Germline mutations in the von Hippel–Lindau gene in Italian patients

von Hippel–Lindau syndrome (VHL) is a dominantly inherited familial cancer syndrome predisposing to a variety of malignant and benign tumours, most frequently retinal, cerebellar, and spinal hemangioblastoma, renal cell carcinoma, pheochromocytoma, and pancreatic tumours.The current study investigated the occurrence of VHL mutations in Italian patients with classic VHL disease or with atypical VHL-like clinical features referred to the Service of Medical Genetics for VHL molecular diagnosis. In addition, an RQ-PCR protocol was validated in order to introduce it in the routine VHL laboratory diagnosis.     

Allelic Deletion of VHL Gene Detected in Papillary Tumors of the Broad Ligament, Epididymis, and Retroperitoneum in von Hippel-Lindau Disease Patients

Although clinically associated with von Hippel-Lindau (VHL) disease, the pathogenesis of papillary tumors of the broad ligament, epididymis, and peritoneum arising in patients with VHL disease is not clear. The "classic" VHL-associated neoplasms, including hemangioblastoma and renal ceil carcinoma, have been found to be associated with the inactivation of both VHL gene copies. It is not known whether a similar inactivation of the VHL gene is also responsible for the development of these uncommon VHL-associated lesions. The authors performed PCR (polymerase chain reaction) and PCR-based SSCP (single-strand conformation polymorphism) analysis on five predominantly papillary tumors in five VHL patients (one papillary cystadenoma of the broad ligament, one endometrioid cystadenoma of the broad ligament, two papillary cystadenomas of the epididymis, one papillary tumor of the retroperitoneum) with four polymorphic markers of VHL gene (D3S1038, D3S1110, D3S2452, 104/105). All five tumors showed allelic loss of VHL gene. The results provide the first genetic evidence for the role of VHL gene in the tumorigenesis of these rare benign neoplasms and confirm these tumors as phenotypic manifestations of VHL disease. Int J Surg Pathol 8(3):207-212, 2000     

Somatic mutations of the von Hippel -- Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma

Loss of heterozygosity (LOH) studies have suggested that somaticmutations of a tumour suppressor gene or genes on chromosome3p are a critical event In the pathogenesls of non-familialrenal cell carcinoma (RCC). Germllne mutations of the von Hippel— Lindau (VHL) disease gene predispose to early onsetand multifocal clear cell renal cell carcinoma, and the mechanismof tumorigenesls In VHL disease is consistent with a one-hitmutation model. To Investigate the role of somatic VHL genemutations in non-familial RCC, we analysed 99 primary RCC forVHL gene mutations by SSCP and heteroduplex analysis. SomaticVHL gene mutations were Identified In 30 of 65 (46%) sporadicRCC with chromosome 3p allele loss and one of 34 (3%) tumourswith no LOH for chromosome 3p. The VHL gene mutations were heterogeneous(17 frameshift deletions, eight missense mutations, four frameshiftinsertions, one nonsense and one splice site mutation), butno mutations were detected in the first 120 codons of clonedcoding sequence. Most RCCs with somatic VHL mutations (23 of27 (85%) informative cases) had chromosome 3p25 allele lossin the region of the VHL gene so that both alleles of the VHLgene had been inactivated as expected from a two–hit modelof tumorigenesis. Detailed histopathology was available for59 of the tumours investigated: 18 of 43 (42%) RCC with a clearcell appearance had a somatic VHL gene mutation but none of16 non–clear cell RCC (eight chromophilic, three chromophobeand five oncocytoma) (x²= 7.77, P<0.025). These results suggestthat somatic mutations of the VHL gene are a critical eventin the pathogenesis of non-familial clear cell renal carcinoma,but do not exclude a role for other chromosome 3p tumour suppressorgenes.     

