[Venous thromboembolism (VTE) - current diagnosis and therapy, with special attention towards oncologic patients]. / A vénás tromboembólia (VTE) korszerû diagnosztikája és kezelése - különös tekintettel az onkológiai betegekre.

Deep vein thrombosis (DVT), pulmonary embolism (PE), or with the common name venous thromboembolism (VTE) are frequent manifestations of pathologic hemostasis in malignancies, thereby contributing to the large number of patients despite recent developments in thrombosis prevention. In the present paper up-to-date practice of diagnosis and therapy will be discussed partly based on the author's previous publications on epidemiology and prophylaxis of VTE in oncological patients.

[DISEASE BURDEN OP DUCHENNE MUSCULAR DYSTROPHY PATIENTS AND THEIR CAREGIVERS]. / DUCHENNE-FÉLE IZOMDISZTRÓFIÁVAL ÉLO BETEGEK ÉS GONDOZÓIK BETEGSÉGTERHEI.

BACKGROUND AND PURPOSE: Data on the disease burden of Duchenne Muscular Dystrophy are scarce in Hungary. The aim of this study was to assess patients' and their caregivers' health related quality of life and healthcare utilisations. METHODS: A cross sectional survey was performed as part of the European BURQOL-RD project. The EQ-5D-5L and Barthel Index questionnaires were applied, health care utilisations and patients' informal carers were surveyed. RESULTS: One symptomatic female carer, 50 children (boys 94%) and six adult patients (five males) participated in the study, the latter two subgroups were included in the analysis. The average age was 9.7 (SD = 4.6) and 24.3 (SD = 9.8) years, respectively. Median age at time of diagnosis was three years. The average EQ-5D score among children and adults was 0.198 (SD = 0.417) and 0.244 (SD = 0.322), respectively, the Barthel Index was 57.6 (SD = 29.9) and 53.0 (SD = 36.5). Score of satisfaction with healthcare (10-point Likert-scale) was mean 5.3 (SD = 2.1) and 5.3 (SD = 2.9). 15 children were hospitalised in the past 12 months for mean 12.9 (SD = 24.5) days. Two patients received help from professional carer. 25 children (mean age 11.1, SD = 4.4 years) were helped/supervisied by principal informal carer (parent) for mean 90.1 (SD = 44.4) hours/week and further family members helped in 21 cases. Correlation between EQ-5D and Barthel Index was strong and significant (0.731; p < 0.01) as well as with informal care time (-0.770; p < 0.01), but correlation with satisfaction with health care was not significant (EQ-5D: 0.241; Barthel Index: 0.219; informal care: -0.142). CONCLUSION: Duchenne muscular dystrophy leads to a significant deterioration in the quality of life of patients. Parents play outstanding role in the care of affected children. This study is the first in the Central and Eastern European region that provides quality of life data in this rare disease for further health economic studies.

Present practice of thrombosis prophylaxis of radical prostatectomy in a European country: a Hungarian multicenter study.

Venous thromboembolism is a possible fatal complication after pelvic surgery. There is a lack of trials assessing the effect of prophylactic measures in urology. The aim of the study was to evaluate the practice of thrombosis prophylaxis in a Central European country. A questionnaire of performed radical prostatectomies, way of thrombosis prophylaxis and number of experienced thrombotic events was posted to all departments of urology in Hungary. With a response rate of 59%, 506 radical prostatectomies were reported. Low molecular weight heparin was administered by 100% of the departments. Graduated support stockings were applied by 37% of the patients. Early mobilization was the most common form of mechanic prophylaxis (57%). Thrombotic events were experienced in 1.4%, 0.2% were fatal. The thrombosis prophylaxis of patients undergoing radical prostatectomy is not unified. Due to the potential mortality of thrombotic complications it should be evaluated and prophylaxis should be recommended in urological guidelines.

[Adult-onset rare diseases]. / Felnottkorban kiteljesedo ritka kórképek.

