Substantial proportion of MODY among multiplex families participating in a Type 1 diabetes prediction programme.

AIMS: Patients with maturity-onset diabetes of the young (MODY) might be over-represented in families with histories of Type 1 diabetes. Our aim was to re-evaluate families participating in the Czech T1D Prediction Programme (PREDIA.CZ) with at least two members affected with diabetes to assess the proportion of MODY among these families and determine its most significant clinical predictors. METHODS: Of the 557 families followed up by the PREDIA.CZ, 53 (9.5%) had two or more family members with diabetes. One proband with diabetes from these families was chosen for direct sequencing of the GCK, HNF1A, HNF4A and INS genes. Non-parametric tests and a linear logistic regression model were used to evaluate differences between MODY and non-MODY families. RESULTS: MODY was genetically diagnosed in 24 of the 53 families with multiple occurrences of diabetes (45%). Mutations were detected most frequently in GCK (58%), followed by HNF1A (38%) and INS (4%). MODY families were more likely to have a parent with diabetes and had a higher proportion of females with diabetes than non-MODY families. Higher age (P < 0.001), a lower level of HbA1c (P < 0.001) at clinical onset and at least two generations affected by diabetes were the variables most predictive for probands of MODY families already presenting with diabetes. CONCLUSIONS: A prediction programme for Type 1 diabetes would provide a useful new source of patients with MODY most likely to benefit from an accurate diagnosis. This identification has implications for patient treatment and disease prognosis.

The dynamic changes of zinc transporter 8 autoantibodies in Czech children from the onset of Type 1 diabetes mellitus.

AIMS: The prevalence of autoantibodies to zinc transporter 8 (ZnT8) in Czech children at the onset of Type 1 diabetes mellitus and dynamic changes in ZnT8 autoantibody levels during disease progression were studied. The value of ZnT8 autoantibody measurements in diagnosis of Type 1 diabetes was assessed. METHODS: Serum samples from 227 children with newly diagnosed Type 1 diabetes and from 101 control children without diabetes were analysed in a retrospective cross-sectional study. One hundred and seventy-one samples from 116 of the patients with diabetes were analysed in a follow-up study at (median) intervals of 1, 3, 5 and 10 years after onset of Type 1 diabetes. ZnT8 autoantibodies were measured using a bridging enzyme-linked immunosorbent assay, while antibodies to glutamic acid decarboxylase, insulinoma antigen 2 and insulin were measured by radioimmunoassays. RESULTS: ZnT8 autoantibodies were detected in 163/227 (72%) of children at Type 1 diabetes onset and in 1/101 (1%) of the control subjects. Sixteen out of 227 (7%) patients with Type 1 diabetes were antibody negative based on three antibodies (glutamic acid decarboxylase, insulinoma antigen 2 and insulin). This false-negative rate was reduced to 10/227 (4.4%) (P < 0.05) after inclusion of ZnT8 autoantibody measurements. Of the children, 142/227 (63%) were positive for at least three antibodies and the most common combination was insulinoma antigen 2, glutamic acid decarboxylase and ZnT8. ZnT8 autoantibody levels decreased over time after Type 1 diabetes onset and the presence and level of ZnT8 autoantibodies correlated with IA-2 autoantibodies. CONCLUSIONS: A ZnT8 autoantibody enzyme-linked immunosorbent assay showed 72% disease sensitivity and 99% specificity at Type 1 diabetes onset. Measurements of ZnT8 autoantibodies are important for Type 1 diabetes diagnosis and should be included in the panel of autoantibodies tested at the onset of Type 1 diabetes.

Low-carbohydrate diet in children and young people with type 1 diabetes: A randomized controlled trial with cross-over design.

AIMS: We investigated whether a short period of tightly controlled low-carbohydrate diet (LCD) leads to higher time in range without increasing the associated risks in children and young people with diabetes (CYPwD). METHODS: Thirty-five (CYPwD) were recruited into this randomized controlled cross-over study (20 female; 20 CSII; age 14.5 ± 2.9 years; HbA1c 48.9 ± 9.4 mmol/mol). The interventions were five and five weeks of ready-made food box deliveries of isocaloric diets in random order: either LCD (94.5 ± 4.7 g/day) or recommended carbohydrate diet (RCD) (191 ± 19.2 g/day). The outcomes were continuous glucose monitoring parameters, anthropometric, laboratory and quality of life (QoL) data. RESULTS: Time in range was significantly higher in the LCD than in the RCD period (77.1 % vs. 73.8 %, P=0.008). Times in hyperglycemia and average glycaemia were significantly lower in the LCD. There was no difference between the diets in time in hypoglycemia or glycemic variability. The subjects' body weight and BMI were significantly lower during the LCD. There was no significant difference in the LDL-cholesterol levels. No significant differences were observed in the self-assessed QoL. CONCLUSIONS: Short-term LCD led to an improvement of glycemic parameters without increasing time in hypoglycemia, disturbing the lipid profile or negatively affecting the quality of life of CYPwD.

