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Background: Agranulocytosis is a rare antithyroid drug treatment (ATD) side effect seen in children suffering from Graves' disease (GD). Neutropenia is a recognized adverse event associated with ATD but has also been reported as pre-treatment neutropenia in GD. Methods: We performed a retrospective cohort study to analyze the longitudinal clinical and biochemical data of 161 pediatric patients with GD who received either methimazole (MMI) or carbimazole (CBZ) as ATD. The inclusion criteria were elevated free thyroxine (fT4 >25 pmol/L), suppressed thyrotropin (TSH <0.05 mlU/mL), and elevated thyrotropin receptor antibodies (TSHRAbs >2.5 IU/L). Absolute neutrophil count (ANC) was used to define neutropenia (ANC <1800/µL) and agranulocytosis (ANC <500/µL). Results: Nine of the 161 patients had neutropenia at diagnosis (ANC: 1348/µL ± 250) without further deterioration under ATD. In this subgroup, we found higher levels of free triiodothyronine (fT3: 31.45 pmol/L ± 3.99) at diagnosis in comparison with those who developed neutropenia (26.29 pmol/L ± 12.96; p = 0.07) and those without neutropenia before and during therapy (23.12 pmol/L ± 13.7; p = 0.003). Thirty-eight patients (23.6%) became neutropenic (ANC: 1479/µL ± 262) while receiving ATD. Neutropenia occurred after a mean of 551.8 (range: 10–1376) days, mostly without further deterioration. Two of these 38 patients developed agranulocytosis and underwent emergency thyroidectomy. The patients with neutropenia were significantly younger (p = 0.031). Neutropenia occurred significantly more often in patients receiving CBZ (50%; n = 20/40) than in those receiving MMI (16.5%; n = 18/110; p = 0.001). The minimum ANC was significantly lower in the CBZ (1971/µL ± 1008) than in the MMI group (2546 ± 959); p = 0.004. Conclusions: Neutropenia occurred significantly more often under CBZ than MMI. As this is potentially due to higher immunogenicity, we suggest that children with GD should be treated with MMI. Frequent measurements of ANC may be needed to detect severe agranulocytosis, although low pre-treatment ANC may not necessarily be a contraindication to ATD treatment. Young age may be potentially associated with an increased risk of reduced ANC. Further investigation is necessary to fully understand risk factors for neutropenia in children with GD. [ABSTRACT FROM AUTHOR]

Aim: To examine the time trends and factors associated with the onset of puberty in children with type 1 diabetes (T1D) using data from the German Diabetes Prospective Follow‐up (Diabetes‐Patienten‐Verlaufsdokumentation [DPV]) registry. Methods: A total of 13 127 children with T1D, aged 6 to 18 years, were included in the analysis. Regression analysis was performed to investigate the relationship between diabetes duration, body mass index (BMI) standard deviation score (SDS), glycated haemoglobin (HbA1c) level, migration background, and the onset of puberty, stratified by sex. Results: Our findings revealed a significant trend towards earlier puberty in both girls and boys with T1D over the observed period (2000 to 2021). Puberty onset in girls (thelarche Tanner stage B2) decreased from 11.48 (11.35‐11.65) years in 2000 to 10.93 (10.79‐11.08) years in 2021 and gonadarche (Tanner stage G2/testicular volume >3 mL) decreased from 12.62 (12.42‐12.82) years in 2000 to 11.98 (11.79‐12.16) years in 2021 in boys (both P < 0.001). Longer diabetes duration, higher BMI SDS, and lower HbA1c level were associated with earlier puberty in both sexes (P < 0.001). Conclusions: Our study highlights earlier puberty in children with T1D, influenced by BMI SDS, HbA1c level, and migration background. This has important implications for diabetes management and supporting healthy development. Further research is needed to understand the underlying mechanisms and develop potential interventions for this vulnerable population. [ABSTRACT FROM AUTHOR]

