Familial Adenomatous Polyposis and Gardner Syndrome

AUTHOR: Sudeep K. Aulakh, MD, FACP, FRCPC

Definition

Familial adenomatous polyposis (FAP) is a highly penetrant, autosomal-dominant condition characterized by hundreds of colorectal adenomatous polyps that inevitably progress to cancer (Fig. E1). Gardner syndrome is a subset of FAP, with prominent extraintestinal manifestations including dental abnormalities, soft tissue lesions, desmoid tumors, and osteomas.

ICD-10CM CODES
D12.2		Benign neoplasm of ascending colon
D12.3		Benign neoplasm of transverse colon
D12.4		Benign neoplasm of descending colon
D12.5		Benign neoplasm of sigmoid colon
D12.6		Benign neoplasm of colon, unspecified

Figure E1 Familial Adenomatous Polyposis with Innumerable Adenomatous Polyps, Increasing in Size and Density from Proximal (Upper Left) to Distal (Lower Right)

From Skarin AT: Atlas of diagnostic oncology, ed 4, St Louis, 2010, Mosby.

Epidemiology & Demographics

FAP occurs in approximately 1 in 10,000 births worldwide.¹
FAP accounts for <1% of all colorectal cancers.
Individuals develop hundreds to thousands of adenomatous colorectal polyps.
Polyps usually present in adolescence.
100% lifetime risk for colorectal cancer; most diagnosed by 40 yr of age.
Gastric, duodenal, periampullary, and small bowel polyps occur but have lower malignant potential.
Increased risk for other tumors: Desmoid (15%), duodenal/periampullary (7%), thyroid (2%), brain (1%), childhood hepatoblastoma (1%), nasopharyngeal angiofibroma (benign), pancreatic (2%), adrenal adenoma (10%), and gastric (1%).²

Physical Findings & Clinical Presentation

Phenotypic variability is seen in individuals and families with the same mutation. Extraintestinal manifestations may precede intestinal disease. These findings are reported in at least 20% of individuals with FAP.

Congenital hypertrophy of the retinal pigment epithelium (CHRPE): Benign fundus lesions, usually present at birth
Dental abnormalities: Supernumerary or unerupted teeth
Soft tissue lesions: Epidermal or sebaceous cysts, fibromas, lipomas, desmoid tumors (benign, locally invasive, aggressive connective tissue tumor)
Osteomas (benign bone growths): Skull, mandible, long bone
Anemia, occult blood in stool, bowel obstruction, weight loss

Etiology

FAP is caused by mutations of the tumor suppressor gene adenomatous polyposis coli (APC) on chromosome 5q21 to q22; more than 1000 disease-causing mutations identified. The site of the mutation often correlates with the extraintestinal findings.³
De novo mutations are responsible for approximately 20% of FAP cases. These may be due to germline mutations or somatic cell mosaicism, which is seen when a new mutation occurs in the APC gene postfertilization and is present in only a subset of cell types or tissues.
Table E1 summarizes the genetics of colonic polyposis.

TABLE E1 Genetics of Colonic Polyposis

Syndrome (Abbreviation, Synonym)	Gene(s)	Molecular Phenotype	Noncolonic Organs Affected
Sporadic adenomatous polyp	Unknown	Chromosomal instability (aneuploidy)	None known
Familial adenomatous polyposis (FAP)	APC	Chromosomal instability (aneuploidy)	Duodenum, stomach, pancreas, thyroid, liver, central nervous system
Attenuated familial adenomatous polyposis (AFAP)	APC	Chromosomal instability (aneuploidy)	Duodenum, thyroid, liver, central nervous system
Hereditary nonpolyposis colon cancer (HNPCC, Lynch syndrome)	hMLH1, hMSH2, hMSH6, hPMS2	MSI	Endometrium, stomach, ovary, biliary and urinary tracts, small bowel, central nervous system
MUTYH-linked adenomatous polyposis (MAP)	MUTYH	Chromosomal instability (aneuploidy)	Duodenum
Peutz-Jeghers syndrome (PJS)	STK1 (70%)	Unknown	Breast, pancreas, stomach, ovary, lung, small bowel, uterus, testis
Juvenile polyposis syndrome	SMAD4, BMPR1A	Unknown	Blood vessels (hereditary hemorrhagic telangiectasia)
Hyperplastic polyposis	SMAD4, BMPR1A (40%), PTEN	Unknown	Stomach, pancreas, small bowel

MSI, Microsatellite instability.

From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

Diagnosis ⬆ ⬇

In individuals with a family history, more than 100 adenomatous colorectal polyps, CHRPE lesions, or positive genetic testing confirms diagnosis. In those without a family history, more than 100 adenomatous colorectal polyps suggest the diagnosis, and genetic testing confirms it. The diagnosis should be considered in individuals with ≥10 adenomatous colorectal polyps or fewer polyps in the presence of extraintestinal findings.⁴

Differential Diagnosis

Turcot syndrome
Attenuated FAP (also APC gene mutation, but presents with fewer polyps [<100], at a later age, and has lower cancer risk than FAP [∼80% lifetime risk])
MUTYH-associated polyposis
Peutz-Jeghers syndrome
Juvenile polyposis syndrome
Cowden disease
Lynch syndrome
Hereditary mixed polyposis syndrome
Polymerase proofreading-associated polyposis
Hyperplastic polyposis
Table 2 compares various adenomatous polyposis syndromes

