Alina German

Objective: Adiposity rebound is the first rise in BMI that occurs after the initial decrease during infancy. Early adiposity rebound, before age 5, is a risk factor for later obesity and metabolic problems. We investigated adiposity rebound in children with Congenital Adrenal Hyperplasia due to 21-hydroxylase deficiency (CAH). Design: Longitudinal observational registry study. Methods: Height, weight, and BMI from patients younger than 20 years in the I-CAH Registry was described by non-linear mixed-effects models. Covariates of glucocorticoid dose, mineralocorticoid dose, 17-Hydroxyprogesterone were assessed on growth and bone age. Results: A total of 10 261 visits within 573 patients (43.6% male) showed significant variation in age at latest peak height velocity [8.4 years (SD = 3.0) in boys; 9.0 years (SD = 1.6) in girls]. Peak height velocity was more blunted in boys [7.7 cm/year (SD = 1.4)] than girls [7.4 cm/year (SD = 1.3)] in comparison to normative values. Adiposity rebound occurred earlier than age 5 years in 82% of the cohort, mean age 3.7 years (SD = 1.3) in boys and 3.9 years (SD = 0.9) in girls. Girls prescribed higher doses of glucocorticoid were associated with heavier weight in adolescence and earlier adiposity rebound. Bone age was increasingly advanced in those prescribed higher doses in both sexes. Conclusions: There is a large variation in the timing of adiposity rebound and SITAR-estimated latest peak height velocity in children with CAH. In addition to identifying individuals with CAH who may be at risk of adverse cardiometabolic outcomes these metrics may serve as early surrogate outcomes in future research investigating early-life treatment strategies.

Children affected by complex endocrine disorders continue to face substantial and persistent barriers in diagnosis, treatment, and long-term care across Europe and worldwide. Diagnostic uncertainty remains common due to non-standardized criteria, limited validation of biomarkers, and unequal access to advanced testing. Fragmented care pathways and insufficient multidisciplinary coordination further undermine optimal management, particularly during the transition from pediatric to adult services. Pediatric drug development is constrained by small patient populations, ethical and regulatory challenges, and limited commercial incentives, resulting in therapeutic gaps. Families frequently shoulder considerable psychosocial and financial burdens, often without adequate educational, psychological, or social support. Addressing these inequalities requires strategic action to stimulate research innovation, harmonize diagnostic and training standards, improve equitable access to care and medicines, and strengthen patient and family empowerment through collaborative networks and advocacy. This document aimed to highlight these unmet medical needs and outline a path forward. By identifying key barriers and proposing strategic directions, ESPE seeks to foster collaboration among clinicians, researchers, policymakers, patient communities, and pharmaceutical partners. Only through coordinated action can we ensure that every child with an endocrine disorder receives equitable, timely, and high-quality care – regardless of where they live.

Objective: Management of 21-hydroxylase deficiency (21-OHD) congenital adrenal hyperplasia (CAH) in early infancy is challenging, with extent of variation in management unclear. Design and Methods: Using the I-CAH Registry, we retrospectively reviewed management over the first 90 days of life of 154 infants with 21-OHD born in 2018-2023, across 33 centers in 18 countries. Results: Of 154 infants (92 female, 62 male), 136 were diagnosed postnatally, with median (10th centile, 90th centile) presentation age of Day 4 (0, 20.8). At initial hospital discharge, median doses of hydrocortisone (HC), fludrocortisone (FC), and salt were 17 (11.4, 39.6) mg/m2/day, 100 (50, 200) mcg/day and 3.5 (1.6, 8.7) mmol/kg/day, and at Day 90 (D90) 14.5 (8.7, 24.1) mg/m2/day, 100 (50, 200) mcg/day, and 2.1 (1.0, 5.2) mmol/kg/day, respectively. Hyponatremia, hyperkalemia, and hypoglycemia were reported in 70.0%, 71.9%, and 13.0% of infants, respectively. At D90, hyponatremia and hyperkalemia were reported in 7.4% and 28.6%, respectively. At D90, BP measurements were recorded in 30.5%, amongst whom 31.9% had hypertension reported. Median total hospitalization duration over 90 days was 9 days (2, 24). Adrenal crises were associated with 40. 6% of hospitalization episodes. Percentages (males:females) of cases seen by a pediatric endocrinologist, psychologist, pediatric endocrine nurse specialist, and surgeon by D90 were 95.9% (58:84), 33.3% (9:35), 42.1% (20:36), and 23.8% (0:35), respectively. Conclusions: Contemporary management of CAH in early infancy varies considerably. Hypertension and hyperkalemia are frequently reported. Our data may help inform development of quality indicators for benchmarking CAH care in infancy.

