The von Hippel-Lindau, also known by its synonyms, familial angiomatosis cerebeloretinal, hemangioblastomatosis or retinal and cerebellar angiofacomatosis, is the abnormal growth of retinal- cerebellar vessels, and is classified as a rare disease of autosomal dominant hereditary character, within the group of phacomatosis. The disease was described by two independent groups, led by Eugen von Hippel (1904) and Arvid Lindau (1927). The cause of the disease is the mutation of both alleles of the VHL group, the one caused by genetic factors, and the second after a de novo mutation. The von Hippel-Lindau syndrome is considered by increased tendency to kidney tumors, central nervous system, including the cerebellum, and by affecting the retina. At the moment, no medical treatment is present for curing this disease, but knowledge of their symptoms and possible genetic research currently makes it possible to establish early diagnosis before the onset of complications arising from the proliferation of tumors (Shuin et al., 2006).
Types of Von Hippel-Lindau
The Von Hippe-Lindau disease is classified into two types depending on the presence or absence of pheochromocytomas: (Maher, Neumann, Richard, 2011)
Type 1: those without pheochromocytomas, account for about 80% of cases.
Type 2 with pheochromocytomas presence of approximately 20% of cases of worse prognosis than type 1.
Type 2A characterized by the absence of renal cell carcinomas and pancreatic cysts.
Type 2B with presence of renal cell carcinomas and pancreatic cysts, which is the group with increased mortality and poor outcome.
The disease is manifested by an autosomal dominant pattern. It is linked to a genetic mutation in the tumor suppressor gene synthesis of von Hippel-Lindau (VHL), located on chromosome 3p25-26. According to the hypothesis of Knudson, it is necessary that the individual with this disease is carrying the mutation previously in one of the alleles, and subsequently the second somatic mutation. This mechanism is known as loss of heterozygosity (LOH). The tumor suppressor gene was identified in 1993 and encodes the VHL protein (He's, Hoppener, Lips, 2003). Tumor development in patients with inherited heterozygous germ line mutations is due to the loss or inactivation of the remaining wild-type allele in a susceptible cell.
In most of the people affected by the von Hippel-Lindau syndrome (80%), the constitutive mutation of the VHL gene is inherited from parent, and the de novo mutation is responsible for 20% cases of the von Hippel-Lindau. The chances of a person suffering from VHL disease transferring it to his/her offspring are 50% (Richard et al., 2004). Very rarely, mutation originates in the embryonic stage. At the embryonic stage the presence of the gene in only partial unformed embryo (mosaicism) but it has been proven that polymorphism in the gene for cyclin D1 (CCND1) in the 11q13 locus phenotypes can be modified by mutation affected VHL gene. The clear protein product VHL gene has a length of 213 amino acids and its operation is related to the clear protein elongina-B and-C (He's, Hoppener, Lips, 2003).
This complex relationship in the VHL-elongina elongina B-C maintains the link between the clear proteins specified (the resort has a protein structure level E3). It is stated that the VBC complex substrates are proteins HIF1? And HIF2? clear, clear with atypical protein ? (of kinaza), When this binding occurs clear DOMENA ? VHL protein is established, hence the proteins are clear subject and are determined by the same, proteasomesm (Richard et al., 2004).
The cause of the disease is a mutation which affects the VHL tumor-suppressor gene, which is located on chromosome 3. Most of the victims of the von Hippel-Lindau inherit an altered copy of the gene from one parent. However, approximately 20% of cases the altered gene is the result of a new mutation that occurs during the formation of germ cells or embryonic development. Since a regular VHL gene copy produces a functional protein (pVHL), which stops the tumors from being created. But if a mutation in the second gene takes place and the functional VHL protein is not produced, the lack of this protein will allow tumors to develop typical of the syndrome (Singh, Shields & Shields, 2001).
In patients of von Hippel-Lindau tumor proliferation is observed, which essentially as from the clinical viewpoint is located in the brain, spinal cord, retina and kidneys. Apart from this, many other clinical changes can affect other organs and systems. Tumors that respond to the von Hippel-Lindau are characterized, generally, by its multiple foci, and likewise multiply faster in a young patient in the older population (Lonser et al., 2003).