The present paper is focusing on rare diseases manifesting in late childhood or adulthood. A part of these syndromes are not of genetic origin, such as relatively or absolutely rare infections, autoimmune diseases, tumours, or diseases due to rare environmental toxic agents. In addition, even a large proportion of genetic disorders may develop in adulthood or may have adult forms as well, affecting are almost each medical specialization. Examples are storage disorders (e.g. adult form of Tay-Sachs disease, Gaucher-disease), enzyme deficiencies (e.g. ornithin-transcarbamylase deficiency of the urea cycle disorders), rare thrombophilias (e.g. homozygous factor V. Leiden mutation, antithrombin deficiency), or some rare monogenic disorders such as Huntington-chorea and many others. It is now generally accepted that at least half of the 6-8000 "rare diseases" belong either to the scope of adult-care (e.g. internal medicine, neurology), or to "age-neutral" specialities such as ophtalmology, dermatology etc.).

Three novel germ-line VHL mutations in Hungarian von Hippel-Lindau patients, including a nonsense mutation in a fifteen-year-old boy with renal cell carcinoma.

BACKGROUND: Von Hippel-Lindau disease is an autosomal dominantly inherited highly penetrant tumor syndrome predisposing to retinal and central nervous system hemangioblastomas, renal cell carcinoma and phaeochromocytoma among other less frequent complications. METHODS: Molecular genetic testing of the VHL gene was performed in five unrelated families affetced with type I VHL disease, including seven patients and their available family members. RESULTS: Molecular genetic investigations detected three novel (c.163 G > T, c.232A > T and c.555C > A causing p.Glu55X, p.Asn78Tyr and p.Tyr185X protein changes, respectively) and two previously described (c.340 + 1 G > A and c.583C > T, resulting in p.Gly114AspfsX6 and p.195GlnX protein changes, respectively) germline point mutations in the VHL gene. Molecular modeling of the VHL-ElonginC-HIF-1alpha complex predicted that the p.Asn78Tyr amino acid exchange remarkably alters the 77-83 loop structure of VHL protein and destabilizes the VHL-HIF-1alpha complex suggesting that the mutation causes type I phenotype and has high risk to associate to renal cell carcinoma. The novel p.55X nonsense mutation associated to bilateral RCC and retinal angioma in a 15-year-old male patient. CONCLUSION: We describe the earliest onset renal cell carcinoma in VHL disease reported so far in a 15-year-old boy with a nonsense VHL mutation. Individual tailoring of screening schedule based on molecular genetic status should be considered in order to diagnose serious complications as early as possible. Our observations add to the understanding of genotype-phenotype correlation in VHL disease and can be useful for genetic counseling and follow-up of VHL patients.

Increased level of platelet P-selectin in nonarteritic anterior ischemic optic neuropathy.

PURPOSE: P-selectin receptor is expressed in platelets and endothelial cells in a cell-activation-dependent manner. Platelet P-selectin (CD62) levels may become elevated in a number of vasoocclusive diseases, including arteriosclerosis, atherothrombosis, and diabetes mellitus (DM). Nonarteritic anterior ischemic optic neuropathy (NAION) is associated with a sudden loss of vision due to the vascular insufficiency of ciliary arteries supplying the optic nerve. In this study, our aim was to investigate the presence of increased platelet reactivity in the development of NAION. METHODS: Twenty-one NAION patients, 39 healthy control subjects, and 44 patients suffering from diabetes mellitus (DM) were examined in our case-control, pilot study. Platelet activation was investigated by flow cytometric analysis of the mean fluorescence intensity (MFI) of CD62 on platelets. These results were compared among the different study groups. RESULTS: NAION patients showed considerably although not significantly (p = 0.2017) higher P-selectin MFI values (71.98 ± 40.30) versus healthy subjects (55.48 ± 20.95), insulin-dependent DM patients (50.02 ± 13.08), and non-insulin-dependent DM subjects (54.72 ± 24.74). However, logistic regression analysis resulted in a statistically significant adjusted effect on the odds of NAION when CD62 MFI values were logarithmically transformed (OR: 3.86, 95 % CI: 1.10 to 13.53, p = 0.0346). CONCLUSION: Elevated platelet CD62 positivity may be related to NAION, suggesting a possible role of enlarged platelet activity in the generation of this type of ischemic optic neuropathy.

