Thalassemia

Thalassemia is an inherited blood disorder that causes the body to produce less hemoglobin than normal. Hemoglobin is the protein in red blood cells that helps them carry oxygen from the lungs to all parts of the body. When this protein is lacking, red blood cells cannot carry out their function properly, leading to mild or severe anemia.

The severity of thalassemia depends on the type. Children with transfusion-dependent thalassemia require blood transfusions throughout their lives. In addition, they need ongoing chelation therapy to remove the excess iron that builds up in the blood from these transfusions. Milder forms of thalassemia, including thalassemia intermedia and thalassemia minor, may require less aggressive treatment or no treatment at all.

Thalassemia is classified based on the severity of symptoms, the need for transfusions, and the type of genetic defect causing the disease. Genetic abnormalities may affect one more genes that produce hemoglobin’s components: two alpha-globin proteins and two beta-globin proteins. 

Thalassemia minor, thalassemia trait, and silent carriers

Children with thalassemia minor or “thalassemia trait” have two alpha-globin genes or one beta-globin gene missing or damaged, while those who are “silent carriers” have a single missing or damaged alpha-globin gene. These children do not experience symptoms (except mild anemia in some cases of thalassemia minor) and they do not require treatment.

Non-transfusion dependent thalassemia (NTDT; thalassemia intermedia)

In children with non-transfusion dependent thalassemia, one or both beta-globin genes are not working properly. They may have mild to severe anemia and sometimes are not diagnosed until later in life. They may need only intermittent blood transfusions during stress or illness, but some will eventually need to start a regular transfusion regimen to prevent complications.

Transfusion-dependent thalassemia (TDT; thalassemia major)

Children with transfusion-dependent thalassemia need ongoing medical care, including blood transfusions to alleviate severe anemia and chelation therapy to remove excess iron from the blood. There are two subtypes of TDT:

• Alpha-thalassemia major: Alpha-thalassemia major is the most serious and most rare form of thalassemia, in which all four alpha genes are missing. If it is discovered early enough during pregnancy, babies may be treated with blood transfusions in the womb. If untreated, alpha-thalassemia major can lead to miscarriage or death of the baby shortly after birth. Babies who survive require lifelong blood transfusions or a stem cell transplant and extensive medical care.
• Beta thalassemia major (Cooley’s anemia): In beta thalassemia major, neither beta gene is working properly. Symptoms typically begin during the first year of life and include severe anemia. Children will need regular blood transfusions, as well as chelation therapy to remove excess iron that builds up in the body due to frequent blood transfusions.

Other types of thalassemia

• Hemoglobin E beta thalassemia: This form of thalassemia is more common in children of Southeast Asian descent. It can range in severity from non-transfusion-dependent to transfusion-dependent thalassemia.
• Hemoglobin H disease alpha-thalassemia: This form of thalassemia is most common in Southern China and Southeast Asia. Many cases are not transfusion-dependent, but some cases may result in transfusion dependence.

The defective genes that cause thalassemia are relatively common, especially in people of Southeast Asian, South Asian, Middle Eastern, African, and Mediterranean descent. However, thalassemia occurs in many populations around the world.

About 300 million people around the world have the “thalassemia trait,” which puts them at risk of having children with some form of thalassemia. More than 1 million people have non-transfusion-dependent thalassemia, while more than 100,000 people have transfusion-dependent thalassemia. In the United States, there are at least 1,200 people with transfusion-dependent thalassemia.

Symptoms of thalassemia depend on the severity of the disease and how it is treated. Each child may experience symptoms differently. Patients with thalassemia trait generally do not experience any symptoms.

Transfusion-dependent thalassemia (TDT)

The main signs and symptoms of TDT in infancy, before diagnosis and treatment, are severe anemia as well as symptoms caused by overproduction of immature, defective red blood cells. This overproduction can weaken the bones, leading to fractures and facial deformity, and cause enlargement of the spleen and liver.

Patients with TDT do not typically experience severe anemia once they have started receiving regular transfusions. Without these transfusions, however, they can develop life-threatening anemia.

Later in childhood and adulthood, TDT symptoms are generally the result of iron overload, a byproduct of the frequent blood transfusions patients require. Symptoms of iron overload may include:

• Chronic fatigue
• Liver disease
• Abdominal pain
• Heart problems
• Joint pain

Non-transfusion-dependent thalassemia (NTDT)

In general, children with non-transfusion-dependent thalassemia experience less severe symptoms. They need regular medical follow-up, but may not require frequent blood transfusions until later in life. The most common symptoms of NTDT are related to anemia and overproduction of immature, defective red blood cells. To avoid these symptoms, a transfusion regimen is often recommended.

