Thalassemia

Thalassemias are inherited, autosomal recessive anemias caused by reduced or absent synthesis of one or more globin chains. There are two main types, based on which globin chain is affected:

• Alpha thalassemia: decreased or absent alpha-globin chain synthesis
• Beta thalassemia: decreased or absent beta-globin chain synthesis

1. Alpha thalassemias: Alpha thalassemia occurs frequently in people from Mediterranean countries, Africa, the Middle East, India, and Central Asia. Alpha chains are normally coded by four alleles carried on two genes, HBA 1 and HBA 2, on chromosome 16. Each gene has two alleles total (one inherited from the father and one from the mother), so each person has four alpha-globin alleles overall. Disease severity depends on how many alleles are dysfunctional.

   ##### Allele deletion and type of alpha thalassemia
   * <strong>One allele deletion, <em>(-α/αα)</em>: </strong>Silent carriers
   * <strong>Two allele deletion: </strong>Alpha thalassemia trait or alpha-thalassemia minor
   * <strong>Three allele deletion: </strong>HbH disease
   * <strong>Four allele deletion: </strong>Hydrops fetalis, Hb Bart's or alpha-thalassemia major
   

   A two-allele (gene) deletion can occur in either cis (–/αα) or trans (-α/-α) form.

   • Cis means both deletions are on the same chromosome.
   • Trans means the deletions are split across the two chromosomes in the pair.

   Cis-type α-thalassemia trait tends to be found in individuals of Asian descent, while trans-type tends to be found in individuals of African descent. If either parent carries a cis-type mutation, there is a higher risk of HbH disease and hydrops fetalis in the offspring.

   HbH is formed by tetramers of excess beta chains, while Hb Bart’s is formed by tetramers of gamma chains.

   Hb Bart syndrome is characterized by fetal-onset generalized edema, pleural and pericardial effusions, and severe hypochromic anemia, hepatosplenomegaly, extramedullary erythropoiesis, hydrocephalus, and cardiac and urogenital defects. Typically, fetal death in utero occurs.

   HbH disease is characterized by microcytic hypochromic hemolytic anemia, splenomegaly, mild jaundice, gallstones, and acute hemolysis in response to drugs like sulphonamides, antimalarials, and infections. Pregnant women with HbH disease are at risk of miscarriage, worsening anemia, preeclampsia, and CCF. Bone changes such as hypertrophy of the maxilla, bossing of the skull, and prominence of the malar eminences may be seen.

2. Beta thalassemia: Beta thalassemia occurs most frequently in people from Mediterranean countries, North Africa, the Middle East, India, Central Asia, and Southeast Asia. Beta thalassemia is caused by mutations (not deletions) in the HBB gene, which codes for the beta-globin chain. Defects in translation, transcription, and mRNA splicing may occur.

The absence of beta-globin production is referred to as beta-zero (B0) thalassemia, while reduced beta-globin production is called beta-plus (B+) thalassemia. Having either B0 or B+ thalassemia does not necessarily predict disease severity. HBB is located on chromosome 11p15.4. Each individual carries two alleles of HBB. Disease severity depends on how many alleles are affected and the specific disease-causing mutation.

Types of beta thalassemia

• Beta thalassemia major or Cooley’s anemia: B0/B0 or B0/B+; 2 defective alleles; most severe
• Beta thalassemia intermedia: B+/B0 or B+/B+; 2 defective alleles
• Beta thalassemia minor or trait:B/B+ or B/B0; one defective allele; asymptomatic, mild to moderate microcytic anemia

Beta thalassemia major presents with severe anemia, typically in early childhood. Findings include jaundice, failure to thrive, hepatosplenomegaly, recurrent infections, bone marrow expansion, extramedullary hematopoiesis, frontal bossing, prominent malar eminence, a depressed bridge of the nose, hypertrophy of the maxillae, increased fracture risk, and knock knees (genu valgum). Complications include iron overload from repeated blood transfusions, which can cause dilated cardiomyopathy, heart failure, cirrhosis, portal hypertension, and diabetes mellitus.

Beta thalassemia intermedia presents with less severe anemia, gallstones, skeletal abnormalities, leg ulcers, and hepatosplenomegaly.

Dominant thalassemia is an extremely rare form in which individuals with one mutated HBB gene develop clinical symptoms of beta thalassemia. The mutated HBB gene leads to the formation of an extremely unstable type of hemoglobin. It presents with mild to moderate anemia, jaundice, and splenomegaly.

Diagnosis of thalassemias: Peripheral smear, electrophoresis, DNA testing, and iron studies help in the laboratory diagnosis of thalassemias.

Peripheral smear shows hypochromic microcytic anemia. Reticulocytosis is seen. RDW is less likely to be elevated in thalassemias compared to IDA or sideroblastic anemia.

Hb electrophoresis will be normal in IDA. It will show:

• 2-4% HbH, HbA, HbA2, and HbF in HbH disease
• 80-90% Hb Bart’s, smaller amounts of HbH and Hb Portland, and absent HbA, HbA2, and HbF in alpha thalassemia major
• Normal Hb electrophoresis in adults with alpha thalassemia trait
• Increased HbA2, decreased HbA, and increased HbF in beta thalassemia

Increased HbA2 is characteristic of beta thalassemia. Persons with a microcytic anemia but milder symptoms that start later in life have beta thalassemia intermedia.

Unconjugated (indirect) bilirubin may be elevated. MCH and MCHC are reduced. Recombinant DNA techniques such as gene mapping and PCR are used for prenatal diagnosis.

Bone marrow shows erythroid hyperplasia. X ray shows cortical thinning, widening of diploic space, “hair-on-end” appearance, and phalanges that appear rectangular or biconvex.

Mentzer Index

Ratio of MCV/RBC count. <13 in thalassemia; >13 in IDA