Thalassemia

Thalassemias are inherited, autosomal recessive anemias caused by reduced or absent synthesis of one or multiple globin chains. There are two main types of thalassemia depending on which type of globin chain synthesis is affected - alpha thalassemia where alpha globin chains are affected and beta thalassemia where beta globin chains are affected.

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. For each of the 2 genes, one allele is inherited from a person’s father, and the other is inherited from a person’s mother - so each person inherits 2 alleles from each parent. Severity of disease depends on the number of dysfunctional alleles.

   Allele deletion and type of alpha thalassemia

   • One allele deletion, (-α/αα): Silent carriers
   • Two allele deletion: Alpha thalassemia trait or alpha-thalassemia minor
   • Three allele deletion: HbH disease
   • Four allele deletion: Hydrops fetalis, Hb Bart’s or alpha-thalassemia major

   Two allele or gene deletion can be in cis(–/αα) or trans(-α/-α) form. Cis or homozygous alpha form occurs on the same chromosome while trans or heterozygous alpha type occurs on both chromosomes in a pair. Cis-type α-thalassemia trait tends to be found in individuals of Asian descent, while trans-type tends to run in individuals of African descent. If either of the parents carries a cis-type mutation, there is a higher risk of developing 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 of 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 of anemia, preeclampsia and CCF. Bone changes like hypertrophy of the maxilla, bossing of the skull, and prominence of the malar eminences are 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. Mutations (not deletions), in the HBB gene that codes for beta globin chain, cause beta thalassemia. Defects in translation, transcription and mRNA splicing are seen. The absence of beta-globin production is referred to as beta-zero (B0) thalassemia while reduced amount of 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 type of 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, associated with jaundice, failure to thrive, hepatosplenomegaly, recurrent infections, bone marrow expansion, extramedullary hematopoiesis, frontal bossing, prominent malar eminence, a depressed bridge of the nose, and hypertrophy of the maxillae, increased fracture risk, knock knees or genu valgum. Complications include iron overload from repeated blood transfusions causing 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 who have 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, 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 or indirect bilirubin may be elevated. MCH and MCHC is reduced. Recombinant DNA techniques of gene mapping, PCR are used for prenatal diagnosis. Bone marrow shows erythroid hyperplasia. X ray shows cortical thinning, widening of diploic space, “hair-on-end” appearance, phalanges appear rectangular or biconvex.

Mentzer Index

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