Von Hippel-Lindau syndrome is a multisystem tumour-predisposition disorder with highly variable presentation. Manifestations and severity vary widely within and between families, even among relatives carrying the same pathogenic variant. Central nervous system hemangioblastoma is the prototypic lesion; approximately 80% of these tumours develop in the brain and 20% in the spinal cord, and they remain the main cause of disease-related mortality. Clear cell renal cell carcinoma occurs in about 70% of affected individuals by age 60 years and is a further leading cause of mortality. Retinal hemangioblastomas affect approximately 70% of individuals, with mean age of detection around 25 years, and may be the initial manifestation in childhood. , pancreatic cysts and neuroendocrine tumours, and epididymal or broad ligament cysts complete the clinical spectrum; endolymphatic sac tumours occur in approximately 10-16% of individuals and may present with unilateral or bilateral hearing loss. Four general VHL phenotypes (type 1, type 2A, type 2B, type 2C) have been suggested based on the likelihood of pheochromocytoma or renal cell carcinoma and some genotype-phenotype correlations are observed, but patterns are not clear-cut.
Biallelic pathogenic variants in VHL cause familial erythrocytosis 2 that is characterized by increased circulating red blood cell mass, increased serum levels of erythropoietin, and normal oxygen affinity. Although thrombosis and/or haemorrhage has occurred in many individuals with familial erythrocytosis 2, no individuals with this disorder or their heterozygous relatives thus far described have developed von Hippel-Lindau syndrome (VHL)-related tumours.
