VHL Syndrome with Diabetes Mellitus, and Pulmonary and ThyroidNodules
Main Article Content
Keywords
Diabetes mellitus; Hereditary tumor syndrome; Insulin therapy；Von Hippel-Lindau syndrome
Abstract
Von Hippel–Lindau (VHL) syndrome is an autosomal dominant hereditary tumor syndrome caused by mutations in the VHL gene. It is characterized
by the occurrence of tumors in multiple organs. Pancreatic involvement in VHL syndrome can present as pancreatic cysts or neuroendocrine
tumors, which may interfere with both pancreatic exocrine and endocrine pancreatic functions. To our knowledge, no patients with VHL
syndrome complicated by diabetes mellitus, pulmonary nodules, and thyroid nodules are reported in the literature. This study aims to explore the
pathogenesis of diabetes, pulmonary nodules, and thyroid nodules in VHL syndrome through the analysis of a patient with VHL syndrome and
to review relevant literature.
References
1. Maher ER, Iselius L, Yates JR, Littler M, Benjamin C, Harris R, et al. Von Hippel-Lindau disease: A genetic study. J Med Genet. 1991 Jul 1;28(7):443–7. https://doi.org/10.1136/jmg.28.7.443
2. Neumann HPH, Wiestler OD. Clustering of features of von Hippel-Lindau syndrome: Evidence for a complex genetic locus. Lancet. 1991 May;337(8749):1052–4. https://doi.org/10.1016/0140-6736(91)91705-Y
3. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003 Dec;3(10):721–32. https://doi.org/10.1038/nrc1187
4. Maynard MA, Qi H, Chung J, Lee EHL, Kondo Y, Hara S, et al. Multiple splice variants of the human HIF-3α locus are targets of the von Hippel-Lindau E3 ubiquitin ligase complex. J Biol Chem. 2003 Mar;278(13):11032–40. https://doi.org/10.1074/jbc.M208681200
5. Lee CM, Hickey MM, Sanford CA, McGuire CG, Cowey CL, Simon MC, et al. VHL type 2B gene mutation moderates HIF dosage in vitro and in vivo. Oncogene. 2009 Apr 9;28(14):1694–705. https://doi.org/10.1038/onc.2009.12
6. Kaelin WG. Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer. 2002 Sep;2(9):673–82. https://doi.org/10.1038/nrc885
7. Ohh M, Kaelin WG Jr. VHL and kidney cancer. Methods Mol Biol. 2003;222:167–83. https://doi.org/10.1385/1-59259-328-3:167
8. Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, et al. von Hippel-Lindau disease. Lancet. 2003;361(9374):2059–67. https://doi.org/10.1016/S0140-6736(03)13643-4
9. Kaelin WG. von Hippel-Lindau disease. Annu Rev Pathol Mech Dis. 2007 Feb 1;2(1):145–73. https://doi.org/10.1146/annurev.pathol.2.010506.092049
10. Hidaka T, Ikawa F, Michihata N, Onishi S, Matsuda S, Ozono I, et al. Perioperative surgical risks in patients with hemangioblastomas: A retrospective nationwide review in Japan. World Neurosurg. 2023 Feb;170:e21–7. https://doi.org/10.1016/j.wneu.2022.10.042
11. Graziani R, Mautone S, Vigo M, Manfredi R, Opocher G, Falconi M. Spectrum of magnetic resonance imaging findings in pancreatic and other abdominal manifestations of von Hippel-Lindau disease in a series of 23 patients: A pictorial review. J Pancreas (JoP). 2014;15(1):1–18.
