Von Hippel-Lindau

Identity

Atlas_Id	10010
Genes implicated in	VHL  CCND1
Note	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
Inheritance	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.

Clinics

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

Gene Name	VHL
Location	3p25-26

DNA/RNA
Description	3 exons

Protein
Description	213 amino acids
Expression	wide
Function	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.

Mutations
Germinal	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	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.

Bibliography

Software and database for the analysis of mutations in the VHL gene.

Béroud C, Joly D, Gallou C, Staroz F, Orfanelli MT, Junien C

Nucleic acids research. 1998 ; 26 (1) : 256-258.

PMID 9399847

Von Hippel-Lindau (VHL) disease with pheochromocytoma in the Black Forest region of Germany: evidence for a founder effect.

Brauch H, Kishida T, Glavac D, Chen F, Pausch F, Höfler H, Latif F, Lerman MI, Zbar B, Neumann HP

Human genetics. 1995 ; 95 (5) : 551-556.

PMID 7759077

Clustering of Caucasian Leber hereditary optic neuropathy patients containing the 11778 or 14484 mutations on an mtDNA lineage.

Brown MD, Sun F, Wallace DC

American journal of human genetics. 1997 ; 60 (2) : 381-387.

PMID 9012411

Renal involvement in von Hippel-Lindau disease.

Chauveau D, Duvic C, Chrétien Y, Paraf F, Droz D, Melki P, Hélénon O, Richard S, Grünfeld JP

Kidney international. 1996 ; 50 (3) : 944-951.

PMID 8872970

Epididymal cystadenomas in von Hippel-Lindau disease.

Choyke PL, Glenn GM, Wagner JP, Lubensky IA, Thakore K, Zbar B, Linehan WM, Walther MM

Urology. 1997 ; 49 (6) : 926-931.

PMID 9187702

von Hippel-Lindau disease.

Couch V, Lindor NM, Karnes PS, Michels VV

Mayo Clinic proceedings. Mayo Clinic. 2000 ; 75 (3) : 265-272.

PMID 10725953

The von Hippel-Lindau tumor suppressor gene. A rare and intriguing disease opening new insight into basic mechanisms of carcinogenesis.

Decker HJ, Weidt EJ, Brieger J

Cancer genetics and cytogenetics. 1997 ; 93 (1) : 74-83.

PMID 9062583

Von Hippel-Lindau syndrome. A pleomorphic condition.

Friedrich CA

Cancer. 1999 ; 86 (11 Suppl) : 2478-2482.

PMID 10630173

Mutations of the VHL gene in sporadic renal cell carcinoma: definition of a risk factor for VHL patients to develop an RCC.

Gallou C, Joly D, Méjean A, Staroz F, Martin N, Tarlet G, Orfanelli MT, Bouvier R, Droz D, Chrétien Y, Maréchal JM, Richard S, Junien C, Béroud C

Human mutation. 1999 ; 13 (6) : 464-475.

PMID 10408776

The impact of molecular genetic analysis of the VHL gene in patients with haemangioblastomas of the central nervous system.

Gläsker S, Bender BU, Apel TW, Natt E, van Velthoven V, Scheremet R, Zentner J, Neumann HP

Journal of neurology, neurosurgery, and psychiatry. 1999 ; 67 (6) : 758-762.

PMID 10567493

Pancreatic involvement in von Hippel-Lindau disease. The Groupe Francophone d'Etude de la Maladie de von Hippel-Lindau.

Hammel PR, Vilgrain V, Terris B, Penfornis A, Sauvanet A, Correas JM, Chauveau D, Balian A, Beigelman C, O'Toole D, Bernades P, Ruszniewski P, Richard S

Gastroenterology. 2000 ; 119 (4) : 1087-1095.

PMID 11040195

von Hippel-Lindau syndrome: target for anti-vascular endothelial growth factor (VEGF) receptor therapy.

Harris AL

The oncologist. 2000 ; 5 Suppl 1 : 32-36.

PMID 10804089

Management of renal cell carcinoma in von Hippel-Lindau disease.

Hes FJ, Slootweg PJ, van Vroonhoven TJ, Hené RJ, Feldberg MA, Zewald RA, Ploos van Amstel JK, Höppener JW, Pearson PL, Lips CJ

European journal of clinical investigation. 1999 ; 29 (1) : 68-75.

