Search

Purpose: To investigate the potential impact of drugs for the treatment of attention deficit hyperactivity disorder (ADHD) on body weight and height in children and adolescents from the LIFE ('Leipzig Research Centre for Civilization Diseases', Leipzig, Germany) Child cohort. Methods: We included 2,115 participants aged ≥6 to <18.25 years who attended the LIFE study center between 2011 and 2020 in our analysis, of whom 48 used ADHD drugs. Anthropometric and medication data from baseline to the third follow-up visit were available for 659 participants. Body height and body weight measurements were subsequently converted to z-scores. A repeated measures analysis of variance (ANOVA) was performed on the z-scores of both ADHD drug users and non-users to determine potential trends in body weight and body height from baseline to the 3 rd annual follow-up. Results: At the last visit with ADHD drug use of the 48 ADHD drug users, 40% (19/48) of the children and adolescents were below the 25 th reference percentile for weight. Z-scores for body height declined from baseline to the 3 rd annual follow-up in individuals who used ADHD drugs (n=10; Difference means =-0.310; p=0.002) compared to non-users (n=649; Difference means =0.102; p<0.001). Body weight also decreased from baseline to 3 rd follow-up in the ADHD drug group (n=10; Difference means =-0.473; p<0.001) compared to the non-user group (n=649; Difference means =0.015; p=0.161). Conclusion: We observed a potential tendency towards lower Z-scores for body height and body weight in individuals taking ADHD medication for an extended period compared to the corresponding age- and sex-matched populations.

In children and adolescents, impaired growth due to tyrosine kinase inhibitor therapy remains an insufficiently studied adverse effect. This study examines demographic, pharmacological, and genetic factors associated with impaired longitudinal growth in a uniform pediatric cohort treated with imatinib. We analyzed 94 pediatric patients with chronic myeloid leukemia (CML) diagnosed in the chronic phase and treated with imatinib for >12 months who participated in the Germany-wide CML-PAEDII study between February 2006 and February 2021 (clinicaltrials gov. Identifier: NCT00445822). During imatinib treatment, significant height reduction occurred, with medians of -0.35 standard deviation score (SDS) at 12 months and -0.76 SDS at 24 months. Cumulative height SDS change (Δ height SDS) showed a more pronounced effect in prepubertal patients during the first year but were similar between prepubertal and pubertal subgroups by the second year (-0.55 vs. -0.50). From months 12 to 18 on imatinib, only 18% patients achieved individually longitudinal growth adequate to the growth standard (Δ height SDS ≥0). When patients were divided into two subgroups based on median Δ height SDS (classifier Δ height SDS > or ≤-0.37) after 1 year on imatinib therapy, cohort 1 (Δ height SDS ≤-0.37) showed younger age at diagnosis, a higher proportion of prepubertal children, but also better treatment response and higher imatinib serum levels. Exploring the association of growth parameters with pharmacokinetically relevant single nucleotide polymorphisms, known for affecting imatinib response, showed no correlation. This retrospective study provides new insights into imatinib-related growth impairment. We emphasize the importance of optimizing treatment strategies for pediatric patients to realize their maximum growth potential.

