遗传性多器官肿瘤综合征应引起重视——龚侃教授谈VHL病

日前,北京大学第一医院泌尿外科龚侃教授向记者介绍了遗传性多器官肿瘤综合征,即VHL病(von Hippel-Lindau disease)的临床情况.龚侃指出,VHL病是由VHL基因突变或启动子高甲基化导致的常染色体显性遗传病,表现为全身多器官的肿瘤综合征.VHL病临床表现复杂,通常累及多个脏器.然而,目前国内很多医生对VHL病的整体性认识不足,往往只针对某一系统的病灶进行治疗,继而不能给予准确诊断和合理治疗.因此,广大医务工作者对VHL病应有更为深入的了解,更好地开展疾病的筛查、诊断和治疗.     

家族性延髓血管母细胞瘤3例报告

目的 探讨家族性延髓血管母细胞瘤的诊断和治疗.方法 分析一个家系3例延髓血管母细胞瘤的临床资料和手术疗效,结合文献讨论.结果 本家系确诊VHL病[Von Hippel-Lindau Syndrome(VHL ),"希佩尔-林道综合征"].3例肿瘤全部切除,随访6～48个月,3例KPS(karnofsky评分)均>90分.结论 延髓血管母细胞瘤诊断主要依靠CT、MRI,基因检测对VHL病诊断有重要价值.显微手术技巧可显著提高本病的疗效.围术期控制"正常灌注压突破综合征".及时发现和处理相关并发症对本病的预后有重要意义.     

VHL病的治疗原则与筛查

一、VHL病各临床表现的治疗原则 以下介绍VHL病各临床表现的治疗原则. 中枢神经系统血管母细胞瘤 对于单发或位于脊髓的中枢神经系统血管母细胞瘤可手术切除.对于多发性中枢神经系统血管母细胞瘤,应根据影像学检查结果选择合适的治疗措施.若肿瘤直径＞2 cm者予以一次或分次手术切除;若肿瘤直径＜2cm应在手术后行γ刀冶疗以控制肿瘤进展.     

VHL病并发双侧肾癌1例报告及文献复习

VHL病是一种家族性常染色体显性遗传性肿瘤病,病变可累及多个器官、表现多样,包括中枢神经系统血管母细胞瘤、内脏肿瘤和内脏多发囊肿等。对本病的了解将有助于对本病的及时诊断,避免误诊和漏诊该病。本文将报道1例并发双侧肾癌的VHL患者并结合文献阐述VHL病的临床特点、诊断方法以及治疗。     

Von Hippel-Lindau(VHL)病诊断与治疗(附3例报告)

目的提高Von Hippel-Lindau病(VHL)并发泌尿系疾病的诊断和治疗水平。方法回顾分析3例VHL病并发泌尿系疾病患者临床资料并结合文献复习讨论。2例为VHLⅠ型,1例为VHLⅢ型。结果1例VHLⅢ型随访3个月。肿瘤无复发。2例VHLⅠ型,其中1例随访26个月未见肿瘤复发,另1例因肾癌晚期远处转移致多脏器功能衰竭术后4个月死亡。结论肾癌、肾囊肿、嗜铬细胞瘤是VHL病在泌尿系的表现而肾癌具有多中心、双侧发病、易复发等特点。薄层CT是主要的诊断和随访手段。手术治疗方式包括双肾切除,肾肿瘤剜除和肾部分切除等,保留肾单位术后应密切随访,及时发现再发的病变。     

VHL病伴发双侧肾癌3例报告并文献复习

目的 初步探讨以冯·希佩尔·林道(Von Hippel-Lindau,VHL)病并发双侧肾癌的发病特点、诊断及治疗.方法 回顾分析2007年2月-2011年6月解放军第309医院收治的3例VHL病并发双侧肾癌的患者,并结合文献复习.结果 3例中1例有家族史,先后行右侧保留肾单位手术,左侧腹腔镜下肾癌根治性切除,病理提示为透明细胞癌,术后规律血液透析,等待肾移植;另2例为多发病变,双侧肾癌伴双侧多发肾囊肿,2例均选择双侧保留肾单位手术和肾囊肿去盖术,术后病理提示为透明细胞癌,肾功能正常.结论 VHL病肾癌有独特的临床特征,不同于散发性肾癌,诊断主要依靠MRI和CT;治疗主要依靠手术,术后易复发,因累及多脏器,需要多学科给予综合治疗.     

