Introduction

The thalassemias are a group of red blood cell disorders that cause anemia. Thalassemias derives from the Greek word thalassemia, which means anemia of the sea. These disorders are prevalent among populations living along the Mediterranean Sea. However, African and Asian people can also be affected. In this article, I will discuss the causes, genetics, characteristics, and treatment of alpha and beta thalassemia.

Basic Terms: Blood is composed of three types of blood cells-red blood cells (RBCs), white blood cells, and platelets. RBCs contain a substance called hemoglobin. The genes that determine the type of hemoglobin a person's RBCs contain are called globin genes. Globin gene mutations or changes may lead to the production of abnormal hemoglobin. Anemia results when blood contains abnormally low numbers of RBCs.


Alpha Thalassemia

General: Alpha thalassemia results from the mutation of two or more alpha globin genes. Normal adult hemoglobin (hemoglobin A) is made up of two alpha chains and two beta chains. A minor type of hemoglobin (hemoglobin A2) is composed of two alpha chains and two delta chains. Overall, there are four alpha globin genes-two on each allele. Children inherit one allele from each of their parents. Therefore, a child normally receives two alpha genes (one allele) from his mother and two alpha genes (one allele) from his father. Any mutations resulting in a deletion of alpha globin genes can result in alpha thalassemia. It is easier to understand alpha thalassemia in terms of how many of the four alpha globin genes are deleted. I will now discuss the genetics, characteristics, and treatment of the four different clinical situations resulting from the deletion of one or more alpha globin genes.

Silent carrier: Children lacking one alpha globin gene are silent carriers. These children do not have anemia and carry on normally. However, they can pass on the mutated allele (missing one of the two genes present on each allele) to their children. Moreover, if a silent carrier's spouse is also a silent carrier, their children can have alpha thalassemia trait (i.e., 25 percent of each pregnancy being normal, 25 percent of each pregnancy affected with alpha thalassemia trait, and 50 percent of each pregnancy being a silent carrier).

Alpha thalassemia trait: Children lacking two alpha globin genes have alpha thalassemia trait. This condition arises from two different clinical scenarios. The first is that each parent is a silent carrier (missing one gene on each allele) and the child inherits only two alpha globin genes. In the second scenario, the child inherits an allele from one parent that has both alpha globin genes deleted. In this case, the parent also has alpha thalassemia trait. These children present to their pediatricians with anemia. Characteristically, their red blood cells are small and have the appearance of a bull's eye (target cell). These children have a normal life span and can enjoy all of life's pleasures. There are two important clinical points that I discuss with the parents of a child with alpha thalassemia trait. First is the need for genetic counseling, which I provide. I explain the genetics of the condition and I stress that their child's future spouse must be tested for thalassemia. Second, I inform the parents that their child's red blood cells are exquisitely sensitive to a Parvovirus infection (Fifth disease). The Parvovirus can infect the developing red blood cells and stop them from maturing. This can cause a profound anemia and may require a red blood cell transfusion. There is no treatment available or necessary for alpha thalassemia trait.


Hemoglobin H Disease and Hemoglobin Barts

Hemoglobin H disease results when three alpha genes are deleted. Hemoglobin H is made up of four beta chains. Remember that Hemoglobin A (the major adult hemoglobin) is composed of two alpha and two beta chains. Children with Hemoglobin H disease will also have an abnormal type of fetal hemoglobin known as Hemoglobin Barts. The normal fetal hemoglobin (Hemoglobin F) is made up of two alpha and two gamma chains, whereas Hemoglobin Barts is made up of four gamma chains. Children with Hemoglobin H disease have a more severe anemia than those with alpha thalassemia trait. Most do not require blood transfusions and can live normal lives. Again, genetic counseling is paramount, and the risks of receiving blood products must be explained to the parents of those few children who require transfusions.


Hydrops Fetalis

This devastating disorder occurs when the fetus does not inherit any alpha globin genes. Alpha thalassemia trait can occur when a child inherits an abnormal allele from each parent (each allele missing one alpha globin gene) or when a child inherits one abnormal allele from one parent (the allele is missing both alpha globin genes). If both parents have alpha thalassemia trait in which one allele is missing both alpha globin genes each fetus has a 25 percent chance of having hydrops fetalis. The fetus develops a severe form of congestive heart failure with resultant liver damage and swelling of the body. Most fetuses die in utero or shortly after birth. However, if the fetus survives intra-uterine life and can be successfully resuscitated, blood transfusions can be life-saving. Moreover, with the clinical and scientific advancements in bone marrow transplantation, this treatment modality can be curative. The infant's siblings should be tested to determine their status as potential donors. If no sibling donors exist, a search for an unrelated donor is commenced. The child can receive blood transfusions until a donor is identified (either related or unrelated). Let me repeat that almost all fetuses with hydrops fetalis die, and it is the uncommon baby that can survive such an insult to the red blood cell forming system.


