Von hippel-lindau disease: A genetic and clinical review

Seminars in Ophthalmology

Volumn 28, Issue 5-6, 2013, Pages 377-386

  Haddad, Nour Maya N ^a   Cavallerano, Jerry D ^a,b   Silva, Paolo S ^a,b  

^a JOSLIN DIABETES CENTER   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

Author keywords

Angiogenesis; Genotype phenotype correlation; Hypoxia induced factor; Optic disc hemangioblastoma; Retinal hemangioblastoma; VEGF

Indexed keywords

BETA CATENIN; BEVACIZUMAB; CD133 ANTIGEN; CHEMOKINE RECEPTOR CXCR4; CYCLIN DEPENDENT KINASE INHIBITOR; DIGOXIN; ERYTHROPOIETIN; ERYTHROPOIETIN RECEPTOR; HYPOXIA INDUCIBLE FACTOR; PEGAPTANIB; RANIBIZUMAB; S PHASE KINASE ASSOCIATED PROTEIN 2; SEMAXANIB; SUNITINIB; TOPOTECAN; UBIQUITIN; VASCULOTROPIN; VASCULOTROPIN INHIBITOR; VON HIPPEL LINDAU PROTEIN; WNT PROTEIN;

ANAMNESIS; BLINDNESS; CARCINOGENESIS; CELL VACUOLE; CHROMOSOME 3P; CRYOTHERAPY; DIAGNOSTIC IMAGING; DIFFERENTIAL DIAGNOSIS; DRUG EFFICACY; FLUORESCENCE ANGIOGRAPHY; FOAM CELL; GENE DELETION; GENE LOCATION; GENETIC SCREENING; GENOTYPE PHENOTYPE CORRELATION; HEMANGIOBLASTOMA; HUMAN; KIDNEY CARCINOMA; LABORATORY TEST; LASER COAGULATION; MEDICAL LITERATURE; MISSENSE MUTATION; OPHTHALMOSCOPY; OPTIC NERVE HEAD CAPILLARY HEMANGIOBLASTOMA; OPTIC NERVE TUMOR; PATHOPHYSIOLOGY; PERSONALIZED MEDICINE; PHEOCHROMOCYTOMA; PHOTODYNAMIC THERAPY; PHYSICAL EXAMINATION; PRIORITY JOURNAL; RETINA HEMANGIOBLASTOMA; RETINA TUMOR; REVIEW; RISK FACTOR; TUMOR CELL; TUMOR GROWTH; TUMOR SUPPRESSOR GENE; VISUAL ACUITY; VISUAL IMPAIRMENT; VON HIPPEL LINDAU DISEASE;

GENETIC ASSOCIATION STUDIES; HEMANGIOBLASTOMA; HUMANS; HYPOXIA-INDUCIBLE FACTOR 1; MUTATION; RETINAL NEOPLASMS; UBIQUITIN; VASCULAR ENDOTHELIAL GROWTH FACTOR A; VON HIPPEL-LINDAU DISEASE; VON HIPPEL-LINDAU TUMOR SUPPRESSOR PROTEIN;

EID: 84886431545     PISSN: 08820538     EISSN: 17445205     Source Type: Journal    
DOI: 10.3109/08820538.2013.825281     Document Type: Review

References (79)

