A 7-year-old boy from Tamil Nadu presents with severe pallor, hepatosplenomegaly, and frontal bossing. His parents are consanguineous. Hemoglobin is 6.5 g/dL with microcytic hypochromic indices (MCV 62 fL, MCH 18 pg). Peripheral blood smear shows target cells, nucleated RBCs, and polychromasia. Hemoglobin electrophoresis shows absent HbA, markedly elevated HbF (80%), and trace HbA2 (2%). What is the most likely diagnosis?

## Diagnosis: Beta-Thalassemia Major ### Clinical Presentation **Key Point:** Beta-thalassemia major typically presents in infancy or early childhood (6–24 months) with severe hemolytic anemia, hepatosplenomegaly, and skeletal deformities (frontal bossing, maxillary prominence). This patient's age (7 years), consanguineous parents, and severe anemia with organomegaly are classic for beta-thalassemia major. ### Hematologic Findings | Feature | Beta-Thalassemia Major | |---------|------------------------| | Hemoglobin | 6–8 g/dL (severe) | | RBC morphology | Target cells, nucleated RBCs, polychromasia | | MCV | Markedly reduced (60–70 fL) | | Reticulocyte count | Elevated (compensatory) | **High-Yield:** The combination of **absent HbA (0%), markedly elevated HbF (>70%), and trace HbA2 (<3%)** is pathognomonic for beta-thalassemia major. ### Hemoglobin Electrophoresis Pattern **Key Point:** In beta-thalassemia major: - **HbA is absent** (complete loss of β-globin production from both alleles) - **HbF is markedly elevated** (80–90%) — γ-globin chains compensate - **HbA2 is normal or low** (<3%) — α~2~δ~2~ is not upregulated This pattern reflects **homozygous or compound heterozygous β-globin mutations** with complete absence of normal adult hemoglobin. ### Pathophysiology **Clinical Pearl:** Beta-thalassemia major results from mutations in both β-globin alleles, leading to: 1. Severe reduction or absence of β-globin chain synthesis 2. Excess α-globin chains → precipitation → hemolysis 3. Ineffective erythropoiesis → extramedullary hematopoiesis → hepatosplenomegaly and skeletal deformities 4. Chronic hemolysis → transfusion dependence (usually by age 2–3 years) ### Management Implications **High-Yield:** Beta-thalassemia major requires: - Regular blood transfusions (target Hb 9–10 g/dL) - Iron chelation therapy - Spleen monitoring (risk of splenic sequestration) - Hematopoietic stem cell transplantation (curative option) [cite:Robbins 10e Ch 12]