Context: Physiological growth hormone is secreted during slow-wave sleep. Traditionally, growth hormone (GH) therapy is given in daily GH injections before sleep. While morning and evening GH injections produce comparable effects on growth and IGF-1 levels, the evening schedule better imitates the physiological diurnal pattern of GH secretion and action. However, the inflexibility of bedtime injection schedules, coupled with the discomfort and psychological distress associated with the injection and local reaction, may cause sleep disturbances in patients, and may significantly burden them and their families.Objective: Our objective was to evaluate evening vs. morning daily GH injections with respect to sleep-wake pattern, duration, and activity index in children treated with growth hormone.Design: An open-label, randomized crossover trial of 20 children (11 boys) 5–14 years of age with isolated growth hormone deficiency (n=12) and idiopathic short stature (n=8) treated with daily injections of median GH dose 33 (range13-46) mcg/kg/d was performed. Each subject received 2 weeks of evening injections and 2 weeks of morning injections. Patients' sleep-wake patterns and activity index were assessed by a 7-day actigraph covering the second week of each treatment schedule.Results: All subjects slept well, within recommended ranges for sleep parameters, regardless of whether they were receiving morning or evening GH injections. Results were comparable for all measures: total time in bed (min), 526.0 ± 51.8 vs 516.9 ± 57.4 for evening and morning GH injections, respectively; total sleep time (min), 512.4 ± 51.1 vs 504.3 ± 57.7; sleep efficiency (%), 93.6 ± 2.6 vs 94.2 ± 2.3; sleep onset latency (min), 8.9 ± 8.1 vs 7.4 ± 6.8; number of arousals per night, 14.5 ± 5.4 vs 12.5 ± 5.2; and 24-hour activity index, 68.3 ± 4.0 vs 67.0 ± 5.0, respectively. No difference was found between the growth hormone deficient and idiopathic short stature group. No difference was found between boys and girls.Conclusions: Sleep-wake patterns and activity index were not affected by treatment schedules. We recommend that growth hormone injections take place at any regular time according to the family's convenience.

Context: Central congenital hypothyroidism (CCH) is a thyroid hormone deficiency at birth caused by inadequate pituitary stimulation of the thyroid gland. Although primary congenital hypothyroidism has been studied extensively, studies on CCH are sparse. Objective: To assess the prevalence of CCH in Israel and describe its clinical features, neonatal screening results, and outcomes. Methods: This multicenter cross-sectional retrospective chart review covered 9 pediatric endocrine units throughout Israel; patients diagnosed with CCH in 1987–2021 were categorized into early (within 14 days of life) and late (after 14 days) diagnosis groups. Newborn screening (NBS) results were retrospectively retrieved from the national NBS program dataset. Results: CCH prevalence in Israel was about 1:42 800 live births. Subjects were 94 patients (54 males), of these, 84% had multiple pituitary hormone deficiencies and 16% had isolated CCH. The median age at diagnosis was 50 days (range, 1-8760), with 66% having moderate to severe hypothyroidism. NBS detected only 3 infants. Early diagnosis occurred in 34% due to hypopituitarism, while 66% were diagnosed later due to growth and developmental delays. Neurodevelopmental sequelae included mental retardation (12%), learning difficulties (18%), delayed speech (27%), and motor clumsiness (19%), with no significant differences in outcomes between early and late diagnosis. Conclusion: Despite high rates of neurodevelopmental sequelae, no differences were found between early and late diagnosis groups. Further research is needed to assess the impact of delayed diagnosis on neurological outcomes in newborns with CCH. Improved strategies for detecting CCH in newborns are also necessary.

Background: Resource trade-off theory suggests that increased performance on a given trait comes at the cost of decreased performance on other traits.Methods: Growth data from 1889 subjects (996 girls) were used from the GrowUp1974 Gothenburg study. Energy Trade-Off (ETO) between height and weight for individuals with extreme body types was characterized using a novel ETO-Score (ETOS). Four extreme body types were defined based on height and ETOI at early adulthood: tall-slender, short-stout, short-slender, and tall-stout; their growth trajectories assessed from ages 0.5-17.5 years.A GWAS using UK BioBank data was conducted to identify gene variants associated with height, BMI, and for the first time with ETOS.Results: Height and ETOS trajectories show a two-hit pattern with profound changes during early infancy and at puberty for tall-slender and short-stout body types. Several loci (including FTO, ADCY3, GDF5, ) and pathways were identified by GWAS as being highly associated with ETOS. The most strongly associated pathways were related to “extracellular matrix,” “signal transduction,” “chromatin organization,” and “energy metabolism.”Conclusions: ETOS represents a novel anthropometric trait with utility in describing body types. We discovered the multiple genomic loci and pathways probably involved in energy trade-off.

