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Over the past year, many cases with newly onset or significantly exacerbated tic disorders were observed worldwide, where some aspects of the clinical presentation or the symptomatology were atypical for established tic diagnoses. Our purpose was to describe the atypical cases and raise relevant diagnostic issues. Consecutive cases with atypical tic presentations were documented. Five atypical tic cases are described. These cases shared some common characteristics, most notably the fact that all of them had been exposed to online presentation of ticking behaviour on social media platforms prior to the de novo development or exacerbation of their tics. Even though the order of events suggests causality and therefore the diagnosis of a functional tic disorder, unambiguous criteria for classifying atypical tics as functional symptoms are lacking. Differentiating neurodevelopmental and functional tics in childhood is currently problematic. Based on the currently unresolved issues in differential diagnosis, the importance of watchful waiting and behavioural interventions is highlighted to avoid unwarranted pharmacotherapy.

Absztrakt: A szerzők egy negatív családi anamnézisű, súlyos, neonatalis kezdetű epilepsziás encephalopathiában szenvedő, jelenleg kétéves fiúgyermek esetét mutatják be. A terápiarezisztens epilepszia és az igen súlyos fejlődésbeli elmaradás etiológiáját kiterjedt klinikai vizsgálatokkal sem sikerült tisztázni. Genetikai okot feltételezve, külföldi genetikai laboratóriumban 128 gént tartalmazó újgenerációs szekvenálási (NGS-) panelvizsgálatot indikáltak epilepsziás encephalopathiát okozó betegségek irányában. A vizsgálat egy eddig ismeretlen hemizigóta misszensz mutációt igazolt a MECP2-génben. A szerzők az esetbemutatás kapcsán áttekintik a lányokban klasszikusan Rett-szindrómát okozó, a MECP2-gén mutációi által előidézett idegfejlődési rendellenességek spektrumát fiúkban. Más, X-hez kötött domináns öröklődésű betegségekhez hasonlóan sokáig úgy gondolták, hogy a MECP2-gén-mutációt hordozó fiúmagzatok életképtelenek, napjainkra azonban ez a nézet megváltozott. A szerzők úgy tudják, hogy betegük az első magyar fiúgyermek, akinél a MECP2-gén mutációja igazolódott. Orv Hetil. 2019; 160(51): 2036–2039.

Abstract: The advances in molecular genetic methods has lead to the discovery of the genetic alterations that underlie the etiology of most diseases previously held to be idiopathic. Targeted genetic examination of a pediatric male patient showing a normal intellect, an extended area of skin hypopigmentation, and suffering from generalized epilepsy displaying a switch in epilepsy syndrome during the course of the disease towards a neurocutaneous syndrome was unsuccessful. Whole-exome sequencing identified a heterozygous missense mutation in a potassium chloride cotransporter gene, which together with the phenotype underscores the diagnosis of an epilepsy syndrome known in the literature as idiopathic generalized epilepsy type 14. Orv Hetil. 2019; 160(21): 835–838.

Background The treatment of acute lymphoblastic leukemia (ALL) and osteosarcoma (OSC) is very effective: the vast majority of patients recover and survive for decades. However, they still need to face serious adverse effects of chemotherapy. One of these is cardiotoxicity which may lead to progressive heart failure in the long term. Cardiotoxicity is contributed mainly to the use of anthracyclines and might have genetic risk factors. Our goal was to test the association between left ventricular function and genetic variations of candidate genes. Methods Echocardiography data from medical records of 622 pediatric ALL and 39 OSC patients were collected from the period 1989–2015. Fractional shortening (FS) and ejection fraction (EF) were determined, 70 single nucleotide polymorphisms (SNPs) in 26 genes were genotyped. Multivariate logistic regression and multi-adjusted general linear model were performed to investigate the influence of genetic polymorphisms on the left ventricular parameters. Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA) method was applied to test for the potential interaction of the studied cofactors and SNPs. Results Our results indicate that variations in ABCC2, CYP3A5, NQO1, SLC22A6 and SLC28A3 genes might influence the left ventricular parameters. CYP3A5 rs4646450 TT was 17% among ALL cases with FS lower than 28, and 3% in ALL patients without pathological FS (p = 5.60E-03; OR = 6.94 (1.76–27.39)). SLC28A3 rs7853758 AA was 12% in ALL cases population, while only 1% among controls (p = 6.50E-03; OR = 11.56 (1.98–67.45)). Patients with ABCC2 rs3740066 GG genotype had lower FS during the acute phase of therapy and 5–10 years after treatment (p = 7.38E-03, p = 7.11E-04, respectively). NQO1 rs1043470 rare T allele was associated with lower left ventricular function in the acute phase and 5–10 years after the diagnosis (p = 4.28E-03 and 5.82E-03, respectively), and SLC22A6 gene rs6591722 AA genotype was associated with lower mean FS (p = 1.71E-03), 5–10 years after the diagnosis. Conclusions Genetic variants in transporters and metabolic enzymes might modulate the individual risk to cardiac toxicity after chemotherapy. Electronic supplementary material The online version of this article (10.1186/s12885-018-4629-6) contains supplementary material, which is available to authorized users.

