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Open access

Uta Neumann, Daniela Burau, Sarah Spielmann, Martin J Whitaker, Richard J Ross, Charlotte Kloft, and Oliver Blankenstein

Objectives

Due to the lack of paediatric-licensed formulations, children are often treated with individualized pharmacy-compounded adult medication. An international web-based survey about the types of medication in children with adrenal insufficiency (AI) revealed that the majority of paediatric physicians are using pharmacy-compounded medication to treat children with AI. Observations of loss of therapy control in children with congenital adrenal hyperplasia with compounded hydrocortisone capsules and regained control after prescribing a new hydrocortisone batch led to this ‘real world’ evaluation of pharmacy-compounded paediatric hydrocortisone capsules.

Methods

Capsule samples were collected randomly from volunteering parents of treated children suffering from congenital adrenal hyperplasia from all over Germany. Analysis of net mass and hydrocortisone content by high-performance liquid chromatography with ultraviolet (HPLC-UV) detection method was performed based on the European Pharmacopeia.

Results

In a total of 61 batches that were sent, 5 batches could not be analysed because of missing dose information, insufficient number of capsules or were not possible to be evaluated. Fifty-six batches containing 1125 capsules were evaluated. 21.4% of the batches revealed insufficiency in uniformity of net mass or drug content and additional 3.6% failed because they did not contain the labelled drug.

Conclusions

Compounded medication is a possible cause of variation of steroid doses in children with adrenal insufficiency or congenital adrenal hyperplasia, putting these vulnerable patients at risk of poor disease control and adrenal crisis. These data may apply to other individualized compounded oral medication as well, emphasizing the need for development of licensed paediatric formulations approved by regulatory authorities.

Open access

D B Allen, P Backeljauw, M Bidlingmaier, B M K Biller, M Boguszewski, P Burman, G Butler, K Chihara, J Christiansen, S Cianfarani, P Clayton, D Clemmons, P Cohen, F Darendeliler, C Deal, D Dunger, E M Erfurth, J S Fuqua, A Grimberg, M Haymond, C Higham, K Ho, A R Hoffman, A Hokken-Koelega, G Johannsson, A Juul, J Kopchick, P Lee, M Pollak, S Radovick, L Robison, R Rosenfeld, R J Ross, L Savendahl, P Saenger, H Toft Sorensen, K Stochholm, C Strasburger, A Swerdlow, and M Thorner

Recombinant human GH (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children and adults has been subject to considerable scrutiny. In 2001, a statement from the GH Research Society (GRS) concluded that ‘for approved indications, GH is safe’; however, the statement highlighted a number of areas for on-going surveillance of long-term safety, including cancer risk, impact on glucose homeostasis, and use of high dose pharmacological rhGH treatment. Over the intervening years, there have been a number of publications addressing the safety of rhGH with regard to mortality, cancer and cardiovascular risk, and the need for long-term surveillance of the increasing number of adults who were treated with rhGH in childhood. Against this backdrop of interest in safety, the European Society of Paediatric Endocrinology (ESPE), the GRS, and the Pediatric Endocrine Society (PES) convened a meeting to reappraise the safety of rhGH. The ouput of the meeting is a concise position statement.

Open access

Tansit Saengkaew, Heena R Patel, Kausik Banerjee, Gary Butler, Mehul T Dattani, Michael McGuigan, Helen L Storr, Ruben H Willemsen, Leo Dunkel, and Sasha R Howard

Context

Pubertal delay can be the clinical presentation of both idiopathic hypogonadotropic hypogonadism (IHH) and self-limited delayed puberty (SLDP). Distinction between these conditions is a common but important diagnostic challenge in adolescents.

Objective

To assess whether gene panel testing can assist with clinical differential diagnosis and to allow accurate and timely management of delayed puberty patients.

Design

Retrospective study.

Methods

Patients presenting with delayed puberty to UK Paediatric services, followed up to final diagnosis, were included. Whole-exome sequencing was analysed using a virtual panel of genes previously reported to cause either IHH or SLDP to identify rarely predicted deleterious variants. Deleterious variants were verified by in silico prediction tools. The correlation between clinical and genotype diagnosis was analysed.

