Von Hippel-Lindau Vignette Flashcards
Recommended screenings for VHL patients age 5-15
Annual physical and neurological exam Annual test for metanephrines Annual abdominal ultrasonography after age 8 Audiology assessment every 2-3 years MRI with contrast of the internal auditory canal to check for ELST
What are the recommended screening tests for VHL patients of any age, and for those <4 years old?
For any age: consider VHL genetic testing From birth to age 4: Annual eye/retinal exams neurological disturbance Nystagmus Strabismus White pearl Abnormal blood pressure, vision, hearing
Recommended screening and follow up for VHL patients 16 and older.
Annual eye/retinal exam Annual physical Annual test for fractionated metanephrines Annual ultrasound, biannual abdominal MRI 2-3 years: MRI of brain and C/T/L spine to find hemangioblastomas and ELST
Two primary types of VHL disease and what separates them
Type 1: VHL Mutation results in total or partial loss of VHL protein Type 2(A,B,C): VHL missense mutation results in less effective protein produced.
What percentage of Renal Cell Carcinomas are caused by Familial VHL mutations, Sporadic VHL mutations, and Sporadic non-VHL mutations, respectively?
4%; 64%; 32%
What clinical manifestations are patients with Type 1 VHL likely to present with?
Hemangioblastomas
Renal Cell Carcinomas
Low risk of Pheochromocytomas
What clinical manifestations are patients with Type 2A VHL mutations likely to present with?
Hemangioblastomas
High risk of Pheochromocytomas
Low risk of Renal Cell Carcinomas
What clinical manifestations are patients with Type 2B VHL likely to present with?
Hemangioblastomas
High risk of Renal Cell Carcinomas
High risk of Pheochromocytomas
What clinical manifestations are patients with Type 2C VHL likely to present with?
Pheochromocytomas only
What role does VHL protein play in the cell?
VHL ubiquitinates HIF-alpha, targeting it for degradation, and preventing it from acting as a TF for several growth factors (VEGF, PDGF, TGF)
HIF-alpha activity is normally controlled by oxygen levels. Inactive in presense of O2.
How does HIF-alpha behave in the absense of VHL?
HIF-alpha dimerizes with HIF-beta and acts as a transcription factor for growth factors. Mimics a hypoxic state, which activates HIF-alpha. PDGF, VEGF, and TGF activation results in angiogenesis, endothelial proliferation, and autocrine growth results in increased survival of cancer cells.
What are the three classes of treatment options for metastatic Renal Cell Carcinomas?
Immunotherapy
Vascular Endothelial Growth Factor Inhibitors
mTOR inhibitors
What are the three targets of VEGF inhibitors in Renal Cell Carcinoma?
Vascular Epithelial Growth Factor inhibitors target :
1 - VEGF directly
2 - VEGF receptor proteins in the plasma membrane
3 - Parallel pathways downstream of the receptor in the cytoplasm
What is the effect of targeting mTOR in Renal Cell Carcinomas?
Upregulating FKBP12 inhibits mTOR, which inhibits the mTOR-related metabolic pathways that induce cell growth.
Alterations in which three genes are associated with ccRCC, and what combinations produce low grade vs high grade tumors?
VHL, BAP1, PRBM1
Mutations in VHL and PRBM1 produce low grade tumors with good prognosis.
Mutations in VHL and BAP1 produce high grade tumors with poor prognosis.