[Severe anemia caused by haemorrhoids: the casae of a young man with toxic cirrhosis]. / Súlyos anaemia aranyeres csomókból: fiatal, toxikus cirrhosisos férfi beteg esete.

A 38-year-old alcoholic man with severe iron deficient anaemia, and bloody-mucous stool was found to have haemorrhoidal bleeding. In spite of intravenous iron supplements haemoglobin levels were falling. He was admitted because of deteriorating condition, jaundice, severe anaemia (haemoglobin, 38 g/l) and iron deficiency. Except of toxic (alcohol) agent all other causes of liver disease could be excluded. Sclero-, and medical therapy, and abstinence resulted in a rapid improvement in his condition and subsequently rectal bleeding also disappeared. Bleeding from the upper gastrointestinal tract is a well known and serious complication in liver cirrhosis, however, a voluminous blood loss resulting in a life-threatening anaemia from lower gastrointestinal tract or haemorrhoids, as it was detected in this patient, is quite rare. Sclerotherapy seems to be an effective method with only minor complications when compared with other invasive techniques. However, the patient's compliance even in liver cirrhosis with haemorrhoidal nodes is essential for long-term success.

Clinical Investigation of Hereditary and Acquired Thrombophilic Factors in Patients with Venous and Arterial Thromboembolism.

Background: The clinical relevance of thrombophilic laboratory factors, especially the "mild" ones, and the need for their screening is not generally recommended in venous (VTE) and/or arterial (ATE) thromboembolism. Methods: Our aim was to investigate possible associations between comorbidities and 16 inherited/acquired "severe" and "mild" laboratory thrombophilic factors (detailed in introduction) in patients (n=348) with VTE/ATE without a serious trigger (high-risk surgical intervention, active cancer and/or chemo-radiotherapy). Cases with VTE/ATE were enrolled when the thrombotic event occurred under the age of 40, in case of positive family history, recurrent thromboembolism, idiopathic event or unusual location. Patients without a detailed thrombophilia screening or who suffered from both ATE/VTE were excluded to find potential distinct thrombosis type specific thrombophilic risks. The possible role of "mild" factor accumulation was also investigated in VTE (n=266). Results: Elevation of factor VIII clotting activity was associated with VTE rather than ATE. Varicose veins together with postthrombotic syndrome were strongly related to several "mild" factors. Besides "severe" we found that the "mild" thrombophilic factors were also strongly associated with VTE/ATE. Comorbidities/conditions such as diabetes and smoking were generally associated with hyperlipidemia; moreover, both had a correlation with lipoprotein (a) in VTE. We also revealed an important contribution of "mild" factors in increasing trends of several types and localizations of VTE. Conclusion: In summary, besides the "severe" thrombophilic factors, the "mild" ones also seem to play a non-negligible role in the manifestation of thrombosis, especially in combination. Therefore, an extended screening might be useful in the personalized recommendation of antithrombotic prophylaxis.

[Advances in the prevention, diagnosis and therapy of vascular diseases]. / Újabb ismeretek a különbözo vascularis kórképek megelozésében, diagnosztikájában és terápiájában.

Atherosclerosis is a systemic disease affecting the coronary, carotid, intracerebral, renal and peripherial arteries. The early morphological and functional impairments could be detected in the second or third decades of life and their progression depend on the number and severity of risk factors and individual susceptility. Although the vascular risk factors (smoking, overweight, age, unhealthy diet, lack of physical exercise, hypertension, diabetes mellitus, chronic kidney disease and dyslipidemia) are the same and common in the different vascular diseases, the present clinical routine artificially classifies the diagnosis and therapy of different vascular diseases into different subfields of medicine with the negative impact of possible polypragmasia. Recently, worldwide health surveys (e.g. REACH registry) have proven the usefulness of a holistic approach in the diagnosis and therapy of multiorgan-affected vascular patients. This review summarizes the multidisciplinary advances and future perspective of vascular diseases.

Rare disease education in Europe and beyond: time to act.