Context: Aromatase excess syndrome (AEXS) is a very rare disorder characterized by prepubertal gynecomastia, bone age acceleration, and early growth arrest. Heterozygote submicroscopic rearrangements within the promotor of CYP19A1 result in overexpression of aromatase and enhanced aromatization of androgens., Objective: The objective was to study long-term treatment effects of an aromatase inhibitor., Methods: Data from 7 boys with AEXS were retrospectively collected. Genetic analysis revealed upstream of CYP19A1 a 165 901 bp deletion in 4 German cousins, a 198 662 bp deletion in 2 Japanese brothers, and a 387 622 bp tandem duplication in a Japanese boy., Results: All boys developed prepubertal gynecomastia, at median 9.0 years of age (range: 7.0-11.0). Height was +1.20 standard deviation score (SDS) (-0.24 to +1.98); predicted adult height was -1.29 SDS (-3.29 to +1.09). Four boys were treated with 1.0 mg of anastrozole daily, while 3 reached adult height untreated. Treatment with anastrozole was stopped after 5.6 years (4.0-6.8). Three treated boys exceeded their prognosis by 2.4, 6.9, and 8.1 cm, while 1 untreated boy fell below the prognosis by 8.6 cm. One treated with a low dose and 2 untreated reached their prognosis. Adult heights were -0.91 SDS with anastrozole (-2.86 to -0.29) and -0.15 SDS without (-2.31 to -0.03). Distance to target height was -0.22 SDS with anastrozole (-1.72 to +0.52) and +0.54 SDS without (+0.23 to +1.30)., Conclusion: Spontaneous growth in AEXS varied, even in the same family. Our data suggest that early started, long-term inhibition by anastrozole promotes adult height in boys with AEXS., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Concerns have been raised over the safety of methylphenidate (MPH), with regard to adverse effects on growth and blood pressure. Our study investigates whether, and to what extent, methylphenidate use in boys with ADHD is associated with having low body mass index (BMI), having low height, and increased systolic and diastolic blood pressure., Methods: Data used for this study stem from the German KiGGS dataset. Three different groups of boys aged 6-15 years were included in the analysis: ADHD patients who used MPH for less than 12 months; ADHD patients who used MPH for 12 months or more; and ADHD patients without current MPH treatment. Each of these three groups was compared to a non-ADHD control group regarding low weight (BMI ≤ 3rd percentile), low height (≤3rd percentile) and raised systolic and diastolic blood pressure. For growth outcomes, boys were categorized according to age (< 11 years/≥11 years, to account for pubertal maturation). Multivariable logistic regression was conducted to test for associations., Results: 4244 boys were included in the study; MPH < 12 months: n = 65 (n = 36 < 11 years), MPH ≥ 12 months: n = 53 (n = 22 < 11 years), ADHD controls: n = 320 (n = 132 < 11 years), non-ADHD controls: n = 3806 (n = 2003 < 11 years). Pre-pubertal boys with MPH use less than 12 months and pubertal/postpubertal boys with MPH use of 12 months or greater were significantly more likely to have a BMI ≤ 3rd percentile compared to non-ADHD controls. Boys from the ADHD control group were significantly less likely to have a raised systolic blood pressure compared to non-ADHD controls. Beyond that, no significant between group differences were observed for any other growth and BP parameter., Conclusion: The analyses of the KiGGS dataset showed that MPH use in boys with ADHD is associated with low BMI. However, this effect was only observed in certain groups. Furthermore, our analysis was unable to confirm that MPH use is also associated with low height (≤3rd percentile) and changes in blood pressure.

Background: We investigated time trends in age, gender, growth hormone (GH) dose and height standard deviation score (SDS) in children with GH deficiency (GHD), born small for gestational age (SGA) or with Turner syndrome (TS) starting GH treatment., Methods: Data were obtained from children enrolled in the NordiNet® International Outcome Study (IOS) between 2006 and 2015 in the Czech Republic, France, Germany, Serbia and Montenegro (all indications), and Switzerland and the UK (GHD only). Trends were analyzed by linear regression. Patients were divided by age into early-, medium- or late-start groups in three different time periods., Results: Approximately one-third of children starting treatment for GHD were girls, with no apparent increase in proportion over time. The mean baseline age for starting treatment decreased significantly (p<0.001) for both GHD and SGA in the Czech Republic and Germany. In the other countries studied, over 40% of children started treatment for GHD and SGA late (girls >10, boys >11 years) between 2013 and 2015. The mean baseline GH doses were largely within recommended ranges for GHD and SGA, but below the lowest recommended starting dose for TS in almost every year since 2011 except in France., Conclusions: Approximately one-third of children starting treatment for GHD were girls. Between 2013 and 2015, more than 40% of children started treatment for GHD and SGA late except in Germany and the Czech Republic. TS patients received below-recommended doses. These results highlight the need for earlier identification of short stature in children, particularly girls, and for dose optimization in TS.

Background: We analyzed the impact of birth parameters and parental height on long-term growth outcome in children with chronic kidney disease (CKD) stage 3-5., Methods: Linear growth was prospectively investigated in 509 children, with a mean follow-up of 4.1 years. Growth outcome was categorized in (i) poor growth (PG): height standard deviation score (SDS) during follow-up < -2.0 and/or actual or previous growth hormone (GH) treatment, and (ii) good growth (GG): height SDS ≥ -2.0 and no need for GH. A multivariate binary logistic regression model was constructed for predictors of PG outcome., Results: PG was observed in 55 % of patients. The rate of pre-term and small for gestational age birth was significantly higher in children with PG compared to GG (43.2 vs. 25.6 % and 36.8 vs. 18.9 %; p < 0.001). Children with PG had significantly lower average values for gestational age, birth weight, length, and head circumference, umbilical cord pH, Apgar scores, and parental height than children with GG. Birth length, umbilical cord pH, and parental height were significant independent predictors of PG outcome (sensitivity 72.8 %, specificity 69.3 %)., Conclusions: Birth parameters and parental height are independent predictors of growth outcome in children with CKD.