Introduction of continuous glucose monitoring (CGM) is a key factor in decreasing HbA1c in war refugee children with type 1 diabetes.

AIMS: Our aim was to describe the changes in therapy and diabetes control in Ukrainian war refugee children with diabetes (CwD) during the first year of their stay in Czechia. METHODS: A total of 124 CwD (62 male, 62 female) were enrolled into this observational study. Anthropometric, laboratory and diabetes management data were acquired at baseline and at 3 months intervals for 12 months. All CwD were offered a CGM device during their first visit. Generalized Estimating Equation models were fitted in order to estimate the dynamics of studied characteristics. RESULTS: Median baseline HbA1c was 58 mmol/mol (IQR [48; 73]mmol/mol) (7.5 %, IQR[6.5;8.8]%). The HbA1c decreased significantly throughout the course of the study at a pace of - 2.2 mmol/mol (-0.2 %pt.) per visit (P = 0.01, CI[-3.2;-1.1]). The pace of the decrease in the average HbA1c was significantly higher in the group of CwD who received CGM in Czechia than in those who already had it from Ukraine by 2.9 mmol/mol (0.27 %pt.) per visit (P < 0.001, CI [-4.4; -1.3]). CONCLUSIONS: The steepest decrease in HbA1c was observed in CwD with newly initiated CGM underlining its vital role in improving the glucose control of CwD regardless of their background.

Healthy first-degree relatives of patients with type 1 diabetes exhibit significant differences in basal gene expression pattern of immunocompetent cells compared to controls: expression pattern as predeterminant of autoimmune diabetes.

Expression features of genetic landscape which predispose an individual to the type 1 diabetes are poorly understood. We addressed this question by comparing gene expression profile of freshly isolated peripheral blood mononuclear cells isolated from either patients with type 1 diabetes (T1D), or their first-degree relatives or healthy controls. Our aim was to establish whether a distinct type of 'prodiabetogenic' gene expression pattern in the group of relatives of patients with T1D could be identified. Whole-genome expression profile of nine patients with T1D, their ten first-degree relatives and ten healthy controls was analysed using the human high-density expression microarray chip. Functional aspects of candidate genes were assessed using the MetaCore software. The highest number of differentially expressed genes (547) was found between the autoantibody-negative healthy relatives and the healthy controls. Some of them represent genes critically involved in the regulation of innate immune responses such as TLR signalling and CCR3 signalling in eosinophiles, humoral immune reactions such as BCR pathway, costimulation and cytokine responses mediated by CD137, CD40 and CD28 signalling and IL-1 proinflammatory pathway. Our data demonstrate that expression profile of healthy relatives of patients with T1D is clearly distinct from the pattern found in the healthy controls. That especially concerns differential activation status of genes and signalling pathways involved in proinflammatory processes and those of innate immunity and humoral reactivity. Thus, we posit that the study of the healthy relative's gene expression pattern is instrumental for the identification of novel markers associated with the development of diabetes.

Glucose evaluation trial for remission (GETREM) in type 1 diabetes: a European multicentre study.