Introduction: BMI or BMI-standardized deviation score (SDS) in children and adolescents is still the standard for weight classification. [BMJ. 2019;366:4293] developed a formula to calculate body fat percentage (%BF) based on age, sex, height, weight, and ethnicity. Using data from the German/Austrian APV registry, we investigated whether the calculated %BF is superior to BMI-SDS in predicting arterial hypertension, dyslipidaemia, and impaired glucose metabolism. Methods: 94,586 children and adolescents were included (12.5 years, 48.3% male). Parental birth country (BC) was used to depict ethnicity (15.8% migration background); 95.67% were assigned to the ethnicity "white." %BF was calculated based on the Hudda formula. The relationship between BMI-SDS or %BF quartiles and outcome variables was investigated by logistic regression models, adjusted for age, sex, and migration background. Vuong test was applied to analyse predictive power. Results: 58.4% had arterial hypertension, 33.5% had dyslipidaemia, and 11.6% had impaired glucose metabolism. Boys were significantly more often affected, although girls had higher calculated %BF (each p < 0.05). After adjustment, both models revealed significant differences between the quartiles (all p < 0.001). The predictive power of BMI-SDS was superior to %BF for all three comorbidities (all p < 0.05). Discussion: The prediction of cardiometabolic comorbidities by calculated %BF was not superior to BMI-SDS. This formula developed in a British population may not be suitable for a central European population, which is applicable to this possibly less heterogeneous collective. Additional parameters, especially puberty status, should be taken into account. However, objective determinations such as bioimpedance analysis may possibly be superior to assess fat mass and cardiometabolic risk than calculated %BF. [ABSTRACT FROM AUTHOR]

Context Low birthweight (bw) and unfavorable intrauterine conditions have been associated with metabolic sequelae in later life, but little is known about their impact on glucocorticoid metabolism. Objective We studied monozygotic twins with intratwin bw differences to analyze the long-term impact of bw on glucocorticoid metabolism. Methods 46 monozygotic twin pairs with bw differences of <1 SDS (concordant; n = 29) and ≥1 SDS (discordant; n = 17) were recruited. At 6.9 years (mean age), saliva samples were collected (at 7 hours, 13 hours, 18 hours and 21 hour) and analyzed with liquid chromatography–tandem mass spectrometry (LC-MS/MS). Results We found significant or highly significant intratwin correlations in all twin pairs at 3 of 4 (cortisol), and 4 of 4 (cortisone) time points. Graphic evaluation of the diurnal cortisol patterns for each twin pair showed a distinct alignment in all groups. Analyses of the change of intratwin differences over the day by mixed linear modeling showed no intratwin differences in diurnal patterns. Regression analyses of intratwin differences at 7:00 hours showed a significant influence of catch-up growth, indicating lower cortisol concentrations in smaller twins with more catch-up growth (adj. R2 = 0.159, P =.014, ß = −3.71, F(1,42) = 9.15, f2 = 0.19). Conclusion In monozygotic twins with intratwin bw differences, intratwin catch-up growth showed a moderate influence on intratwin differences in morning cortisol concentrations. We observed no differences regarding diurnal patterns. In contrast, in all groups, we found significant intratwin correlations for cortisol and cortisone over the day and a pronounced graphic alignment of cortisol diurnal patterns. We therefore suggest a predominant significance of the genetic background compared with bw differences on cortisol metabolism. [ABSTRACT FROM AUTHOR]

Background: Neonatal diabetes with congenital hypothyroidism (NDH) syndrome is a rare condition caused by homozygous or compound heterozygous mutations in the GLI-similar 3 coding gene GLIS3. Almost 20 patients have been reported to date, with significant phenotypic variability. Case presentation: We describe a boy with a homozygous deletion (exons 5-9) in the GLIS3 gene, who presents novel clinical aspects not reported previously. In addition to neonatal diabetes, congenital hypothyroidism and other known multi-organ manifestations such as cholestasis and renal cysts, he suffered from hyporegenerative anemia during the first four months of life and presents megalocornea in the absence of elevated intraocular pressure. Compensation of partial exocrine pancreatic insufficiency and deficiencies in antioxidative vitamins seemed to have exerted marked beneficial impact on several disease symptoms including cholestasis and TSH resistance, although a causal relation is difficult to prove. Considering reports on persistent fetal hemoglobin detected in a few children with GLIS3 mutations, the transient anemia seen in our patient may represent a further symptom associated with either the GLIS3 defect itself or, secondarily, micronutrient deficiency related to exocrine pancreatic deficiency or cholestasis. Conclusions: Our report expands the phenotypic spectrum of patients with GLIS3 mutations and adds important information on the clinical course, highlighting the possible beneficial effects of pancreatic enzyme and antioxidative vitamin substitutions on characteristic NDH syndrome manifestations such as TSH resistance and cholestasis. We recommend to carefully screen infants with GLIS3 mutations for subtle biochemical signs of partial exocrine pancreatic deficiency or to discuss exploratory administration of pancreatic enzymes and antioxidative vitamins, even in case of good weight gain and fecal elastase concentrations in the low-to-normal range. [ABSTRACT FROM AUTHOR]

