Neurologic manifestations of von Hippel-Lindau disease

John A. Butman, MD, PhD; W. Marston Linehan, MD; Russell R. Lonser, MD

JAMA. 2008;300(11):1334-1342.

von Hippel-Lindau disease (VHL) is an autosomal-dominant neoplasia syndrome that is the result of a germline mutation of the VHL tumor suppressor gene on the short arm of chromosome 3. Patients with VHL are predisposed to develop lesions of the central nervous system and viscera. Central nervous system lesions include hemangioblastomas (the most common tumor in VHL) and endolymphatic sac tumors (ELSTs). Visceral manifestations include renal carcinomas and cysts, pancreatic neuroendocrine tumors and cysts, pheochromocytomas, and cystadenomas of the reproductive adnexal organs. Despite their benign pathology, hemangioblastomas and ELSTs are a frequent cause of morbidity and mortality in patients with VHL. Recent molecular biologic investigations into these VHL-associated central nervous system lesions provide new insight into their origin and development. Emerging data from serial imaging and clinical surveillance protocols provide insight into the natural history of these lesions. Because of the dissimilar pathobiology and clinical course between hemangioblastomas and ELSTs, the optimal management strategies for these neurologic manifestations of VHL are very different.

     

von Hippel-Lindau病三例并文献复习

目的:初步探讨VHL病的发病机制、诊断以及治疗。方法:回顾分析既往收治的3例VHL病人并结合文献复习。结果:3例患者中1例有家族史,另2例为多发病变,均未能全切。第1例患者鞍上无症状病变动态观察,第2例患者颈椎HB过小,动态观察,第3例患者一处病变位于颈椎腹侧,无法切除,其余病变全部切除。结论:本病诊断主要依靠MRI,治疗主要依靠手术,因累及脏器多,很难全部切除,易复发,愈后较差。     

Imaging manifestations of von Hippel-Lindau disease: a report of 3 casesImaging manifestations of von Hippel-Lindau disease: a report of 3 cases

Von Hippel-Lindau (VHL) disease is an autosomal dominant here ditary familial neoplasm syndrome characte rized by development of a variety of benign and malignant tumors in multiple organ systems,such as the brain,kidney,pancreas,adrenalgland,and epididymis,with aprev a lence of one in 39000- 53000.1 4 Hallmarks of the condition in clude retinal angiomas,hem angioblastomas of the cerebellum and the spinal cord,renal cell carcinoma and cysts,and pheochrom ocytomas.In this article,we report imaging findings in three cases of VHLdisease.     

Management of solid renal tumour associated with von Hippel-Lindau disease

Von Hippel-Lindau （VHL） disease is a rare autosomal dominant disorder caused by germ line mutations of the VHL tumour suppressor gene. it predisposes affected individuals to develop a variety of neoplasms, including haemangioblastomas of the central nervous system, retinal angiomas, renal cell carcinomas （RCCs）, pheochromocytomas and cysts of the kidneys and epididymis. Germ line VHL mutations have been found in all VHL disease families. RCC occurs in 25% to 45% of patients with VHL disease and is one of the leading causes of death.[第一段]     

Genetic study of a large Chinese kindred with von Hippel-Lindau disease

Background Von HippeI-Lindau (VHL) disease is a heraditary cancer syndrome caused by germline mutations of the VHL tumor on the suppressor gene. This study was to show the clinical characteristics of a large Chinese kindred with yon HippeI-Lindau disease and to evaluate the role of the genetic test of VHL disease in the diagnosis of VHL disease and clinical screening of members of the VHL disease family.Methods DNA extracted from peripheral blood was amplified by PCR to three exons of the VHL gene in 27 members of a large kindred with VHL disease. PCR products were directly sequenced. The involvements of multi-organs in the kindred with VHL disease were confirmed by history taking and radiography.Results Of 47 members in the four generations of the kindred, 18 members were diagnosed as having VHL desease. Clinical manifestations of 18 patients included: central nervous system (CNS)hemangioblastoma (5), renal cell carcinoma and CNS hemangioblastoma (3), renal cell carcinoma and retinal angioma (3), renal cell carcinoma and multiple pancreatic cysts (1), renal cell carcinoma and retinal angioma and multiple pancreatic cysts (2), renal cell carcinoma and CNS hemangioblastomas and multiple pancreatic cysts (1), and multiple pancreatic cysts and multiple renal cysts (1), multiple pancreatic cysts (2). The common lesions of the 18 patients were renal cell carcinoma (55.6%), CNS hemangioblastoma (50.0%), retinal angioma (27.8%), and multiple pancreatic cysts (38.9%). Among the 27 members who volunteered for genetic analysis, 15 members including 9 affected family patients and 2 asymptomatic patients and 4 carriers, who are still alive, presented a codon 78 from Asn to Ser change at nucleotide 446 (A→G) in exon 1. Four members were carriers with the same VHL gene mutation. Two asymptomatic patients were initially diagnosed by genetic testing and subsequently confirmed radiologically and surgically. Members without gene mutation had no clinical evidence of VHL disease.Conclusions The large Chinese kindred with VHL disease was classified as type I . The main characteristics in the kindred were higher incidence of renal cell carcinoma and lower incidence of retinal angioma. Genetic test plays an important role in early detecting asymptomatic patients and the carriers in clinical screening of members of the families with VHL disease. It is also important to prevent the transmission of VHL disease to their offsprings in the kindred.     

