Von Hippel-Lindau (VHL) disease is a rare genetic condition that makes the body grow tumors and fluid-filled cysts in many organs. Most of the tumors are non-cancerous, but some, such as kidney cancer, can be life-threatening. The problem starts with a spelling error (mutation) in a single gene called VHL. Every cell in the body carries two copies of this gene. When one copy is already faulty from birth and the second copy later gets damaged in a single cell, that cell loses its natural “tumor brake,” and a growth can begin. NINDS
Von Hippel–Lindau (VHL) disease is a life-long, inherited condition that makes certain cells grow too easily into benign or cancerous tumors in different body parts—most often the eyes (retina), brain and spinal cord (hemangioblastomas), kidneys (clear-cell renal cell carcinoma and cysts), pancreas (cysts and neuroendocrine tumors), inner ear (endolymphatic sac tumors), and adrenal glands (pheochromocytoma). It happens because a change (mutation) in the VHL gene turns the body’s oxygen-sensing switch “too high,” so HIF (hypoxia-inducible factor) stays on and drives new blood vessel growth and tumor growth. VHL passes in families (autosomal dominant), but new (first-time) mutations can happen. Regular screening and early, targeted treatment help people live much longer, safer lives. NCBI
One key update you should know:
A targeted pill called belzutifan (brand WELIREG, a HIF-2α inhibitor) is now approved for adults with VHL who need treatment for associated RCC, CNS hemangioblastomas, or pancreatic NETs that don’t need immediate surgery. Standard dose is 120 mg by mouth once daily; common issues include anemia and low oxygen (hypoxia), so doctors monitor blood counts and oxygen levels. There’s also a (separate) approval for advanced RCC after prior immunotherapy and VEGF-TKI. FDA Access DataAACR Journals
The gene defect follows an autosomal-dominant pattern. That means a child only needs to inherit one changed copy—from the mother or the father—to be at risk. Each child of an affected parent has a 50 % chance of having the condition. About 20 % of people with VHL, however, are the first in their family to have it; their mutation arose de novo (as a brand-new genetic accident in the egg, sperm, or very early embryo). NCBI
Because the gene is active in almost every tissue, VHL can touch almost any body system. The most common growths are hemangioblastomas—tiny knots of blood vessels—inside the retina, brain, or spinal cord. Others include adrenal gland tumors (pheochromocytomas), tumors of the inner ear, cysts in the pancreas or liver, and clear-cell renal cell carcinoma (a type of kidney cancer). National Organization for Rare Disorders
Inside healthy cells, the VHL protein behaves like a trash-collector. Its main job is to mark an oxygen-sensing protein called HIF-α for destruction when oxygen levels are normal. If VHL is missing or broken, HIF-α piles up. The cell wrongly “believes” it is starved of oxygen and switches on more than 100 emergency genes that build extra blood vessels, encourage cell division, and block normal cell death. Over years, that biochemical confusion helps tumors and cysts form. ScienceDirect
Recognized types of Von Hippel-Lindau disease
Clinicians group VHL into sub-types because certain mutations carry higher or lower risks for specific tumors. Knowing the type guides screening plans for each family member.
Type 1 (classic VHL without pheochromocytoma) – High risk of hemangioblastomas and kidney cancer, but low chance of adrenal tumors.
Type 2A – Adds pheochromocytoma risk while kidney cancer risk stays modest.
Type 2B – High risk of both pheochromocytoma and kidney cancer.
Type 2C – Almost exclusively pheochromocytoma, few other tumors.
Mosaic VHL – The mutation is not in every cell; disease may be milder or limited to one body region.
Sporadic (de novo) VHL – First affected member in a family; future generations face the same 50 % inheritance risk. ACS Journals
Each type shares the same root genetic glitch, but the pattern and timing of tumors differ. That is why lifelong, organ-specific monitoring is essential even when a person feels perfectly healthy.
Causes of tumor
(While the underlying cause is always the inherited VHL mutation, scientists can list many direct molecular or cellular “drivers” that push a VHL-mutant cell toward uncontrolled growth. Each item below names one driver and then explains it in very simple English.)
1. Loss of the second VHL allele – Every cell has two VHL genes. When the second, healthy copy gets damaged later in life, the cell fully loses VHL protection and starts multiplying.
2. HIF-α build-up – Without working VHL protein, HIF-α is not destroyed. It gathers in the nucleus and switches on growth genes.
