Von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary cancer syndrome caused by germline pathogenic variants in the VHL tumor suppressor gene. It is characterized by the development of highly vascularized tumors including clear cell renal cell carcinoma, hemangioblastomas of the CNS and retina, pheochromocytomas, and pancreatic neuroendocrine tumors. VHL disease exemplifies the two-hit hypothesis for tumor suppressor genes and the role of hypoxia signaling dysregulation in tumorigenesis through constitutive HIF activation.
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name: Von Hippel-Lindau Disease
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-04-22T20:13:21Z'
description: >-
Von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary cancer syndrome
caused by germline pathogenic variants in the VHL tumor suppressor gene. It is
characterized by the development of highly vascularized tumors including clear cell
renal cell carcinoma, hemangioblastomas of the CNS and retina, pheochromocytomas,
and pancreatic neuroendocrine tumors. VHL disease exemplifies the two-hit hypothesis
for tumor suppressor genes and the role of hypoxia signaling dysregulation in
tumorigenesis through constitutive HIF activation.
categories:
- Hereditary Cancer Syndrome
- Cancer Predisposition Syndrome
parents:
- hereditary cancer-predisposing syndrome
has_subtypes:
- name: VHL Type 1
description: >-
Characterized by low risk of pheochromocytoma but high risk of renal cell carcinoma,
hemangioblastomas, and pancreatic tumors. Associated with truncating mutations,
large deletions, and missense mutations affecting HIF binding.
- name: VHL Type 2A
description: >-
Characterized by pheochromocytoma and hemangioblastomas but low risk of renal
cell carcinoma. Associated with specific missense mutations.
- name: VHL Type 2B
description: >-
High risk of all VHL-associated tumors including pheochromocytoma, renal cell
carcinoma, and hemangioblastomas. Associated with specific missense mutations.
- name: VHL Type 2C
description: >-
Pheochromocytoma only, without other VHL manifestations. Associated with specific
missense mutations that retain some HIF regulatory function.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_vhl_hif_pseudohypoxia_tumor_model
hypothesis_label: Canonical VHL Loss / HIF Pseudohypoxia / Vascular Tumor Predisposition Model
status: CANONICAL
description: >-
Von Hippel-Lindau (VHL) disease is caused by germline heterozygous loss-of-function variants in VHL
on 3p25.3. The VHL protein is the substrate recognition subunit of an E3 ubiquitin ligase complex
that targets prolyl-hydroxylated HIF-1α/2α for degradation under normoxic conditions. Biallelic VHL
inactivation ('second hit') in susceptible tissues stabilizes HIF-α despite normal oxygen levels — a
'pseudohypoxic' state — and drives constitutive transcription of VEGF, PDGF, EPO, TGF-α, and other
pro-angiogenic and growth-promoting factors. This produces the canonical VHL tumor spectrum: retinal
and CNS hemangioblastomas, clear-cell renal cell carcinoma, pheochromocytoma/paraganglioma,
pancreatic neuroendocrine tumors, and endolymphatic sac tumors. The HIF-2α-selective inhibitor
belzutifan (FDA-approved 2021) shrinks VHL-associated tumors, providing direct pharmacologic
validation of the HIF-pseudohypoxia axis as the canonical pathogenic mechanism.
notes: >-
Retained as CANONICAL with four mandatory
qualifier annotations. The 2026 openscientist hypothesis-
search report
(kb/hypotheses/Von_Hippel-Lindau_Disease/canonical_vhl_hif_pseudohypoxia_tumor_model)
finds STRONGLY SUPPORTED across five convergent evidence
layers: (1) Mendelian genetics with ~95% penetrance by age 60;
(2) atomic-resolution VHL-hydroxyproline crystal structures
defining the oxygen-sensing mechanism; (3) FDA-approved
belzutifan (HIF-2α inhibitor) demonstrating durable tumor
shrinkage across all VHL-associated tumor types;
(4) acquired on-target resistance mutations in the HIF-2α
gatekeeper pocket confirming core HIF-2 dependency;
(5) GWAS identification of EPAS1/HIF-2α as a sporadic RCC
susceptibility locus, linking hereditary and sporadic
pathogenesis. Four mandatory qualifications: (1) HIF-2α (NOT
HIF-1α) is the specific oncogenic isoform in ccRCC, while
HIF-1α functions as a bona fide tumor suppressor on
chromosome 14q; (2) type 2C VHL mutations cause
pheochromocytoma DESPITE retaining normal HIF-α
ubiquitylation, proving the existence of HIF-INDEPENDENT
tumor-suppressor functions of pVHL; (3) VHL loss alone is
necessary but INSUFFICIENT for ccRCC — cooperating mutations
in 3p chromatin remodeling genes (PBRM1, BAP1, SETD2) are
required co-drivers that define distinct molecular and
prognostic subtypes; (4) the tissue specificity of VHL disease
— why only certain organs develop tumors despite ubiquitous
VHL expression — remains mechanistically unexplained.
Belzutifan FDA approval (2021) provides the strongest
pharmacologic validation of the HIF-pseudohypoxia axis.
evidence:
- reference: PMID:37980175
reference_title: "Von Hippel-Lindau disease."
supports: SUPPORT
evidence_source: OTHER
snippet: "von Hippel-Lindau (VHL) disease is characterized by biallelic inactivation of the VHL gene leading to abnormal or absent VHL protein function, and constitutive activation of hypoxia-inducible factors (HIF) that leads to pro-tumorigenic sign"
explanation: >
Existing canonical mechanism citation in the dismech
knowledge base, used as the seed for the hypothesis-search
deep-research run.
pathophysiology:
- name: VHL Tumor Suppressor Loss
description: >-
Germline heterozygous VHL mutations result in one functional allele. Somatic
loss or mutation of the remaining wild-type allele (second hit) eliminates VHL
function, initiating tumorigenesis. This follows Knudson's two-hit hypothesis
for tumor suppressor gene inactivation.
biological_processes:
- preferred_term: cellular response to hypoxia
modifier: ABNORMAL
term:
id: GO:0071456
label: cellular response to hypoxia
downstream:
- target: Loss of HIF Degradation
description: VHL loss prevents ubiquitination of HIF-alpha subunits
evidence:
- reference: PMID:37980175
reference_title: "von Hippel-Lindau disease-related neoplasia with an emphasis on renal manifestations."
supports: SUPPORT
snippet: "von Hippel-Lindau (VHL) disease is characterized by biallelic inactivation of the VHL gene leading to abnormal or absent VHL protein function, and constitutive activation of hypoxia-inducible factors (HIF) that leads to pro-tumorigenic signaling."
explanation: Confirms that biallelic VHL inactivation (consistent with two-hit hypothesis) leads to constitutive HIF activation and pro-tumorigenic signaling.
