von Hippel-Lindau syndrome

Front Horm Res. 2013:41:30-49. doi: 10.1159/000345668. Epub 2013 Mar 19.


von Hippel-Lindau (VHL) disease is an autosomal-dominant familial cancer syndrome associated with mutations of the VHL tumor suppressor gene (3p25-26). Its estimated incidence ranges from 1 in 36,000 to 1 in 53,000 with a penetrance of up to 95% by age 60. Genotype-phenotype correlation divides VHL into two broad clinical subtypes. Type 1 VHL is predominantly associated with large deletion or truncation mutations which result in an encoded protein with very little or no activity. It is associated with retinal and CNS hemangioblastoma and renal cell carcinoma but not pheochromocytoma. Type 2 is usually associated with missense mutations encoding a protein with limited activity and includes pheochromocytoma. It is further classified into three other subtypes (2A, 2B, 2C) based on the presence of hemangioblastoma and renal cell carcinoma. Visceral cysts in the kidney, pancreas and epididymis, nonfunctioning pancreatic neuroendocrine tumors which often show distinctive clear cell cytology, endolymphatic sac tumors and head and neck paragangliomas are well recognized but less common presenting features. Surveillance of carriers can reduce the burden of disease and is best performed in specialist referral centers with due consideration given to both the complex molecular pathogenesis and psychosocial aspects of the disease.

Publication types

  • Review

MeSH terms

  • Adrenal Gland Neoplasms / complications
  • Adrenal Gland Neoplasms / genetics
  • Adult
  • Carcinoma, Renal Cell / complications
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / pathology
  • Ear Neoplasms / genetics
  • Ear Neoplasms / pathology
  • Endolymphatic Sac / pathology
  • Genetic Association Studies
  • Germ-Line Mutation
  • Hemangioblastoma / genetics
  • Hemangioblastoma / pathology
  • Humans
  • Hypoxia-Inducible Factor 1 / genetics
  • Kidney Neoplasms / complications
  • Kidney Neoplasms / genetics
  • Middle Aged
  • Pancreatic Neoplasms / genetics
  • Pheochromocytoma / complications
  • Pheochromocytoma / genetics
  • Retinal Neoplasms / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • von Hippel-Lindau Disease / complications
  • von Hippel-Lindau Disease / diagnosis
  • von Hippel-Lindau Disease / genetics*
  • von Hippel-Lindau Disease / physiopathology


  • Hypoxia-Inducible Factor 1
  • Von Hippel-Lindau Tumor Suppressor Protein