The advances in molecular genetic methods has lead to the discovery of the genetic alterations that underlie the etiology of most diseases previously held to be idiopathic. Targeted genetic examination of a pediatric male patient showing a normal intellect, an extended area of skin hypopigmentation, and suffering from generalized epilepsy displaying a switch in epilepsy syndrome during the course of the disease towards a neurocutaneous syndrome was unsuccessful. Whole-exome sequencing identified a heterozygous missense mutation in a potassium chloride cotransporter gene, which together with the phenotype underscores the diagnosis of an epilepsy syndrome known in the literature as idiopathic generalized epilepsy type 14. Orv Hetil. 2019; 160(21): 835-838.Absztrakt: A molekuláris genetikai technológiák fejlődése következtében egyre több, korábban idiopátiásnak tartott betegség hátterében ismerjük meg a genetikai eltérést. A generalizált epilepsziában szenvedő, a betegség lefolyása során epilepsziaszindrómát váltó, jó intellektusú, kiterjedt hipopigmentált folttal rendelkező fiúgyermek célzott genetikai vizsgálata neurocutan szindróma irányába nem hozott eredményt. Teljesexom-szekvenálás során egy kálium-klorid-kotranszporter génjének heterozigóta misszensz mutációja igazolódott, ami a fenotípussal összevetve, az irodalomban az idiopátiás generalizált epilepszia 14-es típusaként ismert epilepsziaszindróma diagnózisát támasztja alá. Orv Hetil. 2019; 160(21): 835–838.

We investigated whether an altered individual glucocorticoid sensitivity due to particular glucocorticoid receptor single-nucleotide polymorphisms (SNPs) (N363S, ER22/23EK, and Bcl-1) influences the susceptibility to steroid-related toxicities, prognostic factors, and survival rates in children with acute lymphoblastic leukemia. In total, 346 pediatric patients with acute lymphoblastic leukemia were enrolled in our study. Their carrier status was investigated by allele-specific polymerase chain reaction analysis. Clinical and laboratory signs of glucocorticoid-related toxicities, day-8 prednisone response, 5-year event-free survival, and 5-year overall survival rates were analyzed and compared retrospectively. Hepatotoxicity occurred significantly more often in 363S carriers (P=0.004), and glucose metabolism abnormalities were more common in 363S carriers (P=0.001), but did not occur in patients with the ER22/23EK SNP. Hypertension and central nervous system/behavioral changes did not occur in patients with the ER22/23EK SNP. None of the patients with the N363S SNP, the ER22/23EK polymorphism, or the GG genotype for the Bcl-1 polymorphism had a poor prednisone response. The 363S carriers had significantly better 5-year event-free survival (P=0.012) and 5-year overall survival (P=0.013) rates compared with noncarriers. The Bcl-1 SNP was not associated with any of the toxicities investigated or survival. Children with the N363S polymorphism in the glucocorticoid receptor gene were more prone to steroid-related toxicities, whereas those with the ER22/23EK polymorphism were less susceptible. Children with the N363S polymorphism may have more favorable survival rates.

CYP3A4 has an important role in the metabolisms of many drugs used in acute lymphoblastic leukemia (ALL) therapy; still, there are practically no publications about the role of CYP3A4 polymorphisms in ALL pharmacogenomics. We genotyped eight common single-nucleotide polymorphisms (SNPs) in the CYP3A4 and CYP3A5 genes in 511 children with ALL and investigated whether they influenced the survival of the patients. We involved additional 127 SNPs in 34 candidate genes and searched for interactions with respect to the survival rates. Significant association between the survival rates and the common rs2246709 SNP in the CYP3A4 gene was observed. The gender of the patients and the rs1076991 in the MTHFD1 gene strongly influenced this effect. We calculated new risk assessments involving the gender-rs2246709 interaction and showed that they significantly outperformed the earlier risk-group assessments at every time point. If this finding is confirmed in other populations, it can have a considerable prognostic significance.

