Foundations · Year 1 · from Foundations
Case 2: Lynch Syndrome (Mismatch Repair Deficiency)
Clinical Image
Source: Wikipedia - Lynch syndrome - CC BY-SA 3.0
Case Presentation
A 38-year-old woman presents with rectal bleeding and change in bowel habits. Colonoscopy reveals a mass in the ascending colon. Biopsy confirms adenocarcinoma. Given her young age, detailed family history is obtained, revealing her father died of colon cancer at age 45, her paternal aunt had endometrial cancer at 48, and a paternal uncle had urothelial carcinoma at 55. This pattern strongly suggests Lynch syndrome. Immunohistochemistry on her tumor shows loss of MSH2 and MSH6 protein expression. Microsatellite instability (MSI) testing confirms MSI-high status. Germline genetic testing identifies a pathogenic variant in MSH2, confirming Lynch syndrome. She undergoes surgical resection with extended colectomy. She is counseled about her elevated lifetime risks: approximately 80% for colorectal cancer, 40-60% for endometrial cancer, and increased risks for ovarian, gastric, urinary tract, and other cancers. She will undergo colonoscopy every 1-2 years and is offered prophylactic hysterectomy and bilateral salpingo-oophorectomy after completing childbearing. Her siblings and children are offered cascade genetic testing.
Key Learning Points
- Lynch syndrome results from germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2), causing inability to correct replication errors, particularly at microsatellite sequences
- MMR deficiency leads to microsatellite instability (MSI), a hypermutator phenotype; tumors accumulate mutations rapidly, driving cancer development at young ages
- Immunohistochemistry for MMR proteins and MSI testing are used for screening; germline testing confirms diagnosis and enables cascade testing of at-risk relatives