Objective To evaluate the incidence and severity of ketoacidosis (DKA) at type 1 diabetes diagnosis during the first wave of the coronavirus disease 2019 (COVID-19) pandemic in Israel. Research Design and Methods A population-based study the product of a national collaboration of Israeli pediatric diabetes centers investigated the presentation of childhood-onset type 1 diabetes. The frequencies of DKA and severe DKA observed during the COVID-19 period from March 15, 2020 (commencement of the first nationwide lockdown) until June 30, 2020 were compared with the same periods in 2019, 2018, and 2017 using multivariable logistic regression, adjusting for age, sex, and socioeconomic position. Results During the COVID-19 period, DKA incidence was 58.2%, significantly higher than in 2019 (adjusted OR [aOR] 2.18 [95% CI, 1.31-3.60], P = 0.003); 2018 (aOR 2.05 [95% CI, 1.26-3.34], P = 0.004); and 2017 (aOR, 1.79 [95% CI,1.09-2.93], P = 0.022). The incidence of severe DKA was 19.9%, significantly higher than in 2018 (aOR, 2.49 [95% CI, 1.20-5.19], P = 0.015) and 2017 (aOR, 2.73 [95% CI,1.28-5.82], P = 0.009). In 2020, admissions and duration of stay in the intensive care unit were higher than in previous years (P = 0.001). During the COVID-19 pandemic, children aged 6-11 years had higher incidences of DKA (61.3% vs 34.0%, 40.6%, and 45.1%, respectively, P = 0.012), and severe DKA (29.3% vs 15.1%, 10.9%, and 5.9%, respectively, P = 0.002). Conclusions The dramatic increase in DKA at presentation of childhood-onset type 1 diabetes during the COVID-19 pandemic mandates targeted measures to raise public and physician awareness.

Context Prediction of AH is frequently undertaken in the clinical setting. The commonly used methods are based on the assessment of skeletal maturation. Predictive algorithms generated by machine learning, which can already automatically drive cars and recognize spoken language, are the keys to unlocking data that can precisely inform the pediatrician for real-time decision making. Objective To use machine learning (ML) to predict adult height (AH) based on growth measurements until age 6 years. Methods Growth data from 1596 subjects (798 boys) aged 0-20 years from the longitudinal GrowUp 1974 Gothenburg cohort were utilized to train multiple ML regressors. Of these, 100 were used for model comparison, the rest was used for 5-fold cross-validation. The winning model, random forest (RF), was first validated on 684 additional subjects from the 1974 cohort. It was additionally validated using 1890 subjects from the GrowUp 1990 Gothenburg cohort and 145 subjects from the Edinburgh Longitudinal Growth Study cohort. Results RF with 51 regression trees produced the most accurate predictions. The best predicting features were sex and height at age 3.4-6.0 years. Observed and predicted AHs were 173.9 ± 8.9 cm and 173.9 ± 7.7 cm, respectively, with prediction average error of –0.4 ± 4.0 cm. Validation of prediction for 684 GrowUp 1974 children showed prediction accuracy r = 0.87 between predicted and observed AH (R² = 0.75). When validated on the 1990 Gothenburg and Edinburgh cohorts (completely unseen by the learned RF model), the prediction accuracy was r = 0.88 in both cases (R² = 0.77). AH in short children was overpredicted and AH in tall children was underpredicted. Prediction absolute error correlated negatively with AH (P < .0001). Conclusion We show successful, validated ML of AH using growth measurements before age 6 years. The most important features for prediction were sex, and height at age 3.4-6.0. Prediction errors result in over- or underestimates of AH for short and tall subjects, respectively. Prediction by ML can be generalized to other cohorts.

Background: The relationship between pubertal onset and tempo and pubertal growth is controversial. We hypothesized that the age at onset of girls’ puberty predicts pubertal tempo and the rate of pubertal progression. Methods: We analyzed the data of 380 girls from the prospective Study of Early Child Care and Youth Development (SECCYD) who were recruited in the USA from 1991 to 2006 and followed from birth to age 15.5 years. We used the following indicators: thelarche age (Tanner stage B2), pubarche age (P2), menarche age (M), the age when breast (B5) and pubic hair (P5) became fully mature, pubertal growth, pubertal duration (time from B2 to B5) and pubertal progression (time from B2 to M). We clustered the girls according to B2 age into early onset (EO; 10.5 years). Results: All indicators of pubertal onset and conclusion occurred earlier in the EOs than in the LOs; yet, the differences in the age at main pubertal milestones lessened as puberty progressed: 2 years for B2; −1.4 years for M; −1 year for B5. In EOs, puberty was 1 year (average) longer than in LOs. Although EOs grew 7 cm (average) more than LOs, their heights at B5 were comparable. There was a significant relationship between the thelarche age and puberty tempo (r = 0.23, P < 0.0001). Conclusions: The study highlights the predictive nature of variation in the onset age of puberty on its progression and duration. These results are reassuring in this context and will add to clinicians’ and parental understanding of the expected milestones of puberty.