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Familial adenomatous polyposis (FAP) is an inherited condition in which numerous polyps to form in the epithelium of the large intestine. While these are benign, they may become malignant, predisposing patients to colorectal cancer.
Signs and symptoms
From the age of 16 onward, patients develop hundreds to thousands of polyps. These may bleed, leading to admixture of blood in the stool. If the blood is not visible, it is still possible for the patient to develop anemia due to gradually developing iron deficiency. If malignancy develops (the median age in FAP patients is about 40), this may present with weight loss, altered bowel habit, or even with metastasis in the liver or elsewhere.
The genetic determinant in familial polyposis may also predispose carriers to other malignancies, e.g. of the duodenum and stomach. Other signs that may point at FAP are pigmented lesions of the retina ("congenital hypertrophy of the retinal pigment"), jaw cysts, sebaceous cysts, and osteomata (benign bone tumors). The combination of polyposis, osteomas, fibromas and sebaceous cysts is termed Gardner syndrome (with or without abnormal scarring).
Diagnosis and treatment
In patients with a strong family of colorectal cancer and symptoms suggestive of polyposis, colonoscopy is indicated, with biopsy of a number of polyps (especially of those that appear dysplastic).
Blood tests (liver enzymes) and ultrasound of the abdomen are often performed to rule out metastasis to the liver.
Genetic testing provides the ultimate diagnosis in 95%; genetic counseling is usually needed in families where FAP has been diagnosed. Testing may also aid in the diagnosis of borderline cases in families that are otherwise known to have the FAP mutation.
Pathophysiology
FAP is due to mutations in the APC gene, which is located on the fifth chromosome (5q21-q22), or the MUTYH gene located on chromosome 1 (p34.3-p32.1).
APC is a tumour suppressor gene, acting as a "gatekeeper" to prevent development of tumours. Mutation of APC also occurs commonly in incident cases of colorectal carcinoma, emphasizing its importance in this form of cancer.
Although the polyps are inherently benign, the first step of the two-hit hypothesis has already taken place. Often, the remaining "normal" allele is mutated or deleted, accelerating generation of polyps. Further mutations (e.g. in p53 or KRAS) to APC-mutated cells are much more likely to lead to cancer than they would in non-mutated epithelial cells.
The normal function of the APC gene product is still being investigated; it is present both the cell nucleus and the membrane. Possible functions may be related to cell adherence and cytoskeleton organisation.
MUTYH encodes DNA repair enzyme MYH glycosylase. During normal cellular activities, guanine sometimes becomes altered by oxygen, which causes it to pair with adenine instead of cytosine. MYH glycosylase fixes these mistakes by base excision repair so mutations don't accumulate in the DNA and lead to tumor formation and possibly cancer.
When MYH glycosylase does not function correctly, mistakes in the DNA can accumulate and cancer may develop.
Genetics
Familial adenomatous polyposis can have different inheritance patterns and different genetic causes. When this condition results from mutations in the APC gene, it is inherited in an autosomal dominant pattern, which means one copy of the altered gene is sufficient to cause the disorder. In most cases, an affected person has one parent with the condition.
Mutations in the MUTYH gene are inherited in an autosomal recessive pattern, which means two copies of the gene must be altered for a person to be affected by the disorder. Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene.
Prenatal testing is possible if a disease-causing mutation is identified in an affected family member; however, prenatal testing for typically adult-onset disorders is uncommon and requires careful genetic counseling.
Epidemiology
The incidence of the mutation is between 1 in 10,000 and 1 in 15,000 births. By age 35 years, 95% of individuals with FAP have polyps. Without colectomy, colon cancer is virtually inevitable. The mean age of colon cancer in untreated individuals is 39 years (range 34-43 years).
Treatment
Treatment for FAP will require frequent surveillance colonoscopy investigations; in a number of cases, removal of the colon is necessary to prevent (or cure) development to malignancy.
Various medications are being investigated for slowing malignant degeneration of polyps, most prominently the non-steroidal anti-inflammatory drugs (NSAIDs).
References
- Gardner EJ. A genetic and clinical study of intestinal polyposis, a predisposing factor for carcinoma of the colon and rectum. Am J Hum Genet 1951;3:167-76. PMID 14902760
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