Egidio Candela

The studies on statural growth and pubertal development have always represented the hallmark of pediatric endocrinology and a consistent number of studies has been published in the last 50 years. Although the knowledges on growth and, puberty have greatly improved, many questions remain unanswered, particularly about human-environment interactions, genetic background, neuroendocrine regulation, and nutritional and metabolic status. Our special issue, published jointly in Frontiers in Endocrinology and Frontiers in Pediatrics, emphasizes these aspects and aims to add new insights to the existing body of knowledge. Early activation of the hypothalamic-pituitary-gonadal (HPG) axis, which underlies central precocious puberty (CPP), is one of the clearest examples of the complexity of these processes, and several colleagues have contributed to this topic. In their study, Liu et al. analyzed polymorphisms in the estrogen receptor β (ERβ) gene in girls with idiopathic CPP. Certain polymorphisms, primarily the ERβ gene RsaI and Rraa haplotypes, appear to be associated with an increased risk of idiopathic CPP and may therefore serve as prognostic and risk factors. Another study by Morrou et al. highlighted differential expression of circulating microRNAs between girls with CPP and healthy controls, with higher expression in the former of pathways associated with this neurological condition. Specifically, miR-148a-3p increased markedly in extracellular vesicles, supporting the hypothesis that post-transcriptional regulation may contribute to early activation of the HPG axis. The study also lays the groundwork for linking mechanistic research to the identification of minimally invasive biomarkers. As mentioned earlier, environmental factors can also play a key role in this context. Nie et al. focus specifically on the role of exposure to bisphenol A, widely used in plastic manufacturing, in precocious puberty, using computational analyses that link this substance to various potential molecular targets. On the same topic, the mini-review by Maria Elisa Amodeo et al. attempts to bring together the various causes, primarily genetic and environmental, underlying PPC in males. One period when environmental pressure was greatest was the COVID-19 pandemic, during which many centers, including ours, reported a significant increase in CPP cases. (1,2)The increasing biological complexity of CPP has direct implications for its diagnosis. A particularly interesting study by Yuan et al., involving 1,077 premenarcheal girls with idiopathic CPP, found that BMI correlated with basal LH levels and other markers of pubertal development. These findings align with other global evidence, particularly because they highlight the need to assess patients beyond biochemical values and consider a broader range of factors (3). This issue is especially relevant to using basal LH as a diagnostic marker of HPG-axis activation (4).The Endocrine Society's recent 2026 guidelines also point in this direction, suggesting an integrated approach that is not limited to biochemistry (5).During puberty, there is also a particular window of opportunity to assess adrenal function, as shown in the study by Zhang et al., which used liquid chromatography coupled with tandem mass spectrometry in adolescent girls with polycystic ovary syndrome. These methods documented multiple alterations in androgen metabolic pathways in these patients, with the free androgen index also proving particularly effective for diagnosis, in line with other studies (6).The transition from static categories toward longitudinal phenotypes is also evident in growth assessment. Gürlek et al. examined familial, constitutional, and combined forms of idiopathic short stature, emphasizing their heterogeneous developmental trajectories and the importance of pubertal timing in interpreting longitudinal growth in a retrospective cohort of 171 children. In particular, the study recommends that clinicians always conduct a longitudinal growth assessment before starting r-GH therapy, considering a wide range of parameters and the high rate of spontaneous improvement, especially after puberty. Although recombinant GH has an overall favorable safety profile, its systemic growth-promoting effects warrant appropriate clinical surveillance (7). Concerns have been raised about its potential influence on pre-existing structural abnormalities, such as Chiari malformation, although available evidence remains reassuring (8).Ruiz del Olmo-Izuzquiza et al. prospectively assessed cardiac morphology and function alongside aerobic performance. Given the expected increase in left ventricular mass, the study observed physiological cardiac remodeling rather than pathological hypertrophy, with preserved systolic function and early subclinical improvements in cardiac contractility. Alongside these safety considerations, one of the most promising and innovative tools to emerge in recent years is the use of predictive models to tailor follow-up for these patients. Ly et al., using interpretable predictive models in boys receiving growth hormone therapy, identified current IGF-1 SDS as the strongest predictor of subsequent IGF-1 levels, while treatment-and puberty-related variables provided additional predictive information.A review by Li and Wang analyzed the effects of systemic glucocorticoid exposure during childhood, focusing on changes in myocardial structure and cardiac function. The data, broken down by age group, are still limited and suggest that structural changes most often manifest as treatment-reversible myocardial hypertrophy, whilst evidence supporting permanent structural damage remains insufficient.

