Renal cell carcinomas and pancreatic cysts

Von Hippel-Lindau

Von Hippel Lindau Disease

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Von Hippel-Lindau Disease

Von Hippel-Lindau Disease

Von Hippel-Lindau Disease

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

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.

• Resection of solid tumors and renal cysts.

• Medical monitoring and surgical resection of pheochromocytomas, pancreatic islet tumors or adenocarcinomas of the pancreas.

• Medical treatment of states of depression, anxiety and distress, kidney failure, deafness, blindness or neurological deficits.


Currently there are no standard and approved methods of therapies for the treatment of VHL disease. Radiation and chemotherapy are two of the methods which are now less used than before for treating VHL disease because of their side effects. Other therapies also exist but none of them provide an ultimate cure or treatment of this disease (Maher et al., 20011).

Photodynamic therapy is a safe and efficient procedure for the treatment of retinal angiomas in children, however it is not considered as a standard procedure for treatment as of now. In Photodynamic therapy general anesthesia is given to the patient with retrobulbar steroid injection, diode laser photocoagulation of areas of retinal ischemia, and barrage of the retinal detachment. The multiple angiomas can be treated with photodynamic therapy, according to the photodynamic therapy protocol. The patient is carefully turned to one side and moved to the edge of the operating table, with the assistance of a pediatric anesthetist who is experienced in administering anesthesia in this position (Ziemssen et al., 2007). After removal of the head and chin rest of the slit-lamp delivery system, the instrument is positioned on the side of the operating table in front of the eye undergoing treatment. Then a three-mirror contact lens is placed on the cornea and the procedure is performed. Liposomal benzoporphyrin derivative (verteporfin) is used as a photosensitizer. A specific dose is given to the patient (Ziemssen et al., 2007).

In case of Retinal capillary hemangiomas the existing small tumors are treated with photocoagulation, and large hemangioblastomas are treated with cryotherapy. Modern options in the treatment of retinal hemangioma are plaque radiation therapy, perforating diathermy, and, recently, intravitreal anti-vascular endothelial growth factor therapy and photodynamic therapy, alone or combined (Ziemssen et al., 2007). Further improvement of the treatment results with photodynamic therapy could be achieved with the use of a combination of steroids and intravitreal anti-vascular endothelial growth factor agents.


Von Hipel-Lindau is transmitted genetically. It is caused by a dominant gene. Even among people who have this gene, there is a wide variation in the age at which the first symptoms, the organ system where states or the severity with which it is presented. Everyone is different. Since VHL manifestations are so varied, there is a set of symptoms that constantly appear. Every possible manifestation of VHL has a way of diagnosis and corresponding evaluation. If someone in the family have been cases of VHL, it is important to perform screening tests as soon as possible, before any symptoms appear. You should consult your doctor about the best time to start testing and how often must return to the query. It is generally recommended to start with the checks at the age of six years, or even earlier. The check is negative that does not necessarily mean that the person does not suffer VHL. The first manifestation of VHL may appear many years later. Depending on what the tests reveal, the doctor will determine what specific symptoms the person should pay special attention. Certainly, if they vomit, headaches, problems with balance or persistent pain that lasts more than 1-2 days and stay in one place, the person should see a doctor. Once VHL is diagnosed somewhere in the body, it is very important to have a thorough checkup to detect other possible manifestations of the disease in other parts of the body, and return to undergo checks at the intervals recommended by the equipment physician.


He’s FJ, Hoppener JW, Lips CJ (2003). Clinical review 155: pheochromocytoma in Von Hippel-Lindau disease. J Clin Endocrinol Metab; 88: 969 — 974.

Johnston LB, Chew SL, Trainer PJ, Reznek R, Grossman AB, Besser GM, Monson JP, Savage MO (2000). Screening children at risk of developing inherited endocrine neoplasia syndromes. Clin Endocrinol (Oxf); 52: 127 — 136.

Lindau A (1927). On the question of angiomatosis retinae and your brain complicatio. Acta Ophthalmol; 4: 193 — 226.

Lonser R, Glenn G, Walther M, Chew EY, Libutti SK, Linehan WM, et al. (2003). Von Hippel-Lindau disease. Lancet;361:2059-67.

Maher E.R., Neumann H.P. And Richard S. (2011) von Hippel-. Lindau disease: a clinical and scientific review. Eur. J. Hum. Genet. 19, 617 — 623.

Maher ER (2004). Von Hippel-Lindau disease. Curr Mol Med; 4: 833 — 842.

Richard S, Lindau J, Graff J. et al. (2004). Von Hippel-Lindau disease. Lancet; 363: 1231 — 1234.

Shuin T, Yamasaki I, Tamura K, Okuda H, Furihata M, Ashida S (2006). Von Hippel-Lindau disease: molecular pathological basis, clinical criteria, genetic testing, Clinical Features of Tumors and Treatment. Jpn J. Clin Oncol;36(6)337 — 343.

Singh AD, Shields CL & Shields JA (2001): von Hippel-Lindau disease. Surv Ophthalmol 46: 117 — 142.

von Hippel E: (1904). About a very old disease of the retina Albrecht von Graefe’s Arch Ophthalmol; 59: 83 — 106.

Woodward ER, Buchberger A, Clifford SC et al. (2000). Comparative sequence analysis of the VHL tumor suppressor gene. Genomics; 65: 253 — 265.

Ziemssen F, Voelker M, Inhoffen W, Bartz-Schmidt KU & Gelisken F (2007): Combined treatment of a juxtapapillary retinal capillary haemangioma with intravitreal bevacizumab and photodynamic therapy. Eye 21: 1125 — 1126.

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