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NCI CANCERLIT^® Search: Von Hippel-Lindau Syndrome - January 2002

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National Cancer Institute^®
Ultima Vez Modificado: 1 de enero del 2002

Genetic disorders of endocrine neoplasia. Introduction..

von Hippel-Lindau disease: genetic and clinical observations.

Phaeochromocytoma associated with a de novo VHL mutation as form fruste of von Hippel-Lindau disease.

VHL c.505 T>C mutation confers a high age related penetrance but no increased overall mortality.

Suprasellar hemangioblastoma in a patient with von Hippel-Lindau disease confirmed by germline mutation study: case report and review of the

Role of disease-causing genes in sporadic pancreatic endocrine tumors: MEN1 and VHL.

Molecular pathogenesis of the von Hippel-Lindau hereditary cancer syndrome: implications for oxygen sensing.

The von Hippel-Lindau gene product inhibits renal cell apoptosis via Bcl-2-dependent pathways.

Selection of mutant CHO cells with constitutive activation of the HIF system and inactivation of the von Hippel-Lindau tumor suppressor.

Mutation of von Hippel-Lindau tumor suppressor gene in a sporadic endolymphatic sac tumor.

Molecular characterization and ophthalmic investigation of a large family with type 2A Von Hippel-Lindau Disease.

von Hippel-Lindau disease.

Fibrous meningioma in a patient with von Hippel-Lindau disease: a genetic analysis.

Variability in expression of common fragile sites: in search of a new criterion.

Clustering of features of von Hippel-Lindau syndrome: evidence for a complex genetic locus.

Molecular genetic investigations of the mechanism of tumourigenesis in von Hippel-Lindau disease: analysis of allele loss in VHL tumours.

[An underestimated hereditary disease. H. P. H. Neumann, Freiburg, on the significance of von Hippel-Lindau disease. Interview by Elisabeth B.

[Hippel-Lindau syndrome and sporadic renal cell carcinomas. Pathogenesis, morphologic spectrum and molecular genetics]

von Hippel-Lindau disease and familial polyposis coli in the same family.

von Hippel-Lindau disease.

Genetic analysis of 2 cases of clear cell renal cancer in 2 sisters.

[Hippel-Lindau disease]

[Genetic study of a new family with Hippel-Lindau type IIB disease]

A family with von Hippel-Lindau disease revealed by pheochromocytoma.

Characteristic chromosomal aberrations in sporadic cerebellar hemangioblastomas revealed by comparative genomic hybridization.

Tumor suppressor loss in pituitary tumors.

1
UI - 11443848
AU - Dahia PL; Eng C
TI - Genetic disorders of endocrine neoplasia. Introduction..
SO - Front Horm Res 2001;28():1-7

2
UI - 11443850
AU - Iliopoulos O
TI - von Hippel-Lindau disease: genetic and clinical observations.
SO - Front Horm Res 2001;28():131-66
AD - MGH Cancer Center, Harvard Medical School, Boston, Mass., USA. iliopoul@helix.mgh.harvard.edu

3
UI - 11475579
AU - Frenzel S; Apel TW; Heidemann PH; Zerres K; Neumann HP; Dorr HG
TI - Phaeochromocytoma associated with a de novo VHL mutation as form fruste of von Hippel-Lindau disease.
SO - Eur J Pediatr 2001 Jul;160(7):421-4
AD - Division of Paediatric Endocrinology, University Hospital for Children and Adolescents, Loschgestrasse 15, 91054 Erlangen, Germany. HGDoerr@kinder.imed.uni-erlangen.de
Phaeochromocytomas usually occur sporadically but may be associated with dominant inherited cancer syndromes such as multiple endocrine neoplasia type 2 (MEN 2), von Hippel-Lindau disease (VHL) and type 1 neurofibromatosis. We report on a boy presenting at age 8 years with an isolated benign phaeochromocytoma of the left adrenal. Three years later a second adrenal phaeochromocytoma was diagnosed on the right side and removed. His family history was negative. Genetic analysis did not show a mutation in the MEN 2 susceptible proto-oncogene rearranged during transfection; however, we found a germline missense mutation in the VHL gene (nucleotide 695 G to A transversion) which has been described only twice before in the literature. Both parents had normal (wild type) VHL copies indicating that our patient had a de novo germline VHL mutation. Careful clinical evaluation of the patient at 18 years did not reveal any other manifestations of VHL disease. CONCLUSION: Carriers of von Hippel-Lindau germline mutations can present with a form fruste of von Hippel-Lindau disease presenting initially with unilateral phaeochromocytoma and therefore mutation analysis should be carried out.

