Thalassemia — Symptoms, Causes & Treatment | MyMedicPlus

Thalassemia is a group of inherited haemoglobin disorders caused by mutations that reduce or eliminate the production of alpha- or beta-globin chains — the protein subunits of haemoglobin. Imbalanced globin chain production leads to the accumulation of unpaired chains that damage red blood cells, causing ineffective erythropoiesis (defective red cell production in the bone marrow) and haemolytic anaemia (premature destruction of red cells in the spleen). Beta-thalassemia major (also called Cooley's anaemia — homozygous or compound heterozygous HBB mutations) is the most severe transfusion-dependent form, typically presenting in infancy. Beta-thalassemia intermedia causes moderate anaemia without regular transfusion requirements. Thalassemia minor (trait) is the heterozygous carrier state — usually mild microcytic anaemia with no significant clinical impact. Alpha-thalassemia is caused by deletions of alpha-globin genes (HBA1/HBA2 — four copies total); deletion of all four (haemoglobin Bart's) is incompatible with life (hydrops fetalis). Thalassemia is highly prevalent in the Mediterranean basin, Middle East, Indian subcontinent, and Southeast Asia — regions historically endemic for malaria (heterozygotes have a survival advantage against Plasmodium falciparum). Approximately 1.5% of the global population are thalassemia carriers; an estimated 300,000 children with major haemoglobinopathies are born each year.

Thalassemia follows autosomal recessive inheritance — two defective copies (one from each parent) are required for major or intermedia disease. Beta-thalassemia is caused by over 250 identified point mutations or small deletions in the HBB gene on chromosome 11; common mutations vary by ethnicity (e.g., IVS1-110 G>A in Mediterranean populations; codon 41/42 frameshift in Southeast Asians). Mutations are classified as beta-zero (no beta-globin produced) or beta-plus (reduced beta-globin) — beta-zero/beta-zero genotype causes the most severe disease. Alpha-thalassemia results from deletions of alpha-globin genes (HBA1 and HBA2) on chromosome 16 — humans have 4 alpha-globin genes; deletion of 1-2 causes alpha-thalassemia trait (silent or mild); deletion of 3 causes HbH disease (moderately severe haemolytic anaemia); deletion of all 4 causes hydrops fetalis (incompatible with postnatal life). Couples where both partners are beta-thalassemia carriers have a 25% probability with each pregnancy of an affected child, a 50% probability of a carrier child, and a 25% probability of an unaffected child. Geographic risk: Mediterranean countries (Greece, Italy, Cyprus), Middle East, Indian subcontinent, and Southeast Asia (Thailand, Malaysia, Philippines) have the highest carrier rates (up to 10-20% of the population in some regions).

Beta-thalassemia major presents in infancy (typically at age 6-24 months) when foetal haemoglobin (HbF) transitions to adult haemoglobin (HbA) — the deficient globin. Features include: severe microcytic haemolytic anaemia (haemoglobin typically below 7 g/dL without transfusion); pallor, fatigue, and breathlessness from profound anaemia; jaundice and intermittent scleral icterus from haemolysis; progressive hepatosplenomegaly — the spleen enlarges massively from extramedullary erythropoiesis and red cell sequestration; growth retardation — children with undertreated thalassemia fail to thrive and have delayed puberty; and bone deformities — the expanding haematopoietic bone marrow causes frontal bossing, prominent cheekbones (so-called 'chipmunk facies'), and thickening of the skull cortex visible on X-ray. Beta-thalassemia intermedia: haemoglobin typically 7-10 g/dL; splenomegaly; may develop extramedullary haematopoietic masses (particularly paraspinal); usually does not require regular transfusions but may need intermittent support. Thalassemia minor/trait: mild microcytic anaemia (MCV below 80 fL, MCH below 27 pg, haemoglobin mildly reduced or normal); usually asymptomatic; diagnosed incidentally on routine full blood count; can be mistaken for iron deficiency anaemia.

Full blood count (FBC): microcytic hypochromic anaemia (low MCV, low MCH, low MCHC) — red cell count typically elevated relative to haemoglobin (RDW normal in thalassemia trait, unlike iron deficiency where RDW is elevated). Peripheral blood smear: target cells (leptocytes), nucleated RBCs, tear-drop cells, Heinz bodies (with HbH inclusions). HPLC (High-Performance Liquid Chromatography) haemoglobin electrophoresis: the key diagnostic test — elevated HbA2 above 3.5% (normal 2-3.2%) confirms beta-thalassemia trait; elevated HbF in beta-thalassemia major and intermedia; HbH (fast-migrating band) in alpha-thalassemia with 3-gene deletion. DNA mutation analysis: definitive molecular diagnosis — identifies specific mutations for genetic counselling and prenatal diagnosis. Iron studies: ferritin, serum iron, TIBC — ferritin is normal or elevated in thalassemia (distinguishes from iron deficiency anaemia, where ferritin is low); important to avoid inappropriate iron supplementation. Cardiac MRI (T2*): gold standard for quantifying myocardial iron loading — essential for monitoring chelation therapy adequacy and preventing cardiomyopathy; T2* below 20 ms indicates significant cardiac iron. Liver MRI (R2* or T2*): quantifies hepatic iron concentration. Prenatal diagnosis: chorionic villus sampling (CVS) at 10-12 weeks or amniocentesis at 16 weeks for fetal DNA mutation analysis — offered to couples who are both carriers of clinically significant mutations.

