Von Hippel-Lindau Disease: The Inherited Tumor Condition and Its Surveillance Record

Table of Contents

1. The Condition in Brief
2. How the Name Came Together
3. The Gene and the Oxygen Switch
4. Which Tumors and Cysts Occur, and at What Ages
5. Genotype and Phenotype Types
6. Published Surveillance Schedules
7. What Surveillance Has Been Measured to Do
8. Surgery and Other Local Treatment by Tumor Site
9. The 3 cm Kidney-Sparing Threshold
10. Belzutifan Trial Numbers
11. Life Expectancy Data
12. What Is Not Known
13. Key Research Papers
14. Connections
15. Featured Videos

The Condition in Brief

The disease passes through families in a dominant pattern, so one altered copy of the gene is enough, and the child of an affected parent starts with a 50% chance of inheriting it (Maher 2022). Up to 20% of newly diagnosed people have a new change in the gene and no family history (Chittiboina and Lonser 2015).

How common it is depends on who counted and how:

• A 1991 study in the East Anglia region of England estimated about 1 in 36,000 live births and a point prevalence of about 1 in 53,000 people (Maher 1991, PMID 1895313).
• The first national estimate, from Denmark, was 1 in 27,300 live births and 1 in 46,900 people. The same study found that as many as 25% of the people who met the diagnostic criteria had never been diagnosed (Binderup 2017, PMID 27966541).

Nearly everyone who carries the altered gene eventually shows some sign of the disease, but not on a fixed timetable. The 1991 study estimated penetrance, the chance that a carrier has shown the disease, at 0.96 by ages 51 to 60 and 0.99 by ages 61 to 70 (Maher 1991). The Danish cohort found 87% at age 60, and among carriers who had not attended surveillance, 20% still had no symptoms at that age (Binderup 2017).

Back to Table of Contents

How the Name Came Together

The name joins two men who described different ends of the same disease, about two decades apart. The account below follows the history section of a 2015 review (Chittiboina and Lonser 2015), with the dates of von Hippel's and Lindau's work as given in a 2025 review (Jung and Park 2025).

• 1894, Treacher Collins. Collins described the retinal growths in eyes removed from a brother and sister, the first report pointing to a family pattern.
• 1904, Eugen von Hippel. Von Hippel studied the clinical appearance and progression of these retinal lesions, and later, with confirmation from a removed eye, named them angiomatosis retinae.
• 1921, the autopsy. Brandt reported the autopsy of the same patient. Kidney cysts and tumors and epididymal cysts were among the features later linked to the condition, which reached beyond the eye.
• 1926, Arvid Lindau. Lindau reviewed 16 of his own patients and 24 from the literature. He connected cerebellar cysts with small tumor nodules to growths in the medulla and spinal cord, retinal lesions and tumors of internal organs, and proposed the term central nervous system angiomatosis. His work earned a Rockefeller fellowship in Harvey Cushing's Boston laboratory and the Lennmalm Prize (Huntoon 2015, PMID 25748307).
• 1964, the first clinical criteria. Melmon and Rosen, writing under the name "Lindau's disease," studied a large family and defined the disease as a cerebellar hemangioblastoma plus a retinal growth, a pancreatic cyst, or a kidney or epididymal abnormality. They also recognized its inheritance (Melmon and Rosen 1964, PMID 14142412).
• 1993, the gene. The gene was mapped to chromosome 3 in 1988 (Jung and Park 2025, PMID 40109021) and isolated in 1993 by a group that found rearrangements of it in 28 of 221 affected families (Latif 1993, PMID 8493574).

Later authors shortened the descriptive terms to the double name. The two older labels survive in the literature: von Hippel tumors for those in the retina, Lindau's tumors for those in the cerebellum (Chittiboina and Lonser 2015).

Back to Table of Contents

The Gene and the Oxygen Switch

The von Hippel-Lindau gene sits on the short arm of chromosome 3, has three exons, and makes a protein of 213 amino acids. It behaves as a tumor suppressor under the "two-hit" model. A person inherits one faulty copy in every cell, and a tumor starts when a single cell loses the working copy too. In one analysis summarized in the review, that second hit was most often loss of the working copy (49%) or its silencing by chemical marking (35%) (Chittiboina and Lonser 2015).

What that protein does was worked out in a short run of papers:

• 1999. Peter Ratcliffe's group showed in cells that when the von Hippel-Lindau protein is defective, the alpha part of hypoxia-inducible factor, the master regulator of the response to low oxygen, stays stable and active even with oxygen present. Putting the protein back restored its normal oxygen-dependent breakdown (Maxwell 1999, PMID 10353251).
• 2001. William Kaelin's group and Ratcliffe's group reported, in back-to-back papers, that the protein recognizes hypoxia-inducible factor only after a proline in it has been chemically modified, a reaction that needs oxygen and iron (Ivan 2001, PMID 11292862; Jaakkola 2001, PMID 11292861).

