Hormone Research in Paediatrics最新文献

Introduction: Children with type 1 diabetes mellitus (T1D) have an increased risk of developing celiac disease (CeD), and those with comorbid conditions face increased healthcare demands. This study assessed celiac serology diagnostic performance and CeD follow-up rates in children with T1D and CeD.

Methods: Single-center retrospective review of children (≤18 years) diagnosed with T1D between 2000 and 2021. Controls included children with CeD without T1D, matched on age and gender at tissue transglutaminase (TTG) IgA positivity. Screening for CeD was done following T1D diagnosis. AUC-ROC was used to determine a TTG IgA cutoff for discriminating between those with confirmed CeD and those without CeD. Kaplan-Meier and Cox proportional hazard analyses were used to test whether children with T1D+CeD had different times to TTG IgA normalization than children with CeD-only. Negative-binomial regression was used to test whether children with T1D+CeD had different rates of follow-up with pediatric gastroenterology than children with CeD-only.

Results: Among 734 children with T1D, 591 (80.5%) underwent TTG IgA screening. A total of 70 (11.8%) had positive TTG IgA; of those, 43 (61.4%) had confirmed CeD. TTG IgA ≥3.62 times upper limit of normal (ULN) discriminated between biopsy-confirmed CeD and those without CeD (sensitivity 90%, specificity 92%, PPV 93%, NPV 89%). Among 37 children with T1D with positive TTG IgA and endomysial antibody (EMA), 25 had positive EMA (21 confirmed CeD), while 12 had negative EMA (none with CeD) (sensitivity 100%, specificity 75%, PPV 84%, NPV 100%). TTG IgA normalization took longer in T1D+CeD compared to CeD-only (median 6.5 versus 1.2 years, p < 0.001). Pediatric Gastroenterology CeD follow-up rates were lower in T1D+CeD subjects (0.33 versus 0.48 visits per person-year, p < 0.001).

Conclusion: TTG IgA ≥3.6 times ULN or positive EMA is recommended to proceed with CeD confirmation. In cases of mild TTG IgA positivity, EMA can guide CeD confirmation given its high negative predictive value.

Introduction: The COVID-19 pandemic necessitated worldwide lockdowns in 2020 and 2021, with restrictions on physical activity and changes in eating habits. The aim of this study was to investigate temporal trends in body mass index (BMI) and BMI Standard Deviation Score (SDS) in three international type 1 diabetes (T1D) registries between 2018 and 2021.

Methods: Data were extracted from DPV (Germany/Austria/Luxembourg/Switzerland), T1D Exchange Quality Improvement Collaborative (T1DX-QI, USA), and the Australasian Diabetes Data Network (ADDN, Australia/New Zealand). The period affected by the COVID-19 pandemic was defined as March to December 2020 and March to December 2021 and compared with the respective 9-month periods in 2018 and 2019. Estimated mean BMI (adults ≥19 years) and WHO BMI SDS (children and adolescents 5 to <19 years) were calculated, adjusted for sex, age, HbA1c, and diabetes duration. Adjusted mean proportions overweight (BMI ≥25 in adults or BMI SDS >1 in children and adolescents 5 to <19 years) and obese (BMI ≥30 kg/m2 or BMI SDS >2 in children and adolescents 5 to <19 years) were also calculated, adjusted for sex, age, HbA1c, and diabetes duration.

Results: The study population comprised: ADDN (n = 14,624, median age 15.7 years, 51% male); DPV (n = 62,732, 16.1 years, 53.3% male); and T1DX-QI (n = 22,942, 17.1 years, 52.1% male). In the DPV registry, BMI SDS in children and adolescents and BMI in adults increased consistently between 2018 and 2021 (p < 0.001). In ADDN and T1DX-QI, variable changes in BMI and BMI SDS were seen in adults and young people. Close to 50% of people in all registries were either overweight or obese. Proportions overweight remained relatively stable across the 4 years. The proportion of obesity increased in children 5 to <10 years.

Conclusions: A slight increase in BMI and BMI SDS observed before the pandemic continued during the pandemic years. The proportion of overweight and obesity was overall high. Healthy weight remains a priority for people with T1D.

Introduction: Vosoritide is a C-type natriuretic peptide (CNP) analog that binds its receptor on chondrocytes, promoting growth by inhibiting the ERK1/2-MAPK pathway. We previously reported the results of a phase II study in children with hypochondroplasia. Vosoritide led to an average increase in annualized height velocity (AHV) of 1.81 cm/year and gain of 0.36 in height standard deviation (SD) over 12 months. We present here the pharmacokinetic/pharmacodynamic (PK/PD) data from this study and examine the correlations between these parameters and growth outcomes.

