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Free access

Maik Welzel, Leyla Akin, Anja Büscher, Tülay Güran, Berthold P Hauffa, Wolfgang Högler, Julia Leonards, Beate Karges, Heiner Kentrup, Birgul Kirel, Emine Esin Yalinbas Senses, Neslihan Tekin, Paul-Martin Holterhus, and Felix G Riepe

Background

Pseudohypoaldosteronism type 1 (PHA1) is a monogenic disease caused by mutations in the genes encoding the human mineralocorticoid receptor (MR) or the α (SCNN1A), β (SCNN1B) or γ (SCNN1G) subunit of the epithelial Na+ channel (ENaC). While autosomal dominant mutation of the MR cause renal PHA1, autosomal recessive mutations of the ENaC lead to systemic PHA1. In the latter, affected children suffer from neonatal onset of multi-organ salt loss and often exhibit cystic fibrosis-like pulmonary symptoms.

Objective

We searched for underlying mutations in seven unrelated children with systemic PHA1, all offsprings of healthy consanguineous parents.

Methods and results

Amplification of the SCNN1A gene and sequencing of all 13 coding exons unraveled mutations in all of our patients. We found five novel homozygous mutations (c.587_588insC in two patients, c.1342_1343insTACA, c.742delG, c.189C>A, c.1361-2A>G) and one known mutation (c.1474C>T) leading to truncation of the αENaC protein. All parents were asymptomatic heterozygous carriers of the respective mutations, confirming the autosomal recessive mode of inheritance. Five out of seven patients exhibited pulmonary symptoms in the neonatal period.

Conclusion

The α subunit is essential for ENaC function and mutations truncating the pore-forming part of the protein leading to systemic PHA1. Based on current knowledge, the pulmonary phenotype cannot be satisfactorily predicted.

Free access

K Mazor-Aronovitch, D Gillis, D Lobel, H J Hirsch, O Pinhas-Hamiel, D Modan-Moses, B Glaser, and H Landau

Background: Congenital hyperinsulinism (CH) is treated surgically in many centers (near-total and partial pancreatectomy for diffuse and focal disease respectively). Most patients treated with near-total pancreatectomy developed diabetes during childhood/puberty. CH patients are at increased risk of neurodevelopmental disorders, some being severe, which are reported to occur in 14–44% of patients from highly heterogenous cohorts. Over the last few decades, we have treated children with CH conservatively without surgery. The aim of this study was to assess the neurodevelopmental outcome of these patients.

Design and methods: The study included 21 Ashkenazi CH medically treated patients: 11 homozygotes (diffuse disease) and 9 heterozygotes with mutations on the paternal allele (presumed focal disease). The mean age was 13.7 years (range 8–23). Neurodevelopmental outcomes were assessed by telephone interviews of parents, using a standard questionnaire. Closest age siblings of CH patients served as controls.

Results: Ten CH patients had perinatal seizures of short duration. Four had post-neonatal seizures, which remitted entirely. During early childhood, four patients (19%) had hypotonia, eight (38%) had fine motor problems, seven (33%) had gross motor problems (clumsiness), and one had mild cerebral palsy. Three patients (14%) had speech problems. Eight patients required developmental therapy, compared to one in the control group. Most of these problems were resolved by age 4–5 years. At school age, all were enrolled in regular education, some excelled in their studies, 6 out of 21 patients (29%) had learning problems (2 out of 21 controls). None had overt diabetes.

Conclusions: Good neurodevelopmental outcome was observed in our conservatively treated CH patients, with no diabetes as reported in patients undergoing pancreatectomy.

Free access

Tilman Rohrer, Eva Stierkorb, Sabine Heger, Beate Karges, Klemens Raile, K Otfried Schwab, Reinhard W Holl, and on behalf of the Diabetes-Patienten-Verlaufsdaten (DPV) Initiative

Abstract

Objective

To investigate the effect of type 1 diabetes on pubertal onset and development, and to identify factors potentially affecting puberty, including glycemic control, relative diabetes duration, body mass index standard delta score (BMI SDS), insulin dose, and intensity of insulin therapy.

Research design and methods

Initiated in 1990, the Diabetes-Patienten-Verlaufsdaten (DPV) is an ongoing, prospective longitudinal follow-up program to benchmark the quality of diabetes care provided to, predominantly, pediatric patients. Data collection for this non-interventional audit was carried out at 202 German diabetes treatment centers. Patient recruitment was done by referral, clinic/hospital ascertainment, or self-report. Data were analyzed for subcohorts of 1218–2409 boys and 579–2640 girls from a cohort of 24 385 pediatric type 1 diabetic patients. Selection was based on ethnicity and availability of data on Tanner stage 2, or higher, of genital and pubic hair development (boys) or breast and pubic hair development, and menarche (girls).