Aim: This study compares the efficacy and safety of three levothyroxine (LT4) formulations in pediatric patients with congenital hypothyroidism (CH). Methods: This is a retrospective-prospective observational monocentric study conducted at the Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy. Patients’ data were collected from diagnostic confirmation following CH positivity on newborn screening (occurring between January 2019 and April 2024) through age 3 years. According to the LT4 pharmaceutical formulation used in routine clinical practice, patients were assigned to one of three specific groups: T (tablets), D (oral drops), or S (oral solution). Results: 82 patients were enrolled (group D, N = 30; group S, N = 25; group T, N = 27). At 7–15 days of follow-up, the median TSH concentration was significantly higher in group S compared with group T ( p = 0.020). Accordingly, the proportion of patients with serum TSH concentrations above the reference range was significantly higher in group S compared with group T at this time point ( p = 0.005). Another difference was observed at 12 months of follow-up, when the proportion of patients with serum fT4 concentrations below the reference range was higher in group D than in groups S and T ( p = 0.011). No treatment-related adverse effects were observed with any formulation. Conclusion: The three LT4 formulations were equally effective in normalizing and maintaining serum TSH and fT4 within reference ranges. However, the clinical relevance of the differences observed at specific time points requires further investigation.

Background/Objectives: Glycogen storage disease type IX (GSD IX) is an inherited metabolic disorder characterized by marked clinical heterogeneity and variable severity. Dietary therapy is considered the cornerstone of management, but evidence on treatment strategies, efficacy, and safety remains limited. This study aimed to systematically synthesize available data on therapeutic approaches and clinical outcomes in GSD IX. Methods: A focused analysis of treatment-related data was conducted from a previously performed PRISMA-based systematic review. Clinical studies reporting treatment and follow-up data in genetically confirmed GSD IX patients were included. Results: Among 400 patients identified in the original review, 129 from 26 studies had treatment and follow-up data available. Dietary management combined with uncooked cornstarch (UCCS) was the most common approach (96.1%), with highly heterogeneous protocols. Hepatic manifestations improved in 59/129 (45.7%) of patients, and hypoglycemia in 45/129 (34.9%). Growth outcomes were variable, with catch-up growth in 14.0% and persistent impairment in 19.4%, although data were often missing. Muscle involvement was rarely assessed. No treatment-related adverse events were reported. However, disease-related complications were described, including liver cirrhosis, neurological involvement, osteopenia/osteoporosis, and two deaths in GSD IXa patients. Conclusions: Dietary therapy combined with UCCS remains the mainstay of treatment in GSD IX and is associated with improvement in key clinical domains. However, evidence is limited, heterogeneous, and largely based on small studies. Data on modified cornstarch formulations, such as Glycosade^®, are scarce. Prospective studies and standardized treatment protocols are needed to support evidence-based management.

Background - Inherited metabolic diseases (IMDs) are a heterogeneous group of rare disorders in which nutritional management is the cornerstone of therapy, both in chronic and acute phases. In cases of acute metabolic decompensation, the timely implementation of an emergency dietary regimen is crucial to prevent severe complications and permanent neurological damage. Objectives - To provide non-specialist paediatricians with a practical reference on common principles and key nutritional strategies to be adopted in the acute management of IMDs, with specific adaptations according to the underlying disorder. Materials and Methods - Narrative review based on international guidelines, reference textbooks and representative clinical cases (fatty acid β-oxidation defect and type 1 citrullinemia) aimed to illustrate both standardised and individualised nutritional approaches. Results - According to the disorder, common general principles were identified and included: ensuring adequate energy intake, preventing prolonged fasting and temporarily limiting protein or lipid intake. The home-based “emergency regimen,” based on maltodextrin solutions with concentrations and volumes adjusted according to age, is a key tool for reducing hospitalisation risk and improving outcomes. In acute phases, temporary protein suspension with gradual reintroduction is indicated for urea cycle defects and organic acidurias, while specific lipid restriction and reduction of fasting periods are recommended for fatty acid β-oxidation defects. The clinical cases show how targeted nutritional intervention can lead to rapid clinical and metabolic improvement. Conclusions - The knowledge and prompt application of the emergency diet along with specific nutritional adaptations are essential for managing metabolic crises in paediatric patients. The adoption of standardised protocols, combined with the training of primary care paediatricians, can significantly reduce morbidity and long-term complications in patients with IMDs.

