Beta-thalassemia major

Beta-thalassemia major, also known as Cooley's anemia or transfusion-dependent beta-thalassemia, is a severe inherited blood disorder caused by mutations in the HBB gene located on chromosome 11, which encodes the beta-globin chain of hemoglobin. When both copies of the gene carry pathogenic variants, the body produces little or no functional beta-globin, resulting in profoundly ineffective erythropoiesis and severe hemolytic anemia. Without treatment, the condition is life-threatening in early childhood. Symptoms typically appear between 6 months and 2 years of age, as fetal hemoglobin (HbF) production naturally declines and is not adequately replaced by adult hemoglobin (HbA). Key clinical features include severe anemia, pallor, failure to thrive, poor feeding, irritability, and recurrent infections. Without regular transfusions, compensatory bone marrow expansion leads to characteristic skeletal changes such as frontal bossing, maxillary hyperplasia, and thinning of long bones. Hepatosplenomegaly develops due to extramedullary hematopoiesis and increased red blood cell destruction. The disease primarily affects the hematologic system but has significant secondary effects on the skeletal, cardiovascular, endocrine, and hepatic systems. The cornerstone of treatment is lifelong regular red blood cell transfusions, typically administered every two to four weeks to maintain pre-transfusion hemoglobin levels above 9–10 g/dL. However, chronic transfusion therapy inevitably leads to iron overload, which damages the heart, liver, and endocrine organs. Iron chelation therapy using agents such as deferoxamine, deferasirox, or deferiprone is therefore essential. Allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-matched donor remains the only widely established curative option. More recently, gene therapy approaches, including betibeglogene autotemcel (Zynteglo) and gene editing strategies, have emerged as promising curative treatments. Luspatercept, an erythroid maturation agent, may reduce transfusion burden in some patients. With optimal management, patients can achieve significantly improved survival and quality of life.

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