Treatment of children with congenital adrenal hyperplasia (CAH) with corticosteroids (CS) may increase the risk for developing different components of metabolic syndrome (MetS). Aim: We assessed the occurrence of cardiometabolic risk factors in children with CAH on treatment with CS since early infancy. Data of 30 children with CAH were analyzed retrospectively. They have received hydrocortisone (HC; n = 11) or prednisolone (P; n= 19) and fludrocortisone (0.1- 0.15 mg once daily) since early infancy. The different cardiometabolic criteria including blood pressure (BP), fasting glucose, low-density lipoprotein (LDL), and serum cholesterol concentrations were studied and compared with the data for 66 age-matched obese children. Children with CAH on treatment for > 5 years had a high rate of obesity and overweight (60%) and short stature (23.3%), respectively. They had higher occurrences of abnormal cardio-metabolic components including high LDL and triglyceride and BP as well as increased carotid intima-media thickness (CIMT). Females had higher body mass index (BMI) and BP compared to males. The less controlled group was older and had faster linear growth compared to the controls. In the CAH group, BP and CIMT were correlated significantly with BMI-SDS and weight-standard deviation score (Wt-SDS). Neither the level of 17-hydroxy-Progesterone (17-OHP), nor the HC dose was correlated with BP, CIMT or BMI. These findings suggest the role played by excessive weight gain on the increased cardiometabolic risk factors in children with CAH on treatment with CS.

The purpose of this study is to systematically review human evidence linking placental hormones and IGF-1 with fetal growth, birth size, and early-life metabolic programming, and to identify disease-specific translational signals relevant to fetal growth restriction, metabolically complicated pregnancy, and extreme prematurity. A systematic review of PubMed and Scopus was performed for human studies published from January 2000 to March 2025. Eligible studies examined placental growth hormone, human placental lactogen, placental IGF-axis markers, or related stress-hormone pathways in relation to birth size, fetal or infant growth, or early metabolic outcomes. Reporting was aligned with PRISMA 2020. Risk of bias was assessed using RoB 2 for randomized trials and ROBINS-I principles for observational studies. Because of substantial clinical and methodological heterogeneity, findings were synthesized narratively. Thirty-seven included studies showed that mid-gestation placental growth hormone had the most consistent positive associations with fetal growth and birth size, whereas early placental growth hormone was less informative. Cord blood IGF-1 was the most reproducible endocrine correlate of birth length and weight. Reduced maternal or placental lactogen signals and lower placental 11β-HSD2 activity clustered with placental insufficiency and fetal growth restriction, while diabetic pregnancies showed a shift toward adiposity-related outcomes. In extreme prematurity, abrupt loss of placental endocrine support created a translational window in which rhIGF-1/rhIGFBP-3 replacement emerged as the clearest mechanism-based intervention, although current clinical evidence remains preliminary. Conclusion: Placental endocrine markers should not be used as standalone screening tools. Their main value at present is mechanistic and translational: combined hormone patterns may refine biological understanding and risk stratification within defined maternal and neonatal disease frameworks, while IGF-1 replacement in extreme prematurity represents the most credible current therapeutic lead. What is Known: • Placental hormones and IGF-1 are linked with fetal growth, birth size, and neonatal metabolic adaptation, but 45 published evidence is heterogeneous and clinically fragmented. What is New: • This systematic review organizes the human data within fetal growth restriction, diabetic/LGA pregnancy, and extreme prematurity frameworks and identifies translational signals—especially early IGF-1 replacement in extreme prematurity—rather than standalone diagnostic biomarkers. Graphical Abstract The alternative text for this image may have been generated using AI.