4
UI - 11483638
AU - Bender BU; Eng C; Olschewski M; Berger DP; Laubenberger J; Altehofer C;
TI - Kirste G; Orszagh M; van Velthoven V; Miosczka H; Schmidt D; Neumann HP VHL c.505 T>C mutation confers a high age related penetrance but no increased overall mortality.
SO - J Med Genet 2001 Aug;38(8):508-14
AD - Department of Nephrology and Hypertension, Albert-Ludwigs-University, Freiburg, Germany. bender@med1.ukl.uni-freiburg.de
BACKGROUND: Germline mutations of the VHL gene cause von Hippel-Lindau syndrome (VHL). In southern Germany, a specific mutation in this gene, c.505 T>C, is one of the most frequent alterations owing to a founder effect. METHODS: This study was conducted to evaluate morbidity, specific clinical risk profile, and mortality among a series of VHL c.505 T/C mutation carriers. A total of 125 eligible subjects carrying VHL c.505 T/C underwent ophthalmoscopy and gadolinium enhanced magnetic resonance imaging of the brain, the spinal cord, and the abdomen. Age related penetrance, morbidity, and mortality were assessed. RESULTS: Frequently observed lesions were phaeochromocytoma (47%), retinal angiomas (36%), haemangioblastoma of the spine (36%), and haemangioblastoma of the brain (16%). Four patients developed renal cell carcinoma. VHL was symptomatic in 47% of subjects; 30% were asymptomatic despite the presence of at least one VHL related tumour and 23% of the carriers had no detectable VHL lesion. Of the 19 patients who had died (15%), 10 died of symptomatic VHL lesions. Overall penetrance by cumulative incidence functions is estimated at 48% by 35 years and 88% by 70 years. In contrast to the only existing published report based on patients with presumably unselected VHL germline mutations, the mortality rate for c.505 T/C mutation carriers is comparable to that of the general population of Germany. CONCLUSIONS: Our results are an important example that a specific genotype, at least in the case of VHL c.505 T/C, can favourably impact on mortality despite a high age related penetrance. Our study also indirectly provides objective data which might be useful to the life and health insurance industry; it would appear that c.505 T>C mutation positive subjects have similar disease specific mortality to that of the general population owing to a combination of phenotype and timely detection of mutation carrier status followed by aggressive clinical screening and, if necessary, treatment.

5
UI - 11546565
AU - Goto T; Nishi T; Kunitoku N; Yamamoto K; Kitamura I; Takeshima H; Kochi
TI - M; Nakazato Y; Kuratsu J; Ushio Y Suprasellar hemangioblastoma in a patient with von Hippel-Lindau disease confirmed by germline mutation study: case report and review of the literature.
SO - Surg Neurol 2001 Jul;56(1):22-6
AD - Department of Neurosurgery, Kumamoto University School of Medicine, Kumamoto, Japan.
BACKGROUND: Hemangioblastoma (HBL) in the suprasellar region is extremely rare.CASE DESCRIPTION: A suprasellar mass was found in a 33-year-old woman with retinal HBL and bilateral adrenal pheochromocytomas. The diagnosis of von Hippel-Lindau (VHL) disease was confirmed preoperatively not only by these clinical manifestations but also by germline mutation study. The existence of VHL disease indicated a diagnosis of HBL for the suprasellar mass. The results of our mutation study indicated that this patient had type II VHL disease, suggesting that careful follow-up is essential for the early detection of renal cell carcinoma, which is often associated with type II VHL disease. Here, we summarize the previously reported features of sellar and suprasellar HBLs.CONCLUSIONS: HBLs in this region may be one manifestation of VHL disease. Genetic testing of the VHL gene of our patient could provide useful information to determine appropriate medical care and management.

6
UI - 11550286
AU - Moore PS; Missiaglia E; Antonello D; Zamo A; Zamboni G; Corleto V;
TI - Falconi M; Scarpa A Role of disease-causing genes in sporadic pancreatic endocrine tumors: MEN1 and VHL.
SO - Genes Chromosomes Cancer 2001 Oct;32(2):177-81
AD - Department of Pathology, Universita di Verona, Strada le Grazie 8, I-37134 Verona, Italy.
Pancreatic endocrine tumors (PETs) occur in association with multiple endocrine neoplasia type 1 (MEN1) and von Hippel-Lindau (VHL) syndromes caused by germline alterations in MEN1 and VHL, respectively. It is thus expected that these genes will also be altered in a proportion of sporadic PETs. Indeed, MEN1 is altered in about 25% of nonfamilial PETs, although no mutations have been found in VHL. For all clinical subtypes, the frequency of allelic loss on chromosome arm 11q mirrors observed mutational frequencies, with the exception of nonfunctional tumors (NF-PETs), in which mutations have been reported in only 8% of cases. As allelic loss on 11q is the most frequent event found in these neoplasms, this low frequency is somewhat puzzling, particularly in light of the fact that most MEN1-associated PETs are nonfunctioning. To clarify the role of these genes in sporadic PETs, we analyzed 31 sporadic NF-PETs, nine insulinomas, and one VIPoma for alterations in MEN1 and VHL. As somatic mutations were observed in eight (26%) of the NF tumors and in one insulinoma, it would therefore appear unlikely that an additional tumor suppressor gene related to sporadic PET pathogenesis is located on 11q. One insulinoma also had a somatic mutation in VHL, and thus this gene may also be altered in these neoplasms, albeit in a small proportion of cases. Copyright 2001 Wiley-Liss, Inc.

