Von Hippel-Lindau (VHL) is a neurocutaneous syndrome that occurs in 1 of 36,000 people and is inherited as an autosomal dominant trait Autosomal Dominant Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more with variable penetrance. The VHL gene is a tumor-suppressor gene 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
Tumors, including pheochromocytomas Pheochromocytoma A pheochromocytoma is a catecholamine-secreting tumor of chromaffin cells typically located in the adrenals. It causes persistent or paroxysmal hypertension. Diagnosis is by measuring catecholamine... read more 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 Renal Cell Carcinoma Renal cell carcinoma (RCC) is the most common renal cancer. Symptoms can include hematuria, flank pain, a palpable mass, and fever of unknown origin (FUO). However, symptoms are often absent... read more 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 of VHL
Symptoms of Von Hippel-Lindau depend on the size and location of the tumors. Symptoms may include headaches, dizziness, weakness, ataxia, impaired vision, and high blood pressure.
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 of VHL
Central nervous system imaging, typically MRI
Sometimes molecular genetic testing
Von Hippel-Lindau disease is diagnosed when one of the following criteria is met:
Family history of VHL and presence of ≥ 1 VHL tumor (retinal, brain, or spinal hemangioblastoma; pheochromocytoma; renal cell carcinoma; or pancreatic endocrine tumor)
Two or more characteristic VHL tumors in patients with no known family history of VHL
If clinical features are not conclusive, the diagnosis can also be established by using molecular genetic testing to identify a VHL gene mutation.
If a specific mutation for the VHL gene is identified in a patient, genetic testing should be done to determine whether at-risk family members also have that mutation.
Treatment of VHL
Surgery or sometimes radiation therapy
For retinal angiomas, laser coagulation or cryotherapy
Treatment of Von Hippel-Lindau often involves surgical removal of the tumor before it becomes harmful. Pheochromocytomas are surgically removed; sometimes continued treatment of hypertension Treatment Hypertension is sustained elevation of resting systolic blood pressure (≥ 130 mm Hg), diastolic blood pressure (≥ 80 mm Hg), or both. Hypertension with no known cause (primary; formerly, essential... read more is needed. Renal cell carcinomas are surgically removed; advanced cancers may respond to pharmacologic treatment Palliative treatments Renal cell carcinoma (RCC) is the most common renal cancer. Symptoms can include hematuria, flank pain, a palpable mass, and fever of unknown origin (FUO). However, symptoms are often absent... read more . Some tumors can be treated with focused high-dose radiation.
Belzutifan, an oral hypoxia-inducible factor-2 alpha inhibitor, is now available for use in adult patients with renal cell carcinomas, central nervous system hemangioblastomas, or pancreatic endocrine tumors that do not require immediate surgical removal. The recommended dosage is 120 mg orally once a day. This drug can be used until the disease progresses or unacceptable toxicity occurs.
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.
Routine surveillance should include the following (1 Screening reference Von Hippel–Lindau disease is a rare hereditary neurocutaneous disorder characterized by benign and malignant tumors in multiple organs. Diagnosis is made using clinical criteria and/or molecular... read more ):
Annual history and physical examination
Annual dilated eye examination beginning in infancy to screen for retinal hemangioblastomas
Annual blood pressure monitoring beginning at 2 years of age to screen for pheochromocytomas
Annual measurement of urine or plasma fractionated metanephrines beginning at 5 years of age to screen for pheochromocytomas
Brain and spinal MRI every 2 years beginning at 11 years of age to screen for central nervous system hemangioblastomas
Audiography every 2 years beginning at 11 years of age to screen for endolymphatic sac tumors
Abdominal MRI or ultrasonography every 2 years beginning at 15 years of age to screen for renal cell carcinomas, pheochromocytomas, and pancreatic tumors
People who do not meet diagnostic criteria for VHL but who have a germline mutation or who have not been tested but are 1st- and 2nd-degree family members of a VHL patient also should be screened using the following:
Annual evaluation for neurologic symptoms and for vision and hearing problems
Annual ocular examination to look for nystagmus, strabismus, and white pupils
Annual blood pressure monitoring