Background: mTOR inhibitors (mTORI) have emerged as alternative and additive immunosuppressive agents in pediatric renal transplantation (pRTx). Their immunosuppressive, anti-proliferative, and anti-neoplastic mechanisms have been described to be effective, whereas some side effects are alarming. In particular, growth and pubertal development are of concern. The aim of this study was to look for long-term side effects of mTORI therapy in pRTx., Patients and Methods: The retrospective analysis focused on side effects, growth, and pubertal development under mTORI therapy in 31 children. Eighteen children were routinely monitored for estradiol, testosterone, LH, and FSH levels., Results: The occurrence of bacterial infections, lymphoceles, myelosuppression, and the course of overall linear growth was comparable with other pediatric renal transplant cohorts. According to the clinical puberty status, all but one patient showed normal age-related development in parallel to normal serum hormone levels. Only one patient experienced cytomegaly virus infection under mTORI, no post-transplant lymphoproliferative disorders (PTLD) occurred., Conclusions: Long-term mTORI therapy is safe in pRTx. No negative impact on growth and pubertal development was observed.

Background: Ullrich-Turner syndrome (UTS) girls often present with short stature in adolescence to the endocrinologist when the efficacy of growth hormone (GH) to improve growth remains unknown and parameters to estimate individual GH responsiveness have yet to be determined., Objective: Retrospective evaluation of adult height (AH) and predicted adult height at GH start (descriptive model of Ranke, Model PredAH) in early and late GH-treated German UTS patients., Subjects/methods: 313 patients treated with GH, early [chronological age (CA) at GH start <12 years, n = 259] or late (CA at GH start ≥12 years, n = 54) who reached AH were selected from KIGS (Pfizer International Growth Database)., Results: AH (152.5 ± 5.9 vs. 151.1 ± 5.4 cm, p = n.s.) after GH treatment for 7.5 ± 2.12 years (GH start early) and for 5.2 ± 1.2 years (GH start late) were similar (p = n.s.) as Model PredAH (155.7 ± 4.8 vs. 154.7 ± 4.8 cm; p = n.s.) but higher (p < 0.001) than projected adult height (Ranke, ProjAH; 148.2 ± 5.5 vs. 145.2 ± 6.7 cm; p = 0.001). Total height gain over ProjAH was 4.3 ± 4.6 cm (GH start early) and 5.8 ± 4.7 cm (GH start late, p = 0.021), respectively., Conclusions: GH may improve AH in UTS patients even when started late. The individual growth response could be estimated by the descriptive Model PredAH independent of age at treatment start.

Aims and Methods: Prediction algorithms suggest factors determining short- and long-term growth response to growth hormone (GH) in Turner's syndrome (TS). A total of 133 patients (group A; 53% with karyotype 45,X) completed 1 year of treatment and 77 patients (group B) reached adult height (AH) after >4 years on GH treatment. The patients were analysed for factors determining the outcomes, and in addition, the validity of published algorithms was tested., Results: In group A [values are given as medians (10th-90th percentiles)], starting age was 9.4 (4.8-14) years, height was -3.2 (-4.4 to -1.9) SDS (Prader references), and GH dose was 38 (23-48) μg/kg/day. Observed height velocity was 7.7 (5.2-9.8) cm/years and was equal to the predicted height velocity. In group B, projected adult height (PAH) was 147.4 (139.5-154.8) cm. Total gain in height over PAH of 6.1 (2.0-12.6) cm was negatively correlated with height at start, but positively correlated with GH duration, first year Δheight SDS, or index of responsiveness. Observed AH was 153.5 (146.6-160.1) cm and predicted AH was 155.0 (147.4-161.0) cm, which is statistically not different. On GH <5% IGF-I levels were >2 SDS., Conclusions: The published prediction algorithms were found to be valid. If normal AH is to be reached at the lowest costs and risks, probably only TS children with a good growth potential and a high responsiveness to GH can be treated successfully with GH doses of <50 μg/kg/day., (Copyright © 2012 S. Karger AG, Basel.)