中枢神经系统血管母细胞瘤家系及基因学研究

目的探讨家族性中枢神经系统血管母细胞瘤(hemangioblastoma,HB)的临床特点及Von Hippel-Lin-dau(VHL)基因突变情况。方法对一个家族性中枢神经系统血管母细胞瘤所有成员进行临床资料收集及分析,绘制系谱图;并对家系成员进行VHL基因测序。结果该家系有5例患病,其中3例患者均行手术治疗,2例患者因该病死亡。VHL基因检测未发现VHL基因突变。结论早期发现及治疗能降低HB的危害,发现家族性HB应对家系成员进行普查,并行VHL基因检测,确诊为VHL病的患者需终生随访,以便及时处理复发或新发病灶。     

以梗阻性黄疸为主要临床特征的多囊胰腺1例

多囊胰腺是临床上一种少见的疾病,是林岛（ VHL）综合征的一种亚型。国外 VHL 病发病率较高,约为1/36000-1/45500[1],其中,胰腺神经内分泌肿瘤发病率约为10%-17%,胰腺囊肿的发病率约为70%[2]。文献检索显示,国内仅有10例多囊胰腺的报道[3-6],其中有2例以梗阻性黄疸为主要临床表现[5,6]。本文介绍以梗阻性黄疸为主要临床表现的多囊胰腺1例,并结合文献对该病的临床特点和治疗进行总结和探讨。     

脑囊虫病30例临床分析

目的 讨论总结脑囊虫病的临床特点.方法 对30例在我院诊断为脑囊虫病患者的临床表现|、检查资料以及治疗方法进行回顾性分析总结.结果 经治疗,本组患者临床症状及体征都逐渐恢复正常.结论 脑囊虫病临床表现复杂多样,MRI对脑囊虫病的诊断具有重要意义,发病率本地傣族高于其他民族,农村高于城市,吡喹酮具有很高的疗效.     

Von Hippel-Lindau综合征4例影像学表现和遗传史回顾及文献复习

目的总结Von Hippel-Lindau(VHL)综合征的影像学表现和诊断方法。方法回顾分析4例vHL综合征患者的影像学、家族遗传史和其他临床资料,结合复习相关文献,探讨该少见遗传病的诊断方法。结果本组4例患者,男1例,女3例,年龄28⁴1岁,中位年龄34.3岁,影像学均表现为胰腺多发囊实性占位和双肾多发囊实性肿物。既往都有脑内肿瘤手术史和家族多人发病的遗传史,符合Maher等提出的该综合征诊断标准。结论 VHL基因不同突变类型导致不同表现型,临床表现形式复杂多样,认识VHL综合征的影像特征,结合临床病史可以明显提高其诊断水平。     

胰腺囊性病变的64排SCT诊断

目的探讨胰腺囊性病变的64排SCT表现及鉴别诊断。方法结合临床相关病史及病理表现,回顾性分析本院48例经过手术病理证实的胰腺囊性病变的CT表现。结果25例胰腺假性囊肿,1例真性囊肿伴发于von Hipple—Lindau综合征（VHL）,并发双肾多发囊性病灶及占位,4例浆液性囊腺瘤,1例为大囊型,粘液性囊腺瘤5例,1例合并感染,2例囊腺癌,胰腺实性假乳头状9例,均为囊实性成分相仿,胰岛细胞瘤2例,均为囊实性成分。结论胰腺假性囊肿、囊腺瘤及实性假乳头状瘤是胰腺较常见囊性病变,胰腺囊性病变在CT表现上有各自特征也有共性,结合临床及相关病史可作出CT诊断。     

肾脏囊性病变的CT诊断

目的探讨CT对肾脏囊性病变的诊断价值。方法回顾性分析43例经手术或穿刺活检病理证实的肾脏囊性病变的CT表现。结果囊性肾癌5例,多囊肾15例,肾盂源囊肿3例,肾盂旁囊肿4例,髓质海绵肾1例,肾结核14例,双肾囊性病变及占位伴发VHL综合征1例。结论肾脏囊性病变因形成机制及病理特点的不同使其在CT表现上有着各自的特点,结合临床资料更有助于病变的诊断。     

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.     

von Hippel-Lindau syndrome: molecular diagnosis of two Lebanese families and analysis of the genotype-phenotype correlation

The von Hippel-Lindau syndrome (VHL) is a dominantly transmitted hereditary disorder associating multisystemic tumors affecting mainly the central nervous system, the kidneys, the pancreas, as well as pheochromocytomas. Mutations of the tumor suppressor gene VHL on chromosome 3 are responsible for the disease. This article reports for the first time the study of two Lebanese VHL affected families, presenting particularly hemangioblastomas of the central nervous system. Two different mutations of the VHL gene, S65W and F76S, respectively identified in the two families, confirmed the clinical diagnosis of the patients. Molecular diagnosis was then performed for at risk members of these families. This article reveals the importance of molecular diagnosis for suspected patients and of presymptomatic diagnosis for at risk members, especially that a close follow-up of carriers allows an early detection of tumors and prevents the metastasis stage, the most common cause of death of these patients.     