People living with rare diseases (PLWRD) still face huge unmet needs, in part due to the fact that care systems are not sufficiently aligned with their needs and healthcare workforce (HWF) along their care pathways lacks competencies to efficiently tackle rare disease-specific challenges. Level of rare disease knowledge and awareness among the current and future HWF is insufficient. In recent years, many educational resources on rare diseases have been developed, however, awareness of these resources is still limited and rare disease education is still not sufficiently taken into account by some crucial stakeholders as academia and professional organizations. Therefore, there is a need to fundamentally rethink rare disease education and HWF development across the whole spectrum from students to generalists, specialists and experts, to engage and empower PLWRD, their families and advocates, and to work towards a common coherent and complementary strategy on rare disease education and training in Europe and beyond. Special consideration should be also given to the role of nurse coordinators in care coordination, interprofessional training for integrated multidisciplinary care, patient and family-centered education, opportunities given by digital learning and fostering of social accountability to enforce the focus on socially-vulnerable groups such as PLWRD. The strategy has to be developed and implemented by multiple rare disease education and training providers: universities, medical and nursing schools and their associations, professional organizations, European Reference Networks, patient organizations, other organizations and institutions dedicated to rare diseases and rare cancers, authorities and policy bodies.

Bilateral central retinal vein occlusion caused by malignant hypertension in a young patient.

Central retinal vein occlusion (CRVO) occurring simultaneously in both eyes is a rare condition, in such cases usually associated with severe systemic disease. Overall, only 10% of all CRVO patients are younger than 40 years. A relatively young patient reported with simultaneous bilateral CRVO associated with chronic kidney disease and malignant hypertension. A case of a 35-year-old male patient presented with the complaint of decreased vision in both eyes. Ophthalmic examination revealed bilateral CRVO. Chronic kidney disease leading to malignant hypertension and hyperviscosity was diagnosed as the underlying cause. Clinical support and medical therapy effectively controlled the hypertension, leading to improvement of both the systemic and ocular changes. To the best of our knowledge, this is the first case report of simultaneous bilateral CRVO in a young patient associated with chronic renal failure and malignant hypertension. Primary care providers, either ophthalmologists or physicians, need to consider both common and atypical risk factors for retinal vein occlusion, in order to prevent further ocular morbidity and systemic complications.

Current Status of Clinical and Genetic Screening of Hereditary Hemorrhagic Telangiectasia Families in Hungary.

Hereditary hemorrhagic telangiectasia (HHT) is a rare germline vascular malformation syndrome with a prevalence of 1:5000-1:10,000 [...].

Resolving Differential Diagnostic Problems in von Willebrand Disease, in Fibrinogen Disorders, in Prekallikrein Deficiency and in Hereditary Hemorrhagic Telangiectasia by Next-Generation Sequencing.

Diagnosis of rare bleeding disorders is challenging and there are several differential diagnostics issues. Next-generation sequencing (NGS) is a useful tool to overcome these problems. The aim of this study was to demonstrate the usefulness of molecular genetic investigations by summarizing the diagnostic work on cases with certain bleeding disorders. Here we report only those, in whom NGS was indicated due to uncertainty of diagnosis or if genetic confirmation of initial diagnosis was required. Based on clinical and/or laboratory suspicion of von Willebrand disease (vWD, n = 63), hypo-or dysfibrinogenemia (n = 27), hereditary hemorrhagic telangiectasia (HHT, n = 10) and unexplained activated partial thromboplastin time (APTT) prolongation (n = 1), NGS using Illumina platform was performed. Gene panel covered 14 genes (ACVRL1, ENG, MADH4, GDF2, RASA1, F5, F8, FGA, FGB, FGG, KLKB1, ADAMTS13, GP1BA and VWF) selected on the basis of laboratory results. We identified forty-seven mutations, n = 29 (6 novel) in vWD, n = 4 mutations leading to hemophilia A, n = 10 (2 novel) in fibrinogen disorders, n = 2 novel mutations in HHT phenotype and two mutations (1 novel) leading to prekallikrein deficiency. By reporting well-characterized cases using standardized, advanced laboratory methods we add new pieces of data to the continuously developing "bleeding disorders databases", which are excellent supports for clinical patient management.