7
UI - 11571227
AU - Yang H; Kaelin WG Jr
TI - Molecular pathogenesis of the von Hippel-Lindau hereditary cancer syndrome: implications for oxygen sensing.
SO - Cell Growth Differ 2001 Sep;12(9):447-55
AD - Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

8
UI - 11514546
AU - Devarajan P; De Leon M; Talasazan F; Schoenfeld AR; Davidowitz EJ; Burk
TI - RD The von Hippel-Lindau gene product inhibits renal cell apoptosis via Bcl-2-dependent pathways.
SO - J Biol Chem 2001 Nov 2;276(44):40599-605
AD - Department of Pediatrics, Division of Pediatric Nephrology, Albert Einstein College of Medicine, Bronx, New York 10461, USA. pdevaraj@aecom.yu.edu
Previous studies have reported a protective role for the von Hippel-Lindau (VHL) gene products against pro-apoptotic cellular stresses, but the mechanisms remain unclear. In this study, we examined the role of VHL in renal cells subjected to chemical hypoxia, using four VHL-negative and two VHL-positive cell lines. VHL-negative renal carcinoma cells underwent apoptosis following chemical hypoxia (short-term glucose deprivation and antimycin treatment), as evidenced by morphologic changes and internucleosomal DNA cleavage. Reintroduction of VHL expression prevented this apoptosis. VHL-negative cells displayed a significant (greater than 5-fold) activation of caspase 9 and release of cytochrome c into the cytosol following chemical hypoxia. In contrast, VHL-positive cells showed minimal caspase 9 activation, and absence of cytochrome c release under the same conditions. Caspase 8 was only minimally activated in both VHL-negative and -positive cells. In addition, VHL-positive cells displayed a striking up-regulation of Bcl-2 expression (5-fold) following chemical hypoxia. Antisense oligonucleotides to Bcl-2 significantly down-regulated Bcl-2 protein expression in VHL-positive cells and rendered them sensitive to apoptosis. Overexpression of Bcl-2 in VHL-negative cells conferred resistance to apoptosis. Our results suggest that VHL protects renal cells from apoptosis via Bcl-2-dependent pathways.

9
UI - 11555645
AU - Vaux EC; Wood SM; Cockman ME; Nicholls LG; Yeates KM; Pugh CW; Maxwell
TI - PH; Ratcliffe PJ Selection of mutant CHO cells with constitutive activation of the HIF system and inactivation of the von Hippel-Lindau tumor suppressor.
SO - J Biol Chem 2001 Nov 23;276(47):44323-30
AD - Wellcome Trust Center for Human Genetics, The Henry Wellcome Building of Genomic Medicine, Roosevelt Dr., Oxford OX3 7BN, United Kingdom.
Hypoxia-inducible factor (HIF) mediates a widespread transcriptional response to hypoxia through binding to cis-acting DNA sequences termed hypoxia response elements (HREs). Activity of the transcriptional complex is suppressed in the presence of oxygen by processes that include the targeting of HIF-alpha subunits for ubiquitin-mediated proteolysis. To provide further insights into these processes we constructed Chinese hamster ovary (CHO) cells bearing stably integrated plasmids that expressed HRE-linked surface antigens and used these cells in genetic screens for mutants that demonstrated constitutive up-regulation of HRE activity. From mutagenized cultures, clones were isolated that demonstrated up-regulation of HRE activity and increased HIF-1alpha protein levels in normoxic culture. Transfection and cell fusion studies suggested that these cells possess recessive defects that affect one or more pathways involved in HIF-alpha proteolysis. Two lines were demonstrated to harbor truncating mutations in the von Hippel-Lindau (VHL) tumor suppressor gene. In these cells, defects in ubiquitylation of exogenous human HIF-1alpha in vitro could be complemented by wild type pVHL, and re-expression of a wild type VHL gene restored a normal pattern of HIF/HRE activity, demonstrating the critical dependence of HIF regulation on pVHL in CHO cells. In contrast, other mutant cells had no demonstrable mutation in the VHL gene, and ubiquitylated exogenous HIF-1alpha normally, suggesting that they contain defects at other points in the oxygen-regulated processing of HIF-alpha subunits.

