WBR0544

Author	[[PageAuthor::Rim Halaby, M.D. [1], Reviewed by Will Gibson, (Reviewed by Alison Leibowitz)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::Neurology, SubCategory::Oncology
Prompt	[[Prompt::A 14-year-old male is brought to the physician's office by his mother for recent-onset headache, vomiting, and ataxia. Following appropriate work-up, the patient is found to have hemangioblastoma in the cerebellum and bilateral renal cell carcinomas. Genetic testing leads to a diagnosis. Which of the following findings is most likely associated with the patient's condition?]]
Answer A	AnswerA::Hematocrit (Hct) = 58 %
Answer A Explanation	AnswerAExp::Polycythemia is associated with renal cell carcinomas. Both sporadic renal cell carcinomas and Von-Hippel-Lindau associated renal cell carcinomas universally exhibit biallelic inactivation of the VHL tumor suppressor gene.
Answer B	AnswerB::Serum sodium = 122 mmol/L
Answer B Explanation	[[AnswerBExp::Hyponatremia is not frequently associated with VHL. Disorders of sodium can be associated with other cancers. For example, hyponatremia can be caused by an ADH-secreting small cell lung cancer. Conversely, Conn syndrome refers to an aldosterone-secreting adenoma, which typically causes hypernatremia.]]
Answer C	AnswerC::Serum alanine aminotransaminase (ALT) = 241 IU/L
Answer C Explanation	AnswerCExp::Elevated ALT is not frequently associated with VHL. Elevated ALT is associated with liver damage.
Answer D	AnswerD::Platelet count = 43,000 per microliter
Answer D Explanation	AnswerDExp::Thrombocytopenia is not frequently associated with VHL. Thrombocytopenia can occur in hematopoetic malignancy.
Answer E	AnswerE::Serum calcium = 13 mmol/L
Answer E Explanation	AnswerEExp::Hypercalcemia is not frequently associated with VHL.
Right Answer	RightAnswer::A
Explanation	[[Explanation::The patient has von Hippel-Lindau (VHL) disease, an autosomal dominant disorder caused by germline mutation of one copy of the VHL tumor suppressor gene on chromosome 3. VHL is characterized by hemangioblastomas of the retina, cerebellum, and medulla. Also patients frequently present with bilateral renal cell carcinomas or other tumors, such as pheochromocytomas. A common manifestation of VHL in young patients are headaches with neurological symptoms. Symptoms of other tumors may also manifest, such as hypertension in the case of pheochromocytoma. VHL encodes a ubiquitin ligase that targets the HIF (hypoxia inducible factor) protein for degradation. In the absence of VHL protein, renal cell carcinoma cells turn on a transcriptional program mimicking that of an oxygen-deprived state. The cells begin to highly express genes such as VEGF (vascular endothelial growth factor) that induce tumorigenesis. Recall that the kidneys are responsible for coordinating the erythropoetic response to low oxygen tension. Accordingly, renal cell carcinomas express high levels of erythropoietin and patients often develop high hematocrits. Educational Objective: Polycythemia is associated with VHL, due to an overproduction of HIF. References: Kaelin WG. The von Hippel-Lindau tumor suppressor gene and kidney cancer. Clin Cancer Res. 2004; 10(18 Pt 2):6290S-5S]]
Approved	Approved::Yes
Keyword	WBRKeyword::Von hippel lindau, WBRKeyword::Polycythemia, WBRKeyword::Hematocrit, WBRKeyword::HCT, WBRKeyword::Hemangioblastoma, WBRKeyword::Bilateral renal cell carcinoma, WBRKeyword::Renal cell carcinoma, WBRKeyword::Headache, WBRKeyword::Vomiting, WBRKeyword::Pheochromocytoma, WBRKeyword::Hypoxia inducible factor, WBRKeyword::HIF, WBRKeyword::Autosomal, WBRKeyword::Autosomal dominant, WBRKeyword::Genetics, WBRKeyword::Inheritance, WBRKeyword::Cancer, WBRKeyword::Mutation, WBRKeyword::Cancer predisposition syndrome, WBRKeyword::VHL, WBRKeyword::Kidney cancer
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