Von Hippel-Lindau disease (VHL) is an autosomal dominant syndrome that leads to a diversification of tumors in patients. Von Hippel-Lindau disease results in appearance of tumors in numerous vital organs, such as central nervous system (CNS), eyes, kidneys, pancreas, epididymis, adrenal gland, and inner ear. VHL considers being a reason of renal cell carcinoma (RCC), hemangioblastomas of the CNS, pancreatic cysts, solid lesions, endolymphatic sac tumors, pheochromocytoma and retinal angiomas.
Von Hippel-Lindau disease is associated with the names of Eugen von Hippel, the German ophthalmologist and Arvid Lindau, the Swedish pathologist. 1904 was the year when Eugen von Hippel firstly resorted to the description of the anginoma in the eye. After von Hippel’s endeavour, Arvid Lindau in 1927 explained the angioma of the parencephalon and spine. Moreover, the scientists developed more ideas, namely Eugen von Hippel established and reported about distinctive retinal efficiency, and Arvid Lindau invented the recurring contiguity of retinal and cerebellar hemangioblastoma together with tumors and cysts in vital visceral organs. Additionally, Lindau narrowly illustrated the clinical range of the VHL disease in various cases from Sweden and other countries in Europe. Nevertheless, the notion von Hippel-Lindau disease was initially introduced in 1936, Melmon and Rosen established it only in 1964 when it appeared to become a common usage (Blans%uFB01eld & Libutti, 2010).
In spite the fact that contributions of von Hippel and Lindau were determinative, numerous other scientists played a crucial role in the description of clinical indications. In 1872, Jackson designated a cerebellar hemangioblastoma; furthermore, Panas and Rémy were successful in describing retinal hemangioblastoma in 1879. The first registered case of a possible patient with VHL disease appeared to be a 35-year old woman who died in 1864 from eye and brain carcinomas (Lonser et al., 2003).
VHL is an autosomal dominant disorder, which appears to be an outcome of a germline mutation in the VHL gene. This type of gene was initially recognized in 1993. There are approximately 1500 germlines and somatic mutations noticed in von Hippel-Lindau disease. The gene is considered to be a tumor suppressor gene of renal cell carcinoma that appeared to participate in numerous operations, which involve adjustment of ubiquitination, angiogenesis, and guard functions in mitosis. The gene has been restricted to chromosome 3p25.
Each cell in the organism has two examples of each gene. In von Hippel-Lindau disease, one example of the VHL gene has a mutation and creates a defective VHL protein (pVHL). However, the second example is still responsible for a functional protein. Carcinomas are only formulated in cells where the second example of the gene has been mutated. This process is well-known as the two-hit hypothesis. A deficiency of this protein permits tumors features of von Hippel–Lindau disease to expand (Gläsker, Neumann, Koch, & Vortmeyer, 2012).
A specific system of clinical classification categorizes people who are suffering from VHL disease into two types. Those mainly who do not have a pheochromocytoma belong to a VHL type 1. In contrast, those mainly who have pheochromocytoma categorized as VHL type 2. In addition, VHL type 2 subsequently has another detailed division, namely type 2A (those accompanied by a clear-cell carcinoma) and type 2B (those do not accompanied by a clear-cell carcinoma). In type 2C, affected patients develop pheochromocytomas only. Furthermore, at the same time when type 1 VHL distinguished oneself as a one that have a considerably low risk of phaeochromocytomas, it can spread several other types of tumor related to the disease. In contrast, in cases when type 2 VHL patients have a greater chances of developing a phaeochromocytomas, they still have either a low-risk (type 2A) or high-risk (type 2B) for renal cell carcinomas.
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Von Hippel-Lindau disease can have various symptoms during its progress. One of the most harmful and noticeable symptom appears to be a vision loss. Here one can describe the process in greater length: Retinal capillary hemangioblastomas are typically situated in the circumferential retina or in the juxtapapillary region. Numerous traumas can be represented in both eyes, but in most cases there is asymmetry amidst the two of them. These traumas are colored in red or orange, they are also well-regulated vascular tumors accompanied by a sizable feeder vessel and a draining vessel of the same size. These traumas can expand on the surface of the retina (endophytic) or inside the retina (exophytic). Additionally, the loss of vision is another outcome of exudation of fluid into the macula or neuroglial enlargement. Exudation can result into exudative retinal separation, while at the same time neuroglial enlargement can give a rise to tractional retinal separation or macular fold. Hyaline extravasation, iris neovascularization accompanied with glaucoma or cataract may also be apparent (Blans%uFB01eld &Libutti, 2010).
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Apart from visible signs and symptoms, von Hippel-Lindau can also have non-visible or so-called extraocular symptoms. These symptoms involve vomiting, headache, weakness of the limbs, high blood pressure, the loss of the full control of the bodily movements together with the cerebellar hemangioblastomas, regular or occasional hypertension accompanied by the pheochromocytomas, and loss of hearing occurred with endolymphatic sac tumors.
