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Twenty years experience in rapid identification of congenital adrenal hyperplasia in Hungary

The aim of this study was to assess the effectivity of the identification of patients with congenital adrenal hyperplasia (CAH) in Hungary in the absence of systematic neonatal screening and to estimate the incidence. Dried blood-spot samples of patients clinically suspected at any age to have CAH were collected between 1978 and 1998 throughout the whole country. 17-Hydroxyprogesterone (17-OHP) was measured by radioimmunoassay. Age-specific cut-offs were used. The effectivity of the system was retrospectively assessed. Additional cases were sought to assess the overall incidence of CAH in Hungary. Among the 1,837 patients investigated, 185 cases of CAH were identified. The overall effectivity was 94.7%. The sensitivity and the specificity were 98.9% and 94.2%, respectively. Salt-wasting (SW) boys were, on average, diagnosed 2 weeks later than SW girls, while both boys and girls with the simple virilising (SV) form were diagnosed at similar ages (2 versus 2.5 years). An additional 19 cases were diagnosed during the study period using other methods (plasma and urinary steroid profiles without blood-spot 17-OHP measurements). The incidence of classical CAH in Hungary was 1:14,300 (CI 95% between 1:12,450 and 1:16,795). Presuming that the incidence of CAH is the same among boys and girls, one can calculate that the diagnosis was missed in 24 boys (2 SW, 22 SV). Conclusion: it is possible to identify the vast majority of classical cases of congenital adrenal hyperplasia without a neonatal mass screening programme. However, a significant number of boys with the simple virilising form missed whereas both salt-wasting boys and girls are diagnosed safely.

Association of lean and fat body mass, bone biomarkers and gonadal steroids with bone mass during pre- and midpuberty.

Background/Aims: The association of bone mass with body composition, bone turnover markers and gonadal steroids was examined in Hungarian children during pre- and midpuberty. Methods: Two hundred and thirty-seven 7- to 16-year-old subjects (56% girls) were investigated. Bone mineral density (BMD), fat mass and total and appendicular lean mass were estimated with dual-energy X-ray absorptiometry (Lunar Prodigy). The fat mass index and appendicular lean mass index (LMI) were calculated. Serum bone markers, parathyroid hormone, estradiol and testosterone were analyzed. Associations between variables were evaluated by multiple regression analysis. Results: During prepuberty, bone biomarkers, gonadal steroids and appendicular LMI were associated with bone mass in both genders (p < 0.05). During midpuberty, girls’ bone turnover markers were negatively associated with bone mass (p < 0.001). In prepuberty, appendicular LMI and β-crosslaps were predictors of bone mass in both genders. During midpuberty, appendicular LMI and gonadal steroids positively contributed to bone mass in both genders, while osteocalcin exerted a negative influence on total and L1–L4 spine BMD in girls and on L1–L4 BMD in boys (all p < 0.001). Conclusions: Predictors for bone development varied according to Tanner stage and gender. The most significant determinants of bone mass were appendicular LMI and estradiol.

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.

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.