- name: Loss of HIF Degradation
description: >-
VHL protein (pVHL) functions as the substrate recognition component of an E3
ubiquitin ligase complex that targets hydroxylated HIF-alpha subunits for
proteasomal degradation under normoxic conditions. Loss of VHL function prevents
HIF-alpha degradation, allowing HIF accumulation even in the presence of oxygen.
biological_processes:
- preferred_term: proteasome-mediated ubiquitin-dependent protein catabolic process
modifier: DECREASED
term:
id: GO:0043161
label: proteasome-mediated ubiquitin-dependent protein catabolic process
downstream:
- target: Constitutive HIF Activation
description: Stabilized HIF-alpha accumulates and activates target genes
evidence:
- reference: PMID:19671042
reference_title: "The VHL tumor suppressor: master regulator of HIF."
supports: SUPPORT
snippet: "The von-Hippel Lindau tumor suppressor (pVHL) is the substrate recognition component of an E3 ubiquitin ligase and functions as a master regulator of HIF activity by targeting the hydroxylated HIF-alpha subunit for ubiquitylation and rapid proteasomal degradation under normoxic conditions."
explanation: Defines pVHL as the substrate recognition component of an E3 ubiquitin ligase that targets hydroxylated HIF-alpha for proteasomal degradation.
- reference: PMID:15162797
reference_title: "von Hippel-Lindau tumor suppressor: not only HIF's executioner."
supports: SUPPORT
snippet: "VHL tumor suppressor is a specific substrate-recognition component of the E3 ubiquitin complex, which regulates proteasomal degradation of the subunit of the hypoxia inducible transcription factor (HIF). Impaired VHL complex function leads to accumulation of HIF, overexpression of various HIF-induced gene products and formation of highly vascular neoplasia."
explanation: Confirms that impaired VHL function leads to HIF accumulation due to loss of proteasomal degradation.
- name: Constitutive HIF Activation
description: >-
Stabilized HIF-alpha (primarily HIF-2alpha in RCC) dimerizes with HIF-1beta
(ARNT) and translocates to the nucleus where it activates transcription of
hypoxia-responsive genes. This occurs constitutively regardless of oxygen
levels, creating a pseudo-hypoxic state.
biological_processes:
- preferred_term: response to hypoxia
modifier: INCREASED
term:
id: GO:0001666
label: response to hypoxia
downstream:
- target: VEGF Overexpression and Angiogenesis
description: HIF activates VEGF transcription driving neovascularization
- target: Growth Factor and Metabolic Reprogramming
description: HIF activates genes promoting proliferation and altered metabolism
evidence:
- reference: PMID:11114720
reference_title: "Up-regulation of hypoxia-inducible factors HIF-1alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function."
supports: SUPPORT
snippet: "in VHL deficient cell lines, both HIF-alpha subunits are constitutively expressed, whereas re-introduction of a functional VHL gene restores the instability of HIF-1alpha and HIF-2alpha proteins under normoxic conditions."
explanation: Demonstrates that VHL deficiency leads to constitutive HIF-alpha expression even under normoxic conditions, and that VHL restoration can reverse this effect.
- name: VEGF Overexpression and Angiogenesis
description: >-
VEGF (vascular endothelial growth factor) is a direct HIF target gene.
Constitutive HIF activation leads to chronic VEGF overexpression, driving
extensive tumor angiogenesis. This explains the highly vascular nature of
VHL-associated tumors, particularly hemangioblastomas and clear cell RCC.
biological_processes:
- preferred_term: vascular endothelial growth factor signaling pathway
modifier: INCREASED
term:
id: GO:0038084
label: vascular endothelial growth factor signaling pathway
- preferred_term: angiogenesis
modifier: INCREASED
term:
id: GO:0001525
label: angiogenesis
downstream:
- target: Tumor Development
description: Neovascularization supports tumor growth and progression
evidence:
- reference: PMID:11114720
reference_title: "Up-regulation of hypoxia-inducible factors HIF-1alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function."
supports: SUPPORT
snippet: "In a previous study of hemangioblastomas, the most frequent manifestation of hereditary von Hippel-Lindau disease (VHL), we found elevated levels of vascular endothelial growth factor and HIF-2alpha mRNA in stromal cells of the tumors."
explanation: Demonstrates elevated VEGF levels in VHL-associated hemangioblastomas, linking HIF activation to VEGF overexpression.
- reference: PMID:11114720
reference_title: "Up-regulation of hypoxia-inducible factors HIF-1alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function."
supports: SUPPORT
snippet: "The data presented here provide evidence for a role of the VHL protein in regulation of angiogenesis and erythropoiesis mediated by the HIF-1alpha and HIF-2alpha proteins."
explanation: Confirms VHL protein regulates angiogenesis through HIF-mediated mechanisms.
- name: Growth Factor and Metabolic Reprogramming
description: >-
HIF activates transcription of genes including PDGF, TGF-alpha, EGFR, GLUT1,
and glycolytic enzymes. This promotes cell proliferation, survival, and a
shift toward glycolytic metabolism (Warburg effect) that supports tumor growth.
biological_processes:
- preferred_term: cellular glucose homeostasis
modifier: ABNORMAL
term:
id: GO:0001678
label: intracellular glucose homeostasis
- preferred_term: cell population proliferation
modifier: INCREASED
term:
id: GO:0008283
label: cell population proliferation
downstream:
- target: Tumor Development
description: Growth factors and metabolic changes drive tumorigenesis
evidence:
- reference: PMID:37980175
reference_title: "von Hippel-Lindau disease-related neoplasia with an emphasis on renal manifestations."
supports: PARTIAL
snippet: "immunohistochemical studies for markers such as paired box 8 (PAX-8), carbonic anhydrase 9 (CA9), and glucose transporter 1 (GLUT-1) have an important role in routine clinical practice and represent cost-effective diagnostic tools."
explanation: The use of GLUT-1 as a diagnostic marker for VHL-associated tumors reflects HIF-induced metabolic reprogramming with increased glucose uptake.
- name: Tumor Development
description: >-
The combination of increased angiogenesis, growth factor signaling, and
metabolic reprogramming creates a permissive environment for tumor development.
Different tissues show variable susceptibility, explaining the characteristic
tumor spectrum of VHL disease including RCC, hemangioblastomas, and pheochromocytomas.
evidence:
- reference: PMID:19671042
reference_title: "The VHL tumor suppressor: master regulator of HIF."
supports: SUPPORT
snippet: "Mutations in pVHL can be found in familial and sporadic hemangioblastomas, clear cell carcinomas of the kidney, pheochromocytomas and inherited forms of erythrocytosis, illustrating the importance of disrupted molecular oxygen sensing in the pathogenesis of these diseases."
explanation: Documents the characteristic tumor spectrum of VHL disease and links it to disrupted oxygen sensing.
