Von Hippel-Lindau syndrome (VHL) is a genetic disorder that is characterized by the growth of benign and malignancy tumors in the central nervous system (CNS) and viscera. This may include many different types of tumors, such haemangioblastomas, renal cell carcinoma (RCC) renal cysts and phaeochromocytoma.
The name originates from Eugene von Hippel and Arvid Lindau, who described retinal and other tumors in 1904 and 1926 respectively. It is a rare disorder that affects approximately 1 in 36,000 live births. The majority of these involve a gene mutation that has been inherited from a parent that is a carrier for the disease, although approximately 20% of cases are new mutations.
VHL syndrome is caused by mutations in the certain tumor suppression genes (3p25-26), which results in highly vascular tumors.
The genetic mutation is usually inherited from a parent that is affected by the disorder, following an autosomal dominant pattern with high penetrance. This means that only one copy of the gene needs to be inherited in order for an individual to be affected. Approximately 20% of cases present with a spontaneous gene mutation and have no family history of the disease.
The characteristic formation of tumors does not begin, however, until a second gene mutation is acquired at some point in the individual’s lifetime. It is not clear what causes this mutation, but it occurs eventually in almost all individuals with the inherited gene mutation.
Individuals may present with VHL syndrome at any stage of life, from early childhood to elderly individuals. The various tumors are the primary physical sign that may be evident and the types of common tumors include:
- CNS haemangioblastomas affect approximately two-thirds of patients with the disorder, making them the most common type of tumor. Although benign, they can cause significant morbidity depending on their location in the CNS.
- Retinal haemangioblastomas affect up to 60% of patients but are typically asymptomatic until complications arise, such as oedema, retinal detachment or glaucoma.
- Phaeochromocytomas are usually benign but may cause symptoms such as headaches, palpitations and episodes of shock-like signs.
- RCC and cysts affect up to 60% of patients and are usually asymptomatic. RCC requires surgical removal although cysts do not usually need treatment.
- Pancreatic tumors are usually asymptomatic and detected with diagnostic imaging. Benign tumors do not usually need removal but those with metastatic potential should be managed with surgical resection.
- Endolymphatic sac tumors are benign by can erode the bone in the inner ear, leading to tinnitus, vertigo or hearing loss.
- Epididymal cystadenomas are usually asymptomatic and found with ultrasound imaging, without the need for treatment.
- Broad ligament cystadenomas are usually asymptomatic and detected with imaging techniques. Treatment is only required for rare, symptomatic cases.
Early diagnosis of VHL syndrome is preferable to allow timely management of the disorder and reduce the impact on the life expectancy. Previously, life expectancy was approximately 50 years, but this has improved significantly with the introduction of screening and early management.
Patients that have family members with the disease should be screened to detect genetic susceptibility for the syndrome. Genetic testing is very sensitive for affected families but can become more complex for new spontaneous mutations, usually due to mosaicism. Antenatal testing for early diagnosis is an option for families with a known mutation for VHL syndrome.
In order to be diagnosed and individual must have either multiple tumors characteristic of the syndrome or a family history of the syndrome and one characteristic tumor.
There are several different types of gene mutations, including:
- Type 1: may develop or tumor types but low risk of phaeochromocytoma
- Type 2A: phaeochromocytomas present with low risk of RCC
- Type 2B: phaeochromocytomas present with high risk of RCC
- Type 2C: phaeochromocytoma only with no evidence of other tumors