An analysis of phenotypic variation in the familial cancer syndrome von Hippel-Lindau disease: evidence for modifier effects

Am J Hum Genet. 1998 Oct;63(4):1025-35. doi: 10.1086/302037.


von Hippel-Lindau disease (VHL) is a dominantly inherited familial cancer syndrome predisposing to ocular and CNS hemangioblastomas, renal-cell carcinoma (RCC), and pheochromocytoma. Both interfamilial and intrafamilial variability in expression is well recognized. Interfamilial differences in pheochromocytoma susceptibility have been attributed to allelic heterogeneity such that specific missense germ-line mutations confer a high risk for this complication. However, in most cases, tumor susceptibility does not appear to be influenced by the type of underlying VHL mutation. To probe the causes of phenotypic variation, we examined 183 individuals with germ-line VHL gene mutations, for the presence and number of ocular tumors. The prevalence of ocular angiomatosis did not increase with age, and the distribution of these tumors in gene carriers was significantly different than the expected stochastic distributions. Individuals with ocular hemangioblastomas had a significantly increased incidence of cerebellar hemangioblastoma and RCC (hazard ratios 2.3 and 4.0, respectively). The number of ocular tumors was significantly correlated in individuals of 12 degree relatedness but not in more distantly related individuals. These findings suggest that the development of VHL ocular tumors is determined at an early age and is influenced by genetic and/or environmental modifier effects that act at multiple sites. Functional polymorphisms in the glutathione-S-transferase M1 gene (GSTM1) or the cytochrome P450 2D6 gene (CYP2D6) did not show a significant association with the severity of ocular or renal involvement.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Age of Onset
  • Aged
  • Cerebellar Neoplasms / genetics
  • Child
  • Consanguinity
  • Cytochrome P-450 CYP2D6
  • Eye Abnormalities / genetics
  • Eye Neoplasms / genetics
  • Female
  • Genetic Variation
  • Hemangioblastoma / genetics
  • Hemangioma / genetics
  • Heterozygote
  • Humans
  • Kidney / abnormalities
  • Kidney Diseases / genetics
  • Ligases*
  • Male
  • Middle Aged
  • Mutation*
  • Phenotype
  • Proteins / genetics*
  • Sex Factors
  • Syndrome
  • Tumor Suppressor Proteins*
  • Ubiquitin-Protein Ligases*
  • Von Hippel-Lindau Tumor Suppressor Protein
  • von Hippel-Lindau Disease / genetics*


  • Proteins
  • Tumor Suppressor Proteins
  • Cytochrome P-450 CYP2D6
  • Ubiquitin-Protein Ligases
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Ligases
  • VHL protein, human