10
UI - 11727270
AU - Hamazaki S; Yoshida M; Yao M; Nagashima Y; Taguchi K; Nakashima H; Okada
TI - S Mutation of von Hippel-Lindau tumor suppressor gene in a sporadic endolymphatic sac tumor.
SO - Hum Pathol 2001 Nov;32(11):1272-6
AD - Department of Pathology, Okayama University Hospital, Okayama, Japan.
Endolymphatic sac tumor (ELST) is a low-grade adenocarcinoma of the temporal bone that is presumed to originate from the endolymphatic system. Although ELSTs are extremely rare in the general population, a significant number of studies have documented the occurrence of ELST among patients with von Hippel-Lindau (VHL) disease. Because of the rarity of the tumor, however, few cases of ELST have been analyzed for mutations of the VHL tumor suppressor gene. In this study, we reported a Japanese male patient with sporadic ELST, along with a molecular genetic analysis of the VHL gene. The light microscopic and immunohistochemical features and clinical presentations were typical of ELST. Sequencing studies of the tumor DNA disclosed a G to T substitution of nucleotide 564, which resulted in an amino acid substitution (Trp to Cys). This is the first report of the VHL gene mutation in a sporadic Japanese case of ELST. Copyright 2001 by W.B. Saunders Company

11
UI - 11709017
AU - Allen RC; Webster AR; Sui R; Brown J; Taylor CM; Stone EM
TI - Molecular characterization and ophthalmic investigation of a large family with type 2A Von Hippel-Lindau Disease.
SO - Arch Ophthalmol 2001 Nov;119(11):1659-65
AD - Department of Ophthalmology and Visual Sciences, The University of Iowa Hospitals and Clinics, 200 Hawkins Dr, Iowa City, IA 52242, USA.
BACKGROUND: Von Hippel-Lindau (VHL) disease is a dominantly inherited cancer syndrome. Since the identification of the VHL gene, at least 3 clinical-genetic subtypes of the disease have been recognized. OBJECTIVES: To identify the specific abnormality in the VHL gene and to correlate it with the prevalence and severity of ocular involvement in a large family with VHL disease. METHODS: A longitudinal clinical study and DNA analysis of 24 family members. RESULTS: All 14 affected family members exhibited a thymine-to-cysteine change at nucleotide 505 (T505C) in exon 1 of the VHL gene, consistent with the clinical diagnosis of VHL disease subtype 2A. Two asymptomatic gene carriers were also identified. Seventy-five percent (12/16) of the gene carriers had 1 or more ocular angiomas. The mean number of ocular angiomas per gene carrier was 3.3. Six eyes had optic disc angioma. Five gene carriers (31%) had lost vision because of angiomatosis. Cerebellar hemangioblastomas were present in 4 patients (25%) and pheochromocytomas in 11 (69%). No patient was found to have a renal cell carcinoma. CONCLUSIONS: The family shows a low susceptibility to renal carcinoma consistent with the clinical diagnosis of VHL disease type 2A. The prevalence and severity of ocular angiomatosis in this subtype do not significantly differ from those of the other more common subtypes of VHL. Recognition of the VHL disease 2A phenotype suggests the presence of a specific mutation (T505C) in the VHL gene. Confirmation of this genotype increases the clinician's ability to provide favorable prognostic information to affected family members.

12
UI - 11698746
AU - Gauthier D; D'Amico DJ; Mukai S
TI - von Hippel-Lindau disease.
SO - Int Ophthalmol Clin 2001 Fall;41(4):173-87
AD - Massachusetts Eye and Ear Infirmary, Boston 02114, USA.

13
UI - 11765821
AU - Governale LS; Vortmeyer AO; Zhuang Z; Oldfield EH
TI - Fibrous meningioma in a patient with von Hippel-Lindau disease: a genetic analysis.
SO - J Neurosurg 2001 Dec;95(6):1045-9
AD - Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
Meningioma has been included in the constellation of tumors associated with von Hippel-Lindau (VHL) disease in previously published reports. It is unclear whether these tumors are an uncommon component of VHL disease or are more readily detected in these patients because of the frequency with which they undergo central nervous system imaging as part of the routine management of VHL disease. The authors report the case of a patient with VHL disease in whom a progressively enlarging supratentorial mass developed and was diagnosed as a hemangioblastoma because of its appearance on serial magnetic resonance images. At surgery the tumor displayed the typical features of a meningioma and was given the histological diagnosis of fibrous meningioma. Single-stranded conformational polymorphism analysis of the tumor DNA revealed a loss of heterozygosity at the neurofibromatosis Type 2 gene locus, known to be associated with sporadically occurring meningiomas. Despite this finding, the VHL gene locus on the allele from the patient's unaffected parent was normal. Thus it is unlikely that the occurrence of this patient's fibrous meningioma was associated with underlying VHL disease. Given the high frequency of neuroimaging sessions in patients with VHL disease, some supratentorial lesions that have been given radiological diagnoses of hemangioblastomas may be incidental meningiomas.

