Indian Journal of Endocrine Surgery and Research

Register      Login

SEARCH WITHIN CONTENT

FIND ARTICLE

Volume / Issue

Online First

Archive
Volume  18 (2023)
Volume  17 (2022)
Volume  16 (2021)
Volume  15 (2020)
Volume  13 (2018)
Volume  12 (2016)
Volume  11 (2014)
Related articles

VOLUME 16 , ISSUE 2 ( July-December, 2021 ) > List of Articles

REVIEW ARTICLE

Von Hippel Lindau Disease: A Review Article

Loreno Enny, Surabhi Garg

Keywords : Endocrine surgery, Pancreatic mass, Pheochromocytoma, Von Hippel Lindau disease

Citation Information : Enny L, Garg S. Von Hippel Lindau Disease: A Review Article. 2021; 16 (2):92-100.

DOI: 10.5005/jp-journals-10088-11175

License: CC BY-NC 4.0

Published Online: 04-02-2022

Copyright Statement:  Copyright © 2021; The Author(s).


Abstract

Von Hippel Lindau (VHL) disease is an inherited disease, multisystem cancer syndrome owing to genetic mutation of the VHL tumor suppressor gene located at chromosome 3. It is inherited as highly penetrant autosomal dominant trait with affected individuals at risk of developing various benign or malignant lesions of central nervous system, retina, kidney, adrenal glands, pancreas, and reproductive system. The diagnosis of VHL can be made clinically based on the characteristic history and clinical findings. Genetic testing of germline VHL mutation may also be used to confirm the diagnosis of VHL. Treatment should be based on multidisciplinary approach as there are many complexities associated with the management of various tumors manifesting at different time frames.