In plain terms, oxygen allows a small mark to be placed on hypoxia-inducible factor. The von Hippel-Lindau protein reads that mark and tags the factor for disposal. Without a working protein no disposal happens, and the cell behaves as if it were short of oxygen even when it is not. Hypoxia-inducible factor switches on over 50 genes, including those for blood-vessel growth, growth signals and sugar use (Chittiboina and Lonser 2015). The 1999 authors proposed that this constant activation may explain why these tumors are so rich in blood vessels (Maxwell 1999).

The 2019 Nobel Prize in Physiology or Medicine went to Kaelin, Ratcliffe and Gregg Semenza for their discoveries of how cells sense and adapt to oxygen availability. The page on the three laureates covers that history.

The link reached beyond this rare disease. The same gene is altered in up to 90% of non-inherited clear-cell kidney cancers (Chittiboina and Lonser 2015). Kaelin's 2022 review states that hypoxia-inducible factor 2 in particular drives the growth of kidney cancers that lack the protein, which is the basis for the drug class described below (Kaelin 2022).

Back to Table of Contents

Which Tumors and Cysts Occur, and at What Ages

The table sets two published summaries side by side. The middle columns come from a 2015 review (Chittiboina and Lonser 2015) and the last from a 2025 review (Jung and Park 2025). The ranges are wide because the underlying studies differed in who they enrolled and how hard they looked.

The large single cohorts add detail that summary ranges hide.

Retina

Among 335 patients with retinal hemangioblastomas, 57.9% had them in both eyes. Of the affected eyes, 13.4% had been removed or were in the stage before a blind, shrunken eye, and about 1 in 5 patients had at least one such eye (Wong 2008). A 2015 review gives a median onset of 21 years, the earliest of any site (Chittiboina and Lonser 2015).

Brain and spinal cord

A prospective study followed 225 patients who carried 1,921 hemangioblastomas at entry, 45% in the cerebellum and 36% in the spinal cord. Hemangioblastomas are benign under the microscope, but their growth was hard to predict. About half of tumors did not grow at all (51%), and those that did mostly grew in stops and starts (72%). Of the tumors, 159 (6.3%) produced symptoms (Lonser 2014). Symptoms often come from the fluid cyst rather than the tumor. In an earlier series, 72% of symptom-producing cerebellar tumors had a cyst, against 13% of those causing no symptoms, and by the time of surgery cerebellar cysts were about 34 times the size of their tumors. No tumor or cyst shrank on its own (Wanebo 2003).

Kidney

The cancers are of the clear-cell type and tend to be multiple and in both kidneys, often among many cysts. Solid parts within cysts contain cancer (Chittiboina and Lonser 2015). In the United Kingdom audit, the mean age at detection was 39.4 years, and the mean size at detection 2.16 cm (Maher 2022).

Adrenal glands

Of 273 patients in a natural history study, 31% were diagnosed with pheochromocytoma, at a mean age of 28.8 years. The earliest was at 5.5 years, and 25% of these tumors were found before age 19 (Aufforth 2015). These tumors can be silent: in another series, 35% of 37 tumors came with no symptoms, normal blood pressure and normal catecholamine tests (Walther 1999). A plasma normetanephrine and metanephrine test reached 97% sensitivity and 96% specificity in one study of people at inherited risk (Eisenhofer 1999).

The safety fact here is plain: these tumors release stress hormones. Reported effects are sudden or sustained high blood pressure, palpitations, headache, sweating, pallor and nausea, with life-threatening hypertensive crises, heart rhythm problems, fluid in the lungs and heart attack among the complications, and hypertensive crises reported in children under 10 (Chittiboina and Lonser 2015).

Pancreas

In a French study that scanned 158 consecutive patients, 77.2% had pancreatic involvement, mostly true cysts. Only 8.2% of those with pancreatic lesions needed specific treatment (Hammel 2000). At one center, 108 of 633 patients (17%) had pancreatic neuroendocrine tumors, and 9 of the 108 had spread. Tumors over 3 cm were more likely to spread (Blansfield 2007).

Inner ear

Endolymphatic sac tumors grow from part of the inner-ear system, within the temporal bone of the skull. On magnetic resonance imaging of 121 patients with the disease, 13 (11%) had them, and none of 253 screened people without the disease did. All 13 had hearing loss, at a mean onset of 22 years, and it was the first sign of the disease in 8 of them (Manski 1997).

Back to Table of Contents

Genotype and Phenotype Types

Families do not all get the same tumors, and the classic split rests on one question: does pheochromocytoma run in the family. In 1995, a study found changes in the gene in 85 of 114 families (75%). In families without pheochromocytoma, labeled type 1, 56% of the mutations were small deletions or insertions, nonsense changes or deletions. In families with it, labeled type 2, 96% were missense changes, in which a single amino acid is swapped (Chen 1995). Newer testing finds a change in nearly 100% of patients, with mosaicism, a change present in only some of the body's cells, able to produce a false negative blood test (Chittiboina and Lonser 2015).