12. Mohr VH, Vortmeyer AO, Zhuang Z, Libutti SK, Walther MM, Choyke PL, et al. Histopathology and molecular genetics of multiple cysts and microcystic (serous) adenomas of the pancreas in von Hippel-Lindau patients. Am J Pathol. 2000 Nov;157(5):1615–21. https://doi.org/10.1016/S0002-9440(10)64799-2
13. Hammel PR, Vilgrain V, Terris B, Penfornis A, Sauvanet A, Correas J, et al. Pancreatic involvement in von Hippel–Lindau disease. Gastroenterology. 2000 Oct;119(4):1087–95. https://doi.org/10.1053/gast.2000.18143
14. Ganeshan D, Menias CO, Pickhardt PJ, Sandrasegaran K, Lubner MG, Ramalingam P, et al. Tumors in von Hippel–Lindau syndrome: From head to toe—Comprehensive state-of-the-art review. RadioGraphics. 2018 May;38(3):849–66. https://doi.org/10.1148/rg.2018170156
15. Van Asselt SJ, De Vries EG, Van Dullemen HM, Brouwers AH, Walenkamp AM, Giles RH, et al. Pancreatic cyst development: Insights from von Hippel–Lindau disease. Cilia. 2013 Dec;2(1):3. https://doi.org/10.1186/2046-2530-2-3
16. Mukhopadhyay B, Sahdev A, Monson JP, Besser GM, Reznek RH, Chew SL. Pancreatic lesions in von Hippel–Lindau disease. Clin Endocrinol. 2002 Nov;57(5):603–8. https://doi.org/10.1046/j.1365-2265.2002.01637.x
17. Huang Y, Hu W, Huang X. Retinal hemangioblastoma in a patient with von Hippel–Lindau disease: A case report and literature review. Front Oncol. 2022 Nov 2;12:963469. https://doi.org/10.3389/fonc.2022.963469
18. Fernandes DA, Mourão JLV, Duarte JÁ, Dalaqua M, Reis F, Caserta NMG. Imaging manifestations of von Hippel–Lindau disease: An illustrated guide focusing on abdominal manifestations. Radiol Bras. 2022 Oct;55(5):317–23. https://doi.org/10.1590/0100-3984.2021.0121
19. Onishi Y, Shimizu H, Koyasu S, Taura D, Takahashi A, Uza N, et al. Association between pancreatic cysts and diabetes mellitus in von Hippel–Lindau disease. Cureus. 2024 Feb 23;16(2):e54781. https://doi.org/10.7759/cureus.54781
20. Faiyaz-ul-Haque M, Jamil M, Aslam M, Abalkhail H, Al-Dayel F, Basit S, et al. Novel and recurrent germline mutations in the VHL gene in 5 Arab patients with Von Hippel-Lindau disease. Cancer Genet. 2020 May;243:1–6. https://doi.org/10.1016/j.cancergen.2020.02.006
21. Freeman T, Taneja C, Ohori NP, Wald AI, Skaugen J, Yip L, et al. Identifying metastatic renal cell carcinoma in thyroid fine-needle aspirates by molecular testing. Endocr Relat Cancer. 2022 Dec 1;29(12):657–64. https://doi.org/10.1530/ERC-22-0195
22. Wang Y, Liu Z, Zhao W, Cao C, Xiao L, Xiao J. Diversities of mechanism in patients with VHL syndrome and diabetes: A report of two cases and literature review. Diabetes Metab Syndr Obes (DMSO). 2024 Apr;17:1611–9. https://doi.org/10.2147/DMSO.S443495
23. Belaid R, Oueslati I, Chihaoui M, Yazidi M, Grira W, Chaker F. A case of Von Hippel–Lindau disease with bilateral pheochromocytoma and ectopic hypersecretion of intact parathyroid hormone in an adolescent girl. Case Rep Endocrinol. 2020 Aug 7;2020:1–5. https://doi.org/10.1155/2020/8824640
24. Giri S, Sundaram S, Darak H, Kumar S, Bhatia S. Von Hippel–Lindau disease presenting as obstructive jaundice. ACG Case Rep J. 2020 Feb;7(2):e00324. https://doi.org/10.14309/crj.0000000000000324
25. Saowapa S, Ativitavas T, Sriphrapradang C. Bilateral scrotal masses as a clue to diagnosis of genetic disease. Am J Med Sci. 2020 Apr;359(4):250–1. https://doi.org/10.1016/j.amjms.2019.11.014
26. Kaluarachchi VTS, Bulugahapitiya U, Arambewela M, Gunathilake S. Successful management of pheochromocytoma detected in pregnancy by interval adrenalectomy in a VHL patient. Case Rep Endocrinol. 2018 Jul 19;2018(1):9014585. https://doi.org/10.1155/2018/9014585
27. Ayloo S, Molinari M. Pancreatic manifestations in von Hippel–Lindau disease: A case report. Int J Surg Case Rep. 2016;21:70–2. https://doi.org/10.1016/j.ijscr.2016.02.031
28. Panayi C, Antoun N, Sandford R. Bulbar dysfunction and aspiration pneumonia due to a brainstem haemangioblastoma: An unusual complication of von Hippel–Lindau disease. BMJ Case Rep. 2016 Oct 13;2016:bcr2016217076. https://doi.org/10.1136/bcr-2016-217076
29. Heo SJ, Lee C Kun, Hahn KY, Kim G, Hur H, Choi SH, et al. A case of von Hippel–Lindau disease with colorectal adenocarcinoma, renal cell carcinoma and hemangioblastomas. Cancer Res Treat. 2016 Jan 15;48(1):409–14. https://doi.org/10.4143/crt.2014.299
30. Medina DC, Osorno R, Boutros CN. Biliary and gastric drainage in advanced pancreatic serous cystadenoma and portal hypertension in Von Hippel–Lindau syndrome. J GI Oncol. 2014;5(2):E50–3.
