoid tumors after colectomy. Studies have not found a correlation between specific APC mutation sites and desmoid tumor development.⁴ Risk factors include a positive family history. The mortality from these tumors is 10-50%. The second most common malignancy in patients with FAP is adenocarcinoma of the duodenum and the papilla of Vater. It affects as many as 12% of patients.
• Rarer cancers associated with FAP include medulloblastomas (Turcot syndrome), hepatoblastoma, thyroid cancer, gastric cancer, pancreatic cancer, and adrenal cancer.⁵

Race

• FAP has been described in all races.

Sex

• The male-to-female ratio is 1:1.

Age

• The average age of onset of polyposis in FAP is 16 years.
• The average age of onset for colorectal cancer is 39 years.
• The average age of onset for polyps in AAPC is 36 years, and the average age of onset for cancer in AAPC is 54 years. These patients have fewer polyps (approximately 30 polyps) compared to patients with FAP.

Clinical

History

• Most patients with FAP are asymptomatic until they develop cancer. As a result, diagnosing presymptomatic patients is essential.
• Of patients with FAP, 75-80% have a family history of polyps and/or colorectal cancer at age 40 years or younger.
• Nonspecific symptoms, such as unexplained rectal bleeding (hematochezia), diarrhea, or abdominal pain, in young patients may be suggestive of FAP.

Physical

• Congenital hypertrophy of the retinal pigment epithelium is highly specific for FAP and is best seen by slit-lamp examination.
  • They are discrete flat pigmented lesions of the retina. They are often multiple (63%) and bilateral (87%). They do not cause any clinical problems.
  • They indicate that a family member has inherited the gene that causes FAP and is at risk. As a result, they precede polyposis and correlate with mutations between exons 9 and 15 of the gene that causes FAP.
• Some lesions are indicative of a Gardner variant of FAP.
  • Osteomas (painless bony overgrowth) of the skull and the mandible may be present. They usually precede the clinical or radiologic diagnosis of intestinal polyposis.
  • Dental abnormalities, often diagnosed by using x-ray films, may include supernumerary teeth, impacted teeth, dentigerous cysts, and odontomas.
  • In prepubescent patients, epidermoid cysts on the legs, face, scalp, and arms may be present. They are the most common cutaneous manifestation of Gardner syndrome. These cysts are benign and mainly pose a cosmetic concern.
  • Fibromas may be present, located on the scalp, shoulders, arms, and back.
• Desmoid tumors are discussed in Mortality/Morbidity.
• Juvenile nasopharyngeal angiofibromas (JNA) are a rare, invasive, destructive tumor of the nasopharynx that can be sporadic or associated with FAP.⁶
• Fundic gland polyps (FGP) are found in most patients, half of whom will also have dysplastic polyps.⁷ Dysplasia is associated with increased severity of antral gastritis and duodenal polyposis. Acid-suppressive therapy appears to be protective against dysplasia. Helicobacter pylori association is rare.
• A palpable abdominal mass in a young patient is suggestive of FAP.
• A palpable mass upon rectal examination in a young patient is suggestive of FAP.

Causes

• FAP is caused by a germline mutation of the APC tumor suppressor gene, located on band 5q21.
• Most mutations of the APC gene are nonsense or frameshift mutations, leading to truncation of the APC protein (nonfunctional protein).
• More virulent forms of FAP are associated with a mutation in exon 15 between codons 1250 and 1464, the middle portion of the gene.⁸
• In patients with AAPC, mutations of the APC gene occur at the extreme amino terminus of the protein.

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