[Questionnaire for assessing the risk of venous thromboembolism in hospitalized surgical and non-surgical patients in the 4th Hungarian antithrombotic guideline entitled "Risk reduction and treatment of venous thromboembolism"]. / Vénásthromboembolia-kockázati kérdôív kórházban kezelt sebészeti és nem sebészeti betegek részére "A thromboemboliák kockázatának csökkentése és kezelése" címu, 4. magyar antithromboticus irányelvben.

A large proportion of hospitalized surgical and medical patients are at risk for venous thromboembolism. Depending on the type of surgical intervention, venous thrombosis develops in 15-60% of surgical patients without prophylaxis. Although venous thromboembolism is most often considered to be associated with recent surgery or trauma, 50 to 70% of symptomatic thromboembolic events and 70 to 80% of fatal pulmonary embolisms occur in nonsurgical patients. International and national registries show that the majority of at-risk surgical patients actually received the appropriate thromboembolic prophylaxis. However, despite of international and national recommendations, prophylaxis was not provided for a large proportion of at-risk medical patients. The rate of medical patients receiving prophylaxis should be increased, and appropriate thrombosis prophylaxis should be offered to at-risk medical patients. The thrombosis risk assessment is an important tool to identify patients at increased risk for venous thromboembolism, to simplify decision making on prophylaxis administration, and to improve the adherence to guidelines. When the risk is recognized, if there is no contraindication, prophylaxis should be ordered. The 4th Hungarian Antithrombotic Guideline entitled "Risk reduction and treatment of thromboembolism" calls attention to the importance of risk assessment and for the first time it includes and recommends risk assessment models for hospitalized surgical and medical patients. The risk assessment models are presented and the evidence based data for the different risk factors included in these models are reviewed.

[Thromboembolism and its prevention in one-day surgery]. / Thromboemboliás szövodmények elofordulása és megelozése egynapos sebészeti beavatkozások során.

Perioperative antithrombotic prophylaxis as well as surgical and invasive procedures done in anticoagulated patients ("bridging") have primary importance as regards prevention of venous thromboembolism (VTE) and reducing haemorrhagic complications. It is understandable that overwhelming majority of publications are dealing with major surgery (when usually several days hospitalization is required) while much less papers focus on one-day surgery cases. In this paper a brief survey on VTE epidemiology and prevention is carried out based on the new international and the 4th Hungarian Antithrombotic Guideline. The new protocols suggest that beside general measures a perioperative pharmaceutical antithrombotic prophylaxis is necessary if concomittant inherited and/or acquired thrombophilia is present.

Autoimmune progesterone dermatitis diagnosed by intravaginal progesterone provocation in a hysterectomised woman.

We report the case of a 39-year-old Hungarian woman who cyclically experienced painful, erythematous, patchy skin lesions on her face and chest. Because of her irregular menses and hysterectomy performed later on to manage endometriosis, it was difficult to link her symptoms to the menstrual cycle. But on the basis of the cyclic nature of the rash and the previous negative results - acne vulgaris, psoriasis, atopic dermatitis, lichen planus, systemic lupus erythematosus and infections were ruled out - autoimmune progesterone dermatitis was suspected. As progesterone is not available in aqueous solution for intradermal allergen test in Hungary, we performed progesterone provocation vaginally. The patient developed the usual skin lesions to vaginal progesterone exposure, which confirmed the diagnosis. The patient became symptom free to gonadotropine-analogue treatment and remained so even after the cessation of the therapy after 6 months. To our knowledge, this is the first case in the medical literature, in which autoimmune progesterone dermatitis was proved by vaginal progesterone provocation.

[Transformation of chronic lymphocytic leukemia to myelodysplastic syndrome: case presentation and review of the literature]. / Krónikus lymphoid leukaemia transzformációja myelodysplasticus szindrómába: betegismertetés és az irodalom áttekintése.

Chronic lymphocytic leukaemia (CLL) may transform to either malignant lymphoid disorder or increase the occurrence of solid neoplasms. However myeloid malignancies seldom develop. We report a case of a patient who has remained untreated for CLL and developed myelodysplastic syndrome (refracter anemia with ringed sideroblasts) six years after the diagnosis of CLL. Development of myelodysplastic syndrome resulted in concurrent attenuation of CLL. Discussion of the pathogenesis of myeloid disorders occurring with CLL and review of the literature are also presented.

