Beta thalassaemia
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Beta-thalassaemia (β-thalassaemia) is caused by absent or reduced synthesis of the beta-globin chain, leading to an excess of unpaired beta-globin chains, which causes ineffective erythropoiesis and emia of varying severity.
Beta-thalassaemia spans a clinical spectrum from asymptomatic microcytic hypochromic anaemia in heterozygotes (β-thalassaemia minor) through non-transfusion-dependent β-thalassaemia intermedia to transfusion-dependent β-thalassaemia major.
Affected infants with β-thalassaemia major typically come to medical attention between 6 and 24 months of age with progressive pallor, poor weight gain, and stunted growth; feeding problems, diarrhoea, irritability, recurrent fever, and progressive abdominal enlargement from hepatosplenomegaly may occur.
β-thalassaemia intermedia has a more variable age of presentation, typically after age 2 years, with pallor, jaundice, cardiac disease, cholelithiasis, hepatosplenomegaly, moderate-to-severe skeletal changes (long bone deformities, craniofacial changes, osteopenia or osteoporosis), leg ulcers, pulmonary hypertension, extramedullary masses of hyperplastic erythroid marrow, and thrombotic complications. Iron overload from transfusion and increased intestinal absorption may cause stunted growth and failure of sexual maturation in children and cardiac (, ), hepatic (fibrosis, cirrhosis), and endocrine (diabetes mellitus, parathyroid, thyroid, pituitary, and less commonly adrenal insufficiency) involvement in adults.
The estimated carrier prevalence is 1/7 to 1/8 in the highest-incidence Mediterranean regions (Cyprus and Sardinia), with approximately 1.5% of the global population estimated to be carriers. The condition is also common in populations from the Middle East, Central and Southeast Asia, the Indian subcontinent, and those of African descent.
Beta-thalassaemia major is caused by biallelic germline pathogenic variants in HBB (11p15.4), which account for almost 100% of pathogenic variants detected by sequence analysis. Variants either reduce (β+) or abolish (β0) beta-globin chain synthesis. The resulting imbalance between alpha and non-alpha globin chains leads to precipitation of unassembled alpha-globin chains in erythroid precursors, ineffective erythropoiesis, peripheral haemolysis, and anaemia.
The severe form of beta-thalassaemia is inherited in an autosomal recessive manner. Both parents of an affected individual are typically heterozygous carriers; each sibling of an affected individual has a 25% chance of being affected, a 50% chance of being a heterozygous carrier, and a 25% chance of inheriting neither pathogenic variant. Carrier testing of at-risk relatives requires prior identification of the familial pathogenic variants. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.
Diagnosis rests on quantitative haemoglobin analysis by Hb electrophoresis in conjunction with red cell indices. In β-thalassaemia major, HbA is 0-30% (typically near 0%), HbF up to 95%, and HbA2 >5%; in β-thalassaemia intermedia, HbA 10-50%, HbF 10-50%, and HbA2 >4%; in β-thalassaemia minor, HbA 92-95%, HbF 0.5-4%, and HbA2 >3.5%. These findings are combined with microcytic hypochromic anaemia (reduced MCV and MCH) and exclusion of iron deficiency. The peripheral blood smear in β-thalassaemia major shows microcytosis, hypochromia, anisocytosis, poikilocytosis (spiculated teardrop and elongated cells), and nucleated erythroblasts.
Main differential diagnoses include:
- Iron deficiency anaemia: microcytosis with reduced ferritin and other markers of iron deficiency; readily distinguishable by the lack of haemolysis and presence of laboratory evidence of iron deficiency; acquired (non-genetic).
- : ring sideroblasts in the bone marrow and variably elevated erythrocyte protoporphyrin; HbA2 and HbF are not increased; ALAS2 (most common genetic form).
- Congenital dyserythropoietic anaemia type I: multinuclearity of red blood cell precursors on bone marrow examination; HbA2 and HbF are not increased; CDAN1, C15ORF41.
- Establishing the molecular diagnosis confirms the clinical suspicion and provides the basis for genetic counselling of the individual and the family.
- Genetic analysis confirms the diagnosis and allows precise classification of the individual form of β‑thalassaemia. This provides the basis for informed counselling and supports the treating physicians in planning further care together with the affected person.
- Once the familial pathogenic variants are known, predictive and carrier testing of at-risk relatives becomes possible, supporting informed reproductive decision-making.
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- Alam NE, Islam MS, Khabir MIU, Suriea U, Islam MM, Mohiuddin RB, et al. The scenario of knowledge, attitude and practice of the Bangladeshi population towards thalassemia prevention: a nationwide study. PLoS Glob Public Health. 2022;2(10):e0001177. doi:10.1371/journal.pgph.0001177. PMID: . PMCID: PMC10022238.
- Farmakis D, Porter J, Taher A, Cappellini MD, Angastiniotis M, Eleftheriou A. 2021 Thalassaemia International Federation guidelines for the management of transfusion-dependent thalassemia. HemaSphere. 2022;6(8):e732. doi:10.1097/HS9.0000000000000732. PMID: . PMCID: PMC9345633.
- Dordevic A, Ugrin M, Sutic IM, Roganovic J, Pavlovic S. The relevance of β-thalassemia heterozygosity in pediatric clinical practice: Croatian experience. Children (Basel). 2024;11(7):785. doi:10.3390/children11070785. PMID: . PMCID: PMC11276433.
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