von Hippel-Lindau Disease Flashcards by Lindsey Herrera

fibronectin

binds extracellular matrix proteins- important for cell adhesion, growth, migration, and differentiation

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Hemangioblastoma

tumors of the CNS composed of stromal cells in small blood vessels

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HIF is a _____ whose action is _____-dependent.

transcription factor; oxygen

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Accumulation of HIF activates the transcription of ____, _____, and _____.

VEGF, PDGF and TGF alpha and beta.

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What is the molecular defect in type 2C VHL disease?

decreased binding of fibronectin and defective fibronectin matrix assembly

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What is the clinical action to take from age 16 and beyond in VHL pts?

annual physical, eye exam, ultrasound, and fractionated metanephrines; also ab and brain MRI; hearing exam every 2-3 years

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What is the function of normal VHL protein?

it’s a tumor suppressor

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In the presence of ____, HIF-alpha is ubiquitinated by VHL protein and undergoes proteosomal degradation.

normal wild type VHL

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What is the VHL mutation in type 1 VHL disease?

total or partial loss resulting in improper folding

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What is the clinical action to take from birth to age 4 in VHL pts?

annual eye/retinal exam; check for white pupils; check for neuro problems; check for abnormal blood pressure

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Of all clear cell renal cell carcinomas, what percentage are due to VHL?

4% of all cases

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Of all renal cell carcinomas, what percentage are conventional clear cell?

75%

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Patients with VHL are at risk of developing of up to ___ tumors per kidney.

600

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Under normal conditions, HIF-alpha is ______ by _____ and ______.

hydroxylated; proline; asparagine hydroxylase

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BAP1 and PRBM1 are located on ____ and can also be mutated in _____.

Chr 3p; ccRCC

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Cells with a mutated VHL gene behave as if they are ____ and ____ is not degraded.

under hypoxic conditions; HIF

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VEGF-targeted therapy aims to block ____ and _____.

vasculogenesis; angiogenesis

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What are the clinical manifestations of type 2B VHL disease?

Hemangioblastomas; renal cell carcinoma; pheochromocytomas

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What is the molecular defect in type 2A VHL disease?

upregulation of HIF and inability to stabilize microtubules

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What is the molecular defect in type 2B VHL disease?

upregulation of HIF

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What is the VHL mutation in type 2B VHL disease?

missense mutation

Pheochromocytoma

a neuroendocrine tumor of the medulla of the adrenal gland

What are the clinical manifestations of type I VHL disease?

Hemangioblastomas; Renal cell carcinoma

What is the incidence rate of VHL?

1:36,000

What is the VHL mutation in type 2A VHL disease?

missense mutation

What is the VHL mutation in type 2C VHL disease?

missense mutation

\_\_\_\_\_ and ____ are located on Chr 3p and can also be mutated in ccRCC.

BAP1; PRBM1

How is VHL inherited?

it's autosomal dominant

mTOR inhibitors act to block _____ and \_\_\_\_\_.

cell growth; angiogenesis

fractionated metanephrines

metabolite of epinephrine circulating free in the plasma

VHL is the most common cause of \_\_\_\_\_.

clear cell renal carcinoma (ccRCC)

At what age should genetic testing for VHL pts be considered?

any age

What is the molecular defect in type 1 VHL disease?

upregulation of HIF

What are the clinical manifestations of type 2A VHL disease?

Hemangioblastomas

VHL protein is part of a complex that \_\_\_\_.

selects proteins for degradation by ubiquitylation

Sporadic ccRCC accounts for about \_\_\_% of all cases and is typically \_\_\_\_\_, \_\_\_\_\_, and has a \_\_\_\_\_.

96%; solitary, unilateral, later age of onset

Name 3 treatment options for metastatic renal cell carcinoma.

1) immunotherapy 2) vascular endothelial growth factor inhibitors 3) mTOR inhibitors

Name 8 processes regulated by HIF.

1) Angiogenesis 2) Erythopoeisis 3) Anaerobic glycolysis 4) Glucose uptake 5) Extracellular matrix turnover 6) pH control 7) Apoptosis 8) Mitogenesis

\_\_\_\_\_ activates the transcription of VEGF, PDGF and TGF alpha and beta.

Accumulation of HIF

What is the goal of surgical management for VHL?

to prevent metastasis while preserving renal function

VHL is characterized by the formation of cystic and ______ tumors in many organs.

highly vascularized

Where is the VHL gene located?

short arm of ch 3

Where do hemangioblastomas usually occur?

in the cerebellum, brain stem or spinal cord

What is the clinical action to take from 5 to age 15 in VHL pts?

annual physical and neuro exam; test for fractionated metanephrines; ab ultrasound; hearing tests; MRI w/ contrast of internal auditory canal

Familial ccRCC accounts for about \_\_\_% of all cases and is typically \_\_\_\_\_, \_\_\_\_\_, and has a \_\_\_\_\_.

4%; multifocal, bilateral, early age onset

\_\_\_ is the most common cause of ccRCC.

VHL

Cells with a _____ behave as if they are under hypoxic conditions and HIF is not \_\_\_\_\_.

mutated VHL gene; degraded

In the presence of normal wild type VHL, ____ is ubiquitinated by _____ and undergoes proteosomal degradation.

HIF-alpha VHL protein

What are the clinical manifestations of type 2C VHL disease?

Pheochromocytomas only

Hematuria

blood in the urine