Thalassemias

Thalassemias

 

The thalassemias are a group of common inherited hemoglobin disorders that result in the unbalanced synthesis of  beta and alpha globin chains.

Pathophysiology

  • Symptoms result from inadequate hemoglobin (Hb) production and accumulation of globin subunits
  • Disease named according to the defective or absent globin unit
  • Two main types – beta thalassemia and alpha thalassemia

Beta Thalassemia

  • Epidemiology
    • Prevalence – estimated 3% of world’s population is heterozygous for beta thalassemia
    • Ethnic – endemic in Mediterranean, Middle East, Indian subcontinent, Southeast Asia
    • Genetics
      • Usually autosomal recessive
      • The beta globin subunit is synthesized by the epsilon, gamma (2 copies), delta and beta genes on chromosome 11
      • Beta thalassemias are mainly caused by single nucleotide mutations
      • Over 200 known mutations are categorized into 2 classes:
        • Beta-zero (β0)
          • No beta globin synthesis from the affected allele
        • Beta-plus (β+)
          • Decreased beta globin synthesis from the affected allele
      • Beta globin gene deletions are rare
        • Indian – partial deletion of beta globin gene (β0 mutation)
        • Beta delta thalassemia – deletion which removes the entire beta gene and the majority of delta that is only partially compensated by increased gamma globin production (β+ mutation)
        • Hereditary Persistence of Fetal Hemoglobin (HPFH), African type (pancellular) – deletion which removes the beta and delta genes entirely; this deletion is almost fully compensated by increased gamma globin production
    • Forms
      • Beta-thalassemia major (Cooley anemia)
        • Homozygous, or a compound heterozygote, for two β0 mutations
        • Clinical Presentation
          • Asymptomatic at birth since neonates have not yet switched from fetal to adult hemoglobin (gamma genes to beta genes)
          • Symptoms typically first appear at 6-24 months of age
            • Growth retardation
            • Pallor
            • Hepatosplenomegaly
            • Jaundice (Hb F is protective in first 6 months)
          • Iron overload leading to cardiac and liver failure is the main cause of death
        • Diagnosis
          • Laboratory testing
            • Severe, often fatal, microcytic, hypochromic anemia
            • Target cells and nucleated red blood cells present
            • No Hb A and variable amounts of Hb F and Hb A2
            • Elevated bilirubin
        • Treatment
          • Regular transfusions with chelation to prevent iron overload prolongs life expectancy
          • Bone marrow or cord blood transplantation may be curative
      • Beta-thalassemia intermedia
        • β+ homozygote, β0/β+ compound heterozygote, or β0 in combination with a thalassemic hemoglobinopathy (eg, Hb E, Lepore)
        • Clinical Presentation
          • Variable, may be nearly as severe as thalassemia major
          • Pallor, jaundice, cholelithiasis, liver and spleen enlargement, moderate-to-severe skeletal changes, leg ulcers, extramedullary masses of hyperplastic erythroid marrow
        • Diagnosis
          • Laboratory testing
            • Decreased Hb A, increased Hb F, variable Hb A2 levels
            • Often associated with iron overload due to increased intestinal absorption of iron caused by ineffective erythropoiesis
        • Treatment
          • Patients occasionally require transfusions
          • Splenectomy controversial
      • Thalassemia minor
        • Heterozygous for β0 or β+ mutation
        • Typically asymptomatic, mild anemia may be present which is often mistaken for iron deficiency
        • Diagnosis
          • Laboratory diagnosis
            • Microcytic indices present
            • Hb F may be elevated in ~30% of individuals
            • Hb A2 is almost always increased
              • Rare exceptions include beta delta thalassemia Greek beta thalassemia mutations 

Alpha Thalassemia

  • Epidemiology
    • Carrier frequencies in commonly affected populations: Mediterranean (1:30-50), Middle Eastern, Southeast Asian (1:20), African, African American (1:30)
  • Genetics
    • The alpha globin subunit is synthesized by the alpha-1 and alpha-2 genes on chromosome 16
    • Normal individuals have four functioning alpha globin genes (αα/αα)
    • 95% of alpha thalassemia is caused by alpha-1 and alpha-2 deletions; non-deletion or regulatory region mutations are rare
  • Forms
    • Hemoglobin Bart
      • Mutation of four alpha globin genes (--/--)
      • Found in Southeast Asian, Asian Indian and Mediterranean populations but unlikely in African populations
      • Clinical Presentation – hydrops fetalis
    • Hemoglobin H disease
      • Mutation of three alpha globin genes (--/-α)
      • Clinical Presentation
        • Moderately severe hemolytic anemia with Heinz bodies
        • Splenomegaly is always present with rare extramedullary hematopoiesis
      • Diagnosis
        • Laboratory testing
          • Hb H is present (tetramer of beta globin subunits)
            • Hb H may not be detected by electrophoresis in older samples as unstable hemoglobin precipitates in cells; ie, Heinz bodies or in hemolysate
          • In neonates, a large amount of Hb Bart (tetramer of gamma chain) is present
    • Alpha thalassemia-1 trait (alpha thalassemia trait)
      • Mutation of two alpha globin genes (-α/-α; --/αα)
        • Important to define phase for prenatal counseling; homozygosity for alpha-1 and alpha-2 globin gene deletions in cis leads to hydrops fetalis
      • Clinical Presentation
        • Mild microcytic anemia may be present; often misdiagnosed as iron deficiency
      • Diagnosis
        • Laboratory testing
          • Normal hemoglobin electrophoresis
          • Diagnosed by DNA analysis of alpha globin genes, globin chain synthesis assay, or in a neonate when a moderate amount of Hb Bart detected
    • Alpha thalassemia-2 trait (silent carrier)
      • Mutation of a single alpha-2 globin gene (-α/αα)
      • Clinical Presentation
        • Usually asymptomatic
        • Borderline anemia or mild microcytosis may be present; often misdiagnosed as iron deficiency
      • Diagnosis
        • Laboratory testing
          • Normal hemoglobin electrophoresis
          • Diagnosed by DNA analysis of alpha globin genes, globin chain synthesis assay, or in a neonate when a small amount of Hb Bart detected

See Also