Familial Cancer

, Volume 9, Issue 4, pp 635–642 | Cite as

Clinical and molecular characterization of Brazilian families with von Hippel-Lindau disease: a need for delineating genotype-phenotype correlation

  • Israel Gomy
  • Greice Andreotti Molfetta
  • Ester de Andrade Barreto
  • Cristiane Ayres Ferreira
  • Dalila Luciola Zanette
  • José Cláudio Casali-da-Rocha
  • Wilson Araujo SilvaJr.


von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary cancer syndrome that predisposes to the development of a variety of benign and malignant tumours, especially cerebellar haemangioblastomas, retinal angiomas and clear-cell renal cell carcinomas (RCC). The etiology and manifestations are due to germline and somatic mutations in the VHL tumour suppressor gene. VHL disease is classified into type 1 and type 2, showing a clear genotype-phenotype correlation, as type 2 is associated with phaeochromocytoma and essentially caused by missense mutations. The aim of this study is to characterize the phenotype and genotype of families with VHL disease. Eighteen of twenty patients from ten unrelated families underwent genetic testing, nine of them fulfilled VHL disease criteria and one had an apparently sporadic cerebellar haemangioblastoma. Four different germline mutations in the VHL gene were identified: c.226_228delTTC (p.Phe76del); c.217C > T (p.Gln73X); IVS1-1 G > A and IVS2-1 G > C. The first three mutations were associated with type 1 disease and the last one with type 2B, which had never been identified in the germline. The transcriptional processing of a novel splice-site mutation was characterised. Three type 1 VHL families showed large deletions of the VHL gene, two of them encompassed the FANCD2/C3orf10 genes and were not associated with renal lesions. We also suggest that such families should be subclassified according to the risk of RCC and the extent of the VHL gene deletions. This study highlights the need for a through clinical and molecular characterisation of families with VHL disease to better delineate its genotype-phenotype correlation.


Genotype-phenotype correlation Germline mutation von Hippel-Lindau disease VHL 



Alpha subunit of the hypoxia-inducible factor


Vascular endothelial growth factor


Platelet-derived growth factor


Quantitative real-time PCR


Multiplex ligation-dependent probe amplification



The authors are grateful to all families and especially to Adriana Aparecida Marques, Anemarie Dinarte dos Santos, and the Brazilian National Tumor and DNA Bank (BNT) of the Brazilian National Cancer Institute (INCA) for valuable technical assistance. This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação Hemocentro de Ribeirão Preto (FUNDHERP).

Supplementary material

10689_2010_9357_MOESM1_ESM.tif (623 kb)
Six controls showing reduced expression of the VHL isoform II
10689_2010_9357_MOESM2_ESM.pdf (246 kb)
Graphics generate by the Coffalyser® software for MLPA analysis of three patients with VHL disease. Two of them show a complete deletion of the VHL gene (S2, S3) and one has a partial deletion (S4). Two deletions affect the neighboring FANCD2 gene partially (S3,S4). Each bar represents the DNA dosage of each probe of the kit (c: control probes). Cut-off levels for loss of relative copy number were set at 0.7 (black line). The bars related to VHL and FANCD2 losses are all below the cut-off, representing the deletion of one allele


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Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Israel Gomy
    • 1
  • Greice Andreotti Molfetta
    • 1
  • Ester de Andrade Barreto
    • 2
  • Cristiane Ayres Ferreira
    • 3
  • Dalila Luciola Zanette
    • 3
  • José Cláudio Casali-da-Rocha
    • 2
  • Wilson Araujo SilvaJr.
    • 1
    • 3
    • 4
  1. 1.Department of Genetics, Medical School of Ribeirão PretoUniversity of São PauloRibeirão PretoBrazil
  2. 2.Brazilian National Cancer Institute (INCA)Rio de JaneiroBrazil
  3. 3.National Institute of Science and Technology in Stem Cell and Cell Therapy, Center for Cell Therapy and Regional Blood CenterRibeirão PretoBrazil
  4. 4.Centro Regional de Hemoterapia-HC/FMRP/USPRibeirão PretoBrazil

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