WBR0109
| Author | [[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D. and Rim Halaby, M.D. [1])]] |
|---|---|
| Exam Type | ExamType::USMLE Step 1 |
| Main Category | MainCategory::Genetics |
| Sub Category | SubCategory::Renal |
| Prompt | [[Prompt::A 40-year-old man presents to his primary care physician complaining of fatigue and a 15-lbs unintentional weight loss over the past three months. He also complains of a non-specific discomfort in the upper back associated with the onset of his symptoms. In the clinic, his blood pressure is 140/100 mmHg, heart rate is 88/min, and respiratory rate is 16/min. Physical examination is remarkable for a positive Murphy's punch sign bilaterally. Laboratory analysis is notable for a creatinine of 1.5 mg/dL and BUN of 25 mg/dL. Urinalysis reveals free red cells without casts. An MRI of the abdomen shows bilateral solid renal masses. Renal biopsy is shown below. In which of the following genes does this patient most likely harbor a germline defect?
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| Answer A | AnswerA::''TSC1'' |
| Answer A Explanation | [[AnswerAExp::Mutations of TSC1 or TSC2 cause tuberous sclerosis.]] |
| Answer B | AnswerB::''p53'' |
| Answer B Explanation | [[AnswerBExp::Mutations of p53 are involved in almost all cancers. p53 mutations may also cause Li-Fraumeni syndrome.]] |
| Answer C | AnswerC::''RB'' |
| Answer C Explanation | [[AnswerCExp::Mutations of RB cause retinoblastoma.]] |
| Answer D | AnswerD::''PTEN'' |
| Answer D Explanation | [[AnswerDExp::Mutations of PTEN cause Cowden syndrome.]] |
| Answer E | AnswerE::''VHL'' |
| Answer E Explanation | [[AnswerEExp::VHL gene mutations increase the activity of the hypoxia-inducible factor transcription factor (HIF). HIF increases the expression of many pro-angiogenic proteins to promote tumorigenesis. Bilateral renal cell carcinoma is associated with Von Hippel-Lindau (VHL) syndrome, which is caused by mutations in the VHL gene.]] |
| Right Answer | RightAnswer::E |
| Explanation | [[Explanation::Renal cell carcinoma (RCC) is the 7th leading cancer among men and the 12th among women. While most cases of RCC develop sporadically, 2% of RCC are associated with genetic conditions. The hallmark of RCC is the triad of flank pain, hematuria, and palpable abdominal mass or costovertebral angle tenderness (McMurphy's punch sign) bilaterally on physical examination. Nonspecific symptoms, such as fatigue, weight loss, anemia, or even polycythemia may also be present. Nonetheless, the majority of cases are detected incidentally during abdominal imaging for other diseases. The most common risk factors for RCC are smoking, obesity, and hypertension. Other known risk factors include acquired cystic renal disease among patients with end-stage renal disease (ESRD) and Von Hippel Lindau disease, which characteristically presents with bilateral RCC.
VHL is an autosomal dominant familial cancer syndrome that includes hemangioblastomas of the CNS, retinal angiomas, clear-cell type RCC that classically presents as bilateral masses, and pheochromocytoma. Bilateral renal cell carcinoma is highly specific for Von Hippel Lindau syndrome. The disease is caused by a mutation of the von Hippel–Lindau tumor suppressor gene (VHL) on the short arm of chromosome 3. The VHL protein normally promotes the degradation of hypoxia-inducible factor (HIF). This mutation causes a constitutive signaling of hypoxia-inducible factor, which increases the expression of essential pro-angiogenic proteins, including VEGF. First Aid 2014 page 87]] |
| Approved | Approved::Yes |
| Keyword | WBRKeyword::Von hippel lindau, WBRKeyword::Genetics, WBRKeyword::Cancer, WBRKeyword::Oncology, WBRKeyword::Autosomal dominant, WBRKeyword::Renal cell carcinoma, WBRKeyword::Kidney cancer, WBRKeyword::Tumor suppressor gene |
| Linked Question | Linked:: |
| Order in Linked Questions | LinkedOrder:: |