Results

Boys showed significant (P<0.05) delay (years) in mean ages at onset of genital development (12.0 (±0.9) years) and pubarche (12.2 (±0.4) years). In girls, mean ages at thelarche (11.4 (±0.5) years), pubarche (11.5 (±0.1) years), and menarche (13.2 (±0.5) years) were significantly delayed compared with the general population. Sexual maturity (Tanner stage 5) was not delayed in either sex. Elevated glycohemoglobin and decreased BMI SDS were associated with significantly delayed pubertal onset, whereas relative diabetes duration and insulin dose were not.

Conclusions

Pubertal onset, but not sexual maturity, is delayed in children with type 1 diabetes. Delay increases with higher glycohemoglobin and lower BMI SDS.

Free access

F Rutters, A G Nieuwenhuizen, S P M Verhoef, S G T Lemmens, N Vogels, and M S Westerterp-Plantenga

Objective

To investigate the relationship between leptin concentrations, gonadotropic hormone concentrations, and body composition during puberty in a Dutch children cohort.

Design

In a cohort of 98 children, we determined anthropometric measurements, body composition, and concentrations of leptin, FSH, and LH.

Results

Sex differences were observed from Tanner stage 1 onwards in weight, body fat percentage, and leptin/fat mass ratio. In boys and girls, the relationship between leptin concentrations and FM was weaker at Tanner stage 2 (R 2=0.33 and R 2=0.39; P<0.001), 3 (R 2=0.27 and R 2=0.36; P<0.002), and 4 (R 2=0.21 and R 2=0.28; P<0.03) than at Tanner stage 1 (R 2=0.51 and R 2=0.67; P<0.001) and 5 (R 2=0.46 and R 2=0.78; P<0.01). In girls, a peak in leptin concentrations (8.5±6.0 ng/ml) preceded a peak in LH and FSH concentrations (15.1±3.5 and 5.0±4.5 IU/l). A lead/lag relationship was observed of leptin at Tanner stage 1 to LH and FSH at Tanner stage 2 (R 2=0.12, P<0.05 and R 2=0.18, P<0.05). In boys, there was no peak in leptin, LH, and FSH; additionally, leptin at Tanner stage 3 was related FSH at Tanner stage 4 (R 2=0.17, P<0.04).

Conclusion

In boys and girls during puberty, factors independent of fat mass become (transiently) more important in the regulation of plasma leptin concentrations. Moreover, in girls, leptin is suggested to act as a permissive factor for the onset of puberty, while, in boys, leptin has a different timing and possibly different function.

Free access

Katarina Sedej, Primož Kotnik, Magdalena Avbelj Stefanija, Urh Grošelj, Andreja Širca Čampa, Lara Lusa, Tadej Battelino, and Nataša Bratina

Background

Overweight/obesity in children is a worldwide public health problem. Together with hypercholesterolaemia they are associated with early atherosclerotic complications.

Objectives

In this study, we aimed to investigate the anthropometric characteristics and total cholesterol (TC) levels in a population of 5-year-old children, to determine trends in the prevalence of overweight/obesity and hypercholesterolaemia in 5-year-old children over a period of 8 years (2001–2009) and to assess the impact of modified national nutritional guidelines for kindergartens implemented in 2005.

Design

Cross-sectional studies of overweight/obesity prevalence in the years 2001, 2003–2005 and 2009, and hypercholesterolaemia in years 2001 and 2009, in 5-year-old children.

Subjects

Altogether, 12 832 (6308 girls/6524 boys) children were included.

Methods

Overweight/obesity was defined by IOTF criteria. Hypercholesterolaemia was defined by TC level >5 mmol/l. Multivariable logistic regression models were used.

Results

No correlation between BMI values and TC levels was found. Overweight and obesity prevalence were stabilised from 2001 to 2009 (odds ratio (OR) (95% CI): 1.13 (0.99–1.3) and 1.13 (0.89–1.42) respectively). Girls were more frequently overweight/obese than boys (OR (95% CI): 0.71 (0.65–0.79) and 0.75 (0.64–0.89) respectively). Prevalence of hypercholesterolaemia significantly decreased from 2001 to 2009 (OR (95% CI): 0.47 (0.41–0.55)). It was less frequent in boys than in girls (OR (95% CI): O.7 (0.61–0.8)).