HTML PDF Share
  1. Ganeshan D, Menias CO, Pickhardt PJ, et al. Tumors in von HippelLindau syndrome: from head to toecomprehensive stateoftheart review. Radiographics 2018;38(3):849866. DOI: 10.1148/rg.2018170156.
  2. Chittiboina P, Lonser RR. von Hippel-Lindau disease. In: Handbook of clinical neurology. Elsevier; 2015. p. 139156.
  3. Aronoff L, Malkin D, van Engelen K, et al. Evidence for genetic anticipation in vonHippelLindau syndrome. J Med Genet 2018;55(6):395402. DOI: 10.1136/jmedgenet-2017-104882.
  4. Richards FM, Payne SJ, Zbar B, et al. Molecular analysis of de novo germline mutations in the von Hippel-Lindau disease gene. Hum Mol Genet 1995;4(11):2139–2143. DOI: 10.1093/hmg/4.11.2139.
  5. Lonser RR, Glenn GM, Walther M, et al. Von Hippel-Lindau disease. Lancet 2003;361(9374):2059–2067. DOI: 10.1016/S0140-6736(03)13643-4.
  6. Wilding A, Ingham SL, Lalloo F, et al. Life expectancy in hereditary cancer predisposing diseases: an observational study. J Med Genet 2012;49(4):264–269. DOI: 10.1136/jmedgenet-2011-100562.
  7. Hippel E, Netzhaut ED, Beobachtungen K. Über eine sehr seltene Erkrankung der Netzhaut. Graefes Archiv Clin Exp Ophthalmol 1904;59:83–106. DOI: 10.1007/BF01994821.
  8. Lindau A. Zur Frage der Angiomatosis Retinae und Ihrer Hirnkomplikationen. Acta Ophthalmol 1927;4(1–2):193–226. DOI: 10.1111/j.1755-3768.1926.tb07786.x.
  9. Melmon KL, Rosen SW. Lindau's disease. Review of the literature and study of a large kindred. Am J Med 1964;36:595–617. PMID: 14142412.
  10. Maher ER, Neumann HP, Richard S. von Hippel–Lindau disease: a clinical and scientific review. Eur J Hum Genet 2011;19(6):617–623. PMID: 21386872.
  11. Maddock IR, Moran A, Maher ER, et al. A genetic register for von Hippel–Lindau disease. J Med Genet 1996;33(2):120–127. PMID: 8929948.
  12. Evans DG, Howard E, Giblin C, et al. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A 2010;152A(2):327–332. PMID: 20082463.
  13. Poulsen ML, Budtz-Jørgensen E, Bisgaard ML. Surveillance in von Hippel–Lindau disease (vHL). Clin Genet 2010;77(1):49–59. PMID: 19863552.
  14. Maher ER, Yates JR, Harries R, et al. Clinical features and natural history of von Hippel–Lindau disease. Q J Med 1990b;77(283):1151–1163. PMID: 2274658.
  15. Latif F, Tory K, Gnarra J, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993;260(5112):1317–1320. DOI: 10.1126/science.8493574.
  16. 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):521–537. DOI: 10.1002/humu.21219.
  17. Bender BU, Gutsche M, Glasker S, et al. Differential genetic alterations in von Hippel–Lindau syndrome-associated and sporadic pheochromocytomas. J Clin Endocrinol Metab 2000;85(12): 4568–4574. DOI: 10.1210/jcem.85.12.7015.
  18. Li M, Kim WY. Two sides to every story: the HIF-dependent and HIF-independent functions of pVHL. J Cell Mol Med 2011;15(2): 187–195. PMID: 21155973.
  19. McNeill A, Rattenberry E, Barber R, et al. Genotype-phenotype correlations in VHL exon deletions. Am J Med Genet A 2009;149A(10):2147–2151. DOI: 10.1002/ajmg.a.33023.
  20. Maranchie JK, Afonso A, Albert PS, et al. Solid renal tumor severity in von Hippel Lindau disease is related to germline deletion length and location. Hum Mutat 2004;23(1):40–46. DOI: 10.1002/humu.10302.
  21. Hes F, Zewald R, Peeters T, et al. Genotype-phenotype correlations in families with deletions in the von Hippel-Lindau (VHL) gene. Hum Genet 2000;106(4):425–431. DOI: 10.1007/s004390000265.
  22. Chen F, Kishida T, Yao M, et al. Germline mutations in the von Hippel–Lindau disease tumor suppressor gene: correlations with phenotype. Hum Mutat 1995;5(1):66–75. PMID: 7728151.
  23. Crossey PA, Eng C, Ginalska-Malinowska M, et al. Molecular genetic diagnosis of von Hippel–Lindau disease in familial phaeochromocytoma. J Med Genet 1995;32(11):885–886. PMID: 8592333.
  24. Ong KR, Woodward ER, Killick P, et al. Genotype-phenotype correlations in von Hippel–Lindau disease. Hum Mutat 2007;28(2): 143–149. PMID: 17024664.
  25. Maher ER, Webster AR, Richards FM, et al. Phenotypic expression in von Hippel–Lindau disease: correlations with germline VHL gene mutations. J Med Genet 1996;33(4):328–332. PMID: 8730290.
