Clinical diagnosis, treatment and screening of the VHL gene in three von Hippel‑Lindau disease pedigrees

Lin,Guobing; Zhao,Yihua; Zhang,Zhewei; Zhang,Huijiang

doi:10.3892/etm.2020.8829

Clinical diagnosis, treatment and screening of the VHL gene in three von Hippel‑Lindau disease pedigrees

Authors:
- Guobing Lin
- Yihua Zhao
- Zhewei Zhang
- Huijiang Zhang
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Affiliations: Department of Urology, The First People's Hospital of Wenling, Wenling, Zhejiang 317500, P.R. China, Department of Urology, Yueqing People's Hospital, Yueqing, Zhejiang 325600, P.R. China, Department of Urology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China, Department of Urology, Lishui City People's Hospital, Lishui, Zhejiang 323000 P.R. China
Published online on: June 3, 2020 https://doi.org/10.3892/etm.2020.8829
Pages: 1237-1244
Copyright: © Lin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The present study aimed to investigate the clinical characteristics of von Hippel‑Lindau (VHL) disease and the clinical significance of VHL gene detection. The clinical materials of patients with VHL disease were collected from 3 different families between May 1985 and October 2017. A systematic pedigree study and VHL gene detection at the germline level were performed together with a literature review. Of the 22 patients from 3 VHL pedigrees, 10 exhibited VHL gene mutations (3 genotypes) at the germline level. The genotypes of pedigree were VHL‑p.R161Q (c.482G>A), VHL‑p.N78S (c.233A>G), and VHL‑p.R167Q (c.500G>A). During the follow‑up period, the symptoms were stable in 10 patients, including 2 cases of central nervous system hemangioblastomas (CNS‑HB), 3 cases of bilateral multiple renal cell carcinoma (RCC) and 5 cases of adrenal pheochromocytoma without local recurrence or distant metastasis. Patients with p.R161Q and p.N78S were not associated with CNS‑HB, which was different from the clinical phenotype of previously reported families. RCC were Fuhrman II grade, which was consistent with the previous study. The results of the present study indicated that the standardization of early diagnosis and the improvement of long‑term efficacy may be achieved by combining clinical screening and VHL gene detection.

