Familial adenomatous polyposis overview

# Overview
The development of familial adenomatous polyposis (FAP) is the result of multiple genetic mutations. Genes involved in the pathogenesis of familial adenomatous polyposis include APC and MUTYH genes. Many of patients have a positive family history of colorectal cancer or polyps. However, some of them have no previous family history. Familial adenomatous polyposis is associated with different malignancies including stomach cancer, periampullary cancer, pancreatic cancer, hepatoblastoma, bile duct cancer, papillary thyroid cancer, and medulloblastoma. Duodenal adenoma, adrenal masses, desmoid tumor, osteomas, congenital hypertrophy of the retinal pigment epithelium, epidermoid cysts, and fibromas are also associated with familial adenomatous polyposis. Familial adenomatous polyposis may be classified according to severity into three subtypes which include profuse, intermediate, and attenuated. Familial adenomatous polyposis has less severe variants, including Gardner's syndrome and Turcot syndrome. Familial adenomatous polyposis must be differentiated from other diseases that lead to the formation of multiple gastrointestinal polyps, such as PeutzJeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, Carney syndrome, and hereditary nonpolyposis colon cancer (Lynch syndrome). Familial adenomatous polyposis is a rare disease that affects individuals worldwide. The incidence and prevalence of familial adenomatous polyposis is approximately 3-20 and 12 per 100,000 individuals, respectively. Screening for familial adenomatous polyposis by genetic testing and/or colonoscopy is recommended among patients with history of multiple colonic adenomas and family history of familial adenomatous polyposis. Familial adenomatous polyposis is a rare disease that usually starts from childhood. Patients develop hundreds to thousands colon polyps till early twenties. If left untreated, almost all of them develop colorectal cancer around 40 years of age. The majority of patients with familial adenomatous polyposis are asymptomatic till the development ofcolorectal cancer. Common symptoms of familial adenomatous polyposis are gastrointestinal bleeding, pain, and altered bowel habits. patients may feel fatigued after occult bleeding. Colonoscopy is considered as a gold standard for evaluating the intestine, as well as for diagnostic and therapeutic approaches. Tissue biopsy and polypectomy may be done during colonoscopy. Surgery is the mainstay of treatment for familial adenomatous polyposis. The preferred technique of surgery is laparoscopic total proctocolectomy with ileal pouch anal anastomosis(IPAA) and mucosectomy. Effective measures for the primary prevention of familial adenomatous polyposis include genetic counseling. The most common method to detect a mutation is direct sequencing of the APC gene. All patients with familial adenomatous polyposis will develop colorectal cancer. For secondary prevention of colorectal cancer total colectomy must be done. Effective tests for the secondary prevention of other complications and associated conditions include annual pouchoscopy following surgery and annual physical examination and ultrasound.

# Historical Perspective
Familial adenomatous polyposis was first described in 1726 by Menzelio. After 150 years, in 1882, familial nature of the multiple colonic polyposis was reported. Inheritancepredisposition was identified in 1925. Gardner's syndrome was first described in 1950 by Gardner and Stephens. Bussey described clinical features and natural history of familial adenomatous polyposis in 1975. In 1986, genetic abnormality was discovered by Herrera. In 1991, APC gene defect was identified as one of the causes of familial adenomatous polyposis.

# Classification
Familial adenomatous polyposis (FAP) may be classified according to the affected gene into two subtypes including FAP gene and MYH gene associated familial adenomatous polyposis. Familial adenomatous polyposis may be classified according to severity into three subtypes of profuse, intermediate, and attenuated. Familial adenomatous polyposis has less severe variants, including gardner's syndrome and turcot syndrome.

# Pathophysiology
The development of familial adenomatous polyposis is the result of multiple genetic mutations. Genes involved in the pathogenesis of familial adenomatous polyposis include APC and MUTYH genes. Many of patients have a positive family history of colorectal cancer or polyps. However, some of them have no previous family history. Loss of APC gene function is believed to be the first event in pathogenesis of colon cancer leading to formation of an adenoma. Three hundred mutations of APC gene have been discovered for familial adenomatous polyposis. They have premature stop codons and lead to a truncated protein. Familial adenomatous polyposis has autosomal dominant inheritance pattern if it results from mutations in the APC gene and autosomal recessive inheritance pattern if it results from mutations in the MUTYH gene. Mutation is found in 6% of Ashkenazi Jews. Familial adenomatous polyposis is associated with different malignancies including stomach cancer, periampullary cancer, pancreatic cancer, hepatoblastoma, bile duct cancer, papillary thyroid cancer, and medulloblastoma. Duodenal adenoma, adrenal masses, desmoid tumor, osteomas, congenital hypertrophy of the retinal pigment epithelium, epidermoid cysts and fibromas are associated with familial adenomatous polyposis. On gross pathology, numerous polyps are characteristic findings of familial adenomatous polyposis.

