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, malaise, and constipation. The patient has undergone a 15 lbs unintentional weight loss over the past three months. In the clinic, his blood pressure is 140/100 mmHg, heart rate is 88/min, and respiratory rate is 16/min. 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 consolidations. Renal biopsy reveals dysplastic clear cells with several mitotic figures per high-power field. In which of the following genes does this patient most likely harbor a germline defect?]]
Answer A	AnswerA::TSC1
Answer A Explanation	[[AnswerAExp::Mutations of TSC1 cause tuberous sclerosis.]]
Answer B	AnswerB::p53
Answer B Explanation	[[AnswerBExp::Mutations of p53 cause Li-Fraumeni syndrome.]]
Answer C	AnswerC::Rb
Answer C Explanation	[[AnswerCExp::Mutations of Rb cause familial retinoblastoma.]]
Answer D	AnswerD::PTEN
Answer D Explanation	[[AnswerDExp::Mutations of PTEN cause Cowden syndrome.]]
Answer E	AnswerE::VHL
Answer E Explanation	[[AnswerEExp::VHL 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 highly specific for Von Hippel Lindau (VHL) syndrome, caused by mutations in the eponymous VHL gene.]]
Right Answer	RightAnswer::E
Explanation	[[Explanation::The patient in this vignette is experiencing the symptoms of renal compromise due to bilateral renal cell carcinoma. Bilateral renal cell carcinoma is highly specific for Von Hippel Lindau syndrome. Von Hippel–Lindau (VHL) disease is a rare, autosomal dominant genetic condition that predisposes individuals to benign and malignant tumors. The most common tumors found in VHL patients are clear cell renal carcinomas, central nervous system and retinal hemangioblastomas, pheochromocytomas, and pancreatic neuroendocrine tumors. The disease is caused by mutations of the von Hippel–Lindau tumor suppressor (VHL) gene on the short arm of chromosome 3. The VHL protein normally promotes the degradation of hypoxia inducible factor (HIF). These mutations cause constitutive signaling of hypoxia inducible factor, which increases the expression of certain essential pro-angiogenic proteins including VEGF. Educational Objective: Bilateral renal cell carcinoma is highly specific for Von Hippel Lindau (VHL) syndrome, caused by mutations in the eponymous VHL gene. References: 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
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Order in Linked Questions	LinkedOrder::