Results

Forty-six patients were included, 54% with a final clinical diagnosis of SLDP and 46% with IHH. Red flags signs of IHH were present in only three patients. Fifteen predicted deleterious variants in 12 genes were identified in 33% of the cohort, with most inherited in a heterozygous manner. A fair correlation between final clinical diagnosis and genotypic diagnosis was found. Panel testing was able to confirm a diagnosis of IHH in patients with pubertal delay. Genetic analysis identified three patients with IHH that had been previously diagnosed as SLDP.

Conclusion

This study supports the use of targeted exome sequencing in the clinical setting to aid the differential diagnosis between IHH and SLDP in adolescents presenting with pubertal delay. Genetic evaluation thus facilitates earlier and more precise diagnosis, allowing clinicians to direct treatment appropriately.

Open access

Oliver Blankenstein, Marta Snajderova, Jo Blair, Effie Pournara, Birgitte Tønnes Pedersen, and Isabelle Oliver Petit

Objective

To describe real-life dosing patterns in children with growth hormone deficiency (GHD), born small for gestational age (SGA) or with Turner syndrome (TS) receiving growth hormone (GH) and enrolled in the NordiNet International Outcome Study (IOS; Nbib960128) between 2006 and 2016.

Design

This non-interventional, multicentre study included paediatric patients diagnosed with GHD (isolated (IGHD) or multiple pituitary hormone deficiency (MPHD)), born SGA or with TS and treated according to everyday clinical practice from the Czech Republic (IGHD/MPHD/SGA/TS: n = 425/61/316/119), France (n = 1404/188/970/206), Germany (n = 2603/351/1387/411) and the UK (n = 259/60/87/35).

Methods

GH dosing was compared descriptively across countries and indications. Proportions of patients by GH dose group (low/medium/high) or GH dose change (decrease/increase/no change) during years 1 and 2 were also evaluated across countries and indications.

Results

In the Czech Republic, GH dosing was generally within recommended levels. In France, average GH doses were higher for patients with IGHD, MPHD and SGA than in other countries. GH doses in TS tended to be at the lower end of the recommended label range, especially in Germany and the UK; the majority of patients were in the low-dose group. A significant inverse association between baseline height standard deviation score and GH dose was shown (P < 0.05); shorter patients received higher doses. Changes in GH dose, particularly increases, were more common in the second (40%) than in the first year (25%).

Conclusions

GH dosing varies considerably across countries and indications. In particular, almost half of girls with TS received GH doses below practice guidelines and label recommendations.

Open access

Catherine Peters and Nadia Schoenmakers

Transient congenital hypothyroidism (TCH) refers to congenital hypothyroidism which spontaneously resolves in the first few months or years of life. Currently, there is a paucity of reliable markers predicting TCH at diagnosis, and the diagnosis is established following withdrawal of levothyroxine therapy around 3 years of age. The incidence of TCH is increasing, and it is a major contributor to the overall increase in incidence of CH in recent studies. Both genetic factors, in particular mutations affecting DUOX2 and DUOXA2, and environmental factors, e.g iodine deficiency and excess, anti- TSHR antibodies and exposure to anti-thyroid or iodine-rich medications may cause TCH. Resolution of TCH in childhood may reflect both normal thyroid physiology (decreased thyroid hormone biosynthesis requirements after the neonatal period) and clearance or cessation of environmental precipitants. The relative contributions and interactions of genetic and environmental factors to TCH, and the extent to which TCH may be prevented, require evaluation in future population-based studies.

Open access

Huseyin Demirbilek, Ved Bhushan Arya, Mehmet Nuri Ozbek, Jayne A L Houghton, Riza Taner Baran, Melek Akar, Selahattin Tekes, Heybet Tuzun, Deborah J Mackay, Sarah E Flanagan, Andrew T Hattersley, Sian Ellard, and Khalid Hussain

Background

Neonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes and usually presents in the first 6 months of life. We aimed to describe the clinical characteristics and molecular genetics of a large Turkish cohort of NDM patients from a single centre and estimate an annual incidence rate of NDM in South-Eastern Anatolian region of Turkey.

Design and methods

NDM patients presenting to Diyarbakir Children State Hospital between 2010 and 2013, and patients under follow-up with presumed type 1 diabetes mellitus, with onset before 6 months of age were recruited. Molecular genetic analysis was performed.