Ovarian steroid cell tumor associated with von Hippel-Lindau syndrome: a report of two cases and literature review

Steroid cell tumor (SCT) is a rare sex cord-stromal tumor accounting for only 0.1% of ovarian tumors. Steroid cell tumor, not otherwise specified (SCT, NOS) is of uncertain lineage and is the most common among the three subtypes of SCT. Patients often present with endocrine abnormalities. Von Hippel-Lindau (VHL) syndrome is an autosomal dominant disorder resulting from inactivating gene deletions, frameshifts, and missense mutations of the VHL gene. VHL syndrome can involve multiple organs and clinically is subclassified into type 1 and type 2 based on the risk of pheochromocytoma (PCC). The association of VHL syndrome with genital tract tumors is rare, and here we report two cases of SCT, NOS in patients with VHL disease. The first case is a 19-year old female with VHL and prior resection of bilateral cerebellar hemangioblastomas. During the radiological surveillance, she was found to have multiple small enhancing foci in the cerebellar hemispheres and a stable small enhancing focus in the T6 cord with associated edema, likely reflecting a small hemangioblastoma. She had long history of irregular menses and ultrasound of pelvis found a large right ovarian mass. Cystectomy specimen showed a 6.4 cm well-circumscribed lesion with yellow cut surface. Histologic examination and immunohistochemical staining confirmed the diagnosis of SCT, NOS. The second patient is a 39-year-old female with VHL, previous surgery for retinal hemangioblastomatosis and cerebellar hemangioblastoma, history of abnormal uterine bleeding and elevated testosterone. CT of abdomen and pelvis revealed bilateral multiple cystic and solid renal lesions and a large left ovarian complex cyst. Bilateral partial nephrectomy showed multiple renal cysts and clear cell renal cell carcinomas (RCCs). Left salpingo-oophorectomy showed a 7 cm lesion with yellow-orange cut surface and features consistent with SCT, NOS. Review of the previously reported VHL SCT cases (not including the current two cases) indicated a probable link between VHL syndrome and SCT.     

Mutational analysis of the von hippel lindau gene in clear cell renal carcinomas from tuberous sclerosis complex patients.

Tuberous sclerosis complex (TSC) is an autosomal-dominant disorder characterized by seizures, mental retardation, autism, and tumors of multiple organs. Renal disease in TSC includes angiomyolipomas, cysts, and renal cell carcinomas. It is known that somatic mutations in the von Hippel Lindau (VHL) tumor suppressor gene occur in most clear cell renal carcinomas. To determine whether TSC-associated clear cell carcinomas also contain VHL mutations, we analyzed six tumors for loss of heterozygosity in the VHL gene region of chromosome 3p and for mutations in the VHL gene. Four of the patients were women between the ages of 34 and 68 years, and two were males under the age of 21 years. The loss of heterozygosity analysis was performed using polymorphic microsatellite markers, and the mutational analysis was performed using direct sequencing. Chromosome 3p loss of heterozygosity was not detected, and no VHL mutations were identified. These findings suggest that mutations in the TSC1 and TSC2 genes lead to clear cell renal carcinogenesis via an alternate pathway not involving VHL mutations.     

An analysis of five clear cell papillary cystadenomas of mesosalpinx and broad ligament: four associated with von Hippel-Lindau disease and one aggressive sporadic type

Nogales F F, Goyenaga P, Preda O, Nicolae A, Vieites B, Ruiz‐Marcellan M C, Pedrosa A & Merino M J
(2012) Histopathology  60, 748–757
An analysis of five clear cell papillary cystadenomas of mesosalpinx and broad ligament: four associated with von Hippel‐Lindau disease and one aggressive sporadic type Aims: Clear cell papillary cystadenoma (CCPC) is associated with von Hippel‐Lindau disease (VHLD), but rarely involves mesosalpinx and broad ligament (M/BL). This study provides new data about its behaviour and immunophenotype. Methods and results: We performed an analysis of four benign cases of CCPC of M/BL with either characteristic clinical features or genetic markers [loss of heterozygosity (LOH)] of VHLD in patients ranging from 24 to 36 years and a sporadic case in a 52‐year‐old presenting with peritoneal metastases. All CCPCs were papillary but had solid and tubular areas. Haemorrhage, thrombosis and scarring were constant features and related to an unusual pattern of sub‐epithelial vascularity. All clear or oxyphilic cells co‐expressed cytokeratin 7 (CK7), CAM5.2 and vimentin, with strong apical CD10 and nuclear paired box gene 2 (PAX2) immunoreactivity. Three cases also showed positivity for VHL40, epithelial membrane antigen (EMA), Wilms’ tumour suppressor gene (WT‐1) and cancer antigen 125 (CA125) but only one expressed renal cell carcinoma (RCC) antigen. Vascular plexus overexpressed nuclear and cytoplasmic WT‐1. Conclusion: The VHLD‐associated cases appeared to be benign, but the sporadic case exhibited a low malignant potential. CCPCs show histological and immunophenotypical similarities with the recently reported clear cell papillary RCC, although the previously unreported apical CD10 and nuclear PAX2 expression may be related to their mesonephric origin. CCPC has a distinctive sub‐epithelial vascular pattern that is consistent with its pathogenesis.     