3. Over-production of VEGF (vascular endothelial growth factor) – HIF-α tells the cell to pour out VEGF, a signal that orders nearby blood vessels to sprout, feeding the growing tumor.
4. Excess PDGF-β (platelet-derived growth factor beta) – Another HIF-controlled chemical that encourages support cells to wrap around new vessels, stabilizing the tumor’s blood supply.
5. Increased EPO (erythropoietin) – Kidneys or liver cysts may over-secrete EPO, raising red blood cell count and thickening the blood.
6. Metabolic re-programming – VHL-deficient cells rely more on sugar burning (glycolysis), helping them survive in low oxygen pockets inside tumors.
7. Reactive oxygen species (ROS) stress – The altered metabolism produces more ROS, causing DNA damage that can speed further mutations.
8. Failure of cilia maintenance – The VHL protein also helps build tiny cellular antennas (cilia). Without them, kidney tubule cells lose orientation and form cysts.
9. Chromosome instability – VHL loss upsets the machinery that divides chromosomes, so daughter cells inherit random DNA errors and grow even more chaotic.
10. Telomere shortening escape – Some VHL tumors activate the enzyme telomerase, letting them evade the normal age-related stop signal.
11. Abnormal Notch signaling – Missing VHL can crank up Notch pathway messages, pushing cells to keep dividing.
12. Dysregulated mTOR pathway – The mTOR “growth switch” stays on, telling cells they have enough nutrients and should grow, even when they should rest.
13. MicroRNA imbalance – VHL helps control tiny RNA molecules that silence genes. Its absence lets tumor-promoting messages run free.
14. Hypoxia-independent HIF activation – Certain missense mutations allow HIF to accumulate even in oxygen-rich tissues, promoting tumors early in life.
15. Hormonal surges – High adrenaline bursts in pheochromocytoma may generate more oxidative stress, fueling growth in nearby VHL-mutant cells.
16. Chronic inflammation – Cysts can leak proteins that attract immune cells, releasing growth factors that “feed” neighboring mutant cells.
17. UV-light or radiation damage – External DNA damage can strike the remaining healthy VHL copy in the skin or other tissues, triggering local tumors.
18. Chemical carcinogens – Tobacco smoke toxins attack DNA and can knock out the second VHL gene in kidney or pancreatic cells.
19. Age-related wear – Natural cell division over years simply increases the chance that the second allele will mutate by accident.
20. Germline large-scale deletions – Some families carry a big chunk of missing DNA around VHL plus neighboring genes, which may remove extra tumor-suppressor signals and speed disease.
Common symptoms
Each paragraph names one symptom in bold, then details it in simple English.
1. Headache – A benign hemangioblastoma pressing on nearby brain tissue can cause persistent or throbbing headaches that do not ease with usual pain pills.
2. Balance problems – When a tumor sits in the cerebellum (the body’s balance center) people may stagger, veer sideways, or feel dizzy.
3. Vision loss or blurry vision – Small retinal hemangioblastomas can leak fluid and blood, blurring central or side vision; untreated they may cause blindness.
4. Eye “floaters” or flashes – Retinal tumors sometimes bleed tiny specks that look like moving shadows or sparkles to the patient.
5. Hearing loss or ringing (tinnitus) – Tumors in the endolymphatic sac of the inner ear can muffle sounds or create a high-pitched ring.
6. Sudden high blood pressure – Pheochromocytomas surge adrenaline into the bloodstream, causing dangerous spikes in blood pressure, pounding heart, and sweating.
7. Palpitations – The same adrenal hormones can make the heart race or beat irregularly, often in stressful situations but sometimes at rest.
8. Abdominal pain or back pain – Large kidney cysts or pancreatic tumors stretch the capsule of the organ or press on nerves.
9. Blood in the urine – Small fragile vessels in kidney tumors can break, tinting the urine pink, red, or cola-colored.
10. Fatigue – Chronic anemia from hidden bleeding, or high red-cell mass from extra EPO, may both leave patients feeling tired and weak.
11. Weakness or numbness in the limbs – A spinal hemangioblastoma presses on the spinal cord, causing loss of strength or sensation below the level of compression.
12. Loss of fine motor skills – Subtle tumors in brainstem regions may make handwriting sloppy or buttons hard to fasten.
13. Frequent urination – Adrenal tumors can alter kidney blood flow and hormone balance, making the bladder fill quickly.
