Etiology

The beta-globin gene is part of a cluster of genes located on chromosome 11. Its expression is regulated by an upstream locus control region (LCR).[12] A variety of mutations in the gene or its regulatory elements cause defects in the initiation or termination of transcription, abnormal RNA splicing or cleavage, substitutions, and frameshifts. The result is decreased or absent production of beta-globin chains, giving rise to the beta-thalassemia syndromes.[13]

Beta-zero mutations, with complete absence of beta-globin production, are usually nonsense, frameshift, or splicing mutations, whereas beta-plus mutations with some beta-globin production are most often mutations in the promoter regions or splicing defects. Specific mutations have some association with ethnicity, different clusters being prevalent in different parts of the world.[14]

Inheritance follows an autosomal recessive pattern for the most part, with heterozygous individuals having the trait, whereas homozygous or compound heterozygous (the presence of two different mutant alleles at a particular gene locus, one on each chromosome of a pair) individuals manifest with beta-thalassemia major or intermedia. Some dominantly inherited mutations resulting in an intermedia phenotype have also been described.[15]

The silent carrier is a distinct phenotype in which all hematologic parameters, including hemoglobin analysis, are normal. Specific mutations associated with this phenotype have been identified. Coinheritance of alpha-gene mutations, and persistence of fetal hemoglobin production, may restore the globin balance and result in a milder syndrome.[16]

Pathophysiology

The underlying pathophysiology of beta-thalassemia syndromes is ineffective erythropoiesis. Clinical manifestations are usually seen only after the normal transition from fetal hemoglobin (tetramer of 2 alpha- and 2 gamma-globin chains) to adult hemoglobin (2 alpha- and 2 beta-globin chains), due to the defect being in the beta-globin gene.

When the production of beta-globin chains is deficient or absent, the imbalance between alpha and beta chains leads to precipitation of the excess alpha chains in erythroid precursors and maturing red cells, resulting in membrane damage and cell destruction. The inability of these cells to survive is the cause of ineffective erythropoiesis, resulting in anemia and a compensatory erythroid hyperplasia.

Bony changes in the skull (including the flat bones of the cranium, the air spaces of the sinuses, and the vertebral bodies) are due to the marked erythroid hyperplasia. The latter may also lead to extramedullary hematopoiesis in the liver and spleen, resulting in enlargement of these organs.

In beta-thalassemia major there is a complete or near-complete lack of beta-globin, leading to a transfusion-dependent severe anemia. When there is moderate reduction, some people may be less anemic (beta-thalassemia intermedia), and heterozygous individuals (beta-thalassemia trait) have mild anemia with compensatory overexpression of the normal gene.

Mutations of the alpha-, beta-, delta-, and gamma-globin genes modify the severity, and usually result in intermediate phenotypes. Ineffective erythropoiesis and, to a lesser degree, anemia result in downregulation of expression of hepcidin and enhanced absorption of iron from the intestine.[17] This is more pronounced in beta-thalassemia intermedia.[18]

Regular blood transfusions given to patients with beta-thalassemia major, or in some cases beta-thalassemia intermedia, will suppress ineffective erythropoiesis to some extent. However, iron from transfused red cells can accumulate in these patients, which can result in tissue toxicity. Initially, excess iron is sequestered in the cells of the monocyte-macrophage system, but, with continued accumulation, further excess is usually deposited in the liver, heart, pancreas, and other endocrine organs, leading to cellular damage. Without therapy, cirrhosis, heart disease, diabetes, and other disorders develop; death is usually the result of cardiac failure.

Classification

Genotypic classification

  • Heterozygous beta-thalassemia (beta-thalassemia trait)

  • Homozygous beta-thalassemia

Mutations may be either in the beta-globin gene itself, or in the promoter for the gene located toward the 5’ end. Mutations that result in complete lack of expression of the gene are termed beta-zero mutations. Some mutations in the promoter may result in partial expression of the gene, resulting in the production of some normal beta-globin. These mutations are termed beta-plus mutations, and often underlie the intermedia phenotype.

Phenotypic classification

  • Silent carrier: completely asymptomatic with normal hematologic parameters.[1][2]

  • Beta-thalassemia minor (commonly referred to as beta-thalassemia trait): usually asymptomatic; diagnosis is made based on screening when there is a positive family history, or during a workup for mild anemia; the mild microcytic anemia is often misdiagnosed as iron deficiency anemia.

  • Beta-thalassemia intermedia: usually a similar presentation to beta-thalassemia major but as a toddler or older child; symptoms are usually less pronounced and the course is usually more insidious.

  • Beta-thalassemia major (also called Cooley anemia): complete absence of hemoglobin A; often presents at a few months of age with progressive pallor and abdominal distension; perinatal history is most often uneventful, and the infant may be pale, possibly with poor feeding and decreased activity; hepatosplenomegaly and bony abnormalities are often present at presentation, most often of the skull (frontal and parietal bossing, and chipmunk facies).

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