Marta Ramon-Krauel

Background: Long-acting growth hormone (LAGH) formulations have emerged as an alternative to daily recombinant human growth hormone (rhGH) in pediatric growth hormone deficiency (GHD). Although evidence from meta-analyses and randomized trials supports their efficacy and safety, real-life data are still lacking, and therefore clinical guidance on their implementation remains limited. Objective: To develop expert-based recommendations for the clinical use of LAGH in pediatric GHD within Spain. Methods: A two-round Delphi approach was used. Based on a literature review, a scientific committee comprised of pediatric endocrinologists developed a questionnaire structured into three domains: (1) Main benefits of LAGH vs . daily rhGH; (2) Candidate profiles for LAGH therapy; and (3) Considerations for initiating LAGH and treatment monitoring. Panelists rated their level of agreement with each questionnaire statement on a 9-point Likert scale. Consensus was defined as ≥66.67% of responses on the same tertile as the median, labelled as disagreement on scores of 1–3, intermediate on scores of 4–6, and agreement on scores 7–9. Statements that did not reach consensus were reformulated and re-evaluated in round 2. Results: After two rounds, all statements achieved consensus on agreement. Specifically, consensus was reached on 92% of the statements in round 1 and three revised items related to insulin-like growth factor-1 (IGF-1), pharmacokinetics and dose adjustment criteria, as well as the use of LAGH in patients at risk of hypoglycemia, achieved consensus in round 2. The recommendations emphasize the similar efficacy and safety of LAGH compared to rhGH, raising its special interest in cases of poor adherence to daily formulations (e.g. adolescents, injection-related anxiety, multiple comorbid treatments or complex family circumstances), although LAGH should also be considered in other settings in a patient-centered approach. In addition, they provide guidance on key issues related to adequate dose initiation and titration, as well as therapeutic monitoring. Conclusion: This is the first Delphi consensus to provide national-level guidance on integrating LAGH into pediatric GHD care, offering practical recommendations based on current evidence and national expert opinion. Future long-term real-world experience will contribute to address questions regarding long-term efficacy and safety, and practice-related points such as indication and monitoring.

Childhood obesity is a significant concern and its chronic nature results in an increased risk of adulthood obesity. Poorly planned transition from pediatric to adult care may contribute to poor outcomes. Failed transition may result in loss to follow-up or inadequate treatment adherence. In other chronic diseases, the transition is well organized. However, although obesity societies highlight its importance, no specific guidelines are available to properly accomplish this procedure. In order to fill this gap, an interdisciplinary group consisting of pediatric endocrinologists, adult endocrinologists and primary care practitioners combined forces to develop a set of agreed recommendations to guide the transition of adolescents living with obesity (AlwOs) from pediatric to adult healthcare. Three well-defined phases were identified: preparation of transfer, transfer and reception in adult care. Specific suggestions, accompanied by infographic support, are provided for each one of them. The authors agreed to underline several important issues: there is no ideal age to initiate transition, which is contingent upon individual characteristics; the figure of a transition coordinator is pivotal; pre-transfer sessions with participation of pediatric and adult teams are required to guarantee continuity of care; transfer should start only if AlwO/caregivers agree; transfer sessions should start under control of the pediatric provider, and leadership should be progressively taken over by the adult doctor, who should be adequately trained to manage patients with a troublesome condition at a critical age; at reception in adult care, a detailed long-term management and follow-up plan has to be agreed with the AlwO. Finally, tools to assess quality of the procedure are provided. In summary, guidance to manage the AlwO’s transition in the daily practice is supplied.

Context: The Global Increlex® Growth Forum Database (IGFD) Registry monitors real-world effectiveness and safety of recombinant human IGF-1 (rhIGF-1; Increlex® [mecasermin]) treatment in children and adolescents with severe growth failure due to severe primary IGF-I deficiency (SPIGFD). Objective: To report characteristics, effectiveness, and safety data from patients receiving rhIGF-1 treatment who achieved near-adult height (NAH), and determine factors that predict height gain to NAH. Methods: Descriptive analyses of patients included in the Global IGFD Registry (NCT00903110) who achieved NAH are reported for the overall population, treatment-naïve prepubertal (NPP) patients, and patients with Laron syndrome. Linear regression analyses of height gain to NAH are also reported. Results: One hundred and two patients enrolled in the Global IGFD Registry achieved NAH at data cut-off (April 20, 2023). Mean age at rhIGF-1 treatment initiation was 11.8 years; median treatment duration was 3.9 years. Mean (SD) height SD score (HtSDS) gain from rhIGF-1 initiation to NAH was 0.9 (1.1). In NPP patients, mean (SD) HtSDS gain was 1.4 (1.0). Almost half of NPP patients reached NAH within the normal range. Despite improved height in patients with Laron syndrome, only 10.5% reached NAH within the normal range; 3 patients with Laron syndrome were NPP. Treatment naivety was predictive of height gain in the overall NAH population. Safety data aligned with previous reports. Conclusion: In a real-world setting, despite patients with SPIGFD initiating rhIGF-1 treatment at a relatively advanced age, rhIGF-1 treatment resulted in improved NAH. The greatest improvements in height outcomes were observed in NPP patients. Trial registration: NCT00903110.