OBJECTIVE: Strict metabolic control during the 1st year of type 1 diabetes is thought to be a key factor for achieving clinical remission. The aims of this study were two-fold: (i) to evaluate the frequency and duration of spontaneous remission (defined according to the parameters issued by the International Diabetic Immunotherapy Group (IDIG)) in a European population of consecutive recent onset type 1 diabetes patients (aged 5-35 years), followed-up for a period of 36 months with a common protocol of intensive insulin therapy and without adjunct immune-intervention; and (ii) to identify the predictive factors for clinical remission. RESEARCH DESIGN AND METHOD: A total of 189 consecutive patients with newly diagnosed type 1 diabetes according to ADA criteria were recruited in participating centres (Belgium, Czech Republic, Estonia, France, Germany, Hungary, Italy, Poland, Romania, Sweden and Turkey) and followed-up for a period of up to 36 months. In all patients, intensive insulin therapy was implemented consisting of three or four injections of regular insulin daily with NPH insulin at bedtime. Adjustment of insulin dose was made according to a common protocol. Various clinical characteristics (age, gender, severity of presentation, etc.), history (presence of diabetic siblings in the family, etc.) and integrated parameters of metabolic control (HbA(1c), blood glucose, the total insulin dose at hospital discharge adjusted for body weight) were collected. RESULTS: Twenty-two patients (11.6%) experienced remission. The median duration of remission was 9.6 months and the range was 31 months. There was a wide variation among centres. Logistic regression analysis focused on the centre as the main variable in achieving remission. CONCLUSION: Remission was shown to be very heterogeneous between centres depending on 'other factors' such as patient care and family awareness of the disease rather than on 'measurable factors' such as sex, age, HbA(1c) and severity of presentation at diagnosis. Using intensive insulin therapy and optimisation of metabolic control, remission occurred in nearly one out of eight patients.

Severe hypoglycemia and reduction of insulin requirement in a girl with insulin-dependent diabetes mellitus: first sign of a craniopharyngioma.

A girl with a history of insulin-dependent diabetes mellitus since 5.5 years, and Hashimoto's thyroiditis since 12 years, developed episodes of severe hypoglycemia from the age of 12 years. This was associated with falling insulin requirements, from 0.78 U/kg/day at 11 years to 0.34 U/kg/day at 16 years. At 16 years she was found to have GH, gonadotropin, ACTH, and probably also TSH deficiency with hyperprolactinemia. MRI scan revealed a cystic intrasellar craniopharyngioma with moderate suprasellar extension. In spite of cortisol replacement at 17 years, insulin requirement fell further to 0.25 U/kg/day at 18 years. In this girl, decreasing insulin requirements represented an early manifestation of combined growth hormone and cortisol deficiency.

HLA-DQ polymorphisms modify the risk of thyroid autoimmunity in children with type 1 diabetes mellitus.

OBJECTIVE: Type 1 diabetes mellitus (DM1) is frequently accompanied by thyroid autoimmunity (TAI). The aims of the present study were to estimate the prevalence of TAI and to determine the contribution of HLA-DQA1 and -DQB1 polymorphisms to TAI susceptibility among children with DM1. PATIENTS AND METLHODS: Screening for TAI was performed in 285 children with DM1 by measuring autoantibodies against thyroid peroxidase (anti-TPO) and thyroglobulin (anti-Tg). HLA-DQA1 and -DQB1 were genotyped using PCR-SSP. RESULTS: Repeated positivity of anti-TPO and/or anti-Tg was found in 45/285 children with DM1 (15.8%). The prevalence was significantly higher in girls than in boys (26.7% vs 6.7%; p<10(-5)). The HLA-DQB1*0302 allele conferred susceptibility to TAI in children with DM1 (OR 2.7, 95% CI 1.1-6.4), while the DQB1*05 alleles acted protectively (OR 0.2, CI 95% 0.08-0.7). CONCLUSIONS: HLA-DQ polymorphisms significantly modify the risk of TAI in children with DM1.

Premenarchal and postmenarchal girls with insulin-dependent diabetes mellitus: ovarian and other organ-specific autoantibodies, menstrual cycle.

