Congenital dyserythropoietic anemia (CDA) is a rare hereditary disorder marked by ineffective erythropoiesis and iron overload. Data on endocrine involvement in CDA remain limited. This study aimed to evaluate endocrine complications in patients with CDA and to assess their association with clinical and laboratory parameters. We retrospectively analyzed data from 12 patients with CDA (mean age 19.8 years; range: 6-49 years). Two patients were transfusion-dependent, and 10 were non-transfusion-dependent. We collected demographic, clinical, and laboratory data, including ferritin levels, and comprehensively assessed endocrine abnormalities. Endocrine abnormalities were identified in 9 of 12 patients (75%), for a total of 20 abnormalities. The most common findings were low bone mineral density, diabetes mellitus, subclinical hypothyroidism, and hyperprolactinemia. After excluding vitamin D deficiency, ferritin levels showed a significant positive correlation with the number of endocrine abnormalities (p = 0.015). No significant associations were observed between endocrine abnormalities and age, sex, or hemoglobin levels. Endocrine complications are common in CDA and are associated with iron overload, even in non-transfusion-dependent patients. Regular endocrine evaluation and careful monitoring of iron burden are essential for all patients with CDA.

Sickle cell disease (SCD) is characterized by recurrent vaso-occlusive crises (VOCs), which are the primary contributors to morbidity and mortality globally. Conventional clinical markers, including fetal hemoglobin (HbF), reticulocyte count, and lactate dehydrogenase (LDH), offer limited predictive value because of interpatient variability and an inability to capture the complex, multifactorial pathophysiology of VOCs. Recent advances in metabolomics and proteomics have enhanced understanding of VOC biology. Metabolomic profiling has identified perturbations in glycolysis, amino acid metabolism, oxidative stress pathways, and lipid metabolism, while proteomic studies have revealed dysregulation of inflammatory mediators, adhesion molecules, coagulation factors, and endothelial markers. Although significant progress has been made, most reported metabolomic and proteomic signatures remain insufficiently reproducible and are not yet clinically applicable. This limitation is primarily attributed to biological heterogeneity, limited cohort sizes, and methodological inconsistencies across studies. Recent evidence indicates that pathway-level markers, longitudinal sampling strategies, and integrated multi-omics approaches are more likely to yield clinically relevant biomarkers than isolated single-molecule candidates. Significant challenges remain, including limited validation across diverse populations and barriers to implementation in resource-limited settings. Addressing these challenges will require collaborative, multicenter studies, improved analytical harmonization, and the development of accessible diagnostic platforms. This narrative review synthesizes current evidence on metabolomic and proteomic profiling of VOCs, highlights implications for equity and global health, and outlines priorities for translational research to advance personalized care and improve clinical outcomes in SCD.

β-Thalassemia is one of the most prevalent autosomal recessive genetic disorders in Malaysia, with an estimated prevalence of 4.5%, encompassing asymptomatic carriers, intermedia and transfusion-dependent β-thalassemia. Molecular diagnosis has become increasingly important to correlate phenotype to genotype, guiding management, and facilitating genetic counseling, particularly in the prenatal diagnostic setting. This study evaluated a rapid reversed dot-blot-based flow-through-hybridization (RDB-FTH) assay for the molecular detection for β-thalassemia and related variants. A total of 112 DNA samples from patients with β-thalassemia and other hemoglobinopathies were analyzed, comprising thalassemia trait (n = 74), HbE trait (n = 15), HbE/β-thalassemia (n = 10), compound heterozygous β-thalassemia (n = 6), homozygous HbE (n = 4), homozygous HbS (n = 2), and HbS trait (n = 1). Initial diagnoses were based on full blood count and hemoglobin analysis. Genomic DNA was subsequently analyzed using a customized RDB-FTH assay targeting 23 β-globin mutations and two β-globin deletions. The detected point mutations were confirmed by Sanger sequencing, while deletions were validated using multiplex gap-PCR. Reversed dot-blot-based flow-through-hybridization successfully genotyped all samples (100%). Out of the 224 alleles examined, 134 β-thalassemia alleles were identified, representing 14 mutations, two Hb-variant, and one β-globin deletion. The predominant mutation was Cd26(G > A) (24.6%), followed by IVS-I-5(G > C) (12.7%), Cd41/42(-TTCT) (11.9%), while the 45 kb-Filipino deletion accounted for 6.7%. The assay demonstrated 100% concordance in selected cases whose HBB genes were sequenced and had gap-PCR. Reversed dot-blot-based flow-through-hybridization is a rapid and accurate method for β-thalassemia molecular diagnosis, enabling simultaneous detection and genotyping of multiple mutations on a single membrane, thereby improving precision and efficiency in high workload diagnostic settings.

