Familial adenomatous polyposis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2], Mohamad Alkateb, MBBCh [3]

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 Peutz–Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, Carney syndrome, and hereditary non–polyposis 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.

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.

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.

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.

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

Familial adenomatous polyposis must be differentiated from other diseases that cause multiple polyps, such as Peutz–Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, Carney syndrome, and hereditary non–polyposis 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. 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.

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

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 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.

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.

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.

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

There are no ECG findings associated with familial adenomatous polyposis.

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.

There are no echocardiography or ultrasound findings associated with familial adenomatous polyposis.

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

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

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.

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 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.

Effective measures for the primary prevention of familial adenomatous polyposis include genetic counseling. The most common method 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.

​​ ​

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2]

Familial adenomatous polyposis was first described in 1726 by Menzelio. After 150 years, in 1882, familial nature of the multiple colonic polyposis was reported. Inheritance predisposition 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.

Following are a few important aspects about the historical perspective of familial adenomatous polyposis:

• In 1726, Menzelio described multiple polyps of the large bowel clinically.^[1]
• In 1847, familial adenomatous polyposis was first described.^[2]
• In 1882, Cripps reported the familial nature of multiple colonic polyposis.
• In 1925, Lockhart-Mummery suggested an inheritance predisposition for multiple colonic polyposis.
• During 1930s, Cuthbert Dukes created the first register at St. Mark’s Hospital in London and collected data for screening of relatives of patients with polyposis.
• In the 1950s, Gardner and Stephens described a syndrome with colonic and extracolonic features, including soft tissue and bone tumors which is known as Gardner’s syndrome.
• In 1975, Bussey described the clinical characteristics and natural history of familial adenomatous polyposis.^[2]
• In 1986, Herrera discovered genetic abnormality in patient with multiple colorectal polyps.
• In 1987, Leppert mapped gene for FAP to the long arm of chromosome 5.^[3]
• In 1991, the association between mutation of the APC gene (chromosome 5q21-22) and familial adenomatous polyposis was made.^[4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2], Mohamad Alkateb, MBBCh [3]

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 including profuse, intermediate, and attenuated. Familial adenomatous polyposis has less severe variants, including gardner’s syndrome and turcot syndrome.

Familial adenomatous polyposis may be classified according to the affected genes into two subtypes:^[1][2]

• FAP gene associated familial adenomatous polyposis
• MUTYH-associated polyposis (MAP)

Familial adenomatous polyposis may also be classified according to severity into three subtypes:^[3]

• Profuse FAP
• Intermediate FAP
• Attenuated FAP

Familial adenomatous polyposis has less severe variants, including:

• Gardner’s syndrome
• Turcot syndrome

​​​

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2], Mohamad Alkateb, MBBCh [3]

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 patients with familial adenomatous polyposis have a positive family history of colorectal cancer or polyps. However, some of the patients with familial adenomatous polyposis may 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. These mutations 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. APC 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 finding of familial adenomatous polyposis.

• Familial adenomatous polyposis is a genetic disorder that is caused by mutation in APC and MUTYH genes.^[1]
• Many of patients with familial adenomatous polyposis have a positive family history of colorectal cancer or polyps. However, some of the patients with familial adenomatous polyposis have no previous family history.
• Germline mosaicism might be responsible for sudden manifestation of familial adenomatous polyposis.^[2]
• Loss of APC gene function is believed to be the first event in pathogenesis of colon cancer leading to formation of an adenoma.^[3]

• Familial adenomatous polyposis may have different inheritance patterns and genes involved.^[5]
• Familial adenomatous polyposis is due to mutations in different genes, including:^[6][7]
  • APC gene, which is located on chromosome 5 in band q21 or band q22 (5q21-q22)
    • APC gene is a tumor suppressor gene that has an essential role in cell adhesion, signal transduction and transcriptional regulation.
    • Three hundred mutations of APC gene have been discovered for familial adenomatous polyposis.
    • These mutations of APC gene have premature stop codons and lead to a truncated protein.
    • APC gene mutation is seen in 6% of Ashkenazi Jews.^[8]
    • APC gene mutation is seen in about 28% of those of Ashkenazi descent with a family history of colorectal cancer.
  • MUTYH gene, which is located on chromosome 1 between bands p34.2 and p32.1 (1p34.3-p32.1)
• Familial adenomatous polyposis has autosomal dominant inheritance pattern if it results from mutations in the APC gene.
• Familial adenomatous polyposis has autosomal recessive inheritance pattern if it results from mutations in the MUTYH gene.

Familial adenomatous polyposis is associated with other intestinal and extra intestinal conditions such as:^[9][10][1]

• Duodenal adenoma
• Stomach cancer
  • The risk is approximately 0.5%.
• Periampullary cancer
  • The risk is approximately 10%.
• Pancreatic cancer
  • The risk is approximately 2%.
• Hepatoblastoma
  • The risk is approximately 1.5%.
• Bile duct cancer

• Adrenal masses
• Desmoid tumor
  • The risk is approximately 10% to 20%.
  • It mostly happens in small bowel mesentery.
• Papillary thyroid cancer
  • The risk is approximately 2% to 25%.
• Medulloblastoma
• Epidermoid cysts and fibromas
• Osteomas
  • It is a benign bony growth mainly on jaw
• Congenital hypertrophy of the retinal pigment epithelium

On gross pathology, numerous polyps are characteristic findings of familial adenomatous polyposis.

