"Von-Hippel-Lindau Syndrome" – What Is It?
Von Hippel-Lindau syndrome (VHL) is a disease caused by mutations, i.e., genetic changes in the VHL gene. It is characterized by hemangioblastomas (benign vascular tumors) of the brain, spinal cord, and retina of the eye, as well as an increased risk of renal cell carcinoma (malignant kidney tumor) and renal cysts, pheochromocytomas (tumor of the adrenal gland that produces hormones such as adrenaline), cysts and neuroendocrine tumors (e.g., hormone-producing tumors) of the pancreas. Neuroendocrine tumors (partly hormone-producing tumors) of the pancreas, endolymphatic sac tumors (inner ear tumor), and cysts of the epididymis and the ovaries and fallopian tubes.
How Is "Von-Hippel-Lindau Syndrome" Diagnosed?
Suspected Diagnosis
Von Hippel-Lindau syndrome is suspected in the following cases:
- Hemangioblastoma of the retina, especially in young patients
- Hemangioblastoma of the central nervous system (CNS), i.e., brain or spinal cord
- Clear cell renal cell carcinoma (RCC)
- Pheochromocytoma (PHEO)
- Endolymphatic sac tumor (ELST)
- Cysts (cystadenoma) of the ovaries/oviducts or epididymis
- Multiple cysts or neuroendocrine tumor (NET) of the pancreas
- Multiple renal cysts
Diagnostic Criteria
The diagnosis of “Von Hippel-Lindau syndrome” is considered confirmed in the case of a proven mutation, i.e., genetic change in the VHL gene and/or:
- Without VHL in the family in patients with at least two of the following findings:
- ≥2 hemangioblastomas of the retina, spinal cord, or brain, or a single hemangioblastoma together with a manifestation in the abdomen (e.g., several cysts of the kidneys or pancreas), e.g., multiple cysts of the kidneys or pancreas)
- Renal cell carcinoma
- Pheochromocytoma
- ELST, cystadenoma of the ovaries or fallopian tubes/epididymis, or NET of the pancreas
- With VHL in the family in patients with at least one of the following findings:
- Hemangioblastoma of the retina
- Hemangioblastoma of the spinal cord or cerebellum
- Pheochromocytoma
- Renal cell carcinoma
- Multiple cysts of the kidneys or pancreas
Genetic Diagnostics
The diagnosis of “Von Hippel-Lindau syndrome” is confirmed by detecting a mutation, i.e., a genetic change in the VHL gene.
What Is the Risk of Cancer?
The clinical picture depends on the underlying VHL mutation and is highly variable.
Haemangioblastoma
Hemangioblastomas (HB) are benign tumors originating from the blood vessels. They occur in the CNS, i.e., in the brain and spinal cord and the eye’s retina, and usually grow abruptly. Depending on their location, they can cause neurological symptoms such as headaches, vomiting, impaired movement coordination, impaired gait, sensory or motor deficits, and pain. If they occur in the retina, they can cause visual field defects and impaired vision. However, they can also be asymptomatic and are then usually detected during early detection examinations. In the CNS, 20% of hemangioblastomas occur in the spinal cord and 80% in the brain, mainly in the cerebellum.
Manifestations
Studies show that at around the age of 75, all patients with Von Hippel-Lindau syndrome have at least one manifestation of the disease. The following table shows the diseases that occur as part of Von Hippel-Lindau syndrome, the risk of their occurrence, and the youngest and average age at diagnosis in years.
| 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 epididymis | 25% – 60% | 17 / 24 |
| Cystadenoma ovaries/oviducts | 10% | 16 / unknown |
What Is Known About the Development of "Von-Hippel-Lindau Syndrome"?
Von Hippel-Lindau syndrome is caused by mutations, i.e., genetic changes in the VHL gene. This gene codes for the VHL protein, which normally binds to the HIF protein, degrades it and thereby inhibits the release of growth factors (especially for blood vessels).
If the VHL gene is present in an altered form, the VHL protein is also not produced correctly. As a result, it cannot bind to the HIF protein and break it down. This leads to an accumulation of the HIF protein and, thus, to an increased release of growth factors (especially for blood vessels), resulting in tumor growth and improved blood supply to the tumors.
The genetic change is usually inherited from a parent. Around 80% of patients have a parent who also suffers from Von Hippel-Lindau syndrome. The inheritance is autosomal dominant. The remaining cases (20%) are due to a spontaneous or new mutation, known as a de novo mutation.
