Narrative Review of Von Hippel-Lindau Syndrome: From Discovery to Modern Medical and Surgical Therapies
Main Article Content
Keywords
Von Hippel-Lindau syndrome, VHL gene, HIF-2α inhibitors, nephron-sparing surgery, PRISMA, Egger test, targeted therapy, multidisciplinary management.
Abstract
The von Hippel-Lindau (VHL) syndrome is a rare autosomal dominant disorder caused by mutations in the VHL tumor suppressor gene, leading to the development of benign and malignant tumors in multiple organs, including the kidneys, brain, spine, retina, and pancreas. Since its initial description in the early 20th century, significant progress has been made in understanding its pathogenesis, genetic basis, and clinical management. This narrative review provides a comprehensive overview of VHL syndrome, from its discovery to the latest medical and surgical therapies. A systematic literature review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, incorporating the Egger test to assess publication bias. The review highlights the evolution of diagnostic criteria, the role of genetic testing, and the development of targeted therapies such as hypoxia-inducible factor 2-alpha (HIF-2α) inhibitors. Surgical interventions, including nephron-sparing surgery and minimally invasive techniques, are also discussed. This review emphasizes the importance of a multidisciplinary approach to managing VHL syndrome and explores emerging therapies that hold promise for improving patient outcomes.
References
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20. Duffey BG, Choyke PL, Glenn G, et al. The relationship between renal tumor size and metastases in patients with von Hippel-Lindau disease. J Urol. 2004;172(1):63–5. https://doi.org/10.1097/01.ju.0000132127.79974.3f
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22. Choueiri TK, Albiges L, Hammers HJ, et al. Immunotherapy in renal cell carcinoma: The future is now. Nat Rev Clin Oncol. 2020;17(10):621–34.
23. Ong KR, Woodward ER, Killick P, et al. Genotype-phenotype correlations in von Hippel-Lindau disease. Hum Mutat. 2007;28(2):143–9. https://doi.org/10.1002/humu.20385
24. Shen C, Kaelin WG. The VHL/HIF axis in clear cell renal carcinoma. Semin Cancer Biol. 2013;23(1):18–25. https://doi.org/10.1016/j.semcancer.2012.06.001
25. Ricketts CJ, Morris MR, Gentle D, et al. Genome-wide CpG island methylation analysis implicates novel genes in the pathogenesis of renal cell carcinoma. Epigenetics. 2012;7(3):278–90. https://doi.org/10.4161/epi.7.3.19103
26. Janssen I, Chen CC, Taieb D, et al. 68Ga-DOTATATE PET/CT in the localization of head and neck paragangliomas compared with other functional imaging modalities and CT/MRI. J Nucl Med. 2016;57(2):186–91. https://doi.org/10.2967/jnumed.115.161018
27. Rechsteiner MP, von Teichman A, Nowicka A, et al. VHL gene mutations and their effects on hypoxia inducible factor HIFα: Identification of potential driver and passenger mutations. Cancer Res. 2011;71(16):5500–11. https://doi.org/10.1158/0008-5472.CAN-11-0757
28. Harper JC, Wilton LJ, Traeger-Synodinos J, et al. The ESHRE PGD consortium: 10 years of data collection. Hum Reprod Update. 2012;18(3):234–47. https://doi.org/10.1093/humupd/dmr052
29. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: Results of a randomized phase III trial. J Clin Oncol. 2010;28(6):1061–8. https://doi.org/10.1200/JCO.2009.23.9764
30. McDermott DF, Huseni MA, Atkins MB, et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med. 2018;24(6):749–57. https://doi.org/10.1038/s41591-018-0053-3
31. Falconi M, Bartsch DK, Eriksson B, et al. ENETS consensus guidelines for the management of patients with digestive neuroendocrine neoplasms of the digestive system: Well-differentiated pancreatic non-functioning tumors. Neuroendocrinology. 2012;95(2):120–34. https://doi.org/10.1159/000335587
32. Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: An endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915–42. https://doi.org/10.1210/jc.2014-1498
33. Lonser RR, Butman JA, Kiringoda R, et al. Pituitary stalk hemangioblastomas in von Hippel-Lindau disease. J Neurosurg. 2009;110(2):350–3. https://doi.org/10.3171/2008.4.17532
34. Bausch B, Borozdin W, Neumann HP. Clinical and genetic characteristics of patients with neurofibromatosis type 1 and pheochromocytoma. N Engl J Med. 2006;354(25):2729–35.
35. Doudna JA, Charpentier E. Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science. 2014;346(6213):1258096. https://doi.org/10.1126/science.1258096
36. Coco D, Leanza S. A narrative review of pheochromocytoma in VHL. J Kidney Cancer VHL. 2024;11(1):19–23. https://doi.org/10.15586/jkcvhl.v11i1.275. PMID: 38344311; PMCID: PMC10858801.