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Context: Monocarboxylate transporter 8 (MCT8) deficiency is a rare X-chromosomal inherited disease leading to severe cognitive impairment, muscular hypotonia and symptoms of peripheral thyrotoxicosis. Experimental approaches aiming to functionally rescue mutant MCT8 activity by the chemical chaperone phenylbutyrate (PB) demonstrated promising effects in vitro for several MCT8 missense mutations., Objective: The objective was to evaluate biochemical and clinical effects of PB in doses equivalent to those approved for the treatment of urea cycle disorders in a boy with MCT8 deficiency due to a novel MCT8 missense mutation c.703G > T (p.V235L)., Results: During a treatment period of 13 months, PB led to a significant decrease of elevated TSH and T3 serum concentrations, while fT4 increased. Weight z-score of the toddler remained remarkably stable during the treatment period. Neurodevelopmental assessments (BSID-III) revealed a slight increase of gross motor skills from developmental age 4 to 6 months. However, increasing liver enzyme serum activities and accumulation of phenylacetate (PAA) in urine led to treatment interruptions and dose alterations. In vitro analyses in MDCK1 cells confirmed the pathogenicity of MCT8 p.V235L. However, while PB increased expression of the mutant protein, it did not rescue T3 transport, suggesting a PB effect on thyroid function tests independent of restoring MCT8 activity., Conclusion: In a clinical attempt of PB treatment in MCT8 deficiency we observed a significant improvement of thyroid hormone function tests, tendencies towards body weight stabilization and slight neurodevelopmental improvement. Hepatotoxicity of PB may be a limiting factor in MCT8 deficiency and requires further investigation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

While subclinical or overt hypothyroidism are common in Down syndrome (DS); Graves' disease (GD) is rare (ranges 0.6-3%). We aimed to evaluate the clinical features, course, and treatment of GD in children with DS and compare them with those without DS. Among 161 children with GD, 13 (8 female, 5 male) had DS (8%). Data were collected retrospectively from patients' medical records. The mean age at diagnosis was 10.6 ± 4.5 years, with a female-to-male ratio 1.6:1. The main symptoms were weight loss (n = 6), increased irritability (n = 3), and increased sweating (n = 3). None had orbitopathy. Seven of 11 patients with a thyroid ultrasound at diagnosis had a goitre. On admission, all had thyroid-stimulating hormone (TSH) <0.01 mU/L (normal range (NR): 0.51-4.30), free triiodothyronine, free thyroxine (mean ± s.d .), and thyrotrophin receptor antibodies (median, range) were 22.2 ± 10.2 pmol/L (NR: 3.5-8.1), 50.2 ± 18.7 pmol/L (NR 12.6-20.9), and 17.0 (2.89-159.0) U/L (NR <1), respectively. Patients were treated either with methimazole (n = 10) or carbimazole (n = 3), a dose of 0.54 ± 0.36 mg/kg/day. The treatment was 'block and replace' in ten patients and 'dose titration' in three patients, with a mean duration of 43.4 ± 11.0 months. Of 13 patients, four are still receiving primary treatment, three are in remission, one patient had two medically treated recurrences, three underwent surgery without complications, and two patients were lost to follow-up. Our data show that the clinical course of GD in patients with DS was similar to those without DS and suggest that a prolonged medical therapy should be the preferred option.

