VON HIPPEL-LINDAU SYNDROME
Brief Summary
Von Hippel–Lindau disease is a rare hereditary neurocutaneous syndrome characterized by visceral cysts and benign tumors in multiple organ systems most frequently in retinal, cerebellar, and spinal hemangioblastoma, renal cell carcinoma (RCC), pheochromocytoma, and pancreatic tumors. It is linked to a VHL tumor suppressor gene mutation in the germ line on chromosome 3's short arm. Clinical criteria and/or molecular genetic testing are used to make the diagnosis. Surgery, radiation therapy, or laser coagulation or cryotherapy for retinal angiomas are all options for treatment.
Image:
Von Hippel-Lindau syndrome (VHL) with Multiple Renal Carcinoma, Cysts, as well as Haemangioblastoma
Disease Frequency
Von Hippel-Lindau syndrome is estimated to affect 1 in 36,000 people worldwide.
Further details here.
Inheritance
History of the Disease
Von Hippel-Lindau syndrome is inherited in an autosomal dominant manner.
In 1911, German ophthalmologist Eugen von Hippel was the first to describe the condition independently. He identified and described retinal manifestations and hemangioblastomas that had been passed down through generations. In 1926, Swedish
pathologist Arvid Lindau noticed the link between retinal lesions and cerebellar hemangioblastomas, as well as abnormalities in other organs, as part of a familial disease. Clinical diagnostic criteria for VHL disease were established in the following years, and the VHL tumor suppressor gene on the short arm of chromosome 3 was discovered.
Pathogenesis
One of the most common multisystem family cancer illnesses is Von Hippel-Lindau syndrome. It is caused by an autosomal dominant mutation in the VHL tumor suppressor gene on the short arm of chromosome 3, (3p25-26), which results in an aberrant pVHL. HIF-1-alpha, a protein regulated by pVHL, is responsible for the cellular response to hypoxia. Due to mutations, alterations may occur to pVHL at the HIF-1-alpha binding site. As a result, pVHL fails to bind effectively to HIF-1-alpha, causing transcription of numerous genes and consequent upregulation of growth factors such as erythropoietin, vascular endothelial growth factor, and other genes involved in glucose uptake and metabolism. It could also have an impact on transcriptional regulation, extracellular matrix production, apoptosis, and, in particular, the cellular adaptive response to hypoxia.
Image:
Location of the VHL gene. The VHL tumor suppressor gene is located on the short arm of chromosome 3 (3p25-26)
Symptoms
VHL syndrome is characterized by formation of tumors and cysts in multiple organs of the body, which involve the ectodermal structures like the central nervous system (CNS), skin, and eyes.
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The symptoms and signs of VHL that are observed are associated with the following types of tumors:
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1
Hemangiolastomas
Headaches
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Weakness
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Ataxia (loss of muscle coordination)
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Nausea and Vomiting
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Retinal Angioma
2
Renal Cell Carcinoma
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Hematuria (blood in urine)
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Lower back pain
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Anemia
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Loss of appetite & Weight loss
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Fatigue
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Fever
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Development of a lump on one side
3
Pheochromocytomas​
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Headache
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Panic Attacks
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Profuse Sweating
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High Blood Pressure
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Clammy Skin
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Anxiety
4
Endolyphatic Sac Tumors
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Hearing Loss
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Tinittus (ringing in the ears)
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Vertigo (dizziness)
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Facial Paralysis
5
Pancreatic Neuroendocrine Tumors
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Hypoglycemia (low blood sugar)
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Stomach Ulcer
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Gallstones
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Severe Diarrhea
Image:
Characteristic tumor types and locations in von Hippel-Lindau syndrome, from "Friedrich, C. A. Genotype-phenotype correlation in von Hippel-Lindau syndrome. Hum. Mol. Genet. 10, 763-767"
Social Concerns
People with this syndrome often experience several challenges such as limited information about the disease as well as treatment, financial and economic difficulties that can lead to adjustments to daily activities and roles. Individuals with VHL may experience complications upon treatment but with early diagnosis, regular surveillance and living a healthy lifestyle people with the VHL syndrome can lead full and productive lives.
Treatment
Although the Von Hippel-Lindau (VHL) syndrome has no cure, the best way to manage the syndrome is to find and remove as many tumors as possible before it affects the patients’ health. A healthcare professional may recommend surgery to remove tumors whenever possible but some tumors may respond to radiation therapy. If the tumor is left untreated, even noncancerous tumors can lead to blindness or brain damage.
Updates on Clinical Trials
Title: A Phase I/II Trial for Intravitreous Treatment of Severe Ocular Von Hippel-Lindau Disease Using a Combination of the PDGF Antagonist E10030 and the VEGF Antagonist Ranibizumab
Intervention/Treatment: Drug: Ranibizumab
E10030
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Goal: To investigate the safety and possible efficacy of combination investigational treatment with serial intravitreal injections of E10030, a PDGF-B antagonist, and ranibizumab, a VEGF-A antagonist, in participants with severe ocular VHL disease.
Further details here.
Title: 17AAG to Treat Kidney Tumors in Von Hippel-Lindau Disease
Intervention/Treatment: Drug: 17 allylamino-17-demethoxygeldanamycin\
Drug: 18 FDG (Fludeoxyglucose 18F)
Drug: [15-O] H2O
Drug: EPL diluent
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Goal: To evaluate the efficacy of 17 AAG administered as a single agent in von Hippel Lindau patients with renal tumors. The primary endpoint of the trial is response of renal tumors following 3 cycles of therapy.
To study the safety and tolerability of 17 AAG. To evaluate PD modulation of hsp90, and to explore the utility dynamic contrast enhanced MRI in evaluation of blood flow and metabolic changes in renal tumors before and during therapy
Further details here.
Expert Directory
References
FOR INFORMATION
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Rare Disease Report. (2016, October 18). Living with Von Hippel-Lindau Disease [Video]. Youtube.
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Von Hippel-Lindau Syndrome. (n.d.) U.S. National Library of Medicine.
FOR IMAGES