- reference: PMID:15162797
reference_title: "von Hippel-Lindau tumor suppressor: not only HIF's executioner."
supports: SUPPORT
snippet: "Loss of von Hippel-Lindau (VHL) protein function results in an autosomal-dominant cancer syndrome known as VHL disease, which manifests as angiomas of the retina, hemangioblastomas of the central nervous system, renal clear-cell carcinomas and pheochromocytomas."
explanation: Confirms the characteristic tumor spectrum associated with VHL protein loss.
phenotypes:
- category: Neoplastic
name: Clear Cell Renal Cell Carcinoma
frequency: VERY_FREQUENT
diagnostic: true
description: >-
Clear cell RCC occurs in approximately 70% of VHL patients. Tumors are often
bilateral and multifocal. Mean age of diagnosis is 39 years, compared to 62
years for sporadic RCC. Leading cause of mortality in VHL patients.
phenotype_term:
preferred_term: Clear cell renal cell carcinoma
term:
id: HP:0006770
label: Clear cell renal cell carcinoma
evidence:
- reference: PMID:34818478
reference_title: "Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease."
supports: SUPPORT
snippet: >-
Patients with von Hippel-Lindau (VHL) disease have a high incidence of renal
cell carcinoma owing to VHL gene inactivation and constitutive activation of
the transcription factor hypoxia-inducible factor 2α (HIF-2α).
explanation: >-
Confirms high incidence of RCC in VHL disease due to VHL gene inactivation
and constitutive HIF-2α activation.
- category: Neoplastic
name: Cerebellar Hemangioblastoma
frequency: VERY_FREQUENT
diagnostic: true
description: >-
Hemangioblastomas of the cerebellum are the most common CNS manifestation,
occurring in 60-80% of VHL patients. These highly vascular tumors may cause
symptoms through mass effect or associated cyst formation.
phenotype_term:
preferred_term: Hemangioblastoma
term:
id: HP:0010797
label: Hemangioblastoma
- category: Neoplastic
name: Retinal Hemangioblastoma
frequency: FREQUENT
diagnostic: true
description: >-
Retinal hemangioblastomas (also called retinal capillary hemangiomas) occur in
25-60% of VHL patients and may be the presenting manifestation. They can cause
vision loss through exudation, hemorrhage, or retinal detachment.
phenotype_term:
preferred_term: Retinal capillary hemangioma
term:
id: HP:0009711
label: Retinal capillary hemangioma
- category: Neoplastic
name: Pheochromocytoma
frequency: FREQUENT
description: >-
Pheochromocytomas occur in 10-20% of VHL patients overall but are more common
in Type 2 families (up to 60%). Often bilateral and may occur at young ages.
Screening by plasma or urine metanephrines is recommended.
phenotype_term:
preferred_term: Pheochromocytoma
term:
id: HP:0002666
label: Pheochromocytoma
- category: Neoplastic
name: Pancreatic Neuroendocrine Tumor
frequency: OCCASIONAL
description: >-
Pancreatic neuroendocrine tumors occur in 5-17% of VHL patients. Most are
nonfunctional. The main concern is metastatic potential, though most are
indolent. Size-based surveillance guides management.
phenotype_term:
preferred_term: Neuroendocrine neoplasm
term:
id: HP:0100634
label: Neuroendocrine neoplasm
- category: Renal
name: Renal Cysts
frequency: VERY_FREQUENT
description: >-
Multiple renal cysts are common in VHL patients and may precede RCC development.
Some cysts contain foci of clear cell RCC. Surveillance imaging monitors for
solid enhancing components.
phenotype_term:
preferred_term: Renal cyst
term:
id: HP:0000107
label: Renal cyst
- category: Pancreatic
name: Pancreatic Cysts
frequency: FREQUENT
description: >-
Pancreatic cysts (serous cystadenomas) are common in VHL patients but are
almost always benign. They are distinct from pancreatic neuroendocrine tumors.
phenotype_term:
preferred_term: Pancreatic cysts
term:
id: HP:0001737
label: Pancreatic cysts
biochemical:
- name: VHL Genetic Testing
notes: >-
Molecular testing identifies germline VHL mutations in >99% of families meeting
clinical criteria. Mutations include missense variants, truncating mutations,
large deletions (detectable by MLPA), and deep intronic variants. Genotype-
phenotype correlations guide surveillance: Type 1 mutations (truncating) have
low pheochromocytoma risk; Type 2 mutations (missense) have higher risk.
- name: Plasma Metanephrines
notes: >-
Annual screening for pheochromocytoma using plasma fractionated metanephrines
or 24-hour urine catecholamines and metanephrines. Essential for early detection
of pheochromocytoma before hypertensive crises.
genetic:
- name: VHL
association: Germline Loss-of-Function Mutations
evidence:
- reference: CGGV:assertion_30c04ced-b74d-465a-8d7d-eb822109b7f1-2020-05-14T004116.004Z
reference_title: "VHL / von Hippel-Lindau disease (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "VHL | HGNC:12687 | von Hippel-Lindau disease | MONDO:0008667 | AD | Definitive"
explanation: ClinGen classifies the VHL-von Hippel-Lindau disease gene-disease relationship as definitive with autosomal dominant inheritance.
inheritance:
- name: Autosomal Dominant
notes: >-
VHL (3p25.3) encodes the VHL protein, a substrate recognition subunit of an
E3 ubiquitin ligase complex that targets HIF-alpha for degradation. Germline
mutations include missense (particularly in Type 2), nonsense, frameshift,
splice site, and large deletions. De novo mutations account for approximately
20% of cases. Penetrance is nearly complete by age 65.
treatments:
- name: Surveillance Protocol
description: >-
Comprehensive surveillance beginning in childhood includes annual ophthalmologic
examination (from age 1), annual plasma metanephrines (from age 5), annual
abdominal ultrasound (from age 8), and MRI brain/spine every 2 years (from
age 11). Earlier imaging if symptoms occur.
treatment_term:
preferred_term: cancer screening
term:
id: MAXO:0000126
label: cancer screening
- name: Nephron-Sparing Surgery
description: >-
Partial nephrectomy is the preferred approach for renal tumors to preserve
renal function given the high likelihood of bilateral/multifocal disease.
Surgery is typically recommended when tumors reach 3 cm to balance cancer
risk with nephron preservation.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
- name: Belzutifan
description: >-
HIF-2alpha inhibitor FDA-approved for VHL-associated RCC, hemangioblastomas,
and pancreatic neuroendocrine tumors not requiring immediate surgery. First
targeted therapy directly addressing the molecular defect in VHL disease.
Objective response rates of 49% in RCC and 30-77% across tumor types.
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: belzutifan
term:
id: NCIT:C135627
label: Belzutifan
evidence:
- reference: PMID:34818478
reference_title: "Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease."
supports: SUPPORT
snippet: >-
Belzutifan was associated with predominantly grade 1 and 2 adverse events and
showed activity in patients with renal cell carcinomas and non-renal cell carcinoma
neoplasms associated with VHL disease.
explanation: >-
Phase 2 clinical trial demonstrates belzutifan efficacy and tolerability
across VHL-associated tumor types.