14. Unintended weight loss – Malignant kidney cancer or high metabolic stress from repeated surgery can burn calories faster than a person eats.
15. Emotional distress – Living with unpredictable tumors can cause anxiety and depression, which themselves worsen sleep, appetite, and well-being. UCLA Health
Diagnostic tests
(Again, one paragraph for each test explains what it is, how it works, and why doctors use it for VHL.)
A. Physical-Examination & Bedside Tests
1. Comprehensive neurologic exam – The doctor checks eye movements, reflexes, walking pattern, and coordination to spot clues of brain or spinal tumors.
2. Ophthalmoscopy (fundus exam) – Using a handheld light, the provider peers into the back of the eye looking for tiny red retinal hemangioblastomas.
3. Serial blood-pressure readings – Multiple arm measurements—sitting, standing, and during stress—help reveal adrenal hormone surges.
4. Abdominal palpation and percussion – Careful feeling and tapping over the belly may detect enlarged kidneys or tender cystic masses.
5. Bedside hearing test (whisper & tuning fork) – Quick checks can pick up early unilateral hearing loss that hints at an inner-ear lesion.
B. Manual or Functional Tests
6. Finger-to-nose and heel-to-shin test – Simple coordination drills uncover subtle cerebellar dysfunction from brain hemangioblastomas.
7. Romberg test – The patient stands with feet together and eyes closed; swaying signals impaired proprioception from spinal cord compression.
8. Visual-field perimetry – A bowl-shaped device maps missing areas in side vision, spotting retinal or optic-tract defects.
C. Laboratory & Pathological Tests
9. Germline VHL gene sequencing – A blood sample is sent to a genetics lab that reads every “letter” of the VHL gene, confirming the diagnosis with near-definitive accuracy. ACS Journals
10. Multiplex ligation–dependent probe amplification (MLPA) – This test looks for large missing or extra DNA chunks around VHL that regular sequencing can miss.
11. Plasma-free metanephrines – A blood draw measures breakdown products of adrenaline; high levels point to pheochromocytoma.
12. 24-hour urine catecholamines – Collecting a whole day’s urine captures hormone surges that a single blood test might miss.
13. Serum erythropoietin level – Very high EPO can suggest kidney cysts or tumors making the hormone in excess.
14. Tumor biopsy with immunostaining – If imaging shows an unusual mass, a small tissue sample under the microscope can confirm VHL-related tumor types.
D. Electrodiagnostic Tests
15. Brainstem auditory evoked potentials (BAEP) – Sticky scalp electrodes measure tiny electrical responses after a click sound, detecting nerve pathway block from inner-ear tumors.
16. Somatosensory evoked potentials (SSEP) – A mild electrical pulse to a limb while recording signals over the spine shows whether a spinal cord hemangioblastoma is slowing conduction.
17. Electrocardiogram (ECG) during catecholamine surge – Recording heart rhythm while symptoms occur helps link palpitations to adrenal hormone bursts.
E. Imaging Tests
18. Magnetic resonance imaging (MRI) of brain and spine – MRI uses magnets, not X-rays, to create sharp pictures of nervous-system tumors without radiation exposure; it is the gold standard for VHL surveillance. PMC
19. MRI of abdomen with contrast – This scan finds tiny kidney tumors or pancreatic cysts long before they cause trouble.
20. Computed tomography (CT) of chest, abdomen, and pelvis – CT takes many X-ray slices; it is faster than MRI and excellent at spotting lung nodules or bone lesions.
21. Ultrasound scan of kidneys – A quick, radiation-free test that can be repeated often to measure cyst size in children and pregnant patients.
22. Contrast-enhanced ultrasound of pancreas – Micro-bubble contrast highlights blood flow, making small pancreatic neuroendocrine tumors easier to see.
23. Retinal fluorescein angiography – Dye injected into a vein illuminates tiny leaking capillaries in the retina under a special camera.
24. Positron-emission tomography (PET) with DOPA tracer – Shows hyper-active adrenal or extra-adrenal pheochromocytomas when CT/MRI are unclear.
25. 68-Ga-DOTATATE PET-CT – A newer scan that binds to somatostatin receptors on neuroendocrine tumors, spotting lesions missed by older tracers.
26. Whole-body MRI – Some centers offer a single scan from head to thigh each year, reducing the need for multiple separate imaging sessions.
