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N Dermatol Online 2011: 2(1): 14-17
Conflicts of interest: None
 

BASED TO CLINICAL CASE. VON HIPLEA-LINDAU SYNDROME

Brzeziński Piotr

6th Military Support Unit, Ustka, Poland

Corresponding author: Brzeziński Piotr, MD      e-mail: brzezoo@wp.pl

How to cite an article: Brzeziński P. Na podstawie przypadku klinicznego. Zespół von Hiplea-Lindau. Our Dermatol Online 2011: 2(1): 14-17.


 

Abstract
von Hippel-Lindau syndrome (VHL) is a rare, genetic multi-system disorder characterized by the abnormal growth of tumors in certain parts of the body (angiomatosis). The tumors of the central nervous system (CNS) are benign and are comprised of a nest of blood vessels and are called hemangioblastomas. Hemangioblastomas may develop in the brain, the retina of the eyes, and other areas of the nervous system. Other types of tumors develop in the adrenal glands, the kidneys, or the pancreas. Symptoms of VHL vary among patients and depend on the size and location of the tumors. Symptoms may include headaches, problems with balance and walking, dizziness, weakness of the limbs, vision problems, and high blood pressure. Cysts (fluid-filled sacs) and/or tumors (benign or cancerous) may develop around the hemangioblastomas and cause the symptoms listed above. Individuals with VHL are also at a higher risk than normal for certain types of cancer, especially kidney cancer. Based on the case of 30-year old patient with characteristics of von Hippel- Lindau syndrome as phakomatosis.
 
Key words: von Hiplea-Lindau disease, phakomatosis, hemangioblastoma

 

Introduction
Based on clinical case in 30-year-old woman describes the syndrome von Hipple-Lindau. von Hipple-Lindau syndrome (VHL) (von Hipple-Lindau, familial angiomatosis cerebelloretinal, Lat. Hemangioblastomatosis, retinae et cerebelli angiophakomatosis) – rare genetic disorder autosomal dominant, belonging to the phakomatosis group [1]. The team described independently Eugen von Hippel in 1894, and Arvid Lindau in 1926. The cause of the disease is a mutation in both alleles of the VHL gene, one of which is hereditary and the other occurs spontaneously [1]. The syndrome is characterized by increased susceptibility to kidney tumors, central nervous system, particularly the cerebellum, adrenal gland and retina. There is no causal treatment, but counseling and genetic testing allow you to diagnose it more often before they appear lifethreatening tumors [2]. The incidence of heterozygotes in the population east of England has been estimated at 1:53 000, and among live births at 1:36 000 [3]. Population-based studies in Germany have identified the incidence of the disease on the 1:38 951 [4]. It is estimated that in Poland there are about 1000 patients with von Hipple-Lindau [5]. VHL ss associated with germline mutations in the gene encoding the tumor suppressor protein VHL on chromosome 3. Mutation of one allele is inherited, symptoms become apparent when it comes to the second somatic mutation. This mechanism is defined as loss of heterozygosity (LOH – loss of heterozygosity) [1]. Most patients had a constitutional mutation of the VHL gene is inherited from a parent, de novo mutations account for approximately 15% of the VHL Rarely, the mutation occurs at the stage of embryo development. Current is then only part of the patient’s cells (mosaicism). There is evidence that cyclin D1 gene polymorphism (CCND1) locus 11 q13 might modify the phenotype of patients with mutations in the VHL gene [6].
 
Pathophysiology
Protein product of the VHL gene has a length of 213 amino acid residues and acts in a complex with proteins elongina B and C. The function of the complex elongina VHL-elongina B-elongina C (VBC) is the binding of specific proteins and their ubiquitination (complex has E3 ligase activity) [7]. It was found that the VBC complex substrates are proteins and HIF2α HIF1α, and atypical protein kinase λ. Substrate binding site is the β domain of VHL proteins, then proteins are subject to ubiquitination, and so marked, are degraded in proteasomes. VHL gene mutation and protein dysfunction and, consequently, VBC complex dysfunction leads to disturbance of this mechanism, agents are active HIF regardless of partial oxygen concentration in the cell, leading to overproduction of growth factors. This is probably the molecular mechanism responsible for abnormal angiogenesis in the well vascularized tumor syndrome von Hipple spectrum and Lindau. Recently it was found that the substrate is the VBC complex atypical protein kinase λ [8]. Accumulation of this protein leads to overproduction of factor B-jun, inhibiting apoptosis in neuronal cells of the adrenal medulla comb. It is believed that this is one of the mechanisms of molecular pathogenesis of pheochromocytoma in patients with VHL [9].
 
