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Association of patients with Von Hippel-Lindau syndrome
SREN
Rare inherited disorder · ICD-10 Q85.8

What is Von Hippel-Lindau syndrome?

Von Hippel-Lindau (VHL) syndrome is an inherited disorder that leads to the development of multiple tumors and cysts across several organs. Most are benign, but there is a risk of malignant change, which is why early diagnosis and lifelong surveillance are key to the outcome.

Cause

A mutation in the VHL gene

The VHL gene is located on chromosome 3p25 and belongs to the family of tumor-suppressor genes, genes that under normal conditions prevent uncontrolled cell growth.

When the VHL gene is mutated, control over the HIF factor (hypoxia-inducible factor) is lost. HIF accumulates and drives the formation of blood vessels and cell growth, which leads to the development of the characteristic tumors and cysts.

VHL syndrome is autosomal dominant: it is enough for a person to inherit one copy of the mutated gene to develop the disease.

Manifestations

Tumors and cysts across multiple organs

Not all manifestations appear in every person or to the same degree. The combination and severity vary even within the same family.

Brain and spinal cord

Hemangioblastomas, the most common manifestation. They can cause headache, dizziness and loss of balance.

Eyes

Retinal hemangiomas (angiomas). Without surveillance they can lead to loss of vision.

Kidneys

Cysts and clear-cell renal carcinoma. Multiple, bilateral, often before the age of 50.

Pancreas

Cysts (most often benign) and neuroendocrine tumors. Largely asymptomatic.

Adrenal glands

Pheochromocytoma, which can cause hypertension, palpitations and headaches.

Endolymphatic sac

An inner-ear tumor (ELST) can cause hearing loss and tinnitus.

Important note about age: There is no rule about the age at which symptoms appear. They can show up at any time of life, from childhood to later years. They also differ between members of the same family.
Inheritance

A 50% risk for every child

VHL is inherited in an autosomal dominant manner. Every child of an affected parent has a 50% chance of inheriting the mutation, regardless of whether older siblings have the disease.

Family screening

When VHL is found in one family member, genetic testing is recommended for first-degree relatives (parents, siblings, children), even if they have no symptoms.

De novo mutations

About 20% of cases are de novo, the mutation is not inherited but arises for the first time in that patient. Their children still have a 50% risk.

Diagnosis

Clinical and genetic confirmation

A diagnosis of VHL syndrome is made by combining clinical criteria and a genetic test.

  1. 1

    Suspicion based on symptoms or family history

    Several characteristic tumors in one person, or a patient with a single VHL tumor and a positive family history.

  2. 2

    Imaging

    MRI of the brain and spine, abdominal MRI / CT, ophthalmologic examination and a hearing test, to map existing tumors.

  3. 3

    Genetic test

    Sequencing of the VHL gene from blood. It identifies the specific mutation in the family and enables predictive testing of relatives.

  4. 4

    Determining the VHL type

    Type 1 (without pheochromocytoma) and Type 2 (with pheochromocytoma; subgroups 2A, 2B, 2C). The type determines surveillance priorities.

Surveillance

Lifelong, systematic, multidisciplinary

The goal of surveillance is to detect and treat tumors early while they are still small, before they cause lasting damage.

  • MRI of the brain and spine
    Monitoring of hemangioblastomas; interval based on the physician's individual assessment.
  • Ophthalmologic examination
    Retinal fluorescein angiography; annually from early childhood.
  • Abdominal MRI / ultrasound
    Monitoring of the kidneys, pancreas and adrenal glands.
  • Plasma / urine metanephrines
    Screening for pheochromocytoma; timing as advised by the physician.
  • Audiologic examination
    Hearing assessment as part of ELST tumor surveillance.
A note on protocols: In Serbia there are still no formal protocols for the surveillance of VHL patients. The intervals listed above are indicative, based on the international guidelines of the VHL Alliance (USA) and VHL Europa. A specific surveillance plan is agreed with the physicians at UKC Srbije (University Clinical Center of Serbia).
Treatment

A multidisciplinary approach

Treatment of VHL is tailored to the individual, which organs are affected, how fast the tumors are growing, and what the patient's personal priorities are. A team of physicians from different specialties decides together on the next steps, from regular surveillance to surgical interventions.

A team of physicians - the multidisciplinary approach to the surveillance and treatment of VHL patients.

Multidisciplinary surveillance

A neurosurgeon, endocrinologist, urologist, ophthalmologist and oncologist all work with the patient throughout life.

Surgical interventions

When needed, when a tumor causes symptoms or carries a risk of malignant transformation.

Targeted systemic therapy

Belzutifan - a HIF-2α inhibitor, registered in the USA and the EU. *Currently not available in Serbia.*

Modern therapy

Belzutifan - a HIF-2α inhibitor

Belzutifan (brand name Welireg, made by MSD) is an oral medicine that blocks the HIF-2α protein, the very one that accumulates because of the mutated VHL gene. Clinical trials show a reduction in tumor size and a delay of surgical interventions in a significant number of patients.

Status in Serbia

Belzutifan is currently not available in Serbia. There is also no donation program from the manufacturer MSD. The Association is actively working to advocate for access to this therapy for VHL patients in Serbia.

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Frequently asked questions

Questions and answers

What is Von Hippel-Lindau (VHL) syndrome?
VHL is an inherited disorder that leads to the development of multiple tumors and cysts in various organs, most often the brain and spine, eyes, kidneys, pancreas, adrenal glands and inner ear. Most tumors are benign, but there is a risk of malignant change, which is why early diagnosis and lifelong surveillance are essential.
How is VHL syndrome inherited?
VHL is inherited in an autosomal dominant manner, which means that every child of an affected parent has a 50% chance of inheriting the mutation. About 20% of cases are de novo mutations, which are not inherited but arise for the first time in that patient. Their children still have a 50% risk of inheriting it.
At what age do the symptoms of VHL syndrome appear?
There is no rule about age, symptoms can appear at any time of life, from childhood to later years, and they differ from one patient to another, even within the same family. That is why regular surveillance from early childhood is essential for people with a confirmed mutation.
How is VHL diagnosed?
The diagnosis is made by combining clinical criteria (several characteristic tumors in one person, or a patient with a single VHL tumor and a positive family history), imaging (MRI of the brain and spine, abdominal MRI/CT, ophthalmologic examination) and a genetic test that sequences the VHL gene from blood.
Is belzutifan available in Serbia?
Belzutifan (Welireg, made by MSD) is registered in the USA (2021) and the EU (2023), but it is currently NOT available in Serbia. There is no manufacturer donation program nor reimbursement by the RFZO (the national health insurance fund). The Association is actively working to advocate for access to this targeted therapy for VHL patients in Serbia.
Is VHL syndrome curable?
As a genetic disorder, VHL cannot be cured in the sense of removing its cause, but it can be successfully monitored and treated. The goal of care is early detection and intervention while tumors are still small, before they cause lasting damage. A multidisciplinary team of physicians (neurosurgeon, endocrinologist, urologist, ophthalmologist, oncologist) follows the patient throughout life.
Where can I get help and information in Serbia?
The primary reference center for VHL patients in Serbia is UKC Srbije (University Clinical Center of Serbia), the Clinic for Endocrinology, Diabetes and Metabolic Diseases. The Association of Patients with Von Hippel-Lindau Syndrome (founded in December 2025) connects patients, families and physicians, reach out via the contact page.

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