What are the characteristics and inheritance pattern of Familial Adenomatous Polyposis (FAP)?

Familial Adenomatous Polyposis: Characteristics and Inheritance

The correct answer is (a): FAP is caused by inactivation of a tumor suppressor gene. FAP results from germline mutations in the APC gene, a tumor suppressor located on chromosome 5q21-22, which plays a central role in intestinal development and homeostasis 1.

Detailed Analysis of Each Statement

(a) Caused by inactivation of a tumor suppressor gene - CORRECT

• FAP is caused by mutations in the APC (adenomatous polyposis coli) gene, which functions as a tumor suppressor 1, 2.
• The APC gene is located on the long arm of chromosome 5 (5q21-22) 1.
• APC mutations are detected in approximately two-thirds or more of families affected with FAP 1, 2.
• In remaining families without APC mutations, biallelic MUTYH gene mutations may explain a portion of cases, particularly in attenuated disease 1.

(b) Normal life expectancy after prophylactic colectomy - INCORRECT

• While early diagnosis and proper prophylactic treatment results in excellent survival outcomes comparable to the general population 1, this statement oversimplifies the reality.
• After colectomy, patients face significant ongoing morbidity and mortality risks from extracolonic manifestations 1.
• Duodenal cancer and desmoid tumors are the two main causes of mortality after total colectomy 3.
• Morbidity is caused by duodenal cancer (requiring periodic duodenoscopy) and poorly treatable desmoid tumors 1.
• Lifelong surveillance is required for rectal polyps (if rectum preserved), duodenal and periampullary adenomas, and desmoid tumors 4.

(c) Associated with increased risk of right-side colon cancer - INCORRECT

• FAP is characterized by universal distribution of adenomas throughout the colon and rectum, not specifically right-sided predominance 1, 4.
• Classic FAP develops hundreds to thousands of adenomatous polyps throughout the entire colorectum 1, 3.
• The attenuated variant (AFAP) does show polyps that tend to cluster in the proximal colon 1, but this is not the classic presentation.
• Without surgical intervention, patients almost inevitably develop colorectal cancer by mean age 40-50 years, with 100% lifetime cancer risk 1, 3.

(d) Inherited as autosomal recessive trait - INCORRECT

• FAP follows an autosomal dominant inheritance pattern 1, 2, 3.
• Each child of an affected parent has a 50% chance of inheriting the predisposition 1, 2, 4.
• Between one-third and half of new cases represent de novo mutations of the APC gene with no family history 1, 2.
• The only recessive form is MUTYH-associated polyposis (MAP), which requires biallelic MUTYH mutations and represents a different condition 1.

Key Clinical Pitfalls

• Do not confuse classic FAP with MUTYH-associated polyposis (MAP): MAP follows autosomal recessive inheritance and represents a distinct entity 1.
• Do not assume normal life expectancy post-colectomy: Extracolonic manifestations, particularly duodenal cancer and desmoid tumors, remain significant causes of morbidity and mortality 1, 3.
• Do not overlook the need for lifelong surveillance: Even after prophylactic colectomy, patients require ongoing monitoring for upper gastrointestinal tract adenomas and desmoid tumors 1, 4, 3.