von Hippel-Lindau disease: a clinical and scientific review

Abstract

The autosomal dominantly inherited disorder von Hippel-Lindau disease (VHL) is caused by germline mutations in the VHL tumour suppressor gene (TSG). VHL mutations predispose to the development of a variety of tumours (most commonly retinal and central nervous system haemangioblastomas, clear cell renal carcinoma and phaeochromocytomas). Here, we review the clinical and genetic features of VHL disease, briefly review the molecular pathogenesis and outline clinical management and tumour surveillance strategies.

Figure 1

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).

Figure 2

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 Maher).