Von Hippel-Lindau Vignette

Question 1

VHL Clinical Manifestations

Answer 1

Cystic, highly vascularized tumors: spinal cord, cerebellum, renal hemangioblastomas. Bilateral kidney cysts, ccRCC. Phenochromocytomas, panreatic cysts, etc
Diagnosed with 1 lesion and family history or 2 lesions with no history

Question 2

Molecular Basis

Answer 2

Autosomal dominant inheritance of VHL (Chr3p25-26) mutation 1/36,000 births.
VHL in ubiquitin ligase complex, ubiquitinates HIF, suppresses aneuploidy, stabilizes microtubules.
After mutation, HIF activates TFs for PDGF, VEGF, and TGF a/b (angiogenesis, metabolism, apoptosis)

Question 3

ccRCC

Answer 3

In VHL, see many cysts on bilateral kidneys, highly vascularized tumors. Many cysts due to inherited loss of one copy.

Question 4

ccRCC Treatment

Answer 4

surgical resection with partial nephrectomy. Metastatic tumors treated with VEGF-R TKIs, mTOR inhibitors, and immunotherapies against HIF proteins.

Question 5

Hemangioblastoma

Answer 5

Highly vascularized tumor

Question 6

VHL Type 1

Answer 6

Hemangioblastoma & ccRCC

total/partial loss of VHL gene

Question 7

VHL Type 2a

Answer 7

Hemangioblastoma & Phenochromocytoma

VHL missense mutation, HIF up-regulation

Question 8

VHL Type 2b

Answer 8

Hemangioblastoma & Phenochromocytoma & ccRCC

VHL missense, HIF up-regulation

Question 9

VHL Type 2c

Answer 9

Phenochromocytoma only

VHL Missense

Question 10

VHL Gene Location/Function

Answer 10

Chromosome 3p25-26

Targets proteins for proteasomal degradation

Question 11

Sorafenib and Sunitinib

Answer 11

TKIs for VEGFRs and PDGFRs