Genetics of von Hippel-Lindau Disease Follow-up

Because of the pleiotropic clinical manifestations of von Hippel-Lindau (VHL) disease, or von Hippel-Lindau syndrome, and the potential for malignancy, a lifelong strategy of surveillance (particularly for the brain, eyes, and kidneys) is necessary for early detection and treatment of complications. A plan for periodic surveillance should be made and a copy provided to the primary care physician and the patient (to parents for pediatric patients). Compliance with these screening tests at proper intervals has been shown to correlate strongly to the recommendations made by the physician.^[5] A case manager or a nurse practitioner can be assigned to ensure proper surveillance. A reasonable annual surveillance strategy for affected patients and at-risk relatives is as follows:

• Obtain medical history and perform physical examination annually.
• Obtain laboratory studies annually, starting at age 5 years. Testing consists of urinalysis, urine cytologic examination, urinary catecholamine metabolites, CBC count, and plasma catecholamines.
• Perform annual direct and indirect ophthalmoscopic examinations; this is best if started before age 5 years.
• Perform audiologic examination at the first sign of hearing problems, vertigo, or tinnitus. In one study of VHL mutation carriers, more than 90% of radiologically diagnosed endolymphatic sac tumors were associated with abnormal audiometric findings.^[6] When abnormalities are found, a T1-weighted MRI of the temporal bone should be performed.
• Some experts recommend that MRI of the brain to properly assess the posterior fossa should be performed every 2-3 years, beginning at age 10-15 years. This recommendation is controversial. Typically, space-occupying lesions in the CNS causes neurological symptoms. If lesions are present and the patient is asymptomatic, they are usually not resected.
• Perform annual abdominal ultrasonography, beginning at age 16 years, to look for abnormalities in the kidneys, adrenal glands and/or pancreas. Concerning findings warrant further investigation with either CT scans or MRI.
• Screening may be discontinued for at-risk relatives at approximately age 60 years, if no abnormalities have been found.

Genetic testing includes the following:

• Once diagnosed, a search for the causative mutation (in the originally identified patient or "proband") can benefit family members. If the proband's causative mutation can be identified, then its presence or absence in at-risk family members can reliably and unequivocally define their status. Individuals who have not inherited the mutant VHL allele can dispense with the burdensome and expensive task of unnecessary annual screening, and individuals with the mutant allele can be closely monitored for early manifestations.
• Genetic testing for mutations in the VHL gene requires complete sequencing of the coding regions and is approximately 80% sensitive. The addition of Southern blot analysis detects virtually all mutations. In the rare event that no causative mutation is identified in the proband, all at-risk relatives must continue to undergo annual screening at least until age 60 years, as outlined above.

• Genetic testing is performed at several laboratories in the United States, including the following:

  • Boston University School of Medicine, Center for Human Genetics, Boston, Massachusetts
  • Children's Mercy Hospital, Molecular Genetics Laboratory, Kansas City, Missouri
  • Johns Hopkins Hospital, DNA Diagnostic Laboratory, Baltimore, Maryland
  • University of Pennsylvania School of Medicine, Genetic Diagnostic Laboratory, Philadelphia, Pennsylvania
• Patients and families can benefit from contacting the VHL Family Alliance at 800-767-4845 (800-767-4VHL) or by email at info@vhl.org. The VHL Family Alliance Web site is www.vhl.org.
• The National Cancer Institute through the US National Institutes of Health sponsors a Web site (www.cancer.gov) with general information that may be useful to patients with VHL syndrome and their families.
• Additional support organizations are:

  • Kidney Cancer Association at 800-516-8051 or 847-332-1051. The Web site is www.curekidneycancer.org.
  • NIH/National Eye Institute at 301-496-5248. The Web site is www.nei.nih.gov.