• Clinical science



Thalassemias are a heterogeneous group of hereditary blood disorders characterized by faulty globin chain synthesis resulting in defective hemoglobin, which can lead to anemia. Based on the defective globin chain, they are classified as either alpha or beta subtypes. Thalassemias are generally more frequent in areas where malaria is endemic; alpha thalassemias occur most commonly in patients of Asian or African origin, whereas beta thalassemias are predominant in patients of Mediterranean descent. Beta thalassemia can be further divided into a heterozygous minor and a homozygous major variant. The minor variant features only a low risk of hemolysis; however, the major variant presents with severe anemia as early as infancy and often causes growth retardation. The severity of alpha thalassemias varies as well, with significant anemia generally first arising with a deletion of three of the four alleles (HbH disease). Deletion of all four α-globin alleles (Hb Bart disease) is usually fatal in utero or shortly after birth. In all forms of thalassemia, insufficient erythropoiesis can lead to extramedullary hematopoiesis as well as bone marrow hyperplasia. The latter frequently results in periosteal reactions that are observed as the classic "hair-on-end" sign on skull radiographs. Diagnosis is confirmed via electrophoresis or DNA analysis. If a patient with thalassemia requires transfusion therapy, it is important to consider the possible development of secondary iron overload, which should be treated with chelating agents (e.g., deferoxamine).


  • Beta thalassemia: most commonly seen in people of Mediterranean descent
  • Alpha thalassemia: most commonly seen in people of Asian and African descent
  • Thalassemia provides partial resistance against malaria.

Alpha thalassemia is common in Asia and Africa.


Epidemiological data refers to the US, unless otherwise specified.



Beta thalassemia

In a normal cell, the β-globin chains are coded by a total of two alleles Thus, there are two forms of the disease.

Alpha thalassemia

In a normal cell, the α-globin chains are coded by a total of four alleles. Thus, there are four forms of the disease. The severity of alpha thalassemia depends on the number of defective α-globin alleles.

  • Silent carrier (minima form): one defective allele (-α/αα)
  • Alpha thalassemia trait (minor form)
    • Two defective alleles (-α/-α or --/αα)
    • Cis-deletion is common amongst Asian populations, whereas trans-deletions are more common in African populations
    • Children of parents with a two-gene deletion in cis are at higher risk of developing Hb Bart.
  • Hemoglobin H disease (intermedia form): three defective alleles (--/-α) → results in excessive production of pathologically altered HbH
  • Hemoglobin Bart disease (major form): four defective alleles (--/-‑) → results in excessive production of pathologically altered Hb Bart (consists of four γ-chains (γ-tetramers))



Anemia results from a combination of inefficient erythropoiesis and increased hemolysis. The degree to which both mechanisms contribute to the severity of the disease depends on a patient's exact genotype.


Clinical features

Beta thalassemia

Alpha thalassemia



Laboratory tests

Hemoglobin Globin chains Beta thalassemia Alpha thalassemia
Minor (trait)


(Cooley anemia)

Silent carrier




Hb H disease


Hb Bart disease


HbA ααββ Absent Normal ↓↓ Absent
HbA2 ααδδ ↑↑ Normal ↓↓ Absent
HbF ααγγ ↑↑ Normal ↓↓ Absent
HbH ββββ Absent Absent Absent ↑↑ ↑↑
Hb Bart γγγγ Absent Absent Absent Absent ↑↑
HbS ααββ Absent
HbC ααββ Absent


  • Skeletal deformities; (e.g., high forehead, prominent zygomatic bones and maxilla, referred to as “chipmunk facies”) can be seen on all imaging modalities.
  • X-ray: hair-on-end (“crew cut”) sign

Family history plays an important role in diagnosing patients with clinically silent thalassemia. The possibility of thalassemia in these patients may only be investigated once a family member is diagnosed with a more severe form!

Suspect thalassemia in a patient with microcytic anemia that is nonresponsive to iron supplementation!



Minor and minima variants

  • Usually no therapy required
  • Supplementation of iron or folic acid may be indicated in some patients.

Major variants and hemoglobin H disease