RARE DISEASE
Von Hippel-Lindau disease
Von Hippel-Lindau disease
Von Hippel-Lindau disease
Synonyms: Familial cerebelloretinal angiomatosis, Lindau disease, VHL, Von Hippel-Lindau syndrome
Synonyms: Familial cerebelloretinal angiomatosis, Lindau disease, VHL, Von Hippel-Lindau syndrome
Synonyms: Familial cerebelloretinal angiomatosis, Lindau disease, VHL, Von Hippel-Lindau syndrome
Drug discovery
4
drugs
With orphan designations
Overview
Von Hippel-Lindau (VHL) disease is a rare autosomal dominant disorder caused by VHL gene mutations, leading to tumor suppressor dysfunction. It manifests with benign/malignant tumors in the CNS (hemangioblastomas), kidneys (clear cell renal carcinoma), pancreas, adrenal glands (pheochromocytomas), and retina. Clinical features depend on tumor location, with risks of blindness, neurological deficits, and metastatic renal cancer. Diagnosis combines genetic testing and imaging surveillance [1][6][9]. Management emphasizes early tumor detection and intervention to prevent complications [4][16].
Burden
Clinical: Lifelong multisystem monitoring, recurrent surgeries, and cancer risk (25–60% develop renal cell carcinoma) [1][10].
Economic: High healthcare costs from imaging, surgeries, and systemic therapies [10].
Psychological: Anxiety related to disease progression and genetic transmission risks [4][13].
Therapies
Surgical resection for symptomatic or high-risk tumors (CNS, renal, pancreatic) [4][16].
Belzutifan (HIF-2α inhibitor), FDA-approved for VHL-associated renal cell carcinoma, CNS hemangioblastomas, and pancreatic neuroendocrine tumors [7][18].
Surveillance protocols: Annual MRI (brain/spine/abdomen), ophthalmologic exams, and biochemical testing [4][9].
Categories: rare developmental anomalies during embryogenesis, rare endocrine diseases, rare genetic diseases, rare neoplastic diseases, rare neurological diseases, rare ophthalmic disorders, rare renal diseases
Research Papers
974 drug discovery papers about Von Hippel-Lindau disease, with 4 first-in-class and 15 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
974 drug discovery papers about Von Hippel-Lindau disease, with 4 first-in-class and 15 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-13 | Recent advances in etiology and treatment of von Hippel-Lindau Disease (VHLD).
Von Hippel-Lindau disease (VHLD) is a rare autosomal dominant disease, occuring in ~ 1 in 35,000 individuals. Overall, individuals with inherited mutations in the VHL tumor suppressor gene are predisposed to a variety of cancer, including high frequencies of clear cell renal cell carcinoma (ccRCC), pancreatic neuroendocrine tumors, and hemangioblastomas, as well as benign cystic conditions and other cancers. The degree of risk for each of these pathological conditions depends on the location and severity of the inherited germline mutation, and the specific VHL protein interactions and functions disrupted. A core VHL protein function is as the targeting subunit of an E3 ligase complex, with protein degradation activity based on interactions with elongins (ELOB, ELOC), Cullin 2 (CUL2), and RBX1. For ccRCC and some other cancers, loss of VHL-dependent degradation of key substrates-the transcription factors hypoxia-inducible factor alpha (HIF-1α and HIF-2α)-and upregulation of HIF-dependent transcripts are critical to promote tumor formation. For this reason, drugs such as the HIF signaling inhibitor belzutifan have emerged as promising clinical agents for treatment of VHLD patients prone to ccRCC. However, other biological consequences of VHL loss are independent of HIFα degradation, and in some cases independent of the VHL ubiquitin ligase activity. Non-canonical activities of VHL include regulation of microtubule stability, mitotic progression, and ciliation, as well as formation of the extracellular matrix (ECM); the degree to which disruption of these activities contributes to VHLD is currently not well understood. This review provides a concise update of the current literature on VHLD pathogenesis, the relationship of VHL structure and protein interactions to the spectrum of phenotypes associated with VHLD, and current and proposed treatment, prevention, and interception of cancer formation for VHLD patients.
2026-08-05 | Case Report: Diagnosis and treatment report and literature review of 2 cases of VHL-deficient renal cell carcinoma.