Table as given in a 2025 review (Jung and Park 2025). The 2015 review adds that changes at position 167 carried a 60% kidney cancer risk by age 60 and an 82% pheochromocytoma risk by age 50, and that 16 type 2A families from Germany's Black Forest region share one founder mutation (Chittiboina and Lonser 2015).

Two refinements come from later analysis. In 573 people, surface amino-acid swaps carried a higher pheochromocytoma risk than swaps that disrupted the protein's structure, and nonsense or frameshift changes brought an earlier first sign and higher age-related risks of retinal tumors and kidney cancer (Ong 2007).

Types describe family patterns, not one person's future. A large type 2A family, followed over five decades, showed 71% lifetime risk of pheochromocytoma or paraganglioma and 3% for kidney cancer, yet different branches of that one family expressed different tumors (Nielsen 2011).

Back to Table of Contents

Published Surveillance Schedules

Surveillance means repeat testing of carriers and at-risk relatives before symptoms appear. The current international reference is the consensus statement of the International VHL Surveillance Guidelines Consortium and the VHL Alliance, published in 2023 (Daniels 2023). The schedule below is as tabulated in a 2025 review, which later corrected "biannually" to "biennially" in this table (Jung and Park 2025; corrigendum 2025).

How other bodies and groups have set it

Schedules have never been uniform. A 2015 review compared three programs of that time (Chittiboina and Lonser 2015):

Other published positions:

• Pediatric oncology series, 2017. The authors proposed earlier starts and more frequent checks than older programs, with the emphasis on risks in childhood (Rednam 2017, PMID 28620007). The abstract does not list the schedule.
• Denmark, 2022. The updated national guideline states that surveillance starts in childhood in people with or at risk of the disease and covers the retina, brain and spine, inner ear, kidneys, hormone-making glands and pancreas. It was written with input from Danish patients (Binderup 2022, PMID 35709961).
• European review used in the United Kingdom audit. It lists yearly eye examinations beginning in infancy or early childhood, head magnetic resonance imaging every 12 to 36 months from adolescence, abdominal magnetic resonance imaging or ultrasound every 12 months from age 16, and yearly blood pressure and 24-hour urine studies (Maher 2022, PMID 35184155, quoting Maher 2011, PMID 21386872).

The real-world picture varied too. Across 19 United Kingdom centers seeing 842 people, all offered retinal, brain and spine, and abdominal checks, yet details differed. Most (13 of 18 centers with formal clinics) began eye checks at age 5, and not all offered regular brain and spine imaging (Maher 2022).

Back to Table of Contents

What Surveillance Has Been Measured to Do

The studies that exist are observational. In 2010, a Danish group wrote that recommendations then relied on best medical judgment and that no evidence of effect existed, then set out to measure it from the records of 54 living carriers (Poulsen 2010). Findings across the record include:

• Earlier detection. Yearly eye and abdominal checks left a 1.7% and 1.2% risk of a new finding between visits. Brain and spine imaging every 2 years left a 7.2% risk, against 2.7% when done every year. Of the brain and spine findings from surveillance, 71% (106 of 150) had clinical consequences for the patient (Poulsen 2010, PMID 19863552).
• Eye tumors and kidney cancer found sooner. In 573 people, routine surveillance was linked to more retinal tumors detected (73% against 59%) and a lower age at kidney cancer diagnosis (39.7 against 44.0 years) (Ong 2007, PMID 17024664).
• Smaller kidney tumors at detection. In the United Kingdom audit, tumors on a person's first scan averaged 3.07 cm against 1.88 cm on later scans. Of the brain and spine tumors, 62% were found without symptoms on a scan (Maher 2022, PMID 35184155).
• Survival. The Danish survival study concluded that surveillance is especially beneficial for carriers of truncating mutations, who have the greatest risk of kidney cancer and of brain and spine tumors (Binderup 2017, PMID 27539272).

A general limit applies to studies of this kind: finding a disease earlier can lengthen measured survival by itself, because the clock starts sooner (lead-time bias). None of the abstracts read for this page reports a randomized comparison of one schedule against another.

Back to Table of Contents

Surgery and Other Local Treatment by Tumor Site

A 2025 review describes the aim of current management as keeping tumors controlled and function intact over a lifetime, rather than removing every growth (Jung and Park 2025).

