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Familial adenomatous polyposis
ICD9 = 211.3| }} Familial adenomatous polyposis (FAP) is an inherited condition in which numerous polypsform mainly in the epitheliumof the large intestine. While these polyps are benign, they may become malignant, predisposing patients to colorectal cancer.
Signs and symptomsFrom 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 anemiadue to gradually developing iron deficiency. If malignancy develops, this may present with weight loss, altered bowel habit, or even with metastasisin the liveror elsewhere. The genetic determinant in familial polyposis may also predispose carriers to other malignancies, e.g. of the duodenumand 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, fibromasand sebaceous cysts is termed Gardner syndrome (with or without abnormal scarring). Diagnosis and treatmentIn patients with a strong family of colorectal cancer and symptoms suggestive of polyposis, colonoscopyis indicated, with biopsyof a number of polyps (especially of those that appear dysplastic). In severe cases, a full or partial colectomyis required. Blood tests(liver enzymes) and ultrasoundof the abdomen are often performed to rule out metastasisto the liver. Genetic testingprovides the ultimate diagnosis in 95%; genetic counselingis 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. PathophysiologyFAP is due to mutations in the APC gene, which is located on the fifth chromosome(5q21-q22), or in 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 hypothesishas already taken place: the inherited APC mutation. Often, the remaining "normal" alleleis mutated or deleted, accelerating generation of polyps. Further mutations (e.g. in p53or KRAS) to APC-mutated cells are much more likely to lead to cancer than they would in non-mutated epithelialcells. The normal function of the APC gene product is still being investigated; it is present both the cell nucleusand the membrane. The canonical tumor-suppressor function of Apc is suppression of the oncogenic protein beta-catenin. However, other tumor-suppressor functions of Apc may be related to cell adherence and cytoskeletonorganization. MUTYH encodes DNA repairenzyme MYH glycosylase. During normal cellular activities, guaninesometimes becomes altered by oxygen, which causes it to pair with adenineinstead of cytosine. MYH glycosylase fixes these mistakes by base excision repair, such that mutationsdo not accumulate in the DNAand lead to tumor formation. When MYH glycosylase does not function correctly, DNA errors may accrue to initiate tumorigenesis with a clinical presentation similar to that in patients with Apc mutations. GeneticsFamilial 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 dominantpattern, 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 recessivepattern, 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 testingis 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. Animal ModelsThe "ApcMin" mouse model was isolated in 1990 and harbors an Apc allele with a stop codon at position 850. Heterozygosity for this mutation results in a fully penetrant phenotype, with mice on a sensitive background developing over 100 tumors in the intestinal tract. Many other models have since appeared, including a model of attenuated FAP (the 1638N model) and several conditional mutantsthat allow for tissue-specific or temporal ablation of gene function. In 2005, the "ApcPirc" rat model was isolated with a stop codon at position 1137. In constrast to the mouse models where >90% of tumors form in the small intestine, the Pirc rat forms tumors preferentially (>60%) in the large intestine, similar to the human clinical presentation. Genetic screens, pharmacological testing, and other areas of research have allowed for discoveries in the mouse and rat to be applied to the study of human FAP. EpidemiologyThe 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). TreatmentTreatment for FAP will require frequent surveillance colonoscopyinvestigations; in a number of cases, removal of the colon is necessary to prevent the development of malignancy, or to cure it. If a large part of the bowel is removed, construction of an ileostomymay be necessary. Various medications are being investigated for slowing malignant degeneration of polyps, most prominently the non-steroidal anti-inflammatory drugs(NSAIDs). References
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Categories: Gastroenterology| Genetic disorders
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