VON HIPPEL-LINDAU DISEASE: Update on Pathogenesis and Systemic Aspects.

PURPOSE To provide an update summarizing the biologic pathways governing von Hippel-Lindau (VHL) disease pathogenesis and to provide an overview of systemic manifestations as well as screening recommendations. METHODS A PubMed search of the English language literature was reviewed using the following search terms: von Hippel-Lindau, von Hippel-Lindau disease, and VHL. Of 6,696 publications, the most current and pertinent information related to the pathogenesis and systemic aspects of VHL disease were included in this review. RESULTS von Hippel-Lindau disease is one of the most frequently occurring multisystem familial cancer syndromes. The disease results from germline mutation in the VHL tumor suppressor gene on the short arm of chromosome 3. Mutation in the VHL gene affects multiple cellular processes including transcriptional regulation, extracellular matrix formation, apoptosis, and, in particular, the cellular adaptive response to hypoxia. As a result, there is widespread development of vascular tumors affecting the retina, brain, and spine, as well as a spectrum of benign and malignant tumors and/or cysts in visceral organs. CONCLUSION The ophthalmologist plays a key role in VHL disease diagnosis, as retinal hemangioblastoma is frequently the first disease manifestation. Screening guidelines for individuals with known VHL disease, and those at risk of VHL disease, help to ensure early detection of potentially vision-threatening and life-threatening disease.

[1]  W. Chung,et al.  Von Hippel-Lindau Disease: Genetics and Role of Genetic Counseling in a Multiple Neoplasia Syndrome. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  H. Chandarana,et al.  von Hippel-Lindau Disease: Review of Genetics and Imaging. , 2016, Radiologic clinics of North America.

[3]  E. Chew,et al.  Biological and clinical impact of hemangioblastoma-associated peritumoral cysts in von Hippel-Lindau disease. , 2016, Journal of neurosurgery.

[4]  C. Megerian,et al.  Endolymphatic sac tumors. , 2015, Otolaryngologic clinics of North America.

[5]  C. Shields,et al.  Review of spectral domain-enhanced depth imaging optical coherence tomography of tumors of the retina and retinal pigment epithelium in children and adults , 2015, Indian journal of ophthalmology.

[6]  E. Maher,et al.  VHL, the story of a tumour suppressor gene , 2014, Nature Reviews Cancer.

[7]  R. Bennett,et al.  A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment , 2014, Genetics in Medicine.

[8]  Matthew W. Wilson,et al.  Ocular manifestations of hypoxia-inducible factor-2α paraganglioma-somatostatinoma-polycythemia syndrome. , 2014, Ophthalmology.

[9]  E. Chew,et al.  Upregulation of hypoxia-inducible factors and autophagy in von Hippel–Lindau-associated retinal hemangioblastoma , 2014, Graefe's Archive for Clinical and Experimental Ophthalmology.

[10]  W. Linehan,et al.  Prospective natural history study of central nervous system hemangioblastomas in von Hippel-Lindau disease. , 2014, Journal of neurosurgery.

[11]  D. Bu,et al.  Mosaicism in von Hippel–Lindau disease with severe renal manifestations , 2013, Clinical genetics.

[12]  S. Richard,et al.  Von Hippel-Lindau: how a rare disease illuminates cancer biology. , 2013, Seminars in cancer biology.

[13]  A. Lotery,et al.  Photodynamic therapy for retinal capillary hemangioma , 2013, Eye.

[14]  Brian C. Toy,et al.  Longitudinal analysis of retinal hemangioblastomatosis and visual function in ocular von Hippel-Lindau disease. , 2012, Ophthalmology.

[15]  D. Brackmann,et al.  Surgical Management of Endolymphatic Sac Tumors , 2012, Journal of Neurological Surgery—Part B.

[16]  S. Richard,et al.  von Hippel–Lindau disease: A clinical and scientific review , 2011, European Journal of Human Genetics.

[17]  W. Linehan,et al.  Impact of Genetics on the Diagnosis and Treatment of Renal Cancer , 2011, Current urology reports.

[18]  P. Kaiser,et al.  Verteporfin photodynamic therapy of six eyes with retinal capillary haemangioma , 2010, Acta ophthalmologica.