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。     

石蜡包埋肾肿瘤标本VHL基因突变研究

目的：研究石蜡包埋肾肿瘤标本ＶＨＬ基因突变情况。方法：采用ＰＣＲ－ＳＳＣＰ银染法分析３８ 例肾透明细胞癌、１０ 例肾颗粒细胞癌、１０ 例肾盂移行细胞癌、１０ 例肾胚瘤ＶＨＬ基因突变情况。结果：９ 例肾透明细胞癌ＶＨＬ基因外显子２ 发生突变,突变率为２３％ ,其他３ 种肾肿瘤均未发现ＶＨＬ基因突变。结论：ＶＨＬ基因突变与肾透明细胞癌的发生关系密切,ＰＣＲ－ＳＳＣＰ方法检测ＶＨＬ基因突变可用于ＶＨＬ病及肾透明细胞癌的诊断     

Screening for von Hippel-Lindau disease by DNA polymorphism analysis.

OBJECTIVE--Von Hippel-Lindau (VHL) disease is a rare, inherited multisystem neoplastic disorder. There is no biochemical test available to distinguish VHL disease gene carriers from their healthy siblings. We evaluated DNA polymorphism analysis as a method for identifying disease gene carriers. DESIGN--Prospective comparison of the results of DNA analysis with a comprehensive clinical screening examination. SETTING--The Clinical Center of the National Institutes of Health. PATIENTS--Blood was collected from 182 members of 16 families with VHL disease. Forty-eight asymptomatic individuals, at risk of developing this hereditary illness (with an affected parent or sibling), were examined for occult disease at the Clinical Center of the National Institutes of Health and tested by DNA polymorphism analysis. RESULTS--DNA polymorphism analysis predicted nine disease gene carriers and 33 individuals with the wild-type (normal) allele among the 48 individuals at risk of developing VHL disease; the test was not informative in six individuals. All nine individuals predicted to carry the VHL gene had evidence of occult disease on clinical examination. There was no clinical evidence of VHL disease in 32 of 33 individuals predicted to carry the wild-type allele. CONCLUSIONS--DNA polymorphism analysis can identify individuals likely to carry the VHL disease gene among asymptomatic members of disease families. This technique serves to focus attention on those individuals who require periodic medical examination and may help to alleviate the morbidity and mortality associated with this disease.     

Molecular basis of von Hippel-Lindau syndrome in Chinese patients

Background  Von Hippel-Lindau (VHL) syndrome is an autosomal dominant familial cancer syndrome predisposing the affected individuals to multiple tumours in various organs. The genetic basis of VHL in Southern Chinese is largely unknown. In this study, we characterized the mutation spectrum of VHL in nine unrelated Southern Chinese families.

Methods  Nine probands with clinical features of VHL, two symptomatic and eight asymptomatic family members were included in this study. Prenatal diagnosis was performed twice for one proband. Two probands had only isolated bilateral phaeochromocytoma. The VHL gene was screened for mutations by polymerase chain reaction, direct sequencing and multiplex ligation-dependent probe amplification (MLPA).

Results  The nine probands and the two symptomatic family members carried heterozygous germline mutations. Eight different VHL mutations were identified in the nine probands. One splicing mutation, NM_000551.2: c.463+1G>T, was novel. The other seven VHL mutations, c.233A>G [p.Asn78Ser], c.239G>T [p.Ser80Ile], c.319C>G [p.Arg107Gly], c.481C>T [p.Arg161X], c.482G>A [p.Arg161Gln], c.499C>T [p.Arg167Trp] and an exon 2 deletion, had been previously reported. Three asymptomatic family members were positive for the mutation and the other five tested negative. In prenatal diagnosis, the fetuses were positive for the mutation.

Conclusions  Genetic analysis could accurately confirm VHL syndrome in patients with isolated tumours such as sporadic phaeochromocytoma or epididymal papillary cystadenoma. Mutation detection in asymptomatic family members allows regular tumour surveillance and early intervention to improve their prognosis. DNA-based diagnosis can have an important impact on clinical management for VHL families.