• Brain and spinal cord. Microsurgery is reported as the main treatment (Chittiboina and Lonser 2015, PMID 26564077). A series of 44 patients having 55 operations for 86 spinal tumors concluded that these tumors can be removed safely in most patients, generally once they cause symptoms or signs (Lonser 2003, PMID 12546358). Reports on radiation differ. The 2015 review states that treated tumors keep growing in about the proportion natural history would predict (Chittiboina and Lonser 2015, PMID 26564077), while the 2025 review gives 5-year control rates of 91.9–93% for radiosurgery in tumors that are hard to reach surgically (Jung and Park 2025, PMID 40109021).
• Eye. Laser treatment and freezing (cryotherapy) are the mainstays, with drugs injected into the eye against vascular endothelial growth factor used for some small tumors near the optic nerve (Chittiboina and Lonser 2015, PMID 26564077).
• Inner ear. Surgery is the reported treatment, with recurrence of 3% after complete removal. The review describes early removal as recommended to protect hearing and relieve balance symptoms, and the role of radiation is unproven (Chittiboina and Lonser 2015, PMID 26564077).
• Adrenal gland. Reviews describe laparoscopic partial removal of the gland so that some hormone-making tissue remains, with long-term follow-up for recurrence (Chittiboina and Lonser 2015, PMID 26564077). In one cohort, 8 patients had 9 recurrences, as long as 39.7 years after the first operation (Aufforth 2015, PMID 26451910). The stress-hormone hazard is why the review describes 10 to 14 days of alpha-blocking medicine before elective surgery, with hypertensive crisis and heart rhythm problems as the reported risks (Chittiboina and Lonser 2015, PMID 26564077).
• Pancreas. Cysts without symptoms usually need no treatment (Chittiboina and Lonser 2015, PMID 26564077). For neuroendocrine tumors, one center reported selecting surgery on three features: size over 3 cm, changes in exon 3 and rapid doubling (Blansfield 2007, PMID 18063061).

Back to Table of Contents

The 3 cm Kidney-Sparing Threshold

Kidney cancer in this disease creates a problem unlike ordinary kidney cancer. New tumors keep forming in both kidneys for decades, so removing a whole kidney at each discovery leads toward dialysis. The approach that emerged is to watch small solid tumors with repeated imaging and operate, sparing as much kidney as possible, when the largest reaches 3 cm in diameter. The kidney cancer page covers the disease in general.

The evidence comes from one research group's follow-up:

The groups are not a randomized comparison, and the update notes that patients who were not being screened often had large tumors. The proportion of operations that spared kidney tissue was also much higher in the small-tumor group: 96% against 63% in the first report (Walther 1999), and 97% against 69% in the update (Duffey 2004). A United Kingdom audit found every center following what its authors called the "3 cm rule," with ablation sometimes used at 2 to 3 cm (Maher 2022).

The cost: tumors come back

Sparing tissue preserves function but leaves cells carrying the same inherited change.

• In eight centers' 65 patients, cancer-specific survival after kidney-sparing surgery was 100% at 5 years and 81% at 10. Freedom from local recurrence was 71% at 5 years but only 15% at 10. End-stage kidney failure occurred in 23% of all 65 patients (Steinbach 1995, PMID 7752324).
• In a French series of 17 kidney-sparing patients, local recurrence reached 45.6% at 5 years and 83.7% at 10, repeat surgery 23.1% and 63.4%, and disease-specific survival was 93.8% at 10 years. No patient having only this kind of surgery developed spread or chronic kidney failure (Ploussard 2007, PMID 17905091).
• Third or fourth operations on the same kidney are technically possible. In a small National Cancer Institute series, major complications occurred in 6 of 13 patients and a kidney was lost in 3. All were alive without visible spread at a median of 25 months (Bratslavsky 2008, PMID 17997447).

Other options and kidney failure

One center reported watching tumors under 2 cm, ablating those of 2 to 3 cm with radiofrequency, and using kidney-sparing surgery, ablation or embolization above 3 cm or with growth of over 1 cm a year. In 14 patients it reported no spread or dialysis at a median of 41 months, with an 85% success rate for radiofrequency ablation (Carrion 2020). In the United Kingdom audit of 229 kidney cancers with known outcome, 51 were under observation, 134 had surgery and 44 had ablation. Fifteen people (1.8%) reached kidney failure, at a mean age of 40.4 years (Maher 2022).

For people who lose both kidneys, a registry review of 32 transplant recipients with the disease, compared with 32 matched recipients without it, found no significant difference in graft survival, patient survival or kidney function. Three of the 32 died with spread (Goldfarb 1997).

Back to Table of Contents

Belzutifan Trial Numbers

Belzutifan blocks hypoxia-inducible factor 2 alpha, the factor left switched on by the lost protein. The United States Food and Drug Administration approved it on August 13, 2021, for adults with this disease who need treatment for kidney cancer, brain and spinal cord hemangioblastomas, or pancreatic neuroendocrine tumors and do not need immediate surgery (Fallah 2022).

The evidence is one trial, LITESPARK-004: single group, phase 2, with no comparison group. It enrolled 61 adults with at least one measurable kidney cancer, none over 3 cm needing immediate surgery, and no spread, at 11 centers. The trial gave 120 mg by mouth once daily. It was funded by the manufacturer and the National Institutes of Health. Results below use the term objective response, meaning measurable tumor shrinkage by set criteria.

