Pediatric Thalassemia Differential Diagnoses

Updated: Aug 23, 2017
  • Author: Hassan M Yaish, MD; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
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Diagnostic Considerations

The differential diagnoses of thalassemic states in general depend on the age of the child at the time of presentation, the type of thalassemia and its severity, and, in severe cases, whether it is treated and well controlled. Furthermore, the form of thalassemia then has to be identified once the thalassemic condition is suspected because of the numerous thalassemic conditions.

Congenital dyserythropoietic anemia is a condition that may mimic severe forms of thalassemia in children. A bone marrow examination, hemoglobin (Hb) electrophoresis, and other tests reveal the diagnosis. Diamond-Blackfan anemia may also resemble severe forms of thalassemia in young infants.

The α thalassemia trait is similar to the β thalassemia trait. Both traits should be differentiated from iron deficiency anemia, which is the most common cause of hypochromasia and microcytosis in children and should be excluded before considering thalassemia. A child with presumed iron deficiency anemia that has not responded to adequate iron treatment is a good candidate for thalassemia workup.

In β thalassemia, elevated levels of Hb A2, F, or both are usually helpful in confirming the diagnosis. However, in α thalassemia, the Hb electrophoresis results are usually normal; in this case, and in cases in which iron study results are also nondiagnostic, nonspecific tests may help to differentiate iron deficiency anemia or anemia of chronic inflammation from thalassemia. Free erythrocyte protoporphyrin (FEP) levels are usually elevated in patients with iron deficiency or anemia of chronic inflammation but not with thalassemia. The soluble transferrin receptors (sTfR) levels are high in patients with iron deficiency but not in those with anemia of chronic infection or thalassemia.

The process of differentiating thalassemia trait from iron deficiency anemia must include the patient's medical, developmental, nutritional, and family history and a review of the child's CBC count, with emphasis on the RBC indices. Proper interpretation of the CBC count may save the physician time and may save the patient from unnecessary further testing (see Laboratory Studies). The anemia in patients with thalassemia trait is usually mild; the Hb level is rarely, if ever, less than 9 g/dL, unless the cause of the anemia is multifactorial. The RBC count is almost always higher in patients with thalassemia than in those with iron deficiency anemia; in fact, it is frequently higher than the reported reference range for the age.

In thalassemia, the RBC indices, including the mean corpuscular volume (MCV) and mean corpuscular Hb (MCH), are both significantly low for an Hb level that is either normal or only slightly low. In addition, the RBC distribution width (RDW) is usually normal, reflecting the homogenous population of the RBCs in thalassemia, whereas iron deficiency anemia is known to be associated with anisocytosis. Compare the images below. A faint basophilic stippling may be seen in the RBCs of patients with thalassemia but not typically in those of patients with iron deficiency.

Peripheral blood film in thalassemia minor. Peripheral blood film in thalassemia minor.
Peripheral blood in iron deficiency anemia. Peripheral blood in iron deficiency anemia.

Many formulae have been introduced to help in differentiating thalassemia trait from iron deficiency. The most practical and easiest to remember is the Mentzer index, which divides the patient's MCV by the RBC count (MCV/RBC). A result of less than 13 usually suggests thalassemia trait, while a result greater than 13 is indicative of iron deficiency.

Confirmation by Hb electrophoresis in β thalassemia is essential before the patient and the family are counseled. The Mentzer index loses its value if the patient has a combination of thalassemia and iron deficiency. In such patients, Hb electrophoresis results may also be inaccurate and misleading, since iron deficiency suppresses production of all Hbs, including Hb A2. For this reason, the Hb A2 level does not rise and is typically normal in these patients, masking the diagnosis of β thalassemia. In such cases, Hb electrophoresis should be repeated after the iron deficiency has been treated to obtain an accurate Hb A2 fraction.

When β and α thalassemia coexist, the elevated levels of Hb A2 and Hb F usually present in β thalassemia may also be lost. Furthermore, α thalassemia ameliorates the severity of β thalassemia since the decrease in α chains results in less inclusions and, hence, less hemolysis.

However, the confirmation of β thalassemia is easier than that of the α trait. The Hb electrophoresis result is usually normal, and DNA testing or globin chain synthesis enumeration are the only studies that confirm the diagnosis. A moderately severe form of α thalassemia, which some consider equivalent to β thalassemia intermedia, is termed Hb H disease. The disease is characterized by moderately severe anemia, splenomegaly, some jaundice, and, possibly, some bone changes due to marrow expansion. In this form, Hb electrophoresis is diagnostic in revealing the abnormal Hb, which is unstable and may be detected on the supra vital stain as inclusions in the RBCs (Heinz bodies).

The severity of Hb H disease depends on the inherited mutation. Seventy-five percent of Hb H mutations are caused by deletions on chromosome 16, which are usually associated with the milder forms of Hb H. Nondeletional forms are usually associated with severe Hb H and require transfusion. The diagnosis of Hb H may be difficult to establish, since it is unstable and may go undetected. The β tetramers of Hb H are replaced by γ tetramers in the form of Hb Bart. Patients with Hb H disease usually have more than 20% Hb Bart at birth, a finding that has helped to identify 90% of the neonates with Hb H disease in the newborns screening program in California.

Hb Constant Spring (CS) is the most common nondeletional α thalassemia mutation associated with Hb H disease. The cells that contain Hb CS are usually overhydrated, which causes the loss of the traditional microcytosis seen in patients with thalassemia. Hb H/CS disease is more severe than Hb H disease, sometimes requiring splenectomy to improve the anemia, a procedure associated with a high rate of portal vein thrombosis.

Many clinical entities associated with splenomegaly and anemia, such as storage diseases, and other forms of chronic hemolytic anemias are to be considered in the differential diagnosis. The homozygous α thalassemia is not compatible with life (unless intrauterine blood transfusion is administered), and a baby with hydrops fetalis is usually delivered.

Other causes of immune and nonimmune hydrops fetalis are also to be differentiated from the hydrops fetalis of α thalassemia major, a condition that was rarely seen in the past since the mutation that predisposes to this condition is limited to the Southeast Asian population, not the African population.

Rare forms of α thalassemia are also described. Hb CS results from a specific mutation in the α thalassemia gene, leading to the production of elongated α chains. The clinical manifestations in the homozygous state are similar to those encountered in patients with Hb H disease; however, they differ in the electrophoretic pattern. γ tetramers that consist of Hb Bart replace the β tetramers of Hb H.

Thalassemia may also interact with other globin structural variants, whether they involve β, α, or other chains. In the β variants, Bs, Bc, and Be are some of the globin chain's most common mutations. For instance, the interaction of Bs with β thalassemia produces a condition associated with sickle cell disease. Conversely, when Bs (sickle trait gene) interacts with an α thalassemia gene, less Hb S is present in the RBCs than when only Bs is present. Such interactions modify the severity of each separate condition.

The incidence of Hb E/β thalassemia has increased considerably in the United States due to the immigration of individuals from Southeast Asia, where the incidence of both Hg E and β thalassemia is high (see Frequency). Clinically, the severe forms of Hb E/β thalassemia are similar to the transfusion-dependent β thalassemia major. For this reason, the diagnosis Hb E/β thalassemia should be considered in patients of Southeast Asian descent.

Other rare thalassemia variants include Hb Lepore and hereditary persistence of fetal Hb (HPFH).

Differential Diagnoses