1. Kim JJ, Rini BI, Hansel DE. Von Hippel Lindau syndrome. Advances in Experimental Medicine and Biology 2010;685:228-249. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20687511. [last accessed 12 Apr 2013].
2. Rasmussen A, Alonso E, Ochoa A, et al. Uptake of genetic testing and long-term tumor surveillance in von Hippel-Lindau disease. BMC Medical Genetics 2010;11:4.
3. Von Hippel E. Über eine sehr seltene Erkrankung der Netzhaut. Klin Beobachtungen Arch Ophthalmol 1904;59: 83-106.
4. Lindau A. Zur Frage der Angiomatosis retinae und ihrer Hirnkomplikationen. Acta Ophthalmol 1927;4:193-226.
5. Maher ER. Von Hippel-Lindau disease. Current Molecular Medicine 2004;4(8):833-842. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15579030. [last accessed 12 Apr 2013].
6. Dandanell M, Friis-Hansen L, Sunde L, et al. Identification of 3 novel VHL germ-line mutations in Danish VHL patients. BMC Medical Genetics 2012;13:54.
7. Neumann HP, Wiestler OD. Clustering of features of von Hippel-Lindau syndrome: evidence for a complex genetic locus. Lancet 1991;337(8749):1052-1054. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1673491. [last accessed 13 Apr 2013].
8. Hoffman MA, Ohh M, Yang H, et al. von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. Human Molecular Genetics 2001;10(10):1019-1027. Available from: http://www.ncbi.nlm. nih.gov/pubmed/11331612. [last accessed 12 Apr 2013].
9. Brauch H, Kishida T, Glavac D, et al. Von Hippel-Lindau (VHL) disease with pheochromocytoma in the Black Forest region of Germany: Evidence for a founder effect. Human Genetics 1995;95(5):551-556. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7759077. [last accessed 7 Mar 2013].
10. Chew EY. Ocular manifestations of von Hippel-Lindau disease: Clinical and genetic investigations. Transactions of the American Ophthalmological Society 2005;103:495-511. Available from: http://www.pubmedcentral.nih.gov/arti- clerender.fcgi?artid=1447586&tool=pmcentrez&renderty-pe=abstract. [last accessed 12 Apr 2013].
11. Chan C-C, Collins ABD, Chew EY. Molecular pathology of eyes with von Hippel-Lindau (VHL) Disease: A review. Retina (Philadelphia, Pa.) 2007;27(1):1-7.
12. Stebbins CE, Kaelin WG, Pavletich NP. Structure of the VHL-ElonginC-ElonginB complex: Implications for VHL tumor suppressor function. Science (New York, NY) 1999; 284(5413):455-461. Available from: http://www.ncbi.nlm. nih.gov/pubmed/10205047. [last accessed 12 Apr 2013].
13. Kamura T, Koepp DM, Conrad MN, et al. Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase. Science (New York, NY) 1999; 284(5414):657-661. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10213691. [last accessed 12 Apr 2013].
14. Ohh M, Park CW, Ivan M, et al. Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nature Cell Biology 2000; 2(7):423-427.
15. Yang H, Minamishima YA, Yan Q, et al. pVHL acts as an adaptor to promote the inhibitory phosphorylation of the NF-kappaB agonist Card9 by CK2. Molecular Cell 2007; 28(1):15-27.
16. Thoma CR, Toso A, Gutbrodt KL, et al. VHL loss causes spindle misorientation and chromosome instability. Nature Cell Biology 2009;11(8):994-1001.
17. Sharma S V, Lee DY, Li B, et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 2010;141(1):69-80.
18. Mikhaylova O, Ignacak ML, Barankiewicz TJ, et al. The von Hippel-Lindau tumor suppressor protein and Egl-9-Type proline hydroxylases regulate the large subunit of RNA polymerase II in response to oxidative stress. Molecular and Cellular Biology 2008;28(8):2701-2717.
19. Semenza GL. Hypoxia-inducible factor 1 (HIF-1) pathway. Science's STKE: Signal Transduction Knowledge Environment 2007;2007(407):cm8.