Results

Twenty-two patients (59% males) were diagnosed with NDM (TNDM-5; PNDM-17). Molecular genetic analysis identified a mutation in 20 (95%) patients who had undergone a mutation analysis. In transient neonatal diabetes (TNDM) patients, the genetic cause included chromosome 6q24 abnormalities (n=3), ABCC8 (n=1) and homozygous INS (n=1). In permanent neonatal diabetes (PNDM) patients, homozygous GCK (n=6), EIF2AK3 (n=3), PTF1A (n=3), and INS (n=1) and heterozygous KCNJ11 (n=2) mutations were identified. Pancreatic exocrine dysfunction was observed in patients with mutations in the distal PTF1A enhancer. Both patients with a KCNJ11 mutation responded to oral sulphonylurea. A variable phenotype was associated with the homozygous c.-331C>A INS mutation, which was identified in both a PNDM and TNDM patient. The annual incidence of PNDM in South-East Anatolian region of Turkey was one in 48 000 live births.

Conclusions

Homozygous mutations in GCK, EIF2AK3 and the distal enhancer region of PTF1A were the commonest causes of NDM in our cohort. The high rate of detection of a mutation likely reflects the contribution of new genetic techniques (targeted next-generation sequencing) and increased consanguinity within our cohort.

Open access

A Nordenström, S F Ahmed, E van den Akker, J Blair, M Bonomi, C Brachet, L H A Broersen, H L Claahsen-van der Grinten, A B Dessens, A Gawlik, C H Gravholt, A Juul, C Krausz, T Raivio, A Smyth, P Touraine, D Vitali, and O M Dekkers

An Endo-European Reference Network guideline initiative was launched including 16 clinicians experienced in endocrinology, pediatric and adult and 2 patient representatives. The guideline was endorsed by the European Society for Pediatric Endocrinology, the European Society for Endocrinology and the European Academy of Andrology. The aim was to create practice guidelines for clinical assessment and puberty induction in individuals with congenital pituitary or gonadal hormone deficiency. A systematic literature search was conducted, and the evidence was graded according to the Grading of Recommendations, Assessment, Development and Evaluation system. If the evidence was insufficient or lacking, then the conclusions were based on expert opinion. The guideline includes recommendations for puberty induction with oestrogen or testosterone. Publications on the induction of puberty with follicle-stimulation hormone and human chorionic gonadotrophin in hypogonadotropic hypogonadism are reviewed. Specific issues in individuals with Klinefelter syndrome or androgen insensitivity syndrome are considered. The expert panel recommends that pubertal induction or sex hormone replacement to sustain puberty should be cared for by a multidisciplinary team. Children with a known condition should be followed from the age of 8 years for girls and 9 years for boys. Puberty induction should be individualised but considered at 11 years in girls and 12 years in boys. Psychological aspects of puberty and fertility issues are especially important to address in individuals with sex development disorders or congenital pituitary deficiencies. The transition of these young adults highlights the importance of a multidisciplinary approach, to discuss both medical issues and social and psychological issues that arise in the context of these chronic conditions.

Open access

Kristina Laugesen, Henrik Toft Sørensen, Jens Otto L Jorgensen, and Irene Petersen

Objective

Prenatal exposure to excess cortisol can affect postnatal metabolic health by epigenetic mechanisms. We aimed to investigate if prenatal exposure to pharmacological glucocorticoids increases the risk of overweight/obesity in childhood.

Design

A nationwide population registry-based cohort study.

Methods

We identified 383 877 children born in Denmark (2007–2012), who underwent routine anthropometric evaluation at 5–8 years of age. Prenatal exposure to glucocorticoids was divided into systemic and topical glucocorticoids, cumulative systemic dose, and use by trimester. The comparison cohort included children without exposure, born to maternal never-users. Negative control exposures were used to investigate confounding from an underlying disease or unmeasured characteristics. Such exposures included children without glucocorticoid exposure born to maternal users of non-steroidal anti-inflammatory drugs or immunotherapy during pregnancy, maternal former users of glucocorticoids, or paternal users of glucocorticoids during the pregnancy of their partner. We estimated sex-stratified adjusted prevalence ratios (aPR) of overweight/obesity at 5–8 years of age, as epigenetic modifications have shown to be sex-specific.