STUDY OBJECTIVE: To estimate various organ-specific autoantibodies and detect other endocrine autoimmune disorders and menstrual cycle characteristics in girls with Type 1 insulin dependent diabetes mellitus (IDDM). DESIGN: Prospective cohort study from 1993 to 1998, duration 4.5 years. SETTING: Diabetes & Endocrine Clinic of the University Hospital, Motol, Prague. PATIENTS: 53 IDDM girls (group A--43 postmenarchal, group B--10 premenarchal), 15.5 +/- 2.5 (8-19) years old, 6.2 +/- 4.3 years after IDDM onset. MAIN OUTCOME MEASURES: Ovarian autoantibodies directed to ooplasm, zona pellucida, membrana granulosa, theca folliculi interna, and lutein cells, insulin autoantibodies, thyroid peroxidase and thyroglobulin autoantibodies. Menstrual cycle character, endocrine glands disturbance. Diabetes control, body mass index, duration of IDDM. RESULTS: Ovarian autoantibodies in at least one of the followed structures were found in 67.9% of the IDDM girls. In the control group of 21 healthy girls of corresponding age, the positive findings in lutein cells were found in only 4.8% of the girls (P < 0.01 versus IDDM girls). The lutein cells commonly associated with theca folliculi interna cells were the most frequent immunopositive structures in diabetic girls (P < 0.05 versus another positive ovarian autoimmune structure). Autoantibodies directed to ovarian steroid producing cells were frequent in IDDM patients with both irregular and normal menstrual cycles. Irregular menstrual cycles were diagnosed in 27.9% of IDDM girls, polymenorrhea in half of them, and oligomenorrhea in the remainder. Diabetes control in our patients (glycosylated hemoglobin HbA1c in postmenarchal girls 10.1 +/- 2.0%) did not differ between those with regular and those with irregular menstrual cycles. Over a follow-up period one-third of the girls with oligomenorrhea and a long-term noncompliance (HbA1c 13.5%) developed secondary amenorrhea. Insulin autoantibodies were found in 67.8%, thyroid peroxidase autoantibodies in 12.5%, and thyroglobulin autoantibodies in 10.4% of the IDDM girls. Autoimmune thyroiditis was diagnosed in 5 IDDM patients (9.4%); hypothyroidism developed in 3 of them. Menstrual cycle was irregular in 4 of the 5 girls with autoimmune thyroiditis (polymenorrhea in 1, oligomenorrhea in another 3 girls). CONCLUSIONS: An increased incidence of various circulating autoantibodies may be markedly demonstrated in IDDM girls. Their reproductive function might have an important relationship to an evidence of ovarian autoantibodies. Menstrual cycle disturbances could be linked to the poor diabetes control, to the presence of ovarian and other autoantibodies, and also to other autoimmune disease.

[Prediction of type 1 diabetes in the neonates of diabetic mothers or fathers]. / Predikce diabetu 1. typu u novorozencu diabetických matek nebo otcu.

OBJECTIVE: Verification of the possibility to predict diabetes in the neonates of mothers and fathers with Type 1 diabetes. DESIGN: Prospective clinical study. SETTING: Mother and Child Care Institute, Prague. Paediatric Clinic of the 2nd Faculty of Medicine at the Charles University, Prague. METHODS: In 31 neonates of mothers and fathers with Type 1 diabetes, the long-term and short-term risk of the occurrence of Type 1 diabetes was established. The genotypification of HLA, DQB1, HLA DQA1 and DRB1 *04 was carried out by using the PCR method to establish the long-term risk and according to the result of the examination, the examined child was included into one of the five categories of genetic risk. In all the monitored persons, the levels of antibodies against GAD65, IA-2 and IRA insulin were repeatedly identified by means of the methods, which are the markers of autoimmune insulitis and show the short-term risk of the occurrence of diabetes. The function-related examination of secretion of beta cells was carried out by using the intravenous glucose tolerance test (i.v. GTT) in children with significant titres of one or more antibodies. RESULTS: A very high risk of the occurrence of Type 1 diabetes was identified in 1 child with the genotype DQA1*03-DQB1*0201/DQA1*05-DQB1*0302 (3.23%); an increased risk was identified in 12 children (38.71%); a medium risk was identified in 11 children (35.48%); a relatively low risk was identified in 3 child (9,68%) and a low risk was identified in 4 children (12,90%). In 4 children (12.9%), a strongly protective alelle DQB1*0602 was found. In 4 children, positivity for one of the antibodies was identified. In 1 child of a diabetic father with an increased genetic risk, there was a decrease in the titre of antibodies in the case of repeated check and function-related examination of the insulin secretion (FPIR) will be carried out. In another child, disappearance of antibodies was identified when samples were taken for verification; function-related examination of insulin secretion produced normal results, and the child has remained without clinical manifestation of diabetes. In a third child, the positivity of the antibodies from the umbilical blood was only temporary and was probably caused by a passive transfer from the mother; now, when repeated checks were made, the antibodies have remained negative. In a fourth child, the parents refused further examinations after antibody positivity was observed; the child has been without clinical manifestation of diabetes up until now. CONCLUSION: This scheme for predicting diabetes by means of immunogenetic and immunological examination of risk individuals is a rational measure aimed at timely identification of autoimmune insulitis, which precedes the occurrence of Type 1 diabetes, and it should become a standard part of diabetological care.

[Growth and adult height in patients with congenital adrenal hyperplasia]. / Rust a dospelá výska u pacientu s kongenitální adrenální hyperplazií.