Conclusions

This is the first study to describe a negative trend in the prevalence of hypercholesterolaemia in pre-pubertal children. In addition, the prevalence of overweight/obesity in these children has been stabilised. Nationwide changes in public health policies could have influenced these observations.

Free access

A Vatanen, M Wilhelmsson, B Borgström, B Gustafsson, M Taskinen, U M Saarinen-Pihkala, J Winiarski, and K Jahnukainen

Objective

The aim of the study was to evaluate long-term ovarian function after allogeneic hematopoietic stem cell transplantation (HSCT) in childhood and adolescence.

Subjects and methods

Predictive factors for ovarian function were evaluated among 92 adult or pubertal female survivors transplanted at Huddinge and Helsinki University Hospital during 1978–2000, at a mean age of 9±4.3 years (range 1–19). At the time of the study a mean±s.d. of 13±5.5 years (range 6–27) had elapsed since the HSCT and the mean age of the participants was 22±6.3 years (range 9–41).

Results

Spontaneous puberty based on breast development occurred in 40 and menarche in 30 of the 70 girls who were prepubertal at transplantation. Six out of 20 girls who received HSCT after initiation of pubertal development recovered their ovarian function. Younger age at HSCT, conditioning without total body irradiation (TBI), and a non-leukemia diagnosis predicted the spontaneous menarche. The incidence of menarche was higher after fractioned vs single fraction TBI (P<0.05), cyclophosphamide (Cy) vs busulfan (Bu)-based conditioning (P<0.05), and among leukemia patients transplanted at first remission vs later remissions (P<0.01) and with no cranial irradiation (cranial radiotherapy, CRT) vs given CRT (14–24 Gy) (P<0.01). The majority of recipients conditioned with only Cy vs TBI (P<0.001) or vs Bu-based regimens (P<0.01) showed preserved ovarian function and required no estrogen replacement at their latest follow-up visit at a mean age of 23±6.3 years (range 15–41). Ten women became pregnant.

Conclusions

Patients conditioned with TBI or Bu-based regimes are at high risk of ovarian failure. Intensive anti-leukemia therapy before HSCT including CRT especially among relapsed patients may further decrease the possibility of spontaneous menarche.

Free access

Ferenc Peter, Conrad Savoy, Hyi-Jeong Ji, Mihaly Juhasz, Martin Bidlingmaier, and Paul Saenger

Objective

LB03002 is a novel, sustained-release recombinant human GH, developed for once-a-week s.c. injection. To evaluate the suitability for long-term GH replacement therapy in children with GH deficiency (GHD), the present study assessed the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of LB03002 at three doses.

Study design and patients

The randomised, comparator-controlled, assessor-blinded, phase II study assessed 37 (24 boys, 13 girls) pre-pubertal, GH-naïve children with GHD, in 11 European centres, for PK and PD analyses. GH, IGF1 and IGFBP3 concentrations were measured following the last daily GH dose and the first and 13th once-a-week administration of LB03002 at doses of 0.2, 0.5 or 0.7 mg/kg.

Results

GH C max values after the three doses of LB03002 were increased up to fourfold, with a clear dose proportionality. For each LB03002 dose, GH area under the concentration versus time curve did not increase from the first to 13th (month 3) administration, indicating no accumulation of circulating GH. IGF1 C max showed a progressive increase during LB03002 administration. Conversely, IGFBP3 showed a rapid increase in C max. IGF1 SDS were fully normalised after 3 months of treatment, whereas IGFBP3 SDS were already in the normal range for all the three LB03002 dosages after 1 week.

Conclusions

At the doses used, LB03002 has a suitable profile for long-term treatment to promote growth in children with GHD. The quantitative changes in IGF1 and IGFBP3 indicate adequate stimulation of the IGF system by LB03002 and the pattern of increase is comparable with that seen in GHD children in a standard IGF1 generation test using daily GH.

Free access

Helton Estrela Ramos, Melina Morandini, Aurore Carré, Elodie Tron, Corinne Floch, Laurent Mandelbrot, Nathalie Neri, Benoit De Sarcus, Albane Simon, Jean Paul Bonnefont, Jeanne Amiel, Isabelle Desguerre, Vassili Valayannopoulos, Mireille Castanet, and Michel Polak

Context

Monocarboxylate transporter 8 (MCT8 or SLC16A2) mutations cause X-linked Allan–Herndon–Dudley syndrome. Heterozygous females are usually asymptomatic, but pregnancy may modify thyroid function and MCT8 is expressed in the placenta, suggesting that maternal and fetal abnormalities might develop even in the absence of MCT8 fetal mutation. Genetic counseling is so far based on X-linked transmission, and prenatal diagnosis is rarely performed.