2. Neumann HPH, Wiestler OD. Clustering of features of von Hippel-Lindau syndrome: Evidence for a complex genetic locus. Lancet. 1991 May;337(8749):1052–4. https://doi.org/10.1016/0140-6736(91)91705-Y
3. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003 Dec;3(10):721–32. https://doi.org/10.1038/nrc1187
4. Maynard MA, Qi H, Chung J, Lee EHL, Kondo Y, Hara S, et al. Multiple splice variants of the human HIF-3α locus are targets of the von Hippel-Lindau E3 ubiquitin ligase complex. J Biol Chem. 2003 Mar;278(13):11032–40. https://doi.org/10.1074/jbc.M208681200
5. Lee CM, Hickey MM, Sanford CA, McGuire CG, Cowey CL, Simon MC, et al. VHL type 2B gene mutation moderates HIF dosage in vitro and in vivo. Oncogene. 2009 Apr 9;28(14):1694–705. https://doi.org/10.1038/onc.2009.12
6. Kaelin WG. Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer. 2002 Sep;2(9):673–82. https://doi.org/10.1038/nrc885
7. Ohh M, Kaelin WG Jr. VHL and kidney cancer. Methods Mol Biol. 2003;222:167–83. https://doi.org/10.1385/1-59259-328-3:167
8. Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, et al. von Hippel-Lindau disease. Lancet. 2003;361(9374):2059–67. https://doi.org/10.1016/S0140-6736(03)13643-4
9. Kaelin WG. von Hippel-Lindau disease. Annu Rev Pathol Mech Dis. 2007 Feb 1;2(1):145–73. https://doi.org/10.1146/annurev.pathol.2.010506.092049
10. Hidaka T, Ikawa F, Michihata N, Onishi S, Matsuda S, Ozono I, et al. Perioperative surgical risks in patients with hemangioblastomas: A retrospective nationwide review in Japan. World Neurosurg. 2023 Feb;170:e21–7. https://doi.org/10.1016/j.wneu.2022.10.042
11. Graziani R, Mautone S, Vigo M, Manfredi R, Opocher G, Falconi M. Spectrum of magnetic resonance imaging findings in pancreatic and other abdominal manifestations of von Hippel-Lindau disease in a series of 23 patients: A pictorial review. J Pancreas (JoP). 2014;15(1):1–18.
12. Mohr VH, Vortmeyer AO, Zhuang Z, Libutti SK, Walther MM, Choyke PL, et al. Histopathology and molecular genetics of multiple cysts and microcystic (serous) adenomas of the pancreas in von Hippel-Lindau patients. Am J Pathol. 2000 Nov;157(5):1615–21. https://doi.org/10.1016/S0002-9440(10)64799-2
13. Hammel PR, Vilgrain V, Terris B, Penfornis A, Sauvanet A, Correas J, et al. Pancreatic involvement in von Hippel–Lindau disease. Gastroenterology. 2000 Oct;119(4):1087–95. https://doi.org/10.1053/gast.2000.18143
14. Ganeshan D, Menias CO, Pickhardt PJ, Sandrasegaran K, Lubner MG, Ramalingam P, et al. Tumors in von Hippel–Lindau syndrome: From head to toe—Comprehensive state-of-the-art review. RadioGraphics. 2018 May;38(3):849–66. https://doi.org/10.1148/rg.2018170156
15. Van Asselt SJ, De Vries EG, Van Dullemen HM, Brouwers AH, Walenkamp AM, Giles RH, et al. Pancreatic cyst development: Insights from von Hippel–Lindau disease. Cilia. 2013 Dec;2(1):3. https://doi.org/10.1186/2046-2530-2-3
16. Mukhopadhyay B, Sahdev A, Monson JP, Besser GM, Reznek RH, Chew SL. Pancreatic lesions in von Hippel–Lindau disease. Clin Endocrinol. 2002 Nov;57(5):603–8. https://doi.org/10.1046/j.1365-2265.2002.01637.x
17. Huang Y, Hu W, Huang X. Retinal hemangioblastoma in a patient with von Hippel–Lindau disease: A case report and literature review. Front Oncol. 2022 Nov 2;12:963469. https://doi.org/10.3389/fonc.2022.963469
18. Fernandes DA, Mourão JLV, Duarte JÁ, Dalaqua M, Reis F, Caserta NMG. Imaging manifestations of von Hippel–Lindau disease: An illustrated guide focusing on abdominal manifestations. Radiol Bras. 2022 Oct;55(5):317–23. https://doi.org/10.1590/0100-3984.2021.0121