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1	Online Mendelian Inheritance in Man (OMIM) 193300. BioPortal: Nov 18, 2019 (https://www.uniprot.org/database/DB-0062).
2	Ganeshan D, Menias CO, Pickhardt PJ, Sandrasegaran K, Lubner MG, Ramalingam P and Bhalla S: Tumors in von Hippel-Lindau syndrome: From head to toe-comprehensive state-of-the-art review. Radiographics. 38:849–866. 2018.PubMed/NCBI View Article : Google Scholar
3	Chittiboina P and Lonser RR: von Hippel-Lindau disease. In: Handbook of Clinical Neurology. Elsevier, pp139-156, 2015.
4	Aronoff L, Malkin D, van Engelen K, Gallinger B, Wasserman J, Kim RH, Villani A, Meyn MS and Druker H: Evidence for genetic anticipation in vonHippel-Lindau syndrome. J Med Genet. 55:395–402. 2018.PubMed/NCBI View Article : Google Scholar
5	Kruizinga RC, Sluiter WJ, de Vries EG, Zonnenberg BA, Lips CJ, van der Horst-Schrivers AN, Walenkamp AM and Links TP: Calculating optimal surveillance for detection of von Hippel-Lindau-related manifestations. Endocr Relat Cancer. 21:63–71. 2013.PubMed/NCBI View Article : Google Scholar
6	Palmer LS and Linehan WM: Editorial comment. J Urol. 183:2351. 2010.PubMed/NCBI View Article : Google Scholar
7	Iida K, Okimura Y, Takahashi K, Inomata S, Iguchi G, Kaji H and Chihara K: A variety of phenotype with R161Q germline mutation of the von Hippel-Lindau tumor suppressor gene in Japanese kindred. Int J Mol Med. 13:401–404. 2004.PubMed/NCBI
8	Gong K, Zhang N, Zhang K and Na Y: The relationship of erythropoietin overexpression with von Hippel-Lindau tumour suppressor gene mutations between hypoxia-inducible factor-1α and -2α in sporadic clear cell renal carcinoma. Int J Mol Med. 26:907–912. 2010.PubMed/NCBI View Article : Google Scholar
9	David Dornbos 3III, Kim HJ, Butman JA and Lonser RR: Review of the neurological implications of von Hippel-Lindau disease. JAMA Neurol. 75:620–627. 2018.PubMed/NCBI View Article : Google Scholar
10	Asthagiri AR, Mehta GU, Zach L, Li X, Butman JA, Camphausen KA and Lonser RR: Prospective evaluation of radiosurgery for hemangioblastomas in von Hippel-Lindau disease. Neuro Oncol. 12:80–86. 2010.PubMed/NCBI View Article : Google Scholar
11	Lonser RR, Butman JA, Huntoon K, Asthagiri AR, Wu T, Bakhtian KD, Chew EY, Zhuang Z, Linehan WM and Oldfield EH: Prospective natural history study of central nervous system hemangioblastomas in von Hippel-Lindau disease. J Neurosurg. 120:1055–1062. 2014.PubMed/NCBI View Article : Google Scholar
12	Nambu S, Otani R, Higuchi F, Uzuka T, Matsuda H, Kim P and Ueki K: Histology of hemangioblastoma treated with stereotactic radiosurgery confirms its effectiveness. J Clin Neurosci. 51:43–45. 2018.PubMed/NCBI View Article : Google Scholar
13	Kim E and Zschiedrich S: Renal cell carcinoma in von Hippel-Lindau disease-from tumor genetics to novel therapeutic strategies. Front Pediatr. 6(16)2018.PubMed/NCBI View Article : Google Scholar
14	Gossage L, Eisen T and Maher ER: VHL, the story of a tumour suppressor gene. Nat Rev Cancer. 15:55–64. 2015.PubMed/NCBI View Article : Google Scholar
15	Liu SJ, Wang JY, Peng SH, Li T, Ning XH, Hong BA, Liu JY, Wu PJ, Zhou BW, Zhou JC, et al: Genotype and phenotype correlation in von Hippel-Lindau disease based on alteration of the HIF-α binding site in VHL protein. Genetics in Medicine Official Journal of the American College of Medical Genetics, 2018.
16	Liu Q, Yuan G, Tong D, Liu G, Yi Y, Zhang J, Zhang Y, Wang LA, Wang L, Zhang D, et al: Novel genotype-phenotype correlations in five Chinese families with Von Hippel-Lindau disease. Endocr Connect. 7:870–878. 2018.PubMed/NCBI View Article : Google Scholar
17	Smith ZL, Pietzak EJ, Meise CK, Van Arsdalen K, Wein AJ, Malkowicz SB and Guzzo TJ: Simplification of the Fuhrman grading system for renal cell carcinoma. Can J Urol. 22:8069–8073. 2015.PubMed/NCBI
18	Ben-Skowronek I and Kozaczuk S: Von Hippel-Lindau Syndrome. Horm Res Paediatr. 84:145–152. 2015.PubMed/NCBI View Article : Google Scholar
19	Chou A, Toon C, Pickett J and Gill AJ: von Hippel-Lindau syndrome. Front Horm Res. 41:30–49. 2013.PubMed/NCBI View Article : Google Scholar
20	Arjumand W and Sultana S: Role of VHL gene mutation in human renal cell carcinoma. Tumour Biol. 33:9–16. 2012.PubMed/NCBI View Article : Google Scholar
21	Tarade D and Ohh M: The HIF and other quandaries in VHL disease. Oncogene. 37:139–147. 2018.PubMed/NCBI View Article : Google Scholar