VHL-deficient vasculogenesis in hemangioblastoma

Hemangioblasts are capable of differentiation into vascular structures and blood. Patients with von Hippel–Lindau (VHL) disease develop hemangioblastomas which are composed of VHL-deficient tumor cells with protracted hemangioblastic differentiation potential. In a subset of these tumors, hemangioblastic differentiation is characterized by different stages of red blood cell formation. It has remained controversial, however, whether VHL-deficient hemangioblastic cells are similarly capable of differentiating into vascular cells and functioning vascular structures in vivo.     

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。     

Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma

Von Hippel-Lindau (VHL) disease is a dominantly inherited disorder predisposing those afflicted to hemangioblastomas of the central nervous system and the retina, renal cell carcinomas, pheochromocytomas, and pancreatic tumors. The disease has been associated with mutations of the VHL gene. The screening of 92 unrelated patients with VHL disease for point mutations in this gene revealed 61 DNA variants. In addition, a search for EcoR1 rearrangements revealed germline anomalies in 5 patients. The 61 variants could be subdivided in 20 mutations predicted to alter the open reading frame (8 nonsense mutations, 8 frame shift mutations, and 4 mutations in consensus splicing sites) and 43 DNA sequence variants of a priori unknown biological consequence (4 in-frame insertions or deletions, 36 missense mutations, and 3 apparently silent variations). The 3′ end of the coding sequence of the VHL gene, which encodes the Elongin binding domain was the site of 5 of 20 truncating mutations (25%) and of 18 of 41 DNA variants (44%) causing uncertain functional impairment. A similar screening in 18 patients with sporadic hemangioblastoma revealed 2 missense DNA variants. In order to corroborate this latter observation, a systematic screening for germline alteration of the VHL gene might be performed in a larger series of sporadic hemangioblastoma. If this preliminary result is confirmed, more than 10% of sporadic hemangioblastoma might be related to a mild VHL disease, thus a follow-up program similar to that recommended in cases of VHL disease should probably be discussed in the corresponding families. Hum Mutat 12:424–430, 1998. © 1998 Wiley-Liss, Inc.     

青少年肾细胞癌的临床病理及分子遗传学研究

目的 探讨青少年肾细胞癌的临床病理特征、遗传学改变、鉴别诊断及预后.方法 对46例青少年肾细胞癌进行光镜观察及免疫组织化学染色,随访并复习相关文献.对46例肿瘤进行von Hippel-Lindau(VHL)基因区域杂合性缺失(LOH)及VHL基因突变筛查.结果 共诊断19例Xp11.2易位/TFE3基因融合相关性肾癌(Xp11 RCC)、9例透明细胞癌、17例乳头状肾细胞癌(PRCC)和1例不能分类肾细胞癌.19例Xp11 RCC均TFE3阳性,而TFEB阴性.8例肿瘤具有巢状和乳头状结构形态类似t(X;17)ASPL-TFE3型肾癌,6例肿瘤组织学类似t(X;1)PRCC-TFE3型肾癌,4例肿瘤形态像透明细胞癌,1例肿瘤组织学形态文献中未被检索到,表现为细胞核呈毛玻璃样,核仁不明显,可见核沟,肿瘤间质见大量黏液.LOH及VHL突变检测结果显示,仅1例透明细胞癌和1例2型PRCC存在LOH,并且该2型PRCC的VHL基因的一个剪切位点存在胚系突变,553+5 G→C.其余45例均未检测出VHL突变.统计学分析表明TFE3阳性肾细胞癌比TFE3阴性肾细胞癌更倾向于高病理分期(pT3/pT4),并且预后较差(P=0.035).结论 青少年肾细胞癌表现出不同的组织学形态以及分子遗传学背景.其中Xp11 RCC为最常见的肾癌亚型.TFE3阳性肾细胞癌的预后要差于TFE3阴性肾细胞癌.     

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.     