We carried out a detailed comparative study of the pharmacokinetics and toxicity of methotrexate (MTX) and 7-hydroxy-methotrexate (7-OH-MTX) after high-dose intravenous methotrexate (HD-MTX) in children with acute lymphoblastic leukemia (ALL). Overall, 65 children were treated with 5 g/m2/24 h MTX and 88 children were treated with 2 g/m2/24 h MTX according to ALL-BFM 95 and ALL IC-BFM 2002 protocols (mean age: 6.4 years, range 1.0-17.9 years). A total of 583 HD-MTX courses were analyzed. Serum MTX and 7-OH-MTX levels were measured at 24, 36, and 48 h, and cerebrospinal fluid (CSF) MTX levels were determined 24 h after the initiation of the infusion. The area under the concentration-time curve was calculated. Hepatotoxicity, nephrotoxicity, and bone marrow toxicity were estimated by routine laboratory tests. We investigated pharmacokinetics and toxicity in distinct age groups ( 14 years). 5 g/m2/24 h treatments resulted in higher serum and CSF MTX and 7-OH-MTX levels (P < 0.05). The CSF penetration rate of MTX was independent of the MTX dose [2.3% (95% confidence interval: 1.7-2.5%) vs. 2.8% (95% confidence interval: 2.4-3%)]. The CSF MTX concentration was correlated with the 24 h MTX serum level (r = 0.38, P < 0.0001). Repeated treatments did not alter MTX or 7-OH-MTX levels. 7-OH-MTX levels were correlated with nephrotoxicity (r = 0.36, P < 0.0001). Higher MTX levels and toxicity occurred more frequently in children aged older than 14 years (P < 0.05). Therapeutic serum and CSF MTX concentrations can be achieved more reliably with 5 g/m2/24 h treatments. To predict the development of toxicity, monitoring of the level of the 7-OH-MTX is useful. Monitoring of pharmacokinetics is essential to prevent the development of severe adverse events in adolescents.

OBJECTIVES A retrospective study has been done at the Bethesda Children's Hospital Epilepsy Center with those patients whose EEG records fulfilled in one or more records the criteria of electrical status epilepticus in slow wave sleep (ESES) pattern, occupying at least 75% of NREM sleep with bilateral discharges, and had detailed disease history and long term follow-up data, between 2000 and 2012. PATIENTS AND METHODS--Thirty-three patients (mean 11.1 +/- 4.2 years of age) were studied by 171 sleep EEG records. Sleep was recorded after sleep deprivation or during spontaneous sleep at least for one hour length of NREM. From the 492 EEGs, 171 sleep records were performed (average five/patient). Average follow-up time was 7.5 years. Eighty-two ESES records have been analyzed in 15 non-lesional and 18 lesional (11 with dysgenetic and seven with perinatal-asphyxic or vascular origin) patients. Variability of seizure types, seizure frequency and frequency of status epilepticus was higher in the lesional group. Impairment of the cognitive functions was moderate and partial in the non-lesional, while severely damaged in the lesional group. RESULTS EEG records of 29 patients shawed unihemispherial spike fields with a perpendicular axis (in anterior, medial and posterior variants) to the Sylvian fissure, regardless their lesional or non-lesional origin. Only three (lone nonlesional and two lesional) patients had bilateral synchronous spike-wave discharges with bilateral symmetric frontocentral spike fields. The individual discharges of the sleep EEG pattern were very similar to the awake interictal records except their extension in time and field, their increased number, amplitude, and continuity of them and furthermore in the increased trans-hemispheral propagation and their synchronity. CONCLUSIONS Assumed circuits involved in the pathomechanism of discharges during NREM sleep in ESES are discussed based on our findings.

