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Összefoglaló. Bevezetés: Az 1-es típusú diabetes mellitus és a coeliakia gyakori társulása jól ismert. Néhány tanulmány beszámol átmeneti antitranszglutamináz-emelkedésről 1-es típusú diabeteses betegekben, akiknél az emelkedett antitestszint gluténmentes diéta bevezetése nélkül normalizálódik. Célkitűzés: Kutatásunk során az átmeneti antitranszglutamináz-emelkedés gyakoriságának meghatározását tűztük ki célul. További célunk volt a coeliakia gyakoriságának megállapítása 1-es típusú diabetesszel gondozott betegeink között. Módszer: A Semmelweis Egyetem I. Gyermekgyógyászati Klinikáján 1-es típusú diabetesszel gondozott betegeket vontuk be vizsgálatunkba (238 lány, 265 fiú, medián [IR] életkor az 1-es típusú diabetes diagnózisakor: 7,83 [4,67–11] év). Vizsgáltuk a jelenség időbeli megjelenését, az emelkedés mértékét, gyakoriságát és az antitest típusát. Leíró statisztikai módszereket és khi-négyzet-próbát alkalmaztunk. Eredmények: A vizsgált populációban a coeliakia gyakorisága 12,52%. Átmeneti antitranszglutamináztiter-emelkedést 48 gyermeknél (10,9%) észleltünk. Összesen 71-szer mértünk átmeneti antitranszglutamináz-emelkedést. A gyermekek közül 34 esetben (70,83%) egyszer fordult elő emelkedést mutató antitest, a többi betegnél 2–8 alkalommal. Gyakrabban tapasztaltunk izolált IgA-típusú emelkedést, mint izolált IgG-típusút (54 vs. 5). Következtetés: Az átmeneti antitranszglutamináz-emelkedés gyakorisága magas, összevethető a valódi coeliakiás csoporttal. Kutatásunk alátámasztja a nemzetközi ajánlást, miszerint mérsékelt mértékű antitranszglutamináz-emelkedés esetén, tünetmentes 1-es típusú diabetesszel gondozott betegben a gluténfogyasztás folytatása és az antitestszintek gyakori kontrollja javasolt. Orv Hetil. 2021; 162(48): 1924–1930. Summary. Introduction: The frequent association of type 1 diabetes mellitus with coeliac disease is well known. Development of transitional elevation of anti-tissue transglutaminase antibodies in the diagnosis of type 1 diabetes is reported in some studies. In these cases, the anti-tissue transglutaminase antibodies returned to normal without gluten-free diet. Objective: Our aim was to assess the frequency of transitional elevation of anti-tissue transglutaminase in our type 1 diabetes patients. We aimed to investigate the prevalence of coeliac disease in patients with type 1 diabetes. Method: Patients with type 1 diabetes at the Ist Department of Paediatrics, Semmelweis University, were enrolled in the study (238 girls, 265 boys; the median age at the time of type 1 diabetes diagnosis was 7.83 [4.67–11] years). Descriptive statistical analysis was done and the time of appearance, extent, frequency and type of elevated anti-tissue transglutaminase antibodies were examined. Results: The proportion of children with diagnosed coeliac disease was 12.52%. We detected transitional anti-tissue transglutaminase elevation in 48 cases (10.9%). Temporarily elevated antibody levels were measured 71 times. In 34 children (70.83%), the temporary elevation occured once, while in the others, antibody levels became positive 2–8 times. The elevation of the IgA antibody was more frequent than the elevation of the IgG antibody (54 vs. 5). Conclusion: The frequency of temporary elevated anti-tissue transglutaminase levels is considered high. Our study confirms the recommendation that in the case of moderate anti-tissue transglutaminase levels with lack of clinical symptoms, control antibody measurement is necessary with ongoing gluten consumption. Orv Hetil. 2021; 162(48): 1924–1930.

Sex and gender are essential, inalienable characteristics of the human being permeating the biological, psychological, interpersonal, social, transcendental aspects of our existence. Human sexual development takes place in the context of physical, emotional, cognitive, and social development, beginning at conception and continuing throughout life. It is influenced by biological maturation and complex interactions of psychological, interpersonal, cultural factors and (physical) environmental conditions. Using a developmental-psychopathology approach, we summarise our under standing of the life course-specific features of sexual development, placing them in the broader context of development. We will address gender differences, the development of gender-related concepts, sexual orientation, gender identity, and the development of sexual behaviour at different stages of life. In the field of sexual development and gender, science is often pushed to its limits. It is important that professionals express their opinions and make their decisions with due caution and objectivity.

