Saturday, November 10, 2012



This is prevalent throughout tropical and north Africa, Mediterranean, Middle East and South-east Asia, including India. Over 200 different mutations of the β globin gene or its promoter are known to cause β thalassaemia, the majority being single nucleotide substitution (point mutations). Each mutation is linked to specific pattern of RFLPs within β globin gene cluster (or haplotype). In severe forms of β thalassemia (β thalassemia major) there is severe impairment or absence of β chain production. As a consequence excess α chain accumulates and precipitates in red cell precursors leading to their destruction within bone marrow leading to ineffective erythropoiesis. Also there is hemolysis in mature red cells due to inclusions. 

Red cell containing fetal Hb survives preferentially since there is less globin chain imbalance. The anaemia produces tissue hypoxia, which stimulates erythropoietin production and massive expansion of erythropoiesis in bone marrow and extramedullary sites.

If untreated, β thalassemia major leads to severe anaemia, wasting and growth retardation, with death in early childhood. As a result of expansion in erythropoiesis there are bone deformities and enlargement of liver and spleen. Widening of the dipole of the facial bones and skull gives rise to a characteristic thalassaemic facies, splaying of the teeth and frontal bossing.  

The treatment of β thalassemia major is regular blood transfusion to maintain Hb between 10-14 g/dL. But inevitable complication of multiple transfusions is iron overloading. If untreated this leads to haemosiderosis which causes multisystem dysfunction due to abnormal accumulation of iron in tissues. Vitamin C enhances the urinary excretion of iron, so patients receiving iron chelating agents like desferrioxamine to see the efficacy of chelation and is done by measuring ferritin.

Allogenic bone marrow transplantation from HLA matched siblings has been used with considerable success for treatment of β thalassemia major with disease free survival rates up to 95% in younger children.

Mutations that severely disrupts or abolish β globin synthesis (β0 thalassaemia) includes those that prevent normal splicing of mRNA (splice junction or splice site mutations) or generate a non-functional mRNA by premature translation termination (nonsense mutations), and mutation that partially disrupts or reduced β globin synthesis (β+, β++ thalassemia) includes small nucleotide deletions or insertions leading to frameshift mutations.

β-thalassaemia can be co-inherited with α-thalassemia and leads to imbalance in globin chain synthesis and results in more ineffective erythropoiesis, and hereditary persistence of fetal hemoglobin (HPFH). HPFH can be linked to β globin cluster, and includes large deletions and point mutations in promoter regions of the γ globin genes. The heterozygous (carrier) state for β thalassaemia (β thalassaemia trait) is usually without harmful effects. 

Most individuals have slightly reduced Hb concentrations and elevated red cell count. A raised HbA2 concentration is an important diagnostic marker and distinguishes β thalassaemia trait from α thalassemia, in which HbA2 is normal or low. This reflects during β thalassemia there is high output from δ globin gene. Similarly HbF levels are frequently slightly raised in β thalassemia heterozygotes.  




% HbA2
Clinical status
>94% and remainder is HbA2
Thalassaemia major
Thalassaemia major
Slightly reduced
Raised or borderline
Thalassemia intermedia

Sometimes called Cooley’s anaemia after the physician who in 1925 first described the condition in children of Italian and Greek immigrants in New York. This condition results from mutation that interferes with translation, in about 50% of all mutations. There is also frame shift or non sense mutation that prematurely terminates β-globin chain.

Clinical presentation is usually at <1 year of age with features that includes failure to grow, abdominal girth expansion, and failure to thrive. There is frontal bossing (rounded eminence on forehead), pallor, etc. These features are due to marrow expansion caused by ineffective erythropoiesis with production of highly unstable α-globin tetramers leading to increased plasma volume and formation of extramedullary erythropoietic tissue.

Typical CBC results include severe anemia with Hb between 3-6.5 g/dL, MCV <72 fL, and MCHC <320 g/L. There is microcytosis, target cells, polychromasia, nucleated red cells, anisocytosis. There is major HbF band with absence of HbA band and variable HbA2 (1-6%). 

Electrophoresis at alkaline and acid pH shows dominant band in F position.

β-thalassemia (β-thalassemia Intermedia): 

There is reduced production of β-globin chain with subsequent reduction in quantity of HbA. There is large HbF band with reduced HbA. HbA2 is above reference interval. Bands in A and F positions are seen on electrophoresis. The Hb is significantly reduced (6-10 g/dL).

β-thalassemia minor (β-thalassemia trait): 

The CBC shows low normal or decreased Hb and hematocrit, decreased MCV (<72 fL) and MCH (<27 pg). PBS has occasional hypochromia, poikilocytosis, and target cells. The diagnosis of this minor condition with appropriate indices in CBC, is dependent on finding of raised HbA2 concentration (>3.5%). Iron deplete individuals should become iron replete before a definitive diagnosis as HbA2 may be falsely low in iron deficiency individual. HbF will be raised (>1%).


There is deletion of δ- and β-gene. There is increase in HbA with reduced HbA2 and raised HbF. Hb lepore is sometimes classified as this type of thalassemia due to reduction in production of both delta and β globin chain or abnormal Hb chain. Thalassemic indices on CBC includes low MCV, MCH, normal RDW.

Hereditary persistence of Fetal Hemoglobin (HPHF): 

This describes the group of genetic conditions in which the concentration of HbF is increased because of reduction of β-globin synthesis and compensatory increase in δ-globin synthesis. Here Hb, MCV, MCH are within reference intervals. 
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