// Marta Hegyi 1 , Adam Arany 2, 3 , Agnes F. Semsei 4 , Katalin Csordas 1 , Oliver Eipel 1 , Andras Gezsi 2, 4 , Nora Kutszegi 1, 4 , Monika Csoka 1 , Judit Muller 1 , Daniel J. Erdelyi 1 , Peter Antal 2 , Csaba Szalai 4 , Gabor T. Kovacs 1 1 Second Department of Pediatrics, Semmelweis University, H-1094 Budapest, Tűzolto utca 7-9, Hungary 2 Department of Measurement and Information Systems, University of Technology and Economics, H-1111 Budapest, Műegyetem rkp. 3, Hungary 3 Department of Organic Chemistry, Semmelweis University, H-1092 Budapest, Hőgyes Endre u. 7, Hungary 4 Department of Genetics, Cell and Immunobiology, Semmelweis University, H-1089 Budapest, Nagyvarad ter 4, Hungary Correspondence to: Gabor T. Kovacs, email: kovacs.gabor1@med.semmelweis-univ.hu Keywords: osteosarcoma, methotrexate, toxicity, SNP, Bayesian network-based Bayesian multilevel analysis of relevance (BN-BMLA) Received: February 18, 2016 Accepted: August 09, 2016 Published: August 23, 2016 ABSTRACT Inter-individual differences in toxic symptoms and pharmacokinetics of high-dose methotrexate (MTX) treatment may be caused by genetic variants in the MTX pathway. Correlations between polymorphisms and pharmacokinetic parameters and the occurrence of hepato- and myelotoxicity were studied. Single nucleotide polymorphisms (SNPs) of the ABCB1 , ABCC1 , ABCC2 , ABCC3 , ABCC10 , ABCG2 , GGH , SLC19A1 and NR1I2 genes were analyzed in 59 patients with osteosarcoma. Univariate association analysis and Bayesian network-based Bayesian univariate and multilevel analysis of relevance (BN-BMLA) were applied. Rare alleles of 10 SNPs of ABCB1 , ABCC2 , ABCC3 , ABCG2 and NR1I2 genes showed a correlation with the pharmacokinetic values and univariate association analysis. The risk of toxicity was associated with five SNPs in the ABCC2 and NR1I2 genes. Pharmacokinetic parameters were associated with four SNPs of the ABCB1, ABCC3, NR1I2 , and GGH genes, and toxicity was shown to be associated with ABCC1 rs246219 and ABCC2 rs717620 using the univariate and BN-BMLA method. BN-BMLA analysis detected relevant effects on the AUC 0-48 in the following SNPs: ABCB1 rs928256, ABCC3 rs4793665, and GGH rs3758149. In both univariate and multivariate analyses the SNPs ABCB1 rs928256, ABCC3 rs4793665, GGH rs3758149, and NR1I2 rs3814058 SNPs were relevant. These SNPs should be considered in future dose individualization during treatment.

Monitoring the pharmacokinetic parameters of different anticancer drugs is necessary because they might have several side effects. Aim: Pharmacokinetic and toxicity evaluation of high-dose methotrexate treatments in children with acute lymphoblastic leukemia. Patients and methods: 43 children (28 boys, 15 girls, mean age: 7.03 years) in 147 cases were treated with 5 g/m2/24h MTX according to ALL-BFM 1995 and 2002 protocols. Methotrexate and 7-hydroxi-methotrexate levels were measured with high pressure liquid chromatography at 24, 36, 48 hours. Authors registered the development of hepatotoxicity, nephrotoxicity, grade III/IV oral mucositis. Results: Therapeutic methotrexate serum concentrations (30-100µmol/l) were achieved in 72.5% of the cases. Repeated treatments resulted similar serum levels. Hepatotoxicity and hypoproteinemia occurred in 17% and in 48.9% of the cases. There was significant correlation between serum 7-hydroxi-methotrexate and creatinine levels (p2methotrexate resulted reliable therapeutic serum levels with mild and reversible toxicity. 7-hydroxi-methotexate measurements might be more useful than methotrexate levels to detect toxicity. Orv. Hetil., 2011, 152, 1609–1617.

Background The objective of this report was to estimate long-term outcome and prognostic factors in children and adolescents with osteosarcoma. A large group of osteosarcoma patients were analyzed at our national oncology center. Procedure To evaluate the efficacy of surgery and multiagent chemotherapy for treating osteosarcoma, we reviewed 122 cases (65 male, 57 female, mean age 13.8 ± 3.6 years) treated at the Second Department of Pediatrics in Budapest between 1988 and 2006. Demographic parameters, tumor-related and treatment-related variables, response, overall survival (OS) and event-free survival (EFS) were analyzed. Results The 5-year OS was 68% and 5-year EFS was 62%. OS of patients without metastasis was 79%, while OS with early metastasis was 17%. Survival of patients with amputation (n = 30) was not significantly different from patients with limb-salvage surgery (n = 82), but all patients without radical surgery died. Gender and histological classification had no prognostic significance. Patients with localized tumors in extremities had increased survival compared to patients with axial skeleton tumors (P = 0.013). Poor histological response to neoadjuvant chemotherapy (rate of survivor tumor cells >10%) was associated with decreased survival (P = 0.018). Patients under 14 years had better EFS than patients over 14 years (P = 0.008). Conclusions Our results demonstrate that younger patients with localized osteosarcoma of the extremities who receive limb-salvage surgery and chemotherapy have an excellent survival. Pediatr Blood Cancer 2011; 57: 415–422. © 2011 Wiley-Liss, Inc.