20. Niu X, Zhang T, Liao L, et al. The von Hippel-Lindau tumor suppressor protein regulates gene expression and tumor growth through histone demethylase JARID1C. Oncogene 2012;31(6):776-786.
21. Semenza GL. Targeting HIF-1 for cancer therapy. Nature Reviews Cancer 2003;3(10):721-732.
22. Kaelin WG. Molecular basis of the VHL hereditary cancer syndrome. Nature Reviews Cancer 2002;2(9):673-682.
23. Gergics P, Patocs A, Toth M, et al. Germline VHL gene mutations in Hungarian families with von Hippel-Lindau disease and patients with apparently sporadic unilateral pheochromocytomas. European Journal of Endocrinology/ European Federation of Endocrine Societies 2009;161(3): 495-502.
24. Nordstrom-O'Brien M, Van der Luijt RB, Van Rooijen E, et al. Genetic analysis of von Hippel-Lindau disease. Human Mutation 2010;31(5):521-537. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20151405. [last accessed 4 Mar 2013].
25. Crossey PA, Eng C, Ginalska-Malinowska M, et al. Molecular genetic diagnosis of von Hippel-Lindau disease in familial phaeochromocytoma. Journal of Medical Genetics 1995;32(11):885-886. Available from: http://www. pubmedcentral.nih.gov/articlerender.fcgi?artid=1051741& tool= pmcentrez&rendertype=abstract. [last accessed 12 Apr 2013].
26. Woodward ER, Eng C, McMahon R, et al. Genetic predisposition to phaeochromocytoma: analysis of candidate genes GDNF, RET and VHL. Human Molecular Genetics 1997;6(7):1051-1056. Available from: http://www.ncbi. nlm.nih.gov/pubmed/9215674. [last accessed 12 Apr 2013].
27. Champion KJ, Guinea M, Dammai V, Hsu T. Endothelial function of von Hippel-Lindau tumor suppressor gene: Control of fibroblast growth factor receptor signaling. Cancer Research 2008;68(12):4649-4657.
28. Chan DA, Sutphin PD, Denko NC, Giaccia AJ. Role of prolyl hydroxylation in oncogenically stabilized hypoxia-inducible factor-1alpha. The Journal of Biological Chemistry 2002;277(42):40112-40117.
29. Mack FA, Rathmell WK, Arsham AM, et al. Loss of pVHL is sufficient to cause HIF dysregulation in primary cells but does not promote tumor growth. Cancer Cell 2003; 3(1):75-88. Available from: http://www.ncbi.nlm.nih. gov/pubmed/12559177. [last accessed 12 Apr 2013].
30. Iliopoulos O, Levy AP, Jiang C, et al. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proceedings of the National Academy of Sciences of the United States of America 1996;93(20):10595-10599. Available from: http://www.pubmedcentral.nih.gov/ articlerender. fcgi?artid=38198&tool=pmcentrez&rendertype=abstract. [last accessed 12 Apr 2013].
31. Gnarra JR, Duan DR, Weng Y, et al. Molecular cloning of the von Hippel-Lindau tumor suppressor gene and its role in renal carcinoma. Biochimica et Biophysica Acta 1996; 1242(3):201-210. Available from: http://www.ncbi.nlm. nih.gov/pubmed/8603073. [last accessed 12 Apr 2013].
32. Park S, Chan C-C. Von Hippel-Lindau disease (VHL): A need for a murine model with retinal hemangioblastoma. Histology and Histopathology 2012;27(8):975-984. Available from: http://www.pubmedcentral.nih.gov/ articlerender. fcgi?artid=3407271&tool=pmcentrez&rendertype=abstract. [last accessed 12 Apr 2013].
33. Zhang H, Qian DZ, Tan YS, et al. Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth. Proceedings of the National Academy of Sciences of the United States of America 2008;105(50):19579-19586.
34. Bhat Singh R, Amare Kadam PS. Investigation of tumor suppressor genes apart from VHL on 3p by deletion mapping in sporadic clear cell renal cell carcinoma (cRCC). Urologic Oncology 2011; http://dx.doi.org/10.1016/j.urolonc. 2011.08.012.
35. Roe J-S, Kim H-R, Hwang-Y I, et al. von Hippel-Lindau protein promotes Skp2 destabilization on DNA damage. Oncogene 2011;30(28):3127-3138.
36. Escobar B, De Cárcer G, Fernández-Miranda G, et al. Brick1 is an essential regulator of actin cytoskeleton required for embryonic development and cell transformation. Cancer Research 2010;70(22):9349-9359.
