Von Hippel-Lindau

2001-01-01   Stéphane Richard 

Génétique Oncologique EPHE, Faculté de Médecine Paris-Sud, 63 av Gabriel Péri, 94276 LE KREMLIN BICETRE, France



Von Hippel-Lindau


Von Hippel-Lindau (VHL) disease is a hereditary devastating cancer syndrome, predisposing to the development of various benign and malignant tumours (Central Nervous System [CNS] and retinal hemangioblastomas, endolymphatic sac tumours, renal cell carcinoma (RCC) and\/or renal cysts, pheochromocytomas, pancreatic cysts and neuroendocrine tumours, endolymphatic sac tumours, epididymal and broad ligament cystadenomas). VHL disease is the first cause of hereditary kidney cancer


an autosomal dominant disorder with high penetrance (increasing with age: 97% by age 60 yrs) but variable expressivity (with phenotype\/genotype correlations); frequency is estimated at about 2.5\/105; neomutations represent about 20% of cases.






892 Von Hippel-Lindau disease




Phenotype and clinics

onset of the disease usually occurs between 18 and 30 yrs, often with retinal or cerebellar hemangioblastomas, but can also manifests in children, especially by retinal hemangioblastomas and pheochromocytoma.
  • Central nervous system (CNS) hemangioblastomas occur in 60-80% of patients (infratentorial localisation in 60 % of cases, intraspinal in 30-40%; supratentorial in 1%). Multiple tumours are frequent (hemangioblastomatosis).
  • Retinal hemangioblastomas, often multiple and bilateral, occur in about 50% of patients. Most retinal hemangioblastomas occur peripherally but optic disc (papillary or juxtapapillary) locations are encountered in almost 15% of cases.
  • Renal cell carcinomas occur in up to 75% of cases. They are mostly multifocal and bilateral. Tumors have a classical solid or a more specific mixed cystic\/solid appearance and are always of clear cell subtype. Multiple benign cysts are also observed.
  • Pheochromocytomas, often bilateral, are mostly found in a subset of families, where it can be the only sign of VHL. Extraadrenal paragangliomas are sometimes encountered.
  • Pancreas manifestations occur in up to 77% of patients: isolated or multiple cysts and serous cystadenomas are the most frequent lesions, neuroendocrine tumours occur in about 10-15 % of cases.
  • Endolymphatic sac tumours, only recently recognised as a manifestation of VHL disease, occur in up to 11% of cases.
  • Epididymal cysts, often bilateral, occur in about 54% of men.
  • Cystadenomas of the broad ligament (\"adnexal papillary tumour of probable mesonephric origin\") are extremely rare but highly specific.
    There are two main clinical types of VHL according to the absence (type 1) or presence of pheochromocytoma (type 2). The type 2 is subdivised in three subtypes, 2A (with low risk of renal cancer and pancreatic tumors); 2B (the full multi-tissues subtype), and 2C (pheochromocytomas only, recently individualised by molecular genetics).
  • Neoplastic risk

  • Central nervous system (CNS) hemangioblastomas may cause life-threatening complications in spite of their benign nature and classic slow-growing course and remain a major cause of morbidity and mortality in VHL disease.
  • Retinal hemangioblastomas may cause retinal detachment, haemorrhage, glaucoma and cataract, leading to blindness, in absence of early detection and treatment.
  • Renal cell carcinomas is becoming the main cause of death in the disease, because of secondary dissemination mainly due to delay in diagnosis.
  • Pheochromocytomas are malignant in about 5-10% of cases.
  • Neuroendocrine pancreatic tumours tend to be slow growing but have the potential of a truly malignant course with locoregional dissemination.
  • Endolymphatic sac tumours is a low grade papillary adenocarcinoma resulting in progressive hearing loss. It can grow to the pontocerebelline angle and\/or the middle ear, then destroying the temporal bone.
  • Epididymal cysts and cystadenomas of the broad ligament are benign tumors.
  • Treatment

