beta thalassemia

**Genetics/Pathophysiology** - Chromosome 11 (β-globin gene, HBB). Mostly point mutations (promoter, splice site, nonsense), unlike α-thalassemia, which is usually gene deletions. - β0 = no β-chain production; β+ = reduced production. - Decreased β-chains means decreased HbA (α2β2). Excess α-chains are unpaired and precipitate, damaging RBC precursors (ineffective erythropoiesis, in marrow and spleen) and mature RBCs (extravascular hemolysis). - Compensatory ↑HbA2 (α2δ2) and ↑HbF (α2γ2). - Epidemiology: Mediterranean, Middle Eastern, South Asian, Southeast Asian, and African ancestry. Heterozygote advantage against malaria (like sickle cell).

**Clinical forms** 1. **Beta thalassemia minor (trait):** heterozygous (β/β+ or β/β0). Usually asymptomatic with mild microcytic anemia. Mentzer index (MCV/RBC count) <13. Normal or ↑RBC count. Often mistaken for iron deficiency. Electrophoresis: ↑HbA2 (>3.5%), with or without mildly ↑HbF. 2. **Beta thalassemia intermedia:** variable severity. Moderate anemia, with occasional or no transfusions. 3. **Beta thalassemia major (Cooley anemia):** homozygous β0/β0 or severe β+/β0. Presents at 6–12 months, after the switch from HbF to HbA, so the neonate is protected at birth. Findings: - Severe anemia, failure to thrive, jaundice, hepatosplenomegaly (extramedullary hematopoiesis). - Expansion of the marrow cavity gives "crew-cut" skull x-ray, frontal bossing, chipmunk facies, and maxillary overgrowth. - Iron overload from chronic transfusions plus ↑GI iron absorption (suppressed hepcidin). This causes hemochromatosis-like damage: cardiomyopathy and heart failure (the leading cause of death), cirrhosis, diabetes, and hypogonadism and growth failure. - Peripheral smear: microcytosis, hypochromia, target cells, basophilic stippling, teardrop cells, nucleated RBCs. Reticulocyte count is inappropriately low for the degree of anemia. - Electrophoresis: ↑↑HbF, ↑HbA2, and absent or markedly ↓HbA (absent in β0/β0). - Lab: ↑indirect bilirubin, ↑LDH, ↓haptoglobin. Iron studies show normal or ↑ferritin, ↑iron, and ↑transferrin saturation (vs iron deficiency).

**Differential:** Iron deficiency (↓ferritin, ↑RDW, ↑TIBC), α-thalassemia (normal electrophoresis in trait; HbH or Hb Barts in severe forms), sideroblastic anemia, and anemia of chronic disease.

**Management** - Minor: no treatment. Avoid unnecessary iron supplementation. - Major: regular transfusions (keep Hb ~9–10 g/dL) plus **iron chelation** (deferasirox, deferoxamine, deferiprone). Folate supplementation. Splenectomy for hypersplenism (give vaccines against encapsulated organisms). Monitor cardiac and liver iron by MRI T2*. - Curative: allogeneic hematopoietic stem cell transplant. - Gene therapy: betibeglogene autotemcel (Zynteglo, lentiviral β-globin gene addition) and exagamglogene autotemcel (Casgevy, CRISPR-Cas9 editing of BCL11A to ↑HbF) are approved for transfusion-dependent β-thalassemia. - Luspatercept (activin receptor ligand trap that promotes late-stage erythroid maturation) reduces transfusion burden.

**Complications:** Iron overload, infection (Yersinia, from excess iron; encapsulated organisms after splenectomy), pigment gallstones, osteoporosis, extramedullary hematopoiesis (paraspinal masses), aplastic crisis with parvovirus B19, and alloimmunization from transfusions.

**High-yield pearls** - Beta thal: ↑HbA2 and HbF. Alpha thal: normal HbA2. - Signs appear after 6 months, once HbF falls. - Hair-on-end/crew-cut skull from marrow expansion (also seen in sickle cell). - Iron overload can occur even without transfusions (↑GI absorption). - Cardiac failure is the most common cause of death. - Mentzer index <13 suggests thalassemia, and >13 suggests iron deficiency.