37. Dandanell M, Friis-Hansen L, et al. Identification of 3 novel VHL germ-line mutations in Danish VHL patients. BMC Medical Genetics 2012;13:54.
38. Nordstrom-O'Brien M, Van der Luijt RB, Van Rooijen E, et al. Genetic analysis of von Hippel-Lindau disease. Human Mutation 2010;31(5):521-537.
39. Hes FJ, Lips CJ, Van der Luijt RB. Molecular genetic aspects of Von Hippel-Lindau (VHL) disease and criteria for DNA analysis in subjects at risk. The Netherlands Journal of Medicine 2001;59(5):235-243. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11705643. [last accessed 13 Apr 2013].
40. Lamiell JM, Salazar FG, Hsia YE. von Hippel-Lindau disease affecting 43 members of a single kindred. Medicine 1989;68(1):1-29. Available from: http://www.ncbi.nlm. nih.gov/pubmed/2642584. [last accessed 13 Apr 2013].
41. Lonser RR, Glenn GM, Walther M, et al. von Hippel-Lindau disease. Lancet 2003;361(9374):2059-2067. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 12814730. [last accessed 25 Mar 2013].
42. Melmon KL, Rosen SW. Lindau's Disease: Review of the Literature and Study of a Large Kindred. The American Journal of Medicine 1964;36:595-617. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14142412. [last accessed 13 Apr 2013].
43. Webster AR, Maher ER, Moore AT. Clinical characteristics of ocular angiomatosis in von Hippel-Lindau disease and correlation with germline mutation. Archives of Ophthalmology 1999;117(3):371-378. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10088816. [last accessed 12 Apr 2013].
44. Hes FJ, McKee S, Taphoorn MJ, et al. Cryptic von Hippel-Lindau disease: Germline mutations in patients with haemangioblastoma only. Journal of Medical Genetics 2000;37(12):939-943. Available from: http://www. pubmedcentral.nih.gov/ articlerender.fcgi?artid=1734505& tool=pmcentrez&rendertype=abstract. [last accessed 13 Apr 2013].
45. Hogan J, Turner A, Tucker K, Warwick L. Unintended diagnosis of Von Hippel Lindau syndrome using Array Comparative Genomic Hybridization (CGH): Counseling challenges arising from unexpected information. Journal of Genetic Counseling 2013;22(1):22-26.
46. Choyke PL, Glenn GM, Walther MM, et al. von Hippel-Lindau disease: Genetic, clinical, and imaging features. Radiology 1995;194(3):629-642. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7862955. [last accessed 13 Apr 2013].
47. Heimann H, Jmor F, Damato B. Imaging of retinal and choroidal vascular tumours. Eye (London, England) 2013; 27(2):208-216. Available from: http://www.ncbi.nlm.nih. gov/pubmed/23196648. [last accessed 18 Mar 2013].
48. Shields JA, Decker WL, Sanborn GE, et al. Presumed acquired retinal hemangiomas. Ophthalmology 1983; 90(11):1292-1300. Available from: http://www.ncbi.nlm. nih.gov/pubmed/6664668. [last accessed 12 Apr 2013].
49. Gaudric A, Krivosic V, Duguid G, et al. Vitreoretinal surgery for severe retinal capillary hemangiomas in von hippel-lindau disease. Ophthalmology 2011;118(1):142-149. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 20801520. [last accessed 13 Apr 2013].
50. Singh AD, Shields CL, Shields JA. von Hippel-Lindau disease. Survey of Ophthalmology 2001;46(2):117-142. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/11578646. [last accessed 12 Apr 2013].
51. Fraser L, Watts S, Cargill A, et al. Study comparing two types of screening provision for people with von Hippel-Lindau disease. Familial Cancer 2007;6(1):103-111.
52. McCabe CM, Flynn HW, Shields CL, et al. Juxtapapillary capillary hemangiomas. Clinical features and visual acuity outcomes. Ophthalmology 2000;107(12):2240-2248. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 11097604. [last accessed 12 Apr 2013].