Renal tumors with clear cells. A review

The spectrum of primary renal tumors in which clear cells may appear is revisited in this review. The pathologist's viewpoint of this topic is pertinent because not all the tumors with clear cells are carcinomas and not all renal cell carcinomas with clear cells are clear cell renal cell carcinomas. In fact, some of them are distinct entities according to the new WHO classification. The morphological approach is combined with genetics. Renal cell carcinoma related to von Hippel–Lindau disease is reviewed first because many of the genetic disorders underlying this disease are also present in sporadic, conventional renal cell clear cell carcinomas. Subsequently, conventional renal cell clear cell carcinomas, familial, non von Hippel–Lindau-associated renal cell carcinomas, translocation carcinomas, hereditary papillary renal cell carcinomas, carcinomas associated to tuberous sclerosis and to Birt–Hogg–Dubé syndrome, chromophobe renal cell carcinomas, carcinomas associated with end-stage renal disease, and clear cell tubulopapillary carcinomas are reviewed. Finally, epithelioid angiomyolipoma is also considered in this review.     

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。     

Variable penetrance of familial pheochromocytoma associated with the von Hippel Lindau gene mutation,S68W

Von Hippel-Lindau disease (VHL) is an autosomal dominantly inherited disorder, characterised by the development of clear cell renal carcinomas, CNS hemangioblastomas, retinal angiomas, pancreatic tumors, pheochromocytomas and hepatic cysts. Recently a number of families with dominant familial pheochromocytoma as the only clinical manifestation have been reported to carry mutations in the VHL gene. We describe a family in which a novel VHL S68W mutation was segregating and carrier individuals manifested with variable penetrance of isolated pheochromocytomas. Investigation of this kindred confirmed that a mutation in the VHL gene could produce isolated pheochromocytomas as the only clinical feature and was variably penetrant. Hum Mutat 12:71, 1998. © 1998 Wiley-Liss, Inc.     

von Hippel-Lindau综合征及散发性中枢神经系统血管母细胞瘤的临床病理观察

目的 探讨von Hippel-Lindau(VHL)综合征及散发性中枢神经系统(CNS)血管母细胞瘤(HB)的临床病理特征、诊断及鉴别诊断、治疗及预后.方法 应用光镜、电镜及免疫组织化学EnVision法染色,对21例VHL综合征和63例散发性HB进行观察分析,分别获得18例和42例随访资料.结果 21例VHL综合征患者中除4例确诊外均漏诊.平均首诊年龄29.5岁,男11例,女10例.21例患者共发生87个CNS-HB,最多者13年新发12个.10例患者存在其他VHL相关病变:6例视网膜HB、4例胰腺肿瘤(内分泌肿瘤、微囊性腺瘤)、1例透明细胞性肾细胞癌、4例肾囊肿、1例内淋巴囊肿瘤.1例患者4年间发生5种VHL相关肿瘤.63例散发性HB,平均年龄43.0岁,男34例,女29例.随访18例VHL综合征中生存14例,病死4例,生存者中残障(失明、偏瘫)4例、再发11例.42例散发性HB,生存39例(92.9%),其中残障3例;病死3例(7.2%).病理学特征HB间质细胞胞质泡沫样,血管丰富.部分HB可见异形核瘤细胞.HB侵犯脑组织者32例,随访21例患者均生存.HB间质细胞阳性表达:波形蛋白、表皮生长因子受体(EGFR)、Inhibin α及D2-40,CD34及CD68均阴性,3例瘤细胞表达胶质纤维酸性蛋白(GFAP).30例行Ki-67免疫组织化学标记,Ki-67标记指数除7例为2%,2例为5%,余均为1%,随访22例患者均生存.结论 VHL综合征是一组多系统多发性良恶性肿瘤症候群,预后差,漏诊率高.CNS-HB多发于小脑.VHL相关性HB较散发性HB就诊年龄小10岁,易发生于脑干和脊髓.HB肿瘤中异形核细胞、Ki-67标记指数稍高及侵犯脑组织均与预后无关.VHL综合征患者终生存在新发VHL相关肿瘤的可能,因此强调对确诊患者终生随访及定期全面检查,早期发现,早期治疗.     

Papillary cystadenoma of the epididymis. A report of three cases with lectin histochemistry.