Methods: We conducted a phase II trial of daily subcutaneous vosoritide (15 μg/kg/day) in 24 prepubertal subjects with hypochondroplasia (12 females, mean age 5.9 ± 2.3 years, mean height -3.29 + 0.68 SD). Plasma vosoritide levels were assayed using an electrochemiluminescence assay. PD markers including serum collagen X biomarker (CXM) and urine cyclic guanosine monophosphate (cGMP) production were measured at day 1, month 6, and month 12 visits. Pearson correlations and regression analyses were performed between PK and PD parameters and growth outcomes.

Results: Vosoritide PK parameters were similar to those previously reported in patients with achondroplasia. CXM levels increased from a baseline mean of 22.5 ± 6.5 to 41.6 ± 15.9 ng/mL after 12 months of treatment (p < 0.0001). Urine cGMP increased within 1 h and peaked at 2 h after injection. The mean AUC for cGMP production was not significantly different at each study visit. The maximum change in cGMP AUC correlated with PK AUC (r = 0.46, p = 0.0001). However, drug exposure, as measured by average PK AUC, did not correlate with any growth outcome. CXM levels correlated with the prior 6-month interval height velocity (partial correlation coefficient = 0.40, p = 0.0048). However, change in CXM did not correlate with change in height velocity or change in height SD during treatment.

Conclusions: Vosoritide treatment showed improvement in AHV and height SD in children with hypochondroplasia. PK analysis indicates that drug exposure was correlated to global CNP activity as measured by urine cGMP but did not correlate with growth outcomes. More studies are needed to identify specific patient characteristics that can predict response to therapy and clinical outcomes.

In the article by Bayrak Demirel et al. entitled "Thyrotoxic Hypokalemic Periodic Paralysis Induced by High-Dose Insulin in an Adolescent Male with Type 1 Diabetes Mellitus" [Horm Res Paediatr. 2024, DOI: 10.1159/000543329] the license was incorrect, and it has been changed from CCC to CC BY-NC 4.0.

Introduction: Diabetic ketoacidosis (DKA) is the leading cause of mortality among youth with type 1 diabetes (T1D). Guidelines for DKA prevention exist; however, specific guidance about when to check ketones and how to manage youth using insulin pumps and automated insulin delivery (AID) systems is lacking.

Methods: A 35-item online survey exploring clinical ketone management practices for youth with T1D in the USA was distributed to diabetes healthcare professionals (HCPs). Survey responses, including multiple-choice and Likert scale questions, were summarized and rates of agreement and disagreement (Likert scale 4, 5 vs. 1, 2, 3) are reported.

Results: In total, 123 HCPs (51% physicians, 26% diabetes educators, 19% nurse practitioners) from 47 institutions completed the survey. Seventy percent worked at academic specialty centers. Ninety-seven percent reported >50% continuous glucose monitoring use in their clinic and 72% reported >50% insulin pump use. Although 79% reported having ketone management protocols, the level and duration of hyperglycemia at which ketone monitoring was advised ranged from >200 to 350 mg/dL and from 0 min to >6 h of duration. While 72% had distinct ketone management protocols for pump users, only 29% had specific protocols for AID. Sixty-two percent agreed that DKA due to infusion site failure was a significant problem in their practice, and 70% agreed there was a need to standardize ketone management guidelines.

Conclusions: The preventable nature and high incidence of DKA highlight the need to build consensus for clinical ketone management and to develop tools to facilitate management, especially as the use of diabetes technologies continues to increase.

Introduction: Managing exercise remains challenging for adolescent athletes with type 1 diabetes (T1D), especially in contact sports. Even the use of hybrid closed loops can cause problems due to the need to disconnect the pump during some training or competitions. This study evaluated the efficacy of a novel protocol for the use of an advanced hybrid closed-loop system in adolescent football players with T1D during a sports camp.

Methods: Eleven boys aged 14.9 years (25-75th percentile: 14-15.5), with a diabetes duration of 5.7 years (5.2-7) and regular training schedules in junior football leagues, participated in the study. They started AHCL (MiniMed780G, Medtronic) therapy a month before a week-long sports camp and were observed during the sports camp and the preceding week. Daily camp activities included two 1.5-h training sessions. Protocol included a 90-min temporary target of 150 mg/dL before and insulin pump disconnection during training. Physical activity was tracked using wGT3X-BT Actigraph monitors.

Results: The camp provided conditions of demanding physical activity (6.6 [6-6.9] h/day of moderate-to-vigorous intensity). After starting AHCL, the average participant time spent in the target glucose range (70-180 mg/dL) was 79.34 ± 8.46%, and no significant change was observed during the camp (mean difference +0.79 ± 8.24%, p = 0.7581). Median glucose levels dropped by 10.91 ± 12.08 mg/dL (p = 0.0134), and time in the tight target range increased by 11.41 ± 11.60% (p = 0.0008) without increasing the time below range (<70 mg/dL) or glycemic variability. During the camp, daily insulin dose and basal/bolus ratio remained comparable with baseline, but the relative amount of automated bolus insulin decreased by 14.24 ± 4.65% (p < 0.0001).

