中国人一个von Hippel-Lindau病的大家系调查及基因突变研究

目的 探讨中国人一个von Hippel-Lindau(VHL)病家系的临床特点及基因突变研究的临床意义。方法 调查一个von Hippel—Lindau病大家系，制定该家系发病的树状图；抽取27位家族成员外周血，采用聚合酶链反应和扩增产物直接测序进行基因检测；通过病史和影像学检查，获得该病的多脏器肿瘤发生情况。结果 该家族4代47人中18人患von Hippel-Lindau病，其中中枢神经系统成血管细胞瘤5例，肾癌合并中枢神经系统成血管细胞瘤3例，肾癌合并视网膜血管瘤3例，肾癌合并胰腺多发性囊肿1例，肾癌合并视网膜血管瘤及胰腺多发性囊肿2例，肾癌合并中枢神经系统成血管细胞瘤及胰腺多发性囊肿1例，肾脏多发性囊肿合并胰腺多发性囊肿1例和胰腺多发性囊肿2例。本组中，肾癌、中枢神经系统成血管细胞瘤、视网膜血管瘤和胰腺多发性囊肿的发生率分别为56％、50％、28％和39％。基因检测发现VHL基因第1外显子上第446位核苷酸A→G突变，该突变导致第78位编码氨基酸由天冬酰胺转变为丝氨酸。检测的27人中，15人呈现VHL基因突变，其中9例患病者、4例致病基因携带者及2例经影象学检查外科手术证实的无症状患者。其余12人无基因突变，同时无相应临床征象。结论 该家系属于von Hippel—Lindau病I型，肾癌发生率高而视网膜血管瘤发生率低是其主要的临床特点。基因检测在早期发现无症状患者和致病基因携带者及对该病家族成员进行临床监测方面起着重要作用，并在遗传生殖角度阻断该疾病的遗传有重要意义。     

中国人von Hippel-Lindau综合征种系突变研究

目的探讨中国人von Hippel-Lindau综合征（VHL）种系突变的特点及其临床应用价值。方法分析6个VHL家系的临床资料，采用聚合酶链反应和扩增产物直接测序的方法对其中的21位成员进行VHL基因种系突变研究。结果在6个家系中，5个Ⅰ型家系，1个ⅡA型家系。6种不同的VHL基因种系突变被确定，其中包括错义突变4个，无义突变1个，缺失突变1个。4个分布在第1外显子、1个在第2外显子和1个在第3外显子。21人接受基因检测的个体中，14人存在VHL基因种系突变，其中包括10例均符合VH临床诊断标准的患者、1例疑似VHL患者和3例致病基因携带者。结论中国汉族人VHL患者存在基因种系突变且第1外显子的后1／3可能为主要的突变区域；VHL基因种系突变检测在疾病诊断和早期发现无症状患者及致病基因携带者方面具有重要作用。     

两个斑驳病家系KIT基因突变研究

目的 对2个斑驳病家系进行致病基因突变分析,为患者及其家系成员提供遗传咨询和生育指导.方法 分别采集家系1两例患者(先证者及其父亲)、家系2先证者及3名表型正常家系成员的外周血,提取外周血DNA和RNA.应用PCR、逆转录PCR及测序等技术,从基因组水平和表达水平对此两家系先证者和患者进行KIT基因诊断,并初步探讨检测到的突变对KIT基因功能的影响.结果 家系l中两例患者KIT基因均存在IVS12+ 2_+7delinsACATCTTTA的杂合突变,该突变在cDNA水平导致KIT基因c.1765-1779del突变,在氨基酸水平导致p.Gly592Ala/del:E12突变,使得KIT基因剪切位点发生改变,即其中一条cDNA第12外显子被跨越、未转录.家系2中先证者KIT基因存在c.2401A＞C突变,3位表型正常的家系成员未见该突变.结论 确诊了两个斑驳病家系的致病原因.家系1患者KIT基因均存在IVS12+ 2_+ 7delinsACATCTTTA的杂合突变,该突变为人类基因突变数据库未记载的、新的剪切突变;家系2先证者KIT基因存在c.2401A＞C突变,结合3位表型正常的家系成员KIT基因未见c.2401A＞C突变,推测该突变为先证者患斑驳病的致病突变可能性大.为此两家系进行遗传咨询和产前诊断提供了理论依据.     