  26. Zbar B, Kishida T, Chen F, et al. Germline Mutations in the von Hippel–Lindau disease (VrwL) gene families from North America, Europe, and Japan. Hum Mutat 1996;8(4):348–357. PMID: 8956040.
  27. Neumann HP, Eng C, Mulligan LM, et al. Consequences of direct genetic testing for germline mutations in the clinical management of families with multiple endocrine neoplasia, type II. Journal of the American Medical Association 1995;274(14):1149–1151. PMID: 7563486.
  28. Lamiell JM, Salazar FG, Hsia YE. von Hippel–Lindau disease affecting 43 members of a single kindred. Medicine 1989;68(1):1–29. PMID: 2642584.
  29. Stolle C, Glenn G, Zbar B, et al. Improved detection of germline mutations in the von Hippel–Lindau disease tumor suppressor gene. Hum Mutat 1998;12(6):417–423. PMID: 9829911.
  30. Wanebo JE, Lonser RR, Glenn GM, et al. The natural history of hemangioblastomas of the central nervous system in patients with von Hippel–Lindau disease. J Neurosurg 2003;98(1):82–94. PMID: 12546356.
  31. Webster AR, Richards FM, MacRonald FE, et al. An analysis of phenotypic variation in the familial cancer syndrome von Hippel–Lindau disease: evidence for modifier effects. Am J Hum Genet 1998;63(4):1025–1035. PMID: 9758595.
  32. Butman JA, Kim HJ, Baggenstos M, et al. Mechanisms of morbid hearing loss associated with tumors of the endolymphatic sac in von Hippel–Lindau disease. Journal of the American Medical Association 2007;298(1):41–48. PMID: 17609489.
  33. Choo D, Shotland L, Mastroianni M, et al. Endolymphatic sac tumors in von Hippel–Lindau disease. J Neurosurg 2004;100(3):480–487. PMID: 15035284.
  34. Walther MM, Reiter R, Keiser HR, et al. Clinical and genetic characterization of pheochromocytoma in von Hippel–Lindau families: comparison with sporadic pheochromocytoma gives insight into natural history of pheochromocytoma. J Urol 1999;162:659–664. PMID: 10458336.
  35. Charlesworth M, Verbeke CS, Falk GA, et al. Pancreatic lesions in von Hippel–Lindau disease? A systematic review and meta-synthesis of the literature. J Gastrointest Surg 2012;16(7):1422–1428. PMID: 22370733.
  36. Hough DM, Stephens DH, Johnson CD. Pancreatic lesions in von Hippel–Lindau disease: prevalence, clinical significance, and CT findings. Am J Roentgenol 1994;162(5):1091–1094. PMID: 8165988.
  37. Igarashi H, Ito T, Nishimori I, et al. Pancreatic involvement in Japanese patients with von Hippel–Lindau disease: results of a nationwide survey. J Gastroenterol 2014;49(3):511–516. PMID: 23543325.
  38. Lonser RR, Butman JA, Huntoon K, et al. Prospective natural history study of central nervous system hemangioblastomas in von Hippel-Lindau disease. J Neurosurg 2014;120(5):1055–1062. DOI: 10.3171/2014.1.JNS131431.
  39. Kanno H, Kobayashi N, Nakanowatari S. Pathological and clinical features and management of central nervous system hemangioblastomas in von Hippel-Lindau disease. J Kidney Cancer VHL 2014;1(4):46–55. DOI: 10.15586/jkcvhl.2014.12.
  40. Weil RJ, Lonser RR, DeVroom HL, et al. Surgical management of brainstem hemangioblastomas in patients with von Hippel–Lindau disease. J Neurosurg 2003;98(1):95–105. PMID: 12546357.
  41. Wind JJ, Lonser RR. Management of von Hippel–Lindau disease-associated CNS lesions. Expert Rev Neurother 2011;11(10):1433–1441. PMID: 21955200.
  42. Asthagiri AR, Metha GU, Zach L, et al. Prospective evaluation of radiosurgery for hemangioblastomas in von Hippel-Lindau disease. Neuro Oncol 2010;12(1):80–86. DOI: 10.1093/neuonc/nop018.
  43. Simone CB, Lonser RR, Ondos J, et al. Infratentorial craniospinal irradiation for von Hippel-Lindau: a retrospective study supporting a new treatment for patients with CNS hemangioblastomas. Neuro Oncol 2011;13(9):1030–1036. DOI: 10.1093/neuonc/nor085.
  44. Pan J, Ho AL, D'Astous M, et al. Image-guided stereotactic radiosurgery for treatment of spinal hemangioblastoma. Neurosurg Focus 2017;42(1):E12. DOI: 10.3171/2016.10.FOCUS16361.
  45. Manski TJ, Heffner DK, Glenn GM, et al. Endolymphatic sac tumors: a source of morbid hearing loss in von Hippel-Lindau disease. Journal of the American Medical Association 1997;277(18):1461–1466. DOI: 10.1001/jama.277.18.1461.