37. Coco D, Leanza S. Von Hippel-Lindau is associated to pancreatic neuroendocrine tumors: A comprehensive review. J Kidney Cancer VHL. 2023;10(2):13–20. https://doi.org/10.15586/jkcvhl.v10i2.272. PMID: 37251595; PMCID: PMC10219837.
38. Coco D, Leanza S. Von Hippel-Lindau syndrome: Medical syndrome or surgical syndrome? A surgical perspective. J Kidney Cancer VHL. 2021;9(1):27–32. https://doi.org/10.15586/jkcvhl.v9i1.206. PMID: 34963877; PMCID: PMC8652351.
2. Lindau A. Zur frage der angiomatosis retinae und ihrer hirnkomplikationen. Acta Ophthalmol. 1927;4:193–226. https://doi.org/10.1111/j.1755-3768.1926.tb07786.x
3. Latif F, Tory K, Gnarra J, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993;260(5112):1317–20. https://doi.org/10.1126/science.8493574
4. Maher ER, Neumann HP, Richard S. von Hippel-Lindau disease: A clinical and scientific review. Eur J Hum Genet. 2011;19(6):617–23. https://doi.org/10.1038/ejhg.2010.175
5. Kaelin WG. The von Hippel-Lindau tumor suppressor protein and clear cell renal carcinoma. Clin Cancer Res. 2007;13(2 Pt 2):680s–4s. https://doi.org/10.1158/1078-0432.CCR-06-1865
6. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009;6(7):e1000097. https://doi.org/10.1371/journal.pmed.1000097
7. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34. https://doi.org/10.1136/bmj.315.7109.629
8. Nordstrom-O’Brien M, van der Luijt RB, van Rooijen E, et al. Genetic analysis of von Hippel-Lindau disease. Hum Mutat. 2010;31(5):521–37. https://doi.org/10.1002/humu.21219
9. Chen W, Hill H, Christie A, et al. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature. 2016;539(7627):112–7. https://doi.org/10.1038/nature19796
10. Choyke PL, Glenn GM, Walther MM, et al. von Hippel-Lindau disease: Genetic, clinical, and imaging features. Radiology. 1995;194(3):629–42. https://doi.org/10.1148/radiology.194.3.7862955
11. Binderup ML, Jensen AM, Budtz-Jørgensen E, et al. Survival and causes of death in patients with von Hippel-Lindau disease. J Med Genet. 2017;54(1):11–8. https://doi.org/10.1136/jmedgenet-2016-104058
12. Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for renal cell carcinoma in von Hippel-Lindau disease. N Engl J Med. 2021;385(22):2036–46. https://doi.org/10.1056/NEJMoa2103425
13. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): A randomised phase 3 trial. Lancet. 2011;378(9807):1931–9. https://doi.org/10.1016/S0140-6736(11)61613-9
14. Campbell SC, Novick AC, Belldegrun A, et al. Guideline for management of the clinical T1 renal mass. J Urol. 2009;182(4):1271–9. https://doi.org/10.1016/j.juro.2009.07.004
15. Gill IS, Kavoussi LR, Lane BR, et al. Comparison of 1,800 laparoscopic and open partial nephrectomies for single renal tumors. J Urol. 2007;178(1):41–6. https://doi.org/10.1016/j.juro.2007.03.038
16. Lonser RR, Glenn GM, Walther M, et al. von Hippel-Lindau disease. Lancet. 2003;361(9374):2059–67. https://doi.org/10.1016/S0140-6736(03)13643-4
17. Shuch B, Amin A, Armstrong AJ, et al. Understanding pathologic variants of renal cell carcinoma: Distilling therapeutic opportunities from biologic complexity. Eur Urol. 2015;67(1):85–97. https://doi.org/10.1016/j.eururo.2014.04.029
18. Courtney KD, Ma Y, Diaz de Leon A, et al. HIF-2 complex dissociation, target inhibition, and acquired resistance with PT2385, a first-in-class HIF-2 inhibitor, in patients with clear cell renal cell carcinoma. Clin Cancer Res. 2020;26(4):793–803. https://doi.org/10.1158/1078-0432.CCR-19-1459
19. Jonasch E, McCutcheon IE, Gombos DS, et al. Management of von Hippel-Lindau-associated kidney cancer. Nat Rev Urol. 2020;17(3):165–77.
