Note: OP Ghai's Essential Pediatrics (10th edition) is not in the textbook library. The following is a comprehensive, pediatrics-oriented review compiled from Robbins & Cotran Pathologic Basis of Disease, Goldman-Cecil Medicine, Harriet Lane Handbook (23rd ed.), and Emery's Elements of Medical Genetics, covering all topics as presented in Ghai's standard structure.

Thalassemia in Pediatrics

Definition

• Hemoglobin deficiency (hypochromic, microcytic anemia)
• Relative excess of the other (normal) globin chain → intracellular precipitation → hemolysis and ineffective erythropoiesis

Epidemiology & Genetics

• Endemic regions: Mediterranean basin, Middle East, tropical Africa, Indian subcontinent, Southeast Asia
• Autosomal codominant inheritance
• Selective advantage: heterozygotes are protected against P. falciparum malaria
• α-globin genes: 2 genes in tandem on chromosome 16 (total 4 alleles)
• β-globin gene: Single gene on chromosome 11

Classification

β-Thalassemia

α-Thalassemia

Molecular Pathogenesis of β-Thalassemia

1. Splicing mutations — most common cause of β⁺; ectopic splice site allows some normal mRNA
2. Promoter mutations — reduce transcription ~75–80%; cause β⁺⁺
3. Chain terminator mutations — most common cause of β⁰; nonsense or frameshift → no functional β-globin

• Precipitate within erythroid precursors → inclusion bodies
• Membrane damage → ineffective erythropoiesis in the marrow
• Surviving red cells: abnormal, short-lived → hemolysis
• Massive erythroid hyperplasia → bone marrow expansion → skeletal deformities
• Erythroferrone ↑ → hepcidin ↓ → ↑ intestinal iron absorption → secondary hemochromatosis

β-Thalassemia Major — Clinical Features in Children

• Severe progressive anemia (Hb 3–6 g/dL in untransfused)
• Failure to thrive, growth retardation
• Pallor, jaundice, hepatosplenomegaly (extramedullary hematopoiesis)

• "Chipmunk facies" — frontal bossing, maxillary hyperplasia, prominent malar eminences
• "Hair-on-end" (crew-cut) appearance on skull X-ray — perpendicular striations on outer table
• Thinning of cortex, pathological fractures

• Cardiac: dilated cardiomyopathy, arrhythmias — leading cause of death
• Hepatic: cirrhosis
• Endocrine: delayed puberty, hypogonadism, diabetes mellitus, hypothyroidism
• Skin: bronze pigmentation (hemosiderosis)

β-Thalassemia Minor (Trait)

• Usually asymptomatic
• Mild microcytic hypochromic anemia
• MCV <80 fL, MCH <27 pg, HbA₂ >3.5% (diagnostic)
• High RBC count (pseudopolycythemia)
• No specific treatment; genetic counseling mandatory
• Folic acid supplementation in pregnancy

α-Thalassemia in Pediatrics

• Hb 8–9 g/dL; does not require regular transfusion
• Reticulocytosis, target cells, basophilic stippling
• Brilliant cresyl blue stain → multiple inclusion bodies (HbH precipitates)
• Folic acid 2–5 mg/day recommended
• Risk: hemolytic crises during infections

• HbBart (γ₄) has very high O₂ affinity → cannot deliver O₂ → severe fetal hypoxia
• Features: massive organomegaly, heart failure, severe anemia (Hb 3–20 g/dL), generalized edema
• Fatal without intrauterine transfusion
• Maternal risks: retained placenta, eclampsia, sepsis

Diagnosis

CBC & Indices

• ↓ MCV (<80 fL), ↓ MCH (<27 pg), ↑ RBC count
• Normal serum iron/ferritin (to exclude IDA)

Hemoglobin Electrophoresis / HPLC

• β-thalassemia minor: HbA₂ >3.5% (diagnostic); HbF mildly elevated
• β-thalassemia major: HbA markedly ↓ or absent; HbF markedly ↑; HbA₂ variable
• HbH disease: HbA₂ ↓; HbH (β₄) detected

Peripheral Blood Smear

• Microcytosis, hypochromia, anisocytosis, poikilocytosis, target cells, nucleated RBCs, basophilic stippling, tear-drop cells

Bone Marrow (if done)

• Marked erythroid hyperplasia

Molecular Diagnosis

• PCR-based methods (ARMS-PCR, gap-PCR, direct sequencing) — identifies specific mutations
• Multiplex ligation-dependent probe amplification (MLPA) — for α-gene deletions

Management

Blood Transfusion (Thalassemia Major)

• Hypertransfusion regimen: Maintain pre-transfusion Hb >9–10.5 g/dL
• Transfuse every 2–5 weeks with leukoreduced packed red cells
• Initiate when Hb consistently <7 g/dL with failure to thrive or bone changes
• Suppresses ineffective erythropoiesis → prevents skeletal deformity and organomegaly

Iron Chelation Therapy

Splenectomy

• Indicated if transfusion requirement increases markedly (>1.5× baseline)
• Increases risk of overwhelming sepsis (especially S. pneumoniae, H. influenzae, Neisseria)
• Vaccinate against pneumococcus, meningococcus, Hib 4–6 weeks before splenectomy
• Lifelong penicillin prophylaxis post-splenectomy

Folic Acid

• Supplementation due to chronic hemolysis and ↑ demand
• 5 mg/day recommended

Curative Therapy

• Allogeneic hematopoietic stem cell transplantation (HSCT): Best results in pediatric patients with HLA-identical sibling donors; ideally before significant organ damage
• Gene therapy: Corrective gene therapy with encouraging results; approved in some settings for β-thalassemia

Endocrine & Supportive Care

• Monitor for growth retardation, delayed puberty, hypothyroidism, diabetes
• Hormone replacement as needed; calcium + Vitamin D for bone health
• Hepatitis B vaccination; screen for transfusion-transmitted infections (HBV, HCV, HIV)

Prognosis

• Thalassemia minor: Normal life expectancy
• Thalassemia major (well-managed): Survival now into 3rd–4th decade with regular transfusion + chelation; cardiac failure remains the leading cause of death in poorly chelated patients
• Hydrops fetalis: Fatal without intrauterine transfusion

Prevention & Screening

• Carrier detection: MCV, MCH, HbA₂ in high-risk populations
• Prenatal diagnosis: Chorionic villus sampling (10–12 weeks) or amniocentesis (16 weeks) + PCR-based mutation analysis
• Genetic counseling: Both parents with thalassemia trait → 25% chance of affected child; counseling mandatory before pregnancy