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.

Brief Summary

History of the Disease

Frequency

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.

The symptoms and signs of VHL that are observed are associated with the following types of tumors:

Hemangiolastomas

Headaches

Weakness
Ataxia (loss of muscle coordination)
Nausea and Vomiting
Retinal Angioma

Renal Cell Carcinoma

Hematuria (blood in urine)
Lower back pain
Anemia
Loss of appetite & Weight loss
Fatigue
Fever
Development of a lump on one side

Pheochromocytomas

Headache
Panic Attacks
Profuse Sweating
High Blood Pressure
Clammy Skin
Anxiety

Endolyphatic Sac Tumors

Hearing Loss
Tinittus (ringing in the ears)
Vertigo (dizziness)
Facial Paralysis

Pancreatic Neuroendocrine Tumors

Hypoglycemia (low blood sugar)
Stomach Ulcer
Gallstones
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"

Symptoms

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

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

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

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

Jose Eusebio, MD

Department of Surgery, Ophthalmology

Location:

Riverside Medical Center

Contact No:

(034) 433-9979 / 433-9257

Henry L. Geroche, MD

Department of Surgery, Urology

Location:

Riverside Medical Center

Contact No:

(034) 433-7331 Local 7301

Expert Directory

References

FOR INFORMATION

FOR IMAGES

References