Sources: Jonasch 2021; Srinivasan 2025; Iliopoulos 2024; Else 2024; Wiley 2024.

A 2026 single-center report from the National Eye Institute followed 33 patients on doses of 40 to 120 mg a day. Mean total active lesion area per eye fell from 5.8 to 0.5 square millimeters at 2 years, with no new tumors during treatment. Among those who stopped, more than 70% of eyes showed signs of relapse (Ji 2026).

Reported harms

• Anemia and fatigue. Anemia occurred in 90% of participants and fatigue in 66% (Jonasch 2021, PMID 34818478). At nearly 50 months, 18% had severe (grade 3) treatment-related effects (Srinivasan 2025, PMID 40228516).
• Pregnancy. The drug can harm a developing baby and can make some hormonal contraceptives ineffective (Fallah 2022, PMID 35727604).
• Early bleeding. A 2025 report describes a fatal brain bleed within 72 hours of starting the drug in a person with hemangioblastomas, the third post-marketing report of early bleeding from such tumors. The authors suggest a rare but potentially serious effect not listed on labels at the time (Shepherd 2025, PMID 40381358). A case series cannot establish cause.

The belzutifan page covers the label, other reported effects and the drug's uses outside this disease.

Back to Table of Contents

Life Expectancy Data

Older and newer numbers differ a good deal, and the older figures keep being repeated. Reviews from 2015 and 2017 still give 40 to 52 years (Chittiboina and Lonser 2015; Varshney 2017). Cohort data are as follows:

Sources: Wilding 2012; Binderup 2017; Wang 2018; Zhou 2019.

Some reviews name kidney cancer as the most common cause of death, including a recent one (Jung and Park 2025). Two cohorts point elsewhere:

• In Denmark, 79% of deaths (53 of 67) were disease-related and the main cause was brain and spinal cord hemangioblastoma. Kidney cancer deaths had decreased over time. Women had a higher risk of disease-related death than men (hazard ratio 2.25, 95% confidence interval 1.20 to 4.20) (Binderup 2017, PMID 27539272).
• In the Chinese cohort, brain and spinal cord hemangioblastoma and retinal hemangioblastoma were independent risk factors for overall survival. Kidney cancer was not a significant one (Zhou 2019, PMID 31649892).

Earlier onset, a family history and truncating mutations were linked to poorer survival. People whose first sign was a hemangioblastoma had a higher risk of dying from one than those whose first sign was in the abdomen (hazard ratio 8.84, 95% confidence interval 2.04 to 38.37) (Wang 2018).

None of these figures reflects people treated with belzutifan for long periods, since these cohorts were published before or soon after its 2021 approval.

Back to Table of Contents

What Is Not Known

• Whether belzutifan changes the lifelong course. The trial has no comparison group and about 50 months of follow-up in a disease that spans decades. Eye data suggest relapse after stopping, which raises the question of how long treatment would need to continue (Ji 2026, PMID 42918417).
• Whether any schedule extends life. The evidence is observational, schedules differ by program, and none of the records read for this page compares two schedules at random.
• The best starting ages and intervals. Published starting ages for hormone testing run from 2 to 8 years, and the frequency of brain and spine imaging ranges from yearly to every 2 years or longer.
• How firm the 3 cm line is. The numbers come mainly from one research group's cohorts with imaging-defined size. Tumor growth varies widely, and long-term results of ablation rest on small series.
• Which brain and spine tumors will grow. The authors of the largest prospective study call the growth unpredictable, which also makes drug effects harder to judge (Lonser 2014, PMID 24579662).
• Why many patients lose hearing with no visible ear tumor. In one clinic, 65% of 66 patients screened for the disease or at risk had hearing test abnormalities, and whether a tumor too small to see or something else causes this is unknown (Manski 1997, PMID 9145719).
• The effect of pregnancy. A Dutch series of 48 pregnancies concluded that pregnancy drives cerebellar tumor progression, with disease-related complications in 17% of pregnancies, four life-threatening events, and one fetal death from maternal pheochromocytoma (Frantzen 2012, PMID 22875085). A prospective study of 36 women (Ye 2012, PMID 22937928) and a Danish cohort with 30 pregnancies (Binderup 2015, PMID 26408493) found no worsening.