Beta-thalassemia major: regular blood transfusions every 2-4 weeks to maintain a pre-transfusion haemoglobin above 10 g/dL — suppresses ineffective erythropoiesis, prevents compensatory bone marrow expansion, and reduces splenomegaly. Each unit of packed red cells deposits approximately 200-250 mg of iron in the body. Iron chelation therapy is mandatory to prevent fatal iron overload: deferoxamine (desferrioxamine — DFO) subcutaneous infusion over 8-12 hours at night (5-7 nights/week — highly effective but requires needle insertion and pump); deferasirox (Exjade, Jadenu — once-daily oral tablet — preferred for adherence; monitor renal function monthly); deferiprone (oral three times daily — has additional advantage of removing cardiac iron efficiently; risk of agranulocytosis — weekly FBC monitoring required). Luspatercept (Reblozyl): erythroid maturation agent (activin receptor IIA ligand trap) — subcutaneous injection every 3 weeks; reduces transfusion burden by 50% or more in transfusion-dependent patients (BELIEVE trial). Splenectomy: when hypersplenism causes significantly increased transfusion requirements — requires post-splenectomy vaccinations (pneumococcal, meningococcal, Hib) and lifelong penicillin prophylaxis. Allogeneic haematopoietic stem cell transplantation (HSCT): the only established curative treatment — from HLA-matched sibling donor achieves cure in over 90% of low-risk patients (without iron overload or liver fibrosis); matched unrelated donor transplantation is increasingly available. Betibeglogene autotemscel (Zynteglo — gene therapy): FDA and EMA approved (2022) — harvests patient's own stem cells, inserts functional beta-globin gene using lentiviral vector, then reinfuses after myeloablative conditioning; eliminates transfusion dependence in most patients.

Iron overload (haemosiderosis) is the major long-term complication of transfusion-dependent thalassemia: cardiac siderosis and cardiomyopathy (the leading cause of death in undertreated thalassemia major — cardiac T2* MRI detects myocardial iron; T2* below 20 ms indicates significant loading requiring intensified chelation); hepatic cirrhosis and fibrosis (from iron deposition in Kupffer cells and hepatocytes — liver R2* MRI quantifies hepatic iron concentration); endocrine dysfunction (diabetes mellitus from pancreatic siderosis — affects 10-20%; hypogonadotrophic hypogonadism causing delayed puberty and infertility — affects 50% without adequate chelation; hypothyroidism — 10-15%; growth hormone deficiency); osteoporosis (from bone marrow expansion, hypogonadism, and direct iron toxicity — DEXA scan and bone protection from adolescence); skeletal deformities (frontal bossing, maxillary overgrowth — 'chipmunk facies' — from unchecked marrow expansion in undertreated patients); and extramedullary haematopoiesis (paraspinal masses causing spinal cord compression in thalassemia intermedia). Post-splenectomy sepsis: after splenectomy, patients have lifelong risk of overwhelming post-splenectomy infection (OPSI) from encapsulated organisms (Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae) — all patients require pneumococcal, meningococcal, and Hib vaccinations pre-splenectomy plus lifelong penicillin prophylaxis (phenoxymethylpenicillin 500 mg twice daily) and emergency antibiotic supply.

Carrier screening programs (essential in endemic regions), genetic counseling for carrier couples, prenatal diagnosis (CVS or amniocentesis), preimplantation genetic testing (PGT). Folic acid 5 mg daily for hemolytic anemia. Annual cardiac MRI (T2*) to quantify myocardial iron. Adherence to iron chelation therapy. Bone density (DEXA) assessment and management. Endocrine surveillance from age 10. Sustained lifestyle modifications — maintaining a healthy body weight through balanced diet and regular physical activity, avoiding tobacco smoking, limiting alcohol intake, and managing chronic conditions such as hypertension and diabetes — are foundational strategies for reducing the risk of this condition and its complications. Regular health screening in at-risk populations, rigorous adherence to prescribed preventive medications, and proactive monitoring of established risk factors are equally critical and complementary components of a comprehensive and effective long-term prevention strategy.

Take your child to A&E immediately if: they have thalassemia major and develop fever above 38.5°C — post-splenectomy patients with thalassemia are at extremely high risk of overwhelming infection from encapsulated organisms (pneumococcus, meningococcus) and require emergency antibiotics (ceftriaxone IV) without delay; or if symptoms of acute cardiac deterioration develop (breathlessness, chest pain, palpitations — may indicate severe cardiac iron overload). See a haematologist urgently if: a child under 2 years is persistently pale and failing to thrive, particularly in families from Mediterranean, Middle Eastern, or South or Southeast Asian backgrounds — thalassemia major typically presents with transfusion-dependent anaemia between 6 and 24 months of age. Refer for genetic counselling if: you and your partner are both found to be thalassemia carriers on routine full blood count (MCV below 80 fL, MCH below 27 pg with normal ferritin) — preconception or early antenatal genetic testing prevents the birth of affected children in informed families. Book haematology review if: chelation therapy side effects (hearing or visual changes with deferoxamine; rising creatinine with deferasirox) are suspected — dose adjustment or switch to deferiprone may be required. Enquire about gene therapy (betibeglogene autotemscel) eligibility if your haematologist feels transplant is not feasible.