Top panel: in normoxic cells without VHL inactivation a pVHL containing complex ubiquitylates the α-subunits of the HIF transcription factors targeting them for proteasomal degradation. Lower panel: in VHL disease tumour cells the absence of wild type pVHL causes stabilization of the HIF α-subunits and the HIF transcription factors then activate downstream targets including VEGF (vascular endothelial growth factor), PDGF (platelet derived growth factor) and TGFα (transforming growth factor α). Tyrosine kinase inhibitors such as sorafenib and sunitinib inhibit the VEGF and PDGF receptors and so block some of the effects of VHL inactivation (modified from Woodward and Maher⁵⁰).

Main clinical manifestations of von Hippel-Lindau disease. (reprinted with permission from Richard S. von Hippel–Lindau disease: recent advances and therapeutic perspectives. Exp Rev Anticancer Ther 2003, 3: 215–233). (a) Right cerebellar haemangioblastoma with a large cyst in a 17 years old woman (T1-weighted contrast-enhanced MRI). (b) Endolymphatic sac tumor (E) in a 18 years old woman. Note also the presence of one haemangioblastoma cyst (c) and one quiescent cerebellar haemangioblastoma (arrow). (T1-weighted contrast-enhanced MRI). (c) Cervical spinal haemangioblastoma in a 35 yrs patient with a centromedullar cavitation below (c). (T1-weighted contrast-enhanced MRI). (d) Fluorescein angiography revealing two new large retinal haemangioblastomas (arrows) in an already previously laser-treated 44 years-old patient (courtesy of Professor Alain Gaudric). (e) Bilateral solid renal cell carcinoma (R) in a 38 yrs patient. CT scan. (f) Multiple bilateral cysts and cystic renal cell carcinomas in the kidneys of a 40 yrs patient. Note also the numerous pancreatic cysts (arrow). CT scan. (g) Left adrenal phaechromocytoma (P) detected in an asymptomatic 24 yrs patient. CT scan.(h) Large pancreatic neuroendocrine tumor (TNE) in a 45 yrs patient. CT-scan (courtesy of Prof. Pascal Hammel).