19. Onishi Y, Shimizu H, Koyasu S, Taura D, Takahashi A, Uza N, et al. Association between pancreatic cysts and diabetes mellitus in von Hippel–Lindau disease. Cureus. 2024 Feb 23;16(2):e54781. https://doi.org/10.7759/cureus.54781
20. Faiyaz-ul-Haque M, Jamil M, Aslam M, Abalkhail H, Al-Dayel F, Basit S, et al. Novel and recurrent germline mutations in the VHL gene in 5 Arab patients with Von Hippel-Lindau disease. Cancer Genet. 2020 May;243:1–6. https://doi.org/10.1016/j.cancergen.2020.02.006
21. Freeman T, Taneja C, Ohori NP, Wald AI, Skaugen J, Yip L, et al. Identifying metastatic renal cell carcinoma in thyroid fine-needle aspirates by molecular testing. Endocr Relat Cancer. 2022 Dec 1;29(12):657–64. https://doi.org/10.1530/ERC-22-0195
22. Wang Y, Liu Z, Zhao W, Cao C, Xiao L, Xiao J. Diversities of mechanism in patients with VHL syndrome and diabetes: A report of two cases and literature review. Diabetes Metab Syndr Obes (DMSO). 2024 Apr;17:1611–9. https://doi.org/10.2147/DMSO.S443495
23. Belaid R, Oueslati I, Chihaoui M, Yazidi M, Grira W, Chaker F. A case of Von Hippel–Lindau disease with bilateral pheochromocytoma and ectopic hypersecretion of intact parathyroid hormone in an adolescent girl. Case Rep Endocrinol. 2020 Aug 7;2020:1–5. https://doi.org/10.1155/2020/8824640
24. Giri S, Sundaram S, Darak H, Kumar S, Bhatia S. Von Hippel–Lindau disease presenting as obstructive jaundice. ACG Case Rep J. 2020 Feb;7(2):e00324. https://doi.org/10.14309/crj.0000000000000324
25. Saowapa S, Ativitavas T, Sriphrapradang C. Bilateral scrotal masses as a clue to diagnosis of genetic disease. Am J Med Sci. 2020 Apr;359(4):250–1. https://doi.org/10.1016/j.amjms.2019.11.014
26. Kaluarachchi VTS, Bulugahapitiya U, Arambewela M, Gunathilake S. Successful management of pheochromocytoma detected in pregnancy by interval adrenalectomy in a VHL patient. Case Rep Endocrinol. 2018 Jul 19;2018(1):9014585. https://doi.org/10.1155/2018/9014585
27. Ayloo S, Molinari M. Pancreatic manifestations in von Hippel–Lindau disease: A case report. Int J Surg Case Rep. 2016;21:70–2. https://doi.org/10.1016/j.ijscr.2016.02.031
28. Panayi C, Antoun N, Sandford R. Bulbar dysfunction and aspiration pneumonia due to a brainstem haemangioblastoma: An unusual complication of von Hippel–Lindau disease. BMJ Case Rep. 2016 Oct 13;2016:bcr2016217076. https://doi.org/10.1136/bcr-2016-217076
29. Heo SJ, Lee C Kun, Hahn KY, Kim G, Hur H, Choi SH, et al. A case of von Hippel–Lindau disease with colorectal adenocarcinoma, renal cell carcinoma and hemangioblastomas. Cancer Res Treat. 2016 Jan 15;48(1):409–14. https://doi.org/10.4143/crt.2014.299
30. Medina DC, Osorno R, Boutros CN. Biliary and gastric drainage in advanced pancreatic serous cystadenoma and portal hypertension in Von Hippel–Lindau syndrome. J GI Oncol. 2014;5(2):E50–3.
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Sep 18, 2025
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VHL Syndrome with Diabetes Mellitus, and Pulmonary and ThyroidNodules. (2025). Journal of Kidney Cancer, 12(3), 37-46. https://doi.org/10.15586/jkcvhl.v12i3.412
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Kidney Cancer: Case Reports
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How to Cite
VHL Syndrome with Diabetes Mellitus, and Pulmonary and ThyroidNodules. (2025). Journal of Kidney Cancer, 12(3), 37-46. https://doi.org/10.15586/jkcvhl.v12i3.412