SUMMARYAim.The aim of this article is to review criticaly the Electrical Status Epilepticus in Slow Sleep (ESES) phenomenon from a neurophysiological mechanisms aspect as well as terminological and classification issues.Methods.The review includes all the relevant papers published during the last 43 years on the subject of ESES and Continous Spike – Wave in Sleep (CSWS).These papers were identified in various large databases via the internet.Rewiev and remarks.ESES/CSWS phenomena can be held as a common final pathway originating from different etiologies, including patients with early brain damage (probably involving thalamic structures), but also patients without structural pathology as in atypical evolution of idiopathic regional childhood hyperexcitability syndromes (with Rolandic epilepsy as a prototype). There are hints that genetic predisposition might be an important factor in the development of this process. The two large patient groups (lesional and non-lesional) show the same EEG evolution and encephalopathic cognitive consequences. The sleep EEG activation can be held as a common endophenotype. ESES represents an extreme sleep activation/potentiation of the local/regional interictal discharges, enhancing them in frequency, territorial extension, intra and trans-hemispherial propagation, synchrony and continuity. This process is most probably not identical with the development of bilateral spike-wave pattern in „generalized” epilepsies which involves primarily or secondarily the thalamocortical system as it had been explored by Gloor (1979) for idiopathic generalized rpilepsy and Steriade and Amzica (2003) for different types of generalized spike and wave discharges.Conclusions and syndromological embedding of ESES.In an overwhelming majority of the investigated cases, the maps of the single discharges constituting sleep activation are identical; with focal/regional interictal spikes followed by slow closing wave, as it is seen in childhood regional age dependent hyperexcitability syndromes (prototype of the centro-temporal spikes of Rolandic epilepsy). The main mechanism of the developing cognitive impairment is most probably the consequence of interference with plastic function of slow wave sleep by obliterating synaptic decline during sleep. Presently, the consensus and co-operative research is highly obstacled by the terminological chaos, the controversial definitions and views around this still striking and enigmatic phenomenon.

Summary: Purpose: Severe myoclonic epilepsy in infancy (SMEI; Dravet's syndrome) is a malignant epilepsy syndrome characterized by early prolonged febrile convulsions (PFCs) with secondary psychomotor delay and a variety of therapy-resistant seizures. Although the initial symptoms are repeated PFCs, the MRI performed at the onset of disease shows no hippocampal structural abnormalities. We aimed to assess clinical and serial MRI data of patients with SMEI with a special attention to the temporomedial structures. To our knowledge, this is the first systematic MRI study in this disease. Methods: Clinical and MRI data of all SMEI patients treated in our hospitals between 1996 and 2004 were reviewed. Results: Twenty-eight MRIs from 14 children (one to four images/patient) were included. Age at disease onset was between 3 and 9 months; age at initial MRI was 5 months to 13 years. Ten of 14 patients showed hippocampal sclerosis (HS) during the course of the disease (nine unilateral, one bilateral). Six of these 10 had a normal initial MRI. Age at the first verified HS was between 14 months and 13 years. Neither complex partial seizures nor anterior temporal irritative zone was recorded in these children. Conclusions: After initially normal structures, in most patients with SMEI, HS develops several months or years after the first PFC. These data support the hypothesis that PFC might be responsible for HS, but other factors and individual sensitivity should play a role in this process.

Summary High-dose methotrexate (HD-MTX) plays an important role in the consolidation therapy of acute lymphoblastic leukaemia (ALL) in many treatment regimens worldwide. However, there is a large interpatient variability in the pharmacokinetics and toxicity of the drug. We investigated the influence of single nucleotide polymorphisms (SNPs) in genes of the folate metabolic pathway, transporter molecules and transcription proteins on the pharmacokinetics and toxicity of MTX and 7-hydroxy-methotrexate (7-OH-MTX). 63 SNPs of 14 genes were genotyped and a total of 463 HD-MTX courses (administered according to the ALL-BFM 95 and ALL IC-BFM 2002 protocols) were analysed. Haematological, hepatic and renal toxicities, estimated by routine laboratory parameters were evaluated. Random forest and regression trees were used for variable selection and model building. Linear mixed models were established to prove the significance of the selected variables. SNPs (rs4948502, rs4948496, rs4948487) of the ARID5B gene were associated with the serum levels of MTX (P