Symptoms and course
In patients with VHL observed in multiple tumors, of which the most important, from a clinical point of view, localized in the cerebellum, spinal cord, retina, adrenal medulla and kidney. Besides these, a number of less clinically relevant changes can occur in other organs. Tumors developing in a VHL are usually multifocal, bilateral, and occur in a much younger age than the average population. In many patients the first symptom is the occurrence of organ damage in central nervous system of an embryonic malformations. The most common (75%) are in the cerebellum (haemangioblastoma cerebelli), outside the cerebellum, localized tumors of this type are also in the medulla (haemangioblastoma oblongatae medullae), and spinal cord (medullae spinalis haemangioblastoma). Symptoms caused by tumor depend on its location and size [1,10-12].
Ocular
The earliest observed change in the course of the VHL are embryonic retinal angiomas (haemangioblastoma retinae). Untreated tumors of the retina lead to progressive loss of vision. Kidneys
In the kidneys of patients with VHL develop noncancerous changes in the nature of true cysts (cystes renis), benign tumors of a cystadenomata and cancer – renal cell carcinoma (carcinoma renocellulare).
Pancreas
The pancreas may be single or multiple cysts true.
Hearing organ
Against the background of the VHL may develop a rare tumor of the bag endoliphhomatic (endolymphatic sac tumor, ELST).
Other organs
Papillary epididymis are frequent changes in men, but not giving the symptoms and not requiring treatment. Their equivalent in women are the broad ligament cysts. Hemangioma embryonic cerebellum and spinal cord often show over-expression of erythropoietin, which is manifested clinically polycythemia. Dermatologists rarely meet with VHL. Sometimes it can be observed, mostly on the face of a port-wine stains.
 
Treatment
So far, the possibility of causal treatment of the VHL, ie gene therapy, are only theoretical. The treatment is surgical removal of tumors, hence the great role of the periodic inspection and imaging tests. In the phase of clinical and preclinical studies, a number of compounds that inhibit the receptors for PDGF, VEGF and TGFα. Two of these drugs, sunitinib and sorafenib, have given promising results of treatment of metastatic clear cell renal carcinoma and were approved by the FDA for the treatment of advanced renal cell carcinoma [13].
 
Prognosis
For most people with VHL syndrome clinical complications occur between 15 and 30 years old, but in some cases the symptoms are not seen until the age of 50 years. The prognosis for patients with the VHL is closely related to the age of diagnosis and frequency of periodic testing performance. Since approximately 97% of cases occur in families, there are opportunities for appropriate early diagnosis [1,14]. Untreated VHL may result in blindness and/or permanent brain damage. Hence the importance of recommendations for patients established by the National Institutes of Health (tabl.1). With early detection and treatment the prognosis is significantly improved. Death is usually caused by complications of brain tumors or kidney cancer.
The data was collected, analysed and the following results were obtained.
 
Age (years)
(Featured research)
0-2
(The annual physical examination and ophthalmologic)
2
(Examination of the level of catecholamines in the urine every 1-2 years)
11
(MRI of the brain and spinal cord, 2 times a year)
 
(Abdominal ultrasound examination every year)
(If you are found to contain cysts or tumors – CT examination every 6 months)
20
(Instead of an annual ultrasound examination to enter the annual CT)
60
(In the absence of symptoms, MRI every 3-5 years)
 
(CT carried out each year in which MRI has not been studied)
Table 1. Recommendations for patients and their family members (National Institutes of Health) 
 
REFERENCES
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