PMID 10092992

The VHL tumour-suppressor gene paradigm.

Kaelin WG Jr, Maher ER

Trends in genetics : TIG. 1998 ; 14 (10) : 423-426.

PMID 9820032

von Hippel-Lindau disease affecting 43 members of a single kindred.

Lamiell JM, Salazar FG, Hsia YE

Medicine. 1989 ; 68 (1) : 1-29.

PMID 2642584

Identification of the von Hippel-Lindau disease tumor suppressor gene.

Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L

Science (New York, N.Y.). 1993 ; 260 (5112) : 1317-1320.

PMID 8493574

Attitudes of von Hippel-Lindau disease patients towards presymptomatic genetic diagnosis in children and prenatal diagnosis.

Levy M, Richard S

Journal of medical genetics. 2000 ; 37 (6) : 476-478.

PMID 10928862

Identification of the von Hippel-Lindau (VHL) gene. Its role in renal cancer.

Linehan WM, Lerman MI, Zbar B

JAMA : the journal of the American Medical Association. 1995 ; 273 (7) : 564-570.

PMID 7837390

A genetic register for von Hippel-Lindau disease.

Maddock IR, Moran A, Maher ER, Teare MD, Norman A, Payne SJ, Whitehouse R, Dodd C, Lavin M, Hartley N, Super M, Evans DG

Journal of medical genetics. 1996 ; 33 (2) : 120-127.

PMID 8929948

von Hippel-Lindau disease.

Maher ER, Kaelin WG Jr

Medicine. 1997 ; 76 (6) : 381-391.

PMID 9413424

Clinical features and natural history of von Hippel-Lindau disease.

Maher ER, Yates JR, Harries R, Benjamin C, Harris R, Moore AT, Ferguson-Smith MA

The Quarterly journal of medicine. 1990 ; 77 (283) : 1151-1163.

PMID 2274658

Endolymphatic sac tumors. A source of morbid hearing loss in von Hippel-Lindau disease.

Manski TJ, Heffner DK, Glenn GM, Patronas NJ, Pikus AT, Katz D, Lebovics R, Sledjeski K, Choyke PL, Zbar B, Linehan WM, Oldfield EH

JAMA : the journal of the American Medical Association. 1997 ; 277 (18) : 1461-1466.

PMID 9145719

The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis.

Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ

Nature. 1999 ; 399 (6733) : 271-275.

PMID 10353251

Prevalence, morphology and biology of renal cell carcinoma in von Hippel-Lindau disease compared to sporadic renal cell carcinoma.

Neumann HP, Bender BU, Berger DP, Laubenberger J, Schultze-Seemann W, Wetterauer U, Ferstl FJ, Herbst EW, Schwarzkopf G, Hes FJ, Lips CJ, Lamiell JM, Masek O, Riegler P, Mueller B, Glavac D, Brauch H

The Journal of urology. 1998 ; 160 (4) : 1248-1254.

PMID 9751329

The von Hippel-Lindau tumour suppressor protein: new perspectives.

Ohh M, Kaelin WG Jr

Molecular medicine today. 1999 ; 5 (6) : 257-263.

PMID 10366821

The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix.

Ohh M, Yauch RL, Lonergan KM, Whaley JM, Stemmer-Rachamimov AO, Louis DN, Gavin BJ, Kley N, Kaelin WG Jr, Iliopoulos O

Molecular cell. 1998 ; 1 (7) : 959-968.

PMID 9651579

Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma.

Olschwang S, Richard S, Boisson C, Giraud S, Laurent-Puig P, Resche F, Thomas G

Human mutation. 1998 ; 12 (6) : 424-430.

PMID 9829912

Constitutional von Hippel-Lindau (VHL) gene deletions detected in VHL families by fluorescence in situ hybridization.

Pack SD, Zbar B, Pak E, Ault DO, Humphrey JS, Pham T, Hurley K, Weil RJ, Park WS, Kuzmin I, Stolle C, Glenn G, Liotta LA, Lerman MI, Klausner RD, Linehan WM, Zhuang Z

Cancer research. 1999 ; 59 (21) : 5560-5564.

PMID 10554035

The von Hippel-Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal.

Pause A, Lee S, Lonergan KM, Klausner RD

Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (3) : 993-998.

