Note: Ghai's Essential Pediatrics is not in this textbook library. The content below is drawn from Robbins & Kumar Basic Pathology, Robbins, Cotran & Kumar Pathologic Basis of Disease, and Goldman-Cecil Medicine - all authoritative sources covering thalassemia comprehensively.

Thalassemia - Pediatric

Definition & Epidemiology

• Endemic in the Mediterranean basin (thalassa = "sea" in Greek), Middle East, tropical Africa, Indian subcontinent, and Asia
• Among the most common inherited disorders of humans
• Prevalence is maintained because heterozygous carriers are protected against falciparum malaria
• The two α-chains of HbA are encoded by two α-globin genes on chromosome 16; the β-chain by a single β-globin gene on chromosome 11

Classification

β-Thalassemia (most clinically important)

α-Thalassemia

Molecular Pathogenesis of β-Thalassemia

1. Splicing mutations - most common cause of β⁺-thalassemia; some create ectopic splice sites within introns
2. Promoter region mutations - reduce transcription by 75-80%; result in β⁺ alleles
3. Chain terminator mutations (nonsense mutations, frameshifts) - most common cause of β⁰-thalassemia; completely block β-globin translation

Pathophysiology

1. Inadequate HbA formation → small (microcytic), poorly hemoglobinized (hypochromic) red cells
2. Accumulation of unpaired α-globin chains → toxic precipitates that severely damage red cell and erythroid precursor membranes → apoptosis of erythroid precursors in bone marrow = ineffective erythropoiesis

• Erythropoietin surge → massive marrow expansion → bone deformities (frontal bossing, maxillary hypertrophy = "thalassemic facies")
• Extramedullary hematopoiesis → hepatosplenomegaly, paravertebral masses (sternum, ribs)
• Suppression of hepcidin → increased dietary iron absorption → iron overload (even without transfusions)

• Aggregate-containing red cells destroyed by splenic macrophages
• Splenomegaly → hypersplenism → pancytopenia, increased transfusion requirement

Clinical Features

β-Thalassemia Major (Cooley's Anemia) - Pediatric Presentation

• Symptoms appear during the first year of life (as γ→β switching occurs after birth)
• Without treatment: hemoglobin cannot be maintained above 5 g/dL
• Pallor, failure to thrive, jaundice, progressive abdominal distension
• Thalassemic facies: frontal bossing, prominent malar eminences, protruding jaw (due to marrow expansion)
• Hepatosplenomegaly - constant finding; leads to pancytopenia
• Growth retardation and delayed puberty in inadequately treated children
• Recurrent infections, spontaneous fractures, gallstones (cholelithiasis), leg ulcers in early childhood
• Skeletal deformities from marrow expansion (hair-on-end appearance on skull X-ray)

Iron Overload Complications (in older children/adolescents)

• Heart failure - multifactorial (chronic anemia + myocardial iron toxicity); leading cause of death
• Liver disease - cirrhosis from iron overload (± hepatitis B/C from transfusions)
• Endocrinopathies - diabetes mellitus, hypothyroidism, hypogonadism (delayed puberty/primary amenorrhea)
• Osteoporosis/osteopenia

β-Thalassemia Minor

• Asymptomatic, or mild microcytic hypochromic anemia
• Commonly mistaken for iron deficiency anemia - do not respond to iron
• Key distinction: elevated HbA₂ (>3.5%) on HPLC/electrophoresis

HbH Disease (3-gene α-thalassemia)

• Moderate hemolytic anemia; Hb usually 8-9 g/dL
• Does not require regular transfusions
• Hemolytic crises during acute infections
• Requires folic acid supplementation (2-5 mg/day), especially in children

Diagnosis

• β-Thal major: absent or markedly reduced HbA, elevated HbF (20-90%), elevated HbA₂
• β-Thal minor: HbA₂ > 3.5% (most reliable marker)
• HbH: HbH band on electrophoresis Serum ferritin & iron studies: Elevated (iron overload) - helps distinguish from iron deficiency DNA analysis: Definitive diagnosis; identifies specific mutations MRI liver/heart: Quantifies iron overload (T2* MRI)

Treatment

Transfusion Therapy

• Goal: Maintain pre-transfusion Hb > 9-10.5 g/dL (suppresses ineffective erythropoiesis, prevents marrow expansion and skeletal deformities)
• Transfusions given every 2-5 weeks
• Use leukoreduced packed red cells to minimize transfusion reactions and pathogen transmission
• Initiation requires: definitive molecular diagnosis + severity of anemia on repeated measurement + clinical criteria (failure to thrive, bone changes)

Iron Chelation Therapy

Splenectomy

• Indicated when annual blood consumption increases progressively (>200 mL/kg/year of packed RBCs) and is responsible for significant iron accumulation despite good chelation, OR symptomatic splenomegaly/hypersplenism
• Delay until child is at least 5 years old (risk of overwhelming post-splenectomy infection ~50% mortality)
• Mandatory vaccinations before splenectomy: pneumococcus, meningococcus, H. influenzae type b
• Post-splenectomy: lifelong penicillin prophylaxis + increased thrombosis risk

Curative Options

• Allogeneic bone marrow/stem cell transplantation - best results in pediatric patients with HLA-identical sibling donors (Goldman-Cecil, 2024); adults have more iron overload and worse outcomes
• Gene therapy - corrective gene therapy now approved as safe and effective for β-thalassemia; increasingly available (Harrison's Principles, 2025)

Newer Therapies

• Luspatercept (recombinant fusion protein, activin receptor type IIB ligand trap) - approved for adults with transfusion-dependent β-thalassemia; reduces transfusion burden by ≥33%; given SC 1.0-1.25 mg/kg every 3 weeks
• Hydroxyurea - can increase HbF levels; more benefit in sickle cell disease than thalassemia
• α-globin expression reduction - experimental approach for HbE β-thalassemia

Prevention & Genetic Counseling

• Carrier screening (CBC: low MCV/MCH → confirm with HPLC) for at-risk ethnic populations
• Both parents must be carriers for a child to have thalassemia major
• Prenatal diagnosis possible by chorionic villus sampling (CVS) at 10-12 weeks or amniocentesis
• Preimplantation genetic diagnosis (PGD) available
• Carriers (thalassemia minor) should receive appropriate genetic counseling
• During pregnancy, carrier mothers may become more anemic - monitor in 2nd/3rd trimesters + folic acid supplementation

Key Points for Exams

• Robbins & Kumar Basic Pathology, pp. 387-390
• Robbins, Cotran & Kumar Pathologic Basis of Disease, pp. 602-607
• Goldman-Cecil Medicine, Chapter 148, pp. 1710-1715