家族性Peutz-Jeghers综合征患者LKB1基因胚系突变的分析

目的 研究家族性Peutz-Jeghers综合征患者中LKB1基因胚系突变特征.方法 收集11个Peutz-Jeghers综合征家系,各家系先证者均有典型的黏膜黑斑以及肠道错构瘤性息肉.提取先证者外周血DNA,PCR扩增LKB1基因的9个外显子及其侧翼的部分内含子序列,测序并分析其变异情况和突变性质.收集250名正常人外周血并提取DNA,聚合酶链反应-变性高效液相色谱筛查验证.结果 11个家系先证者中有8例患者LKB1基因外显子及侧翼碱基序列存在杂合性变异,变异类型共9种,包括7种点突变,1种外显子区域小片段碱基缺失以及1种侧翼内含子小片段碱基插入.其中4种考虑为病理性突变,还有4种仅为基因多态性表现,另外有1种变异性质未定.结论 LKB1基因病理性突变是中国人家族性Peutz-Jeghers综合征患者的常见病因,且以点突变为主.     

散发型Ⅰ型神经纤维瘤的基因突变鉴定与家系分析

目的对一例先证者为Ⅰ型神经纤维瘤病的患儿进行基因突变鉴定与家系研究。方法采用高通量测序技术对NF1基因进行点突变和基因拷贝数检测,应用MLPA技术对患者NF1、NF2基因进行大片段变异研究,采用STR连锁分析对先证者及其父母进行亲缘关系鉴定,对其父母进行体格检查和表型分析,采用Sanger测序方法对高通量测序点突变进行先证者和家系验证。结果高通量测序检出患者NF1基因致病变异c.1013AG,该突变为已报道的Ⅰ型神经纤维瘤致病突变,其生物学父母未见神经纤维瘤表型且无上述突变。结论该神经纤维瘤患儿是由NF1新发突变所致,高通量测序技术对检测致病基因含较多外显子的遗传性疾病具有显著优势。     

中国人遗传性非息肉病性结直肠癌错配修复基因大片段缺失研究

目的了解中国人遗传性非息肉病性结直肠癌(hereditary nonpolyposis colorectal cancer．HNPCC)家系中MSH和MLH1基因大片段缺失情况及特点，以进一步完善中国人HNPCC家系遗传检测内容。方法取14个符合中国人HNPCC诊断标准的HNPCC家系肿瘤先证者外周血DNA，用荧光标记多重PCR技术结合GeneScan分析系统检测MSH2和MLH1基因大片段缺失。结果14例患者中有1例检测到MSH2基因第1～7外显子缺失，该家系另1例大肠癌患者和3个家系成员有同样的基因片段缺失。结论中国人HNPCC家系错配修复基因大片段缺失可能以MSH2比较常见。建议在中国人HNPCC家系遗传检测中常规包含错配修复基因大片段缺失检测。     

中国皖南地区家族性肥厚型心肌病MYH7基因筛查结果及临床特征

目的研究皖南地区汉族人群家族性肥厚型心肌病（HCM）的致病基因β肌球蛋白重链（MYH7）突变,并分析基因型与表型的关系。方法对4个HCM家系先证者的MYH7基因,经PCR扩增其外显子片段,用双脱氧末端终止法测序做突变初筛,对阳性结果患者进行家系调查,分析其临床表型。结果在MYH7基因18外显子中发现其中一家系中患者发现Arg663His突变,另一家系患者发现nt2013c缺失、nt2025C插入,此为一国内罕见移码突变。结论MYH7基因可能是皖南地区HCM较常见致病相关基因之一,其某些突变可在同一家系内遗传并致病,所致HCM临床症状较轻,症状出现较晚、进展较慢。同一突变携带者的临床表型存在异质性提示多因素参与了HCM的发生和发展。     