Von Hippel-Lindau (VHL) disease is a rare familial autosomal dominant disorder with an incidence rate of approximately 1 in 36,000. It primarily results from mutations or inactivation of the VHL tumor suppressor gene located on chromosome 3p25-p26. The hallmark of this disease is hereditary hemangioblastoma, which can affect multiple organs and systems, including the brain (commonly infratentorial), spinal cord, retina, and internal organs such as the kidneys, adrenal glands, and pancreas. Less commonly, lesions may include papillary cystadenomas and endolymphatic sac tumors (ELST), which can form in the epididymis or broad ligament. The leading causes of death in these patients are hemangioblastomas and renal cell carcinoma of the central nervous system. Due to the multidisciplinary nature of the disease, diagnosis and management require a multidisciplinary team (MDT) consultation and collaboration among various specialties. Clinical diagnosis, genetic implications, and prognosis must be assessed comprehensively, with genetic testing confirming the diagnosis. Cases of VHL are exceptionally rare in clinical practice, and there remains a significant unmet need for effective treatments, particularly in rare tumors. Misdiagnosis and mistreatment are common, and repeated surgical interventions can exacerbate kidney damage. Early and accurate diagnosis, followed by proactive treatment, can significantly improve prognosis. Recently, our department admitted two patients with VHL-deficient renal cell carcinoma. Through surgery, radiofrequency ablation, and subsequent targeted therapy, the therapeutic outcomes were highly favorable. This report introduces the treatment of these two cases and provides a literature review on the current progress in the diagnosis, treatment, and prognosis of VHL-deficient renal cell carcinoma. Additionally, it discusses data on the screening of VHL patients and their close relatives, while emphasizing the optimization of individualized management for renal cell carcinoma to enhance the understanding, diagnosis, and treatment of the disease.
2026-08-03 | Diabetic ketoacidosis associated with pancreatic involvement in a patient with von Hippel-Lindau syndrome: a case report
Background Von Hippel–Lindau (VHL) disease is a rare autosomal dominant disorder predisposing individuals to multisystem neoplasms. While pheochromocytoma is a well-recognized endocrine manifestation of VHL, pancreatic involvement leading to clinically significant endocrine dysfunction is less frequently emphasized. We report a case of VHL syndrome in which diabetic ketoacidosis (DKA) occurred in the context of underlying pancreatic pathology, highlighting a potential but underexplored metabolic complication in these patients. Case summary A 31-year-old man came to the emergency department with a three-year history of polydipsia, polyuria, and hyperglycemia, and was diagnosed with diabetic ketoacidosis (DKA). His history included resection of cerebellar hemangioblastoma in 2009 and again in 2017, as well as subtotal pancreatectomy (head and body) for pancreatic lesions in 2017. At that time, his blood glucose was normal. His mother and maternal aunt both had hemangioblastoma. During this admission, we found severely impaired islet function in the residual pancreatic tail. Autoimmune diabetes was ruled out by negative anti-GAD, anti-IA-2, and anti-ZnT8 antibodies. There was no sign of infection or steroid use. Genetic testing showed a heterozygous deletion in exon 3 of the VHL gene, confirming VHL syndrome. With no other triggers identified, we attributed the DKA to acute decompensation from markedly reduced beta-cell reserve, likely due to both prior pancreatic resection and chronic VHL-related pancreatic disease. However, without serial imaging or histopathology to confirm progressive changes in the remnant tail, we could not establish a definitive causal relationship. Conclusion This case highlights that DKA can occur as an acute metabolic decompensation in patients with VHL-related pancreatic disease, particularly in those with prior pancreatic resections and progressive beta-cell loss over time. Nevertheless, the exact pathophysiological link between VHL-associated pancreatic involvement and the onset of DKA remains speculative and likely multifactorial. Clinicians should maintain vigilance for endocrine pancreatic insufficiency in VHL patients who present with unexplained hyperglycemia, even in the absence of a prior diabetes diagnosis. Further studies and accumulated case evidence are needed to clarify the mechanisms and risk factors for DKA in this specific population.
2026-07-28 | Endovascular Embolization in Neurovascular Disease: Material Science, Multimodal Management, and Future Horizons.