Objective Despite published guidelines no unified approach to hormone replacement in congenital adrenal hyperplasia (CAH) exists. We aimed to explore geographical and temporal variations in the treatment with glucocorticoids and mineralocorticoids in CAH. Design This retrospective multi-center study, including 31 centers (16 countries), analyzed data from the International-CAH Registry. Methods Data were collected from 461 patients aged 0–18 years with classic 21-hydroxylase deficiency (54.9% females) under follow-up between 1982 and 2018. Type, dose and timing of glucocorticoid and mineralocorticoid replacement were analyzed from 4174 patient visits. Results The most frequently used glucocorticoid was hydrocortisone (87.6%). Overall, there were significant differences between age groups with regards to daily hydrocortisone-equivalent dose for body surface, with the lowest dose (median with interquartile range) of 12.0 (10.0–14.5) mg/m2/day at age 1–8 years and the highest dose of 14.0 (11.6–17.4) mg/m2/day at age 12–18 years. Glucocorticoid doses decreased after 2010 in patients 0–8 years (P < 0.001) and remained unchanged in patients aged 8–18 years. Fludrocortisone was used in 92% of patients, with relative doses decreasing with age. A wide variation was observed among countries with regards to all aspects of steroid hormone replacement. Conclusions Data from the I-CAH Registry suggests international variations in hormone replacement therapy, with a tendency to treatment with high doses in children.

Background Although congenital adrenal hyperplasia (CAH) is known to be associated with adrenal crises (AC), its association with patient- or clinician-reported sick day episodes (SDE) is less clear. Methods Data on children with classic 21-hydroxylase deficiency CAH from 34 centers in 18 countries, of which 7 were Low or Middle Income Countries (LMIC) and 11 were High Income (HIC), were collected from the International CAH Registry and analyzed to examine the clinical factors associated with SDE and AC. Results A total of 518 children—with a median of 11 children (range 1, 53) per center—had 5388 visits evaluated over a total of 2300 patient-years. The median number of AC and SDE per patient-year per center was 0 (0, 3) and 0.4 (0.0, 13.3), respectively. Of the 1544 SDE, an AC was reported in 62 (4%), with no fatalities. Infectious illness was the most frequent precipitating event, reported in 1105 (72%) and 29 (47%) of SDE and AC, respectively. On comparing cases from LMIC and HIC, the median SDE per patient-year was 0.75 (0, 13.3) vs 0.11 (0, 12.0) (P Conclusions The real-world data that are collected within the I-CAH Registry show wide variability in the reported occurrence of adrenal insufficiency–related adverse events. As these data become increasingly used as a clinical benchmark in CAH care, there is a need for further research to improve and standardize the definition of SDE.

Abstract: Introduction: It is known that lactate concentration is increased in diabetic ketoacidosis (DKA), however, the pathophysiology and kinetics of lactate changes are still unclear. Normally, L-lactate is the major form in the human body. According to previous data, also D- and L-lactate might be increased in hyperglycaemic disorders. Aim: We aimed to describe the kinetics and mechanisms of lactate concentration changes in ketoacidosis and newly diagnosed diabetes. Method: We performed a prospective study, including 5–18-year-old children with ketoacidosis (DKA, n = 13) and with newly diagnosed type 1 diabetes without ketoacidosis (T1DM, n = 6). We performed routine blood gas analysis 0–12–24–48 hours after admission, which also measured L-lactate levels. We also determined total venous serum lactate level by gas chromatography–mass spectrometry. Results: Initial plasma lactate concentration was increased in ketoacidosis as compared to the newly diagnosed diabetes group (p