两个X连锁少汗性外胚层发育不良家系的基因突变分析

目的 对两个X连锁隐性遗传少汗性外胚层发育不良(X-linked hypohidrotic ectodermal dysplasia,XLHED)家系进行ED1基因突变分析,为罹患家庭提供遗传咨询及产前诊断.方法 综合应用序列分析及多重连接依赖性探针扩增方法,对两个家系的先证者进行ED1基因突变分析,并针对检测到的突变位点对女性成员进行检测.采集家系1胎儿的羊水细胞进行产前诊断,包括致病突变位点的分析、ED1基因内4个短串联重复序列(short tandem repeat,STR)位点的单倍型连锁分析、性别鉴定及核型分析.结果 家系1先证者缺失ED1基因第1外显子及下游2个STR位点DXS8269,DXS1422区域,其余外显子序列分析未见异常,其女儿为该缺失突变的携带者;结合连锁分析、性别鉴定及核型分析结果,家系1胎儿为男性非ED1基因缺失突变携带者,胎儿足月分娩后随访,为健康个体.家系2先证者经序列分析检测到ED1基因第3外显子c.463C＞T(R155C)错义突变,母亲为c.463C＞T(R155C)杂合突变携带者.结论 ED1基因第1外显子区域缺失和错义突变R155C是导致2个少汗性外胚层发育不全家系患者临床表型的主要原因,ED1基因的突变检测结合单倍型分析,能准确地对该类家系提供产前诊断.     

三个Fabry病家系GLA基因突变与临床表型

目的 分析3个Fabry病家系GLA基因突变及其与临床表型的关系.方法 应用PCR结合DNA测序技术,检测先证者及相关成员GLA基因编码序列与剪切位点DNA序列变异,分析致病性突变与临床表型关系.结果 在家系1先证者GLA基因第5外显子中发现1个未经报道的错义突变c.797A＞C(D266A),家系2先证者GLA基因第5外显子中发现1个错义突变c.644A＞G(N215S),家系3先证者GLA基因第2外显子中发现1个无义突变c.355C＞T(Ql19X).家系1与家系3先证者主要表现为皮肤损害和慢性肾功能不全,家系2先证者临床则以肥厚性心肌病为特点.结论 首次发现的GLA基因c.797A＞C(D266A)突变是第266位密码子第6个被证实的错义突变,已报道的另5种突变均有致病性,在正常非相关对照中未发现该突变,提示GLA基因c.797A＞C突变很可能是该家系的致病原因.N215S和Q119X系首次发现于中国Fabry病家系的突变.GLA基因不同位点的突变具有较为显著的表型差异.     

GJB2基因p.V37I突变致病性及家系临床表型分析

目的探讨GJB2基因突变耳聋家系p.V37I(c.109GA)突变致病性及分析家系患者临床表型。方法收集6个GJB2基因p.V37I(c.109GA)突变耳聋患者及家系的临床资料及外周血样本,运用PCR产物直接测序技术对家系耳聋患者进行GJB2、GJB3基因编码区、SLC26A4基因外显子7和8、以及线粒体m.1494CT、m.1555AG位点检测分析,另对家系5先证者行高通量全外显子序列检测。结果 6个家系均检出GJB2基因p.V37I突变,其中家系3、5为纯合突变,家系1、2、6先证者另复合GJB2基因c.235del C杂合突变,家系4患者另检出c.299-300del AT杂合突变;全部家系均未检出GJB3基因编码区、SLC26A4基因外显子7和8、以及线粒体m.1494CT、m.1555AG位点突变,家系5先证者高通量全外显子序列检测结果亦提示GJB2基因p.V37I纯合突变为其致聋原因。结论 GJB2基因p.V37I突变具有一定致病性,该位点纯合突变可导致轻度至中度听力损失,而p.V37I突变复合c.299-300del AT、c.235del C杂合突变可导致中度至重度感音神经性耳聋。     

Germline mutations of the VHL gene in seven Chinese families with von Hippel-Lindau disease

Von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome caused by mutations or deletions within the VHL tumor-suppressor gene, but VHL germline mutations in the Chinese have rarely been studied. To investigate the genetic profile of VHL mutations in the Chinese population, we evaluated the clinical characteristics of seven Chinese families suffering from VHL disease and determined the particular germline mutations in their VHL genes. Direct sequencing and real-time quantitative PCR was carried out. Disease-associated genetic abnormalities were identified in all of the seven families examined. Two novel intragenic germline mutations (645 G insertion and 417 G deletion) were identified and are reported for the first time. Partial VHL gene deletions in exon 1 were found in two of the seven families. Three clinically asymptomatic mutation carriers were also identified. The spectrum of VHL gene abnormalities in our group is distinct from that observed in North America, Europe and Japan. These mutations are also different from those previously identified in other Chinese VHL patients. Future meta-analysis will provide greater perspective on the Chinese VHL genetic profile. VHL gene screening can play a key role in identifying asymptomatic patients who are carriers of VHL-predisposing genetic abnormalities.     