Although bariatric and metabolic surgery (BS) has proved effective in the treatment of obesity based on the reduction in fat mass and the remission of comorbidities, there is also loss of lean mass after BS which could compromise muscle functionality. According to the European Working Group on Sarcopenia in Older People (EWGSOP), sarcopenia is a disease associated with loss of muscle mass, strength, and function. Through a comprehensive review of the literature, we identified a range of studies focusing on evaluating sarcopenia-related parameters according to the EWGSOP2 consensus criteria, before and after BS. Although most studies reported reductions in skeletal muscle mass and absolute muscle strength after surgery, improvements in muscle functionality were generally achieved, independent of the type of BS.

Nutritional challenges and obesity can contribute to the transmission of metabolic diseases through epigenetic mechanisms. Among them, DNA methylation stands out as a potential carrier of information because germline cytosine methylation responds to environmental factors and can be transmitted across generations. Yet, it remains unclear whether inherited DNA methylation plays an active role in the inheritance of metabolic phenotypes or solely influences expression of a few genes that cannot recapitulate the whole metabolic spectrum in the next generation offspring. Previously, we established a mouse model of childhood obesity by reducing litter size at birth. Mice raised in small litters (SL) developed obesity, insulin resistance, and hepatic steatosis. The offspring (SL-F1) and grand-offspring (SL-F2) of SL males also exhibited hepatic steatosis. Here, we aimed to investigate whether germline DNA methylation could serve as a carrier of phenotypic information, hepatic steatosis, between generations. Litter size reduction significantly altered global DNA methylation profile in the sperm of SL-F0 males. Remarkably, 8% of these methylation marks remained altered in the sperm of SL-F1 mice and in the liver of SL-F2 mice. These data suggest that germline DNA methylation is sensitive to environmental challenges and holds significant heritability, either through direct germline transmission and/or through sequential erasure and reestablishment of the marks in the following generations. Yet, DNA methylation did not strongly correlate with the hepatic transcriptome in SL-F2 mice, suggesting that it does not directly drive phenotypes in the F2. As an alternative, germline DNA methylation could potentially influence the phenotype of the next generation by modulating the expression of a reduced number of key transcription factors that, through an amplification cascade, drive phenotypic outcomes in subsequent generations.

Context The European Increlex® Growth Forum Database (Eu-IGFD) is an ongoing surveillance registry (NCT00903110) established to collect long-term safety and effectiveness data on the use of recombinant human insulin-like growth factor-1 (rhIGF-1, mecasermin, Increlex) for the treatment of children/adolescents with severe primary insulin-like growth factor-1 deficiency (SPIGFD). Objective This analysis of Eu-IGFD data aimed to identify the frequency and predictive factors for hypoglycemia adverse events (AEs) in children treated with rhIGF-1. Methods Data were collected from December 2008 to May 2021. Logistic regression was performed to identify predictive risk factors for treatment-induced hypoglycemia AEs. Odds ratios (ORs) are presented with 95% CIs for each factor. Results In total, 306 patients were enrolled in the registry; 84.6% were diagnosed with SPIGFD. Patients who experienced ≥ 1 hypoglycemia AE (n = 80) compared with those with no hypoglycemia AEs (n = 224) had a lower mean age at treatment start (8.7 years vs 9.8 years), a more frequent diagnosis of Laron syndrome (27.5% vs 10.3%), and a history of hypoglycemia (18.8% vs 4.5%). Prior history of hypoglycemia (OR 0.25; 95% CI: [0.11; 0.61]; P = .002) and Laron syndrome diagnosis (OR 0.36; 95% CI: [0.18; 0.72]; P = .004) predicted future hypoglycemia AEs. Total hypoglycemia AEs per patient per treatment year was 0.11 and total serious hypoglycemia AEs per patient per treatment year was 0.01. Conclusion Hypoglycemia occurs more frequently in patients with prior history of hypoglycemia and/or Laron syndrome compared with patients without these risk factors, and these patients should be carefully monitored for this AE throughout treatment.