Back to Table of Contents

Key Research Papers

1. Aufforth RD, Ramakant P, Sadowski SM, Mehta A, Trebska-McGowan K, Nilubol N, et al. Pheochromocytoma Screening Initiation and Frequency in von Hippel-Lindau Syndrome. J Clin Endocrinol Metab. 2015;100(12):4498-504. PubMed PMID: 26451910
2. Binderup ML, Budtz-Jørgensen E, Bisgaard ML. New von Hippel-Lindau manifestations develop at the same or decreased rates in pregnancy. Neurology. 2015;85(17):1500-3. PubMed PMID: 26408493
3. Binderup ML, Galanakis M, Budtz-Jørgensen E, Kosteljanetz M, Luise Bisgaard M. Prevalence, birth incidence, and penetrance of von Hippel-Lindau disease (vHL) in Denmark. Eur J Hum Genet. 2017;25(3):301-307. PubMed PMID: 27966541
4. Binderup ML, Jensen AM, Budtz-Jørgensen E, Bisgaard ML. Survival and causes of death in patients with von Hippel-Lindau disease. J Med Genet. 2017;54(1):11-18. PubMed PMID: 27539272
5. Blansfield JA, Choyke L, Morita SY, Choyke PL, Pingpank JF, Alexander HR, et al. Clinical, genetic and radiographic analysis of 108 patients with von Hippel-Lindau disease (VHL) manifested by pancreatic neuroendocrine neoplasms (PNETs). Surgery. 2007;142(6):814-8; discussion 818.e1-2. PubMed PMID: 18063061
6. Bratslavsky G, Liu JJ, Johnson AD, Sudarshan S, Choyke PL, Linehan WM, et al. Salvage partial nephrectomy for hereditary renal cancer: feasibility and outcomes. J Urol. 2008;179(1):67-70. PubMed PMID: 17997447
7. Carrion DM, Linares-Espinós E, Ríos González E, Bazán AA, Alvarez-Maestro M, Martinez-Pineiro L. Invasive management of renal cell carcinoma in von Hippel-Lindau disease. Cent European J Urol. 2020;73(2):167-172. PubMed PMID: 32782836
8. Chen F, Kishida T, Yao M, Hustad T, Glavac D, Dean M, et al. Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. Hum Mutat. 1995;5(1):66-75. PubMed PMID: 7728151
9. Chittiboina P, Lonser RR. Von Hippel-Lindau disease. Handb Clin Neurol. 2015;132:139-56. PubMed PMID: 26564077
10. Daniels AB, Tirosh A, Huntoon K, Mehta GU, Spiess PE, Friedman DL, et al. Guidelines for surveillance of patients with von Hippel-Lindau disease: Consensus statement of the International VHL Surveillance Guidelines Consortium and VHL Alliance. Cancer. 2023;129(19):2927-2940. PubMed PMID: 37337409
11. Duffey BG, Choyke PL, Glenn G, Grubb RL, Venzon D, Linehan WM, et al. The relationship between renal tumor size and metastases in patients with von Hippel-Lindau disease. J Urol. 2004;172(1):63-5. PubMed PMID: 15201738
12. Eisenhofer G, Lenders JW, Linehan WM, Walther MM, Goldstein DS, Keiser HR. Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel-Lindau disease and multiple endocrine neoplasia type 2. N Engl J Med. 1999;340(24):1872-9. PubMed PMID: 10369850
13. Else T, Jonasch E, Iliopoulos O, Beckermann KE, Narayan V, Maughan BL, et al. Belzutifan for von Hippel-Lindau Disease: Pancreatic Lesion Population of the Phase 2 LITESPARK-004 Study. Clin Cancer Res. 2024;30(9):1750-1757. PubMed PMID: 38393723
14. Fallah J, Brave MH, Weinstock C, Mehta GU, Bradford D, Gittleman H, et al. FDA Approval Summary: Belzutifan for von Hippel-Lindau Disease-Associated Tumors. Clin Cancer Res. 2022;28(22):4843-4848. PubMed PMID: 35727604
15. Frantzen C, Kruizinga RC, van Asselt SJ, Zonnenberg BA, Lenders JW, de Herder WW, et al. Pregnancy-related hemangioblastoma progression and complications in von Hippel-Lindau disease. Neurology. 2012;79(8):793-6. PubMed PMID: 22875085
16. Goldfarb DA, Neumann HP, Penn I, Novick AC. Results of renal transplantation in patients with renal cell carcinoma and von Hippel-Lindau disease. Transplantation. 1997;64(12):1726-9. PubMed PMID: 9422410
17. Hammel PR, Vilgrain V, Terris B, Penfornis A, Sauvanet A, Correas JM, et al. Pancreatic involvement in von Hippel-Lindau disease. The Groupe Francophone d'Etude de la Maladie de von Hippel-Lindau. Gastroenterology. 2000;119(4):1087-95. PubMed PMID: 11040195
18. Huntoon K, Oldfield EH, Lonser RR. Dr. Arvid Lindau and discovery of von Hippel-Lindau disease. J Neurosurg. 2015;123(4):1093-7. PubMed PMID: 25748307