• On microscopic histopathological analysis, serration of the luminal surface and normal nuclei are characteristic findings of hyperplastic polyps.
• On microscopic histopathological analysis, branched tubular glands are characteristic findings of tubular adenoma.
• On microscopic histopathological analysis, long finger-like projections are characteristic findings of villous adenoma.
• On microscopic histopathological analysis, branched and dilated glands, no cytological atypia, eosinophilic cytoplasm, and luminal epithelial tufting are characteristic findings of sessile serrated adenoma.

​​ ​

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2]

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

Familial adenomatous polyposis may be caused by mutation in the following genes:^[1][2][3]

• APC gene located on chromosome 5 which is either nonsense or frameshift
• MUTYH gene located on chromosome 1

List the causes of the disease in alphabetical order.

​​ ​

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2], Mohamad Alkateb, MBBCh [3]

Familial adenomatous polyposis must be differentiated from other diseases that cause multiple polyps, such as Peutz–Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, Carney syndrome, and hereditary non–polyposis colon cancer (Lynch syndrome).

Familial adenomatous polyposis must be differentiated from other diseases that cause multiple polyps including:^{[1][2][3][4][5]}

• Peutz–Jeghers syndrome
• Juvenile polyposis syndrome
• Cowden syndrome
• Carney syndrome
• Hereditary Non–Polyposis Colon Cancer (Lynch syndrome)

​​ ​

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2], Mohamad Alkateb, MBBCh [3]

Familial adenomatous polyposis is a rare disease that affects individuals worldwide. The incidence and prevalence of familial adenomatous polyposis is approximately 3 to 20 and 12 per 100,000 individuals, respectively. Surgical mortality rate is approximately 4400 per 100,000 individuals (4.4%) in Sweden. Patients usually develop familial adenomatous polyposis in their first and second decades of life. Familial adenomatous polyposis affects men and women equally and there is no racial predilection. All of the patients with familial adenomatous polyposis without treatment, will develop colorectal cancer by age of 39.

• The incidence of familial adenomatous polyposis is approximately 12 per 100,000 births in the Europe.^[1]

• The prevalence of familial adenomatous polyposis is approximately 10 to 20 per 100,000 individuals in the United States.^[2]
• The prevalence of familial adenomatous polyposis is approximately 3 to 10 per 100,000 individuals in the Europe.^[1]

• In 1975, the incidence of familial adenomatous polyposis is approximately 13 per 100,000 individuals with a surgical mortality rate of 4400 per 100,000 individuals (4.4%) in Sweden.^[3]

• The mean age for developing colon polyps in patients with familial adenomatous polyposis is 13 years.^[4]
• Patients in their first and second decades usually develop familial adenomatous polyposis.
• All the patients with familial adenomatous polyposis without treatment will develop colorectal cancer by age of 39.^[5]

• There is no racial predilection to familial adenomatous polyposis.

• Familial adenomatous polyposis affects men and women equally.^[1]

• Familial adenomatous polyposis is a rare disease that tends to affect individuals worldwide.^[6]

​​ ​

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2], Mohamad Alkateb, MBBCh [3]

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

Common risk factor associated with familial adenomatous polyposis is:^[1][2]

• Positive family history of familial adenomatous polyposis

​​​

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2], Mohamad Alkateb, MBBCh [3]

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.

Screening for familial adenomatous polyposis is recommended in the following patients:^[1][2]

• Positive family history of FAP in the first degree relative
• It must be started at the age of the youngest family member’s polyps or symptoms

Screening for familial adenomatous polyposis for individuals at high risk may be done by:

• Sigmoidoscopy every 2 years beginning at age of 10 years
• Colonoscopy every year following finding an adenoma
• Endoscopy concomitant with colonoscopy
• Side viewing endoscopy beginning at age 15 years to evaluate ampulla
• Genetic testing^[3]

​​ ​

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2], Mohamad Alkateb, MBBCh [3]

Familial adenomatous polyposis is a rare disease that usually starts from childhood. Patients with familial adenomatous polyposis develop numerous colon polyps, which may vary from hundreds to thousands, by early twenties. If patients with FAP left untreated, almost all of the colon polyps develop colorectal cancer around 40 years of age. Patients with FAP may have polyps in different organs including the upper gastrointestinal tract. However, the progression of these extra colonic polyps, to malignancy is less than colon polyps. Patients with FAP might develop duodenal and ampullary cancer which are major causes of death following polypectomy. The prognosis of familial adenomatous polyposis is excellent with treatment.

Following are a few important facts about the natural history of familial adenomatous polyposis:

• Familial adenomatous polyposis is a rare disease that usually starts during teenage years.^[1]
• Patients with FAP usually develop hundreds to thousands colon polyps by the age of early twenties.^[2]
• Patients with FAP might be asymptomatic till third decade of their lives or whenever they have malignant transformation to colorectal cancer.
• If left untreated, almost all of the patients with FAP develop colorectal cancer around 40 years of age.
• Patients with FAP might have polyps in different organs including upper gastrointestinal tract. However, their progression to malignancy is less than colon polyps.

Complications that can develop as a result of familial adenomatous polyposis include:^[3][4]

• Colon cancer which has two different pathways according to defect on APC gene:
  • 1- Molecular pathogenesis of sporadic colon cancer is as follows:

• 2- Molecular pathogenesis of colitis-associated colon cancer is as follows:

• Duodenal and ampullary cancer:
  • They are major causes of death following polypectomy.
  • End-viewing and side-viewing duodenoscopy are conducted for surveillance.

• The prognosis of familial adenomatous polyposis is excellent with treatment.
• Without treatment, all patients with familial adenomatous polyposis develop colon cancer at age of 40-50.^[2]

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