What is the etiopathogenesis of thalassemia major in pediatric patients?

Etiopathogenesis of Thalassemia Major in Children

Thalassemia major is an autosomal recessive genetic disorder caused by mutations in the β-globin gene (HBB) on chromosome 11, resulting in severe reduction or complete absence of functional β-globin chain synthesis, leading to profound anemia and a cascade of pathophysiologic consequences that dominate the clinical course. 1

Genetic Basis

• The fundamental defect involves homozygosity or compound heterozygosity for β-thalassemia mutations, which determines whether patients have β+ (reduced β-globin production) or β0 (absent β-globin production) phenotypes 1
• The β-globin gene cluster is located on chromosome 11, and mutations are typically point mutations or, less commonly, deletions 2
• Inheritance follows an autosomal recessive pattern, meaning both parents must be carriers for a child to develop thalassemia major 2

Primary Pathophysiologic Mechanism

The core pathophysiology stems from the imbalance between α-globin and β-globin chains:

• Absent or severely reduced β-globin chains lead to excess unpaired α-globin chains that precipitate within red blood cell precursors 3
• This precipitation causes ineffective erythropoiesis (destruction of developing red cells in the bone marrow before they mature) and hemolysis (premature destruction of circulating red cells) 3, 2
• The result is severe, life-threatening anemia that emerges at approximately 1-2 years of age 1, 2

Timing of Clinical Manifestation

A critical aspect of the etiopathogenesis is the developmental timing:

• Infants are healthy at birth because fetal hemoglobin (HbF, composed of α2γ2 chains) does not require β-globin chains 1
• Symptoms emerge at 1-2 years of age as the physiologic switch from fetal to adult hemoglobin occurs and γ-globin production declines 1, 2
• This developmental switch unmasks the β-globin deficiency, leading to the clinical presentation of severe anemia, growth retardation, hepatosplenomegaly, and skeletal changes from bone marrow expansion 2

Secondary Pathophysiologic Consequences

The disease creates a vicious cycle of complications:

Bone Marrow Expansion

• Ineffective erythropoiesis drives massive compensatory expansion of erythroid marrow 2
• This causes skeletal deformities, osteoporosis, and extramedullary hematopoiesis (blood cell production outside the bone marrow in organs like the spleen and liver) 2

Transfusion-Related Iron Overload

• Each unit of transfused blood contains approximately 200-250 mg of elemental iron 1, 4
• Humans lack physiological mechanisms for iron excretion, leading to progressive iron accumulation in tissues 1, 4
• Cardiac iron loading becomes the leading cause of death, accounting for approximately 70% of mortality in transfusion-dependent patients 1, 4
• Iron deposits damage organs through lipid peroxidation, mitochondrial damage, interference with electrical function, and promotion of fibrosis 5

Cardiac Pathophysiology

• In untreated thalassemia major, chronic profound anemia causes high-cardiac-output heart failure and is fatal at a young age 5
• Iron toxicity in the heart occurs through multiple mechanisms including membrane damage, mitochondrial dysfunction, and altered gene expression 5
• Before modern chelation therapy, patients typically died by age 10 from cardiac complications 4

Clinical Definition

Thalassemia major is operationally defined as requiring more than 8 transfusion events per year in adults over 16 years of age 1, 4

Common Pitfall

The most critical pitfall is delayed diagnosis in the first 1-2 years of life. Clinicians must recognize that infants appear normal at birth due to protective fetal hemoglobin, but severe anemia will inevitably develop as the hemoglobin switch occurs. Early identification through newborn screening or family history is essential to initiate lifelong regular red blood cell transfusions, which are mandatory for survival, and lifelong iron chelation therapy to prevent or reverse iron-related organ damage 1, 4.