Andrea Luczay

NSD1 duplication in Silver-Russell syndrome (SRS): molecular karyotyping in patients with SRS features.

Silver–Russell syndrome (SRS) is a growth retardation syndrome characterized by intrauterine and postnatal growth retardation, relative macrocephaly and protruding forehead, body asymmetry and feeding difficulties. Nearly 50% of cases show a hypomethylation in 11p15.5, in 10% maternal uniparental disomy of chromosome 7 is present. A significant number of patients with SRS features also exhibit chromosomal aberrations. We analyzed 43 individuals referred for SRS genetic testing by molecular karyotyping. Pathogenic variants could be detected in five of them, including a NSD1 duplication in 5q35 and a 14q32 microdeletion. NSD1 deletions are detectable in overgrowth disorders (Sotos syndrome and Beckwith–Wiedemann syndrome), whereas NSD1 duplications are associated with growth retardation. The 14q32 deletion is typically associated with Temple syndrome (TS14), but the identification of a patient in our cohort reflects the clinical overlap between TS14 and SRS. As determination of molecular subtypes is the basis for a directed counseling and therapy, the identification of pathogenic variants in >10% of the total cohort of patients referred for SRS testing and in >16% of characteristic individuals with the characteristic SRS phenotype confirms the need to apply molecular karyotyping in this cohort.

Some GCR Polymorphisms (N363S, ER22/23EK, and Bcl-1) May Influence Steroid-induced Toxicities and Survival Rates in Children With ALL.

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.

Paediatric Endocrinology Subspecialty – The European Map, 55 Years Later

a Department of Paediatrics, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic; b 1st Department of Paediatrics, Semmelweis University, Budapest, Hungary; c Department of Paediatrics, Istanbul University, Istanbul, Turkey; d Institute of Endocrinology, Kaunas, Lithuania Received: September 11, 2017 Accepted: September 11, 2017 Published online: November 7, 2017 HORMONE RESEARCH IN PÆDIATRICS

A danazolkezelés hatása C1-inhibitor-hiány okozta hereditaer angiooedemás gyermekek növekedésére

Absztrakt: Bevezetes: Az attenualt androgeneket gyakran alkalmazzak C1-inhibitor-hianyos hereditaer angiooedema akut epizodjainak megelőzesere. Praepubertason tuli alkalmazasuk az epifizisfugak korai zarodasahoz, ezaltal novekedes-visszamaradashoz vezethet. Celkitűzes: A danazol hereditaer angiooedemas gyermekek hossznovekedesere kifejtett hatasanak felmerese. Modszer: Retrospektiv tanulmanyunk negyvenkettő, 21 evesnel idősebb hereditaer angiooedemas beteg adatait elemezte. A betegek eseteben meghataroztuk a varhato testmagassagtol valo elterest, majd azt a betegek neme, valamint a 21 eves kor előtt vegzett danazolkezeles osszdozisa es időtartama fuggvenyeben elemeztuk. Danazollal 16 eves kora előtt kezelt betegek eseteben osszefuggest kerestunk a varhato testmagassagtol valo elteres, valamint a kezeles időtartama, illetve kumulativ dozisa kozott. Eredmenyek: Nem talaltunk szignifikans kulonbseget a varhato testmagassagtol valo elteresben danazolt szedő/nem szedő, illetve fiu es leany betegek kozott. Ezt ...

The influence of treatment, age at onset, and metabolic control on height in children and adolescents with type 1 diabetes-A SWEET collaborative study

To describe the association between height, demographics, and treatment in youths with type 1 diabetes participating in an international network for pediatric diabetes centers (SWEET).

Elsődleges genetikai vizsgálat Prader–Willi-szindróma igazolására

Absztrakt: Bevezetes: A nemzetkozi szakirodalmi adatok alapjan az SNRPN genlocus promoter regiojanak DNS-metilacios vizsgalata jelenleg a legerzekenyebb es leghatekonyabb kezdeti lepes a Prader–Willi-szindroma-gyanus betegek genetikai vizsgalatakor. Celkitűzes: Celunk egy egyszerű, megbizhato, konnyen hozzaferhető, elsődlegesen diagnosztikus, DNS-metilacion alapulo eljaras kidolgozasa volt Prader–Willi-szindroma igazolasara. Modszer: Vizsgalatunk soran az altalunk modositott, koltseghatekony, metilacioszenzitiv, nagy felbontasu olvadaspont-elemzeses technikat hasonlitottuk ossze a leginkabb elterjedt, koltseges metilaciospecifikus multiplex ligatiofuggő probaamplifikacios technikaval. Klinikailag a Prader–Willi-szindroma tobb tunetet mutato 17 gyermek DNS-metilacios vizsgalatat vegeztuk el sajat tervezesű primerekkel: biszulfitszekvenalo polimeraz-lancreakcio, metilacioszenzitiv nagy felbontasu olvadaspont-elemzes es kontrollkent metilaciospecifikus multiplex ligatiofuggő probaamplifikacio tortent. Eredme...