The only Hungarian video EEG laboratory where children of ages 0-18 can be continuously monitored for several days was opened 1 June 2001 at Department of Neurology of Bethesda Children's Hospital.Summarizing our 10 years of experience with the video EEG monitoring (VEM) of children and defining the place of VEM in the treatment of childhood epilepsy in Hungary.We have processed data from 597 monitoring sessions on 541 patients between June 1, 2001 and 31 May, 2011 based on our database and the detailed summaries of the procedures.509 patients were under the age of 18. The average length of the sessions was 3.1 days. We have observed habitual episodes or episodes in question in 477 (80%) sessions. 241 (40%) sessions were requested with an epilepsy surgery indication, and 74 patients had 84 operations. 356 (60%) were requested with a differential diagnosis indication, and 191 (53%) cases of epilepsy were diagnosed. We most commonly diagnosed symptomatic generalized epilepsy (57 cases). In 165 sessions the episode in question was not diagnosed as epilepsy. Among the paroxysmal episodes we have identified events of psychogenic origin, movement disorders, sleep disorders and behavioral disorders. Only 3% of the differential diagnosis procedures brought no additional clinical information.The diagnostic efficiency in our VEM laboratory is in accordance with the data found in the literature. Besides epilepsy surgery VEM is recommended if suspected epileptic episodes occur and interictal epileptiform signs are not present or are not in accordance with the symptoms, if there is no explanation for therapy resistance and if paroxysmal episodes of non-epileptic origin are suspected but they cannot be identified based on the anamnesis. VEM is also helpful in diagnosing subtle seizures. The procedure has numerous additional benefits in patient care and in training the parents and hospital staff.

Background We carried out a candidate gene association study in pediatric acute lymphoblastic leukemia (ALL) to identify possible genetic risk factors in a Hungarian population. Methods The results were evaluated with traditional statistical methods and with our newly developed Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA) method. We collected genomic DNA and clinical data from 543 children, who underwent chemotherapy due to ALL, and 529 healthy controls. Altogether 66 single nucleotide polymorphisms (SNPs) in 19 candidate genes were genotyped. Results With logistic regression, we identified 6 SNPs in the ARID5B and IKZF1 genes associated with increased risk to B-cell ALL, and two SNPs in the STAT3 gene, which decreased the risk to hyperdiploid ALL. Because the associated SNPs were in linkage in each gene, these associations corresponded to one signal per gene. The odds ratio (OR) associated with the tag SNPs were: OR = 1.69, P = 2.22x10-7 for rs4132601 (IKZF1), OR = 1.53, P = 1.95x10-5 for rs10821936 (ARID5B) and OR = 0.64, P = 2.32x10-4 for rs12949918 (STAT3). With the BN-BMLA we confirmed the findings of the frequentist-based method and received additional information about the nature of the relations between the SNPs and the disease. E.g. the rs10821936 in ARID5B and rs17405722 in STAT3 showed a weak interaction, and in case of T-cell lineage sample group, the gender showed a weak interaction with three SNPs in three genes. In the hyperdiploid patient group the BN-BMLA detected a strong interaction among SNPs in the NOTCH1, STAT1, STAT3 and BCL2 genes. Evaluating the survival rate of the patients with ALL, the BN-BMLA showed that besides risk groups and subtypes, genetic variations in the BAX and CEBPA genes might also influence the probability of survival of the patients. Conclusions In the present study we confirmed the roles of genetic variations in ARID5B and IKZF1 in the susceptibility to B-cell ALL. With the newly developed BN-BMLA method several gene-gene, gene-phenotype and phenotype-phenotype connections were revealed. We showed several advantageous features of the new method, and suggested that in gene association studies the BN-BMLA might be a useful supplementary to the traditional frequentist-based statistical method.