Context: Low birthweight (bw) and unfavorable intrauterine conditions have been associated with metabolic sequelae in later life, but little is known about their impact on glucocorticoid metabolism., Objective: We studied monozygotic twins with intratwin bw differences to analyze the long-term impact of bw on glucocorticoid metabolism., Methods: 46 monozygotic twin pairs with bw differences of <1 SDS (concordant; n = 29) and ≥1 SDS (discordant; n = 17) were recruited. At 6.9 years (mean age), saliva samples were collected (at 7 hours, 13 hours, 18 hours and 21 hour) and analyzed with liquid chromatography-tandem mass spectrometry (LC-MS/MS)., Results: We found significant or highly significant intratwin correlations in all twin pairs at 3 of 4 (cortisol), and 4 of 4 (cortisone) time points. Graphic evaluation of the diurnal cortisol patterns for each twin pair showed a distinct alignment in all groups. Analyses of the change of intratwin differences over the day by mixed linear modeling showed no intratwin differences in diurnal patterns. Regression analyses of intratwin differences at 7:00 hours showed a significant influence of catch-up growth, indicating lower cortisol concentrations in smaller twins with more catch-up growth (adj. R2 = 0.159, P = .014, ß = -3.71, F(1,42) = 9.15, f2 = 0.19)., Conclusion: In monozygotic twins with intratwin bw differences, intratwin catch-up growth showed a moderate influence on intratwin differences in morning cortisol concentrations. We observed no differences regarding diurnal patterns. In contrast, in all groups, we found significant intratwin correlations for cortisol and cortisone over the day and a pronounced graphic alignment of cortisol diurnal patterns. We therefore suggest a predominant significance of the genetic background compared with bw differences on cortisol metabolism., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To compare the changes in body weight and glycemic control before and during the COVID-19 pandemic in people with type 1 diabetes (T1D)., Methods: In 47,065 individuals with T1D from the German Diabetes Prospective Follow-up Registry (DPV), we compared the adjusted mean changes in BMI-Z-scores and HbA1c as well as the distribution of individual changes between four periods from March 2018 to February 2022, by sex and age group (4- < 11, 11- < 16, 16-50 years)., Results: At population level, the only significant pandemic effects were a slight increase in BMI Z-score in prepubertal children (girls: + 0.03 in the first COVID year vs. before, P < 0.01; boys: + 0.04, P < 0.01) as well as a stabilization of HbA1c in all subgroups or even improvement in women (- 0.08%, P < 0.01). At individual level, however, heterogeneity increased significantly (p < 0.01), especially in children. More prepubertal children gained weight (girls: 45% vs. 35% before COVID; boys: 39% vs. 33%). More pubertal girls lost weight (30% vs. 21%) and fewer gained weight (43% vs. 54%). More children had a decreasing HbA1c (prepubertal group: 29% vs. 22%; pubertal girls: 33% vs. 28%; pubertal boys: 32% vs. 25%) and fewer had increasing values. More women had stable HbA1c and fewer had increasing values (30% vs. 37%). In men, no significant changes were observed., Conclusion: This real-world analysis shows no detrimental consequences of the two first COVID years on weight and HbA1c in T1D on average, but reveals, beyond the mean trends, a greater variability at the individual level., Competing Interests: Competing InterestsThe authors declare no conflicts of interest., (© The Author(s) 2023.)

Background: Genes, hormones and factors such as nutrition and psychosocial environment affect growth., Objective: What is the significance of various psychosocial factors on growth?, Methods: Evaluation of results of a working meeting of paediatric endocrinologist with current literature research., Results: Psychosocial deprivation in children can be associated with growth hormone deficiency (GHD) and short stature. GHD can be reversed by a change of environment and psychosocial support. War and migration are often associated with underweight, growth disturbances and poor health care. These factors can improve after the end of conflicts, but children often remain too short. Consumption of alcohol or opiates during pregnancy are associated with lower birth weight and increased risk of early and small for gestational age (SGA) childbirth. Children with attention deficit hyperactivity disorder show a slight slowdown in growth after they started stimulant therapy. However, they reach normal adult height., Conclusions: In children with idiopathic short stature, psychosocial causes should be taken into account in the differential diagnosis. Notably there is an increased risk of growth disturbances in children from conflict regions or after prenatal drug exposure., Competing Interests: Im Rahmen des Workshops „Wachstum-Plus“ am 08.11.2019 in Frankfurt/Main wurden von den Autoren nach aktueller Literaturrecherche Vorträge zum Thema „Wachstum und Psyche bzw. Drogen“ gehalten, die Themen mit allen Co-Autoren diskutiert und im Konsensus in diesem Manuskript zusammengefasst. Der Workshop „Wachstum-Plus“ wurde von der Pfizer Pharma GmbH ausgerichtet und finanziert. Pfizer hatte dabei keinen Einfluss auf die inhaltliche Ausgestaltung und die Ergebnisse. Alle Autoren erhielten für die Literaturrecherche und Vorstellung der Ergebnisse ein Honorar von Pfizer. Ferner wurden die Reisekosten von der Firma Pfizer übernommen., (Thieme. All rights reserved.)