19. Iliopoulos O, Iversen AB, Narayan V, Maughan BL, Beckermann KE, Oudard S, et al. Belzutifan for patients with von Hippel-Lindau disease-associated CNS haemangioblastomas (LITESPARK-004): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2024;25(10):1325-1336. PubMed PMID: 39284337
20. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, et al. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292(5516):464-8. PubMed PMID: 11292862
21. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292(5516):468-72. PubMed PMID: 11292861
22. Ji MH, Thavikulwat AT, Agrón E, Hébert M, Indurkar A, Ward C, et al. Efficacy of Oral Belzutifan for Retinal Capillary Hemangioblastomas in von Hippel-Lindau Disease. Ophthalmol Retina. 2026. PubMed PMID: 42918417
23. Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan VK, Maughan BL, et al. Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease. N Engl J Med. 2021;385(22):2036-2046. PubMed PMID: 34818478
24. Jung NY, Park JB. Von Hippel-Lindau Disease : A Comprehensive Review of Diagnosis, Genetics, Clinical Challenges, and Surveillance. J Korean Neurosurg Soc. 2025;68(3):338-349. PubMed PMID: 40109021
25. Kaelin WG. Von Hippel-Lindau disease: insights into oxygen sensing, protein degradation, and cancer. J Clin Invest. 2022;132(18). PubMed PMID: 36106637
26. Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993;260(5112):1317-20. PubMed PMID: 8493574
27. Lonser RR, Weil RJ, Wanebo JE, DeVroom HL, Oldfield EH. Surgical management of spinal cord hemangioblastomas in patients with von Hippel-Lindau disease. J Neurosurg. 2003;98(1):106-16. PubMed PMID: 12546358
28. Lonser RR, Butman JA, Huntoon K, Asthagiri AR, Wu T, Bakhtian KD, et al. Prospective natural history study of central nervous system hemangioblastomas in von Hippel-Lindau disease. J Neurosurg. 2014;120(5):1055-62. PubMed PMID: 24579662
29. Louise M Binderup M, Smerdel M, Borgwadt L, Beck Nielsen SS, Madsen MG, Møller HU, et al. von Hippel-Lindau disease: Updated guideline for diagnosis and surveillance. Eur J Med Genet. 2022;65(8):104538. PubMed PMID: 35709961
30. Maher ER, Iselius L, Yates JR, Littler M, Benjamin C, Harris R, et al. Von Hippel-Lindau disease: a genetic study. J Med Genet. 1991;28(7):443-7. PubMed PMID: 1895313
31. Maher ER, Neumann HP, Richard S. von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet. 2011;19(6):617-23. PubMed PMID: 21386872
32. Maher ER, Adlard J, Barwell J, Brady AF, Brennan P, Cook J, et al. Evaluation of tumour surveillance protocols and outcomes in von Hippel-Lindau disease in a national health service. Br J Cancer. 2022;126(9):1339-1345. PubMed PMID: 35184155
33. Manski TJ, Heffner DK, Glenn GM, Patronas NJ, Pikus AT, Katz D, et al. Endolymphatic sac tumors. A source of morbid hearing loss in von Hippel-Lindau disease. JAMA. 1997;277(18):1461-6. PubMed PMID: 9145719
34. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399(6733):271-5. PubMed PMID: 10353251
35. MELMON KL, ROSEN SW. LINDAU'S DISEASE. REVIEW OF THE LITERATURE AND STUDY OF A LARGE KINDRED. Am J Med. 1964;36:595-617. PubMed PMID: 14142412
36. Nielsen SM, Rubinstein WS, Thull DL, Armstrong MJ, Feingold E, Yip L, et al. Long-term outcomes, branch-specific expressivity, and disease-related mortality in von Hippel-Lindau type 2A. Fam Cancer. 2011;10(4):701-7. PubMed PMID: 21713522
37. Ong KR, Woodward ER, Killick P, Lim C, Macdonald F, Maher ER. Genotype-phenotype correlations in von Hippel-Lindau disease. Hum Mutat. 2007;28(2):143-9. PubMed PMID: 17024664
38. Ploussard G, Droupy S, Ferlicot S, Ples R, Rocher L, Richard S, et al. Local recurrence after nephron-sparing surgery in von Hippel-Lindau disease. Urology. 2007;70(3):435-9. PubMed PMID: 17905091
39. Poulsen ML, Budtz-Jørgensen E, Bisgaard ML. Surveillance in von Hippel-Lindau disease (vHL). Clin Genet. 2010;77(1):49-59. PubMed PMID: 19863552
40. Rednam SP, Erez A, Druker H, Janeway KA, Kamihara J, Kohlmann WK, et al. Von Hippel-Lindau and Hereditary Pheochromocytoma/Paraganglioma Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood. Clin Cancer Res. 2017;23(12):e68-e75. PubMed PMID: 28620007
41. Shepherd STC, Kelly-Morland C, Drage S, Brady AF, Macwana R, Pickering L, et al. Fatal intracranial haemorrhage shortly after belzutifan initiation in von Hippel-Lindau (VHL) disease-associated haemangioblastoma. ESMO Open. 2025;10(5):105109. PubMed PMID: 40381358