A SHOX géndeletio előfordulása idiopáthiás alacsonynövésben. Multicentrikus tanulmány

INTRODUCTION The isolated haploinsufficiency of the SHOX gene is one of the most common cause of short stature determined by monogenic mutations. The heterozygous deviation of the gene can be detected in 2-15% of patients with idiopathic short stature (ISS), in 50-90% of patients with Leri-Weill dyschondrosteosis syndrome (LWS), and in almost 100% of patients with Turner syndrome. AIM The aim of our study was to evaluate the frequency of SHOX gene haploinsufficiency in children with ISS, LWS and in patients having Turner syndrome phenotype (TF), but normal karyotype, and to identify the dysmorphic signs characteristic for SHOX gene deficiency. METHOD A total of 144 patients were included in the study. Multiplex Ligation-dependent Probe Amplification (MLPA) method was used to identify the SHOX gene haploinsufficiency. The relationships between clinical data (axiological parameters, skeletal disorders, dysmorphic signs) and genotype were analyzed by statistical methods. RESULTS 11 (7.6%) of the 144 patients showed SHOX gene deficiency with female dominance (8/11, 81% female). The SHOX positive patients had a significantly higher BMI (in 5/11 vs. 20/133 cases, p<0.02) and presented more frequent dysmorphic signs (9/11vs 62/133, p = 0.02). Madelung deformity of the upper limbs was also significantly more frequent among the SHOX positive patients (4/11, i.e. 36%, vs. 14/133, i.e. 10%, p = 0.0066). There were no statistically significant differences between the mean age, mean height and auxological measurements (sitting height/height, arm span/height) between the two groups of patients. CONCLUSIONS The occurrence of SHOX gene haploinsufficiency observed in our population corresponds to the literature data. In SHOX positive patients, in addition to short stature, the dysmorphic signs have a positive predictive value for SHOX gene alterations. However, the SHOX deletion detected in a patient with idiopathic short stature without dysmorphic signs suggest that SHOX deletion analysis can be recommended in patients with ISS. Orv Hetil. 2017; 158(34): 1351-1356.Absztrakt: Bevezetes: A SHOX gen izolalt haploinsufficientiaja az alacsonynovest okozo monogenes elvaltozasok leggyakoribb oka. A gen heterozigota elterese az idiopathias alacsonynovessel (ISS) diagnosztizalt betegek 2–15%-aban, Leri–Weill-dyschondrosteosis szindroma (LWS) 50–90%-aban, valamint a Turner-szindromaban szenvedők csaknem 100%-aban igazolhato. Celkitűzes: A SHOX gen haploinsufficientiaja gyakorisaganak meghatarozasa ISS-sel es LWS-sel diagnosztizalt, valamint Turner-fenotipusu, de normalis karyotypussal rendelkező betegek (TF) koreben, valamint beazonositani a SHOX genelteresre jellemző dysmorphias jeleket. Modszer: Osszesen 144 betegben kerult sor a SHOX gen haploinsufficientia-vizsgalatara multiplex ligatios proba Amplifikacio (MLPA) modszerrel. A betegek klinikai adatai (auxologiai parameterek, csontrendszeri rendellenessegek, dysmorphias tunetek) es a pozitiv genotipus kozotti osszefuggeseket statisztikai modszerekkel elemeztek. Eredmenyek: A vizsgalt 144 betegből 11 (7,6%) eseteben igazol...

Methylation Status of CYP27B1 and IGF2 Correlate to BMI SDS in Children with Obesity

Objective: Worldwide increasing childhood obesity is due to interactions between environmental and genetic factors, linked together by epigenetic mechanisms such as DNA methylation. Methods: 82 obese children (>95th BMI percentile , age: 3-18 years) were included. Anthropometric data, metabolic parameters, 25-OH vitamin D (25OHD), and pubertal status were recorded, 24-hour blood pressure monitoring was performed. BMI standard deviation score (SDS) was calculated. Using candidate gene approach, obesity- (insulin-like growth factor 2 (IGF2), proopiomelanocortin (POMC)) and vitamin D metabolism-related genes (1-alfa-hydroxylase (CYP27B1), VDR) regulated by DNA methylation were selected. After isolating DNA from peripheral blood, bisulfite conversion, bisulfite specific polymerase chain reaction (BS-PCR), and pyrosequencing were carried out. Results: No significant correlation between 25-OHD and metabolic parameters and DNA methylation status, but a tendency of positive correlation between VDR methylation status and 25-OHD (r = 0.2053,p = 0.066) were observed. Significant positive correlations between BMI SDS and CYP27B1 hypermethylation (r = 0.2371,p = 0.0342) and a significant negative correlation between IGF2 hypomethylation and BMI SDS (r = -0.305,p = 0.0059) were found. Conclusions Rate of obesity shows correlation with DNA methylation. Hypomethylation of IGF2 and hypermethylation of CYP27B1 genes might positively influence the rate of BMI observed in obese children.

Quantifying adherence to growth hormone treatment: the easypod™ connect observational study (ECOS)

Recombinant human growth hormone (r-hGH) is indicated for pediatric patients with a variety of growth disorders. Until recently, analysis of adherence to treatment has been limited by recall bias and reliance on self-reporting. Accurate recorded data on r-hGH use can now be collected using the easypod™ auto-injector. The multinational easypod™ connect observational study (ECOS) was launched in 2010 to collect and analyze r-hGH dosing, clinical and auxological data from patients prescribed r-hGH via easypod™. Twelve countries are currently recruiting patients. The primary objective is to assess adherence in patients receiving r-hGH via easypod™. Secondary objectives include describing the impact of adherence on clinical outcomes and identifying adherence patterns. Data will be obtained from patients’ medical notes and uploaded from auto-injectors. Auxological parameters are collected, and prescribed dosing data recorded at clinic visits as per routine clinical practice. Annual adherence will be calculated (number of days the patient administered injections divided by the expected number of injection days over 1 year, as a percentage). Dose intensity (total amount of dose received divided by planned amount of dose over 1 year, as a percentage) will be analyzed. Adherence data will be correlated with clinical outcomes. An adherence pattern will also be developed based on patients’ age, sex, indication, self-injection, and time on treatment. The study will run until 2015, with yearly analyses, and will be overseen by a multinational scientific steering committee. With data from ECOS, it will be possible to accurately assess r-hGH treatment adherence in various growth disorders and explore its potential impact on growth. Ultimately, drivers of and barriers to treatment adherence will be identified, allowing appropriate support programs to be developed.