Beta Thalassemia

General: Beta thalassemia results from a deletion of one or both beta globin genes. Beta thalassemia is mostly seen in people from Spain, Italy, Greece, and Northern Africa; however, anyone can be affected. Community education and screening programs for beta thalassemia trait (lacking one beta globin gene) have reduced the incidence of beta thalassemia disease (lacking both beta globin genes). I will now discuss the genetics, characteristics, and treatment of beta thalassemia.

Beta thalassemia trait: Children lacking one beta globin gene have beta thalassemia trait. These children present with pallor and have anemia. Their red blood cells are small and have the appearance of a bull's eye (target cells). Children with beta thalassemia trait are clinically indistinguishable from children with alpha thalassemia trait. The only distinguishing feature is the presence of an elevated Hemoglobin A2 (two alpha chains and two delta chains) in children with beta thalassemia trait. There is no treatment for the anemia and these children should not take iron because iron overload may occur. I always tell the parents of children with beta thalassemia trait that their children can live normal lives. As with children with alpha thalassemia trait, children with beta thalassemia trait are susceptible to Parvovirus infection. Moreover, their future spouses must be tested for thalassemia and genetic counseling must be provided.


Beta Thalassemia Intermedia and Disease

Children lacking two beta globin genes can either have beta thalassemia intermedia or beta thalassemia disease. The clinical difference is that children with intermedia do not require red blood cell transfusions to maintain their hemoglobin at a safe level. Children with intermedia are clinically similar to children with Hemoglobin H disease (three alpha globin genes deleted). By contrast, children with beta thalassemia disease require monthly transfusions to maintain an adequate hemoglobin. An adequate hemoglobin is required for proper growth and development. Not only do the red blood cells of these children undergo hemolysis (destruction) outside the bone marrow, the red blood cells also undergo ineffective erythropoiesis (defective maturation due to abnormal alpha chain hemoglobins). The bone marrow of children with beta thalassemia disease is highly active, and the liver and spleen of these children also participate in producing red blood cells. This increased bone marrow and extramedullary (outside the bone marrow) activity give children with beta thalassemia disease their characteristic facial appearance and enlarged organs. Moreover, these children can have "islands" or centers of blood formation along their spine (paraspinal masses).

Monthly transfusions can result in transfusion reactions, alloantibody formation (a result of exposure to different donors), viral infections (hepatitis B, hepatitis C, cytomegalovirus, and human immunodeficiency virus), and iron overload. Directed or specifically-assigned donors can decrease the incidence of these adverse side effects except iron overload. Each milliliter of blood contains about one milligram of iron. Since the body has very poor mechanisms to dispose of iron, the iron starts to deposit in the kidneys, gonads, pancreas, liver, spleen, and ultimately, the heart. Iron deposition in the heart can cause abnormal rhythms and death. Therefore, it is imperative that iron status is determined during transfusions. All children ultimately require chelation therapy, a specific treatment that helps the body to excrete the iron. Unfortunately, chelation therapy is cumbersome (either intravenous or subcutaneous), and children, especially teenagers, find it difficult to adhere to this form of intense therapy. It is my philosophy that children with beta thalassemia disease should be referred to a transplant center as soon as possible. Bone marrow transplantation is curative, and should be performed before the toxicities of red blood cell transfusions occur. This statement is buttressed by the clinical studies performed in Italy where younger children treated with bone marrow transplants do better than do older children and adults. The reason for this is that older children have a higher incidence of viral infections and organ damage, which make them poorer candidates for transplantation.


Conclusion

The thalassemias are relatively common diseases. Genetic counseling is paramount, and may even decrease the incidence of the more serious conditions (hydrops fetalis and beta thalassemia disease). Most children tolerate the anemia quite well and do not require any interventions. Oral drugs may improve the compliance with chelation therapy. To date bone marrow transplantation remains the only cure for children with beta thalassemia disease.