- name: Genetic Counseling
description: >-
Genetic counseling and testing for at-risk family members. Children of affected
parents have 50% risk. Predictive testing allows targeted surveillance in
mutation carriers and can reassure non-carriers. Prenatal and preimplantation
genetic testing are options.
treatment_term:
preferred_term: genetic counseling
term:
id: MAXO:0000079
label: genetic counseling
disease_term:
preferred_term: von Hippel-Lindau disease
term:
id: MONDO:0008667
label: von Hippel-Lindau disease
references:
- reference: DOI:10.1007/s11060-024-04676-5
title: Screening and surveillance recommendations for central nervous system hemangioblastomas in pediatric patients with Von Hippel-Lindau disease
found_in:
- Von_Hippel-Lindau_Disease-deep-research-falcon.md
findings:
- statement: Von Hippel-Lindau (VHL) disease is an autosomal-dominantly inherited tumor predisposition syndrome.
supporting_text: Von Hippel-Lindau (VHL) disease is an autosomal-dominantly inherited tumor predisposition syndrome.
evidence:
- reference: DOI:10.1007/s11060-024-04676-5
reference_title: Screening and surveillance recommendations for central nervous system hemangioblastomas in pediatric patients with Von Hippel-Lindau disease
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Von Hippel-Lindau (VHL) disease is an autosomal-dominantly inherited tumor predisposition syndrome.
explanation: Deep research cited this publication as relevant literature for Von Hippel-Lindau Disease.
- reference: DOI:10.1038/s41598-021-94132-5
title: VHL suppresses RAPTOR and inhibits mTORC1 signaling in clear cell renal cell carcinoma
found_in:
- Von_Hippel-Lindau_Disease-deep-research-falcon.md
findings:
- statement: Inactivation of the tumor suppressor von Hippel–Lindau (VHL) gene is a key event in hereditary and sporadic clear cell renal cell carcinomas (ccRCC).
supporting_text: Inactivation of the tumor suppressor von Hippel–Lindau (VHL) gene is a key event in hereditary and sporadic clear cell renal cell carcinomas (ccRCC).
evidence:
- reference: DOI:10.1038/s41598-021-94132-5
reference_title: VHL suppresses RAPTOR and inhibits mTORC1 signaling in clear cell renal cell carcinoma
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Inactivation of the tumor suppressor von Hippel–Lindau (VHL) gene is a key event in hereditary and sporadic clear cell renal cell carcinomas (ccRCC).
explanation: Deep research cited this publication as relevant literature for Von Hippel-Lindau Disease.
- reference: DOI:10.1158/1078-0432.ccr-23-2592
title: 'Belzutifan for von Hippel–Lindau Disease: Pancreatic Lesion Population of the Phase 2 LITESPARK-004 Study'
found_in:
- Von_Hippel-Lindau_Disease-deep-research-falcon.md
findings:
- statement: 'Belzutifan for von Hippel–Lindau Disease: Pancreatic Lesion Population of the Phase 2 LITESPARK-004 Study'
supporting_text: 'Primary analysis of the ongoing, single-arm, phase 2 LITESPARK-004 study (NCT03401788) showed clinically meaningful antitumor activity in von Hippel–Lindau (VHL) disease–associated renal cell carcinoma (RCC) and other neoplasms with belzutifan treatment.'
evidence:
- reference: DOI:10.1158/1078-0432.ccr-23-2592
reference_title: 'Belzutifan for von Hippel–Lindau Disease: Pancreatic Lesion Population of the Phase 2 LITESPARK-004 Study'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'Primary analysis of the ongoing, single-arm, phase 2 LITESPARK-004 study (NCT03401788) showed clinically meaningful antitumor activity in von Hippel–Lindau (VHL) disease–associated renal cell carcinoma (RCC) and other neoplasms with belzutifan treatment.'
explanation: Deep research cited this publication as relevant literature for Von Hippel-Lindau Disease.
- reference: DOI:10.1158/1078-0432.ccr-24-3525
title: Update on Surveillance in Von Hippel–Lindau Disease
found_in:
- Von_Hippel-Lindau_Disease-deep-research-falcon.md
findings:
- statement: Von Hippel–Lindau disease (VHL) is a genetic condition characterized by a high lifetime risk for tumors and cysts throughout the body, including the central nervous system, visual–auditory systems, and intra-abdominal organs.
supporting_text: Von Hippel–Lindau disease (VHL) is a genetic condition characterized by a high lifetime risk for tumors and cysts throughout the body, including the central nervous system, visual–auditory systems, and intra-abdominal organs.
evidence:
- reference: DOI:10.1158/1078-0432.ccr-24-3525
reference_title: Update on Surveillance in Von Hippel–Lindau Disease
supports: SUPPORT
evidence_source: OTHER
snippet: Von Hippel–Lindau disease (VHL) is a genetic condition characterized by a high lifetime risk for tumors and cysts throughout the body, including the central nervous system, visual–auditory systems, and intra-abdominal organs.
explanation: Deep research cited this publication as relevant literature for Von Hippel-Lindau Disease.
- reference: DOI:10.1172/jci162480
title: 'Von Hippel–Lindau disease: insights into oxygen sensing, protein degradation, and cancer'
found_in:
- Von_Hippel-Lindau_Disease-deep-research-falcon.md
findings:
- statement: 'Von Hippel–Lindau disease: insights into oxygen sensing, protein degradation, and cancer'
supporting_text: 'Von Hippel–Lindau disease: insights into oxygen sensing, protein degradation, and cancer'
- reference: DOI:10.1172/jci175703
title: Von Hippel Lindau tumor suppressor controls m6A-dependent gene expression in renal tumorigenesis
found_in:
- Von_Hippel-Lindau_Disease-deep-research-falcon.md
findings:
- statement: Von Hippel Lindau tumor suppressor controls m6A-dependent gene expression in renal tumorigenesis
supporting_text: Von Hippel Lindau tumor suppressor controls m6A-dependent gene expression in renal tumorigenesis
- reference: DOI:10.1186/s13023-024-03060-w
title: Epidemiology and economic burden of Von Hippel-Lindau Disease-associated central nervous system hemangioblastomas and pancreatic neuroendocrine tumors in the United States
found_in:
- Von_Hippel-Lindau_Disease-deep-research-falcon.md
findings:
- statement: To date, real-world evidence around the clinical and economic burden related to von Hippel-Lindau (VHL) disease is limited.
supporting_text: To date, real-world evidence around the clinical and economic burden related to von Hippel-Lindau (VHL) disease is limited.
evidence:
- reference: DOI:10.1186/s13023-024-03060-w
reference_title: Epidemiology and economic burden of Von Hippel-Lindau Disease-associated central nervous system hemangioblastomas and pancreatic neuroendocrine tumors in the United States
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: To date, real-world evidence around the clinical and economic burden related to von Hippel-Lindau (VHL) disease is limited.
explanation: Deep research cited this publication as relevant literature for Von Hippel-Lindau Disease.
