What is Von Hippel-Lindau syndrome?
Von Hippel-Lindau syndrome (VHL) is a disease caused by mutations – or genetic changes – in the VHL gene. It is characterized by hemangioblastomas (benign vascular tumors) of the brain, the bone marrow, and the retina, along with an increased risk of renal cell carcinomas (malignant kidney tumors) and renal cysts, pheochromocytomas (tumors of the adrenal glands, which produce hormones such as adrenalin), cysts and neuroendocrine tumors (some of which produce hormones) of the pancreas, endolymphatic sac tumors (inner ear tumors), and cysts of the epididymis and of the ovaries and fallopian tubes.
How is Von Hippel-Lindau syndrome diagnosed?
Suspected Diagnosis
Von Hippel-Lindau syndrome is suspected with presentation of the following:
Diagnostic Criteria
The diagnosis of “Von Hippel-Lindau syndrome” is confirmed by detection of a mutation – or genetic change – in the VHL gene and/or:
Genetic Diagnostics
The diagnosis of “Von Hippel-Lindau syndrome” is confirmed by detection of a mutation – or genetic change – in the VHL gene.
What is the risk of cancer?
The clinical picture depends on the underlying VHL mutation and varies a lot.
Hemangioblastomas
Hemangioblastomas (HB) are benign tumors arising from the vessels. They occur in the CNS – i.e. the brain and spinal cord – and in the retina and usually grow in spurts. Depending on their location, they can cause various neurological symptoms, such as headaches, vomiting, movement coordination disorders, gait impairment, sensory or motor failure symptoms, and pain. Whenever they occur in the retina, they can trigger blind spots and limited vision. However, they may also progress without symptoms, in which case they are usually discovered during early-detection examinations. In the CNS, 20% of hemangioblastomas occur in the spinal cord and 80% in the brain, most of which affect the cerebellum.
Manifestations
Studies show that all patients with Von Hippel-Lindau syndrome have developed at least one manifestation by around the age of 75. The following table shows the diseases that occur as part of Von Hippel-Lindau syndrome, the associated risks, and the youngest and average age in years at the time of diagnosis.
Tumor | Risk | Youngest/Average Age at Diagnosis |
---|---|---|
CNS hemangioblastoma | 60% – 80% | 9 / 30 |
HB of the retina | 25% – 60% | 0 / 25 |
Kidney
|
25% – 75%
|
12 / 39
|
Pheochromocytoma | 10% – 25% | 12 / 27 |
Endolymphatic sac tumor | 10% – 15% | 6 / 22 |
Pancreas
|
35% – 75%
|
5 / 36
|
Cystadenoma of the epididymus | 25% – 60% | 17 / 24 |
Cystadenoma of the ovaries / fallopian tubes | 10% | 16 / unknown |
What causes Von Hippel-Lindau syndrome?
The Von Hippel-Lindau syndrome is caused by mutations – or genetic changes – in the VHL gene. This gene encodes for the VHL protein, which normally binds the HIF protein and breaks it down, thereby blocking the release of growth factors (mainly for vessels).
Now if the VHL gene is altered, the VHL protein will not be produced correctly and will then be unable to bind to the HIF protein and break it down. This will cause the HIF protein to accumulate, thereby leading to an increased release of growth factors (mainly for vessels), which promotes tumor growth and enhances the blood supply to the tumors.
Most of the people affected inherited the genetic change from a parent. Around 80% of patients have a parent who also suffers from Von Hippel-Lindau syndrome. Heredity is autosomal dominant. The remaining cases (20%) are due to a spontaneous or new mutation, called a de novo mutation.
Is there a treatment?
Von Hippel-Lindau syndrome is treated by addressing existing symptoms.
CNS Hemangioblastoma
Hemangioblastomas of the CNS that cause symptoms should be surgically removed. The approach for asymptomatic hemangioblastomas is still controversial. Spinal cord cysts should also be surgically removed.
Hemangioblastomas of the Retina
Hemangioblastomas of the retina should be treated as early as possible. Various options, such as laser therapy, xenon therapy, or cryoablation, are available for this. The success of the treatment depends on the location, size, and number of lesions. The use of radiation therapy is an option if standard therapy is unsuccessful.
Renal Cell Carcinomas
Renal cell carcinomas should be surgically treated as early as possible. The kidneys should be preserved or only partially removed whenever feasible. The removal of adrenal glands should also be avoided if at all possible. Cryoablation and radiofrequency ablation are options for treating small tumors (< 3 cm). A kidney transplant is required whenever it is necessary to remove both kidneys.
Pheochromocytomas
Pheochromocytomas should be surgically removed. Since they are hormone-producing tumors, it makes sense to administer medicinal therapy before an operation. Partial removal of the adrenal glands is the treatment of choice for children and can also be considered for adults.
Cysts and Neuroendocrine Tumors of the Pancreas
Cysts generally do not need to be surgically removed. Tumors should be surgically removed whenever they are ≥ 3 cm in size, grow rapidly, or exhibit certain genetic changes.
Endolymphatic Sac Tumors (Inner Ear Tumors)
Early surgical removal is advised. However, it is important to bear in mind that the possibility of deafness after an operation cannot be ruled out.
Cystadenomas of the Ovaries / Fallopian Tubes or of the Epididymis
Surgical treatment is generally not necessary if they are not causing symptoms or threatening fertility.
Surveillance Recommendations for the Early Detection of Cancer
Surveillance Recommendations
Regardless of age, every person with Von Hippel-Lindau syndrome should undergo annual clinical examinations that include blood pressure checks, neurological examinations, and vision or hearing tests. In addition, people with VHL should be informed about the symptoms and signs of their disease. It would be ideal for all VHL patients to be treated by a physician who is familiar with Von Hippel-Lindau syndrome and has access to a multidisciplinary team.
The American Association for Cancer Research (AACR) makes the following surveillance recommendations concerning the individual manifestations associated with VHL:
Hemangioblastomas of the Retina
Pheochromocytoma
Endolymphatic Sac Tumors
CNS Hemangioblastoma
Renal Cell Carcinomas
Neuroendocrine Tumors of the Pancreas
Self-Care and Support
What should I pay special attention to?
You should consult a doctor as soon as neurological complaints such as headaches, vomiting, coordination difficulties, unsteady gait, sensor or motor failure symptoms, or pain occur. Moreover, changes in vision or hearing should be noted and reported to a doctor as well. You should also see a doctor right away if you notice any other newly occurring abnormalities or symptoms, such as abdominal pain, a rapid heartbeat, or dizziness.