β-Hemoglobinopathies, including sickle cell disease (SCD) and β-thalassemia, are inherited disorders caused by mutations in the β-globin gene (HBB), leading to defective production of adult hemoglobin (HbA), vaso-occlusive crises, and rapid destruction of erythrocytes as they leave the bone marrow, resulting in hemolytic anemia. In recent years, CRISPR-based genome-editing technologies have emerged as promising therapeutic strategies to reactivate fetal hemoglobin (HbF) expression by targeting key regulatory elements, including the BCL11A enhancer and the HBG1/HBG2 promoters. This review aimed to synthesize available scientific evidence from PubMed, Scopus, Web of Science, and ClinicalTrials.gov on preclinical and clinical studies evaluating CRISPR-based genome-editing approaches for the treatment of SCD and β-thalassemia. This review was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) Statement. A total of 247 records were identified; 20 studies met the inclusion criteria and were included in the qualitative synthesis. The included studies investigated various CRISPR-based platforms, including nuclease-mediated editing and base-editing strategies, to reactivate HbF expression. The studies reported durable increases in HbF levels, with therapeutic effects persisting for up to 22 months after treatment. Clinically, these outcomes were associated with the elimination or marked reduction of vaso-occlusive crises in patients with SCD and with transfusion independence in patients with β-thalassemia. Overall, the available evidence suggests that CRISPR-based HbF reactivation is a promising therapeutic approach for β-hemoglobinopathies, although long-term efficacy and safety data remain necessary.

Alpha-thalassemia is a genetically and clinically heterogeneous hemoglobin disorder caused by deletions or mutations of the α-globin genes (HBA1 and HBA2) on chromosome 16. We aimed to evaluate the hematologic impact of single- and multiple-α-globin gene deletions and to characterize genotype-related laboratory phenotypes in α-thalassemia carriers. This retrospective study included 599 individuals aged 18-64 years: 229 in the genotype-negative comparison group and 370 genetically confirmed α-thalassemia carriers with diverse mutation profiles. Participants were categorized into five groups by genotype: Group I, genotype-negative comparison group; Group II, carriers of the -[3.7 ]kb deletion; Group III, carriers of the Constant Spring (CS) mutation; Group IV, carriers of the --[SEA] deletion; and Group V, individuals with compound or more severe genotypes, including -α[3.7]/-α[4.2], --[SEA], and HbH-related genotypes. Significant intergroup differences were observed in hematologic parameters. The -α[3.7] and Hb Constant Spring groups had relatively preserved MCV and MCH values compared with the --[SEA] and compound/HbH-related groups. The --[SEA] group showed a microcytic erythrocytosis pattern, whereas the compound/HbH-related group showed the most pronounced hematologic disturbance. In conclusion, distinct α-globin genotype groups and defect categories are associated with markedly different hematologic phenotypes. Although the molecular mechanisms underlying these differences remain incompletely understood, deletional burden and genotype complexity appear to have clinically meaningful effects on red cell indices. Integrating molecular genotyping with hematologic profiling may therefore improve diagnostic interpretation and genotype-phenotype assessment in α-thalassemia.

