Beta-thalassemia major

The most severe form of β-thalassemia (homozygous β⁰ or β⁺ mutations) causing near-complete absence of β-globin chains. Presents with profound anemia in infancy (Cooley's anemia) requiring lifelong transfusions.

• Untreated, it is fatal in early childhood. Regular transfusions have transformed prognosis but lead to iron overload that must be managed. Classic example of extramedullary hematopoiesis causing bone deformities and growth failure. Often tested on boards as an infant with severe microcytic anemia, "crew-cut" skull, and hepatosplenomegaly.

• Well in neonatal period (due to protective fetal Hb), then at 6–12 months develops severe anemia: pallor, jaundice, irritability, FTT. Extramedullary hematopoiesis → frontal bossing, maxillary overgrowth (chipmunk facies), pathological fractures. Massive hepatosplenomegaly (abdominal distension) from RBC destruction and extramedullary hematopoiesis.
• Labs: Very low Hb (often <7 g/dL). Microcytic, hypochromic RBCs with target cells, anisopoikilocytosis, nucleated RBCs on smear. Electrophoresis: little to no HbA, markedly elevated HbF (majority) and HbA2.
• Complications: Iron overload from transfusions (hemochromatosis in heart -> cardiomyopathy/arrhythmias, endocrine glands -> diabetes, growth delay). Also risk of infection (especially after splenectomy) and folate deficiency (high RBC turnover).

1. Suspect in infant with severe microcytic anemia after 6 months and family history. Differentiate from iron deficiency: thalassemia major has normal iron studies, higher RBC count, and signs of hemolysis (↑bilirubin).
2. Confirm with hemoglobin analysis: Electrophoresis shows HbF as dominant fraction, HbA2 elevated, and absent/near-zero HbA.
3. Initiate chronic transfusion therapy early to support growth and development. Monitor ferritin and organ function for iron overload; start chelation by 10–20 transfusions or if ferritin >1000 ng/mL.
4. Screen for complications: periodic cardiac MRI for iron, endocrine evaluation (growth, puberty, glucose), liver imaging for cirrhosis. Immunize against encapsulated organisms if splenectomy is performed.

1. Lifelong transfusions (packed RBCs) every 2–5 weeks to maintain Hb ~9–10 g/dL and suppress extramedullary hematopoiesis.
2. Iron chelation therapy (e.g., subcutaneous deferoxamine, oral deferasirox) to prevent iron overload – start early, monitor ferritin and organ iron.
3. Splenectomy if hypersplenism (worsening anemia or high transfusion needs); after splenectomy, give vaccines (pneumococcal, etc.) and prophylactic penicillin.
4. Endocrine support for iron overload effects (e.g., hormone replacement for hypogonadism, manage diabetes and hypothyroid if they occur).
5. Curative: Hematopoietic stem cell transplant ideally in early childhood (best outcomes if done <5 years); experimental gene therapy now available for transfusion-dependent β-thalassemia.

• Mnemonic: Cooley's anemia = Crew-cut skull X-ray (marrow expansion).
• HbF is elevated (α₂γ₂) and is protective in infancy – symptoms start when HbF naturally falls.
• Untreated, causes death by heart failure by puberty – hence early transfusion support is lifesaving.

• Fever in a splenectomized thalassemia patient – assume sepsis (encapsulated organisms); start broad-spectrum antibiotics immediately.
• Signs of heart failure (tachycardia, edema) or new arrhythmia in a transfused patient – evaluate for cardiac iron overload (cardiac MRI) and intensify chelation.

1. Infant with severe anemia → confirm thalassemia major (CBC, smear, electrophoresis).
2. Initiate regular transfusions to maintain safe Hb; monitor growth and development.
3. Start iron chelation after ~10–20 transfusions to keep ferritin <2500 ng/mL and prevent organ damage.
4. Periodic screening for complications: heart (ECHO/MRI), liver (MRI, LFTs), endocrine labs every 6–12 months.
5. Evaluate for bone marrow transplant if a suitable donor is available (best done in early childhood for cure).

• Irritable 9-month-old with severe microcytic anemia, massive splenomegaly, and frontal bossing; both parents of Mediterranean origin → β-thalassemia major (confirm with electrophoresis showing no HbA).
• Short adolescent with diabetes and heart failure who has been getting transfusions for anemia since infancy → complications of iron overload in β-thalassemia major.