Background & Objectives: Endovascular embolization has matured into a sophisticated, precision-guided discipline that is central to the management of complex neurovascular pathologies. This review synthesizes contemporary treatment strategies, evaluating the advanced material characteristics of conventional inert liquid polymers, specifically non-adhesive ethylene vinyl alcohol (EVOH) copolymers and adhesive cyanoacrylates, alongside their targeted clinical applications in brain arteriovenous malformations (bAVMs), dural arteriovenous fistulas (dAVFs), hypervascular intracranial tumors, and chronic subdural hematomas (CSDHs). Furthermore, it examines the critical material and hemodynamic constraints that limit these agents in cerebral aneurysm repair. Methods: A comprehensive literature synthesis through 3 July 2026 was integrated with peer-reviewed clinical illustrations to evaluate both procedural mechanics and the necessity of post-procedural physiological management. Review Findings: Embolization serves a critical dual role: as a definitive curative therapy and as an essential preoperative or radiosurgical adjunct. As demonstrated by recent clinical validations, technical angiographic success must be closely coupled with vigilant neurocritical oversight to manage profound, localized hemodynamic shifts. While these conventional methods represent established clinical practice, the field is evolving away from inert mechanical occlusion toward a highly integrated approach. The convergence of stimuli-responsive "smart" hydrogels and endovascular robotics is being evaluated for potential roles in transforming these interventions into dynamic, bioactive platforms capable of modulating disease-specific mechanisms, such as Rat Sarcoma-Mitogen-Activated Protein Kinase (RAS-MAPK) and Bone Morphogenetic Protein (BMP) signaling in bAVMs or the Von Hippel-Lindau/Vascular Endothelial Growth Factor (VHL/VEGF) axis in hypervascular tumors. This review further analyzes landmark data, including the Squid Trial For the Embolization of the Middle Meningeal Artery for Treatment of Chronic Subdural Hematoma (STEM) trial for CSDH, providing a synthesis for translating these advanced material sciences into standardized, multidisciplinary neurointerventional care.
2026-07-09 | Regression of retinal capillary hemangioblastoma with systemic belzutifan in von Hippel–Lindau disease: a case report
Purpose To report a case of retinal capillary hemangioblastoma (RCH) regression in a patient with von Hippel–Lindau (VHL) disease following treatment with systemic belzutifan. Case presentation A 49-year-old female with VHL disease presented with a retinal capillary hemangioblastoma in the left eye that had been previously treated with laser therapy. She subsequently developed a new retinal lesion and interval growth of a renal intraparenchymal mass, for which systemic belzutifan was initiated. Four months after treatment initiation, a reduction in the size of the retinal lesions was observed, along with decreased perfusion and vascularity. Conclusion Systemic belzutifan therapy for VHL disease may induce regression of retinal capillary hemangioblastomas and can be effective as either a primary or an adjunctive treatment modality.
2026-08-13 | Recent advances in etiology and treatment of von Hippel-Lindau Disease (VHLD).
Von Hippel-Lindau disease (VHLD) is a rare autosomal dominant disease, occuring in ~ 1 in 35,000 individuals. Overall, individuals with inherited mutations in the VHL tumor suppressor gene are predisposed to a variety of cancer, including high frequencies of clear cell renal cell carcinoma (ccRCC), pancreatic neuroendocrine tumors, and hemangioblastomas, as well as benign cystic conditions and other cancers. The degree of risk for each of these pathological conditions depends on the location and severity of the inherited germline mutation, and the specific VHL protein interactions and functions disrupted. A core VHL protein function is as the targeting subunit of an E3 ligase complex, with protein degradation activity based on interactions with elongins (ELOB, ELOC), Cullin 2 (CUL2), and RBX1. For ccRCC and some other cancers, loss of VHL-dependent degradation of key substrates-the transcription factors hypoxia-inducible factor alpha (HIF-1α and HIF-2α)-and upregulation of HIF-dependent transcripts are critical to promote tumor formation. For this reason, drugs such as the HIF signaling inhibitor belzutifan have emerged as promising clinical agents for treatment of VHLD patients prone to ccRCC. However, other biological consequences of VHL loss are independent of HIFα degradation, and in some cases independent of the VHL ubiquitin ligase activity. Non-canonical activities of VHL include regulation of microtubule stability, mitotic progression, and ciliation, as well as formation of the extracellular matrix (ECM); the degree to which disruption of these activities contributes to VHLD is currently not well understood. This review provides a concise update of the current literature on VHLD pathogenesis, the relationship of VHL structure and protein interactions to the spectrum of phenotypes associated with VHLD, and current and proposed treatment, prevention, and interception of cancer formation for VHLD patients.