# Causes
Familial adenomatous polyposis may be caused by mutation in APC or MUTYH genes.

# Differentiating Familial Adenomatous Polyposis from Other Diseases
Familial adenomatous polyposis must be differentiated from other diseases that cause multiple polyps, such as PeutzJeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, Carney syndrome, and hereditary nonpolyposis colon cancer (Lynch syndrome).

# Epidemiology and Demographics
Familial adenomatous polyposis is a rare disease that affects individuals worldwide. The incidence and prevalence of familial adenomatous polyposis is approximately 3-20 and 12 per 100,000 individuals. Surgical mortality rate is approximately 4.4%. Patients in their first and second decades usually develop familial adenomatous polyposis. Familial adenomatous polyposis affects men and women equally and there is no racial predilection. Up to 100% of patients with familial adenomatous polyposis without treatment will develop colorectal cancer by age of 39.

# Risk Factors
The most potent risk factor in the development of familial adenomatous polyposis is positive family history of FAP.

# Screening
Screening for familial adenomatous polyposis by genetic testing and/or colonoscopy is recommended among patients with history of multiple colonic adenomas and family history of familial adenomatous polyposis.

# Natural History, Complications, and Prognosis
Familial adenomatous polyposis is a rare disease that usually starts from childhood. Patients develop hundreds to thousands colon polyps till early twenties. If they left untreated, almost all of them develop colorectal cancer around 40 years of age. They might have polyps in different organs including upper gastrointestinal tract. However, their progression to malignancy is less than colon polyps. They might develop duodenal and ampullary cancer which are major causes of death following polypectomy. The prognosis of familial adenomatous polyposis is excellent with treatment.

# Diagnosis

## Diagnostic Study of Choice
Familial adenomatous polyposis is mainly diagnosed based on clinical presentation and family history. Familial adenomatous polyposis must be confirmed by a sigmoidoscopy or a full colonoscopy depending on the age of the patient.

## History and Symptoms
The majority of patients with familial adenomatous polyposis are asymptomatic till colorectal cancer happens. Common symptoms of familial adenomatous polyposis are gastrointestinal bleeding, pain, and altered bowel habits. They might have fatigue following occult bleeding.

## Physical Examination
Patients with familial adenomatous polyposis usually appear normal. Physical examination of patients with familial adenomatous polyposis may have palpable abdominal mass, multiple small rectal polyps, and pallor.

## Laboratory Findings
Laboratory findings that may present with familial adenomatous polyposis include anemia due to gastrointestinal bleeding and abnormal liver function tests due to colon cancer metastasis.

## Electrocardiogram
There are no ECG findings associated with familial adenomatous polyposis.

## X-ray
Double-contrast Barium enema may be helpful in the diagnosis of familial adenomatous polyposis. Familial adenomatous polyposis might be presented as multiple outgrowths with lobulation or indentation and filling defects on x-rays.

## Echocardiography and Ultrasound
There are no echocardiography or ultrasound findings associated with familial adenomatous polyposis.

## CT scan
CT scan with contrast and CT colonography or virtual colonoscopy may be helpful in the diagnosis of familial adenomatous polyposis. Multiple outgrowths and filling defects are suggestive of familial adenomatous polyposis.

## MRI
MRI may be helpful in the diagnosis of familial adenomatous polyposis. Diffusion-weighted magnetic resonance imaging (DWI) and MRI colonography are used to detect polyps.

## Other Imaging Findings
Colonoscopic spectroscopy and narrow-band imaging (NBI) may be helpful in the diagnosis of familial adenomatous polyposis.

## Other Diagnostic Studies
Colonoscopy is considered as a gold standard for evaluating intestine, diagnostic and therapeutic approaches. Tissue biopsy and polypectomy could be done during colonoscopy. Findings on a colonoscopy and flexible sigmoidoscopy suggestive of familial adenomatous polyposis include visual detection of multiple colon polyps. Colonoscopy has 0.02% mortality and 0.2% morbidity. Colonoscopy has side effects including pain, risk of perforation and bleeding.

# Treatment

## Medical Therapy
The mainstay of treatment for familial adenomatous polyposis is surgery. However, non-steroidal anti-inflammatory drugs (NSAIDs) such as sulindac and celecoxib are recommended to decrease the size and number of colon polyps.

## Surgery
Surgery is the mainstay of treatment for familial adenomatous polyposis. The preferred surgery technique is laparoscopic total proctocolectomy with ileal pouch anal anastomosis(IPAA) and mucosectomy. Another technique is total colectomy with ileorectal anastomosis.

## Primary Prevention
Effective measures for the primary prevention of familial adenomatous polyposis include genetic counseling. The most common method is direct sequencing of the APC gene.

## Secondary Prevention
All patients with familial adenomatous polyposis will develop colorectal cancer. For secondary prevention of colorectal cancer total colectomy must be done. Effective tests for the secondary prevention of other complications and associated conditions include annual pouchoscopy following surgery and annual physical examination and ultrasound.