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Difficulty: Very hardGastroenterology and Hepatology

Match each clinical presentation of a hereditary gastrointestinal polyposis or cancer syndrome to its corresponding underlying molecular genetic defect.

  • A 24-year-old male with hematochezia has over 200 colonic adenomas. He recently had a mandibular osteoma removed, and funduscopic examination reveals congenital hypertrophy of the retinal pigment epithelium.Autosomal dominant defective regulation of the Wnt/beta-catenin signaling pathway
  • A 39-year-old female is diagnosed with endometrial carcinoma. Her father died of proximal colon cancer at age 44. Colonoscopy reveals a solitary, right-sided sessile polyp.Germline mutation resulting in defective DNA mismatch repair and microsatellite instability
  • A 21-year-old female requires surgery for small bowel intussusception due to jejunal hamartomas. She has distinct dark blue-brown macules on her buccal mucosa and lips.Autosomal dominant mutation in the STK11 (LKB1) serine/threonine kinase gene
  • A 48-year-old male has 45 adenomatous colonic polyps. He has no family history of colon cancer, and both parents lived into their 80s. Genetic testing for a common dominant adenomatous polyposis gene is negative.Biallelic mutation causing defective base excision repair of oxidative DNA damage
  • A 42-year-old male with macrocephaly has asymptomatic colonic hamartomas. Skin examination reveals facial trichilemmomas and acral keratoses. He has a prior history of follicular thyroid carcinoma.Autosomal dominant mutation in the PTEN lipid phosphatase gene

Answer

The patient with over 200 adenomas and CHRPE (Gardner syndrome) matches defective Wnt/beta-catenin signaling. The patient with endometrial cancer and a family history of colon cancer (Lynch syndrome) matches the mismatch repair defect. The patient with jejunal hamartomas and mucosal hyperpigmentation (Peutz-Jeghers syndrome) matches the STK11 mutation. The patient with 45 adenomas and an autosomal recessive pattern (MUTYH-associated polyposis) matches the base excision repair defect. The patient with macrocephaly, trichilemmomas, and thyroid cancer (Cowden syndrome) matches the PTEN mutation.
Each clinical presentation distinctly describes a specific hereditary gastrointestinal polyposis or cancer syndrome, which must be matched with its exact underlying molecular genetic defect.

SyndromeGene / PathwayInheritanceGI FindingsKey Extraintestinal Manifestations
FAP / GardnerAPC (Wnt/beta-catenin)Dominant>100 adenomasOsteomas, CHRPE, desmoid tumors
Lynch SyndromeMLH1, MSH2 (Mismatch repair)DominantFew polyps, rapid sequenceEndometrial, ovarian cancer
Peutz-JeghersSTK11 (Serine/threonine kinase)DominantHamartomasMucocutaneous hyperpigmentation
MUTYH PolyposisMUTYH (Base excision repair)Recessive10-100 adenomasNone specific
Cowden SyndromePTEN (Lipid phosphatase)DominantHamartomasMacrocephaly, trichilemmomas, thyroid cancer
Identifying these subtle extraintestinal signs is critical for differentiating the conditions and determining the correct genetic workup.

Step-by-Step Solution

1
Analyze the first clinical vignette to diagnose the syndrome and identify its genetic basis.
Over 200 adenomas, osteomas, and CHRPE indicate Gardner syndrome (FAP variant), caused by an APC mutation leading to aberrant Wnt/beta-catenin signaling.
Identifying the distinct extraintestinal manifestations is necessary to differentiate FAP from other polyposis syndromes.
2
Evaluate the second vignette focusing on the patient's personal and family cancer history.
Early-onset right-sided colon cancer and endometrial cancer point to Lynch syndrome, caused by a DNA mismatch repair defect.
Lynch syndrome is the most common inherited colorectal cancer syndrome and does not present with diffuse polyposis.
3
Assess the third vignette featuring gastrointestinal intussusception and distinct skin findings.
Jejunal hamartomas and perioral hyperpigmentation are pathognomonic for Peutz-Jeghers syndrome, caused by STK11 mutations.
Hamartomatous polyposis syndromes must be differentiated primarily by their extraintestinal signs and affected genes.
4
Analyze the fourth vignette describing a moderate adenoma burden with negative family history.
An autosomal recessive pattern (healthy parents) with 10-100 adenomas indicates MUTYH-associated polyposis (MAP), which involves a defect in base excision repair.
MAP is the primary autosomal recessive polyposis syndrome and should be suspected when APC testing is negative.
5
Evaluate the fifth vignette highlighting macrocephaly and specific dermatological lesions.
Facial trichilemmomas, macrocephaly, hamartomas, and thyroid cancer describe Cowden syndrome, driven by a PTEN lipid phosphatase mutation.
PTEN normally regulates cell growth, and its loss leads to hamartoma formation across multiple tissue types.

Key Concept

Hereditary Polyposis and Colorectal Cancer Syndromes: Clinical Manifestations and Molecular Genetics
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Topics

Gastroenterology and Hepatology

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