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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Question 1HematologyMedium
A 4-year-old boy of Mediterranean descent is brought to clinic for evaluation of pallor and poor growth. His mother reports he has been chronically fatigued and has fallen below the 5th percentile for height and weight. On exam, he has frontal bossing, maxillary prominence, and a palpable spleen 4 cm below the costal margin. Labs show Hgb 6.2 g/dL, MCV 58 fL, and numerous target cells and nucleated RBCs on smear. Hemoglobin electrophoresis shows HbF 85%, HbA2 6%, and HbA <2%. Which of the following is the most appropriate long-term management?
AChronic transfusion with iron chelation
BEarly splenectomy at diagnosis
COral ferrous sulfate supplementation
DHydroxyurea monotherapy
Reveal answer & full explanation
Correct answer: A — Chronic transfusion with iron chelation
AChronic transfusion with iron chelation✓
BEarly splenectomy at diagnosis
COral ferrous sulfate supplementation
DHydroxyurea monotherapy
Why A) Chronic transfusion with iron chelation is correct
This child has beta thalassemia major (Cooley anemia), caused by homozygous beta-globin gene mutations that abolish beta-chain production
Ineffective erythropoiesis drives severe microcytic anemia, extramedullary hematopoiesis (frontal bossing, maxillary prominence, hepatosplenomegaly), and growth failure
Hemoglobin electrophoresis classically shows markedly elevated HbF (85%), elevated HbA2, and absent or near-absent HbA (<2%)
Standard of care is lifelong chronic transfusion therapy targeting a pre-transfusion Hgb around 9-10.5 g/dL to suppress ineffective erythropoiesis
Iron chelation (deferasirox, deferoxamine, or deferiprone) is combined to prevent transfusion-related hemosiderosis
Allogeneic hematopoietic stem cell transplant is curative in eligible patients
Why the others are wrong
C) Oral ferrous sulfate supplementation — treats iron deficiency, which is not the underlying problem here; risks compounding iron overload
D) Hydroxyurea monotherapy — increases HbF and is the mainstay in sickle cell disease and useful in some beta thalassemia intermedia patients, but does not replace transfusion in transfusion-dependent thalassemia major
B) Early splenectomy at diagnosis — reserved for patients with hypersplenism causing rising transfusion requirements; delayed until at least age 5 due to overwhelming post-splenectomy infection risk
Question 2HematologyEasy
A 9-month-old infant of Greek descent is brought in for progressive pallor and irritability over the past 3 months. He has fallen off his growth curve. Exam shows pale conjunctivae and a spleen tip 3 cm below the left costal margin. Hgb is 5.8 g/dL, MCV 56 fL, RDW elevated, and smear shows target cells, marked anisopoikilocytosis, and nucleated RBCs. Iron studies are normal. Which of the following studies will most likely confirm the diagnosis?
ABone marrow aspirate and biopsy
BDirect antiglobulin (Coombs) test
COsmotic fragility test
DHemoglobin electrophoresis
Reveal answer & full explanation
Correct answer: D — Hemoglobin electrophoresis
ABone marrow aspirate and biopsy
BDirect antiglobulin (Coombs) test
COsmotic fragility test
DHemoglobin electrophoresis✓
Why Hemoglobin electrophoresis is correct
This infant presents with severe microcytic anemia, target cells, marked anisopoikilocytosis, nucleated RBCs, and splenomegaly beginning after 6 months of age — the classic presentation of beta thalassemia major
Symptoms begin after 6 months because that is when fetal HbF production declines and the beta-chain requirement rises
With normal iron studies, the differential narrows to a hemoglobinopathy
Hemoglobin electrophoresis is the confirmatory test, showing markedly elevated HbF, elevated HbA2, and absent or near-absent HbA due to homozygous beta-globin mutations abolishing beta-chain synthesis
Why the others are wrong
B) Direct antiglobulin (Coombs) test — identifies autoimmune hemolytic anemia, which is typically normocytic with spherocytes, not microcytic with target cells
C) Osmotic fragility test — used to diagnose hereditary spherocytosis, which presents with spherocytes and a normal MCV
A) Bone marrow aspirate and biopsy — would show only nonspecific erythroid hyperplasia from ineffective erythropoiesis; it is invasive and cannot distinguish beta thalassemia from other hemoglobinopathies, which electrophoresis does noninvasively
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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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