The survival rates in childhood acute lymphoid leukemia (ALL) have improved dramatically; however, patients still suffer from a variety of drug-related toxicities. Individualized therapy regimens promise the least toxic therapy regimen with the best hematologic outcome. Our aim was to investigate whether increased individual glucocorticoid sensitivity due to the N363S polymorphism of the glucocorticoid receptor increased susceptibility to steroid-related toxicities during ALL therapy. A total of 346 pediatric ALL patients were involved in the present study. N363S carrier status was investigated by allele-specific PCR. Clinical and laboratory signs of glucocorticoid-related toxicities, Day 8 prednisone response, and 5-year event-free survival were analyzed and compared retrospectively. Thirty-two of the 346 patients were heterozygous carriers (9.2 %). Hepatotoxicity (31.3 vs. 11.2 %, p = 0.004, carriers and non-carriers, respectively) and glucose metabolism abnormalities (18.8 vs. 3.8 %, p = 0.001, carriers and non-carriers, respectively) were significantly more frequent among carriers. There was no difference in the incidence of hypertension and encephalopathy/psychosis among carriers and non-carriers. Carriers were also more prone to have a combination of toxicities. All 363S carriers were good prednisone responders (100 %) and had significantly better 5-year event-free survival rates (93.1 vs. 71.86 %, p = 0.012), whereas among non-carriers there were more poor prednisone responders (8.28 %) and worse 5-year event-free survival rates. Patients with the N363S polymorphism in the glucocorticoid receptor are more prone to steroid-related toxicity during ALL therapy and should be monitored more closely. Patients with N363S polymorphism of the glucocorticoid receptor may be appropriate candidates for inclusion in the design of individualized therapies.

Anthracyclines are potent cytostatic drugs, the correct dosage being critical to avoid possible cardiac side effects. ABCC1 [ATP-binding cassette, sub-family C, member 1; also denoted as MRP1 (multidrug resistance-associated protein 1)] is expressed in the heart and takes part in the detoxification and protection of cells from the toxic effects of xenobiotics, including anthracyclines. Our objective was to search for associations between LV (left ventricular) function and single-nucleotide polymorphisms of the ABCC1 gene in children receiving anthracycline chemotherapy. Data of 235 paediatric patients with acute lymphoblastic leukaemia was analysed. Patients were followed-up by echocardiography (median follow-up 6.3 years). Nine polymorphisms in the ABCC1 gene were genotyped. The ABCC1 rs3743527TT genotype and rs3743527TT–rs246221TC/TT genotype combination were associated with lower LVFS (left ventricular fractional shortening) after chemotherapy. The results suggest that genetic variants in the ABCC1 gene influence anthracycline-induced LV dysfunction.

The objective of this report was to estimate long-term outcome and prognostic factors in children and adolescents with osteosarcoma. To evaluate the efficacy of surgery and multiagent chemotherapy for treating osteosarcoma, we reviewed 122 cases (65 males, 57 females, mean age 13.8 ± 3.6 years) treated at the Second Department of Pediatrics in Budapest between 1988 and 2006. Demographic parameters, tumor-related and treatment-related variables, response, overall survival (OS) and event-free survival (EFS) were analyzed. The 5-year OS and EFS were 68% and 61.5%, respectively. OS of patients without metastasis was 79%, while OS with early metastasis was 17%. Survival of patients with amputation (n=30) was not significantly different from that of patients with limb-salvage surgery (n=82), but all patients without radical surgery died. Gender and histological classification had no prognostic significance. Patients with localized tumors in extremities had increased survival compared to those with axial skeleton tumors (p=0.013). Poor histological response to neoadjuvant chemotherapy (rate of survivor tumor cells10%) was associated with decreased survival (p=0.018). Patients under 14 years had better EFS than patients over 14 years (p=0.008). Our results demonstrate that younger patients with localized osteosarcoma of the extremities who receive limb-salvage surgery and chemotherapy have an excellent survival.

Severe myoclonic epilepsy in infancy (SMEI; Dravet's syndrome) is a malignant epilepsy syndrome characterized by prolonged febrile hemiconvulsions or generalized seizures starting in the first year of life. Later on myoclonic, atypical absence, and complex partial seizures appear. When one of these seizure forms is lacking the syndrome of borderline SMEI (SMEB) is defined. Psychomotor delay resulting in mental retardation is observed during the second year of life. In most patients a de novo sodium channel alpha-1 subunit (SCN1A) mutation can be identified. By reviewing the clinical, laboratory, and neuroimaging data of our SMEI patients diagnosed between 2000 and 2008, we would like to share our experiences in this rare but challenging syndrome. Our results will facilitate the earlier and better diagnosis of Hungarian children with SMEI.Clinical, EEG, MRI and DNA mutation data of 20 SMEI patients treated in the Bethesda Children's Hospital (Budapest) were reviewed.The first seizure appeared at age 6.3+/-3.0 months. At least one of the first two seizures were complex febrile seizures in 19/20 and unilateral seizures in 12/20 children. All children except for one showed hemiconvulsions at least once; all children had seizures lasting longer than 15 minutes. Eight of twenty patients had SMEB. DNA diagnostics identified an SCN1A mutation in 17 patients (6 missense, 4 nonsense, 4 frameshift, 2 splice site, 1 deletion) while 3 children had no mutation.Early diagnosis of SMEI is important for the avoiding unnecessary examinations and false therapies as well as for genetic counselling. Typical symptoms of SMEI are early and prolonged febrile hemiconvulsions with neurological symptoms, mental retardation and secondary seizure types later on. The presence of an SCN1A mutation supports the diagnosis. We propose the availability of molecular diagnostics and stiripentol therapy for SMEI children in Hungary