MODY2 is caused by heterozygous inactivating mutations in the glucokinase (GCK) gene that result in persistent, stable and mild fasting hyperglycaemia (5.6–8.0 mmol/L, glycosylated haemoglobin range of 5.6–7.3%). Patients with GCK mutations usually do not require any drug treatment, except during pregnancy. The GCK gene is considered to be responsible for about 20% of all MODY cases, transcription factors for 67% and other genes for 13% of the cases. Based on our findings, GCK and HNF1A mutations together are responsible for about 90% of the cases in Hungary, this ratio being higher than the 70% reported in the literature. More than 70% of these patients have a mutation in the GCK gene, this means that GCK-MODY is the most prevalent form of MODY in Hungary. In the 91 index patients and their 72 family members examined, we have identified a total of 65 different pathogenic (18) and likely pathogenic (47) GCK mutations of which 28 were novel. In two families, de novo GCK mutations were detected. About 30% of the GCK-MODY patients examined were receiving unnecessary OAD or insulin therapy at the time of requesting their genetic testing, therefore the importance of having a molecular genetic diagnosis can lead to a major improvement in their quality of life.

Összefoglaló. Bevezetés: Az 1-es típusú diabetes mellitus és a coeliakia gyakori társulása jól ismert. Néhány tanulmány beszámol átmeneti antitranszglutamináz-emelkedésről 1-es típusú diabeteses betegekben, akiknél az emelkedett antitestszint gluténmentes diéta bevezetése nélkül normalizálódik. Célkitűzés: Kutatásunk során az átmeneti antitranszglutamináz-emelkedés gyakoriságának meghatározását tűztük ki célul. További célunk volt a coeliakia gyakoriságának megállapítása 1-es típusú diabetesszel gondozott betegeink között. Módszer: A Semmelweis Egyetem I. Gyermekgyógyászati Klinikáján 1-es típusú diabetesszel gondozott betegeket vontuk be vizsgálatunkba (238 lány, 265 fiú, medián [IR] életkor az 1-es típusú diabetes diagnózisakor: 7,83 [4,67-11] év). Vizsgáltuk a jelenség időbeli megjelenését, az emelkedés mértékét, gyakoriságát és az antitest típusát. Leíró statisztikai módszereket és khi-négyzet-próbát alkalmaztunk. Eredmények: A vizsgált populációban a coeliakia gyakorisága 12,52%. Átmeneti antitranszglutamináztiter-emelkedést 48 gyermeknél (10,9%) észleltünk. Összesen 71-szer mértünk átmeneti antitranszglutamináz-emelkedést. A gyermekek közül 34 esetben (70,83%) egyszer fordult elő emelkedést mutató antitest, a többi betegnél 2-8 alkalommal. Gyakrabban tapasztaltunk izolált IgA-típusú emelkedést, mint izolált IgG-típusút (54 vs. 5). Következtetés: Az átmeneti antitranszglutamináz-emelkedés gyakorisága magas, összevethető a valódi coeliakiás csoporttal. Kutatásunk alátámasztja a nemzetközi ajánlást, miszerint mérsékelt mértékű antitranszglutamináz-emelkedés esetén, tünetmentes 1-es típusú diabetesszel gondozott betegben a gluténfogyasztás folytatása és az antitestszintek gyakori kontrollja javasolt. Orv Hetil. 2021; 162(48): 1924-1930.The frequent association of type 1 diabetes mellitus with coeliac disease is well known. Development of transitional elevation of anti-tissue transglutaminase antibodies in the diagnosis of type 1 diabetes is reported in some studies. In these cases, the anti-tissue transglutaminase antibodies returned to normal without gluten-free diet.Our aim was to assess the frequency of transitional elevation of anti-tissue transglutaminase in our type 1 diabetes patients. We aimed to investigate the prevalence of coeliac disease in patients with type 1 diabetes.Patients with type 1 diabetes at the Ist Department of Paediatrics, Semmelweis University, were enrolled in the study (238 girls, 265 boys; the median age at the time of type 1 diabetes diagnosis was 7.83 [4.67-11] years). Descriptive statistical analysis was done and the time of appearance, extent, frequency and type of elevated anti-tissue transglutaminase antibodies were examined.The proportion of children with diagnosed coeliac disease was 12.52%. We detected transitional anti-tissue transglutaminase elevation in 48 cases (10.9%). Temporarily elevated antibody levels were measured 71 times. In 34 children (70.83%), the temporary elevation occured once, while in the others, antibody levels became positive 2-8 times. The elevation of the IgA antibody was more frequent than the elevation of the IgG antibody (54 vs. 5).The frequency of temporary elevated anti-tissue transglutaminase levels is considered high. Our study confirms the recommendation that in the case of moderate anti-tissue transglutaminase levels with lack of clinical symptoms, control antibody measurement is necessary with ongoing gluten consumption. Orv Hetil. 2021; 162(48): 1924-1930.