2026-08-05 | Case Report: Diagnosis and treatment report and literature review of 2 cases of VHL-deficient renal cell carcinoma.
Von Hippel-Lindau (VHL) disease is a rare familial autosomal dominant disorder with an incidence rate of approximately 1 in 36,000. It primarily results from mutations or inactivation of the VHL tumor suppressor gene located on chromosome 3p25-p26. The hallmark of this disease is hereditary hemangioblastoma, which can affect multiple organs and systems, including the brain (commonly infratentorial), spinal cord, retina, and internal organs such as the kidneys, adrenal glands, and pancreas. Less commonly, lesions may include papillary cystadenomas and endolymphatic sac tumors (ELST), which can form in the epididymis or broad ligament. The leading causes of death in these patients are hemangioblastomas and renal cell carcinoma of the central nervous system. Due to the multidisciplinary nature of the disease, diagnosis and management require a multidisciplinary team (MDT) consultation and collaboration among various specialties. Clinical diagnosis, genetic implications, and prognosis must be assessed comprehensively, with genetic testing confirming the diagnosis. Cases of VHL are exceptionally rare in clinical practice, and there remains a significant unmet need for effective treatments, particularly in rare tumors. Misdiagnosis and mistreatment are common, and repeated surgical interventions can exacerbate kidney damage. Early and accurate diagnosis, followed by proactive treatment, can significantly improve prognosis. Recently, our department admitted two patients with VHL-deficient renal cell carcinoma. Through surgery, radiofrequency ablation, and subsequent targeted therapy, the therapeutic outcomes were highly favorable. This report introduces the treatment of these two cases and provides a literature review on the current progress in the diagnosis, treatment, and prognosis of VHL-deficient renal cell carcinoma. Additionally, it discusses data on the screening of VHL patients and their close relatives, while emphasizing the optimization of individualized management for renal cell carcinoma to enhance the understanding, diagnosis, and treatment of the disease.
2026-08-03 | Diabetic ketoacidosis associated with pancreatic involvement in a patient with von Hippel-Lindau syndrome: a case report
Background Von Hippel–Lindau (VHL) disease is a rare autosomal dominant disorder predisposing individuals to multisystem neoplasms. While pheochromocytoma is a well-recognized endocrine manifestation of VHL, pancreatic involvement leading to clinically significant endocrine dysfunction is less frequently emphasized. We report a case of VHL syndrome in which diabetic ketoacidosis (DKA) occurred in the context of underlying pancreatic pathology, highlighting a potential but underexplored metabolic complication in these patients. Case summary A 31-year-old man came to the emergency department with a three-year history of polydipsia, polyuria, and hyperglycemia, and was diagnosed with diabetic ketoacidosis (DKA). His history included resection of cerebellar hemangioblastoma in 2009 and again in 2017, as well as subtotal pancreatectomy (head and body) for pancreatic lesions in 2017. At that time, his blood glucose was normal. His mother and maternal aunt both had hemangioblastoma. During this admission, we found severely impaired islet function in the residual pancreatic tail. Autoimmune diabetes was ruled out by negative anti-GAD, anti-IA-2, and anti-ZnT8 antibodies. There was no sign of infection or steroid use. Genetic testing showed a heterozygous deletion in exon 3 of the VHL gene, confirming VHL syndrome. With no other triggers identified, we attributed the DKA to acute decompensation from markedly reduced beta-cell reserve, likely due to both prior pancreatic resection and chronic VHL-related pancreatic disease. However, without serial imaging or histopathology to confirm progressive changes in the remnant tail, we could not establish a definitive causal relationship. Conclusion This case highlights that DKA can occur as an acute metabolic decompensation in patients with VHL-related pancreatic disease, particularly in those with prior pancreatic resections and progressive beta-cell loss over time. Nevertheless, the exact pathophysiological link between VHL-associated pancreatic involvement and the onset of DKA remains speculative and likely multifactorial. Clinicians should maintain vigilance for endocrine pancreatic insufficiency in VHL patients who present with unexplained hyperglycemia, even in the absence of a prior diabetes diagnosis. Further studies and accumulated case evidence are needed to clarify the mechanisms and risk factors for DKA in this specific population.
