At a Glance

Delta-beta-thalassemia should be suspected in a patient with microcytic red blood cells and erythrocytosis but no significant anemia.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

If there is any anemia, tests to rule out an iron deficiency anemia should be performed, as this is the most common cause of a microcytic anemia. Serum iron, total iron binding capacity (TIBC), %saturation, and ferritin should be checked. Examination of the automated red blood cell (RBC) indices can be helpful as an initial screen to determine if the patient has thalassemia. Patients with an erythrocytosis (RBC count > 5.5 mil/μl) and microcytosis (mean cell volume; MCV < 80 fL) should be suspected of having thalassemia. If the MCV/RBC ratio is less than 13, additional testing for thalassemia should be performed.

If the RBC indices suggest a thalassemia, then high pressure liquid chromatography (HPLC) should be performed on lysed RBCs to measure hemoglobin A22delta2) concentration and hemoglobin F (α2gamma2) concentration. As these 2 forms of hemoglobin do not utilize beta chains, both are elevated in beta-thalassemia but not in alpha-thalassemia. However, in delta-beta-thalassemia, hemoglobin F will be high (5-15% of hemoglobin; normal hemoglobin F is <1% outside the newborn age), but the hemoglobin A2 level will be low to normal (<3.5%) due to the additional deletion of the delta chain gene.

A distinguishing feature of delta-beta-thalassemia from hereditary persistence of fetal hemoglobin (HPFH) is the cell distribution of hemoglobin F. It is generally uniform (pancellular) in HPFH, whereas it is heterogeneous in delta-beta-thalassemia. The distribution of hemoglobin F can be measured by the Kleihauer-Betke acid elution test or by flow cytometry with a fluorescence labeled anti-hemoglobin F antibody.

A follow-up test to distinguish delta-beta-thalassemia from HPFH is the globin chain synthesis assay. Red blood cells are incubated with radiolabelled amino acids, and then α and β globin chains are separated by urea carboxymethylcellulose chromatography. Comparison of the radioactivity incorporated in each chain gives the relative rate of synthesis. In delta-beta-thalassemia, there will be a mild alpha chain imbalance with an alpha to non-alpha ratio of about 1.5, whereas there will be balanced production of alpha and beta chains in HPFH.(Table 1)

Table 1

Hemoglobin Analysis in beta-Thalassemias
Classification Hemoglobin A Hemoglobin A2 Hemoglobin F Cell Distribution of Hemoglobin F
Normal Normal (97%) Normal (1.6-3.5%) Normal (<1%) Heterogeneous
HPFH Present, decreased Normal (1-2.1%) Increased (20-30%) Uniform
β+Thalassemia, heterozygous Decreased (>90%) Increased (3.5-8%) Normal or slightly incr. (usually <5%) Heterogeneous
β+Thalassemia, homozygous Present, decreased Variably increased Increaased (<100%) Heterogeneous
βo Thalassemia Absent Mild increase (1.5-4%) Increased (nearly 100%) Heterogeneous
δ-βThalassemia Absent Absent Increased (5-15% if heterozygous, 100% if homozygous) Heterogeneous

What Lab Results Are Absolutely Confirmatory?

Southern blot analysis with appropriate restriction digestion of genomic DNA and probes to the delta chain gene and the beta chain gene on chromosome 11 will demonstrate a deletion that encompasses the delta chain and the beta chain. These genes are contiguous on the genomic DNA. The most common mutation of this region is called the Sicilian type, which is a 13.4 kB deletion.

Gap-PCR (polymerase chain reaction) can also be used to diagnose the delta-beta-thalassemias, using primers on either side of the deletion mutation. Of course, this technique requires knowledge of the sequences on each side of the deletion. There are at least 9 characterized mutations resulting in delta-beta-thalassemias; gap-PCR using primers that would detect the mutations most likely to occur in the patient's population of origin would be a reasonable approach for definitive diagnosis.

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