    Regular clinical follow-up of patients and gene-carriers is imperative in order to detect manifestations early and to avoid complications;
  • Treatment of symptomatic CNS hemangioblastoma remains mainly neurosurgical, often in emergency, but stereotactic radiosurgery is emerging as an alternative therapeutic procedure in patients with multifocal solid hemangioblastomas.
  • Retinal hemangioblastoma are treated by cryotherapy or laser depending on the location, size and number of tumours.
  • Endolymphatic sac tumours require surgical treatment with the help of ENT specialists as soon as possible in order to prevent definitive hearing loss. Preoperative embolisation is sometimes performed to avoid bleeding.
  • Renal cell carcinomas have to be treated when their size is about 3 cm in diameter. Nephron sparing surgery is the choice method and may delay bilateral nephrectomy and dialysis. When binephrectomy is inevitable, renal transplantation can be discussed after a 2 year period without metastasis
  • Pheochromocytomas have to be surgically removed, preferentially with the use of laparoscopy. When possible, partial adrenalectomy appears to be a safe method of preserving adrenocortical function and quality of life.
  • Pancreatic neuroendocrine tumours require surgical removal at a 2-3 cm size in order to avoid metastatic dissemination.
  • Pancreatic cysts and serous cystadenomas do not require resection but sometimes a percutaneous drainage or endoscopic implantation of a biliary stent is indicated in cases of compression.
  • Surgery is indicated for broad ligament cystadenomas and for symptomatic epididymal cystadenomas.
  • Medical perspectives: several clinical studies are on-going with specific drugs that block VEGF in the hope of causing stabilisation or recession of CNS and retinal hemangioblastomas. Such clinical trials are in processing in France, England and Poland.
  • Prognosis

    according to the severity of the disease in a given patient, and to the quality of a regular follow up. Mean age at death is about 50 yrs and renal cell carcinomas and CNS hemangioblastomas are the major causes of death. As treatment of VHL manifestations in first stages will improve significantly the clinical outcome and the quality of life of patients, early and unambiguous diagnosis is mandatory. Thus, DNA testing is emerging as a major progress in this consideration, pawing the way to an effective presymptomatic diagnosis.

    Genes involved and Proteins


    3 exons
    Atlas Image
    Functional domains of pVHL and distribution of germline point mutations.


    213 amino acids




    tumour-suppressor gene. pVHL interacts with elongins B and C and cullin 2 through a complex exhibiting ubiquitine ligase activity. Its main function is to negatively regulate VEGF mRNAs (and angiogenesis as a result) by targeting hypoxia inducible transcription factors HIF for degradation by the proteasome. pVHL has also major functions in extra cellular matrix formation and cell cycle control.


    causes VHL disease.
    more than 400 mutations have been identified, comprising for more than 150 independent intragenic mutational events; virtually 100% of mutations are detectable. The majority of mutations are represented by point mutations including missense, nonsense mutations, splicing, microinsertions or microdeletions. In about 25 % of cases, a large deletion of the VHL gene is observed.
    Mutations resulting in a truncated protein are mostly associated with type 1 VHL. In type 2, mutations are generally missense mutations affecting preferentially the critical contact region between pVHL and elongin C (residues 157-171) with an hot-spot at codon 167. In type 2A there is a founder effect for a specific missense mutation at codon 98. In type 2C, mutations occur in regions potentially involved in critical function exclusive to the adrenals (as codon 188). Last, patients with identical VHL germline mutations may display different phenotypes, indicating that the issue of genotype-phenotype correlations is complex in VHL. Evidence was recently provided that unknown modifier genes and environmental influences could play an additional role in the clinical expression of the disease.


    Somatic VHL gene inactivation is frequent in sporadic hemangioblastomas and moreover in sporadic renal cell carcinoma, representing a significant event in the development of these tumors. Different mutational mechanisms lead to the inactivation of the VHL gene including loss of heterozygosity, small intragenic mutations or hypermethylation of the promoter.

