Shayma Ahmed

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.

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.

The kidney plays an important role in normal linear growth throughout childhood by regulating systemic insulin-like growth factor-1 (IGF-1) bioavailability through the filtration and processing of IGF-binding proteins and by serving as a target organ for growth hormone (GH). In pediatric chronic kidney disease (CKD), impaired renal function is associated with reduced availability of bioactive IGF-1 despite normal or modestly elevated total IGF-1 concentrations, reflecting altered binding protein dynamics and functional GH–IGF resistance. These changes are frequently accompanied by impaired growth velocity and reduced height, particularly in advanced CKD stages. This review synthesizes experimental and observational evidence examining the role of the kidney and IGF-1 axis in physiological linear growth and CKD-related growth failure. Observational studies demonstrate consistent associations between renal volume, IGF-1 parameters, and height outcomes. Across CKD stages, progressive reductions in free IGF-1 parallel worsening renal function and growth impairment. Recombinant human GH therapy improves growth velocity and may help children achieve near-adult height closer to their genetic potential when initiated early and appropriately monitored. Collectively, these findings support a renal–endocrine model of pediatric growth regulation in health and disease.

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.

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.

Background: Type 2 diabetes mellitus (T2DM) in children and adolescents represents a rapidly escalating global public-health crisis. Evidence drawn from multiple continents indicates that the disease follows an accelerated, more aggressive course in youth than in adults, with multi-organ complications appearing far earlier than historically anticipated. Objectives: [1] To characterize the prevalence and cumulative incidence of each major complication domain in youth-onset T2DM using data from international cohorts; [2] to compare complication burden across geographic regions and ethnic populations; and [3] to identify modifiable risk factors to guide evidence-based clinical management. Methods: PubMed/MEDLINE, EMBASE, and the Cochrane Library were searched systematically from January 1995 to December 2023. Eligible studies enrolled participants aged ≤18 years with T2DM and reported at least one complication outcome. Thirty-eight studies (N = 42,610 participants across North America, Europe, Asia-Pacific, the Middle East, and Australia) met inclusion criteria. Quality was assessed using the Newcastle-Ottawa Scale (NOS) and the Cochrane RoB-2 tool; pooled estimates were generated using random-effects meta-analysis. Results: Across all regions, hypertension was the most frequent complication (pooled prevalence 42–68%), followed by diabetic kidney disease (DKD; 22–55%), dyslipidemia (38–52%), retinopathy (13–51%), and peripheral neuropathy (12–32%). MASLD/NAFLD affects 40–70% of patients globally. Data from the USA (TODAY, SEARCH), Asia-Pacific (JADE program), Europe (UK and Italian cohorts), multi-national meta-analyses (Nanayakkara et al., 26 countries), and Australia were convergent in demonstrating that each additional year of younger age at diagnosis conferred a 4–5% incremental increase in vascular complication risk. Mental health disorders affected 15–32% of youth with T2DM across all populations studied. Youth-onset T2DM consistently showed higher complication rates than both adult-onset T2DM of equivalent duration and youth-onset T1DM. Conclusions: Youth-onset T2DM imposes an internationally consistent, uniquely aggressive complication phenotype that transcends ethnic and geographic boundaries. Complications worldwide must implement complication screening from the time of diagnosis, integrate psychosocial support, and adopt newer pharmacotherapies with organ-protective properties. Investment in equitable, globally applicable, pediatric-specific protocols is urgently needed