BACKGROUND: The growth of children with congenital adrenal hyperplasia (CAH) can be impaired by overproduction of endogenous androgens which after the initial growth acceleration lead to early ossification of the growth plates and a low adult height, and by excessive glucocorticoid treatment as the latter antagonize the effect of growth hormone and cause growth retardation. In order to identify the life period decisive for the adult height of patients with CAH the authors analyzed retrospectively their growth data. METHODS AND RESULTS: In 35 children with 21-hydroxylase deficiency (24 girls, age 4.8 - 22.3 years and 11 boys, age 6.3 - 22.3 years) the height and bone maturation was evaluated at the age of 3, 7, 10 and 12 years and the adult height. In all girls and in 5/11 boys treatment of CAH was started at the age of 0.0 - 1.5 years (median 0.1) (early diagnosis), in 6/11 boys at the age of 4.5 - 7.0 years (median 5.2) (late diagnosis). In children with an early diagnosis growth retardation by the age of 3 years occurred (SDS of the girls' height' -1.4 +/- 0.2, n = 24, boys -0.7 +/- 0.4, n = 5). The height deficit in girls at the age of 3 predicted significantly the loss of adult height, as compared with the expected height in the family (r = 0.68, p = 0.02). By the age of 7 years the height deficit declined insignificantly (SDS of girls' height -1.0 +/- 0.2, n = 21), but bone maturation proceeded rapidly (3 years: SDS 0.1 +/- 0.4, n = 7, 7 years: SDS 1.4 +/- 0.5, n = 11). The adult height of girls (n = 12) is 147.0 - 162.5 cm (mean 156.7), i.e. -1.6 +/- 0.2 SDS, in early diagnosed boys (n = 4) 159 - 176.6 cm (mean 167.6), i.e. -1.7 +/- 0.5 SDS, in boys with a late diagnosis (n =4) 165.0 - 172.0 (mean 169.5), i.e. -1.5 +/- 0.3 SDS. CONCLUSIONS: In treated children with CAH growth retardation occurs already from the age of 3 years, apparently due to excessive glucocorticoid doses. This retardation predicts a loss of adult height. Between the age of 3 and 7 years the growth prognosis deteriorates further due to accelerated bone maturation resulting from inadequate suppression of androgens. Optimal treatment during these periods in life can improve the prerequisites for attaining the predicted adult height.

[Growth hormone therapy in children with growth hormone deficiency: study of dose-response relationship]. / Lécba rustovým hormonem u detí s jeho deficitem: studie vztahu dávky a úcinku.

BACKGROUND: Despite different age, stature, severity of hormone deficiency and target height children with growth hormone deficiency are usually given a uniform therapeutic dose of the preparation. Knowledge of the basic variables which influence individual therapeutic effects of growth hormone would make it possible to elaborate for individual patients a specific therapeutic strategy with the aim to cath up with the deficiency in height at an appropriate calendar age. METHODS AND RESULTS: The authors treated for a period of one year, using three different dosages of growth hormone, 25 prepubertal children with growth hormone deficiency (post-stimulation level < 8 mIU/l). Group A (9 children aged 11.2 +/- 2.0 years) were treated with 0.42 IU/kg/week, group B (7 children, aged 11.4 +/- 4.6 years) 0.7 IU/kg/week and group C (9 children, aged 10.2 +/- 2.4 years) 1.0 IU/kg/week. The preparation was administered daily before bedtime by the s.c. route. The growth rate during treatment increased from (mean +/- SD) 2.6 +/- 0.9 to 9.3 +/- 1.5 cm/year (group A), from 2.3 +/- 1.0 to 10.4 +/- 2.5 cm/year (group B) and from 3.1 +/- 0.7 to 12.6 +/- 1.9 cm/year (group C, p < 0.05 as compared with group A). The height age increased per year of treatment significantly more in children of group C (by 2.1 +/- 0.3 year) than in group A (by 1.6 +/- 0.3 year) or in group B (by 1.7 +/- 0.3 year). No difference was found between the groups in the ratio of changes in height and bone age. From 10 analyzed variables the growth rate during treatment is predicted above all by the therapeutic dose (r = 0.60), and to a lesser extent by the target height (r = 0.53). CONCLUSIONS: The therapeutic dose is the decisive parameter for prediction of the therapeutic effect of growth hormone in children with growth hormone deficiency. It is justified to modify the therapeutic dose individually with regard to the initial characteristic and therapeutic target of every given patient.

[Differential diagnosis in children with small stature]. / Diferenciální diagnostika u detí s malým vzrustem.