14
UI - 2227930
AU - Jordan DK; Burns TL; Divelbiss JE; Woolson RF; Patil SR
TI - Variability in expression of common fragile sites: in search of a new criterion.
SO - Hum Genet 1990 Oct;85(5):462-6
AD - Department of Pediatrics, University of Iowa College of Medicine, Iowa City 52242.
Fragile sites are nonrandom, heritable sites on chromosomes that can be induced to form gaps, breaks, and rearrangements under specific conditions. There is currently no established criterion to define a common fragile site. We applied seven published criteria to our data from three groups of subjects: (1) three pairs of like-sexed twins, (2) four unaffected von Hippel-Lindau (VHL) family members, and (3) six patients affected with VHL disease. Substantial differences were present in the numbers of sites considered positive by these criteria. While some of this variability can be attributed to technical factors, our data illustrate the problems in comparing results from different studies to assess the significance of fragile sites. A recently published criterion is based upon the Poisson distribution. We found this criterion to be flawed in its presentation, and furthermore, the Poisson distribution did not provide an adequate approximation to our data. We propose here an alternative approach based upon the negative binomial distribution.

15
UI - 1673491
AU - Neumann HP; Wiestler OD
TI - Clustering of features of von Hippel-Lindau syndrome: evidence for a complex genetic locus.
SO - Lancet 1991 May 4;337(8749):1052-4
AD - Department of Medicine, Albert-Ludwigs-Universitat, Freiburg, Germany.
von Hippel-Lindau syndrome (HLS), an autosomal-dominant inherited disease, was studied in 92 affected subjects from 29 kindreds. In an initial survey to identify HLS gene carriers, all patients treated at the University of Freiburg for angiomatosis retinae (22), haemangioblastoma of the central nervous system (CNS) (63), and phaeochromocytoma (54) were examined as potential HLS gene carriers. HLS was diagnosed in 86% of the patients with angiomatosis retinae, 19% of the patients with haemangioblastoma of the CNS, and 19% of the patients with phaeochromocytoma. Based on these and on an additional 49 newly diagnosed cases (24 by clinical examination and 25 by pedigree analysis), the calculated prevalence of the disease in the district of Freiburg, Germany, with a population of 1.909 million is 1/38 951. There was a striking tendency for familial clustering of HLS features in affected kindreds. Both angiomatosis retinae and haemangioblastoma of the CNS occurred in most families, whereas renal lesions and/or pancreatic cysts and phaeochromatocytoma were mutually exclusive. This finding suggests that HLS is caused by different mutations within a complex genetic locus, or additional genetic lesions, which cooperate with the HLS gene on chromosome 3p. The data point to a linear sequence of features as follows: phaeochromocytoma, angiomatosis retinae, haemangioblastoma of the CNS, renal lesions, pancreatic cysts, and epididymal cystadenoma.

16
UI - 8270255
AU - Crossey PA; Foster K; Richards FM; Phipps ME; Latif F; Tory K; Jones MH;
TI - Bentley E; Kumar R; Lerman MI; et al Molecular genetic investigations of the mechanism of tumourigenesis in von Hippel-Lindau disease: analysis of allele loss in VHL tumours.
SO - Hum Genet 1994 Jan;93(1):53-8
AD - Cambridge University Department of Pathology, UK.
Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome characterised by the development of retinal and central nervous system haemangioblastomas, renal cell carcinoma (RCC), phaeochromocytoma and pancreatic tumours. The VHL disease gene maps to chromosome 3p25-p26. To investigate the mechanism of tumourigenesis in VHL disease, we analysed 24 paired blood/tumour DNA samples from 20 VHL patients for allele loss on chromosome 3p and in the region of tumour suppressor genes on chromosomes 5, 11, 13, 17 and 22. Nine out of 24 tumours showed loss of heterozygosity (LOH) at at least one locus on chromosome 3p and in each case the LOH included the region to which the VHL gene has been mapped. Chromosome 3p allele loss was found in four tumour types (RCC, haemangioblastoma, phaeochromocytoma and pancreatic tumour) suggesting a common mechanism of tumourigenesis in all types of tumour in VHL disease. The smallest region of overlap was between D3S1038 and D3S18, a region that corresponds to the target region for the VHL gene from genetic linkage studies. The parental origin of the chromosome 3p25-p26 allele loss could be determined in seven tumours from seven familial cases; in each tumour, the allele lost had been inherited from the unaffected parent. Our results suggest that the VHL disease gene functions as a recessive tumour suppressor gene and that inactivation of both alleles of the VHL gene is the critical event in the pathogenesis of VHL neoplasms. Four VHL tumours showed LOH on other chromosomes (5q21, 13q, 17q) indicating that homozygous VHL gene mutations may be required but may not be sufficient for tumourigenesis in VHL disease.

