Hemoglobinopathies

Alpha Thalassemia

Alpha thalassemia results from absence or decreased of production alpha globin chains. Each erythrocyte precursor cell has two alpha globin genes on each chromosome 16 that determine alpha globin production. Thus, there are a total of four alpha globin genes. The types of alpha thalassemia result from deletion of one or more of these genes.

There have been two major variations of alpha thalassemia arise in human history. One variation, most prevalent in Southeast Asia, is known as alpha thalassemia 1. In this variant, two alpha globin genes are deleted on one chromosome 16.

The other variant, known as alpha thalassemia 2, is most common in Africa and the Mediterranean region, and differs in that a single alpha globin gene is missing from one chromosome 16.

Alpha Thalassemia Minor

Alpha thalassemia 2 can be present either as deletion of a single alpha globin gene on one chromosome 16, or as deletion of an alpha globin gene on each chromosome 16. The single gene deletion is clinically insignificant, or "silent", with no anemia or RBC abnormality detectable in adults. The only clue for its presence may be the detection of 1 to 3% hemoglobin Bart's (a tetramer of gamma chains) in an affected neonate.

The absence of two alpha globin genes leads to one form of alpha thalassemia minor ("homozygous" alpha thalassemia 2, because each chromosome is affected), which has minimal or no anemia, and microtytosis with a decreased MCV of RBC's. Though hemoglobin electrophoresis will be normal in adults, neonates will have about 4 to 10% hemoglobin Bart's. It may also be detected by staining of RBC's (in the neonate or adult) for the presence of hemoglobin H.

Alpha thalassemia 1, since it presents as deletions of both alpha globin chains on a single chromosome 16, can have more ominous implications for offspring. However, affected persons (heterozygotes) develop alpha thalassemia minor, and have minimal or no anemia with only RBC microcytosis as evidence in the adult of this condition, though neonates may have 4 to 10% hemoglobin Bart's by Hgb electrophoresis. It may also be detected by staining of RBC's (in the neonate or adult) for the presence of hemoglobin H.

Alpha Thalassemia Major

Alpha thalassemia 1, with alpha globin gene deletions on a single chromosome 16, can give rise to alpha thalassemia major in the homozygous state, when both chromosomes are affected. Affected persons become anemic in utero, because even fetal hemoglobin cannot be produced, and severe hydrops fetalis results, which leads to stillbirth, or death soon after birth from pulmonary hypoplasia or cardiac failure.

Hemoglobin electrophoresis will reveal affected fetuses or neonates to have about 80% hemoglobin Bart's (a tetramer of gamma chains) and about 20% hemoglobin Portland (or sometimes hemoglobin Gower 1) normally present only in embryonic life in the first trimester. Alpha thalassemia major is the most common cause for hydrops fetalis in persons of Southeast Asian ancestry.

The following images illustrate pathologic findings with alpha thalassemia:

1. Hemoglobin Bart's, peripheral blood smear.
2. Alpha thalassemia trait, peripheral blood smear.
3. Adrenal gland with marked extramedullary hematopoiesis in fetus with alpha thalassemia major, high power microscopic.

Hemoglobin H Disease

The presence of only a single functional alpha globin gene results in hemoglobin H disease. Affected persons can survive to adulthood, and hemoglobin electrophoresis will reveal the presence of about 10 to 25% hemoglobin H (a tetramer of beta chains) both in neonates and adults. This tetramer is somewhat unstable, and can precipitate as Heinz bodies (hemoglobin inclusions in RBC's) or lead to increased RBC poikilocytosis (abnormally shaped RBC's).

Hemoglobin H disease can arise in two ways:

In the marriage of persons, one with alpha thalassemia 1 minor and the other with alpha thalassemia 2 minor, offspring missing three alpha globin genes can be born, but this would be unusual, given the marked disparity in geographic and racial distribution of these two types of alpha thalassemia minor, except that there are a small number of persons in Southeast Asia who have alpha thalassemia 2.

More cases arise from an additional inherited variation in alpha globin called hemoglobin Constant Spring, which is present in the Southeast Asian population along with alpha thalassemia 1. Hemoglobin Constant Spring (Hgb-CS) is characterized by the presence of a non-functional alpha globin gene on one chromosome 16. Hgb-CS also produces deleterious effects upon the RBC membrane. Heterozygotes have no detectable abnormality, while homozygotes with an abnormal gene on each chromosome 16 will have a mild hemolytic anemia that is normocytic. Marriage of a heterozygote for alpha thalassemia 1 and a person homozygous or heterozygous for hemoglobin Constant Spring can result in offspring with hemoglobin H disease.