Introduction: 46,XX ovotesticular disorder of sex development (DSD), as defined by the Chicago consensus in 2006, is characterized by histologically confirmed testicular and ovarian tissue in an individual with a 46,XX karyotype and a wide phenotypic spectrum from female to male appearance. Case Presentation: We report the case of two 46,XX sex determining region Y (SRY) gene-negative siblings and their 46,XY father with an approximately 150 kilobase pair (kbp) duplication upstream of SOX9 (SRY-box 9) gene’s transcriptional start site on chromosome 17 (chr17), which involved SOX9’s minimal critical 46,XX sex reversal region. This duplication is sufficient to trigger male development in the absence of Y-chromosomal material and can lead to various degrees of masculinization in 46,XX individuals by overexpression of SOX9. Based on anamnestic information and pedigree analysis, another possible carrier of this copy number variation (CNV) could have been the father’s sister. Discussion: By comparing the duplications of our two sibling patients and previously reported similar cases, we suggest that the small differences between their breakpoints could alternatively modify the inner structure and functioning of SOX9’stopologically associated domain (TAD) due to the differing fine TAD arrangements. Our data support the phenotypic modularity impact – incomplete penetrance and variable expressivity – of very similar but non-identical CNVs, which are possibly inherited across three generations.

Abstract: Congenital adrenal hyperplasia is a group of genetic diseases due to the disablement of 7 genes; one of them is steroid 21-hydroxylase deficiency. The genes of congenital adrenal hyperplasia encode enzymes taking part in the steroidogenesis of adrenal gland. Steroid 21-hydroxylase deficiency is an autosomal recessive disorder caused by mutations of the steroid 21-hydroxylase gene. The mutations of steroid 21-hydroxylase gene cause 95% of the congenital adrenal hyperplasia cases. Although the non-classic steroid 21-hydroxylase deficiency with mild symptoms is seldom diagnosed, the classic steroid 21-hydroxylase deficiency may lead to life-threatening salt-wasting and adrenal crises due to the insufficient aldosterone and cortisol serum levels. The classic type requires life-long steroid replacement which may result in cushingoid side effects, and typical comorbidities may be also developed. The patients’ quality of life is decreased, and their mortality is much higher than that of the population without steroid 21-hydroxylase deficiency. The diagnosis, consequences and the patients’ life-long clinical care require a multidisciplinary approach: the specialists in pediatrics, internal medicine, endocrinology, laboratory medicine, genetic diagnostics, surgery, obstetrics-gynecology and psychology need to work together. Orv Hetil. 2018; 159(7): 269–277.

Abstract: 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

Abstract: Introduction: Attenuated androgens are used for the prevention of angioedema attacks of hereditary angioedema with C1-inhibitor deficiency. After prepuberty, their use can lead to growth retardation. Aim: We assessed the effect of danazol on the growth of pediatric patients with hereditary angioedema. Method: In the retrospective study on 42 patients diagnosed with hereditary angioedema, we calculated the deviation from the mid-parental target height, and analyzed it against the gender, the dose and duration of danazol treatment administered before the age of 21 years and before the age of 16 years. Results: Regarding the deviation from the mid-parental target height, we did not find any significant difference between patients taking vs. not taking danazol, males vs. females taking danazol. The dose and the duration of danazol treatment did not influence that value neither before 21, nor before 16 years of age. Conclusions: Our findings suggest that treatment with the lowest effective doses of danazol does not influence growth. Orv Hetil. 2017; 158(32): 1269–1276.

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.

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.

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.