Thalassemia syndromes affect millions worldwide, with the highest prevalence in the Mediterranean basin, the Middle East, South Asia, and southern China. For decades, standard care relied on lifelong transfusion and iron chelation, a management paradigm that extended survival without offering a cure. The first curative option, allogeneic hematopoietic stem cell transplantation (HSCT), emerged in the early 1980s; the first gene-editing therapy, Casgevy, followed in 2023, marking the latest step in this trajectory. Yet the research landscape underlying the broader management-to-cure transition has not been systematically characterized. We applied BERTopic, a transformer-based semantic topic model, to 17,651 PubMed-indexed thalassemia abstracts spanning 1990-2026, tracking topic prevalence over 37 years and comparing trajectories across seven national research communities. The model independently identified a thematic structure that separated management-oriented research (iron chelation, cardiac monitoring, prenatal screening) from curative research (hematopoietic stem cell transplantation [HSCT], gene therapy); the crossover point occurred around 2020, three years before the first gene-editing approval. By 2025, curative topics accounted for 14% of publications, versus 9% for management topics. Country-level analysis revealed marked divergence: US research focused more heavily on gene therapy (10.0% vs. 4.1% in China), while Chinese research maintained a stronger HSCT focus (6.3% vs. 4.0% in the US). These findings chart the course of a major therapeutic transition and carry direct implications for research funding allocation, global strategies for equitable access to curative therapies, and computational literature surveillance to inform clinical guideline updates.

Sickle cell disease (SCD) is the most common genetic blood disorder worldwide. It encompasses a group of hemoglobinopathies caused by inheriting the sickle hemoglobin (HbS) gene, either in homozygous or heterozygous form. This results in variable clinical presentations and severity by genotype. HbSC is the most common compound heterozygous form and is generally mild, whereas HbSO-Arab, a rare hemoglobinopathy, is considered severe. Accurate diagnosis requires detection of HbS using at least two methods. This case describes an unusually severe course in a child initially diagnosed with HbSC but later confirmed to have HbSO-Arab.

Beta-thalassemia is associated with systemic complications from chronic anemia, iron overload, and long-term transfusion therapy, which may also affect ocular structures. This study aimed to compare the frequency and patterns of ocular complications between patients with β-thalassemia major and β-thalassemia intermedia. This comparative cross-sectional study included 30 patients (60 eyes) with β-thalassemia major or β-thalassemia intermedia, recruited via convenience nonprobability sampling. All participants underwent comprehensive optometric and ophthalmic evaluation, including assessments of visual acuity, intraocular pressure, stereopsis, tear break-up time, visual field testing, and slit-lamp examination of the anterior and posterior segments. Serum ferritin levels were also recorded, and statistical analysis was performed using SPSS version 21. The mean age of participants was 20. 20.67 ± 7. 44 years, and 60% were female. Serum ferritin levels were significantly higher in patients with β-thalassemia major than in those with β-thalassemia intermedia (4056. 47 ± 2415. 28; p < 0. 001). Uncorrected visual acuity and superior visual field extent were significantly better in the intermedia group (0. 913 ± 0. 196 decimal and 52. 67 ± 7. 74 degrees, respectively; p < 0. 05). Tear break- up time was significantly longer in the major group (9. 87 ± 4. 25 seconds) than in the intermedia group (6. 27 ± 3. 91 seconds; p < 0. 005). Patients receiving chelation therapy for more than 5 years had significantly lower tear break-up time values (p = 0. 04). Lenticular abnormalities were observed in 10% of eyes in both groups, whereas vitreous condensations and peripheral fundus atrophic changes were more frequent in β-thalassemia intermedia. In conclusion, patients with β-thalassemia major have higher serum ferritin levels and poorer visual function, whereas certain posterior segment changes appear more prevalent in β-thalassemia intermedia. These findings highlight the importance of regular ophthalmic screening in patients with thalassemia.