[19]  E. Agrón,et al.  Genotype-phenotype correlation in ocular von Hippel-Lindau (VHL) disease: the effect of missense mutation position on ocular VHL phenotype. , 2010, Investigative ophthalmology & visual science.

[20]  Arun D. Singh,et al.  Vascular Tumors of the Retina and Choroid: Diagnosis and Treatment , 2010, Middle East African journal of ophthalmology.

[21]  A. V. D. van den Ouweland,et al.  Genetic analysis of von Hippel‐Lindau disease , 2010, Human mutation.

[22]  Peter A Pinto,et al.  The clinical implications of the genetics of renal cell carcinoma. , 2009, Urologic oncology.

[23]  E. Chew,et al.  Intravitreal ranibizumab therapy for retinal capillary hemangioblastoma related to von Hippel-Lindau disease. , 2008, Ophthalmology.

[24]  S. Richard,et al.  Endocrine Pancreatic Tumors in von Hippel-Lindau Disease: Clinical, Histological, and Genetic Features , 2008, Pancreas.

[25]  R. Weil,et al.  Surgical management of brainstem hemangioblastomas in patients with von Hippel-Lindau disease. , 2008, Journal of neurosurgery.

[26]  P. Pearson,et al.  Frequency of Von Hippel‐Lindau germline mutations in classic and non‐classic Von Hippel‐Lindau disease identified by DNA sequencing, Southern blot analysis and multiplex ligation‐dependent probe amplification , 2007, Clinical genetics.

[27]  F. Ferris,et al.  INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY WITH PEGAPTANIB FOR ADVANCED VON HIPPEL-LINDAU DISEASE OF THE RETINA , 2007, Retina.

[28]  H. Zentgraf,et al.  The von Hippel-Lindau tumor suppressor protein controls ciliogenesis by orienting microtubule growth , 2006, The Journal of cell biology.

[29]  Kentaro Takahashi,et al.  Von Hippel-Lindau Disease , 2024 .

[30]  Claudio R. Thoma,et al.  Priming-Dependent Phosphorylation and Regulation of the Tumor Suppressor pVHL by Glycogen Synthase Kinase 3 , 2006, Molecular and Cellular Biology.

[31]  E. Oldfield,et al.  Long-term natural history of hemangioblastomas in patients with von Hippel-Lindau disease: implications for treatment. , 2006, Journal of neurosurgery.

[32]  W. Drake,et al.  Benefits of Screening in von Hippel-Lindau Disease – Comparison of Morbidity Associated with Initial Tumours in Affected Parents and Children , 2006, Hormone Research in Paediatrics.

[33]  R. Johnson,et al.  pVHL Function Is Essential for Endothelial Extracellular Matrix Deposition , 2006, Molecular and Cellular Biology.

[34]  M. Ohh,et al.  Characterization of a von Hippel Lindau pathway involved in extracellular matrix remodeling, cell invasion, and angiogenesis. , 2006, Cancer research.

[35]  Peter A Pinto,et al.  Management of von Hippel–Lindau-associated kidney cancer , 2005, Nature Clinical Practice Urology.

[36]  E. Voest,et al.  The von Hippel-Lindau tumor suppressor protein influences microtubule dynamics at the cell periphery. , 2004, Experimental cell research.

[37]  E. Maher,et al.  Genotype–phenotype correlations in von Hippel‐Lindau disease , 2004, Human mutation.

[38]  S. Richard,et al.  Treatment of von Hippel-Lindau retinal hemangioblastoma by the vascular endothelial growth factor receptor inhibitor SU5416 is more effective for associated macular edema than for hemangioblastomas. , 2003, American journal of ophthalmology.

[39]  R. R. Lonser,et al.  von Hippel-Lindau disease , 2003, The Lancet.

[40]  S. Richard,et al.  Retinal hemangioblastoma in von Hippel-Lindau disease: a clinical and molecular study. , 2002, Investigative ophthalmology & visual science.

[41]  U. Schmidt-Erfurth,et al.  Benefits and complications of photodynamic therapy of papillary capillary hemangiomas. , 2002, Ophthalmology.

[42]  M. Baghai,et al.  Pheochromocytomas and paragangliomas in von Hippel-Lindau disease: a role for laparoscopic and cortical-sparing surgery. , 2002, Archives of surgery.