PMID 9448273

Central nervous system hemangioblastomas, endolymphatic sac tumors, and von Hippel-Lindau disease.

Richard S, David P, Marsot-Dupuch K, Giraud S, Béroud C, Resche F

Neurosurgical review. 2000 ; 23 (1) : 1-22.

PMID 10809480

La maladie de von Hippel-Lindau: une maladie à impact tissulaire multiple (REVIEW)

Richard S, Giraud S, Hammel P, B?roud C, Joly D, Olschwang S, Resche FE

Presse M..

Expression of von Hippel-Lindau protein in normal and pathological human tissues.

Sakashita N, Takeya M, Kishida T, Stackhouse TM, Zbar B, Takahashi K

The Histochemical journal. 1999 ; 31 (2) : 133-144.

PMID 10416685

Mosaicism in von Hippel-Lindau disease: lessons from kindreds with germline mutations identified in offspring with mosaic parents.

Sgambati MT, Stolle C, Choyke PL, Walther MM, Zbar B, Linehan WM, Glenn GM

American journal of human genetics. 2000 ; 66 (1) : 84-91.

PMID 10631138

Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function.

Stebbins CE, Kaelin WG Jr, Pavletich NP

Science (New York, N.Y.). 1999 ; 284 (5413) : 455-461.

PMID 10205047

Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene.

Stolle C, Glenn G, Zbar B, Humphrey JS, Choyke P, Walther M, Pack S, Hurley K, Andrey C, Klausner R, Linehan WM

Human mutation. 1998 ; 12 (6) : 417-423.

PMID 9829911

Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein.

Tanimoto K, Makino Y, Pereira T, Poellinger L

The EMBO journal. 2000 ; 19 (16) : 4298-4309.

PMID 10944113

Clinical and genetic characterization of pheochromocytoma in von Hippel-Lindau families: comparison with sporadic pheochromocytoma gives insight into natural history of pheochromocytoma.

Walther MM, Reiter R, Keiser HR, Choyke PL, Venzon D, Hurley K, Gnarra JR, Reynolds JC, Glenn GM, Zbar B, Linehan WM

The Journal of urology. 1999 ; 162 (3 Pt 1) : 659-664.

PMID 10458336

Clinical characteristics of ocular angiomatosis in von Hippel-Lindau disease and correlation with germline mutation.

Webster AR, Maher ER, Moore AT

Archives of ophthalmology. 1999 ; 117 (3) : 371-378.

PMID 10088816

Comparative sequence analysis of the VHL tumor suppressor gene.

Woodward ER, Buchberger A, Clifford SC, Hurst LD, Affara NA, Maher ER

Genomics. 2000 ; 65 (3) : 253-265.

PMID 10857749

Third International Meeting on von Hippel-Lindau disease.

Zbar B, Kaelin W, Maher E, Richard S

Cancer research. 1999 ; 59 (9) : 2251-2253.

PMID 10232616

Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan.

Zbar B, Kishida T, Chen F, Schmidt L, Maher ER, Richards FM, Crossey PA, Webster AR, Affara NA, Ferguson-Smith MA, Brauch H, Glavac D, Neumann HP, Tisherman S, Mulvihill JJ, Gross DJ, Shuin T, Whaley J, Seizinger B, Kley N, Olschwang S, Boisson C, Richard S, Lips CH, Lerman M

Human mutation. 1996 ; 8 (4) : 348-357.

PMID 8956040

Citation

This paper should be referenced as such :

Richard, S

Von Hippel-Lindau

Atlas Genet Cytogenet Oncol Haematol. 2001;5(2):145-149.

Free journal version : [ pdf ]   [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Tumors/VHLKprID10010.html

History of this paper:

Capodano, AM. Von Hippel-Lindau. Atlas Genet Cytogenet Oncol Haematol. 1998;2(4):155-156.

http://documents.irevues.inist.fr/bitstream/handle/2042/37469/04-1998-VHLKpr10010.pdf

External links

OMIM	193300
Orphanet	Von Hippel-Lindau disease
MeSH	D006623
MedGen	D006623
UMLS	C0019562
ICD-10	Q85.8
HGMD	120488
Other database	VHL mutation database
Association	VHL Famimy Alliance

REVIEW articles	automatic search in PubMed
Last year articles	automatic search in PubMed

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