17
UI - 7759037
AU - Neumann HP
TI - [An underestimated hereditary disease. H. P. H. Neumann, Freiburg, on the significance of von Hippel-Lindau disease. Interview by Elisabeth B. Moosmann.]
SO - Fortschr Med 1995 Mar 20;113(8):20, 22

18
UI - 7479604
AU - Brauch H; Bohm J; Hofler H
TI - [Hippel-Lindau syndrome and sporadic renal cell carcinomas. Pathogenesis, morphologic spectrum and molecular genetics]
SO - Pathologe 1995 Sep;16(5):321-7
AD - Institut fur Pathologie and Pathologische Anatomie, Technischen Universitat, Klinikum rechts der Isar, Munchen.
von Hippel-Lindau (VHL) disease is an autosomal dominant heritable disease that often occurs in association with various benign and malignant tumours. Clinically the disease is classified as VHL 1 (without phaeochromocytoma) and VHL 2 (with phaeochromocytoma). Genetically, VHL is caused by germline mutations in the VHL tumour suppressor gene. More than 100 germline mutations and rearrangements have been identified, but the biological function of a hypothetical VHL protein is not yet known. Genotype-phenotype correlations should aid in the understanding of this biological role. All VHL manifestations subsequently develop to VHL mutations, but some mutations may act in a tissue-specific manner. Whereas missense mutations cause tumour suppression to fail in adrenal cells, more severe structural mutations are usually necessary for tumour development in renal cells. As predicted by the tumour suppressor theory, the VHL gene also plays a critical part in the pathogenesis of sporadic non-VHL-associated tumours. In a large number of sporadic renal clear cell carcinomas, mutations and hypermethylation cause inactivation of the VHL gene. Together with allelic 3p loss, these constitute rate-limiting events in renal tumourigenesis. Insights into the molecular basis of phenotypic variability in VHL disease and the confirmation of the tumour-suppressor criteria in VHL and non-VHL sporadic tumours indicate an important role of the VHL gene in the development of these tumours.

19
UI - 8859104
AU - Kilmartin DJ; Mooney DJ; Acheson RW; Payne SJ; Maher ER; Eustace P
TI - von Hippel-Lindau disease and familial polyposis coli in the same family.
SO - Arch Ophthalmol 1996 Oct;114(10):1294
AD - Research Foundation, Royal Victoria Eye and Ear Hospital, Dublin 2, Ireland.

20
UI - 9413424
AU - Maher ER; Kaelin WG Jr
TI - von Hippel-Lindau disease.
SO - Medicine (Baltimore) 1997 Nov;76(6):381-91
AD - Division of Medical Genetics, University of Birmingham, Birmingham Women's Hospital, UK.
von Hippel-Lindau disease is a hereditary cancer syndrome characterized by the development of vascular tumors of the central nervous system and retina, clear cell renal carcinomas, pheochromocytomas, pancreatic islet cell tumors, endolymphatic sac tumors, and benign cysts affecting a variety of organs. VHL disease is caused by germline mutations of the von Hippel-Lindau tumor suppressor gene located on chromosome 3p25. Tumor development in this setting is due to inactivation or loss of the remaining wild-type allele in a susceptible cell. The highly vascular nature of VHL-associated neoplasms can be understood in light of the recent finding that the VHL gene product (pVHL) inhibits the accumulation of hypoxia-inducible mRNAs, such as the mRNA encoding vascular endothelial growth factor (VEGF), under normoxic conditions. This property of pVHL appears to be linked to its ability to bind to complexes containing elongin B, elongin C, and cullin 2 (Cul2). Elongin C and Cul2, based on their homology with Skp1 and Cdc53, respectively, are suspected of targeting certain proteins for covalent modification with ubiquitin and hence for degradation. One model, which remains to be tested, is that the binding of pVHL to elongins B/C and Cul2 affects the ubiquitination of RNA-binding proteins that regulate the stability of hypoxia-inducible mRNAs.