BACKGROUND: Physiological growth is a sensitive long-term indicator of child health. Impaired growth of children may be the first manifestation of a serious chronic disease. In order to find a rational examination procedure, the authors analyzed retrospectively the diagnosis in children with impaired growth who were referred for examination to the university hospital. METHODS AND RESULTS: In the course of 5.5 years 190 children (boys/girls, 124/66) with short stature, age 2.5 to 16.5 years were examined. In 93 (68/25, 48.9%) the condition was classified as short-normal, i.e. short but healthy, incl. 25 (11/14, 13.2%) with familial short stature, in 26 (21/5, 13.7%) constitutional growth retardation (and retarded puberty) and in 42 (36/6, 22.1%) a combination of the two conditions. In 97 children (56/41, 51.1%) a pathological condition was found: in 14 girls (7.4%) Turner's syndrome, in 55 children (37/18, 29.0%) deficiency of growth hormone, incl. 11 as a results of a tumour or anomaly of the CNS, and in 28 children (19/9, 14.7%) another serious cause of a growth disorder. In three families the authors detected an autosomal dominant disorder in a parent-child pair, the parent not being aware of the disorder (renal tubular acidosis, vitamin D resistant rickets, hypochondroplasia). Based on analysis of these data the authors suggest a rational differential diagnostic procedure in children with short stature. CONCLUSIONS: The stepwise examination of children with short stature is based on the unequivocal differentiation of short-normal children and assessment of the cause of the growth disorder in the other affected children. The procedure is focused on a sparing, rapid and accurate diagnosis with subsequent early treatment of children with a serious pathological condition.

[The effect of treatment on growth in children with central precocious puberty]. / Vliv lécby na rust detí s centrální predcasnou pubertou.

BACKGROUND: Modern treatment of central precocious puberty (CPP) by agonist analogues of gonadoliberin (aGnRH) block the development of secondary sex characteristics, it delays bone maturation and improves the prospects of reaching optimal height. The objective of the present study was to compare the effect of formerly used treatment with synthetic progestin, Cyproterone acetate (Androcur, Schering), with contemporary treatment using aGnRH Triptoreline (D-Trp-6-LHRH, Decapeptyl depot, Ferring) on growth parameters of female patients. METHODS AND RESULTS: The authors treated 12 girls with CPP. The first group comprised 7 girls treated solely with Cyproterone acetate (first signs of CPP at the age of 4.9 +/- 1.8 years, onset of study at calendar age (CA) 7.1 +/- 1.3 years, bone age (BA) 10.2 +/- 1.3 years, follow-up period 1.8 +/- 0.8 years). The second group was formed by five girls originally treated for a period of 1.8 +/- 1.7 years (4-56 months) with Cyproterone acetate and subsequently with Triptoreline for a period of 1.5 +/- 0.3 years. The latter group developed signs of CPP at the age of 4.9 +/- 2.6 years. At the onset of Triptoreline treatment and thus at the onset of the study the girls' age was 7.4 +/- 0.7 years and BA 9.6 +/- 1.9 years. Secondary sex characteristics did not progress in either of the investigated groups during the study period. The authors observed in both groups before the investigation an acceleration of BA per calendar year (dBA/CA) of 1.5 +/- 0.6 SD (p < 0.01), as compared with standards of the healthy population. In the course of the investigation in the first group dBA/CA of 1.4 +/- 0.6 years (p < 0.01) persisted, in the second group a decline of dBA/CA to a normal level occurred (0.9 +/- 0.4 years). The growth rate in the two groups did not differ during the investigation from standards for the healthy population. Height in relation to bone age (BH/BA SDS) declined in the first group during the investigation from -1.8 +/- 0.9 SDS to -2.2 +/- 1.0 SDS (p = 0.06). In the second group this indicator did not change. CONCLUSIONS: During Triptoreline treatment, as compared with Cyproterone acetate treatment, in patients with CPP the rate of bone maturation declined to normal and their height in relation to bone age did not decline. This led to the assumption of a smaller future adult height loss in patients treated with aGnRH Triptoreline.

[Autoantibodies to GAD65, IA2 and insulin in Czech children with type 1 diabetes]. / Autoprotilátky proti GAD65, IA2 a inzulinu u ceských detí pri manifestaci diabetu 1. typu.

