Epidemiological study of a von Hippel-Lindau family in northwest China

Abstract

von Hippel-Lindau (VHL) disease is a rare, inherited neoplastic disease characterized by hemangioblastomas (HBL) of the central nervous system (CNS), retinal angiomas, renal cell carcinomas (RCC), pancreatic endocrine tumors (PETs), pheochromocytomas, paragangliomas, and visceral cysts. We encountered a large VHL family in northwest China and conducted a systematic screening of the family members based on their epidemiological and clinical characteristics. A self-designed questionnaire was used to collect the general sociodemographic and health information of the family members. For the preliminary family screening, physical examination and abdomen B ultrasonography were performed. The suspected patients were subjected to cranial computerized tomography and fundus examination. The clinical data of the patients with confirmed VHL disease were collected from hospital records. A total of 63 lineal descendants in six generations were observed in the family (generations O, A, B, C, D, E), including 9 dead suspected cases (6 males, 3 females) and 10 living cases (2 males, 8 females). Among the 10 living cases, 4, 2, 1, 3, 4, 8, and 2 manifested HBLs of the CNS, PETs, RCC, pancreatic cysts, renal cysts, pheochromocytomas (4 hemi and 4 bilateral), and paragangliomas, respectively. Data showed that the morbidity of VHL disease in generation C was lower than that in generation B, but the age of onset was younger. This study is the first to report VHL disease in northwest China and VHL-associated PET cases in Chinese. Therefore, follow-up checkups of the family should be focused on younger generations. Proper family screening protocols should be followed for the treatment of patients with VHL disease.

Keywords

von Hippel-Lindau disease / epidemiology / family screening / pancreatic endocrine tumor

References

[1] Richard S, Graff J, Lindau J, Resche F. Von Hippel-Lindau disease. Lancet2004; 363(9416): 1231–1234

[2] Maher ER, Neumann HP, Richard S. von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet2011; 19(6): 617–623

[3] Zbar B, Kishida T, Chen F, Schmidt L, Maher ER, Richards FM, Crossey PA, Webster AR, Affara NA, Ferguson-Smith MA, Brauch H, Glavac D, Neumann HP, Tisherman S, Mulvihill JJ, Gross DJ, Shuin T, Whaley J, Seizinger B, Kley N, Olschwang S, Boisson C, Richard S, Lips CH, Lerman M, .Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat1996; 8(4): 348–357

[4] Bader HL, Hsu T. Systemic VHL gene functions and the VHL disease. FEBS Lett2012; 586(11): 1562–1569

[5] Padhi S, Sarangi R, Challa S, Bussary P, Panigrahi MK, Purohit AK. A 10-year retrospective study of hemangioblastomas of the central nervous system with reference to von Hippel-Lindau (VHL) disease. J Clin Neurosci2011; 18(7): 939–944

[6] Neumann HP, Eggert HR, Scheremet R, Schumacher M, Mohadjer M, Wakhloo AK, Volk B, Hettmannsperger U, Riegler P, Schollmeyer P, . Central nervous system lesions in von Hippel-Lindau syndrome. J Neurol Neurosurg Psychiatry1992; 55(10): 898–901

[7] Filling-Katz MR, Choyke PL, Oldfield E, Charnas L, Patronas NJ, Glenn GM, Gorin MB, Morgan JK, Linehan WM, Seizinger BR, Zbar B. Central nervous system involvement in Von Hippel-Lindau disease. Neurology1991; 41(1): 41–46

[8] Arjumand W, Sultana S. Role of VHL gene mutation in human renal cell carcinoma. Tumour Biol 2012; 33(1): 9–16

[9] Choyke PL, Glenn GM, Walther MM, Patronas NJ, Linehan WM, Zbar B. von Hippel-Lindau disease: genetic, clinical, and imaging features. Radiology1995; 194(3): 629–642

[10] Neumann HP, Dinkel E, Brambs H, Wimmer B, Friedburg H, Volk B, Sigmund G, Riegler P, Haag K, Schollmeyer P, . Pancreatic lesions in the von Hippel-Lindau syndrome. Gastroenterology1991; 101(2): 465–471 PMID:2065922

[11] Hammel PR, Vilgrain V, Terris B, Penfornis A, Sauvanet A, Correas JM, Chauveau D, Balian A, Beigelman C, O’Toole D, Bernades P, Ruszniewski P, Richard S. Pancreatic involvement in von Hippel-Lindau disease. The Groupe Francophone d’Etude de la Maladie de von Hippel-Lindau. Gastroenterology2000; 119(4): 1087–1095