21
UI - 9679747
AU - Bos SD; van den Berg E; Dijkhuizen T; van den Berg A; Draaijers TG;
TI - Mensink HJ Genetic analysis of 2 cases of clear cell renal cancer in 2 sisters.
SO - Int J Cancer 1998 Aug 12;77(4):494-7
AD - Department of Urology, Medical Centre Alkmaar, The Netherlands. med.bibliotheek.oo@mca.alkmaar.nl
Two sisters affected with renal cell carcinoma (RCC) is an extremely rare finding, and may indicate a hereditary pattern or the presence of other predisposing factors. We describe here 2 sisters presenting with clear cell renal cell cancer. Examination for von Hippel-Lindau (VHL)-related features and tuberous sclerosis (M. Bourneville) was negative and both had a normal constitutional karyotype. Cytogenetic analysis of the tumor tissue of both patients showed a translocation involving chromosomes 3 and 5, resulting in loss of 3p sequences and gain of part of 5q. The 5q breakpoints were similar, but the breakpoints at 3p appeared to differ. Allelic imbalance analysis supported our observations. Microsatellite analysis revealed that both sisters inherited different chromosome 3 parental alleles. For chromosome 5, 3 different haplotypes could be deduced, but the chromosome 5 alleles overrepresented in the different tumor tissues were from different parental origin. The development of the 2 RCCs in these 2 sisters thus cannot be explained by the inheritance of a mutated VHL gene located at 3p25, nor by the inheritance of other gene defects at chromosomes 3p or 5q. Although the chance that 2 sisters develop sporadic RCC is very low, in the presented case it is probably coincidental or related to another genetic predisposition.

22
UI - 10463227
AU - Krzystolik K; Cybulski C; Lubinski J
TI - [Hippel-Lindau disease]
SO - Neurol Neurochir Pol 1998 Sep-Oct;32(5):1119-33
AD - Zaklad Genetyki i Patomorfologii, Pomorskiej Akademii Medycznej w Szczecinie.
Hippel-Lindau disease is one of inherited tumour susceptibility syndromes. The most common lesions are located in central nervous system, retina and visceral organs. In Poland the disease was rarely diagnosed although the prevalence is much higher than it was supposed and is estimated as 1: 30-50,000. It is inherited in an autosomal dominant manner with age related penetrance reaching almost 98% penetrance at the age of 60 and variable expression. The VHL gene is located near the tip of the short arm of chromosome 3 (3p25-26). Classical lesions in VHL patients are: haemangioblastomas of CNS, retina, cysts and clear cell carcinoma of kidney, cysts and tumours of pancreas, phaeochromocytoma and paraganglioma, papillary cystadenoma of epididymis and endolymphatic sac tumours. Multifocal, often bilateral lesions in form of benign cysts, vascular tumours or carcinomas occur. Management of the lesions often differs from that in sporadic cases of the tumours. Non-symptomatic lesions of CNS need no treatment, neither do non-symptomatic tumours of epididymis and some of phaeochromocytomas. Kidney carcinoma is treated when it reaches a certain size preferably by nephron-sparing surgery. Special care should be provided to pregnant VHL patients. Available DNA testing enables to identify VHL carriers. Although the mean age of death in VHL patients is 41 at the moment a proper prophylactic, diagnostic and treatment management can probably prolong survival of the patients and limit complications of the disease. The coordination between genetic consultants and clinicians is crucial in the management of the patients. The authors coordinate work of Polish VHL Registry and Polish VHL Association.

23
UI - 10363243
AU - Cuatrecasas G; Oriola J; Granada ML; Florensa R; Salinas I
TI - [Genetic study of a new family with Hippel-Lindau type IIB disease]
SO - Med Clin (Barc) 1999 Apr 24;112(14):546-8
AD - Servicio de Endocrinologia, Hospital Universitari Germans Trias i Pujol, Badalona.
BACKGROUND: Von Hippel-Lindau disease is characterized by the variable presence of cerebellar and retinal haemangioblastomas, phaeocromocytomas and hypernephromas, beginning at early stages of life. Von Hippel-Lindau gene has been located in the short arm of chromosome 3 (3p25.5) and has been involved in the regulation of DNA transcription acting as a suppressor gene. More than 500 different mutations have been described. SUBJECTS AND METHODS: We describe a new family with the type IIB Von Hippel-Lindau disease in which, apart from clinical studies, we performed a genetic screening trying to identify germinal mutations. RESULTS: So far, we have point out 6 patients with the G-->A transversion at codon 167 (R167Q). Two of them with overt clinical disease (phaeocromocytoma in case II.1 and haemangioblastoma in the II.2) at the beginning of the study and one with a non-suspected clinical presentation (phaeocromocytoma and renal carcinoma in case I.1) out of 8 family members studied in three generations. CONCLUSIONS: The genetic screening in this family permitted us to identify three subjects before their clinical onset. The absence of the mutation in two of the younger patients will simplify the clinical follow-up of this family. Genetic screening must be generalized in the follow-up of Von Hippel-Lindau disease families, because of economic advantages and clinical efficacy.