Congenital adrenal hyperplasia is a group of genetic diseases due to the disablement of 7 genes; one of them is steroid 21-hydroxylase deficiency. The genes of congenital adrenal hyperplasia encode enzymes taking part in the steroidogenesis of adrenal gland. Steroid 21-hydroxylase deficiency is an autosomal recessive disorder caused by mutations of the steroid 21-hydroxylase gene. The mutations of steroid 21-hydroxylase gene cause 95% of the congenital adrenal hyperplasia cases. Although the non-classic steroid 21-hydroxylase deficiency with mild symptoms is seldom diagnosed, the classic steroid 21-hydroxylase deficiency may lead to life-threatening salt-wasting and adrenal crises due to the insufficient aldosterone and cortisol serum levels. The classic type requires life-long steroid replacement which may result in cushingoid side effects, and typical comorbidities may be also developed. The patients' quality of life is decreased, and their mortality is much higher than that of the population without steroid 21-hydroxylase deficiency. The diagnosis, consequences and the patients' life-long clinical care require a multidisciplinary approach: the specialists in pediatrics, internal medicine, endocrinology, laboratory medicine, genetic diagnostics, surgery, obstetrics-gynecology and psychology need to work together. Orv Hetil. 2018; 159(7): 269-277.

According to the international literature, DNA methylation analysis of the promoter region of SNRPN locus is the most efficient way to start genetic investigation in patients with suspected Prader-Willi syndrome.Our aim was to develop a simple, reliable first-tier diagnosis to confirm Prader-Willi syndrome, therefore to compare our self-designed simple, cost-efficient high-resolution melting analysis and the most commonly used methylation-specific multiplex ligation-dependent probe amplification to confirm Prader-Willi syndrome.We studied 17 clinically suspected Prader-Willi syndrome children and their DNA samples. With self-designed primers, bisulfite-sensitive polymerase chain reaction, high-resolution melting analysis and, as a control, methylation-specific multiplex ligation-dependent probe amplification were performed.Prader-Willi syndrome was genetically confirmed in 6 out of 17 clinically suspected Prader-Willi syndrome patients. The results of high-resolution melting analysis and methylation-specific multiplex ligation-dependent probe amplification were equivalent in each case.Using our self-designed primers and altered bisulfite-specific PCR conditions, high-resolution melting analysis appears to be a simple, fast, reliable and effective method for primarily proving or excluding clinically suspected Prade-Willi syndrome cases. Orv Hetil. 2018; 159(2): 64-69.

OBJECTIVE: 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). METHODS: Data were collected from 55 centers with documented patients' height. All subjects below 20 years of age, diabetes duration >1 year, and without celiac disease were included. World Health Organization growth charts were used to calculate height and body mass index z-scores. Multiple hierarchic regression models adjusting for known confounders were applied. RESULTS: Data on 22 941 subjects (51.8% male) were analyzed with a median and interquartile range for age 14.8 years (11.2, 17.6), diabetes duration 5.6 years (3.1, 8.9), and height z-score 0.34 (-0.37, 1.03). Children were taller in the youngest age groups: adjusted height z-scores of 0.31 (±0.06) and 0.39 (±0.06), respectively; with shorter diabetes duration (three injections/day and 0.19 ± 0.06 [0-3 injections daily]), respectively. High hemoglobin A1c (HbA1c) and low to normal weight were associated with a lower height z-score. Trends were identical in all models except for gender. No gender differences were found except in the final height model where females exhibited higher z-score than males. CONCLUSION: For youths treated at centers offering modern diabetes management, major growth disturbances are virtually eliminated. For children with a young age at onset, high HbA1c, injections, and/or non-intensive diabetes, treatment still requires attention in order to attain normal growth.

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.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.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.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, p0.02) 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.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.

Attenuated androgens are used for the prevention of angioedema attacks of hereditary angioedema with C1-inhibitor deficiency. After prepuberty, their use can lead to growth retardation.We assessed the effect of danazol on the growth of pediatric patients with hereditary angioedema.In the retrospective study on 42 patients diagnosed with hereditary angioedema, we calculated the deviation from the mid-parental target height, and analyzed it against the gender, the dose and duration of danazol treatment administered before the age of 21 years and before the age of 16 years.Regarding the deviation from the mid-parental target height, we did not find any significant difference between patients taking vs. not taking danazol, males vs. females taking danazol. The dose and the duration of danazol treatment did not influence that value neither before 21, nor before 16 years of age.Our findings suggest that treatment with the lowest effective doses of danazol does not influence growth. Orv Hetil. 2017; 158(32): 1269-1276.