BACKGROUND: Autoimmune insulitis leading to insulin dependent diabetes mellitus (IDDM, Type 1 Diabetes) is accompanied by autoantibodies as its invaluable markers. The aim of the study was to determine the frequency of autoantibodies against GAD65, IA2 and insulin in Czech diabetic children at the disease onset. METHODS AND RESULTS: Sera of 105 newly diagnosed children with IDDM drawn within 24 hours after the first insulin dose were investigated for anti-GAD65, anti-IA2 and insulin autoantibodies (IAA) using RIA methods. The cut-off normal levels were determined as the 99th percentile of 105 non-diabetic children. At given 99% specificity, the sensitivity was 71% for anti-GAD65, 73% for anti-IA2, and 46% for IAA. 29% diabetic children were positive for all three autoantibodies, 25% had anti-GAD65 and anti-IA2 (IAA negative), 5.7% anti-GAD65 and IAA (anti-IA2 negative), 7.6% anti-IA2 and IAA (anti-GAD65 negative). As the only positive autoantibody, anti-GAD65 was found in 12%, anti-IA2 in 11%, and IAA in 3.8% children. In 5.7% children, none of the investigated autoantibodies was positive. Diabetic children diagnosed before the age of 5 years had significantly higher prevalence of IAA than the older ones. CONCLUSIONS: We have determined normal levels in healthy children, and prevalence at childhood IDDM onset of autoantibodies against three main molecular-defined autoantigens.

[Late sequelae of comprehensive antineoplastic therapy in children and adolescents with solid extracranial tumors. Effect on growth, pubertal development and gonadal function]. / Pozdní následky komplexní protinádorové lécby u detí a mladistvých s extrakraniálními solidními nádory. Vliv na rust, pubertální vývoj a funkci gonád.

BACKGROUND: Modern treatment of oncological diseases increases markedly the chance of long-term survival and permanent recovery. Due to frequently highly aggressive treatment it is however associated with the risk of late sequelae in the surviving patients. Comprehensive care of patients includes therefore not only control of the neoplastic disease but also efforts of maximal improvement of the quality of life of the patients. In young subjects, in view of their long-term perspective, this problem is particularly important. METHODS AND RESULTS: In 32 patients (25 boys and 7 girls) with extracranial solid tumours without primary endocrinological symptomatology (m. Hodgkin, neuroblastoma, ganglioneuroblastoma, nephroblastoma, Ewings sarcoma and others) a single examination was made assessing height, body weight, grade of sexual maturation according to Tanner, in boys testicular volume by means of a orchidometer and 20 other anthropometric dimensions. The mean age at the time of examination was 16.5 +/- 4.1 years, the mean age at the onset of treatment 6.1 +/- 4.8 years. The patients height, -0.4 +/- 0.9 SD, differs from the Czech national standard (p = 0.025). Impaired growth was recorded in 12.5% patients and had heterogenous causes. The authors proved a negative effect of radiotherapy on the growth of the spine, most markedly in children subjected to irradiation of the abdomen and chest and a highly significant reduction of the testicular volume in boys after cytostatic treatment of m. Hodgkin. CONCLUSIONS: The results are consistent with studies made abroad and indicate the necessity of comprehensive long-term follow-up of somatic growth and development of the gonads in oncological child patients.

[Prediction of insulin-dependent diabetes mellitus in children of first-degree relatives of diabetic patients]. / Predikce inzulin dependentního diabetes mellitus u detských prvostupnových príbuzných diabetických pacientu.

BACKGROUND: Individuals at risk for insulin dependent diabetes mellitus (IDDM) can be identified using a combination of genetic, immunological and metabolic markers. Our study was aimed at prediction of IDDM in a cohort of children having a first-degree relative with IDDM. METHODS AND RESULTS: In the period of three years, we investigated 208 non-diabetic children and adolescents, aged 10.0 +/- 5.3 (mean +/- SD), mostly siblings of diabetic children. The genetic risk was determined by the HLA-DQB1, -DQA1 genotyping and subtyping of the DRB1*04 alleles carried on the DQB1*0302 haplotypes. Insulitis was detected using a combination of autoantibody tests against three molecular-defined antigens (insulin, GAD65, IA-2). Prevalence of insulitis (defined as confirmed positivity of at least one autoantibody) was 9/208 (4.3%). In children carrying the IDDM highest-risk genotype (HLA-DQB1*0201-DQA1*05/DQB1*0302-DQA1*03), insulitis was almost 10 times more frequent (5/24, 21%) than in children with other genotypes (4/184, 2.2%, P = 0.003). In all subjects with insulitis, the first phase insulin response (FPIR) was determined by the intravenous glucose tolerance test. Three of the nine children had decreased FPIR, of whom two were later diagnosed with IDDM. None of the remaining children developed IDDM. CONCLUSIONS: We present the first IDDM prediction study in the Czech population, emphasising the utility of genetic risk investigation in the prediction scheme.