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

Von Hippel-Lindau (VHL) disease is an autosomal dominant familial cancer syndrome caused by germline mutations in VHL tumor suppressor gene. It is characterized by hemangioblastoma in central nervous system and retina, renal cell carcinoma or cyst, pheochromocytoma, pancreatic cyst and tumor, endolymphatic-sac tumor, and papillary cystadenoma in epididymis and broad ligament. Here, we used PCR-direct sequencing and universal primer quantitative fluorescent multiplex PCR (UPQFM-PCR) to detect VHL mutations in 16 patients clinically diagnosed with VHL disease. PCR-direct sequencing detected 12 germline mutations (75%, 12/16), in which a novel mutation of c.451A>T/p.Ile151Phe found in one proband had not been reported previously. UPQFM-PCR found two large deletions (12.5%, 2/16). The two remaining patients carried non-typical disease-causing mutations, including one silent mutation (c.481C>A/p.Arg161Arg) and one mutation in 3'-UTR (c.642+70C>A). Remarkably, 56.3% (9/16) probands did not have family history of VHL disease, suggesting the higher frequency of de novo mutations in Chinese patients. We also summarized Chinese VHL disease patients with VHL mutation findings published in the literature to provide information about the spectrum of VHL mutations in Chinese VHL disease patients.     

Rapid detection of VHL exon deletions using real-time quantitative PCR

Various types of mutations exist that exert an effect on the normal function of a gene. Among these, exon/gene deletions often remain unnoticed in initial mutation screening. Until recently, no fast and efficient methods were available to detect this type of mutation. Molecular detection methods for gene copy number changes included Southern blot (SB) and fluorescence in situ hybridisation, both with their own intrinsic limitations. In this paper, we report the development and application of a fast, sensitive and high-resolution method for the detection of single exon or larger deletions in the VHL gene based on real-time quantitative PCR (Q-PCR). These deletions account for approximately one-fifth of all patients with the von Hippel-Lindau syndrome, a dominantly inherited highly penetrant familial cancer syndrome predisposing to specific malignancies including phaeochromocytomas and haemangioblastomas. Our VHL exon quantification strategy is based on SYBR Green I detection and normalisation using two reference genes with a normal copy number, that is, ZNF80 (3q13.31) and GPR15 (3q12.1). Choice of primer sequences and the use of two reference genes appears to be critical for accurate discrimination between 1 and 2 exon copies. In a blind Q-PCR study of 29 samples, all 14 deletions were detected, which is in perfect agreement with previously determined SB results. We propose Q-PCR as the method of choice for fast (within 3.5 h), accurate and sensitive (ng amount of input DNA) exon deletion screening in routine DNA diagnosis of VHL disease. Similar assays can be designed for deletion screening in other genetic disorders.     

Solid renal tumor severity in von Hippel Lindau disease is related to germline deletion length and location

von Hippel Lindau disease (VHL) is an autosomal dominant familial cancer syndrome linked to alteration of the VHL tumor suppressor gene. Affected patients are predisposed to develop pheochromocytomas and cystic and solid tumors of the kidney, CNS, pancreas, retina, and epididymis. However, organ involvement varies considerably among families and has been shown to correlate with the underlying germline alteration. Clinically, we observed a paradoxically lower prevalence of renal cell carcinoma (RCC) in patients with complete germline deletion of VHL. To determine if a relationship existed between the type of VHL deletion and disease, we retrospectively evaluated 123 patients from 55 families with large germline VHL deletions, including 42 intragenic partial deletions and 13 complete VHL deletions, by history and radiographic imaging. Each individual and family was scored for cystic or solid involvement of CNS, pancreas, and kidney, and for pheochromocytoma. Germline deletions were mapped using a combination of fluorescent in situ hybridization (FISH) and quantitative Southern and Southern blot analysis. An age-adjusted comparison demonstrated a higher prevalence of RCC in patients with partial germline VHL deletions relative to complete deletions (48.9 vs. 22.6%, p=0.007). This striking phenotypic dichotomy was not seen for cystic renal lesions or for CNS (p=0.22), pancreas (p=0.72), or pheochromocytoma (p=0.34). Deletion mapping revealed that development of RCC had an even greater correlation with retention of HSPC300 (C3orf10), located within the 30-kb region of chromosome 3p, immediately telomeric to VHL (52.3 vs. 18.9%, p <0.001), suggesting the presence of a neighboring gene or genes critical to the development and maintenance of RCC. Careful correlation of genotypic data with objective phenotypic measures will provide further insight into the mechanisms of tumor formation.     