22	Ordóñez-Navadijo Á, Fuertes-Yebra E, Acosta-Iborra B, Balsa E, Elorza A, Aragonés J and Landazuri MO: Mutant versions of von Hippel-Lindau (VHL) can protect HIF1α from SART1-mediated degradation in clear-cell renal cell carcinoma. Oncogene. 35:587–594. 2016.PubMed/NCBI View Article : Google Scholar
23	Clifford SC, Cockman ME, Smallwood AC, Mole DR, Woodward ER, Maxwell PH, Ratcliffe PJ and Maher ER: Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease. Hum Mol Genet. 10:1029–1038. 2001.PubMed/NCBI View Article : Google Scholar
24	Shuin T, Ashida S, Yao M and Kanno H: Von Hippel-Lindau disease. Nihon Rinsho. 58:1448–1454. 2000.PubMed/NCBI(In Japanese).
25	Nordstrom-O'Brien M, van der Luijt RB, van Rooijen E, van den Ouweland AM, Majoor-Krakauer DF, Lolkema MP, van Brussel A, Voest EE and Giles RH: Genetic analysis of von Hippel-Lindau disease. Hum Mutat. 31:521–537. 2010.PubMed/NCBI View Article : Google Scholar
26	Liu SJ, Wang JY, Peng SH, Li T, Ning XH, Hong BA, Liu JY, Wu PJ, Zhou BW, Zhou JC, et al: Genotype and phenotype correlation in von Hippel-Lindau disease based on alteration of the HIF-alpha binding site in VHL protein. Genet Med. 20:1266–1273. 2018.PubMed/NCBI View Article : Google Scholar
27	Young RM and Simon MC: Untuning the tumor metabolic machine: HIF-α: pro- and antitumorigenic? Nat Med. 18:1024–1025. 2012.PubMed/NCBI View Article : Google Scholar
28	Hoffman MA, Ohh M, Yang H, Klco JM, Ivan M and Kaelin WG Jr: von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. Hum Mol Genet. 10:1019–1027. 2001.PubMed/NCBI View Article : Google Scholar
29	Niemelä M, Lemeta S, Sainio M, Rauma S, Pukkala E, Kere J, Böhling T, Laatikainen L, Jääskeläinen J and Summanen P: Hemangioblastomas of the retina: Impact of von Hippel-Lindau disease. Invest Ophthalmol Vis Sci. 41:1909–1915. 2000.PubMed/NCBI
30	González Escobar AB, Morillo Sánchez MJ and García-Campos JM: Von Hippel-Lindau disease: Family study. Arch Soc Esp Oftalmol. 87:368–372. 2012.PubMed/NCBI View Article : Google Scholar : (In Spanish).
31	Richard S, Gardie B, Couvé S and Gad S: Von Hippel-Lindau: How a rare disease illuminates cancer biology. Semin Cancer Biol. 23:26–37. 2013.PubMed/NCBI View Article : Google Scholar
32	Lefevre A, Mathis T, Denis P and Kodjikian L: Retinal hemangioblastoma: Treatment strategy and long-term follow-up in a retrospective cohort. J Fr Ophtalmol. 41:164–169. 2018.PubMed/NCBI View Article : Google Scholar : (In French).
33	Woodward ER and Maher ER: Von Hippel-Lindau disease and endocrine tumour susceptibility. Endocr Relat Cancer. 13:415–425. 2006.PubMed/NCBI View Article : Google Scholar
34	Sovinz P, Urban C, Uhrig S, Stepan V, Lackner H, Schwinger W, Benesch M, Moser A, Spuller E and Speicher MR: Pheochromocytoma in a 2.75-year-old-girl with a germline von Hippel-Lindau mutation Q164R. Am J Med Genet A. 152A:1752–1755. 2010.PubMed/NCBI View Article : Google Scholar
35	Colvin A, Saltzman AF, Walker J, Bruny J and Cost NG: Metastatic pheochromocytoma in an asymptomatic 12-Year-Old with von Hippel-Lindau disease. Urology. 119:140–142. 2018.PubMed/NCBI View Article : Google Scholar
36	Petr EJ and Else T: Genetic predisposition to endocrine tumors: diagnosis, surveillance and challenges in care. Semin Oncol. 43:582–590. 2016.PubMed/NCBI View Article : Google Scholar
37	Lenders JW, Duh Q-Y, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, Naruse M, Pacak K and Young WF Jr: Endocrine Society. Pheochromocytoma and paraganglioma: An endocrine society clinical practice guideline. J Clin Endocrinol Metab. 99:1915–1942. 2014.PubMed/NCBI View Article : Google Scholar
38	Tirosh A, Sadowski SM, Linehan WM, Libutti SK, Patel D, Nilubol N and Kebebew E: Association of VHL genotype with pancreatic neuroendocrine tumor phenotype in patients with von Hippel-Lindau disease. JAMA Oncol. 4:124–126. 2018.PubMed/NCBI View Article : Google Scholar
39	Krauss T, Ferrara AM, Links TP, Wellner U, Bancos I, Kvachenyuk A, Villar Gómez de Las Heras K, Yukina MY, Petrov R, Bullivant G, et al: Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors. Endocr Relat Cancer. 25:783–793. 2018.PubMed/NCBI View Article : Google Scholar
40	Wang J-Y, Peng S-H, Li T, Ning XH, Liu SJ, Hong BA, Liu JY, Wu PJ, Zhou BW, Zhou JC, et al: Risk factors for survival in patients with von Hippel-Lindau disease. J Med Genet. 55:322–328. 2018.PubMed/NCBI View Article : Google Scholar