[43]  T. Aikou,et al.  Influence of Exogenous Fat Emulsion on Pulmonary Gas Exchangeafter Major Surgery , 2002, World Journal of Surgery.

[44]  C. Shields,et al.  Retinal capillary hemangioma: a comparison of sporadic cases and cases associated with von Hippel-Lindau disease. , 2001, Ophthalmology.

[45]  Ashutosh Kumar Singh,et al.  Solitary retinal capillary hemangioma: hereditary (von Hippel-Lindau disease) or nonhereditary? , 2001, Archives of ophthalmology.

[46]  D. Long,et al.  Hemangioblastomas of the Central Nervous System in von Hippel-Lindau Syndrome and Sporadic Disease , 2001, Neurosurgery.

[47]  C. Shields,et al.  Juxtapapillary capillary hemangiomas. Clinical features and visual acuity outcomes. , 2000, Ophthalmology.

[48]  S. Libutti,et al.  Clinical and genetic analysis of patients with pancreatic neuroendocrine tumors associated with von Hippel-Lindau disease. , 2000, Surgery.

[49]  J. Mnif,et al.  Endolymphatic sac tumor and von Hippel-Lindau disease: imaging features. , 2000, AJR. American journal of roentgenology.

[50]  P. Schirmacher,et al.  Inverse regulation of vascular endothelial growth factor and VHL tumor suppressor gene in sporadic renal cell carcinomas is correlated with vascular growth: an in vivo study on 29 tumors , 1999, Journal of Molecular Medicine.

[51]  P L Choyke,et al.  Renal cancer in families with hereditary renal cancer: prospective analysis of a tumor size threshold for renal parenchymal sparing surgery. , 1999, The Journal of urology.

[52]  H. Grossniklaus,et al.  The two-stage mutation model in retinal hemangioblastoma. , 1998, Ophthalmic genetics.

[53]  J. Adler,et al.  Treatment of hemangioblastomas in von Hippel-Lindau disease with linear accelerator-based radiosurgery. , 1998, Neurosurgery.

[54]  W. Linehan,et al.  Loss of heterozygosity and somatic mutations of the VHL tumor suppressor gene in sporadic cerebellar hemangioblastomas. , 1998, Cancer research.

[55]  W. Kaelin,et al.  von Hippel-Lindau disease. , 1997, Medicine.

[56]  W. Poon,et al.  Molecular genetic analysis of the von Hippel-Lindau disease tumor suppressor gene in familial and sporadic cerebellar hemangioblastomas. , 1997, American journal of clinical pathology.

[57]  S. Richard,et al.  Somatic inactivation of the VHL gene in Von Hippel-Lindau disease tumors. , 1997, American journal of human genetics.

[58]  R. Klausner,et al.  The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[59]  F. Chen,et al.  Genotype-phenotype correlation in von Hippel-Lindau disease: identification of a mutation associated with VHL type 2A. , 1996, Journal of medical genetics.

[60]  G. Reifenberger,et al.  MUTATION OF THE VON HIPPEL–LINDAU TUMOUR SUPPRESSOR GENE IN CAPILLARY HAEMANGIOBLASTOMAS OF THE CENTRAL NERVOUS SYSTEM , 1996, The Journal of pathology.

[61]  A. Webster,et al.  Phenotypic expression in von Hippel-Lindau disease: correlations with germline VHL gene mutations. , 1996, Journal of medical genetics.

[62]  D. Duan,et al.  Inhibition of transcription elongation by the VHL tumor suppressor protein , 1995, Science.

[63]  A. Kibel,et al.  Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C , 1995, Science.

[64]  J. Nadol,et al.  Endolymphatic sac tumors: Histopathologic confirmation, clinical characterization, and implication in von hippel‐lindau disease , 1995, The Laryngoscope.

[65]  P. Choyke,et al.  von Hippel-Lindau disease: genetic, clinical, and imaging features. , 1995, Radiology.

[66]  T. Shuin,et al.  Somatic mutations of the von Hippel-Lindau tumor suppressor gene in sporadic central nervous system hemangioblastomas. , 1994, Cancer research.

[67]  M. Lerman,et al.  Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. , 1994, Human molecular genetics.

[68]  J. Brooks,et al.  Mutations of the VHL tumour suppressor gene in renal carcinoma , 1994, Nature Genetics.