- reference: DOI:10.1186/s43042-024-00506-5
title: Germline variants in the Von Hippel-Lindau tumor suppressor gene in Cuban patients
found_in:
- Von_Hippel-Lindau_Disease-deep-research-falcon.md
findings:
- statement: Von Hippel-Lindau (VHL) syndrome is an autosomal dominantly inherited disorder that predisposes to multiple neoplasms.
supporting_text: Von Hippel-Lindau (VHL) syndrome is an autosomal dominantly inherited disorder that predisposes to multiple neoplasms.
evidence:
- reference: DOI:10.1186/s43042-024-00506-5
reference_title: Germline variants in the Von Hippel-Lindau tumor suppressor gene in Cuban patients
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Von Hippel-Lindau (VHL) syndrome is an autosomal dominantly inherited disorder that predisposes to multiple neoplasms.
explanation: Deep research cited this publication as relevant literature for Von Hippel-Lindau Disease.
- reference: DOI:10.15586/jkcvhl.v11i4.324
title: Is the TriNetX Database a Good Tool for Investigation of Real-World Management of Von Hippel–Lindau?
found_in:
- Von_Hippel-Lindau_Disease-deep-research-falcon.md
findings:
- statement: Von Hippel–Lindau (vHL) is a hereditary disease characterized by the development of benign and malignant tumors across multiple organ systems.
supporting_text: Von Hippel–Lindau (vHL) is a hereditary disease characterized by the development of benign and malignant tumors across multiple organ systems.
evidence:
- reference: DOI:10.15586/jkcvhl.v11i4.324
reference_title: Is the TriNetX Database a Good Tool for Investigation of Real-World Management of Von Hippel–Lindau?
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Von Hippel–Lindau (vHL) is a hereditary disease characterized by the development of benign and malignant tumors across multiple organ systems.
explanation: Deep research cited this publication as relevant literature for Von Hippel-Lindau Disease.
- reference: DOI:10.15586/jkcvhl.v11i4.362
title: 'Surveillance in Children and Adolescents with von Hippel-Lindau (VHL)-Related Pheochromocytomas and Paragangliomas: A Survey of MET and Freiburg-VHL Registries in Germany'
found_in:
- Von_Hippel-Lindau_Disease-deep-research-falcon.md
findings:
- statement: Early identification of patients at risk with von Hippel-Lindau (VHL) syndrome-related pheochromocytoma and paraganglioma (PPGL) is crucial to prevent morbidity.
supporting_text: Early identification of patients at risk with von Hippel-Lindau (VHL) syndrome-related pheochromocytoma and paraganglioma (PPGL) is crucial to prevent morbidity.
evidence:
- reference: DOI:10.15586/jkcvhl.v11i4.362
reference_title: 'Surveillance in Children and Adolescents with von Hippel-Lindau (VHL)-Related Pheochromocytomas and Paragangliomas: A Survey of MET and Freiburg-VHL Registries in Germany'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Early identification of patients at risk with von Hippel-Lindau (VHL) syndrome-related pheochromocytoma and paraganglioma (PPGL) is crucial to prevent morbidity.
explanation: Deep research cited this publication as relevant literature for Von Hippel-Lindau Disease.
- reference: DOI:10.3390/cancers15061657
title: Unique Characteristics of Patients with Von Hippel–Lindau Disease Defined by Various Diagnostic Criteria
found_in:
- Von_Hippel-Lindau_Disease-deep-research-falcon.md
findings:
- statement: Unique Characteristics of Patients with Von Hippel–Lindau Disease Defined by Various Diagnostic Criteria
supporting_text: 'Von Hippel–Lindau (VHL) disease diagnosis is based on two criteria sets: International criteria (IC, two hemangioblastomas, one hemangioblastoma plus one visceral lesion, or VHL family history/pathogenic variant plus hemangioblastoma/visceral lesion); or Danish criteria (DC, two clinical manifestations, or VHL family history/pathogenic variant plus hemangioblastoma/visceral lesion).'
evidence:
- reference: DOI:10.3390/cancers15061657
reference_title: Unique Characteristics of Patients with Von Hippel–Lindau Disease Defined by Various Diagnostic Criteria
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'Von Hippel–Lindau (VHL) disease diagnosis is based on two criteria sets: International criteria (IC, two hemangioblastomas, one hemangioblastoma plus one visceral lesion, or VHL family history/pathogenic variant plus hemangioblastoma/visceral lesion); or Danish criteria (DC, two clinical manifestations, or VHL family history/pathogenic variant plus hemangioblastoma/visceral lesion).'
explanation: Deep research cited this publication as relevant literature for Von Hippel-Lindau Disease.
- reference: DOI:10.3390/diagnostics14171909
title: Genetics, Pathophysiology, and Current Challenges in Von Hippel–Lindau Disease Therapeutics
found_in:
- Von_Hippel-Lindau_Disease-deep-research-falcon.md
findings:
- statement: This review article focuses on von Hippel–Lindau (VHL) disease, a rare genetic disorder characterized by the development of tumors and cysts throughout the body.
supporting_text: This review article focuses on von Hippel–Lindau (VHL) disease, a rare genetic disorder characterized by the development of tumors and cysts throughout the body.
evidence:
- reference: DOI:10.3390/diagnostics14171909
reference_title: Genetics, Pathophysiology, and Current Challenges in Von Hippel–Lindau Disease Therapeutics
supports: SUPPORT
evidence_source: OTHER
snippet: This review article focuses on von Hippel–Lindau (VHL) disease, a rare genetic disorder characterized by the development of tumors and cysts throughout the body.
explanation: Deep research cited this publication as relevant literature for Von Hippel-Lindau Disease.
- reference: DOI:10.7554/elife.80774
title: Hypoxia-inducible factor underlies von Hippel-Lindau disease stigmata
found_in:
- Von_Hippel-Lindau_Disease-deep-research-falcon.md
findings:
- statement: Hypoxia-inducible factor underlies von Hippel-Lindau disease stigmata
supporting_text: von Hippel-Lindau (VHL) disease is a rare hereditary cancer syndrome that causes a predisposition to renal clear-cell carcinoma, hemangioblastoma, pheochromocytoma, and autosomal-recessive familial polycythemia. pVHL is the substrate conferring subunit of an E3 ubiquitin ligase complex that binds to the three hypoxia-inducible factor alpha subunits (HIF1-3α) for polyubiquitylation under conditions of normoxia, targeting them for immediate degradation by the proteasome.
evidence:
- reference: DOI:10.7554/elife.80774
reference_title: Hypoxia-inducible factor underlies von Hippel-Lindau disease stigmata
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: von Hippel-Lindau (VHL) disease is a rare hereditary cancer syndrome that causes a predisposition to renal clear-cell carcinoma, hemangioblastoma, pheochromocytoma, and autosomal-recessive familial polycythemia. pVHL is the substrate conferring subunit of an E3 ubiquitin ligase complex that binds to the three hypoxia-inducible factor alpha subunits (HIF1-3α) for polyubiquitylation under conditions of normoxia, targeting them for immediate degradation by the proteasome.
explanation: Deep research cited this publication as relevant literature for Von Hippel-Lindau Disease.
