Rare genetic disorders: Von Hippel-Lindau disease

Von Hippel-Lindau disease is a traditionally rare genetic disorder with an estimated incidence of approximately 1 in every 36,000 people according to Genetics Home Reference. The disorder affects cell growth, especially the growth of blood vessels. Mutations in the tumor suppressor gene VHL on chromosome 3 cause the growth of blood vessel tumors, called angiomas, which may be cancerous (malignant) or cyst-like (benign). The growths can appear in various parts of the body, leading to various symptoms, though hemangioblastomas, benign tumors in the central nervous system, are most common.

Mutations in von Hippel-Lindau disease

The majority of VHL mutations are inherited from an affected parent, but the National Institutes of Health (NIH) Genetics Home Reference notes that one-fifth are de novo mutations. De novo mutations are new mutations that occur in the embryo of the affected individual or prior to conception in the gametes that create the embryo. Though the mutations are inherited in an autosomal dominant manner, two copies of the gene generally need to be mutated for the disease to manifest. However, the risk of tumor development is increased with the presence of a single mutated copy of the VHL gene. A second mutation can occur due to environmental stresses during an individual’s lifetime, allowing symptoms to appear at any point in life, even in one’s 80s.

Parts of the body affected by VHL disease

According to the VHL Alliance, retinal angiomas were first described by Dr. Eugen von Hippel in 1904. Dr. Arvid Lindau described brain and spinal cord angiomas in 1926, broadening the definition of the disease. Cysts are also common in the kidney, pancreas and scrotum (in males), and individuals with von Hippel-Lindau disease are susceptible to clear cell renal cell carcinoma, a form of kidney cancer, as well as pheochromocytoma, a tumor that affects the adrenal gland. Type 1 VHL has a low risk of pheochromocytoma formation. Type 2 VHL has a higher risk of this form of tumor, with subtypes based on the risk of other tumors. In addition, one-tenth of VHL patients develop endolymphatic sac tumors in the inner ear according to Genetics Home Reference, and women with von Hippel-Lindau sometimes experience cystadenoma growth in the reproductive tissues.

Symptoms of VHL

Symptoms occur in patients with the disease because the angiomas put pressure on the surrounding tissue, which can also lead to fluid accumulation and cysts. Symptoms depend on the location of the tumors.

  • Hemangioblastomas in the central nervous system can cause dizziness, headaches, nausea and vomiting, weakness and ataxia (loss of muscle coordination).
  • The presence of these tumors in the eye affect the retina and can cause vision loss.
  • Pheochromocytomas and kidney tumors can cause changes in blood pressure, particularly hypertension.
  • Tumors in the inner ear can cause hearing loss, tinnitus (ringing in the ears) and balance issues.

Tumors can be treated surgically or with radiation to minimize symptoms and avoid blindness, deafness and/or brain damage.

Von Hippel-Lindau

Research into the diagnosis and treatment of VHL is ongoing. Due to the genetic mutations underlying the disease, screening is likely to play an important role in preventing the tumors, or at the very least treating them early. Because of the traditional rarity of the condition, much work is still needed. The ClinicalTrials registry includes information on studies recruiting individuals with VHL if you or a loved one has the disease and would like to participate in the research.