Von-Hippel Lindau

Question 1

At risk for tumors in?

Answer 1

Cerebellar, spinal cord, retinal hemangioblasotmas
Endolymphatic sac (inner ear) tumors
Bilateral kindey cysts (renal cell carcinomas)
Pheochromocytomas
Cystadenomas of genitourinary tract

Question 2

Screening?

Answer 2

Any age? genetic testing for VHL
birth to 4: annual eye exam, pediatrician to look for signs of neurological disturbance (nystagmus, strabismus)
5-15: physical and neurological annual, opthamologist, test for fracitonated metanephrines, abdnominal sonography after age 8, audioloigst, MRI for ear
16 and up: same + abdomen scan, brain MRI

Question 3

Type I VHL

Answer 3

Total or partial VHL loss, improper folding. Up-regulation of HIP. Get hemangioblastoma, renal cell carcinoma, LOW risk pheochromocytoma.

Question 4

Type 2A

Answer 4

VHL missense. Up-regulation of HIP. inability to stabilize MT’s. Hemangioblastoma, low risk of renal cell carcinoma, HIGH risk of pheochromocytoma.

Question 5

Type 2B

Answer 5

VHL missense. Hemangioblastoma. High risk renal cell carcinoma. High risk pheochromocytoma.

Question 6

Type 2C

Answer 6

VHL missense. pVHL maintains ability to down-regulate HIF. decreased binding to fibronectin, defective fibronective matrix. PHEOCHROMOCYTOMA ONLY.

Question 7

Mechanism of VHL?

Answer 7

Under normal (e.g. normal 02) conditions it is involved in ubiquination/hydroxylation of HIF so it's degraded by proteosome. 
Hypoxia HIF not degraded goes to nucleus causes trx of genes like VEGF and upregulate angiogenesis, glucose uptake etc.

Question 8

Treatment options for RCC

Answer 8

Immunotherapy
VEGF (tyrosine kinase) inhibs (against angiogenesis) (sorafenib, sornitinib, pazopanib, axitinib)
mTOR inhibs

Question 9

AE’s with VEGF therapy

Answer 9

GI issues, fatigue, hair changes, HYPERTENSION, stomatitis, hand foot syndrome, heart failure, thyroid issues, hypoglycemia, periorbital edema, risk of squamos cell cancer.

Question 10

Targeting mTOR in RCC

Answer 10

Akt/mTOr is a parallel (compensatory) pathway. Temsirolimus, everolimus.

Question 11

AE’s with mTOR

Answer 11

infections, stomatitis, skin rash, asthenia and fatigue, GI issues, pulmonary issues, non-infection pneumonitis

Question 12

Other genetic alterations in ccRCC

Answer 12

VHL, BAP1, PRBM1 all on chromo 3.
Loss of 3p.. heterozygous loss.
Subsequent PRBM1 or BAP1 mutations results in ccRCC w/ diff features and outcomes.
VHL mutations can be in sporadic as well.