von Hippel-Lindau disease
von Hippel-Lindau (vHL) disease (ORPHA:892, OMIM-number 193300) is a rare, hereditary cancer syndrome characterized by predisposition to development of multiple benign as well as malignant tumours and cysts in various organs. Characteristic neoplasms are especially hemangioblastomas in the cerebellum, retina and spine, renal cell carcinomas, pheochromocytomas, neuroendocrine pancreas and endolymphatic sac tumours. The severity and specific manifestations of vHL can vary significantly among affected individuals.
vHL is considered a rare disease, with estimated prevalence rates ranging from 1 in 36,000 - 91,000 individuals worldwide. It affects both males and females equally, and there are no known ethnic or geographic predispositions.
vHL disease is caused by pathogenic variants in the tumour suppressor gene VHL. The VHL gene is responsible for producing a protein called von Hippel-Lindau tumour suppressor protein (pVHL). A main function of pVHL is E3 ubiquitin ligase activity which leads to degradation of HIFs (Hypoxia inducible factors), that mediate angiogenesis.
Individuals with vHL disease carry a pathogenic variant in one copy of the VHL gene. This variant prevents the production or function of pVHL, leading to a loss of its tumour-suppressing capabilities. As a result, regulation of angiogenesis and cell division is impaired leading to development of tumours and cysts in various organs.
The majority of vHL cases (around 80%) are inherited in an autosomal dominant pattern, meaning that an affected individual has a 50% chance of passing the pathogenic variant to each of their offspring. In about 20% of cases, vHL arises due to a spontaneous (de novo) mutation, meaning there is no prior family history of the condition.
According to “Von Hippel-Lindau disease: Updated guideline for diagnosis and surveillance, Marie Louise M Binderup et al.” a guideline endorsed by ERN GENTURIS in June 2022:
Surveillance is recommended for:
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Age interval |
Recommendation |
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Eye clinical exam |
CNS clinical exam |
Biochemistry |
Imaging |
Hearing exam |
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|
0 - 4 years |
Annual retinal inspection |
Annual general paediatric examination including growth parameters |
– |
– |
– |
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5 - 14 years |
Annual retinal inspection |
Annual general paediatric examination including growth parameters |
Annual plasma metanephrine and plasma normetanephrine |
MRI of the CNS (brain and neuroaxis) including the inner ear with contrast: Baseline scan at age 10 years |
Annual hearing examination
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|
From 15 years |
Annual retinal inspection |
Annual neurological evaluation |
Every second year:
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Every second year: Hearing examination |
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CNS: central nervous system, exam: examination, MRI: Magnetic Resonance Imaging.
Endorsed guidelines for other genturis - von Hippel-Lindau disease: Updated guideline for diagnosis and surveillance.
* ERN GENTURIS uses AGREE II as a tool for the endorsement of guidelines. The quality of the guideline is evaluated through assessing the rigor and transparency of the guideline development process. The content of the guideline is not evaluated, although selection of the guideline for endorsement includes expert opinion on the usefulness of the content of the guideline.
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Thematic Group 4: Other rare – predominantly malignant – genturis
A list of healthcare providers with expertise in Thematic Group 4: Other rare - predominantly malignant - genturis can be found here.
A non-exhaustive list of patient associations for genetic tumour risk syndromes in EU member states can be found here.