Familial Adenomatous Polyposis: Symptoms, Types, Causes and Treatment

Familial Adenomatous Polyposis (FAP) is a rare but serious hereditary disorder that dramatically increases the risk of developing colorectal cancer. Characterized by the growth of hundreds to thousands of polyps in the colon and rectum, FAP often goes unnoticed until symptoms or complications arise. Understanding the nuances of FAP—including its diverse symptoms, distinct types, genetic causes, and evolving treatment strategies—is essential for affected individuals, their families, and healthcare professionals. This comprehensive guide will walk you through every key aspect of FAP, grounded in the latest scientific evidence.

Symptoms of Familial Adenomatous Polyposis

FAP’s symptoms can be subtle, especially in its early stages, making early detection challenging but crucial. While many individuals remain asymptomatic for years, the condition can eventually cause a range of intestinal and extraintestinal symptoms that may prompt medical attention.

Symptom	Description	Typical Onset	Source
Rectal bleeding	Blood in stool, often the first symptom	Adolescence–20s	1 4 11
Diarrhea	Frequent, loose bowel movements	Adolescence–20s	1 4 11
Anemia	Fatigue/weakness from chronic blood loss	Early adulthood	1 4
Abdominal pain	Cramping, discomfort, or palpable masses	Variable	1 4 11
Weight loss	Often late, sign of advanced disease	Late	1 4 11
Dental anomalies	Unerupted/supernumerary teeth, jaw tumors	Childhood–teens	1 5 6
Osteomas	Benign bone growths (skull, jaw)	Adolescence–adulthood	1 3 5
CHRPE	Retinal pigment changes	Childhood	1 6 10
Desmoid tumors	Benign soft tissue tumors	Adolescence–adulthood	1 3 10

Table 1: Key Symptoms

Gastrointestinal Symptoms

Most people with FAP develop symptoms related to the gastrointestinal tract. The earliest and most common signs include rectal bleeding and changes in bowel habits, such as diarrhea or constipation. These symptoms arise due to the sheer number of adenomatous polyps carpeting the colon and rectum. As polyps grow larger or more numerous, they may cause abdominal pain, bloating, or even the formation of palpable masses. Weight loss and signs of anemia often indicate advanced disease or cancer development 1 4 11.

Extraintestinal Manifestations

FAP is more than just a colon disease. Many individuals, especially those with certain variants like Gardner syndrome, may present with:

• Dental anomalies: Unerupted or extra teeth, jaw cysts, and odontomas often appear before intestinal symptoms, making dentists pivotal in early detection 1 5 6.
• Osteomas: Benign bone growths, particularly of the skull and jaw, are classic features 1 3 5.
• CHRPE (Congenital Hypertrophy of the Retinal Pigment Epithelium): These retinal changes, detectable by ophthalmologists, may serve as a clue to FAP in at-risk individuals 1 6 10.
• Desmoid tumors: Noncancerous but potentially aggressive growths in connective tissue, often in the abdomen, occur in some patients and can cause significant morbidity 1 3 10.

Cancer Risk and Progression

Without treatment, virtually all patients with classic FAP will develop colorectal cancer, usually by their late 30s or 40s. The risk of extracolonic cancers (thyroid, liver, pancreas, CNS) is also increased, and may be the first sign of FAP in some patients 1 3.

Types of Familial Adenomatous Polyposis

FAP is not a one-size-fits-all diagnosis. Several clinically distinct forms exist, each with unique features, inheritance patterns, and cancer risks.

Type	Defining Features	Inheritance	Source
Classic FAP	>100 colorectal polyps, early onset	Autosomal dominant	1 6 11
Attenuated FAP (AFAP)	10–100 polyps, later onset, more proximal colon	Autosomal dominant	1 2 6 7
Gardner Syndrome	Classic FAP + extraintestinal features (osteomas, dental, skin cysts, desmoids)	Autosomal dominant	1 5 6 9 10
Turcot Syndrome	FAP with CNS tumors (esp. medulloblastoma)	Autosomal dominant (APC) or mismatch repair gene mutations	6 9
MAP	<100 polyps, upper/lower GI involvement, lower cancer risk	Autosomal recessive	1 6 11

Table 2: FAP Types and Variants

Classic Familial Adenomatous Polyposis

• Definition: Characterized by the appearance of hundreds to thousands of adenomatous polyps in the colon and rectum, typically during the second decade of life.
• Cancer Risk: Approaches 100% by the fourth decade if untreated.
• Other Features: May also have upper GI polyps and various extraintestinal manifestations 1 6 11.

Attenuated FAP (AFAP)

• Definition: Fewer colorectal polyps (often 10–100), later onset (mean diagnosis in the 40s), and frequently a predilection for the proximal colon.
• Inheritance: Still autosomal dominant, but with different mutations in the APC gene 1 2 6 7.
• Cancer Risk: Lower and later compared to classic FAP, but still significant if not managed.

Gardner Syndrome

• Definition: A variant of FAP with prominent extraintestinal features, including osteomas, dental anomalies, skin cysts, and desmoid tumors.
• Historical Note: Once considered a separate syndrome, now recognized as part of the FAP spectrum 1 5 6 9 10.

Turcot Syndrome

• Definition: FAP or Lynch syndrome coupled with central nervous system tumors, particularly medulloblastoma.
• Genetics: Can result from mutations in APC or mismatch repair genes 6 9.

MUTYH-Associated Polyposis (MAP)

• Definition: Fewer polyps (usually <100), with involvement of both upper and lower GI tract.
• Inheritance: Autosomal recessive, due to biallelic mutations in the MUTYH gene.
• Cancer Risk: Lower but still elevated compared to the general population 1 6 11.