2026-07-28 | Endovascular Embolization in Neurovascular Disease: Material Science, Multimodal Management, and Future Horizons.
Background & Objectives: Endovascular embolization has matured into a sophisticated, precision-guided discipline that is central to the management of complex neurovascular pathologies. This review synthesizes contemporary treatment strategies, evaluating the advanced material characteristics of conventional inert liquid polymers, specifically non-adhesive ethylene vinyl alcohol (EVOH) copolymers and adhesive cyanoacrylates, alongside their targeted clinical applications in brain arteriovenous malformations (bAVMs), dural arteriovenous fistulas (dAVFs), hypervascular intracranial tumors, and chronic subdural hematomas (CSDHs). Furthermore, it examines the critical material and hemodynamic constraints that limit these agents in cerebral aneurysm repair. Methods: A comprehensive literature synthesis through 3 July 2026 was integrated with peer-reviewed clinical illustrations to evaluate both procedural mechanics and the necessity of post-procedural physiological management. Review Findings: Embolization serves a critical dual role: as a definitive curative therapy and as an essential preoperative or radiosurgical adjunct. As demonstrated by recent clinical validations, technical angiographic success must be closely coupled with vigilant neurocritical oversight to manage profound, localized hemodynamic shifts. While these conventional methods represent established clinical practice, the field is evolving away from inert mechanical occlusion toward a highly integrated approach. The convergence of stimuli-responsive "smart" hydrogels and endovascular robotics is being evaluated for potential roles in transforming these interventions into dynamic, bioactive platforms capable of modulating disease-specific mechanisms, such as Rat Sarcoma-Mitogen-Activated Protein Kinase (RAS-MAPK) and Bone Morphogenetic Protein (BMP) signaling in bAVMs or the Von Hippel-Lindau/Vascular Endothelial Growth Factor (VHL/VEGF) axis in hypervascular tumors. This review further analyzes landmark data, including the Squid Trial For the Embolization of the Middle Meningeal Artery for Treatment of Chronic Subdural Hematoma (STEM) trial for CSDH, providing a synthesis for translating these advanced material sciences into standardized, multidisciplinary neurointerventional care.
2026-07-09 | Regression of retinal capillary hemangioblastoma with systemic belzutifan in von Hippel–Lindau disease: a case report
Purpose To report a case of retinal capillary hemangioblastoma (RCH) regression in a patient with von Hippel–Lindau (VHL) disease following treatment with systemic belzutifan. Case presentation A 49-year-old female with VHL disease presented with a retinal capillary hemangioblastoma in the left eye that had been previously treated with laser therapy. She subsequently developed a new retinal lesion and interval growth of a renal intraparenchymal mass, for which systemic belzutifan was initiated. Four months after treatment initiation, a reduction in the size of the retinal lesions was observed, along with decreased perfusion and vascularity. Conclusion Systemic belzutifan therapy for VHL disease may induce regression of retinal capillary hemangioblastomas and can be effective as either a primary or an adjunctive treatment modality.
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Drug Discovery Landscape
4 orphan drug designations for Von Hippel-Lindau disease, including 1 approved therapy.
4 orphan drug designations for Von Hippel-Lindau disease, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Belzutifan | small molecules | EMA | 2020-08-21 | — | Merck Sharp & Dohme B.V. |
belzutifan [Welireg] | small molecules | FDA | 2020-06-24 | 2021-08-13 | Merck Sharp & Dohme, LLC |
Propranolol hydrochloride | small molecules | EMA | 2017-02-27 | — | Consejo Superior de Investigaciones Cientificas (CSIC) |
3-(3,5-Dimethyl-1H-2ylmethylene)-1,3-dihydro-indol-2-one | small molecules | FDA | 2000-03-23 | — | Sugen, Inc. |
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