Conclusion: The predefined regimen, including a temporary target before and disconnection of AHCL during football training, was safe and may provide satisfactory glucose control in active adolescents with T1D. This protocol could be adapted for use in other intensive contact sports.

Introduction: Pathogenic variants in the genes involved in the formation of thyroid tissue and thyroid hormone secretion have been reported to cause congenital hypothyroidism (CH) in some cases. This study aimed to evaluate the clinical and genetic findings of CH cases thought to be due to genetic variants.

Methods: The study included cases whose genetic analysis was performed in accordance with the Congenital Hypothyroidism: A 2020-2021 Consensus Guidelines Update Guidelines recommendations criteria and analyzed them using the next-generation sequencing panel.

Results: Sixty one Turkish patients from 45 families were included in the study. The overall frequency of variant detection was 37.7% (out of 45 families, 17 had a positive mutation). Segregation was carried out for all families with positive variants. Variants in the TPO gene are the most frequently encountered, and this situation was identified in 10 families. Variants followed this in the TSHR gene in 7 families, variants in the DUOX2 gene in 5 families, and two variants in the TG and NKX2-1 genes in 2 families each, which are six novel variants. Furthermore, among the NKX2-1 cases, one had thyroid involvement only, while the other had chorea only. We did not find differences between cases with detected mutations and mutation-negative cases regarding gender, neonatal/perinatal parameters, initial thyroid function values, and thyroid morphology.

Conclusion: In the current investigation, rare new variations in genes known to be related to CH were discovered, adding to the molecular genetic spectrum. When we compare the overall variant detection frequency, the selection criterion for genetic analysis based on the current guidelines is quite rational, considering the benefits and costs, on the other hand, present in new genes awaiting discovery. Also, TSHR mutations are likely to be common and may account for more than 5% of thyroid dysgenesis cases if we include nonfamilial thyroid dysgenesis.

Introduction: This survey investigates brain MRI practices for isolated GHD among Pediatric Endocrine Society (PES) members, focusing on gadolinium-based contrast agents (GBCAs) versus non-contrast MRI.

Methods: A 15-question survey was distributed to 1,553 PES members, capturing data on GBCA usage, non-contrast imaging access, and awareness of gadolinium retention.

Results: A total of 85% of respondents routinely order brain MRIs for isolated GHD, with 60% using GBCAs. Most respondents have access to high-resolution non-contrast imaging, though 54% are unaware of gadolinium retention risks.

Conclusion: High-resolution non-contrast MRI demonstrates diagnostic efficacy, suggesting a shift away from GBCAs in clinic practice for isolated GHD. The survey forms the basis to update PES guidelines in the evaluation of isolated GHD.

Introduction: Precocious puberty is defined as the appearance of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. Central precocious puberty (CPP) is a rare condition that is diagnosed when premature activation of the hypothalamic-pituitary-gonadal axis is detected, in association with precocious breast development or testicular growth. Idiopathic CPP is historically considered to be the most common form, but in recent years defects in a small but growing number of genes regulating the timing of puberty have been identified in an increasing proportion of cases of CPP. Delta-like non-canonical Notch ligand 1 (DLK1) is understood to be one of the key genes involved in the etiology of CPP, although its mechanistic role is not yet fully understood.

Case presentation: We identified a novel de novo variant of DLK1 (c.835C>T; p.Gln279*) in an 8-year-old girl of Bangladeshi origin. She presented with an advanced Tanner staging of B4P4A2, significantly advanced bone age (BA, 13 years), a near-adult proportioned uterus, with a history of menarche at the age of 7.4 years. Diagnosis was confirmed by raised basal luteinizing hormone concentration. She was found to have truncal obesity associated with abnormal fasting insulin levels and mildly elevated cholesterol levels. These findings are consistent with previous literature describing an association between patients with DLK1 deficiency and an impaired metabolic profile. The patient was treated for 2 years with GnRH agonists with ongoing biochemical follow-up into adolescence.

Conclusion: This case illustrates the susceptibility to metabolic derangement for patients with mutations in DLK1 and the need for ongoing monitoring after puberty. Our summary of previously identified DLK1 variants and their metabolic consequences demonstrates the frequency of obesity, lipid abnormalities, and insulin dysregulation in this patient cohort in childhood and beyond. This knowledge can guide future clinical practice for patients with CPP patients due to DLK1 deficiency.