von Hippel-Lindau disease

Definitions & Key takeaways

Von-Hippel Lindau (VHL) is a genetic disease that increases the risk of tumor formation in the CNS, kidneys, adrenal glands, and pancreas. It is caused by a mutated tumor suppressor gene, VHL, which increases the risk of tumor formation by upregulating genes that promote cell growth. VHL is inherited in an autosomal dominant pattern and can lead to various benign and malignant tumors. Hemangioblastoma is the most common tumor type, occurring in about 60% of VHL patients, followed by clear cell renal cell carcinoma, pancreatic neuroendocrine tumors, and pheochromocytomas. Regular surveillance is crucial for improving quality of life and lifespan. Treatment recommendations depend on the tumor type and aim to preserve the function of the affected organ.

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Von Hippel-Lindau or VHL is a genetic disease that affects people of all ethnicities and is characterized by tumor development in the CNS, kidneys, adrenal glands and pancreas.
Okay, the VHL gene is a tumor suppressor gene on the short arm of chromosome 3. It codes for proteins that degrade hypoxia-inducible transcription factor, or HIF.
HIF upregulates genes that code for platelet-derived and vascular endothelial growth factors, both of which promote new blood vessel formation and cell growth.In VHL disease, this tumor suppressor gene is mutated which increases HIF, PDGF, VEGF, and ultimately the risk of tumor formation.
VHL disease is about as common as Huntington Disease, occurring in 1 in 36,000 people. It is inherited in an autosomal dominant pattern, meaning that a VHL patient has a 50% chance of passing it on to each kid they have.
20% of VHL patients have a de novo or new mutation, meaning they are the first VHL patient in their family. Alright, the most common tumor type in VHL is hemangioblastoma, a benign blood vessel tumor occurring in about 60% of VHL patients.
In the central nervous system, these can occur in the retina, brain, and spinal cord. In the eyes, it can cause blindness by detaching the retina.
In the brain and spinal cord, a tumor or the accompanying cyst causes problems when it pushes against surrounding tissue.
For example, if the tumor is in the cerebellum, it can cause ataxia, or the loss of balance. If it blocks the flow of cerebrospinal fluid, intracranial pressure can rise causing headaches, nausea, and vomiting.
Less common are benign cysts and cyst-like tumors called cystadenomas. The most concerning, occurring in ~25% of VHL patients, is the endolymphatic sac tumor of the inner ear which can cause deafness.
Cystadenomas can develop in the broad ligament in women, and the epididymis in men, and incidental cysts can occur in the liver, lung, kidney and pancreas in both men and women.
Some tumors associated with VHL can be cancerous. Clear cell renal cell carcinoma, or RCC occurs in ~60% of VHL patients and can develop in both kidneys Pancreatic neuroendocrine tumors grow in ~15% of VHL patients and can also metastasize.
Two other typically benign endocrine tumors occurring in ~20% of VHL patients are pheochromocytomas in the adrenal glands, and when they elsewhere, they are called paragangliomas.
These tumors erratically pump catecholamines like norepinephrine and epinephrine, individuals may present with sudden symptoms of sympathetic overactivity, such as headaches, sweating, palpitations and hypertension.
A “pheo crisis” can occur when catecholamine levels are extremely high, and can be fatal. VHL patients on average, develop their first lesion by their mid-twenties, but the age of onset varies with the lesion type.
For example, hemangioblastomas usually occur earlier in life then RCC tumors. Not every VHL patient will get every type of VHL lesion, but they will almost always get at least one.
AND, since new lesions can develop repeatedly in the same organs, regular surveillance is crucial for improving quality of life and lifespan.
Treatment recommendations are designed to preserve the function of the organ, and again depend on tumor type.. For example, if you surgically remove RCC every time it appears, even when it was small and asymptomatic, VHL patients may quickly require dialysis.
But once the cancer is at least 3cm, the high risk of metastasizing justifies the surgery. Retinal hemangioblastomas, however, should be treated when found, because each laser treatment doesn’t cause appreciable vision loss.
Alright, a quick recap. Von Hippel Lindau is an autosomal dominant disease caused by a mutation in the VHL gene on chromosome 3.
This leads to unregulated high levels of hypoxia-inducible-factor which causes tumor formation. VHL patients can develop lesions in many different organs, including the eye, ear, brain, spinal cord, kidneys, pancreas, and adrenal glands.
Most of these are benign tumors, but they also have the potential to become metastatic such as bilateral clear cell renal cell carcinoma and pancreatic neuroendocrine tumors.
Because VHL is highly penetrant and the lesions can occur repeatedly throughout a person’s lifetime, routine screening and careful management is crucial!