Constitutional delay of growth and puberty (CDGP), the most common cause of delayed puberty in boys, accounts for the majority of pediatric endocrinology referrals. Although traditionally viewed as a variant of normal development, affected adolescents frequently experience short stature relative to their peers, delayed secondary sexual characteristics, and clinically meaningful psychosocial distress. Short-course low-dose testosterone has been used for more than 5 decades to accelerate pubertal progression and linear growth; however, the evidence base is heterogeneous and has not been synthesized in a PubMed-indexed review anchored in original testosterone studies. To systematically review PubMed-indexed studies from the last 40 years evaluating testosterone therapy in boys with CDGP or closely related self-limited delayed puberty and perform an exploratory meta-analysis of outcomes for which directly extractable comparative data are available. PubMed was searched from January 1, 1986, to March 10, 2026, for relevant original studies, systematic reviews, and meta-analyses. Eligible reports enrolled boys with CDGP or self-limiting delayed puberty treated with testosterone and reported growth, pubertal progression, bone age, predicted or near-adult height, or safety outcomes. Randomized studies were appraised by the Cochrane revised tool for risk of bias in randomized trials, while nonrandomized studies were appraised using the Risk of Bias in Non-randomized Studies - of Interventions. Random-effects mean differences (MDs) for height velocity were calculated when comparative means and dispersions were extractable. Twenty original studies involving 1,329 boys met the qualitative inclusion criteria, together with 2 supporting evidence syntheses. Across formulations (intramuscular testosterone enanthate or cypionate, depot ester mixtures, oral testosterone undecanoate, and transdermal gel), the literature consistently showed greater short-term height velocity and more rapid pubertal progression in treated boys without a clinically meaningful adverse effect on near-adult height when conservative regimens were used. Only 2 controlled studies (46 boys) directly provided pooled height velocity data. Random-effects pooling showed a statistically significant increase in short-term height velocity with testosterone versus placebo or no treatment (MD, 2.40 cm/yr; 95% confidence interval, 1.49-3.32; I²=0%). Narrative evidence from long-term studies does not support the detrimental effects of brief low-dose testosterone administration on near-adult or adult height. Testosterone therapy in boys with CDGP was associated with faster short-term growth and pubertal maturation, and long-term data did not show a detrimental effect on near-adult height when conservative time-limited regimens were used. The quantitative evidence base is small and methodologically heterogeneous, and modern multicenter randomized trials incorporating validated patient-reported outcomes and long-term follow-ups are necessary.

Youth-onset type 2 diabetes mellitus (T2DM) is a rapidly growing pediatric metabolic disorder that parallels the global childhood obesity epidemic. Despite multiple population-based registries and a global meta-analysis documenting near-universal obesity at the time of a T2DM diagnosis, no integrated synthesis spanning 25 years and including diverse populations has been performed. Here we conducted a systematic review of PubMed and Scopus (January 2000 to March 2025) using longitudinal data from population-based registries in the USA (SEARCH), Canada (Manitoba), England and Wales (National Paediatric Diabetes Audit), Israel, Australia, and New Zealand as well as cross-sectional burden from a global meta-analysis (53 studies, n=8,942) and national audits. Study quality was appraised using the Newcastle-Ottawa Scale and A Measurement Tool to Assess Systematic Reviews v2. All registries showed a temporally parallel increase in the incidence of pediatric obesity and youth-onset T2DM. In the USA, the T2DM incidence rose 79% (3.8 → 6.8 per 100,000/yr, 2002–2018); in Manitoba, it nearly doubled (16.0 → 31.1 per 100,000/yr, 2009–2018); and Israel showed a 441% rise (0.63 → 3.41 per 100,000/yr, 2008–2019). The global pooled obesity prevalence at the T2DM diagnosis was 75.3% (95% confidence interval, 72.1%–78.5%), with approximately 41,600 new youth cases annually worldwide. Once-weekly semaglutide 2.4 mg (STEP TEENS trial) reduced the average body mass index by 16.1% at 68 weeks with concurrent glycemic improvement, while bariatric surgery achieved 95% T2DM remission at 3 years in adolescents (Teen-LABS cohort). Multicontinental evidence confirmed a robust temporally consistent obesity–T2DM link; obesity precedes T2DM at the population level and is present in approximately 75% of affected youths at diagnosis worldwide. Weight-reduction interventions, particularly glucagon-like peptide-1 receptor agonists and bariatric surgery, offer meaningful glycemic benefits; however, primary prevention of childhood obesity remains the most powerful strategy to arrest this epidemic.