Is There Any Form of Treatment Available?
The treatment of Von Hippel-Lindau syndrome depends on the disease in question.
CNS Haemangioblastoma
Hemangioblastomas of the CNS that cause symptoms should be surgically removed. The procedure for non-symptomatic hemangioblastomas is still controversial. Cysts of the spinal cord should also be surgically removed.
Hemangioblastomas of the Retina
Hemangioblastomas of the retina should be treated as early as possible. Various options exist, such as laser, xenon, or cryoablation. The success of the treatment depends on the localization, size, and number of lesions. If standard therapy is unsuccessful, a certain form of radiotherapy is an option.
Renal Cell Carcinomas
Renal cell carcinomas should be treated surgically at an early stage. If possible, the kidney should be preserved or only partially removed. The adrenal gland should also not be removed if possible. Cryoablation or radiofrequency ablation are options for treating small tumors (<3cm). A kidney transplant is necessary if both kidneys need to be removed.
Pheochromocytomas
Pheochromocytomas should be surgically removed. As these are hormone-producing tumors, drug therapy is advisable before surgery. Partial removal of the adrenal glands is the treatment for children and can also be considered for adults.
Cysts and Neuroendocrine Tumors of the Pancreas
Cysts do not usually need to be surgically removed. Tumors should be surgically removed, if they are larger than 3 cm, grow rapidly, or have certain genetic changes.
Endolymphatic Sac Tumors (Inner Ear Tumors)
Early surgical removal is recommended. However, deafness cannot be ruled out after surgery.
Cystadenomas of the Ovaries/Oviducts and Epididymis
As a rule, no surgical treatment is required as long as they do not cause any symptoms or threaten fertility.
Diagnosis of " Von-Hippel-Lindau Syndrome" What's Next?
If you have been diagnosed with this cancer predisposition syndrome, it is important to see a specialist. The following section explains whether cancer screening tests or other measures are needed and how they should be carried out. We also give you some valuable tips on what you can do yourself. If you have any questions, please do not hesitate to contact us or your doctor.
Diagnosis of " Von-Hippel-Lindau Syndrome" What's Next?
If you have been diagnosed with this cancer predisposition syndrome, it is important to see a specialist. The following section explains whether cancer screening tests or other measures are needed and how they should be carried out. We also give you some valuable tips on what you can do yourself. If you have any questions, please do not hesitate to contact us or your doctor.
Medical Measures for Early Detection
Regardless of age, every person with Von Hippel-Lindau syndrome should have an annual clinical examination. This medical check-up includes blood pressure checks, neurological examinations, and a visual or hearing examination. In addition, people with VHL should be informed about the symptoms and signs of the disease. Ideally, all VHL patients should be cared for by a doctor familiar with Von Hippel-Lindau syndrome and can draw on a multidisciplinary team.
With regard to the individual manifestations of VHL, the American Association for Cancer Research (AACR) suggests the following early detection recommendations:
Hemangioblastomas of the Retina
- Annual ophthalmologic examination including examination of the retina from birth
Pheochromocytoma
- Blood pressure checks at every medical appointment from 2 years of age
- Annual blood or urine test for adrenal hormones from 2 years of age
In the event of abnormalities, imaging or a repeat examination should be carried out after 2 or 6 months, depending on the values
Endolymphatic Sac Tumors
- Audiogram every two years from the age of 5
CNS Haemangioblastoma
- Every two years (annually from adulthood if necessary) MRI of the head with and without contrast medium + thin-layer images of the internal auditory canal from 8 years of age
- MRI of the spinal cord with contrast medium every two years (annually from adulthood if necessary) from 8 years of age
Renal Cell Carcinomas
- Annual MRI of the abdomen from the age of 10 (can be done together with screening for NET of the pancreas)
Neuroendocrine Tumor of the Pancreas
- Annual MRI of the abdomen from the age of 10 (can be carried out together with screening for renal cell carcinoma)
Von-Hippel-Lindau Syndrome- What You Can Do Yourself
You Should Pay Attention to This
You should consult a doctor when neurological symptoms such as headaches, vomiting, coordination difficulties, gait instability, sensory or motor deficits, or pain occur. Changes in vision or hearing should also be noted and reported to a doctor. You should also consult a doctor if you experience any new abnormalities or complaints, e.g., abdominal pain, palpitations, or dizziness.
Further Information
Patients can also register for the CPS registry at any time or have this done by their doctors in charge.
Any further questions?
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