Papillary cystadenoma of the epididymis is an uncommon benign tumor associated with von Hippel-Lindau disease. Since metastatic renal cell carcinoma may be histologically similar to papillary cystadenoma, and both are associated with von Hippel-Lindau disease, differentiation between these two entities may be difficult. We performed lectin histochemistry studies on three papillary cystadenomas and compared the results with the staining observed in epididymal ducts, epididymal efferent ductules, and three renal cell carcinomas. Common positive staining was observed following incubation with soybean agglutinin in epididymal ducts and two of the three papillary cystadenomas, while the three renal cell carcinomas did not stain. When epididymal tumors histologically consistent with papillary cystadenoma fail to react with soybean agglutinin, thorough clinical evaluation for an occult renal cell carcinoma should be performed.     

中国人von Hippel-Lindau病家系致病基因大片段缺失研究

目的 研究中国人von Hippel-Lindau病(von Hippel-Lindau syndrome,VHL)家系致病基因大片段缺失情况及其表型特点.方法 采用通用引物荧光定量PCR(universal primer quantitative fluorescent multiplex-polymerase chain reaction,UPQFM-PCR)技术结合GeneSean分析系统对新发现的20个VHL病家系的先证者及部分自愿者进行VHL基因胚系突变大片段缺失检测.结果 20例先证者中检测到VHL基因大片段缺失6例,其中第1外显子缺失3例、第3外显子缺失1例、VHL基因完全缺失2例.进一步检测其中2个家系其他患者和部分成员也存在与先证者相同的VHL基因缺失.2个VHL基因完全缺失的家系,其患者表现为中枢神经系统血管母细胞瘤和视网膜血管瘤但无肾癌表型.结论 中国汉族人VHL患者基因种系突变存在VHL基因大片段缺失;VHL病诊断应常规开展VHL基因大片段缺失检测;VHL基因完全缺失和中枢系统血管母细胞瘤和视网膜血管瘤可能存在一定关系并需进一步研究.     

A family with hydrocephalus as a complication of cerebellar hemangioblastoma: identification of Pro157Leu mutation in the VHL gene

Various mutations in the VHL gene on chromosome 3p25–26 are responsible for von Hippel-Lindau (VHL) syndrome. We report on a Japanese VHL family in which two of the three affected members developed acute occlusive hydrocephalus that necessitated emergency surgery for ventricular shunt or drainage. Direct sequencing and restriction fragment length polymorphism analysis identified a germline missense mutation, Proline-to-Leucine, caused by a C-to-T transition at the second nucleotide of codon 157. Received: September 1, 1999 / Accepted: September 22, 1999     

Cryptic von Hippel-Lindau disease: germline mutations in patients with haemangioblastoma only

OBJECTIVES— Central nervous system haemangioblastoma (HAB) is a major feature of von Hippel-Lindau (VHL) disease, and it is estimated that about 30% of HAB patients have VHL disease. Consequently, it is widely recommended that sporadic HAB patients are screened for clinical and radiological features of VHL disease because of the risk of multiple tumours. We investigated the frequency of VHL germline mutations in patients with HAB only with no clinical or radiological evidence of VHL disease to define the role of molecular genetic analysis in the management of such patients.
METHODS—Eighty four patients with a single HAB (23 Dutch, 61 UK) and four with multiple HAB (two Dutch, two UK) were studied by direct sequencing of the coding region and quantitative Southern blotting.
RESULTS—A VHL germline mutation was found in three of 69 (4.3%) single HAB patients aged 50 years or less (three of 84 (3.6%) total single HAB patients). A germline VHL mutation was detected in a 44 year old woman with a solitary cerebellar HAB, as well as in four clinically unaffected close relatives, and in two single HAB cases presenting at the ages of 29 and 36 years. Germline VHL mutations were detected in two of four cases with multiple HAB.
CONCLUSIONS—Early detection of VHL disease is important to reduce morbidity and mortality and therefore we recommend that, in addition to conventional clinical and radiological investigations, VHL gene mutation analysis should be offered to all HAB patients younger than 50 years. HAB patients aged >50 years will have a lower a priori risk of VHL disease and further data are required to evaluate the role of routine molecular genetic investigations in late onset HAB cases. The failure to detect germline VHL mutations in some patients with multiple HAB may indicate the presence of somatic mosaicism or additional HAB susceptibility genes.


Keywords: haemangioblastoma; von Hippel-Lindau disease; VHL; germline mutation