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a Department of
Medical Genetics, University Medical Centre, Utrecht, The Netherlands, b Department of Internal Medicine,
University Medical Centre, Utrecht, The Netherlands, c West Midlands Regional
Genetics Service, Birmingham Women's Hospital, Edgbaston, Birmingham
B15 2TG, UK, d Department
of Neurology, University Medical Centre, Utrecht, The Netherlands, e East Anglian Genetics
Service, Addenbrooke's Hospital, Cambridge, UK, f Clinical
Genetics Centre Leiden, PO Box 9600, 2300 RC Leiden, The Netherlands, g Section of Medical and
Molecular Genetics, Department of Paediatrics and Child Health,
University of Birmingham, Birmingham, UK
Correspondence to: Professor Maher, E.R.Maher{at}bham.ac.uk
Revised version received 1 May 2000;
Accepted for publication 26
September 2000
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.
METHODSEighty 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.
RESULTSA
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.
CONCLUSIONSEarly 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.
This article has been cited by other articles:
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  E. R. Woodward, K. Wall, J. Forsyth, F. Macdonald, and E. R. Maher VHL mutation analysis in patients with isolated central nervous system haemangioblastoma Brain, March 1, 2007; 130(3): 836 - 842. [Abstract] [Full Text] [PDF]
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 F. J. Hes, J. W. M. Hoppener, and C. J. M. Lips Pheochromocytoma in Von Hippel-Lindau Disease J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 969 - 974. [Full Text] [PDF]
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G. Weirich, B. Klein, T. Wohl, D. Engelhardt, and H. Brauch VHL2C Phenotype in a German von Hippel-Lindau Family with Concurrent VHL Germline Mutations P81S and L188V J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 5241 - 5246. [Abstract] [Full Text] [PDF]
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 C Cybulski, K Krzystolik, A Murgia, B Gorski, T Debniak, A Jakubowska, M Martella, G Kurzawski, M Prost, I Kojder, et al. Germline mutations in the von Hippel-Lindau (VHL) gene in patients from Poland: disease presentation in patients with deletions of the entire VHL gene J. Med. Genet., July 1, 2002; 39(7): e38 - 38. [Full Text] [PDF]
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