The Adult Sickle Cell Quality-of-Life Measurement Information System (ASCQ-Me), developed in the USA, assesses disease-specific health-related quality of life in adults with sickle cell disease (SCD). This study aims to evaluate the psychometric properties of ASCQ-Me for use among adults with SCD in Jamaica. Cronbach's α assessed the internal consistency reliability of each ASCQ-Me impact domain. Convergent validity was evaluated using Pearson's correlations between ASCQ-Me impact scores and the previously validated 36-item short-form health survey (SF-36 version 2) scale and component summary scores. Known-groups validity was examined using t-tests comparing ASCQ-Me impact scores between study-designated more-severe and less-severe disease groups. Confirmatory factor analysis (CFA) using structural equation modeling was conducted to investigate the construct validity of the ASCQ-Me. The study enrolled 366 adult participants (60.1% females; mean age 34.5 ± 12.2 years; 74.6% SS). Cronbach's α (range: 0.80-0.94) indicated excellent consistency across all ASCQ-Me impact domains. Pearson's correlations tested were all statistically significant (p-value < 0.01), except for the ASCQ-Me sleep impact with the SF-36 physical component summary. Persons with 'less severe disease' scored higher on ASCQ-Me impact in all five domains than those with 'more severe disease.' On CFA, the standardized coefficients for all items ranged from 0.61 to 0.95, with p-values < 0.001. All model fit indices showed moderate fit (Comparative Fit Index: 0.915; Tucker-Lewis Index: 0.904; Root Mean Squared Error of Approximation: 0.076; and Standardized Root Mean Square Residual: 0.047). The study confirms the ASCQ-Me is a reliable and valid tool for use in Jamaica.

Alpha- and beta-thalassemia are inherited hemoglobinopathies caused by defects in the α- and β-globin genes, with carrier states typically showing mild or no clinical manifestations. However, co-inheritance of different globin gene defects may result in a more severe or atypical phenotype. Here, we report a unique case of co-inherited rare -α[20.5] deletion, associated with α-thalassemia carrier status, and the common IVS-I-1 G > A (HBB: c0.92 + 1G > A) splice-site mutation, associated with β[0]-thalassemia trait. To our knowledge, this combination has not been previously reported.

Hemoglobin E (HbE) is a common structural hemoglobin variant with a β[+]-thalassemic effect. Hemoglobin Constant Spring (HbCS) is the most prevalent non-deletional α-thalassemia variant and is characterized by low expression and marked instability, making detection difficult. The coexistence of both variants may produce atypical hematologic and electrophoretic profiles, complicating diagnosis. We describe two patients with combined HbE and HbCS: a 12-month-old girl heterozygous for HbE and a 58-year-old man homozygous for HbE. Both presented with microcytosis and characteristic patterns on capillary electrophoresis and high-performance liquid chromatography, which were performed simultaneously as part of routine diagnostic testing. Molecular analysis using StripAssay, MLPA (multiplex ligation-dependent probe amplification), and next-generation sequencing (NGS) confirmed heterozygous HbCS in both cases, with no additional alterations in the α- and β-globin gene clusters. The association of HbE and HbCS poses significant diagnostic challenges. These cases highlight the limitations of phenotypic techniques used in isolation and underscore the value of an integrated diagnostic approach that incorporates complementary molecular methods, such as NGS-based platforms.

Elevated hemoglobin (Hb) concentration, erythrocytosis, is a common phenomenon that can be caused by primary or secondary underlying conditions. In this report, we describe a previously unknown mutation in the β globin gene resulting in high Hb concentrations combined with elevated reticulocytes in two family members spanning two generations. In the index patient the variant was first noted during HbA1c monitoring. While both ion-exchange chromatograms used for HbA1c analysis and isoelectric focusing indicated the presence of a β globin variant, the chromatographic method used for hemoglobinopathy screening mostly failed to detect the variant. Mass spectrometry demonstrated a -60 Da β globin variant and Sanger sequencing revealed a previously unknown p.Phe104Ser substitution in the HBB gene [HBB:c.311T > C]. This mutation affects the interaction with heme and results in increased oxygen affinity as well as instability. Common causes of acquired as well as congenital erythrocytosis were ruled out. This novel variant was named Hb Koskullskulle (IthaID 4114) from the place of origin of the family in which it was found.