53. Inoue M, Yamazaki K, Shinoda K, et al. A clinicopathologic case report on macular hole associated with von Hippel-Lindau disease: A novel ultrastructural finding of wormlike, wavy tangles of filaments. Graefe's Archive for Clinical and Experimental Ophthalmology = Albrecht von Graefes Archiv für Klinische und Experimentelle Ophthalmologie 2004; 242(10):881-886.
54. Aumiller MS. Juxtapapillary hemangioma: A case report and review of clinical features and management of von Hippel-Lindau disease. Optometry (St. Louis, Mo) 2005; 76(8):442-449.
55. Aumiller MS. Juxtapapillary hemangioma: A case report and review of clinical features and management of von Hippel-Lindau disease. Optometry (St. Louis, Mo) 2005; 76(8):442-449.
56. Toy BC, Agrón E, Nigam D, et al. Longitudinal analysis of retinal hemangioblastomatosis and visual function in ocular von Hippel-Lindau disease. Ophthalmology 2012; 119(12):2622-2630. Available from: http://www.ncbi.nlm. nih.gov/pubmed/22906772. [last accessed 13 Apr 2013].
57. Wong WT, Agrón E, Coleman HR, et al. Genotype-phenotype correlation in von Hippel-Lindau disease with retinal angiomatosis. Archives of Ophthalmology 2007; 125(2):239-245. Available from: http://www.pubmedcentral. nih.gov/articlerender.fcgi?artid=3019103&tool=pm centrez&rendertype= abstract. [last accessed 13 Apr 2013].
58. Mettu P, Agrón E, Samtani S, et al. Genotype-phenotype correlation in ocular von Hippel-Lindau (VHL) disease: The effect of missense mutation position on ocular VHL phenotype. Investigative Ophthalmology & Visual Science 2010;51(9):4464-4470. Available from: http://www.pubmedcentral.nih.gov/ articlerender.fcgi? artid=2941163&tool=pmcentrez&rendertype=abstract. [last accessed 13 Apr 2013].
59. Chan CC, Vortmeyer AO, Chew EY, et al. VHL gene deletion and enhanced VEGF gene expression detected in the stromal cells of retinal angioma. Archives of Ophthalmology 1999;117(5):625-630. Available from: http://www.ncbi.nlm.nih. gov/pubmed/10326959. [last accessed 12 Apr 2013].
60. Los M, Aarsman CJ, Terpstra L, et al. Elevated ocular levels of vascular endothelial growth factor in patients with von Hippel-Lindau disease. Annals of Oncology: Official Journal of the European Society for Medical Oncology/ESMO 1997; 8(10):1015-1022. Available from: http://www.ncbi.nlm. nih.gov/pubmed/ 9402176. [last accessed 12 Apr 2013].
61. Böhling T, Hatva E, Kujala M, et al. Expression of growth factors and growth factor receptors in capillary hemangio-blastoma. Journal of Neuropathology and Experimental Neurology 1996;55(5):522-527. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8627342. [last accessed 19 Apr 2013].
62. Ivan M, Kaelin WG. The von Hippel-Lindau tumor suppressor protein. Current Opinion in Genetics & Development 2001;11(1):27-34. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11163147. [last accessed 12 Apr 2013].
63. Kaelin WG. Cancer: Many vessels, faulty gene. Nature 1999;399(6733):203- 204.
64. Senger DR, Galli SJ, Dvorak AM, et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science (New York, NY) 1983; 219(4587):983-985. Available from: http://www.ncbi.nlm. nih.gov/pubmed/6823562. [last accessed 14 Mar 2013].
65. Leung DW, Cachianes G, Kuang WJ, et al. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science (New York, NY) 1989;246(4935):1306-1309. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 2479986. [last accessed 21 Mar 2013].
66. Keck PJ, Hauser SD, Krivi G, et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science (New York, NY) 1989;246(4935):1309-1312. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 2479987. [last accessed 6 Mar 2013].
