Inherited disorders of globin chain synthesis causing microcytic hypochromic anemia of varying severity.
Also known as: alpha thalassemia, beta thalassemia, thalassemia major, thalassemia trait, Cooley anemia
Overview
Group of inherited anemias resulting from reduced or absent synthesis of one or more globin chains of hemoglobin. Alpha-thalassemia is caused by deletion of one or more of the four alpha-globin genes (chromosome 16); beta-thalassemia is caused by point mutations in one or both beta-globin genes (chromosome 11) reducing or eliminating beta-chain production.
Epidemiology
Most common monogenic disease worldwide. Alpha-thalassemia: Southeast Asian, African, Mediterranean ancestry. Beta-thalassemia: Mediterranean (Greek, Italian), Middle Eastern, North African, Indian, Southeast Asian. Heterozygote advantage against malaria.
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Family history; both parents must carry the variant for severe disease
Ethnic origin: Mediterranean, Middle Eastern, Southeast Asian, African, Indian
Consanguinity
Pathophysiology
Imbalanced globin chain synthesis produces ineffective erythropoiesis and hemolysis. In beta-thalassemia, excess alpha chains precipitate in erythroid precursors, causing intramedullary destruction. In alpha-thalassemia, excess beta or gamma chains form unstable tetramers (HbH = beta4, Hb Barts = gamma4). Bone marrow expansion compensates (skull, facial bones), and chronic anemia drives extramedullary erythropoiesis and iron overload from increased absorption and transfusion.
Clinical presentation
Symptoms
Alpha-thalassemia silent carrier (1 gene deleted) and trait (2 genes): asymptomatic or mild microcytosis
Short stature, delayed puberty, skeletal deformities
Skin bronzing (iron overload)
Classic findings
Beta-thalassemia major: 'crew-cut' skull on X-ray (vertical striations from marrow expansion) and chipmunk facies.
Differential diagnosis
Iron deficiency anemia — Microcytic but with elevated RDW, low ferritin, high TIBC; Mentzer index (MCV/RBC) >13 suggests IDA; thalassemia has near-normal RDW and Mentzer <13
Anemia of chronic disease — Normal or low MCV, low TIBC, normal/high ferritin, inflammatory context
Sideroblastic anemia (congenital) — Ringed sideroblasts on marrow iron stain; iron overload from inception
Lead poisoning — Microcytosis with basophilic stippling, elevated lead level, environmental history
Hemoglobin electrophoresis pattern (elevated HbA2 ± HbF for beta-thal; HbH band for HbH disease) or molecular genetic testing (alpha-thal gene deletions). Family studies useful.
Labs
CBC — microcytic anemia (MCV often very low, 60-70), elevated RBC count, normal RDW, target cells
Iron studies normal or elevated (distinguishes from iron deficiency)
Hemoglobin electrophoresis (or HPLC): beta-thal trait shows elevated HbA2 (>3.5%) and often elevated HbF; beta-thal major shows mostly HbF, little or no HbA
Alpha-thalassemia: electrophoresis typically normal in trait (silent or minor); HbH disease shows HbH band; molecular genetic testing (gap-PCR) for definitive diagnosis
Mentzer index = MCV / RBC count; <13 suggests thalassemia, >13 suggests iron deficiency
Imaging
Skull X-ray — 'hair-on-end' or 'crew-cut' appearance in thalassemia major
MRI T2* of liver and heart — quantifies iron overload in chronically transfused patients
Bone age, growth assessment
Diagnostic algorithm
Type
Genotype
Hemoglobin Pattern
Clinical Severity
Alpha silent carrier
-α/αα (1 gene deleted)
Normal
Asymptomatic
Alpha trait
--/αα or -α/-α (2 genes)
Normal or mild ↑Hb Barts at birth
Mild microcytosis
HbH disease
--/-α (3 genes deleted)
HbH (β4) present
Moderate hemolytic anemia
Hb Barts hydrops
--/-- (4 genes deleted)
Hb Barts (γ4)
Hydrops fetalis, fatal
Beta-thal minor
β/β+ or β/β0
↑HbA2 (>3.5%), ↑HbF
Asymptomatic microcytic anemia
Beta-thal intermedia
β+/β+ (mild)
↑HbF, variable HbA
Symptomatic, occasional transfusions
Beta-thal major
β0/β0
Mostly HbF, no HbA
Transfusion-dependent from infancy
Thalassemia syndromes — genotype, hemoglobin pattern, and clinical severity.
Treatment
First-line
Thalassemia minor/trait: no treatment; genetic counseling regarding partner carrier status and prenatal options
Thalassemia trait shows microcytosis OUT OF PROPORTION to mild anemia, with normal RDW — contrast with iron deficiency where RDW is high and microcytosis tracks with anemia severity.
Mentzer index = MCV/RBC: <13 suggests thalassemia, >13 suggests iron deficiency. Useful but imperfect.
Elevated HbA2 (>3.5%) on electrophoresis is diagnostic for beta-thalassemia minor.
Alpha-thalassemia trait often has NORMAL hemoglobin electrophoresis — diagnosis is by exclusion plus genetic testing.
Hb Barts hydrops fetalis (no alpha genes) causes severe intrauterine anemia and hydrops; incompatible with life without intrauterine transfusion and stem cell rescue.
Crew-cut/hair-on-end skull X-ray reflects marrow expansion in severe untreated beta-thalassemia major.
Iron chelation is the most important intervention reducing mortality in chronically transfused thalassemia patients.
References
TIF 2021 — Thalassaemia International Federation Guidelines for the Management of Transfusion Dependent Thalassaemia (4th edition)
BSH 2016 — Significant haemoglobinopathies: guidelines for screening and diagnosis (Ryan et al., Br J Haematol)
BELIEVE Trial — Luspatercept in Patients with Transfusion-Dependent β-Thalassemia (Cappellini et al., NEJM 2020)
Locatelli et al. — Exagamglogene autotemcel for Transfusion-Dependent β-Thalassemia (NEJM 2024)
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