Von Hippel-Lindau syndrome

Synonyms

2

Overview

Von Hippel–Lindau syndrome (VHL, Von hippel-Lindau disease) is a disease which results from a mutation in the von Hippel–Lindau tumor suppressor gene on chromosome 3p25.3.

Symptoms

Signs and symptoms associated with VHL syndrome include headaches, problems with balance and walking, dizziness, weakness of the limbs, vision problems, and high blood pressure. Conditions associated with VHL disease include angiomatosis, hemangioblastomas, pheochromocytoma, renal cell carcinoma, pancreatic cysts (pancreatic serous cystadenoma), endolymphatic sac tumor, and bilateral papillary cystadenomas of the epididymis (men) or broad ligament of the uterus (women). Angiomatosis occurs in 37.2% of patients presenting with VHL disease and usually occurs in the retina. As a result, loss of vision is very common. However, other organs can be affected: strokes, heart attacks, and cardiovascular disease are common additional symptoms. Approximately 40% of VHL disease presents with CNS hemangioblastomas and they are present in around 60-80%. Spinal hemangioblastomas are found in 13-59% of VHL disease and are specific because 80% are found in VHL disease. Although all of these tumours are common in VHL disease, around half of cases present with only one tumour type.

Causes

The disease is caused by mutations of the von Hippel–Lindau tumor suppressor (VHL) gene on the short arm of chromosome 3 (3p25-26). There are over 1500 germline mutations and somatic mutations found in VHL syndrome.

Every cell in the body has 2 copies of every gene. In VHL disease, one copy of the VHL gene has a mutation and produces a faulty VHL protein (pVHL). However, the second copy still produces a functional protein. Tumours form from only those cells where the second copy of the gene has been mutated. This is known as the two-hit hypothesis. A lack of this protein allows tumors characteristic of von Hippel–Lindau syndrome to develop.

Approximately 20% of cases of VHL disease are found in individuals without a family history, known as de novo mutations. An inherited mutation of the VHL gene is responsible for the remaining 80 percent of cases.

30-40% of mutations in the VHL gene consist of 50-250kb deletion mutations that remove either part of the gene or the whole gene and flanking regions of DNA. The remaining 60-70% of VHL disease is caused by the truncation of pVHL by nonsense mutations, indel mutations or splice site mutations.


Prevention

Screening exams are important medical tests done when you're at risk but don't have symptoms. They help find disease at its earliest stage. In von Hippel Lindau disease, early diagnosis increases your chance for successful treatment and better quality of life.

Screening Guidelines for People with VHL syndrome Who Do Not Have Symptoms:

10 Years Old and Under

  • Complete general history and physical exam, including blood pressure measurement and neurological exam, every year
  • Thorough eye exam at diagnosis and every year
  • Ultrasound (link to definition) of the abdomen at diagnosis and every two years
  • CT (computed axial tomography) scan (link) or MRI (magnetic resonance imaging) (link) if a problem is found on the ultrasound or if laboratory tests for pheochromocytoma are abnormal
  • MRI of the brain and spine if you have neurologic symptoms
  • Tests for pheochromocytoma at diagnosis and every year if you have a family history of VHL 2 or mutations associated with VHL 2. If you have a family history of VHL1 or a mutation not associated with pheochromocytoma, you may want to be tested every two years
  • Tests for pheochromocytoma before any surgery
  • Hearing exam at diagnosis and every two years or as needed. This should include an MRI or CT scan of ear canals if you have hearing loss, ringing in the ears, dizziness or problems with balance

10 to 15 Years Old

  • Complete general history and physical exam, including blood pressure measurement and neurological exam, every year
  • Eye exam at diagnosis and every year; every six months during puberty
  • Ultrasound of the abdomen at diagnosis and every two years
  • CT (computed axial tomography) scan or MRI (magnetic resonance imaging) if a problem is found on the ultrasound or if laboratory tests for pheochromocytoma are abnormal
  • MRI of the brain and spine at diagnosis and every year
  • Tests for pheochromocytoma at diagnosis and every year in patients with a family history of VHL type 2 or mutations associated with VHL 2. If you have a family history of VHL1 or in patients with mutations not associated with pheochromocytoma, you may want to be tested every two years.
  • Tests for pheochromocytoma before any surgery
  • Hearing exam at diagnosis and every two years or as needed. This should include an MRI or CT scan of ear canals if you have hearing loss, ringing in the ears, dizziness or problems with balance.

15 Years Old and Older

  • Complete general history and physical exam, including blood pressure measurement and neurological exam, every year
  • Thorough eye exam at diagnosis and every year
  • Ultrasound of the abdomen at diagnosis and every year from ages 15 to 20
  • MRI of the brain and spine at diagnosis and then every year. If your doctor says you are at low risk, you may need an MRI every two years
  • CT or MRI scan of the abdomen at 20 or at diagnosis, then every two years. Alternate with ultrasound of every other year
  • Tests for pheochromocytoma at diagnosis and every year in patients with a family history of VHL type 2 or mutations associated with VHL 2. If you have a family history of VHL1 or gene mutations not associated with pheochromocytoma, you may want to be tested every two years
  • Tests for pheochromocytoma before any surgery and during pregnancy
  • Hearing exam at diagnosis and every two years or as needed. This should include an MRI or CT scan of ear canals if you have hearing loss, ringing in the ears, dizziness or problems with balance

If one of your parents has von Hippel Lindau syndrome, you have a 50% chance of getting it. Genetic testing is a way to look at the VHL gene to see if it has any changes. It is a good idea for all family members of a person with VHL to be tested.

Diagnosis

The detection of tumours specific to VHL syndrome is important in the disease's diagnosis. In individuals with a family history of VHL disease, one hemangioblastoma, pheochromocytoma or renal cell carcinoma may be sufficient to make a diagnosis. As all the tumours associated with VHL disease can be found sporadically, at least two tumours must be identified to diagnose VHL disease in a person without a family history.

Genetic diagnosis is also useful in VHL disease diagnosis. In hereditary VHL, disease techniques such as southern blotting and gene sequencing can be used to analyse DNA and identify mutations. These tests can be used to screen family members of those afflicted with VHL disease; de novo cases that produce genetic mosaicism are more difficult to detect because mutations are not found in the white blood cells that are used for genetic analysis.

Prognosis

Owing largely to the high incidence of clear cell renal cell carcinoma associated with von Hippel-Lindau (VHL) syndrome, the average life expectancy in affected individuals is 49 years. However, diligent surveillance enabling early treatment interventions can increase life expectancy. The morbidity of VHL disease varies depending on the particular organ system involved and the extent of the organ-system insult.

Treatment

There is no way to reverse VHL mutations, but early recognition and treatment of specific manifestations of VHL can substantially decrease complications and improve quality of life. For this reason, individuals with VHL disease are usually screened routinely for retinal angiomas, CNS hemangioblastomas, clear-cell renal carcinomas and pheochromocytomas. CNS hemangioblastomas are usually surgically removed if they are symptomatic. Photocoagulation and cryotherapy are usually used for the treatment of symptomatic retinal angiomas, although anti-angiogenic treatments may also be an option. Renal tumours may be removed by a partial nephrectomy or other techniques such as radiofrequency ablation.