Features

VHL: a diagnostic dilemma

Payel Bhattacharya

doi:10.1038/nindia.2009.251 Published online 22 July 2009

Payel Bhattacharya

Most Indians are not aware of Von Hippel-Lindau Syndrome or VHL. It is a genetic condition that results in abnormal capillary growth in visceral organs of the body. Normally, our capillaries branch out gracefully like trees. In VHL patients, little knots of extra capillaries forms tumors.

I have lived with VHL for a while now and know it isn't easy since diagnosis itself has been a real challenge in India, where I am probably the only reported and well chronicled case apart from an unusual case of VHL syndrome with renal cell carcinoma1. It is listed as a 'rare disease' by the Office of Rare Diseases (ORD) of the National Institutes of Health (NIH)2.

What is it?

VHL is an autosomal dominant inherited cancer syndrome characterised by the development of specific tumors, both benign and malignant with high penetrnce and variable expression. In literature, data on the natural history of VHL is scarce3, mostly pointing to an incidence of around one in 36,000. It is caused by deletions or point mutations in a tumor suppressor gene.

Those who inherit a mutated gene are predisposed to hemangioblastomas (tumors formed from a nest of blood vessels) of the brain, spinal cord, and retina; kidney cysts and clear cell kidney cell carcinoma; pheochromocytoma (a type of noncancerous tumor that affects the adrenal glands); and endolymphatic sac tumors (tumors of the inner ear area called the endolymphatic sac)4,5 .

Up to 50% of patients in VHL families show only one manifestation of the syndrome. The age of onset of VHL is variable and depends on the expression of the disease within an individual. Large deletions and gene rearrangements of the gene or regulatory mutations could be responsible for the individual's clinical features. Most people with the syndrome inherit an altered copy of the gene from one parent. In about 20% of cases, however, the altered gene is a result of a new mutation.

The VHL gene is mapped to chromosome 3p25–26 . Inactivation of the VHL- protein(pVHL) leads to increased expression of hypoxia (inadequate oxygenation of the blood) induced growth factors in normal concentration of oxygen.

VHL is called a cancer syndrome because it includes a number of different kinds of tumors, some of which can grow to be cancers that spread to other organs via lymph or blood. Because VHL can cause malignant tumors in the visceral organ systems, it is considered one of a group of familial cancer risk factors, which are transmitted genetically.

Why diagnosis eludes?

Because VHL has historically been described as a very rare disorder, few doctors come into contact with a VHL patient, and may not consider this diagnosis. Most doctors have little or no experience with VHL. Most of them might remember one paragraph from medical school, but have never themselves seen a person with VHL. Thousands of people may be suffering from this syndrome without knowing it. Instead of being extremely rare, it is in the mid-range of genetic disorders, one of the most common of the familial cancers.

VHL happens to be more common than previously thought but is under-diagnosed. Diagnosis is possible if doctors are more familiar with VHL and consider VHL to be a reason behind the symptoms produced in a patient with inexplicable complications. Because of the complexities associated with management of the various types of tumours in this disease, treatment is multidisciplinary.

The traditional clinical diagnosis or a simplex case (an individual with no known or significant family history of VHL syndrome) diagnosis is presence of two or more characteristic lesions (two or more tumors) in association with visceral manifestations (liver, kidney, brain, spinal cord or retina). Because VHL varies so widely, there is not a consistent set of symptoms in each person. Every incidence of the disease has its own diagnostic evaluation. Even in people who have this gene, however, there is a wide variation in the date of onset of the disease, the organ system in which the problem occurs, or the severity of the involvement. Every person is different.

Is it curable?

There is yet no cure for VHL, but early diagnosis helps in prognosis. We are still looking forward to a therapeutic answer predicted by researchers. Living with VHL is a challenge though it demands less attention than diabetes. Exploring cancer prevention tips and maintaining a healthy lifestyle is useful. Considering that large number of prostate and breast cancer patients now survive without a curing drug, the most important advances for VHL patients are early detection and better treatment. Meanwhile a better management is required with affected ones keeping their mind body and spirits strong.

Building public education is necessary. It would be a good idea to introduce some feelers of the disease at school biology level.

The author was diagnosed with VHL after a liver transplant in August 2008. To support her expensive treatment, please contact payel.bh@gmail.com.


References

  1. Dogra, P. et al. An unusual case of Von Hipple Lindau (VHL) syndrome with bilateral mutlicentric renal cell carcinoma with synchronous solitary urinary bladder metastasis. Int. Urol. Nephrol. 39, 11-14 (2007) | Article |
  2. Office of Rare Diseases Research,  NIH.
  3. Maher, E. R. et al. Clinical Features and Natural History of von Hippel-Lindau Disease. Q. J. Med. 77, 1151-1163 (1990)
  4. Schimke, R. N. et al. Von Hippel-Lindau Syndrome. Gene Reviews (2007)
  5. Von Hippel-Lindau Syndrome.  Genetics Home Reference (2008)