67. Aiello LP, George DJ, Cahill MT, et al. Rapid and durable recovery of visual function in a patient with von Hippel-Lindau syndrome after systemic therapy with vascular endothelial growth factor receptor inhibitor su5416. Ophthalmology 2002;109(9):1745-1751. Available from: http://www.ncbi.nlm.nih. gov/pubmed/12208726. [last accessed 12 Apr 2013].
68. Ferrara N, Davis-Smyth T. The biology of vascular endo-thelial growth factor. Endocrine Reviews 1997;18(1):4-25. Available from: http://www.ncbi.nlm. nih.gov/pubmed/9034784. [last accessed 23 Mar 2013].
69. Benjamin LE, Keshet E. Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: Induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal. Proceedings of the National Academy of Sciences of the United States of America 1997;94(16):8761-8766. Available from: http://www.pubmedcentral.nih.gov/ articlerender. fcgi?artid=23118&tool=pmcentrez&rendertype=abstract. [last accessed 13 Apr 2013].
70. Mendel DB, Laird AD, Smolich BD, et al. Development of SU5416, a selective small molecule inhibitor of VEGF receptor tyrosine kinase activity, as an anti-angiogenesis agent. Anti-Cancer Drug Design 2000;15(1):29-41. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10888034. [last accessed 13 Apr 2013].
71. Ryan AM, Eppler DB, Hagler KE, et al. Preclinical safety evaluation of rhuMAbVEGF, an antiangiogenic humanized monoclonal antibody. Toxicologic Pathology 1999;27(1): 78-86. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 10367678. [last accessed 13 Apr 2013].
72. Drevs J, Hofmann I, Hugenschmidt H, et al. Effects of PTK787/ZK 222584, a specific inhibitor of vascular endo-thelial growth factor receptor tyrosine kinases, on primary tumor, metastasis, vessel density, and blood flow in a murine renal cell carcinoma model. Cancer Research 2000; 60(17):4819-4824. Available from: http://www.ncbi.nlm. nih.gov/pubmed/10987292. [last accessed 13 Apr 2013].
73. Via LE, Gore-Langton RE, Pluda JM. Clinical trials referral resource: Current clinical trials administering the antian-giogenesis agent SU5416. Oncology (Williston Park, NY) 2000;14(9):1312, 1315-6, 1321-3. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11033829. [last accessed 13 Apr 2013].
74. Chan C-C, Chew EY, Shen D, et al. Expression of stem cells markers in ocular hemangioblastoma associated with von Hippel-Lindau (VHL) disease. Molecular Vision 2005;11: 697-704. Available from: http://www.pubmedcentral.nih. gov/articlerender.fcgi?artid=1876780&tool=pmcentrez&-rendertype= abstract. [last accessed 13 Apr 2013].
75. Vogel TWA, Brouwers FM, Lubensky IA, et al. Differential expression of erythropoietin and its receptor in von hippel-lindau-associated and multiple endocrine neoplasia type 2-associated pheochromocytomas. The Journal of Clinical Endocrinology and Metabolism 2005;90(6):3747-3751. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15769989. [last accessed 13 Apr 2013].
76. Rosenblatt MI, Azar DT. Anti-angiogenic therapy: Prospects for treatment of ocular tumors. Seminars in Ophthalmology 2006;21(3):151-160. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16912013. [last accessed 13 Apr 2013].
77. Girmens JF, Erginay A, Massin P, 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. American Journal of Ophthalmology 2003;136(1):194-196. Available from: http://www.ncbi. nlm.nih.gov/pubmed/12834696. [last accessed 13 Apr 2013].
78. Von Buelow M, Pape S, Hoerauf H. Systemic bevacizumab treatment of a juxtapapillary retinal haemangioma. Acta Ophthalmologica Scandinavica 2007;85(1):114-116. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17244223. [last accessed 13 Apr 2013].
79. Melillo G. Targeting hypoxia cell signaling for cancer therapy. Cancer Metastasis Reviews 2007;26(2):341-352. Available from: http://www.ncbi.nlm.nih. gov/pubmed/17415529. [last accessed 13 Apr 2013].