    To be noted




    http:\/\/www.vhl.org\/ VHL Famimy Alliance


    http:\/\/www.umd.necker.fr:2005\/ VHL mutation database


    Pubmed IDLast YearTitleAuthors
    93998471998Software and database for the analysis of mutations in the VHL gene.Béroud C et al
    77590771995Von Hippel-Lindau (VHL) disease with pheochromocytoma in the Black Forest region of Germany: evidence for a founder effect.Brauch H et al
    90124111997Clustering of Caucasian Leber hereditary optic neuropathy patients containing the 11778 or 14484 mutations on an mtDNA lineage.Brown MD et al
    88729701996Renal involvement in von Hippel-Lindau disease.Chauveau D et al
    91877021997Epididymal cystadenomas in von Hippel-Lindau disease.Choyke PL et al
    107259532000von Hippel-Lindau disease.Couch V et al
    90625831997The von Hippel-Lindau tumor suppressor gene. A rare and intriguing disease opening new insight into basic mechanisms of carcinogenesis.Decker HJ et al
    106301731999Von Hippel-Lindau syndrome. A pleomorphic condition.Friedrich CA et al
    104087761999Mutations of the VHL gene in sporadic renal cell carcinoma: definition of a risk factor for VHL patients to develop an RCC.Gallou C et al
    105674931999The impact of molecular genetic analysis of the VHL gene in patients with haemangioblastomas of the central nervous system.Gläsker S et al
    110401952000Pancreatic involvement in von Hippel-Lindau disease. The Groupe Francophone d'Etude de la Maladie de von Hippel-Lindau.Hammel PR et al
    108040892000von Hippel-Lindau syndrome: target for anti-vascular endothelial growth factor (VEGF) receptor therapy.Harris AL et al
    100929921999Management of renal cell carcinoma in von Hippel-Lindau disease.Hes FJ et al
    98200321998The VHL tumour-suppressor gene paradigm.Kaelin WG Jr et al
    26425841989von Hippel-Lindau disease affecting 43 members of a single kindred.Lamiell JM et al
    84935741993Identification of the von Hippel-Lindau disease tumor suppressor gene.Latif F et al
    109288622000Attitudes of von Hippel-Lindau disease patients towards presymptomatic genetic diagnosis in children and prenatal diagnosis.Levy M et al
    78373901995Identification of the von Hippel-Lindau (VHL) gene. Its role in renal cancer.Linehan WM et al
    89299481996A genetic register for von Hippel-Lindau disease.Maddock IR et al
    94134241997von Hippel-Lindau disease.Maher ER et al
    22746581990Clinical features and natural history of von Hippel-Lindau disease.Maher ER et al
    91457191997Endolymphatic sac tumors. A source of morbid hearing loss in von Hippel-Lindau disease.Manski TJ et al
    103532511999The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis.Maxwell PH et al
    97513291998Prevalence, morphology and biology of renal cell carcinoma in von Hippel-Lindau disease compared to sporadic renal cell carcinoma.Neumann HP et al
    103668211999The von Hippel-Lindau tumour suppressor protein: new perspectives.Ohh M et al
    96515791998The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix.Ohh M et al
    98299121998Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma.Olschwang S et al
    105540351999Constitutional von Hippel-Lindau (VHL) gene deletions detected in VHL families by fluorescence in situ hybridization.Pack SD et al
    94482731998The von Hippel-Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal.Pause A et al
    108094802000Central nervous system hemangioblastomas, endolymphatic sac tumors, and von Hippel-Lindau disease.Richard S et al
    104166851999Expression of von Hippel-Lindau protein in normal and pathological human tissues.Sakashita N et al
    106311382000Mosaicism in von Hippel-Lindau disease: lessons from kindreds with germline mutations identified in offspring with mosaic parents.Sgambati MT et al
    102050471999Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function.Stebbins CE et al
    98299111998Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene.Stolle C et al
    109441132000Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein.Tanimoto K et al
    104583361999Clinical and genetic characterization of pheochromocytoma in von Hippel-Lindau families: comparison with sporadic pheochromocytoma gives insight into natural history of pheochromocytoma.Walther MM et al
    100888161999Clinical characteristics of ocular angiomatosis in von Hippel-Lindau disease and correlation with germline mutation.Webster AR et al
    108577492000Comparative sequence analysis of the VHL tumor suppressor gene.Woodward ER et al
    102326161999Third International Meeting on von Hippel-Lindau disease.Zbar B et al
    89560401996Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan.Zbar B et al