  46. Patel NP, Wiggins RH 3rd, Shelton C. The radiologic diagnosis of endolymphatic sac tumors. Laryngoscope 2006;116(1):40–46. DOI: 10.1097/01.mlg.0000185600.18456.36.
  47. Mukherji SK, Albernaz VS, Lo WW, et al. Papillary endolymphatic sac tumors: CT, MR imaging, and angiographic findings in 20 patients. Radiology 1997;202(3):801–808. DOI: 10.1148/radiology.202.3.9051037.
  48. Kim HJ, Hagan M, Butman JA, et al. Surgical resection of endolymphatic sac tumors in von Hippel–Lindau disease: findings, results, and indications. Laryngoscope 2013;123(2):477–483. PMID: 23070752.
  49. Walther MM, Lubensky IA, Venzon D, et al. Prevalence of microscopic lesions in grossly normal renal parenchyma from patients with von Hippel-Lindau disease, sporadic renal cell carcinoma and no renal disease: clinical implications. J Urol 1995;154(6):2010–2014. PMID: 7500446.
  50. Singer EA, Vourganti S, Lin KY, et al. Outcomes of patients with surgically treated bilateral renal masses and a minimum of 10 years of followup. J Urol 2012;188(6):2084–2088. DOI: 10.1016/j.juro.2012.08.038.
  51. Steinbach F, Novick AC, Zincke H, et al. Treatment of renal cell carcinoma in von Hippel-Lindau disease: a multicenter study. J Urol 1995;153(6):1812–1816. PMID: 7752324.
  52. Choyke PL, Glenn GM, Walther MM, et al. The natural history of renal lesions in von Hippel-Lindau disease: a serial CT study in 28 patients. AJR Am J Roentgenol 1992;159(6):1229–1234. DOI: 10.2214/ajr.159.6.1442389.
  53. Jilg CA, Neumann HP, Gläsker S, et al. Growth kinetics in von Hippel-Lindau-associated renal cell carcinoma. Urol Int 2012;88(1):71–78. DOI: 10.1159/000333348.
  54. Matin SF, Ahrar K, Wood CG, et al. Patterns of intervention for renal lesions in von Hippel-Lindau disease. BJU Int 2008;102(8):940–945. DOI: 10.1111/j.1464-410X.2008.07718.x.
  55. NIH U.S. National Library of Medicine. Pazopanib in von Hippel-Lindau (VHL) syndrome. 2011. Available from: https://clinicaltrials.gov/ct2/show/NCT01436227. [Accessed May 15, 2017].
  56. Jonasch E, McCutcheon IE, Waguespack SG, et al. Pilot trial of sunitinib therapy in patients with von Hippel-Lindau disease. Ann Oncol 2011;22(12):2661–2666. DOI: 10.1093/annonc/mdr011.
  57. Mukhopadhyay B, Sahdev A, Monson JP, et al. Pancreatic lesions in von Hippel-Lindau disease. Clin Endocrinol (Oxf) 2002;57(5):603–608. DOI: 10.1046/j.1365-2265.2002.01637.x.
  58. Hammel PR, Vilgrain V, Terris B, et al. Pancreatic involvement in von Hippel-Lindau disease: the Groupe Francophone d'Etude de la Maladie de von Hippel-Lindau. Gastroenterology 2000;119(4):1087–1095. DOI: 10.1053/gast.2000.18143.
  59. Keutgen XM, Hammel P, Choyke PL, et al. Evaluation and management of pancreatic lesions in patients with von Hippel-Lindau disease. Nat Rev Clin Oncol 2016;13(9):537–549.
  60. Weisbrod AB, Kitano M, Thomas F, et al. Assessment of tumor growth in pancreatic neuroendocrine tumors in von Hippel Lindau syndrome. J Am Coll Surg 2014;218(2):163–169. PMID: 24440063.
  61. Libutti SK, Choyke PL, Alexander HR, et al. Clinical and genetic analysis of patients with pancreatic neuroendocrine tumors associated with von Hippel–Lindau disease. Surgery 2000;128:1022–1027. Discussion 1027–1028. PMID: 11114638.
  62. Blansfield JA, Choyke L, Morita SY, et al. Clinical, genetic and radiographic analysis of 108 patients with von Hippel–Lindau disease (VHL) manifested by pancreatic neuroendocrine neoplasms (PNETs). Surgery 2007;142(6):814–818. DOI: 10.1016/j.surg.2007.09.012.
  63. Sadowski SM, Weisbrod AB, Ellis R, et al. Prospective evaluation of the clinical utility of 18-fluorodeoxyglucose PET CT scanning in patients with von Hippel–Lindau-associated pancreatic lesions. J Am Coll Surg 2014;218(5):997–1003. PMID: 24661849.
  64. Prasad V, Tiling N, Denecke T, et al. Potential role of (68)Ga-DOTATOC PET/CT in screening for pancreatic neuroendocrine tumour in patients with von Hippel-Lindau disease. Eur J Nucl Med Mol Imaging 2016;43(11):2014–2020. DOI: 10.1007/s00259-016-3421-6.