[69]  J. Gnarra,et al.  Identification of the von Hippel-Lindau disease tumor suppressor gene. , 1993, Science.

[70]  H. Brambs,et al.  Pancreatic lesions in the von Hippel-Lindau syndrome. , 1991, Gastroenterology.

[71]  O. Wiestler,et al.  Clustering of features and genetics of von Hippel-Lindau syndrome , 1991, The Lancet.

[72]  N. Morton,et al.  Von Hippel-Lindau disease: a genetic study. , 1991, Journal of medical genetics.

[73]  M. Ferguson-Smith,et al.  Clinical features and natural history of von Hippel-Lindau disease. , 1990, The Quarterly journal of medicine.

[74]  J. Heiken,et al.  Papillary cystadenoma of the broad ligament in a patient with von Hippel-Lindau disease. , 1989, AJR. American journal of roentgenology.

[75]  D. P. O'brien,et al.  Bilateral clear cell papillary cystadenoma of the epididymides presenting as infertility: an early manifestation of von Hippel-Lindau's syndrome. , 1985, The Journal of urology.

[76]  U. Dyreborg,et al.  Polycystic kidneys as the renal lesion in Lindau's disease. , 1981, The Journal of urology.

[77]  R. Harris,et al.  Genetics of Human Cancer , 1977, British Journal of Cancer.

[78]  A. Knudson,et al.  Mutation and cancer: neuroblastoma and pheochromocytoma. , 1972, American journal of human genetics.

[79]  C. Shields,et al.  CLINICALLY INVISIBLE RETINAL HEMANGIOBLASTOMAS DETECTED BY SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY AND FLUORESCEIN ANGIOGRAPHY IN TWINS , 2018, Retinal cases & brief reports.

[80]  S. Richard,et al.  Vitreoretinal surgery for severe retinal capillary hemangiomas in von hippel-lindau disease. , 2011, Ophthalmology.

[81]  H. DeVroom,et al.  Surgical management of cerebellar hemangioblastomas in patients with von Hippel-Lindau disease. , 2008, Journal of neurosurgery.

[82]  C. Shields,et al.  Endolymphatic sac tumor as initial manifestation of von hippel-lindau syndrome. , 2008, Retinal cases & brief reports.

[83]  E. Agrón,et al.  Clinical characterization of retinal capillary hemangioblastomas in a large population of patients with von Hippel-Lindau disease. , 2008, Ophthalmology.

[84]  S. Rankin,et al.  Imaging features of von Hippel-Lindau disease. , 2008, Radiographics : a review publication of the Radiological Society of North America, Inc.

[85]  N. Zhang,et al.  Long-term results of Leksell gamma knife surgery for trigeminal schwannomas. , 2005, Journal of neurosurgery.

[86]  E. Chew Ocular manifestations of von Hippel-Lindau disease: clinical and genetic investigations. , 2005, Transactions of the American Ophthalmological Society.

[87]  E. Oldfield,et al.  The natural history of hemangioblastomas of the central nervous system in patients with von Hippel-Lindau disease. , 2003, Journal of neurosurgery.

[88]  P. Choyke,et al.  Mosaicism in von Hippel-Lindau disease: lessons from kindreds with germline mutations identified in offspring with mosaic parents. , 2000, American journal of human genetics.

[89]  C. Junien,et al.  Mutations of the VHL gene in sporadic renal cell carcinoma: Definition of a risk factor for VHL patients to develop an RCC , 1999, Human mutation.

[90]  Christophe Béroud,et al.  Software and database for the analysis of mutations in the VHL gene , 1998, Nucleic Acids Res..

[91]  E. Gragoudas,et al.  Advances in Treatment of Retinal Angiomas , 1997, International ophthalmology clinics.

[92]  W. Linehan,et al.  Characterization of the renal pathology of a familial form of renal cell carcinoma associated with von Hippel-Lindau disease: clinical and molecular genetic implications. , 1995, The Journal of urology.

[93]  W. Linehan,et al.  Germline mutations in the von Hippel–Lindau disease tumor suppressor gene: Correlations with phenotype , 1995, Human mutation.

[94]  A. Knudson,et al.  Genetics of human cancer. , 1986, Annual review of genetics.