[Growth in children with the exudative enteropathy syndrome due to a congenital heart defect--cor triatriatum dextrum]. / Rust u dítete se syndromem exsudativní enteropatie na podklade vrozené srdecní vady--cor triatriatum dextrum.

Retarded growth in a child can be the sign of serious chronic disease. The authors present an account of a six-year-old boy where growth retardation persisted at least from the age of three. During this period his height dropped from the zone between the 25th and 50th percentile into the zone between the 3rd and 10th percentile. From the clinical point of view a large abdomen, loose stools and hypocalcaemia with tetany were striking, as they were moreover refractory to vitamin D2, calcitriol and calcium administration by the oral route. The authors revealed severe hypoproteinaemia, a 150 times increased value of alpha-1-antitrypsin in faeces, and exudative enteropathy syndrome was diagnosed. The cause was venous congestion due to a rare heart disease--cor triatriatum dextrum. The septum in the right atrium was resected. Immediately after surgery the consistency and frequency of stool decreased. Calcaemia and plasma protein levels reached normal levels within two months. A growth spurt of 11 cm/year followed. Fifteen months after operation the patient's height reached almost the 50th percentile.

[The effect of enalapril on the development of diabetic nephropathy in children and adolescents]. / Vliv enalaprilu na rozvoj diabetické nefropatie u detí a mladistvých.

Diabetic nephropathy is the most frequent cause of chronic renal insufficiency in adults. Its early stage, characterized by increased albuminuria, develops in susceptible subjects already manifestation of diabetes. This stage can be treated by inhibitors of the angiotensin-converting enzyme which reduce the pathologically elevated intraglomerular pressure even in normotonic subjects. Enalapril was administered for a period of 12 weeks to eight children and adolescents with a normal blood pressure and albuminuria of 30-300 mg/24 hours during repeated assessments. During treatment there was not only a significant decline of albuminuria (from 104.6 +/- 42.7 mg/24 hours to 47.2 +/- 15.4, p = 0.003) but also a drop of the pathological glomerular hyperfiltration (from 3.38 +/- 1.87 ml/s to 1.48 +/- 0.54 ml/s within six weeks - p = 0.02 and to 2.05 +/- 0.80 ml/s resp. within 12 weeks, n.s.). The favourable effect persisted also for some time after discontinuation of treatment. Treatment was relatively well tolerated by the patients. The problem remains whether it is possible to retard or prevent in this way the development of further stages of diabetic nephropathy, include chronic renal failure.

[The effect of growth hormone therapy on thyroid parameters]. / Vliv lécby rustovým hormonem na tyroidální parametry.

Clinical observations and experimental studies indicate that administration of growth hormone (GH) affects thyroid parameters either via inhibited TSH secretion or via activation of the peripheral conversion of T4 to T3. For a period of six months after the onset of GH treatment basic thyroid parameters (TSH and total T3 and T4) were followed up in two groups of children: in 10 euthyroid girls with Turner's syndrome (TS) (age 6.2-11.3 years), hitherto not treated with GH and in six children (2 boys) with isolated idiopathic growth hormone deficiency (IGHD) (age 9.5-14.1 years). In the latter group GH treatment, 0.37 to 0.47 IU/kg/week for a period of 0.8 to 4.3 years preceded. This treatment was discontinued for 30 days before the investigation was started. During this treatment the condition was assessed as euthyroid without administration of L-thyroxine. Both groups of children were treated with GH administered by daily injection, girls with TS had a dose of 1 IU/kg/week, children with IGHD 0.42 IU/kg/week. In these girls with TS in the course of six months no change of the investigated parameters was recorded. In children with IGHD after three months' treatment a drop of T4 from (mean +/- SD) of 119 +/- 11 to 84 +/- 21 nmol/l (p = 0.01) occurred and a rise of the T3/T4 (x 100) index from 1.77 +/- 0.24 to 2.73 +/- 0.69 (p = 0.01) and of TSH from 1.1 +/- 0.7 to 2.2 +/- 0.6 mU/l (p = 0.005). The T3 level did not change. Within 6 months of treatment these changes receded completely and the levels returned to baseline values.(ABSTRACT TRUNCATED AT 250 WORDS)