Nada Alaaraj

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.

Early puberty (EP) in girls is defined as the onset of thelarche that begins after 6 years and before 8 years and/or acceleration in the tempo of pubertal development. The stage of puberty and the ovarian volume at presentation and the effect of treatment with GnRH analogue (GnRHa) on final adult height are still debated. We analyzed the data of 22 girls, who presented early and fast puberty (FEP). The clinical stage of puberty, hormonal levels and the ovarian volume (OV) (measured by ovarian ultra-sonography) at presentation were studied. We recorded the effects of 3 years treatment with GnRHa on their growth in relation to their mid parental height, pubertal progression, and bone maturation. GnRHa therapy decreased the fast progress of puberty, skeletal maturation, and GV/year. It was successful in increasing the predicted final adult height comparable to or surpassing their mid-parenteral height. A larger OV at presentation was associated with reduced Ht-SDS after 3 years of GnRHa treatment. Clearly, a definitive evaluation of the efficacy of GnRHa as treatment for EFP in girls will require expanded and concerted studies.

The term double diabetes or "Hybrid Diabetes (HD)" describes diabetes with combined features of type 1 and type 2 diabetes (T2DM). We report the clinical and biochemical characteristics of 7 children with HD and the course of their disease including the response to treatment. The data were compared to 59 children with a diagnosis of T2DM. Variables examined included age, height, weight, body mass index (BMI), triglycerides (Tg), high-density lipoprotein (HDL), and blood pressure. The Weiss criteria were used to diagnose metabolic syndrome (MetS). The atherogenic index of plasma (AIP) was calculated from the standard lipid profile. Four autoantibodies against pancreatic β-cell were measured in all patients. Significant clinical and biochemical differences were detected among children with HD versus T2DM. The mean BMI of children with T2DM was significantly higher than for the HD group. At presentation, the mean C peptide level was significantly lower in HD versus T2DM group and 28% presented with diabetic ketoacidosis (DKA). The percentage of those with full criteria of MetS was significantly higher in T2DM versus HD group as well as the percentage of children with high atherogenic index. After a mean duration of 2.3 months from diagnosis, 4/7 of HD patients stopped insulin therapy and 3 patients had a marked reduction in the insulin requirement. During the follow-up (after 15 ±5 months), 5/7 HD patients required an increase in their insulin dose, one was controlled on a markedly low dose of basal insulin and the last patient did not require any insulin therapy for 40 months. Appropriate assessment of HD is necessary for early and correct diagnosis. Increasing awareness of HD among the general population and primary care practitioners is necessary for successfully and properly treating this complex disease.

Linear growth failure (stunting) in childhood is the most prevalent form of undernutrition globally. The debate continues as to whether children who become stunted before age 24 months can catch up in growth and cognitive functions later in their lives. The potentially irreparable physical and neurocognitive damage that accompanies stunted growth is a major obstacle to human development. This review aims at evaluation and summarizing the published research covering the different aspects of stunting from childhood to adulthood.

Individuals with Down syndrome (DS) are at an increased risk of developing thyroid disease, primarily autoimmune, with a lifetime prevalence ranging from 13% to 63%. Unfortunately, there are few studies systematically examining the frequency of thyroid disease in very young children. The aim of the present study was to investigate the prevalence of different thyroid dysfunctions (TD) in a cohort of infants and children with DS and the growth parameters in subjects with normal versus abnormal thyroid function, followed for 3 years. All children (n = 102; 48 males and 54 females, aged 2.3±3 years) with the diagnosis of DS who were seen at the General Pediatric Clinic of Hamad General Hospital in Doha (Qatar) from 2014 to 2018 were enrolled in our study. We recorded thyroid function and linear growth parameters [BMI, length/height SDS (Ht-SDS) and weight gain/day] and divided them into 3 groups according to their thyroid function. Group 1: (n = 36 subjects) with normal free T4 (FT4) and TSH; Group 2 (n = 44 subjects) with high TSH >5 and 12 mIU/L and/or FT4 5 mIU/L), especially in those with TSH >12 mIU/L.