  65. Krausz Y, Freedman N, Rubinstein R, et al. 68Ga-DOTANOC PET/CT imaging of neuroendocrine tumors: comparison with 111In-DTPA-octreotide (OctreoScan®). Mol Imaging Biol 2011;13(3):583–593. DOI: 10.1007/s11307-010-0374-1.
  66. Lubensky IA, Pack S, Ault D, et al. Multiple neuroendocrine tumors of the pancreas in von Hippel-Lindau disease patients: histopathological and molecular genetic analysis. Am J Pathol 1998;153(1):223–231. DOI: 10.1016/S0002-9440(10)65563-0.
  67. Odrzywolski KJ, Mukhopadhyay S. Papillary cystadenoma of the epididymis. Arch Pathol Lab Med 2010;134(4):630–633. DOI: 10.5858/134.4.630.
  68. Wong WT, Agrón E, Coleman HR, et al. Clinical characterization of retinal capillary hemangioblastomas in a large population of patients with von Hippel-Lindau disease. Ophthalmology 2008;115(1):181–188. DOI: 10.1016/j.ophtha.2007.03.009.
  69. Singh AD, Nouri M, Shields CL, et al. Treatment of retinal capillary hemangioma. Ophthalmology 2002;109(10):1799–1806. PMID: 12359597.
  70. Aufforth RD, Ramakant P, Sadowski SM, et al. Pheochromocytoma screening initiation and frequency in von Hippel-Lindau syndrome. J Clin Endocrinol Metab 2015;100(12):4498–4504. DOI: 10.1210/jc.2015-3045.
  71. Bausch B, Wellner U, Bausch D, et al. Long-term prognosis of patients with pediatric pheochromocytoma. Endocr Relat Cancer 2013;21(1):17–25. DOI: 10.1530/ERC-13-0415.
  72. Kudva YC, Sawka AM, Young WF. Clinical review 164: the laboratory diagnosis of adrenal pheochromocytoma: the Mayo Clinic experience. J Clin Endocrinol Metab 2003;88(10):4533–4539. DOI: 10.1210/jc.2003-030720.
  73. Sawka AM Jaeschk R, Singh RJ, et al. A comparison of biochemical test for pheochromocytoma: measurement of fractionated plasma metanephrine compared with the combination of 24-hour urinary metanephrines and catecholamines. J Clin Endocrinol Metab 2003;88(2):553–558. DOI: 10.1210/jc.2002-021251.
  74. Chen Y, Xiao H, Zhou X, et al. Accuracy of plasma free Metanephrines in the diagnosis of pheocromocytoma and paraganglioma: a systemic review and meta-analysis. Endocr Pract 2017;23(10):1169–1177. DOI: 10.4158/EP171877.OR.
  75. Lenders JWM, Eisenhofer G, Mannelli M, et al. Phaeochromocytoma. Lancet 2005;366(9486):665–675. PMID: 16112304.
  76. Sahdev A, Sohaib A, Monson JP, et al. CT and MR imaging of unusual locations of extra-adrenal paragangliomas (pheochromocytomas). Eur Radiol 2005;15(1):85–92. PMID: 15290072.
  77. Northcutt BG, Raman SP, Long C, et al. MDCT of adrenal masses: can dual-phase enhancement patterns be used to differentiate adenoma and pheochromocytoma? AJR Am J Roentgenol 2013;201(4):834–839. DOI: 10.2214/AJR.12.9753.
  78. Janssen I, Chen CC, Millo CM, et al. PET/CT comparing (68)Ga-DOTATATE and other radiopharmaceuticals and in comparison with CT/MRI for the localization of sporadic metastatic pheochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging 2016;43(10):1784–1791. DOI: 10.1007/s00259-016-3357-x.
  79. Tan TH, Hussein Z, Saad FF, et al. Diagnostic performance of (68)Ga-DOTATATE PET/CT, (18)F-FDG PET/CT and (131)I-MIBG scintigraphy in mapping metastatic pheochromocytoma and paraganglioma. Nucl Med Mol Imaging 2015;49(2):143–151. DOI: 10.1007/s13139-015-0331-7 [Published correction appears in Nucl Med Mol Imaging 2015;49(2):152].
  80. Agarwal G, Sadacharan D, Aggarwal V, et al. Surgical management of organ-contained unilateral pheochromocytoma: comparative outcomes of laparoscopic and conventional open surgical procedures in a large single-institution series. Langenbecks Arch Surg 2012;397(7):1109–1116. DOI: 10.1007/s00423-011-0879-3.
  81. Volkin D, Yerram N, Ahmed F, et al. Partial adrenalectomy minimizes the need for long-term hormone replacement in pediatric patients with pheochromocytoma and von Hippel-Lindau syndrome. J Pediatr Surg 2012;47(11):2077–2082. DOI: 10.1016/j.jpedsurg.2012.07.003.
  82. VHL Family Alliance. The VHL handbook: what you need to know about VHL—a reference handbook for people with von Hippel-Lindau disease, their families, and support personnel. Boston, Mass: CreateSpace (Amazon's independent publishing platform); 2014.
PDF Share
PDF Share

© Jaypee Brothers Medical Publishers (P) LTD.