The authors would like to make the following correction to their published paper

Autosomal recessive DNAJC12 disease, the most recently identified disorder of biogenic amine synthesis, presents with a broad clinical spectrum and variable outcomes, ranging from asymptomatic patients to early-onset parkinsonism. This study aimed to better outline the clinical phenotype and outcomes of DNAJC12 disease, the prognostic value of the metabolic and genetic biomarkers, and the treatment response. We systematically collected clinical, biochemical, and genetic data from 56 patients with DNAJC12 disease in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines: 51 from the literature since the disease was first described and 5 unpublished personal cases. Three prevalent clinical patterns of presentation and outcome were identified: (1) asymptomatic condition, (2) neurodevelopmental disorders (NDD) leading to intellectual disability with psychiatric issues and dystonia-parkinsonism (D-P) during the second decade of life in some patients, and (3) early-onset static l-dopa–responsive parkinsonism in previously asymptomatic adult patients. Hyperphenylalaninemia was the most consistent metabolic alteration. CSF depletion of homovanillic acid (HVA) and 5-HIAA was detected in 18 and 20 of 29 symptomatic patients, respectively. Three stepwise regression analyses identified significant predictors of clinical outcomes in patients with phenylketonuria (PKU). CSF HVA levels and phenylalanine levels at diagnosis predicted the occurrence of D-P, while 26% of intellectual disability variability was explained by CSF HVA at diagnosis, and 31% of psychiatric disorder variability by later age at diagnosis. The phenotype was consistently associated with only a few DNAJC12 pathogenic variants, primarily for phenotypes A and C. Movement disorders responded positively to the various therapies in all symptomatic patients. The preventive effects on NDD and psychiatric problems were less clear. DNAJC12 disease is a new metabolic neurodevelopmental disorder linked to parkinsonism. The combined effects of neurotransmitter depletion and disrupted enzyme proteostasis in dopaminergic and serotoninergic neurons may underlie the early neurodevelopmental presentation and subsequent neurologic and psychiatric disorders.

Background: Complementary feeding has traditionally relied on traditional spoon feeding (TSF), in which parents gradually introduce semi-solid foods under close supervision. More recently, Baby-Led Weaning (BLW) has become popular, promoting infant autonomy in handling solid foods. To address concerns regarding choking and nutritional adequacy, the Baby-Led Introduction to SolidS (BLISS) method was developed. Some families instead adopt autonomous responsive feeding, which combines structured guidance with respect for the infant’s self-regulation. Although concerns about foreign body aspiration (FBA) persist among caregivers and pediatricians, current evidence shows that, when conducted safely, BLW may not increase this risk compared with TSF. This study investigated the prevalence of complementary feeding practices and their perceived relationship to FBA, exploring perspectives of caregivers and primary care pediatricians in Emilia-Romagna, Northern Italy. Methods: Between March 2022 and May 2024, 149 parents and 126 pediatricians completed anonymous questionnaires. Results: Among parents, 67% initiated complementary feeding at ≥6 months; 43.6% reported autonomous responsive, 32.8% BLW, and 23.5% strict TSF. Pediatricians more frequently endorsed flexible approaches: 61.1% supported autonomous responsive feeding, 37.1% BLW, and 12.7% TSF. Notably, strict TSF was applied by 23.3% of parents, almost twice the proportion recommended by pediatricians. Suspected choking episodes were reported by 41.6% of parents but showed no significant association with feeding method or demographic factors. Conclusions: BLW and related flexible practices are increasingly adopted and, when implemented safely, may not increase FBA risk. Pediatricians appear to recommend BLW, or hybrid approaches, more often than parents apply them, suggesting possible gaps in communication and shared decision-making.

Background/Objectives: Biotinidase deficiency (BD) is a treatable autosomal recessive disorder included in many newborn screening (NBS) programs. The importance of early diagnosis and treatment is now well established. However, recent studies are emerging on the possibility of increased enzyme activity with age, an observation that raises questions about the long-term validity of the initial classification of these patients. This study aimed to assess the incidence, genetic and clinical features, and, notably, the longitudinal enzymatic trajectory of BD in a cohort identified by NBS in Emilia-Romagna, Italy, with implications for diagnostic re-evaluation and therapeutic decisions. Methods: A retrospective and prospective analysis was conducted on 64 infants recalled after NBS for suspected BD between 2016 and 2020. Biochemical, molecular, and clinical data were collected, and biotinidase (BTD) activity was monitored longitudinally. Affected individuals were supplemented with biotin and followed clinically for at least 5 years. Results: Thirty-one patients were diagnosed with BD (30 partial, 1 profound; incidence 1:5448). A significant and sustained increase in BTD activity was observed from diagnosis through early childhood (p < 0.001 up to 60 months), particularly among patients carrying the p.Asp444His variant. This enzymatic trend suggests a potential remodulation of biochemical classification over time. Genotype–phenotype concordance was high (92%), and clinical outcomes were favorable across the cohort. Conclusions: This study provides new evidence that BTD activity in patients with BD increases progressively, supporting the concept of age-dependent enzyme recovery. Our results support the need for systematic re-evaluation of diagnosis and treatment, especially at 12 months of age, and particularly in patients with evidence of partial activity deficiency and the p.Asp444His mutation.