Causes of Familial Adenomatous Polyposis

Understanding the genetic roots of FAP is essential for diagnosis, family counseling, and future therapies. The condition is primarily driven by specific gene mutations affecting how cells grow and repair DNA.

Cause	Key Mutation/Mechanism	Inheritance Pattern	Source
APC gene mutation	Germline mutation in tumor-suppressor APC gene	Autosomal dominant	1 6 8 9 11
MUTYH gene mutation (MAP)	Biallelic mutation in DNA repair gene	Autosomal recessive	1 6 11
Genotype-phenotype correlation	Mutation location affects severity and features	N/A	8 9

Table 3: Genetic Causes of FAP

The APC Gene

• Role: The adenomatous polyposis coli (APC) gene is a tumor suppressor gene located on chromosome 5q21. It is vital in regulating cell growth and death.
• Pathogenesis: Mutations in APC lead to uncontrolled cell proliferation and polyp formation in the gastrointestinal tract 1 6 8 11.
• Inheritance: Classic FAP and its variants are inherited in an autosomal dominant fashion—each child of an affected parent has a 50% chance of inheriting the mutation.

MUTYH Gene and MAP

• Role: The MUTYH gene is involved in repairing DNA damage caused by oxidative stress.
• Pathogenesis: Biallelic (both gene copies) mutations result in defective DNA repair, leading to polyp formation and increased cancer risk, albeit to a lesser extent than classic FAP 1 6 11.
• Inheritance: MAP is inherited in an autosomal recessive manner.

Genotype-Phenotype Correlations

• Mutation Location: The location of mutations within the APC gene influences the severity and specific features of FAP:
  • Mutations between codons 1250–1464 are linked with classic FAP (thousands of polyps).
  • Mutations at the ends of the gene are associated with attenuated FAP.
  • Certain mutations predispose to specific extraintestinal features (e.g., CHRPE, desmoid tumors) 8 9.
• Clinical Utility: Knowing the mutation can help guide surveillance and treatment strategies for patients and families 8.

Treatment of Familial Adenomatous Polyposis

The primary goal of FAP management is cancer prevention and maintaining quality of life. Treatment is multifaceted, combining surgical, medical, and surveillance strategies tailored to the individual.

Treatment	Approach/Goal	Timing/Indication	Source
Prophylactic surgery	Remove colon/rectum to prevent cancer	Late teens–early 20s or earlier if needed	1 6 15
Endoscopic surveillance	Detect/monitor polyps and cancers	Start age 10–12, lifelong	1 6 15
Chemoprevention	NSAIDs (e.g., sulindac, celecoxib) to reduce polyp burden	Adjunctive, not curative	12 14
Genetic counseling	Identify at-risk family members	At diagnosis and for relatives	1 6
Management of extraintestinal disease	Treat desmoids, thyroid/cancers	As needed	1 3 15

Table 4: FAP Treatment Modalities

Surgical Management

• Mainstay of Therapy: Prophylactic colectomy is the only proven way to prevent colorectal cancer in FAP.
  • Procedures: Options include total proctocolectomy with ileal pouch-anal anastomosis or subtotal colectomy with ileorectal anastomosis (IRA), especially in AFAP or when rectum is less affected 1 6 15.
  • Timing: Surgery is typically recommended in the late teens or early twenties, or earlier if cancer or high-risk polyps are detected.
  • Personalization: Decision-making considers age, genotype, family history, sphincter function, desmoid risk, and patient preference 15.

Endoscopic Surveillance

• Purpose: To detect polyps and cancers early, both in the colon/rectum (if not yet removed) and in the upper GI tract (duodenum, ampulla).
• Timeline: Surveillance begins as early as age 10–12 for at-risk individuals and continues for life 1 6 15.
• Extraintestinal Surveillance: Regular screening for thyroid, liver, and other potential cancers is also recommended, particularly in those with relevant family histories or mutations 1 3.

Chemoprevention

• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Sulindac and celecoxib have shown efficacy in reducing the number and size of polyps, but do not eliminate the need for surgery 12 14.
• Limitations: Polyps usually recur after stopping medication; NSAIDs are considered adjunctive, not curative.
• Other Agents: Trials of other agents, such as curcumin, have not shown consistent benefit 13.

Novel and Adjunctive Therapies

• Mutation Read-Through Therapy: Early-phase trials using antibiotics to induce read-through of APC nonsense mutations have shown promise in reducing polyp burden, but are not yet standard of care 16.
• Desmoid Tumor Management: May include surgery, medical therapy (e.g., NSAIDs, hormonal agents), or chemotherapy for aggressive cases 1 3 15.

Genetic Counseling and Testing

• Family Screening: All first-degree relatives of an affected individual should undergo genetic counseling and testing if the family mutation is known.
• Prenatal/Preimplantation Testing: Available for at-risk families wishing to prevent transmission 1 6.

Conclusion

Familial Adenomatous Polyposis is a complex, inherited disorder with profound implications for affected individuals and their families. Early recognition and intervention are critical to preventing cancer and improving outcomes.

Key Points:

• FAP often presents with rectal bleeding or changes in bowel habits, but may also manifest through dental, bone, or eye findings.
• Multiple types exist, including classic FAP, attenuated FAP, Gardner syndrome, Turcot syndrome, and MAP, each with unique clinical features and genetic causes.
• FAP is primarily caused by mutations in the APC gene (autosomal dominant) or, less commonly, the MUTYH gene (autosomal recessive).
• Management centers on prophylactic surgery, regular surveillance, chemoprevention, and comprehensive genetic counseling.
• New therapies and improved surveillance are enhancing quality of life and survival for patients with FAP.

By staying informed and proactive, patients and families can manage FAP effectively and significantly reduce the risk of cancer.