VHL disease is a rare, inherited tumor predisposition syndrome characterized by development of benign and malignant tumors and cysts across multiple organs (CNS, retina, kidneys, pancreas, adrenals, and others). (gomezvirgilio2024geneticspathophysiologyand pages 1-2, kaelin2022vonhippel–lindaudisease pages 1-2)
Not available from the retrieved evidence excerpts: Orphanet ORPHA code, MeSH unique ID, MONDO ID, ICD-11 code. These would normally be sourced from Orphanet/MeSH/MONDO directly, but they were not present in the accessible text segments used here (alvarez2024germlinevariantsin pages 1-2, gomezvirgilio2024geneticspathophysiologyand pages 1-2, hochberg2024isthetrinetx pages 1-2).
Explicitly used name variants in retrieved sources include: - “Von Hippel–Lindau disease” / “von Hippel–Lindau (VHL) disease” / “VHL disease” / “VHL” (gomezvirgilio2024geneticspathophysiologyand pages 1-2) - “Von Hippel-Lindau syndrome” / “VHL syndrome” (alvarez2024germlinevariantsin pages 1-2) - “Von Hippel–Lindau (vHL) disease” / “vHL” (hochberg2024isthetrinetx pages 1-2)
The report synthesizes aggregated disease-level reviews (e.g., 2024 Diagnostics review; 2022 JCI review) and primary/real-world studies (claims-based epidemiology; clinical trial report; cohort analyses). (jonasch2024epidemiologyandeconomic pages 1-2, else2024belzutifanforvon pages 5-6, gomezvirgilio2024geneticspathophysiologyand pages 1-2, kaelin2022vonhippel–lindaudisease pages 1-2, zhang2024vonhippellindau pages 1-2)
No explicit protective factors or gene–environment interaction data were identifiable in the retrieved evidence excerpts.
A 2023 case-based genetic analysis suggests that additional germline variants (e.g., CHEK2) may contribute to unusually severe hemangioblastoma burden in some families, consistent with a modifier model; however, this is currently case-report level and not established for broad risk stratification. (gomezvirgilio2024geneticspathophysiologyand pages 11-13)
From a 2024 U.S. claims-based study (background frequencies drawn from prior literature in that paper): - CNS hemangioblastoma: occurs in ~70–80% of cases; described as “typically the first manifestation.” (jonasch2024epidemiologyandeconomic pages 1-2) - Pancreatic neuroendocrine tumors (pNET): occur in ~9–17% of cases. (jonasch2024epidemiologyandeconomic pages 1-2)
From a 2023 cohort/review focused on VHL-related pancreatic neuroendocrine tumor and diagnostic criteria: - vPNET prevalence across cohorts reported as ~5% on average, up to 17% in some cohorts. (halperin2023uniquecharacteristicsof pages 1-2)
Additional classic manifestations described across sources include retinal hemangioblastomas, clear-cell RCC, pheochromocytoma/paraganglioma (PPGL), pancreatic cystic lesions, endolymphatic sac tumors, and reproductive-tract cystadenomas. (gomezvirgilio2024geneticspathophysiologyand pages 1-2, halperin2023uniquecharacteristicsof pages 1-2)
While the excerpts do not include validated QoL scales (e.g., SF-36/EQ-5D), the 2024 claims-based analysis and pediatric registry data emphasize high healthcare utilization, repeated procedures, and recurrence (especially PPGL), implying significant burden and care intensity. (jonasch2024epidemiologyandeconomic pages 1-2, kotsis2024surveillanceinchildren pages 1-2)
Note: Specific HPO IDs were not present in the retrieved excerpts; mapping to exact HP identifiers would require HPO lookup outside the retrieved papers.
No clear environmental/lifestyle/infectious triggers were identified in the retrieved evidence excerpts as causal or modifying factors for VHL disease.
Upstream trigger: germline VHL loss-of-function variant + somatic “second hit” in susceptible cells (tumor suppressor model). (kaelin2022vonhippel–lindaudisease pages 1-2, ohh2022hypoxiainduciblefactorunderlies pages 1-2)
Core molecular mechanism: pVHL is the substrate-recognition subunit of a Cullin2-based E3 ubiquitin ligase that targets hydroxylated HIFα for proteasomal degradation in oxygen-dependent fashion; VHL loss stabilizes HIFα, especially HIF2α. (kaelin2022vonhippel–lindaudisease pages 1-2, gomezvirgilio2024geneticspathophysiologyand pages 11-13)
Downstream consequences: stabilized HIFα translocates to the nucleus, dimerizes with HIFβ, and activates gene expression programs promoting angiogenesis, altered metabolism, and tumor growth, helping explain the vascular nature of many VHL-associated tumors. (gomezvirgilio2024geneticspathophysiologyand pages 11-13)
Therapeutic connection: VEGF pathway inhibitors are a mainstay of ccRCC treatment; an allosteric HIF2 inhibitor (belzutifan) is approved for VHL-associated ccRCC based on this mechanistic dependency. (kaelin2022vonhippel–lindaudisease pages 1-2)
A review and supporting primary data describe a HIF-independent mechanism: VHL can repress RAPTOR and thereby inhibit mTORC1 signaling; loss of VHL derepresses mTORC1, which is frequently hyperactivated in ccRCC. (ganner2021vhlsuppressesraptor pages 1-2, gomezvirgilio2024geneticspathophysiologyand pages 11-13)
A 2024 JCI mechanistic study reports that VHL binds and promotes METTL3/METTL14 complex formation; VHL depletion suppresses m6A modification. The study identifies PIK3R3 as a VHL–m6A-regulated target whose mRNA stability is controlled in an m6A-dependent but HIF-independent manner; PIK3R3 suppresses renal tumor growth by restraining PI3K/AKT signaling. (zhang2024vonhippellindau pages 1-2)
Exact GO/CL identifiers were not present in the retrieved excerpts and would require ontology lookup.