To characterize the hematologic effects of hemoglobin D (HbD) alone and in the presence of co-inherited α- or β-thalassemia, and to quantify associations with anemia, microcytosis, and hypochromia relative to normal-CBC controls. This retrospective comparative study included 202 adults with molecularly confirmed HbD-Punjab, HbD only (n = 79), HbD plus β-thalassemia (n = 78), and HbD plus α-thalassemia (n = 45), and 100 normal-CBC controls. Hematologic indices were compared using Welch's one-way ANOVA or the Kruskal-Wallis test, with appropriate post hoc analyses. Case-control analyses evaluated anemia (Hb <12 g/dL), microcytosis (MCV <80 fL), and hypochromia (MCH <26 pg). A post hoc analysis used sex-specific anemia thresholds. WBC, RBC, Hb, MCV, MCH, HCT, and MCHC differed across the four groups (all p ≤ 0.002), whereas HCT did not (p = 0.523). HbD plus β-thalassemia had the lowest MCV (65.67 ± 6.85 fL) and MCH (21.12 ± 2.55 pg), which were significantly lower than in the HbD-only and HbD plus α-thalassemia groups (all p < 0.01). Hemoglobin did not differ significantly among the three HbD subgroups. Compared with controls, anemia was associated with HbD only (OR = 8.3, 95% CI 3.22-25.74), HbD plus β-thalassemia (OR = 11.9, 95% CI 4.68-36.59), and HbD plus α-thalassemia (OR = 11.5, 95% CI 4.16-37.68). Microcytosis and hypochromia also differed significantly between HbD groups and controls (Fisher's exact p < 0.001). Sex-specific sensitivity analyses preserved all associations with anemia. β-Thalassemia co-inheritance produced the most pronounced microcytic-hypochromic phenotype, whereas α-thalassemia had a less pronounced effect. HbD alone was associated with relatively mild changes in red-cell indices, but co-inherited thalassemia, particularly β-thalassemia, substantially altered the hematologic phenotype. Integrated hematologic, electrophoretic, and molecular assessment is important for accurate classification.

Hemoglobin Constant Spring (HbCS) is the most common non-deletional α-thalassemia mutation in Southeast Asia (SEA) and is frequently missed during routine Hb analysis because of its extremely low expression in peripheral blood. This study aims to evaluate the efficacy of three hemoglobin analysis systems: Capillarys 2 Flex Piercing (CE), Premier Resolution (PR)-HPLC, and VARIANT II-HPLC for the detection of HbCS. A total of 40 EDTA blood samples suspected of carrying HbCS were analyzed. Hb analysis was performed using the three analytical systems, while molecular confirmation of Hb CS/Paksé (PS) mutations was carried out using multiplex AS-PCR. In addition, α[0]-thalassemia deletions (-[SEA], -[THAI], and -[CR]) were identified using real-time PCR with high-resolution melting analysis. Four Hb typing patterns were identified: CSA2A (n = 26), CSA2ABart'sH (n = 8), CSEABart's (n = 4), and CSEA (n = 2). Molecular analysis confirmed the presence of the HbCS mutation in all 40 samples. The correct identification rates were 90.0% for CE and 87.5% for both PR-HPLC and VARIANT II-HPLC. Misidentification occurred most frequently in the CSA2A group, likely due to the extremely low proportion of HbCS in individuals without co-inherited α-thalassemia. In addition, PR-HPLC misidentified HbCS in one sample from each of the CSA2ABart'sH, CSEABart's, and CSEA groups. These findings suggest that CE provides higher efficiency than HPLC systems for detection of HbCS. However, molecular confirmation remains essential for accurate diagnosis.

In β-thalassemia carriers, the presence of one or two extra copies of the α-globin genes may exacerbate clinical manifestations and lead to a more severe phenotype than would normally be expected. Given the high prevalence of thalassemia in Iran and the limited number of studies on ααα[anti-3.7], the aim of this study was to conduct a population-based study in Iran and to develop a practical, cost-effective method to detect the most common ααα[anti-3.7] variants in the Iranian population. A total of 110 individuals with β-thalassemia minor whose hematological parameters were below the mean of the study population were analyzed for the ααα[anti-3.7] triplication, which was characterized in six carriers by MLPA. Based on these data, a novel PCR test was developed to detect the most common ααα[anti-3.7] variants and was evaluated using samples with known genotypes. Among β-thalassemia minor carriers with below-average hematological parameters, the frequency of ααα[anti-3.7] carriers was 5.5% (6/110). MLPA analysis identified D and F as the ααα[anti-3.7] variants in Iranian carriers. The newly developed PCR method successfully identified the triplication in all positive samples. This study provides a foundation for large-scale epidemiological investigations of the ααα[anti-3.7] triplication in Iran. The developed method has the potential for routine diagnostic screening of ααα[anti-3.7] in the Iranian population.