42. Srinivasan R, Iliopoulos O, Beckermann KE, Narayan V, Maughan BL, Oudard S, et al. Belzutifan for von Hippel-Lindau disease-associated renal cell carcinoma and other neoplasms (LITESPARK-004): 50 months follow-up from a single-arm, phase 2 study. Lancet Oncol. 2025;26(5):571-582. PubMed PMID: 40228516
43. Steinbach F, Novick AC, Zincke H, Miller DP, Williams RD, Lund G, et al. Treatment of renal cell carcinoma in von Hippel-Lindau disease: a multicenter study. J Urol. 1995;153(6):1812-6. PubMed PMID: 7752324
44. Varshney N, Kebede AA, Owusu-Dapaah H, Lather J, Kaushik M, Bhullar JS. A Review of Von Hippel-Lindau Syndrome. J Kidney Cancer VHL. 2017;4(3):20-29. PubMed PMID: 28785532
45. Walther MM, Reiter R, Keiser HR, Choyke PL, Venzon D, Hurley K, et al. Clinical and genetic characterization of pheochromocytoma in von Hippel-Lindau families: comparison with sporadic pheochromocytoma gives insight into natural history of pheochromocytoma. J Urol. 1999;162(3 Pt 1):659-64. PubMed PMID: 10458336
46. Walther MM, Choyke PL, Glenn G, Lyne JC, Rayford W, Venzon D, et al. Renal cancer in families with hereditary renal cancer: prospective analysis of a tumor size threshold for renal parenchymal sparing surgery. J Urol. 1999;161(5):1475-9. PubMed PMID: 10210376
47. Wanebo JE, Lonser RR, Glenn GM, Oldfield EH. The natural history of hemangioblastomas of the central nervous system in patients with von Hippel-Lindau disease. J Neurosurg. 2003;98(1):82-94. PubMed PMID: 12546356
48. Wang JY, Peng SH, Li T, Ning XH, Liu SJ, Hong BA, et al. Risk factors for survival in patients with von Hippel-Lindau disease. J Med Genet. 2018;55(5):322-328. PubMed PMID: 29330336
49. Wilding A, Ingham SL, Lalloo F, Clancy T, Huson SM, Moran A, et al. Life expectancy in hereditary cancer predisposing diseases: an observational study. J Med Genet. 2012;49(4):264-9. PubMed PMID: 22362873
50. Wiley HE, Srinivasan R, Maranchie JK, Chhablani J, Iversen ABB, Kruse A, et al. Oral Hypoxia-Inducible Factor 2α Inhibitor Belzutifan in Ocular von Hippel-Lindau Disease: Subgroup Analysis of the Single-Arm Phase 2 LITESPARK-004 Study. Ophthalmology. 2024;131(11):1324-1332. PubMed PMID: 38849055
51. Wong WT, Agrón E, Coleman HR, Tran T, Reed GF, Csaky K, et al. Clinical characterization of retinal capillary hemangioblastomas in a large population of patients with von Hippel-Lindau disease. Ophthalmology. 2008;115(1):181-8. PubMed PMID: 17543389
52. Ye DY, Bakhtian KD, Asthagiri AR, Lonser RR. Effect of pregnancy on hemangioblastoma development and progression in von Hippel-Lindau disease. J Neurosurg. 2012;117(5):818-24. PubMed PMID: 22937928
53. Zhou B, Wang J, Liu S, Peng X, Hong B, Zhou J, et al. Hemangioblastoma Instead of Renal Cell Carcinoma Plays a Major Role in the Unfavorable Overall Survival of Von Hippel-Lindau Disease Patients. Front Oncol. 2019;9:1037. PubMed PMID: 31649892
54. [No authors listed]. Corrigendum to "Von Hippel-Lindau Disease : A Comprehensive Review of Diagnosis, Genetics, Clinical Challenges, and Surveillance" by Jung et al. (J Korean Neurosurg Soc 68 : 338-349, 2025). J Korean Neurosurg Soc. 2025;68(4):494. PubMed PMID: 40532743

PubMed Topic Searches

1. PubMed: von Hippel-Lindau disease surveillance guidelines
2. PubMed: kidney-sparing surgery in von Hippel-Lindau disease
3. PubMed: belzutifan and von Hippel-Lindau disease
4. PubMed: von Hippel-Lindau disease survival and life expectancy

Back to Table of Contents

Connections

• Oncology — the parent section
• Belzutifan — the hypoxia-inducible factor 2 alpha blocker, its label and all its uses
• Kidney Cancer — the disease in general, including non-inherited clear-cell cancer
• Renal Cell Carcinoma — the urology view of the same cancer
• Pheochromocytoma — the adrenal tumor seen in type 2 families
• Paraganglioma — the related tumor outside the adrenal gland
• Neuroendocrine Tumors — the wider family of tumors that includes the pancreatic ones
• Kaelin, Ratcliffe and Semenza — the 2019 Nobel laureates in oxygen sensing

Back to Table of Contents

Featured Videos