Symptoms may include:

• Pale skin, lips, hands, or paleness under the eyelids
• Increased heart rate (tachycardia)
• Breathlessness or difficulty catching a breath (dyspnea)
• Lack of energy or tiring easily (fatigue)
• Dizziness or vertigo, especially upon standing
• Headache
• Irritability
• Irregular menstrual cycles
• Absent or delayed menstruation (amenorrhea)
• Slow or delayed growth and development
• Bony overgrowth or deformities
• An increased risk of bone fractures
• Enlargement of the spleen or liver

Thalassemia is caused by an abnormality or mutation in DNA that affects the genes responsible for hemoglobin production. Hemoglobin is made up of four parts: two alpha-globin proteins and two beta-globin proteins. Thalassemia is caused by abnormalities in one or more of the genes that produce these proteins.

Children inherit thalassemia from their parents. When one parent is a carrier for thalassemia, a child may develop a mild form of the condition called thalassemia minor, also called “thalassemia trait.” When both parents are carriers of thalassemia, there is a greater chance their child or children will inherit a more serious form of the condition.

A diagnosis of thalassemia is made after tests to discover which type of thalassemia a child might have. Those tests include:

• A complete blood count (CBC) to measure the number of red blood cells and their concentration of hemoglobin, as well as many other red cell features
• Hemoglobin electrophoresis, which measures the amount and type of hemoglobin in the blood
• Genetic tests to identify specific genetic defects that cause thalassemia
• In some cases, special testing, including chorionic villus sampling and amniocentesis, can be done before birth to determine if a baby has thalassemia and how severe the condition is

Once thalassemia is diagnosed in a child, treatment may involve many specialists, including specialists in hematology and transfusion medicine as well as cardiologists, endocrinologists, gastroenterologists, nephrologists, audiologists, ophthalmologists, infectious disease specialists, geneticists, and genetic counselors as necessary.

Treatment for thalassemia depends on its severity. If your child has transfusion-dependent thalassemia (TDT), they will require life-long, ongoing medical care, which may include:

• Medications and supplements to counteract anemia, including luspatercept (Reblozyl), a novel therapy for anemia in TDT
• Medications such as hydroxyurea, which can stimulate the production of fetal hemoglobin
• Blood transfusions from healthy donors to alleviate anemia. How often a child will need transfusions will depend on the type of thalassemia.
• Monitoring for iron overload in children receiving regular transfusions to prevent complications (iron overload can cause organ damage.) We use specialized magnetic resonance imaging (MRI) technologies to measure the degree of iron overload.
• Iron chelation therapy, which reduces the amount of iron in the body and prevents or treats iron overload. Treatments we use include oral deferasirox (Jadenu or Exjade), oral deferiprone (Ferriprox), and intravenous or subcutaneous deferoxamine (Desferal).
• Stem cell transplantation to replace the defective blood-forming stem cells with healthy stem cells from a donor. This treatment can cure thalassemia, but it may not be an option for everyone. Success depends on many factors, such as the child’s age, health of their bone marrow, and how close the match is between child and donor (matched siblings are best; if your child has a sibling, there is a 1 in 4 chance they will be a match). The decision of whether to proceed with a stem cell transplant should be discussed with your child’s hematologist and a stem cell transplant team.

In the past, children with transfusion-dependent thalassemia had a significantly reduced life expectancy. Today, however, thanks to blood transfusion therapy and effective iron chelators, the life expectancy for children with severe thalassemia is constantly improving. Survival to older adulthood was once rare but should now be expected. With a gene therapy now available, fewer patients may need to have frequent transfusions.

At the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center's Thalassemia Program, our experts provide diagnostic testing and comprehensive care for children and adults with all forms of thalassemia. For many appointments and certain procedures, your child also can receive care at one of our satellite offices. Treatment for thalassemia depends on the subtype of the disorder, but may include:

• Blood transfusions for anemia, based on severity
• Regular and comprehensive monitoring for complications of thalassemia and of treatments
• Iron chelation therapy, to remove excess iron from the body
• Medications to counteract anemia
• For certain cases, stem cell transplantation to replace the blood-forming stem cells with the defective hemoglobin gene(s), or autologous genetic therapy such as gene therapy or gene editing, sometimes as a part of a clinical trial
• A gene therapy called Zynteglo®, approved by the U.S. Food and Drug Administration in August 2022 for eligible patients with transfusion-dependent beta thalassemia.