A 7-year-old boy from Tamil Nadu presents with severe pallor, jaundice, and hepatosplenomegaly. His mother reports he has required blood transfusions every 4–6 weeks since age 2. Hemoglobin is 7.2 g/dL, MCV 62 fL, reticulocyte count 8%, and serum ferritin 2800 ng/mL. Peripheral blood smear shows hypochromic microcytic RBCs with target cells and nucleated RBCs. Hemoglobin electrophoresis reveals absent HbA, elevated HbF (80%), and HbA2 2%. What is the most likely diagnosis?

Explanation

## Diagnosis: β-Thalassemia Major ### Clinical Presentation This child exhibits the classic triad of β-thalassemia major: 1. **Early-onset transfusion dependence** (by age 2) — indicates severe hemolytic anemia requiring regular transfusions to maintain viable hemoglobin levels 2. **Severe hepatosplenomegaly** — from extramedullary hematopoiesis and iron overload 3. **Jaundice** — from chronic hemolysis ### Laboratory Findings | Feature | This Case | β-Thal Major | β-Thal Intermedia | HbH Disease | |---------|-----------|--------------|-------------------|-------------| | **Hb (g/dL)** | 7.2 | 6–8 (transfusion-dependent) | 7–10 (transfusion-independent) | 9–11 | | **HbA** | Absent | Absent or <10% | 10–30% | Normal | | **HbF** | 80% | 50–90% | 10–50% | <1% | | **HbA2** | 2% | 2–3% | 2–3% | Normal | | **Nucleated RBCs** | Present | Present (severe) | Mild/absent | Absent | | **Transfusion need** | Every 4–6 wks | Frequent (life-long) | Rare or none | None | **Key Point:** The **absence of HbA** (normal adult hemoglobin) is pathognomonic for β-thalassemia major. Both β-globin alleles are non-functional, preventing any HbA synthesis. ### Pathophysiology 1. Homozygous or compound heterozygous β-globin mutations → **no functional β-globin chains** 2. Excess α-globin chains precipitate → **hemolysis and ineffective erythropoiesis** 3. Severe anemia → **transfusion dependence from infancy** 4. Chronic hemolysis + transfusions → **iron overload** (ferritin 2800 ng/mL is markedly elevated) 5. Compensatory erythropoiesis → **hepatosplenomegaly and extramedullary hematopoiesis** ### Hemoglobin Electrophoresis Interpretation - **Absent HbA** = no normal β-globin production - **Elevated HbF (80%)** = γ-globin chains compensate (fetal hemoglobin) - **HbA2 2%** = δ-globin chains also present (δ-globin is less affected) **High-Yield:** In β-thalassemia major, HbF is the **only functional hemoglobin** that can bind oxygen effectively; patients survive because HbF is not suppressed (unlike in normal adults). ### Clinical Pearl The **ferritin level of 2800 ng/mL** indicates significant iron overload — a hallmark of transfusion-dependent thalassemia. This leads to cardiac, hepatic, and endocrine complications (secondary hemochromatosis) by adolescence if not managed with iron chelation therapy. ### Management Implications - **Regular transfusions** to maintain Hb >9–10 g/dL - **Iron chelation** (deferasirox, deferiprone, or deferoxamine) - **Spleen monitoring** (risk of hypersplenism) - **Bone marrow transplantation** (curative in matched siblings, especially if HLA-matched) - **Gene therapy** (emerging option) [cite:Robbins 10e Ch 13]