FBN1 gene mutations in 26 Hungarian patients with suspected Marfan syndrome or related fibrillinopathies.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder mainly affecting the cardiovascular, ocular and musculo-skeletal systems. FBN1 gene mutations lead to MFS and related connective tissue disorders. In this work we described clinical and molecular data of 26 unrelated individuals with suspected MFS who were referred for FBN1 mutation analysis. FBN1 gene sequencing was performed by next generation sequencing and Sanger sequencing methods. We identified 23 causal or potentially causal (including variants of uncertain significance) FBN1 variants, seven of them was novel (˜30%). About 30% of the cases were sporadic. FBN1 mutations were associated with MFS in the majority of the patients, in two cases with severe and early onset manifestation of the syndrome. Missense mutations were detected in 69.6% (16/23), the majority of them were located in one of the cbEGF motifs and ˜70% of them substituted conserved cystein residues. Small deletions/duplications were identified in 13% of the cases (3/23), while splice site variants were detected in 17.4% (4/23). In three unrelated patients a low frequency recurrent silent variant (c.3294C > T (p.Asp1098=) was identified. FBN1 mRNA analysis showed that the mutation does not lead to aberrant splicing, based on available data the mutation was classified as benign.

[Hyperinsulinemic hypoglycemia in adults. Case reports and a short review]. / Hyperinsulinaemiás hypoglykaemia felnottkorban. Esetismertetések és rövid áttekintés.

UNLABELLED: Persistent hyperinsulinemic hypoglycemia (nesidioblastosis) not caused by an insulinoma is rare in adults. Morphologically no insulin secreting tumor is present. Keystones of diagnosis are not only low glucose levels but to maintain normoglycemia by use of intravenous glucose and the presence of high insulin and C-peptide levels. Noninvasive and invasive diagnostic techniques are required to rule out a hormone secreting tumor. Both conservative and/or surgical therapy are suggested to prevent damaging effects of repeated hypoglycemia. CASE REPORT: Two patients with frequent and serious episodes of hypoglycemia are reported. In the 34-year-old female symptoms appeared with sweating, dizziness, trembling, nervousness and serious neuroglycopenic signs. In the 22-year-old male the main complaint was tympany, a rare and unusual sign of hypoglycemia, and intense feeling of esurience. The 24-hour fasting test was positive in both cases, i.e. it had to be stopped because of symptomatic hypoglycemia. No insulinoma could be localized, despite extensive search, therefore in both cases the diagnosis of adult-onset nesidioblastosis was set up, despite lack of histological confirmation. Diazoxide therapy resulted in symptom-free life for both patients. CONCLUSION: Several diagnostic methods and treatment options are suggested for the rare disease nesidioblastosis to balance defective insulin secretion. However, once the decision is made in favour of surgical therapy, there is a thin line between successful treatment, persistence of the disease, and pancreatic insufficiency. Therefore it is worth considering to try conservative therapy especially when surgery is of high risk. Our cases suggest that diazoxide therapy is an effective and safe alternative in the treatment of adult-onset nesidioblastosis.

Transient visual loss triggered by scuba diving in a patient with a petrous epidermoid and combined thrombotic risk factors.

A 25-year-old woman who developed transient neurological abnormalities after scuba diving is reported. The subsequent day she experienced transient left-side monocular blindness. Arterial ocular occlusion in apparently healthy young women is unusual, and a search for the cause of this devastating vascular event is mandatory. Occlusion of the left branch retinal artery, total occlusion of the left internal carotid artery, and a petrous apex epidermoid were found, together with a shortened prothrombin time (INR: 0.73), a slightly elevated serum cholesterol level (6.1 mmol/l) and combined thrombophilia (elevated FVIIIC plus type 2 sticky platelet syndrome). This case underlines the complex mechanism of thromboembolic diseases, and the importance of the acquired trigger (in the present case scuba diving) in addition to the long-term anatomical and biochemical risk factors.