There is a difficulty in the molecular diagnosis of congenital adrenal hyperplasia (CAH) due to the c.955C>T (p.(Q319*), formerly Q318X, rs7755898) variant of the CYP21A2 gene. Therefore, a systematic assessment of the genetic and evolutionary relationships between c.955C>T, CYP21A2 haplotypes and the RCCX copy number variation (CNV) structures, which harbor CYP21A2, was performed. In total, 389 unrelated Hungarian individuals with European ancestry (164 healthy subjects, 125 patients with non-functioning adrenal incidentaloma and 100 patients with classical CAH) as well as 34 adrenocortical tumor specimens were studied using a set of experimental and bioinformatic methods. A unique, moderately frequent (2%) haplotypic RCCX CNV structure with three repeated segments, abbreviated to LBSASB, harboring a CYP21A2 with a c.955C>T variant in the 3'-segment, and a second CYP21A2 with a specific c.*12C>T (rs150697472) variant in the middle segment occurred in all c.955C>T carriers with normal steroid levels. The second CYP21A2 was free of CAH-causing mutations and produced mRNA in the adrenal gland, confirming its functionality and ability to rescue the carriers from CAH. Neither LBSASB nor c.*12C>T occurred in classical CAH patients. However, CAH-causing CYP21A2 haplotypes with c.955C>T could be derived from the 3'-segment of LBSASB after the loss of functional CYP21A2 from the middle segment. The c.*12C>T indicated a functional CYP21A2 and could distinguish between non-pathogenic and pathogenic genomic contexts of the c.955C>T variant in the studied European population. Therefore, c.*12C>T may be suitable as a marker to avoid this genetic confound and improve the diagnosis of CAH.

Objective: Congenital adrenal hyperplasia (CAH) shows a range of severity which is explained in part by the different mutations of the CYP21 gene. To better understand the incomplete concordance between genotype and phenotype in CAH the role of the sensitizing N363S polymorphism of the glucocorticoid receptor (GR) was examined in CAH patients. Design: CAH patients were screened for N363S. Laboratory findings and clinical characteristics of carriers and non-carriers were analyzed retrospectively. Methods: The CYP21 gene of 200 CAH patients was analyzed by allele-specific PCR. The GR gene was tested for N363S by PCR followed by restriction fragment length polymorphism. Antropometric data (height, weight), degree of intrauterine virilization, hormone concentrations (17-OH-progesterone, dehydroepiandrosterone (DHEA), aldosterone, testosterone, plasma renin activity), substitution doses and clinical course were analyzed. Results: The carrier frequency of N363S in CAH patients was equivalent to that of the general Hungarian population (6% vs 7.8%). Interestingly, none of the non-classical CAH (NC-CAH) patients were carriers of the polymorphism. Carrier girls had milder genital virilization than mutation-matched non-carrier controls. There was no significant difference between the carriers and non-carriers in either the substitution doses, the hormonal, or the auxiological parameters. Conclusions: The association of sensitizing the GR variant with impaired cortisol production in CAH might be compensatory in mild NC-CAH and may prevent severe intrauterine virilization in classical form. Although the exact role of N363S in extrauterine life should be further investigated, the consideration of certain genetic polymorphisms of CAH patients may lead to better, individualized therapeutic regimes.

The mechanisms of sodium retention in edema-forming minimal change nephrotic syndrome (MCNS) have not been completely evaluated. The aim of this study was to characterize the transmembrane sodium transport in nephrotic syndrome by measuring the erythrocyte sodium-lithium countertransport (SLC) in vitro. Eighteen children with MCNS were studied in the edema-forming state, and subsequently at the beginning of remission. Nephrotic children with edema retained sodium (10+/-12 micromol/day) and had a higher SLC [426+/-118 vs. 281+/-60 micromol/l red blood cells (RBC) per hour, P=0.003). The intracellular sodium concentration of nephrotics was 6.1+/-2.1 mmol/l RBC, which did not differ from that of controls (6.42+/-2.24, n=13). In remission sodium balance became negative (-30+/-21 mmol/day), and the SLC decreased but still differed significantly from control values (P=0.009). The intracellular sodium content decreased to 4.4+/-0.9 mmol/l RBC (P=0.002). There was a negative correlation between erythrocyte SLC and plasma albumin concentration (r=0.48, P=0.003), and urinary sodium excretion rate (r=0.66, P=0.001). In conclusion, erythrocyte SLC is high in the edema-forming state of childhood nephrotic syndrome and decreases with the onset of remission. A role for the SLC in the altered sodium homeostasis of nephrotic syndrome is suggested.