Background: We hypothesized that overweight children with growth hormone deficiency (GHD) demonstrate a lower response to growth hormone (GH) as a result of a misclassification since obesity is associated with lower GH peaks in stimulation tests., Methods: Anthropometric data, response, and responsiveness to GH in the first year of treatment were compared in 1.712 prepubertal children with GHD from the German KIGS database according to BMI (underweight=group A, normal weight=group B, overweight=group C) (median age: group A, B, C: 7.3, 7.28, and 8.4 years)., Results: Maximum GH levels to tests (median: group A, B, C: 5.8, 5.8, and 4.0 µg/ml) were significantly lower in group C. IGF-I SDS levels were not different between the groups. Growth velocity in the first year of GH treatment was significantly lower in the underweight cohort (median: group A, B, C: 8.2, 8.8, and 9.0 cm/yr), while the gain in height was not different between groups. The difference between observed and predicted growth velocity expressed as Studentized residuals was not significantly different between groups. Separating the 164 overweight children into obese children (BMI>97th centile; n=71) and moderate overweight children (BMI>90th to 97th centile, n=93) demonstrated no significant difference in any parameter., Conclusions: Overweight prepubertal children with idiopathic GHD demonstrated similar levels of responsiveness to GH treatment compared to normal weight children. Furthermore, the IGF-I levels were low in overweight children. Therefore, a misclassification of GHD in overweight prepubertal children within the KIGS database seems unlikely. The first year growth prediction models can be applied to overweight and obese GHD children., (© J. A. Barth Verlag in George Thieme Verlag KG Stuttgart · New York.)

A growing number of innovative, high-cost drugs call for assessment from social medicine. Synthetic human growth hormone (somatropin, STH) is a prominent example. The use of STH in children greatly increased over the last few years. Treatment extends over years and cost may add up to 30,000 to 70,000 DM/year. STH is licensed for treatment of insufficient secretion of growth hormone, in girls with Ullrich Turner Syndrome and in prepubertal children with chronic renal failure. Off-label use of STH is widespread. The following questions arise: Is STH treatment medically necessary? Must social security (health insurance) carriers pay for STH treatment? Which methods are appropriate to analyse growth and to ascertain growth hormone deficiency? The stated target of STH treatment is a relevant increase of body height. Is this target achieved in the various indications? Special problems arise where psychosocial considerations are put forward.

Final height was evaluated in 369 patients with idiopathic growth hormone deficiency (IGHD) enrolled in KIGS--the Pharmacia & Upjohn International Growth Database. At the start of growth hormone (GH) therapy, the patients were 9.8 years of age, their mid-parental height SDS was -0.8, and their height SDS was -3.1. Of the 369 patients, 50% had multiple hormone deficiencies, and puberty was induced in 31%. Patients were 18 years of age at completion of GH therapy, and had received GH at a dose of 0.49 IU/kg/week (0.16 mg/kg/week), with a mean of 5.2 injections/week for 8.1 years. Final height SDS was -1.5, final minus initial height SDS was 1.7 and final minus mid-parental height SDS was -0.5. A Swedish subgroup (n = 69) received conventional GH therapy throughout at 0.65 IU/kg/week (0.22 mg/kg/week), with seven injections/week for a mean of 9.4 years. These patients achieved their genetic potential (final minus mid-parental height SDS, 0.03), with a normal final height SDS of -0.3. For the total group, the following variables were associated with final height: mid-parental height SDS (r = 0.62), injection frequency (r = 0.37), duration of GH treatment (r = 0.28), peak stimulated GH concentration (r = -0.25), age (r = -0.19) (all p < 0.001) and height velocity SDS in the first year of treatment (r = 0.20, p = 0.004). In conclusion, genetic potential, expressed as the mid-parental height, is the variable with the greatest identified influence on final height during GH treatment in IGHD. Current GH regimens will lead to a normal height and attainment of mid-parental height. However, higher dose, individualized GH regimens are likely to be necessary for patients with IGHD who are disadvantaged at the time of commencing GH therapy, such as those with short parents, those whose treatment began in late childhood or adolescence and those with less severe GHD.

Final height was investigated in 85 patients from a German multicentre trial of human growth hormone (GH) therapy in Turner syndrome. Six patients (mean age, 15.4 +/- 1.0 years; mean duration of therapy, 4.4 +/- 1.0 years) fulfilled the criteria for having reached final height (i.e. a height velocity < 0.5 cm/year). Four subjects had stopped therapy and two were still receiving GH. The mean final height of patients was 150.9 +/- 4.7 cm (range, 143.3-154.9 cm). In 3 subjects, projected final height was exceeded by 1.4, 6.5 and 10.8 cm, 1 patient just failed to reach projected final height by -1.7 cm and the 2 remaining patients did not attain projected final height by -3.2 and -12.1 cm. In the latter case, lack of height gain was associated with early onset and rapid progress of spontaneous puberty. The changes in height SDS were analysed in the other patients still receiving GH therapy over a period of 6 years, and it appeared that 2 IU/m2/day was less effective than 3 or 4 IU/m2/day, but that 4 IU/m2/day was no more effective than 3 IU/m2/day. These limited, non-controlled results indicate that GH therapy may be effective in increasing final height in Turner syndrome, though some patients may not benefit.