Thalassemia represents the world’s most prevalent inherited hemoglobin disorder, affecting approximately 4.4 per 10,000 live births globally. Accurate genetic characterization is indispensable both for definitive diagnosis and for lifetime clinical monitoring. The past two decades have witnessed a paradigm shift from conventional protein-based assays toward comprehensive molecular techniques, including next-generation sequencing (NGS) and third-generation (long-read) sequencing, which in turn have enabled reproductive applications such as preimplantation genetic testing for monogenic disease (PGT-M) to identify unaffected embryos before implantation. (1) To systematically evaluate the molecular techniques available for confirming the diagnosis of alpha- and beta-thalassemia, including their diagnostic accuracy, indications, and limitations; (2) to examine how genotype–phenotype correlation and genetic modifier profiling inform clinical prognosis and therapeutic decision-making; and (3) to define evidence-based genetic monitoring parameters for longitudinal follow-up of patients receiving transfusions, iron chelation, and novel curative therapies including gene therapy. A comprehensive narrative review was conducted by systematically searching PubMed/MEDLINE for English-language peer-reviewed articles published between January 2000 and December 2024. Forty-three studies were ultimately included after applying predefined inclusion and exclusion criteria. Quality of included studies was assessed using SANRA (Scale for the Assessment of Narrative Review Articles). HPLC and capillary electrophoresis remain first-line phenotyping tools; DNA-based confirmation is mandatory for complete genotyping. Among known, previously characterized mutations, NGS-based targeted panels achieve > 95% detection sensitivity, but they require MLPA co-testing or long-read sequencing to detect structural variants such as large deletions. Genotype–phenotype prediction is substantially improved, though not rendered fully deterministic, by profiling three major modifier loci: XmnI (Gγ), BCL11A, and HBS1L-MYB. PGT-M using NGS achieves near-complete genotyping accuracy (>99%) with live birth rates of 40–60% per frozen embryo transfer cycle. For patients receiving curative gene therapy (exagamglogene autotemcel/Casgevy), molecular follow-up protocols spanning 15 years are now recommended. Cardiac T2* MRI remains the most reliable non-invasive tool for iron overload follow-up, superior to serum ferritin alone. A tiered, genotype-informed approach—combining HPLC/CE phenotyping, targeted molecular diagnostics, genetic modifier profiling, and periodic re-evaluation—optimizes diagnostic precision and guides individualized management across the thalassemia spectrum. Integration of PGT-M and long-read sequencing into standard care pathways, alongside robust gene therapy follow-up protocols, will define the next era of thalassemia genetics.

Background: Thalassemia represents the world’s most prevalent inherited hemoglobin disorder, affecting approximately 4.4 per 10,000 live births globally. Accurate genetic characterization is indispensable both for definitive diagnosis and for lifetime clinical monitoring. The past two decades have witnessed a paradigm shift from conventional protein-based assays toward comprehensive molecular techniques, including next-generation sequencing (NGS), third-generation (long-read) sequencing, and preimplantation genetic testing for monogenic disease (PGT-M). Objectives: (1) To systematically evaluate the molecular techniques available for confirming the diagnosis of alpha- and beta-thalassemia, including their diagnostic accuracy, indications, and limitations; (2) to examine how genotype–phenotype correlation and genetic modifier profiling inform clinical prognosis and therapeutic decision-making; and (3) to define evidence-based genetic monitoring parameters for longitudinal follow-up of patients receiving transfusions, iron chelation, and novel curative therapies including gene therapy. Methods: A comprehensive narrative review was conducted by systematically searching PubMed/MEDLINE for English-language peer-reviewed articles published between January 2000 and December 2024. Forty-three studies were ultimately included after applying predefined inclusion and exclusion criteria. Quality of included studies was assessed using SANRA (Scale for the Assessment of Narrative Review Articles). Results: HPLC and capillary electrophoresis remain first-line phenotyping tools; DNA-based confirmation is mandatory for complete genotyping. NGS-based targeted panels detect >95% of common mutations but require MLPA co-testing or long-read sequencing for structural variants. Genotype–phenotype prediction is substantially enhanced by profiling three major modifier loci: XmnI (Gγ), BCL11A, and HBS1L-MYB. PGT-M using NGS achieves near-complete genotyping accuracy (>99%) with live birth rates of 40–60% per frozen embryo transfer cycle. For patients receiving curative gene therapy (exagamglogene autotemcel / Casgevy), molecular follow-up protocols spanning 15 years are now recommended. Cardiac T2* MRI remains the most reliable non-invasive tool for iron overload follow-up, superior to serum ferritin alone. Conclusion: A tiered, genotype-informed approach—combining HPLC/CE phenotyping, targeted molecular diagnostics, genetic modifier profiling, and periodic re-evaluation—optimizes diagnostic precision and guides individualized management across the thalassemia spectrum. Integration of PGT-M and long-read sequencing into standard care pathways, alongside robust gene therapy follow-up protocols, will define the next era of thalassemia genetics.