Imaging manifestations of von Hippel-Lindau disease： a report of 3 cases

Von HippeI-Lindau ( VHL ) disease is an autosomal-dominant hereditary familial neoplasm syndrome characterized by development of a variety of benign and malignant tumors in multiple organ systems, such as the brain, kidney,pancreas, adrenal gland, and epididymis, with a prevalence of one in 39000 -53000.     

Von Hippel-Lindau disease in a Newfoundland kindred.

Von Hippel-Lindau disease, an autosomal dominant condition with complete penetrance, has been recognized in a large family that originated in Newfoundland but has some members who live in New Brunswick and Ontario. A collaborative investigation was begun in 1982 to document the number of affected members and the extent of their disease and to improve management of the disease. The condition has been documented in 38 members of the family, 28 living and 10 dead. The most common manifestations are retinal angioma (present in 60% of the gene carriers) and pheochromocytoma (present in 53%). Of the 28 living affected members 14 had been identified before the study began. Only 3 of the 14 patients in whom the disease was subsequently diagnosed presented with symptoms; in the remaining 11 the condition was detected by routine screening. Overall the mean age at the time of diagnosis was 23 years; in the 21 affected members of the fourth generation it was 18 years. The authors outline a regimen of regular screening for members at risk that has evolved as a result of their experience with this family.     

Mechanisms of morbid hearing loss associated with tumors of the endolymphatic sac in von Hippel-Lindau disease

Context  Endolymphatic sac tumors (ELSTs) are associated with von Hippel-Lindau disease and cause irreversible sensorineural hearing loss (SNHL) and vestibulopathy. The underlying mechanisms of audiovestibular morbidity remain unclear and optimal timing of treatment is not known. Objective  To define the mechanisms underlying audiovestibular pathophysiology associated with ELSTs. Design, Setting, and Patients  Prospective and serial evaluation of patients with von Hippel-Lindau disease and ELSTs at the National Institutes of Health between May 1990 and December 2006. Main Outcome Measures  Clinical findings and audiologic data were correlated with serial magnetic resonance imaging and computed tomography imaging studies to determine mechanisms underlying audiovestibular dysfunction. Results  Thirty-five patients with von Hippel-Lindau disease and ELSTs in 38 ears (3 bilateral ELSTs) were identified. Tumor invasion of the otic capsule was associated with larger tumors (P = .01) and occurred in 7 ears (18%) causing SNHL (100%). No evidence of otic capsule invasion was present in the remaining 31 ears (82%). SNHL developed in 27 of these 31 ears (87%) either suddenly (14 ears; 52%) or gradually (13 ears; 48%) and 4 ears had normal hearing. Intralabyrinthine hemorrhage was found in 11 of 14 ears with sudden SNHL (79%; P < .001) but occurred in none of the 17 ears with gradual SNHL or normal hearing. Tumor size was not related to SNHL (P = .23) or vestibulopathy (P = .83). Conclusions  ELST-associated SNHL and vestibulopathy may occur suddenly due to tumor-associated intralabyrinthine hemorrhage, or insidiously, consistent with endolymphatic hydrops. Both of these pathophysiologic mechanisms occur with small tumors that are not associated with otic capsule invasion.      

应用单核苷酸多态性技术筛查2型糖尿病易感基因

目的利用单核苷酸多态性(SNP)标记,在中国北方汉族2型糖尿病相关基因定位区域(1p36.33-p36.23、1q24.3-25.1及1q42.12-42.13)内寻找疾病易感基因位点以及与疾病相关的单倍型.方法通过公共SNP数据库和对样本库全基因测序寻找SNP位点的途径,在定位区域内选择了33个候选基因中的124个SNP位点,用测序法对236例北方汉族散发2型糖尿病患者及152例正常对照个体进行SNP基因分型及病例-对照关联分析,并对具显著性差异的SNP位点进行单倍型分析.结果124个SNP位点中有4个SNP位点的分布频率在病例组和正常对照组存在显著差异(P＜0.05),分别为sAC基因中的rs203849(P=0.005,OR=1.60)和rs203826(P=0.016,OR=1.60),PANK4基因中的rs7535528(P=0.028,OR=1.45)和CASP9基因中的rs884363(P=0.043,OR=1.37).在这4个SNP位点构成的组合型中发现,有2种组合型的频率分布在病例组与对照组之间差异有显著性(P＜0.001).此外,对sAC基因的单倍型分析发现,有4种单倍型与疾病发生相关.结论sAC、PANK4和CASP9基因为中国北方汉族人群2型糖尿病候选易感基因,这3个基因可能在2型糖尿病易感性上有协同作用.