To evaluate the efficacy and tolerability of levetiracetam in children with drug resistant epilepsy from a retrospective study.We report the result of a study of 85 pediatric patients (mean 10.5 years, range: 1-24) with refractory generalized and focal epilepsy, who received levetiracetam as add-on treatment. The average duration of epilepsy was eight years, and the patient were treated with mean of 6.0 antiepileptic drugs before levetiracetam was introduced.Ten patients (12%) became seizure-free, three (3%) responded with seizure reduction of more than 90%, 32 (38%) responded with seizure reduction of more than 50% following introduction of levetiracetam. No response to levetiracetam was reported in 34% (n: 29). Positive psychotropic effect was observed in 26 patient (30%). Mild to moderate side effects were reported in 11 patients (13%), consisting most frequently general behavioral changes, aggression, sleep disturbances, but they ceased after decreasing the dose of levetiracetam. Mental retardation was associated with poor response and associated with more side effects.Levetiracetam is a well tolerated new antiepileptic drug that may effectively improve seizures control as an add-on drug in resistant epilepsy in childhood with good tolerability.

Summary: Purpose: To describe predictive clinical factors for the differentiation between childhood frontal lobe epilepsy (FLE) and posterior cortex epilepsy (PCE). Methods: Two independent, blinded investigators analyzed 177 seizures from 35 children (aged 11 months to 12 years) with extratemporal epilepsy selected by postoperative seizure-free outcome. Semiologic seizure components and different periictal signs were observed. Age at onset, auras, seizure frequency, and nocturnal dominance, as well as surgical and histopathologic data, were collected from medical charts. Results: Twenty patients had FLE, and 15 had PCE. Patients from both groups had daily seizures without significant differences in frequency but with higher nocturnal dominance in children with FLE (p < 0.05). Visual aura, nystagmus, and versive seizure were observed exclusively in the PCE group, whereas somatosensory aura and hypermotor seizures appeared only in FLE. Tonic seizures were significantly more frequent in FLE (p < 0.01), whereas the presence of clonic seizure (FLE; p = 0.07) and postictal nose-wiping (PCE; p = 0.05) showed only a trend to localize the seizure-onset zone. Myoclonic seizures, epileptic spasms, psychomotor seizures, atonic seizures, oral and manual automatisms, as well as vocalization and eye deviation appeared in both groups without significant differences in their frequency. Conclusions: Characteristic features described in adults' extratemporal epilepsies were frequently missing during childhood seizures, especially in infants and preschool children. Ictal features help only a little in differentiating childhood FLE from PCE. Nocturnal appearance and the type of aura have high localizing value; therefore an accurate history taking is still an essential element of pediatric presurgical evaluation.

Background and purpose Rasmussen's encephalitis (RE) is a rare condition of unknown cause characterized by intractable seizures, progressive hemiparesis, mental impairment, and inflammatory histological findings in the cortex. The primary diagnosis is based on biopsy to confirm the typical clinical, electroencephalography, and brain imaging findings. The main objective of this study was to compare simultaneous structural and functional neuroimages in RE. Methods Concomitant magnetic resonance imaging and 2-deoxy-2-[18F]-fluoro-D-glucose positron emission tomography data from the authors' series of 5 children and 8 patients described in the literature were analyzed and compared. Results Typical early findings of RE include metabolic abnormalities (hypermetabolism and hypometabolism) starting in the frontal or temporal regions or, occasionally, involving the whole hemisphere. Focal abnormalities of cerebral glucose metabolism indicate lesions sooner and depict their extent better than concomitant magnetic resonance images. The major structural abnormality remains unilateral; however, contralateral frontal lobe hypometabolism or crossed cerebellar diaschisis can be a finding of this disease. Basal ganglia involvement and whole hemispheric metabolic abnormality appear typically only after several months of disease onset. Conclusion Concomitant structural and functional neuroimaging provide possibly complementary information in the early noninvasive workup of RE and may facilitate the early diagnosis of this rare disorder.