TABLE E2 Adenomatous Polyposis Syndromes

Syndrome	Gene Mutation	Polyps	Extraintestinal Abnormalities
Classic FAP	APC (usually truncated protein)	Colonic adenomas (thousands) Duodenal, periampullary adenomas Gastric fundic gland polyps Jejunal and ileal adenomas Ileal lymphoid polyps	Mandibular osteomas Dental abnormalities
Gardner variant of FAP	APC	Same as FAP	Osteomas (mandible, skull, long bones) CHRPE Desmoid tumors Epidermoid and sebaceous cysts Fibromas, lipomas Thyroid, adrenal tumors
Turcot variant of FAP	APC DNA MMR ∗	Colonic adenomas (sometimes fewer than in classic FAP)	Medulloblastoma Glioblastoma multiforme CHRPE
Attenuated FAP	APC 5′ and 3′ regions	Colonic adenomas (<100; proximal colon) Duodenal, periampullary adenomas Gastric fundic gland polyps	Mandibular osteomas (rare)
Familial tooth agenesis	Axin2 (APC pathway)	Colonic adenomas Hyperplastic polyps	Agenesis of teeth
Bloom syndrome	BLM	Colonic adenomas	Small stature Facial erythema/telangiectasia Male sterility Adenocarcinomas, leukemia, lymphoma
MUTYH polyposis	MUTYH (MYH)	Colonic adenomas (5-100)	CHRPE
		Duodenal polyposis Gastric cancer	Osteomas

APC, Adenomatous polyposis coli; CHRPE, congenital hypertrophy of the retinal pigment epithelium; DNA, deoxyribonucleic acid; FAP, familial adenomatous polyposis; MMR, mismatch repair.

^∗May be more appropriately classified under hereditary nonpolyposis colon cancer.

From Feldman M et al (eds): Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Saunders.

Workup

History, physical examination, laboratory tests, imaging studies

Diagnostic Screening Options

Genetic Testing

NOTE: Genetic counseling should be performed and written informed consent obtained before testing. Refer to a specialized center for counseling and evaluation.

Should be offered to first-degree relatives of affected individuals (with an identified mutation) at age 10 to 12 yr and clinically suspected individuals.⁵
Able to identify a mutation in approximately 80% of families. To ensure that the family has a detectable mutation, test an affected family member first.
If positive in the affected individual, the test can differentiate with 100% accuracy affected and unaffected family members. If negative in the affected individual, screening family members will not be useful in determining disease status.
If no known family history exists, screening the clinically suspected individual is reasonable. A positive test rules in FAP, but a negative test does not rule it out.
Numerous testing techniques available; may require multiple tests to identify the mutation.

Sigmoidoscopy

Individuals with a positive genetic test: Annual flexible sigmoidoscopy or colonoscopy beginning at 10 to 12 yr of age.¹
Untested at-risk family members or individuals from families with an unidentified APC mutation: Annual flexible sigmoidoscopy or colonoscopy beginning at 10 to 12 yr of age. Screening frequency can decrease at 24 yr of age if no polyps detected.
Once adenomatous polyps are detected, patients should undergo colonoscopy and evaluation for colectomy.
Negative genetic test in patients from families with an identified mutation: Average risk screening.

CHRPE

Lesions occur in up to 80% of families and are a reliable indicator of affected status in these families.

Treatment ⬆ ⬇

Prophylactic colectomy or proctocolectomy: Timing determined by polyp number, size, and degree of dysplasia. Postsurgical endoscopic surveillance annually.⁶
Additional screening:
1. Annual physical examination: History, examination (including thyroid), and blood tests
2. Upper endoscopy to screen for gastric/duodenal polyps (include visualization of duodenal papilla): Baseline at age 25 yr (earlier if colon polyps detected) and repeated every 3 mo to 3 yr based on findings ⁴
3. Thyroid ultrasound: Begin in teenage years and repeat every 2 to 5 yr based on findings ⁴
4. Other possible cancer sites imaged if symptoms occur or if these cancers have occurred in relatives
Treat soft tissue lesions and osteomas for symptoms or cosmetic concerns. Treat desmoid tumors if they pose a risk to adjacent structures.

Disposition

100% chance of colorectal cancer in untreated individuals. Many other neoplasms occur at higher rates.
Metastatic colorectal cancer is the leading cause of death (58%), followed by desmoid tumors (11%), and duodenal/periampullary adenocarcinoma (8%).

Referral

Patients should be managed at centers with expertise in FAP, including a gastroenterologist, medical geneticist, and surgeon.
Genetic counselors can be found at http://www.nsgc.org/.
Genetic clinics and laboratories can be found at www.ncbi.nlm.nih.gov/gtr.

Pearls & Considerations ⬆ ⬇

Management should be individualized based on genotype, phenotype, and individual preferences.
Sulindac (NSAID) and celecoxib (COX-2 inhibitor) can cause duodenal and colorectal polyp regression in individuals with FAP. Low dose aspirin suppresses the reoccurrence of colorectal polyps >5 mm in patients with FAP.⁷ Preliminary studies with other agents also show polyp regression/growth suppression. Their ability to reduce cancer risk remains unknown; they do not replace colon resection for cancer prevention.^7-10
Desmoid tumors usually present in the 30s, frequently occur in the abdomen, and are difficult to treat with high rates of recurrence. Growth and recurrence are stimulated by surgery.
Offer screening to children of affected parents (from infancy to age 7 yr) biannually with alpha-fetoprotein level and liver ultrasound to rule out hepatoblastoma.²
Preimplantation and prenatal genetic testing is available.
Attenuated FAP: Screening colonoscopy every 1 to 2 yr starting at 20 yr of age.

Related Content

Familial Adenomatous Polyposis and Polyposis Syndromes (Patient Information)

Colorectal Cancer (Related Key Topic)

Lynch Syndrome (Related Key Topic)

Peutz-Jeghers Syndrome and Other Polyposis Syndromes (Related Key Topic)

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Basic Information ⬇

Diagnosis ⬆ ⬇

Treatment ⬆ ⬇

Pearls & Considerations ⬆ ⬇

Related Content ⬆