Genotype-phenotype correlation in von Hippel-Lindau syndrome

The von Hippel-Lindau (VHL) syndrome (OMIM 193300) is an autosomal dominant disorder caused by deletions or mutations in a tumor suppressor gene on human chromosome 3p25. It is characterized clinically by vascular tumors including benign hemangioblastomas of the cerebellum, spine, brain stem and retina. Clear-cell renal cell carcinoma is a frequent cause of death, occurring in up to 70% of patients with VHL. Pheochromocytomas occur in association with specific alleles (usually mutations as opposed to deletions), therefore a family history of pheochromocytoma in association with VHL is an indication for thorough surveillance for pheochromocytoma in affected family members.The VHL gene coding sequence contains three exons. Two isoforms of mRNA exist, reflecting the presence or absence of exon 2. Tumors arise following the loss or inactivation of the wild-type allele in a cell. In initial studies approximately 20% of patients had large germline mutations detectable by Southern blot analysis, 27% had missense mutations and 27% had nonsense or frameshift mutations. Advances in mutation analysis now allow for a 100% mutation detection rate in families with definite VHL. Families may be characterized by the presence [type 2 (7-20% of families)] or absence (type 1) of pheochromocytomas. Most type 2 families are affected by missense mutations, whereas most type 1 families have deletions or premature termination mutations. The prognosis for the lifetime risk of pheochromocytoma can be estimated by determination of the underlying mutation even if there is no family history of VHL.     

Germline mutations in the von Hippel–Lindau disease tumor suppressor gene: Correlations with phenotype

Von Hippel-Lindau disease (VHL) is an inherited neoplastic disease characterized by a predisposition to develop retinal angiomas, central nervous system hemangioblastomas, renal cell carcinomas, pancreatie cysts, and pheochromocytomas. The VHL gene was recently isolated by positional cloning. The cDNA encodes 852 nucleotides in 3 exons. The VHL gene is unrelated to any known gene families. We identified germline mutations in 85/114 (75%) of VHL families. Clinical heterogeneity is a well-known feature of VHL. VHL families were classified into 2 types based on the presence or absence of pheochromocytoma. The types of mutations responsible for VHL without pheochromocytoma (VHL type 1) differed from those responsible for VHL with pheochromocytoma (VHL type 2). Fifty-six % of the mutations responsible for VHL type l were microdeletions/insertions, nonsense mutations, or deletions; 96% of the mutations responsible for VHL type 2 were missense mutations. Specific mutations in codon 238 accounted for 43% of the mutations responsible for VHL type 2. The mutations identified in these families will be useful in presymptomatic diagnosis. The identification of mutations associated with phenotypes contributes to the understanding of fundamental genetic mechanisms of VHL disease. © 1995 Wiley-Liss, Inc.     

Somatic mosaicism in von Hippel-Lindau Disease

von Hippel-Lindau (VHL) disease is an autosomal dominant familial cancer syndrome predisposing to the development of retinal and central nervous system haemangioblastomas, pheochromocytomas, renal and pancreatic cancer. In the course of a molecular analysis conducted to detect germline mutations of this gene in von Hippel-Lindau patients and individuals affected by sporadic tumors, we have identified a case of somatic mosaicism in the asymptomatic mother of a VHL patient who was subsequently diagnosed with pheochromocytoma. This is the first report providing molecular evidence of somatic mosaicism in von Hippel-Lindau disease. Mosaicism could provide some genetic explanation for the clinical heterogeneity and variable severity of the VHL phenotype, and should be considered, as a possible event when evaluating sporadic cases of VHL or patients with isolated VHL-related tumors. Hum Mutat 15:114, 2000.     

Phenotypic expression in von Hippel-Lindau disease: correlations with germline VHL gene mutations.