[12] Lubensky IA, Pack S, Ault D, Vortmeyer AO, Libutti SK, Choyke PL, Walther MM, Linehan WM, Zhuang Z. Multiple neuroendocrine tumors of the pancreas in von Hippel-Lindau disease patients: histopathological and molecular genetic analysis. Am J Pathol1998; 153(1): 223–231

[13] Blansfield JA, Choyke L, Morita SY, Choyke PL, Pingpank JF, Alexander HR, Seidel G, Shutack Y, Yuldasheva N, Eugeni M, Bartlett DL, Glenn GM, Middelton L, Linehan WM, Libutti SK. Clinical, genetic and radiographic analysis of 108 patients with von Hippel-Lindau disease (VHL) manifested by pancreatic neuroendocrine neoplasms (PNETs). Surgery2007; 142(6): 814–818, discussion e1–e2

[14] Hough DM, Stephens DH, Johnson CD, Binkovitz LA. Pancreatic lesions in von Hippel-Lindau disease: prevalence, clinical significance, and CT findings. AJR Am J Roentgenol1994; 162(5): 1091–1094

[15] Bender BU, Gutsche M, Gläsker S, Müller B, Kirste G, Eng C, Neumann HP. Differential genetic alterations in von Hippel-Lindau syndrome-associated and sporadic pheochromocytomas. J Clin Endocrinol Metab2000; 85(12): 4568–4574

[16] Wu P, Zhang N, Wang X, Ning X, Li T, Bu D, Gong K. Family history of von Hippel-Lindau disease was uncommon in Chinese patients: suggesting the higher frequency of de novo mutations in VHL gene in these patients. J Hum Genet 2012; 57(4): 238–243

[17] Huang Y, Zhou D, Liu J, Zhou P, Li X, Wang Z. Germline mutations of the VHL gene in seven Chinese families with von Hippel-Lindau disease. Int J Mol Med2012; 29(1): 47–52

[18] Melmon KL, Rosen SW. Lindau’s disease. Am J Med1964; 36(4): 595–617

[19] Vortmeyer AO, Gnarra JR, Emmert-Buck MR, Katz D, Linehan WM, Oldfield EH, Zhuang Z. von Hippel-Lindau gene deletion detected in the stromal cell component of a cerebellar hemangioblastoma associated with von Hippel-Lindau disease. Hum Pathol1997; 28(5): 540–543

[20] Fishbein L, Nathanson KL. Pheochromocytoma and paraganglioma: understanding the complexities of the genetic background. Cancer Genet2012; 205(1–2): 1–11

[21] Baghai M, Thompson GB, Young WF Jr, Grant CS, Michels VV, van Heerden JA. Pheochromocytomas and paragangliomas in von Hippel-Lindau disease: a role for laparoscopic and cortical-sparing surgery. Arch Surg2002; 137(6): 682–688, discussion 688–689

[22] Walther MM, Reiter R, Keiser HR, Choyke PL, Venzon D, Hurley K, Gnarra JR, Reynolds JC, Glenn GM, Zbar B, Linehan WM. Clinical and genetic characterization of pheochromocytoma in von Hippel-Lindau families: comparison with sporadic pheochromocytoma gives insight into natural history of pheochromocytoma. J Urol1999; 162(3): 659–664

[23] Mugawar M, Rajender Y, Purohit AK, Sastry RA, Sundaram C, Rammurti S. Anesthetic management of von Hippel-Lindau Syndrome for excision of cerebellar hemangioblastoma and pheochromocytoma surgery. Anesth Analg 1998; 86(3): 673–674

[24] Walther MM, Keiser HR, Choyke PL, Rayford W, Lyne JC, Linehan WM. Management of hereditary pheochromocytoma in von Hippel-Lindau kindreds with partial adrenalectomy. J Urol 1999; 161(2): 395–398

[25] Libutti SK, Choyke PL, Alexander HR, Glenn G, Bartlett DL, Zbar B, Lubensky I, McKee SA, Maher ER, Linehan WM, Walther MM. Clinical and genetic analysis of patients with pancreatic neuroendocrine tumors associated with von Hippel-Lindau disease. Surgery2000; 128(6): 1022–1027, discussion 1027–1028

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