Table of Contents
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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