The distinctive diagnosis for von Hippel-Lindau disease involves vasoproliferative tumors of the retina, Coats disease, Wyburn-Mason syndrome, retinal cavernous hemangioma and racemose hemangioma. With these organisms, the outmost distinctive feature is the lack of a great feeder vessel resulting into the trauma. Accompanied by juxtapapillary and endophytic RCH, there might be considered other entities, including choroidal neovascularization, disc oedema, and ischemic optic neuropathy. Earlier, the diagnosis of VHL disease was based upon two principles: a positive family history coexisted with one or more ordinary traumas, or no family history; however, two or more retinal traumas or one retinal and one other visceral trauma.
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Precise diagnosis of VHL disease now is predominantly performed by gene analysis. Occurred with modern genetic testing, those who suffer from only one VHL-like trauma and a negative gene analysis are efficaciously excluded from having VHL disease, although in rare cases there still observed a slight possibility of somatical mosaicism for the gene mutation. These people should be examined at all costs. Mostly, a younger individual with one or more VHL-like traumas has bigger chances to have VHL than an older person with only one trauma (Maestro, Martinez-Piñeiro, & Gonzalez, 2011).
The prevalence of von Hippel-Lindau disease is approximately one in 36000 births. People suffering from this disease are mostly between the ages of 10 and 40; however, with the average age of 26. Race or gender predisposition plays no vital role in VHL occurrence. While VHL is considered to be an autosomal dominant, children of ill parents have considerably higher risk of developing it, approximately half of them. In spite of that, new mutations sometimes happen in about 20% of sufferers. Nearly 100% of those accompanied by mutation will disclose symptoms to some extent. Retinal capillary hemangioblastoma (RCH) is considered to be one of the most common traumas, which develop itself in nearly 85% of patients with the VHL mutation. The RCH traumas are known to be nonmalignant hamartomas and may be the initial symptom of VHL. Before computerized tomography (CT) and other imaging medical devices were established and before the emergence of comprehensive screening in patients, the average survival rate in those sufferers was less than 50 years. The reason of death in those people was, in most cases, either metastases from renal cell carcinoma or manifestations associated with the hemangioblastomas of central nervous system. In this day and age, being accompanied by a multifunctional approach to these comprehensive patients, survival rates have sufficiently increased (Hes, Höppener, Luijt, & Lips, 2005).
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Like many complicated diseases, von Hippel-Lindau disease has a specific way of treatment. There considered to be two main treatment variants:
- Photocoagulation on smaller traumas;
- Cryotherapy for larger traumas.
Multifarious treatments accompanied by photocoagulation or cryotherapy have to fully eradicate the cancerous growth. Examining smaller traumas may be a possible variant, as some have been known to keep unvarying for years or even to degenerate. It is also now known that Retinal capillary hemangioblastomas lead to considerable increase of regulation of numerous growth factors, or become vulnerable to many of them, such as VEGF and PDGF. Antiangiogenic drugs, such as bevacizumab, or in other words Avastin and ranibizumab, also known as Lucentis, have consequently been utilized both intravenously and intravitreally. To a certain limited extent, restricted studies, involving several institutional experiences, have concluded that anti-VEGF therapy diminished the quantity of exudation and may ameliorate eyesight; however, it does not alter the dimensions of the trauma. It is also worth paying attention, that both somatic anti-VEGF treatment and photodynamic treatment incorporated with intravitreal anti-VEGF treatment for cerebellar hemangioblastoma have been tested with some favorable outcomes (Davis, 2007).
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In general, people suffering from von Hippel-Lindau disease have an average life expectancy of 50 years. Regular incidence is predominantly the result of renal cell carcinoma and pheochromocytoma. For ophthalmologists, an investigation concerning the visual effect of VHL concluded that the extensiveness of acute bilateral loss of vision is approximately one in 18. The chances of vision loss are considerably higher in older patients, namely in those accompanied by juxtapapillary traumas and a greater number of retinal capillary hemangioblastomas. Around a quarter of those occurred with RCH will have visual acuity worse than 20/160, and around one-fifth of those will have an extreme vision loss and in rare cases tuberculosis, eventually requiring enucleation (Hes, Höppener, Luijt, & Lips, 2005).
The incidence of von Hippel-Lindau disease differs, hanging on the specific organ system concerned with. The cancerous degeneracy of renal sac is generally considered to be the most acute VHL indication. Nearly 75% of patients indicate various renal sacs. Renal sacs are widespread in the general population and are seldom clinically important.
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Recently, genetic examination has permitted to diagnose these patients at an earlier stage and in younger age. Sometimes, it is also possible to foresee what types of tumor they may be more likely to advance. The most pivotal concern is what chances such patients have to develop pheochromocytomas since these carry important incidence and the death rate. In recent times, a profound investigation looked at ocular RCH and various VHL gene mutations and concluded that numerous mutations had an impact on both the danger of expanding ocular VHL and the position of the RCH. It is obvious that these analysis findings may assist in possible future screening guidelines and consulting of patients, and may eventually give rise to the significant improvement the prognosis (Gläsker, Neumann, Koch, & Vortmeyer, 2012).
All in all, each distinct type of VHL-related carcinoma is connected to a distinct histology and distinct clinical procedure, and might react to distinct forms of treatment. Comprehension of the genetic basis of VHL disease associated with a comprehension of the specific anatomical venue makes provision to a unique chance for the growth of allele-specific forms of treatment.