24
UI - 11510758
AU - Tomita N; Moriguchi A; Yamasaki K; Taniyama Y; Kotani N; Hashiya N;
TI - Yoshida M; Yao M; Higaki J; Ogihara T A family with von Hippel-Lindau disease revealed by pheochromocytoma.
SO - Hypertens Res 2001 Jul;24(4):445-50
AD - Department of Geriatric Medicine, Osaka University Medical School, Suita, Japan. tomita@hp-gm.med.osaka-u.ac.jp
Von Hippel-Lindau (VHL) disease is an inherited neoplastic disease characterized by a predisposition to develop retinal angiomas, central nervous system hemangioblastomas, renal cell carcinomas, pancreatic cysts and pheochromocytomas. Recently, we encountered three members of the same family who each had both VHL disease and pheochromocytoma. As in all three patients we suspected pheochromocytoma, the diagnosis of VHL disease should be considered. The possible presence of VHL disease was initially investigated in all three patients based on the presence of pheochromocytoma. A mutational analysis of the VHL gene revealed the presence of a missense mutation, consisting of a G to A transversion, at nucleotide 713 in all three patients. This germline point mutation in the VHL gene is often detected in type 2 VHL disease with pheochromocytoma. Genetic analysis seems to be useful for early detection of VHL disease, even when the formal criteria for diagnosis of this disease are lacking.

25
UI - 11519854
AU - Sprenger SH; Gijtenbeek JM; Wesseling P; Sciot R; van Calenbergh F;
TI - Lammens M; Jeuken JW Characteristic chromosomal aberrations in sporadic cerebellar hemangioblastomas revealed by comparative genomic hybridization.
SO - J Neurooncol 2001 May;52(3):241-7
AD - Department of Neurology, University Medical Center Nijmegen, The Netherlands.
Hemangioblastomas (HBs) of the central nervous system are benign tumors and occur as sporadic (sp) tumors (75%) or as a manifestation of the von Hippel-Lindau (VHL) disease (25%). VHL-disease is an autosomal dominant disorder characterized by HBs of the central nervous system and retina, renal cell carcinoma (RCC), phaeochromocytoma (PHEO), islet tumors of the pancreas, and endolympatic sac tumors as well as cysts and cystadenoma in the kidney, pancreas and epididymis. In VHL patients a large spectrum of germline mutations in the VHL gene has been detected. In spHBs VHL alleles are reported to be inactivated in up to 50% of the tumors. To our knowledge the involvement of other genes in spHBs has not been investigated. To elucidate the oncogenesis of spHBs, we performed CGH on 10 spHBs to screen for chromosomal imbalances throughout the entire tumor genome. Aberrations most frequently detected are losses of chromosomes 3 (70%), 6 (50%), 9 (30%), and 18q (30%) and a gain of chromosome 19 (30%). Based on these frequencies and the co-occurrence of these aberrations in the analyzed tumors we hypothesize that loss of chromosome 3 (harboring the VHL gene) is an early event in the oncogenesis of spHBs, followed by loss of 6, and then losses of chromosomes 9, 18q and gain of chromosome 19. Comparison of the chromosomal imbalances in spHBs to those previously reported in RCCs and PHEOs reveals that the pathway of spHBs shows similarities to both the RCCs and PHEOs.

26
UI - 11414476
AU - Alexander JM
TI - Tumor suppressor loss in pituitary tumors.
SO - Brain Pathol 2001 Jul;11(3):342-55
AD - Harvard Medical School, Boston, MA, USA. jalexand@caregroup.harvard.edu
The current model of human neoplasia invokes a number of potential genomic alterations that impact cellular phenotype and proliferative rates. In the majority of human tumor models, the transformation from normal cells to neoplastic lesion is a multistep process. This review offers a specific overview of the involvement of tumor suppressor genes (TSGs) in the pathogenesis of human pituitary adenomas. TSG genetic lesions, such as BRCA1 in breast cancer and p53 in Li-Fraumeni Syndrome, have been identified in both sporadic and heritable human endocrine tumors. Familial neoplastic syndromes like multiple endocrine neoplasia type 1 (MEN1) that include pituitary tumor formation as part of a broad clinical spectrum of disease represent a unique opportunity to investigate the general mechanisms of tumorigenesis, and well as genes responsible for sporadic endocrine tumors. Similarly, homologous recombination knockout mice with selectively ablated candidate TSGs have also shed light on the molecular mechanisms of pituitary cell proliferation and tumor suppression. However, despite insights into pituitary tumorigenesis generated by heritable neoplasia syndromes and mouse knockout of critical TSGs that display a pituitary tumor phenotype, the molecular pathogenesis of human pituitary adenomas remains largely an enigma. Thus, the role of TSGs, if any, in sporadic pituitary adenoma formation has yet to be determined, despite our greater understanding of the molecular mechanisms underlying pituitary cell function and phenotype.

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