20. Duffey BG, Choyke PL, Glenn G, et al. The relationship between renal tumor size and metastases in patients with von Hippel-Lindau disease. J Urol. 2004;172(1):63–5. https://doi.org/10.1097/01.ju.0000132127.79974.3f
21. Richard S, Gardie B, Couvé S, et al. von Hippel-Lindau: How a rare disease illuminates cancer biology. Semin Cancer Biol. 2013;23(1):26–37. https://doi.org/10.1016/j.semcancer.2012.05.005
22. Choueiri TK, Albiges L, Hammers HJ, et al. Immunotherapy in renal cell carcinoma: The future is now. Nat Rev Clin Oncol. 2020;17(10):621–34.
23. Ong KR, Woodward ER, Killick P, et al. Genotype-phenotype correlations in von Hippel-Lindau disease. Hum Mutat. 2007;28(2):143–9. https://doi.org/10.1002/humu.20385
24. Shen C, Kaelin WG. The VHL/HIF axis in clear cell renal carcinoma. Semin Cancer Biol. 2013;23(1):18–25. https://doi.org/10.1016/j.semcancer.2012.06.001
25. Ricketts CJ, Morris MR, Gentle D, et al. Genome-wide CpG island methylation analysis implicates novel genes in the pathogenesis of renal cell carcinoma. Epigenetics. 2012;7(3):278–90. https://doi.org/10.4161/epi.7.3.19103
26. Janssen I, Chen CC, Taieb D, et al. 68Ga-DOTATATE PET/CT in the localization of head and neck paragangliomas compared with other functional imaging modalities and CT/MRI. J Nucl Med. 2016;57(2):186–91. https://doi.org/10.2967/jnumed.115.161018
27. Rechsteiner MP, von Teichman A, Nowicka A, et al. VHL gene mutations and their effects on hypoxia inducible factor HIFα: Identification of potential driver and passenger mutations. Cancer Res. 2011;71(16):5500–11. https://doi.org/10.1158/0008-5472.CAN-11-0757
28. Harper JC, Wilton LJ, Traeger-Synodinos J, et al. The ESHRE PGD consortium: 10 years of data collection. Hum Reprod Update. 2012;18(3):234–47. https://doi.org/10.1093/humupd/dmr052
29. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: Results of a randomized phase III trial. J Clin Oncol. 2010;28(6):1061–8. https://doi.org/10.1200/JCO.2009.23.9764
30. McDermott DF, Huseni MA, Atkins MB, et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med. 2018;24(6):749–57. https://doi.org/10.1038/s41591-018-0053-3
31. Falconi M, Bartsch DK, Eriksson B, et al. ENETS consensus guidelines for the management of patients with digestive neuroendocrine neoplasms of the digestive system: Well-differentiated pancreatic non-functioning tumors. Neuroendocrinology. 2012;95(2):120–34. https://doi.org/10.1159/000335587
32. Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: An endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915–42. https://doi.org/10.1210/jc.2014-1498
33. Lonser RR, Butman JA, Kiringoda R, et al. Pituitary stalk hemangioblastomas in von Hippel-Lindau disease. J Neurosurg. 2009;110(2):350–3. https://doi.org/10.3171/2008.4.17532
34. Bausch B, Borozdin W, Neumann HP. Clinical and genetic characteristics of patients with neurofibromatosis type 1 and pheochromocytoma. N Engl J Med. 2006;354(25):2729–35.
35. Doudna JA, Charpentier E. Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science. 2014;346(6213):1258096. https://doi.org/10.1126/science.1258096
36. Coco D, Leanza S. A narrative review of pheochromocytoma in VHL. J Kidney Cancer VHL. 2024;11(1):19–23. https://doi.org/10.15586/jkcvhl.v11i1.275. PMID: 38344311; PMCID: PMC10858801.
37. Coco D, Leanza S. Von Hippel-Lindau is associated to pancreatic neuroendocrine tumors: A comprehensive review. J Kidney Cancer VHL. 2023;10(2):13–20. https://doi.org/10.15586/jkcvhl.v10i2.272. PMID: 37251595; PMCID: PMC10219837.
38. Coco D, Leanza S. Von Hippel-Lindau syndrome: Medical syndrome or surgical syndrome? A surgical perspective. J Kidney Cancer VHL. 2021;9(1):27–32. https://doi.org/10.15586/jkcvhl.v9i1.206. PMID: 34963877; PMCID: PMC8652351.
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Sep 5, 2025
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Narrative Review of Von Hippel-Lindau Syndrome: From Discovery to Modern Medical and Surgical Therapies. (2025). Journal of Kidney Cancer, 12(3), 16-24. https://doi.org/10.15586/jkcvhl.v12i3.396
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Narrative Review of Von Hippel-Lindau Syndrome: From Discovery to Modern Medical and Surgical Therapies. (2025). Journal of Kidney Cancer, 12(3), 16-24. https://doi.org/10.15586/jkcvhl.v12i3.396