Across sources, VHL disease affects: - CNS (brain/spinal cord): CNS hemangioblastomas (jonasch2024epidemiologyandeconomic pages 1-2) - Eye/retina: retinal hemangioblastomas (halperin2023uniquecharacteristicsof pages 1-2) - Kidney: cysts and clear-cell RCC (halperin2023uniquecharacteristicsof pages 1-2) - Pancreas: pancreatic lesions including pNETs and serous cystadenomas (else2024belzutifanforvon pages 5-6) - Adrenal/paraganglia: pheochromocytoma/paraganglioma (halperin2023uniquecharacteristicsof pages 1-2)
Disease-level prevalence estimates (review): prevalence described as approximately 1 in 36,000 worldwide in a 2024 review; another estimate range given is 1 in 39,000 to 1 in 91,000. (gomezvirgilio2024geneticspathophysiologyand pages 1-2, gomezvirgilio2024geneticspathophysiologyand pages 22-24)
U.S. real-world prevalence for selected VHL manifestations (claims-based, 2019): - VHL-associated CNS hemangioblastoma: 1.12 per 100,000 (estimated 3,678 patients) - VHL-associated pancreatic NET: 0.12 per 100,000 (estimated 389 patients) (jonasch2024epidemiologyandeconomic pages 1-2)
A 2023 study highlights that VHL can be clinically diagnosed via differing criteria sets (International vs Danish) and argues for genetic testing to improve diagnostic accuracy, especially in visceral-only presentations. In their cohort, vPNET patients meeting International Criteria had 90% germline VHL PV and 70% family history vs 20% and 10% in Danish-only cases. (halperin2023uniquecharacteristicsof pages 1-2)
A 2024 pediatric cohort recommends starting CNS MRI at 12 years with intervals every (1–)2 years depending on involvement; truncating variants showed higher manifestation and surgery rates (HR 3.7 and 3.3). (knoblauch2024screeningandsurveillance pages 1-2)
The surveillance update explicitly uses fractionated metanephrines (plasma or urine) as screening biochemistry for PPGL beginning at age 5. (rednam2025updateonsurveillance pages 11-13)
Survival curves and life expectancy estimates were not present in the retrieved excerpts.
For selected lesion types, management commonly involves surveillance with intervention thresholds: - CNS hemangioblastoma: active surveillance for asymptomatic lesions; surgery for symptomatic or CSF-obstructing lesions (as summarized in the 2024 claims-based study background). (jonasch2024epidemiologyandeconomic pages 1-2) - pNET: lesions >2–3 cm recommended for surgical removal (background statement in 2024 claims-based study). (jonasch2024epidemiologyandeconomic pages 1-2)
Mechanistic rationale: HIF2 drives VHL-defective ccRCC growth; HIF2 inhibition is mechanistically aligned with the central VHL pathway. (kaelin2022vonhippel–lindaudisease pages 1-2)
Key 2024 clinical trial evidence (pancreatic lesions, LITESPARK-004): - Study: single-arm phase 2 LITESPARK-004 (NCT03401788), belzutifan 120 mg once daily. (else2024belzutifanforvon pages 5-6) - Pancreatic lesion population: 61/61 (100%) had ≥1 pancreatic lesion; 22/61 (36%) had measurable pNET at baseline; median follow-up 37.8 months. (else2024belzutifanforvon pages 5-6) - Objective response rate (ORR): pancreatic lesions 84% (51/61) with 17 complete responses; pNETs 91% (20/22) with 7 complete responses. (else2024belzutifanforvon pages 5-6) - Safety: 18% had ≥1 grade 3 treatment-related AE; no grade 4/5 treatment-related AEs reported. (else2024belzutifanforvon pages 5-6)
Real-world relevance: A 2024 U.S. claims analysis highlights the high costs of surgery for VHL-CNS hemangioblastoma and VHL-pNET, providing a health-economic rationale for effective medical therapies that could reduce surgical frequency/burden. (jonasch2024epidemiologyandeconomic pages 1-2)
Not applicable in the classic infectious/toxic exposure sense; VHL is a genetic condition.
The updated pediatric/adolescent surveillance framework (blood pressure, metanephrines, eye exams, MRIs) is a central preventive strategy intended to enable early detection and timely intervention. (rednam2025updateonsurveillance pages 8-10, rednam2025updateonsurveillance pages 11-13, rednam2025updateonsurveillance pages 13-13, knoblauch2024screeningandsurveillance pages 1-2)
No naturally occurring non-human VHL disease analogs were identified in the retrieved excerpts.
Evidence excerpts supporting models/mechanistic conservation include: - C. elegans: loss of vhl-1 increased mTORC1 activity, supporting evolutionary conservation of VHL–mTORC1 regulation. (ganner2021vhlsuppressesraptor pages 1-2)
Detailed mouse/zebrafish models for VHL-associated tumor phenotypes were not available in the retrieved evidence excerpts used for citations in this report.
| Topic | Key data (numbers) | Population/setting | Source (first author, year, journal) | DOI/URL |
|---|---|---|---|---|
| Population prevalence / penetrance / onset | Worldwide prevalence ≈ 1 in 36,000; median age of onset 26 years; penetrance of manifestations ~97% by age 65; up to 20% de novo cases (gomezvirgilio2024geneticspathophysiologyand pages 1-2) | Disease-level review of VHL syndrome | Gómez-Virgilio, 2024, Diagnostics | https://doi.org/10.3390/diagnostics14171909 |
| Alternative prevalence estimates | Prevalence estimated 1 in 39,000 to 1 in 91,000 (gomezvirgilio2024geneticspathophysiologyand pages 22-24) | Disease-level review | Gómez-Virgilio, 2024, Diagnostics | https://doi.org/10.3390/diagnostics14171909 |
| Major phenotype frequencies | CNS hemangioblastoma occurs in 70–80% of cases; pancreatic NETs in 9–17% (jonasch2024epidemiologyandeconomic pages 1-2) | U.S. claims-based epidemiology background summary | Jonasch, 2024, Orphanet Journal of Rare Diseases | https://doi.org/10.1186/s13023-024-03060-w |
| vPNET frequency and mortality context | vPNET prevalence averages ~5%, up to 17% in some cohorts; leading causes of death reported as CNS hemangioblastoma then RCC (halperin2023uniquecharacteristicsof pages 1-2) | Cohort and review of diagnostic criteria in VHL patients with pNET comparison | Halperin, 2023, Cancers | https://doi.org/10.3390/cancers15061657 |
| U.S. real-world prevalence of VHL manifestations | 2019 prevalence: VHL-associated CNS hemangioblastoma 1.12/100,000 (3,678 patients); VHL-associated pNET 0.12/100,000 (389 patients) (jonasch2024epidemiologyandeconomic pages 1-2) | Optum Clinformatics claims, United States | Jonasch, 2024, Orphanet Journal of Rare Diseases | https://doi.org/10.1186/s13023-024-03060-w |
| Economic burden | Annual healthcare costs vs controls: VHL-CNS-Hb +$49,645; VHL-pNET +$56,580 (jonasch2024epidemiologyandeconomic pages 1-2) | U.S. matched claims cohorts: VHL-CNS-Hb N=220; VHL-pNET N=20 | Jonasch, 2024, Orphanet Journal of Rare Diseases | https://doi.org/10.1186/s13023-024-03060-w |