Von Hippel-Lindau disease is an autosomal dominantly inherited familial cancer syndrome predisposing to retinal and central nervous system haemangioblastomas, renal cell carcinoma, and phaeochromocytoma. VHL disease shows variable expression and interfamilial differences in predisposition to phaeochromocytoma. In a previous study of 65 VHL kindreds with defined VHL mutations we detected significant differences between VHL families with and without phaeochromocytoma such that missense mutations were more common and large deletions or protein truncating mutations less frequent in phaeochromocytoma positive families. To investigate the significance and cause of this association further, we studied 138 VHL kindreds for germline mutations and calculated the age related tumour risks for different classes of VHL gene mutations. Using SSCP, heteroduplex and Southern analysis we identified a germline VHL gene mutation in 101 families (73%). Direct sequencing of the VHL coding region further increased the mutation detection rate to 81%. In addition to precise presymptomatic diagnosis, identification of a VHL gene mutation can provide an indication of the likely phenotype. We found that large deletions and mutations predicted to cause a truncated protein were associated with a lower risk of phaeochromocytoma (6% and 9% at 30 and 50 years, respectively) than missense mutations (40% and 59%, respectively) and that missense mutations at codon 167 were associated with a high risk of phaeochromocytoma (53% and 82% at ages 30 and 50 years). Cumulative probabilities of renal cell carcinoma did not differ between the two groups (deletion/ truncation mutations: 8% and 60%, and missense mutations: 10% and 64% at ages 30 and 50 years, respectively). Age related risks for haemangioblastoma were similar in the two mutation groups, with the age related risks of cerebellar haemangioblastoma slightly less (35% and 64% v 38% and 75% at ages 30 and 50 years) and retinal haemangioblastoma slightly higher (45% and 72% v 37% and 64% at ages 30 and 50 years) in the missense mutation group than in the deletion/protein truncation group. These results provide valuable data for counselling VHL families and indicate that specific VHL mutations may be associated with different tumour susceptibility risks. There was no evidence of a generalised increase in age related tumour risks for missense mutations, suggesting that missense mutations predisposing to phaeochromocytoma have tissue specific effects, possibly because the VHL protein has several functions, the importance of which varies from tissue to tissue, or because the proteins which interact with VHL differ between different tissues.     

Identification of 3 novel VHL germ-line mutations in Danish VHL patients

ABSTRACT: BACKGROUND: von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome in which the patients develop retinal and central nervous system hemangioblastomas, pheochromocytomas and clear-cell renal tumors. The autosomal dominant disease is caused by mutations in the VHL gene. METHODS: VHL mutational analysis was carried out by sequencing of the coding sequence and by multiplex ligation-dependent probe amplification analysis. The functional consequence of the variants was investigated using in silico prediction tools. RESULTS: A total of 289 probands suspected of having VHL syndrome have been screened for mutations in the VHL gene. Twenty-six different VHL mutations were identified in 36 families including one in-frame duplication, two frame-shift mutations, four nonsense mutations, twelve missense mutations, three intronic mutations and four large genomic rearrangements. Three of these mutations (c.319 C > T, c.342_343dupGGT and c.520_521dupAA) were novel. CONCLUSIONS: In this study we report the VHL germ-line mutations found in Danish families. We found three novel VHL mutations where two were classified as pathogenic and the latter was classified as a variant of unknown significance. Together, our findings contribute to the interpretation of the potential pathogenicity of VHL germ-line mutations.     

Von Hippel-Lindau Syndrome

After a decade of intensive clinical and molecular genetic efforts the von Hippel-Lindau (VHL) gene was cloned in 1993. The open reading frame encodes the putative protein of 284 amino acids. A large number of different mutations have been identified so far, including single base mutations, deletions, rearrangements and more complex mutations. So far, in about 75% of the VHL families germline mutations were detected. Geno-phenotypic comparision has revealed specific mutations with distinct manifestation patterns. Not all of the 6 classical lesions (hemangioblastoma of the CNS, retinal angiomatosis, pancreatic cysts, renal cysts and carcinoma, pheochromocytoma and epididymal cystadenoma) are present in VHL families. Pedigrees with pheochromocytoma but without renal cancer in general have point mutations. These recent results provide insight in the pathogenesis of a multiorgan cancer susceptibility tumor suppressor gene and allow determination of carrier status.