Although the prevalence of pediatric obesity is rising, understanding of the perceptions, attitudes, behaviors, and barriers to effective obesity care among Spanish adolescents living with obesity (ALwO), their caregivers, and healthcare professionals (HCPs) is lacking. In 2021, the cross-sectional ACTION Teens survey study was conducted in 10 countries; results from the Spanish cohort are presented herein. The survey was completed by 648 ALwO, 644 caregivers, and 251 HCPs in Spain. A total of 25% of ALwO and 43% of caregivers thought that their/their child’s weight was normal, and more caregivers than ALwO perceived the ALwO’s health to be at least good (95% vs. 59%, respectively). Only 53% of ALwO and 9% of caregivers reported receiving an obesity diagnosis, despite HCPs reporting they provide diagnoses to 87% of ALwO/caregivers. Although 65% of HCPs felt that ALwO may not be comfortable discussing weight, only 26% of ALwO who had discussed weight with an HCP (n = 488) reported not feeling comfortable. Inability to control hunger was a key barrier to ALwO losing weight identified by ALwO/caregivers, but not HCPs. Improved communication between the three groups, a better understanding of barriers to weight loss, and improved health education on obesity are needed in order to enhance obesity care in Spain.

Childhood obesity increases the risk of developing metabolic syndrome later in life. Moreover, metabolic dysfunction may be inherited into the following generation through non-genomic mechanisms, with epigenetics as a plausible candidate. The pathways involved in the development of metabolic dysfunction across generations in the context of childhood obesity remain largely unexplored. We have developed a mouse model of early adiposity by reducing litter size at birth (small litter group, SL: 4 pups/dam; control group, C: 8 pups/dam). Mice raised in small litters (SL) developed obesity, insulin resistance and hepatic steatosis with aging. Strikingly, the offspring of SL males (SL-F1) also developed hepatic steatosis. Paternal transmission of an environmentally induced phenotype strongly suggests epigenetic inheritance. We analyzed the hepatic transcriptome in C-F1 and SL-F1 mice to identify pathways involved in the development of hepatic steatosis. We found that the circadian rhythm and lipid metabolic process were the ontologies with highest significance in the liver of SL-F1 mice. We explored whether DNA methylation and small non-coding RNAs might be involved in mediating intergenerational effects. Sperm DNA methylation was largely altered in SL mice. However, these changes did not correlate with the hepatic transcriptome. Next, we analyzed small non-coding RNA content in the testes of mice from the parental generation. Two miRNAs (miR-457 and miR-201) appeared differentially expressed in the testes of SL-F0 mice. They are known to be expressed in mature spermatozoa, but not in oocytes nor early embryos, and they may regulate the transcription of lipogenic genes, but not clock genes, in hepatocytes. Hence, they are strong candidates to mediate the inheritance of adult hepatic steatosis in our murine model. In conclusion, litter size reduction leads to intergenerational effects through non-genomic mechanisms. In our model, DNA methylation does not seem to play a role on the circadian rhythm nor lipid genes. However, at least two paternal miRNAs might influence the expression of a few lipid-related genes in the first-generation offspring, F1.

Background: Children with obesity have a higher risk of future health and psychological problems. Executive functions (EFs) play a key role in successful dietetic and exercise planning; therefore, new treatments aimed at improving EFs may optimize outcomes. Objectives: This study evaluates the impact of EF training on body mass index (BMI), food choice, and cognition in children with obesity. We also examine their real-life executive functioning, emotional state, and quality of life. Methods: Randomized controlled double-blind trial. Forty-six children with obesity were randomly allocated into an executive functions training or a control task training group and attended 30–45 min of daily training (5/week over 6 weeks), with both groups receiving counseling on diet and wearing an activity/sleep tracker. Participants were evaluated at baseline and after treatment. Results: BMI decreased over time in the whole sample, although there were no differences between groups at post-training in BMI, food choice, and cognition. Both groups showed significant improvements in attention, speed, cognitive flexibility, and inhibitory control. Additionally, there were some benefits in real-life executive functioning and self-esteem. Over the 6 weeks, participants showed worse food choices in both groups. Conclusions: EFs training showed a lack of significant effects. The executive function enhancement alone did not explain these changes, as there were no significant differences between the experimental groups. It might be that the control task training could also produce some benefits, and multi-component interventions might be useful for weight loss.