| Diagnostic criteria cohort data | Among vPNET patients meeting International Criteria: germline VHL pathogenic variant 90% and family history 70% vs Danish-only group 20% and 10%; vPNET diagnosis age 51.6 ± 4.1 vs sporadic PNET 62.8 ± 1.5 years (halperin2023uniquecharacteristicsof pages 1-2) | 33 VHL patients (20 vPNET) and 65 sporadic PNET comparators | Halperin, 2023, Cancers | https://doi.org/10.3390/cancers15061657 |
| Pediatric PPGL timing / recurrence | Mean age at first PPGL 12.4 ± 0.41 years (range 4–18); recurrence 46%; other tumors during follow-up: hemangioblastomas 73%, retinal angiomas 58%, RCC 21%, pNET 12% (kotsis2024surveillanceinchildren pages 1-2) | German pediatric/adolescent VHL registries, 75 patients | Kotsis, 2024, Journal of Kidney Cancer and VHL | https://doi.org/10.15586/jkcvhl.v11i4.362 |
| Pediatric CNS hemangioblastoma surveillance | Start MRI at age 12 years; repeat every 1–2 years depending on CNS involvement; truncating variants had higher manifestation rate (HR 3.7, 95% CI 1.9–7.4) and surgery rate (HR 3.3, 95% CI 1.2–8.9) (knoblauch2024screeningandsurveillance pages 1-2) | Monocentric pediatric cohort, 99 VHL patients | Knoblauch, 2024, Journal of Neuro-Oncology | https://doi.org/10.1007/s11060-024-04676-5 |
| Updated pediatric/adolescent surveillance: blood pressure & PCC biochemistry | Blood pressure at all visits starting at 2 years; annual fractionated metanephrines starting at 5 years; test for PCC before major surgery (rednam2025updateonsurveillance pages 8-10, rednam2025updateonsurveillance pages 11-13) | 2023 AACR Childhood Cancer Predisposition Workshop update summarized in 2025 perspective | Rednam, 2025, Clinical Cancer Research | https://doi.org/10.1158/1078-0432.CCR-24-3525 |
| Updated surveillance: ophthalmology / audiology / neuroimaging | Eye exams at least annually from diagnosis; in younger children, every 6 months may be considered. Audiograms: biennial from 11 years (Daniels) or annual age 5–13 then biennial (Binderup). Brain/spine MRI: baseline at 10 years then, if negative, resume at 15 years and continue biennially, or begin biennial MRI at 11 years depending on guideline set (rednam2025updateonsurveillance pages 8-10) | Comparative consensus recommendations summarized in AACR update | Rednam, 2025, Clinical Cancer Research | https://doi.org/10.1158/1078-0432.CCR-24-3525 |
| Updated surveillance: abdominal MRI | Contrast abdominal MRI for RCC/PanNET every 2 years starting at 15 years (rednam2025updateonsurveillance pages 11-13, rednam2025updateonsurveillance pages 13-13) | Pediatric/adolescent surveillance update | Rednam, 2025, Clinical Cancer Research | https://doi.org/10.1158/1078-0432.CCR-24-3525 |
| Local pediatric registry surveillance practice | Annual hormone measurements; eye exam starting at 6 years; CNS/abdominal MRI starting at 12 years; regular screening may begin at 5 years in known variant families; intervals 1–2 years depending on stage/risk (kotsis2024surveillanceinchildren pages 1-2) | Freiburg-VHL screening/surveillance program | Kotsis, 2024, Journal of Kidney Cancer and VHL | https://doi.org/10.15586/jkcvhl.v11i4.362 |
| Belzutifan phase 2 trial design | LITESPARK-004 / NCT03401788; adults with germline VHL alteration; 61 patients enrolled; belzutifan 120 mg once daily; endpoints included ORR, DOR, PFS, linear growth rate, safety (else2024belzutifanforvon pages 5-6) | Single-arm phase 2 VHL disease study | Else, 2024, Clinical Cancer Research | https://doi.org/10.1158/1078-0432.CCR-23-2592 |
| Belzutifan pancreatic lesion efficacy | All 61/61 (100%) had ≥1 pancreatic lesion; 22/61 (36%) had measurable pNET at baseline; median follow-up 37.8 months; ORR 84% (51/61) in pancreatic lesions with 17 complete responses; ORR 91% (20/22) in pNETs with 7 complete responses; median pNET linear growth rate −4.2 mm/year; grade 3 treatment-related AEs 18%; no grade 4/5 treatment-related AEs (else2024belzutifanforvon pages 5-6) | Pancreatic lesion population of LITESPARK-004 | Else, 2024, Clinical Cancer Research | https://doi.org/10.1158/1078-0432.CCR-23-2592 |
Table: This table compiles the key 2023-2025 quantitative findings and surveillance recommendations extracted so far for von Hippel–Lindau disease. It emphasizes epidemiology, phenotype frequency, pediatric surveillance timing, and belzutifan phase 2 efficacy data relevant for a disease knowledge base.
References
(gomezvirgilio2024geneticspathophysiologyand pages 1-2): Laura Gómez-Virgilio, Mireya Velazquez-Paniagua, Lucero Cuazozon-Ferrer, Maria-del-Carmen Silva-Lucero, Andres-Ivan Gutierrez-Malacara, Juan-Ramón Padilla-Mendoza, Jessica Borbolla-Vázquez, Job-Alí Díaz-Hernández, Fausto-Alejandro Jiménez-Orozco, and Maria-del-Carmen Cardenas-Aguayo. Genetics, pathophysiology, and current challenges in von hippel–lindau disease therapeutics. Diagnostics, 14:1909, Aug 2024. URL: https://doi.org/10.3390/diagnostics14171909, doi:10.3390/diagnostics14171909. This article has 8 citations.
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(hochberg2024isthetrinetx pages 1-2): Aaron R. Hochberg, Patrick T. Gomella, Brian Im, Anushka Ghosh, Sohan Shah, Rasheed A.M. Thompson, Kevin K. Zarrabi, Mihir S. Shah, J. Ryan Mark, Joseph K. Izes, Costas D. Lallas, Leonard G. Gomella, and Adam R. Metwalli. Is the trinetx database a good tool for investigation of real-world management of von hippel–lindau? Journal of Kidney Cancer and VHL, 11:28-38, Dec 2024. URL: https://doi.org/10.15586/jkcvhl.v11i4.324, doi:10.15586/jkcvhl.v11i4.324. This article has 4 citations.
(gomezvirgilio2024geneticspathophysiologyand pages 11-13): Laura Gómez-Virgilio, Mireya Velazquez-Paniagua, Lucero Cuazozon-Ferrer, Maria-del-Carmen Silva-Lucero, Andres-Ivan Gutierrez-Malacara, Juan-Ramón Padilla-Mendoza, Jessica Borbolla-Vázquez, Job-Alí Díaz-Hernández, Fausto-Alejandro Jiménez-Orozco, and Maria-del-Carmen Cardenas-Aguayo. Genetics, pathophysiology, and current challenges in von hippel–lindau disease therapeutics. Diagnostics, 14:1909, Aug 2024. URL: https://doi.org/10.3390/diagnostics14171909, doi:10.3390/diagnostics14171909. This article has 8 citations.
(halperin2023uniquecharacteristicsof pages 1-2): Reut Halperin, Liat Arnon, Yehudit Eden-Friedman, and Amit Tirosh. Unique characteristics of patients with von hippel–lindau disease defined by various diagnostic criteria. Cancers, 15:1657, Mar 2023. URL: https://doi.org/10.3390/cancers15061657, doi:10.3390/cancers15061657. This article has 9 citations.
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