Even within the same family, each person can have one or more symptoms of VHL. Since it is impossible to predict which symptoms or symptoms will occur in every person with VHL, it is important to closely monitor all possible complications.
The Von Hippel Lindau disease is very variable and symptoms depend on the size and location of tumors (Lonser et al., 2003).
The angiomatosis in the retina can cause hemorrhage and retinal detachment eventually blindness.
The central nervous system hemangioblastomas produce different symptoms such as: headache (headache), unsteadiness of gait, vomiting, balance problems and weakness in upper and lower extremities.
Pheochromocytomas can be asymptomatic or produce a variety of symptoms, the most common: headache, sweating, palpitations with or without tachycardia (abnormally rapid heart-beat), nervousness, weight loss, abdominal pain and chest, nausea, vomiting, asthenia (general weakening), hypertension, orthostatic hypotension (significant decrease in blood pressure in the upright position, which may be accompanied by dizziness and fainting), hyperhidrosis (excessive sweating) and arrhythmia (irregular heartbeat).
Other less common symptoms include visual disturbances, dyspnea (difficulty in breathing), paresthesia (abnormal sensation of the senses or sensation), polyuria (extremely abundant secretion and emission of urine), polydipsia (excessive thirst), dizziness, crisis type "grand mal" (variety of epilepsy characterized by crisis suddenly attacking the entire body, with loss of consciousness, falling and motor disorders, usually rhythmic contractions and shaking) apparent, pallor, bradycardia (unusually slow heartbeat), hematuria (blood in urine) painless, dysarthria (difficulty articulating words), and tremor (Lonser et al., 2003).
The prognosis of patients with von Hippel-Lindau is directly related to the knowledge of the genetic background of the family, and the frequency of personal periodic reviews. Since about 97% of the cases have no known family history, it is possible to establish an early diagnosis that is based on family genetic history. In studies on a large scale with groups affected by von Hippel-Lindau syndrome, the most common cause of death is vascular complications in the cerebellum (47.7%), and life expectancy in that case is about 41 years (Woodward et al., 2000).
Clinical diagnosis is based on two standards:
• A case where there is no family history of VHL however there is a presence of two or more lesion characteristics.
• A case where there is a family history of VHL and a presence of one or more of the lesions present in the areas: retina, central nervous system, kidneys and pancreas.
Gene mutation analysis is recommended in patients with classic VHL disease and first-degree family members, in VHL-suspected patients (i.e. one with multi-centric tumors in one organ, bilateral tumors, two organ systems affected, or one VHL-associated tumor at a young age) and patients from a family with haemangioblastoma, RCC, or phaeochromocytoma only (Johnston et al., 2000).
If a child has inherited a VHL mutation and no mutation can be identified in the affected parent, then clinical screening is recommended. Clinical screening firstly detects asymptomatic tumors at an earlier age, enabling early treatment and secondly, when positive, confirms that the person is affected if genetic testing was not possible. It is accepted logic that clinical and genetic screening is likely to improve the outcome of patients with VHL (Maher, 2004). Endolymphatic sac tumors and multiple pancreatic cysts also suggest a positive carrier status in those families and are uncommon in the general population.
Molecular Genetic Testing
The VHL gene is the only gene which is identified to be related to VHL disease. To detect the presence of mutations in this gene might lead to the disease. Clinical tests which are currently performed are the following:
Sequence analysis defines the genetic sequence of the three constituents of the gene exons to detect point mutations and small deletions or insertions in the VHL gene. These changes represent approximately 72% of VHL mutations (Woodward et al., 2000).
Analysis of Deletion / Duplication
Tests such as FISH, quantitative PCR, real time PCR are used to detect duplications / or complete deletions of VHL gene which are not easily detectable by the analysis of the genomic DNA sequence (Lonser et al., 2003).
Currently considered the most effective treatment is prevention of complications related to tumor growth. This approach requires a pre-symptomatic diagnosis and regular monitoring throughout life, made by a multidisciplinary team (Shuin et al., 2006). Treatment may include:
• Laser therapy of retinal angiomas.
• Surgical resection of hemangioblastomas in the central nervous system.