Objective

To describe thyroid function and the prenatal diagnosis in pregnant mothers harboring heterozygous MCT8 mutations and management of the persistent maternal hypothyroxinemia.

Patients

Two women heterozygous for MCT8 mutations (c.1690G>A and c.1393-1G>C) were monitored throughout pregnancy.

Methods

Prenatal diagnosis included sex determination, direct MCT8 sequencing, and familial linkage analysis. Ultrasonography and hormonal assays for maternal thyroid function evaluation were performed serially during pregnancy. Neonatal thyroid hormonal status was assessed.

Results

None of the three fetuses (two males and one female) carried MCT8 mutations. One of the two heterozygous mothers revealed gestational hypothyroxinemia, prompting early levothyroxine (l-T4) therapy until delivery. The second heterozygous mother showed normal thyroid function but was preventively traited by l-T4 and all of the three neonates had normal thyroid hormone levels and thyroid gland at birth, suggesting advantages of prenatal care and/or compensatory mechanisms.

Conclusion

Heterozygous MCT8 women should be monitored for requirement of l-T4 therapy to prevent fetal and neonatal hypothyroidism and to avoid risk of potential cognitive delay due to gestational hypothyroxinemia. Moreover, when the disease-causing mutation is known and/or the first child is affected, prenatal diagnosis for male fetuses should be assessed early for MCT8 mutations by direct sequencing.

Free access

Juliane Léger

Congenital hypothyroidism (CH) is the most common congenital endocrine disorder. The early treatment of CH patients has successfully improved the prognosis and management of this disorder. Optimal treatment and management throughout the patient's life, beginning in the neonatal period, are required to ensure long-term health. Affected patients should be offered assessments of associated medical conditions and provided with accurate information about their condition throughout their lives, but particularly during the transition from pediatric to adult services. This review provides a summary of current knowledge about the long-term outcomes of these patients and appropriate management into early adulthood. We carried out a systematic search of the Medline database to identify relevant articles. Despite major improvements in prognosis, the impact of CH is clearly not uniform, and management should take into account a broader range of relevant indicators, including CH severity, associated comorbid conditions and the adequacy of treatment during childhood and adulthood. The early diagnosis and management of associated medical conditions, and better educational strategies to improve compliance with treatment, should improve the long-term prognosis. Further studies are required to explore changes with aging.

Free access

N H Birkebæk, A Lange, P Holland-Fischer, K Kristensen, S Rittig, H Vilstrup, A Handberg, and H Gronbaek

Objective

Obesity in men is associated with reduced insulin sensitivity and hypoandrogenism, while obesity in women is associated with reduced insulin sensitivity and hyperandrogenism. In children, the effect of obesity and weight reduction on the hypothalamo-pituitary–gonadal axis is rarely investigated. The aim of the present study was to investigate the effect of weight reduction in obese Caucasian children on insulin sensitivity, sex hormone-binding globulin (SHBG), DHEAS and the hypothalamo-pituitary–gonadal axis.

Methods

One hundred and sixteen (65 females) obese children with a median age of 12.3 (7–15) years were examined before and after a 10-week stay at a weight loss camp. Examination included anthropometry and fasting blood samples measuring plasma glucose, serum insulin, SHBG, DHEAS, testosterone, 17β-oestradiol, FSH and LH.

Results

Body mass index (BMI) decreased (P<0.01), insulin sensitivity and SHBG increased (P<0.01), independent of gender and puberty. The changes in insulin sensitivity and the changes in SHBG correlated significantly (P<0.01) independent of gender, puberty and the changes in BMI. Testosterone increased in boys (P<0.01) and tended to decrease in girls (P=0.05, in girls after menarche (P=0.03)). FSH increased in boys and girls. LH increased in boys and was unchanged in girls.

Conclusions

During weight loss, insulin sensitivity and SHBG increased significantly in obese children, and the changes in insulin sensitivity and the changes in SHBG correlated significantly independent of gender, puberty and the changes in BMI. There was sexual dimorphism in the changes of testosterone, with the changes in boys towards increased virilisation and the changes in girls towards less virilisation.