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.

Nucleotide sequence variants of the glucocorticoid receptor gene and their significance in determining glucocorticoid sensitivity. The physiologic response and sensitivity to glucocorticoids may significantly differ among species, individuals, tissues and cell types. The variability of the effect of endogenous and exogenous glucocorticoids is largely determined by genetic components, of which the authors review the knowledge on the glucocorticoid receptor gene. The authors describe the genomic and non-genomic pathways of receptor function, the significance of isoforms produced during receptor protein formation, the pathomechanism of glucocorticoid resistance syndrome and the results of clinical investigations related to receptor gene polymorphisms. Through subtle alteration of receptor function, the gene polymorphisms may increase or diminish sensitivity to glucocorticoids and may play a role in the pathogenesis of metabolic disorders. In their own studies the authors found, that the N363S polymorphism, which increases glucocorticoid sensitivity, may play a role in the pathogenesis of bilateral adrenal adenomas, it may modify the clinical phenotype of patients with congenital adrenal hyperplasia, and may have an impact on steroid-induced ocular hypertension. It is presumed that further research in other diseases will continue to complete our knowledge on the pathophysiology of glucocorticoid receptor gene polymorphisms.

In the androgen insensitivity syndrome (AIS) the androgen effect is decreased in the fetus and the youth despite the adequate testosterone production. Usually the mutation of the androgen receptor is responsible for the disease. In the presented case the external genitalia were similar to female genitalia but masses were palpable in the labioscrotal fold. The karyotype was 46,XY. There was no increase in the testosterone level during the first three months of life. The stimulation test by stanazolol and the androgen receptor gene analysis verified the androgen insensitivity. The mutation was absent in the mother's leukocytes. This fact makes the genetic advising difficult in this family.

A case of pancreatic acinar cell tumor (ACC) is presented in a 10-year-old boy. The tumor manifested clinically with Cushing's syndrome, high serum adrenocorticotropic hormone (ACTH) and cortisol concentrations. In addition, excessive serum levels of alpha-fetoprotein (AFP) were detected. Surgical resection was not possible due to retroperitoneal invasion. Biopsy of the mass showed a solid, poorly differentiated ACC of the pancreas. Periodic acid Schiff positive cytoplasmic granules, trypsinogen, keratins, alpha-1-antitrypsin, and AFP were identified in the tumor cells. Electron microscopy demonstrated zymogen granules as well as isolated dense core granules. Using immunochemiluminometric assay, a high quantity of ACTH was found in the fresh frozen tumor extract. ACTH, chromogranin A, and corticotropin-releasing factor were identified only in a few cells by immunohistochemistry. Combined radiochemotherapy was temporarily effective in reducing the tumor mass and serum AFP. Serum ACTH and cortisol levels dropped progressively and definitively to normal values after chemotherapy, and the Cushing's syndrome subsided. Two years later, the patient died with metastatic disease. The presented case of ACC is interesting due to high serum AFP values and ectopic ACTH secretion resulting in Cushing's syndrome.

Patients with cystic fibrosis (CF) exhibit normal concentrations of sodium and chloride in spite of the disturbance of Cl- and Na+ transport in epithelial cells. To characterize compensatory mechanisms in the regulation of sodium homeostasis, erythrocytes of 13 CF patients were analysed for sodium-lithium counter-transport (SLC), Na+/K(+)-ATPase activity and intracellular sodium content. Values were compared to those of healthy controls. Patients with CF had normal serum sodium and chloride concentrations and renal excretions of these ions were within the physiological range. Intracellular sodium concentration was similar in the CF and the control group (6.8 +/- 2.2 vs 5.7 +/- 1.0 mmol/l RBCs). Red blood cells' SLC and Na+/ K(+)-ATPase activity were elevated in CF patients (381 +/- 106 mumol/h/l RBCs vs 281 +/- 64; p < 0.01) and (445 +/- 129 mumol ATP mg prot/h vs 322 +/- 84, p < 0.01). Our study demonstrates that transmembrane cation transport systems are highly activated in CF. The increased sodium transport may be part of a compensatory mechanism of sodium homeostasis in children with CF.