Results

In the study, 21 246 (11%) boys and 27 851 (15%) girls were overweight/obese at 5–8 years of age. Overall, neither systemic nor topical glucocorticoids were associated with overweight/obesity. In boys, high-dose systemic glucocorticoids was associated with higher prevalence of overweight/obesity vs the comparison cohort (aPR: 1.41 (95% CI: 1.07–1.86), prevalence: 16% vs 11%). Negative control exposures indicated robustness to confounding.

Conclusion

Overweight/obesity might be an adverse effect of prenatal exposure to high-dose systemic glucocorticoids in boys. We found no association for neither prenatal exposure to lower doses of systemic nor topical glucocorticoids. These results merit clinical attention.

Open access

Peter Bang, Joachim Woelfle, Valerie Perrot, Caroline Sert, and Michel Polak

Objective

The European Increlex® Growth Forum Database Registry monitors the effectiveness and safety of recombinant human insulin-like growth factor-1 (rhIGF1; mecasermin, Increlex®) therapy in patients with severe primary IGF1 deficiency (SPIGFD). We present data from patients with and without a reported genetic diagnosis of Laron syndrome (LS).

Design

Ongoing, open-label, observational registry (NCT00903110).

Methods

Children and adolescents receiving rhIGF1 therapy from 10 European countries were enrolled in 2008–2017 (n = 242). The treatment-naïve/prepubertal (NPP) cohort (n = 138) was divided into subgroups based on reported genetic diagnosis of LS (n = 21) or non-LS (n = 117). Multivariate analysis of the NPP-non-LS subgroup was conducted to identify factors predictive of growth response (first-year-height standard deviation score (SDS) gain ≥ 0.3). Assessments included change in height and weight over 5 years and adverse events (AEs).

Results

Height SDS gain from baseline was greater in the NPP-LS than the NPP-non-LS subgroup after 1 years’ treatment (P < 0.05). In the NPP-non-LS subgroup, 56% were responders; young age at baseline was a positive independent predictive factor (P < 0.001). NPP-non-LS-responders and the NPP-LS subgroup had a similar mean age (6.07 years vs 7.00 years) at baseline and height SDS gain in year 1 (0.64 vs 0.70), although NPP-non-LS-responders were taller (P < 0.001) at baseline. BMI SDS changes did not differ across subgroups. Treatment-emergent AEs were experienced by 65.3% of patients; hypoglycaemia was most common.

Conclusions

In most NPP children with SPIGFD, with or without LS, rhIGF1 therapy promotes linear growth. The safety profile was consistent with previous studies.

Open access

Anuradhaa Subramanian, Jan Idkowiak, Konstantinos A Toulis, Shakila Thangaratinam, Wiebke Arlt, and Krishnarajah Nirantharakumar

Context

The incidence of gestational diabetes mellitus (GDM) has been on the rise, driven by maternal obesity. In parallel, pubertal tempo has increased in the general population, driven by childhood obesity.

Objective

To evaluate the available evidence on pubertal timing of boys and girls born to mothers with GDM.

Data sources

We searched MEDLINE, EMBASE, CINAHL Plus, Cochrane library and grey literature for observational studies up to October 2019.

Study selection and extraction

Two reviewers independently selected studies, collected data and appraised the studies for risk of bias. Results were tabulated and narratively described as reported in the primary studies.

Results

Seven articles (six for girls and four for boys) were included. Study quality score was mostly moderate (ranging from 4 to 10 out of 11). In girls born to mothers with GDM, estimates suggest earlier timing of pubarche, thelarche and menarche although for each of these outcomes only one study each showed a statistically significant association. In boys, there was some association between maternal GDM and earlier pubarche, but inconsistency in the direction of shift of age at onset of genital and testicular development and first ejaculation. Only a single study analysed growth patterns in children of mothers with GDM, describing a 3-month advancement in the age of attainment of peak height velocity and a slight increase in pubertal tempo.

Conclusions

Pubertal timing may be influenced by the presence of maternal GDM, though current evidence is sparse and of limited quality. Prospective cohort studies should be conducted, ideally coupled with objective biochemical tests.