Introduction
Von Hippel Lindau disease (VHL) is a rare hereditary disease characterized by the development of highly vascularised tumors of various types. The disease can express itself in many different ways. More than 40 types of lesions have been found in 14 organs and 6 categories of lesions are associated with significant clinical signs e.g. retinal angiomatosis, cerebellar angiomatosis, medullary angiomatosis, spinal hemangioblastoma, renal carcinoma and pheochromocytoma.
VHL disease is diagnosed from a combination of lesions with multiple characteristics or from a single lesion discovered in a patient with a family history of the disease.
Epidemiology
The incidence of Von Hippel Lindau disease is approximately one case in 36,000 to 40,000 people. A retinal angioma is often the first indication of the disease. The age at which RCH appear varies from 2 to 80 (mean age approximately 29 years). There is no predominance of males or females.
Etiology/Pathophysiology
VHL disease is an autosomal dominant, hereditary disease. In three out of four cases, questioning reveals a family history. In other cases, it is a de novo mutation i.e. a mutation that appears in the absence of any known genetic abnormality in the family.
The gene responsible for the disease is located on the short arm of chromosome 3p25-26. It is a tumor-suppressant gene consisting of three exons encoding for a protein with 213 amino acids, pVHL, which usually has a cytoplasmic location. pVHL is ubiquitous (the protein is present in all types of cells) and the protein binds with other components to create a multi-enzyme complex that causes the impairment of various protein substrates, in particular factors involved in the expression of VEGF (vascular endothelial growth factor). More than one hundred mutations have been reported. In 70% of cases, they are ad hoc mutations distributed across the entire encoding sequence. One-third of the remaining mutations consist of deletions of one part or of the complete gene. Both paternal and maternal genes have to mutate or disappear from within a single cell before a tumor can form. In the familial (hereditary) type, a mutated VHL gene is passed on to descendants. This means that, in each cell, there is only one function gene with, one “margin of error”. This gene may be subject to mutation anywhere in the body, more or less by chance, leading to the development of a vascularised tumor. This explains the significant individual differences in age at onset and in the type of abnormality, sometimes within a single family.
RCH appear as small pink nodules containing a network of wide capillaries consisting of a continuous, unfenestrated endothelium, a basal membrane and pericytes.
Diagnosis
The diagnosis of Von Hippel Lindau disease is based on the following:
- in patients with no family history, the presence of two major lesions, including one hemangioblastoma
- in patients with a family history, on the presence of a single lesion.
The major lesions are :
- hemangioblastoma in the central nervous system (cerebellum, spinal cord)
- hemangioblastoma in the retina
- clear-cell renal cancer and/or renal cysts
- and/or neuroendocrine pancreatic tumors
- a tumor in the endolymphatic sack (inner ear).
Minor lesions should also be detectable e.g. cystadenomas of the epididymus and cystadenomas of the broad ligament.
RCH are present in approximately 70% of patients suffering from VHL disease and are frequently the first clinical sign of the disease. RCH are often asymptomatic when they are discovered. In 50% of cases, the attack is bilateral. The cumulative risk of finding a RCH increases with age, making regular ophthalmological screening absolutely essential.
An examination of the fundus (the retina) is necessary to show RCH. The retina must be very carefully examined and the investigation should include an examination of the peripheral retina (including the anterior portion of the retina).
RCH are visible in the form of intraretinal lesions that are rounded, reddish, and of very different sizes and locations. When the RCH are sufficiently large, they are associated with a vascular pedicle including marked dilatation of the artery and the retinal vein supplying and draining the RCH. The number of RCH present when the disease is diagnosed varies from 1 to 5. Their location is variable. In 6 out of 10 cases, they are found in the mid-periphery but, in 30% of cases, their position is significantly anterior, making them difficult to detect. In more rare cases, they may be sited in the posterior pole or the papillary. Their size also varies greatly – from 0.1 to 6 times the diameter of the papillary.
An examination of the fundus may also reveal a hemorrhage of the vitreous or a tractional or exudative retinal detachment in the later stages of the disease.
Fluorescein angiography is an important examination because it reveals small lesions in their early stages that may not be detected by a biomicroscopic examination of the fundus. During angiography, RCH gradually become colored; at later stages, they diffuse the dye.
Clinical Description
RCH are often asymptomatic when discovered.
Some 50% of patients develop new RCH over a 5-year period and lifelong. Regular ophthalmological screening is therefore necessary.
In the absence of treatment, the prognosis is very poor. The RCH develop, increase in size and produce severe complications :
Three stages of development have been described :
- In the pretumoral stage, the lesions are small (less than 1/5th the size of the pupillary diameter), discrete and characterized by a fine capillary network that can easily remain unnoticed. Fluorescein angiography can be used to reveal these lesions in their early stages.
- The tumoral stage corresponds to the presence of a large lesion (between 1 and 5 times the papillary diameter) that is uniformly red in color. The RCH is associated with a dilated, tortuous arterio-venous pedicle.
- The third stage, when complications arise, occurs in the absence of treatment. The RCH are associated with vitreous hemorrhage, intra- and sub-retinal exudation possibly leading to a exudative retinal detachment and fibroglial proliferation with retinal retraction (proliferation on the periphery of the RCH retracting and causing a tractional and reghmatogenous retinal detachment).
Treatment
The treatment of RCH includes laser photocoagulation, cryotherapy and endo-ocular surgery depending on the size, number and stage of development of the angiomas.
The aim of the treatment is to destroy the retinal angiomas as quickly as possible after discovery to avoid secondary complications.
Small RCH are destroyed by laser photocoagulation, which is highly effective. The advantage of this treatment is its simplicity and the fact that it can be carried out during a standard consultation, without the need for hospitalization. One or more laser treatments may be required. Absence of diffusion on angiography carried out after treatment indicates that the RCH have been completely destroyed.
For larger RCH, a range of different options is available but, in all cases, careful monitoring is required after each treatment because of the risk of hemorrhagic complications and of post-operative exudative reactions. The commonest treatment is cryotherapy (low-temperature treatment). It has the advantage of being quick and effective, especially in the treatment of large RCH.
Treatment for complicated forms with fibroglial retractions associated with retinal detachment may require vitreo-retinal surgery.
For all matters relating to the diagnosis of VHL disease, non-ophthalmological signs and genetic screening, contact Prof. Stéphane Richard, Hopital Necker Enfants-Malades et Hopital de Bicêtre,l Laboratoire d'oncogénétique, Tel/Fax: +33 (1) 49 59 67 28; E-mail: stephane.richard@kb.u-psud.fr
