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Von Hippel–Lindau Disease (VHL)

By Margaret C. McBride, MD, Professor of Pediatrics (Neurology);Director, Neurodevelopmental Center, Northeastern Ohio Universities Colleges of Medicine and Pharmacology, Rootstown;Akron Children’s Hospital

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Von Hippel–Lindau disease is a rare hereditary neurocutaneous disorder characterized by benign and malignant tumors in multiple organs. Diagnosis is with ophthalmoscopy or imaging to check for tumors. Treatment is with surgery or sometimes radiation therapy or, for retinal angiomas, laser coagulation or cryotherapy.

Von Hippel-Lindau (VHL) is a neurocutaneous syndrome that occurs in 1 of 36,000 people and is inherited as an autosomal dominant trait with variable penetrance. The VHL gene is located on the short arm of chromosome 3 (3p25.3). Over 1500 different mutations in this gene have been identified in patients with VHL. In 20% of affected people, the abnormal gene appears to be a new mutation.

VHL most commonly causes cerebellar hemangioblastomas and retinal angiomas. Tumors, including pheochromocytomas and cysts (renal, hepatic, pancreatic, or genital tract), can occur in other organs. About 10% of people with VHL develop an endolymphatic tumor in the inner ear, threatening hearing. Risk of developing renal cell carcinoma increases with age and by age 60 may be as high as 70%.

Manifestations typically appear between ages 10 and 30 but can appear earlier.

Symptoms and Signs

Symptoms of VHL depend on the size and location of the tumors. Symptoms may include headaches, dizziness, weakness, ataxia, impaired vision, and high BP.

Retinal angiomas, detected by direct ophthalmoscopy, appear as a dilated artery leading from the disk to a peripheral tumor with an engorged vein. These angiomas are usually asymptomatic, but if they are centrally located and enlarge, they can result in substantial loss of vision. These tumors increase risk of retinal detachment, macular edema, and glaucoma.

Untreated, VHL can result in blindness, brain damage, or death. Death usually results from complications of cerebellar hemangioblastomas or renal cell carcinoma.

Diagnosis

  • Direct ophthalmoscopy

  • CNS imaging, typically MRI

  • Genetic testing

Von Hippel-Lindau disease is diagnosed when typical tumors are detected and one of the following criteria is met:

  • More than one tumor in the brain or eye

  • Single tumor in the brain or eye and one elsewhere in the body

  • Family history of VHL and presence of a tumor

Children who have a parent or sibling with the disorder should be evaluated before age 5 yr; evaluation should include ophthalmoscopy and brain MRI to determine whether the diagnostic criteria are met. If a specific mutation for VHL gene is identified in a patient, genetic testing should be done to determine whether at-risk family members also have that mutation.

Treatment

  • Surgery or sometimes radiation therapy

  • For retinal angiomas, laser coagulation or cryotherapy

  • Regular monitoring

Treatment often involves surgical removal of the tumor before it becomes harmful. Some tumors can be treated with focused high-dose radiation. Typically, retinal angiomas are treated with laser coagulation or cryotherapy to preserve vision.

Use of propranolol to reduce the size of the hemangiomas is being studied.

Screening to check for complications and early treatment can improve prognosis.

Screening for complications

If the diagnostic criteria for VHL are met, patients should be regularly screened to check for complications of VHL because early detection is key to preventing serious complications.

Annual screening should include neurologic examination, BP monitoring, hearing screening, ophthalmoscopy, and measurement of urine or plasma fractionated metanephrines (to screen for pheochromocytoma). Formal audiologic evaluation should be done at least every 3 yr. After age 16, abdominal ultrasonography should be done annually to screen for renal tumors; every 2 yr, MRI of the brain and spinal cord should be done to screen for new CNS tumors or changes in existing tumors.