NORD gratefully acknowledges Herbert L. Muncie, Jr. MD, Professor of Family Medicine, Director of Student Education, Department of Family Medicine, Louisiana State University School of Medicine, for assistance in the preparation of this report.
Beta thalassemia is an inherited blood disorder characterized by reduced levels of functional hemoglobin. Hemoglobin is found is red blood cells; it is the red, iron-rich, oxygen-carrying pigment of the blood. A main function of red blood cells is to deliver oxygen throughout the body. There are three main forms of beta thalassemia – minor, intermedia and major, which indicate the severity of the disease. Individuals with beta thalassemia minor usually do not have any symptoms (asymptomatic) and individuals often are unaware that they have the condition. Some individuals do experience a very mild anemia. Individuals with beta thalassemia major have a severe expression of the disorder; they often require regular blood transfusions and lifelong, ongoing medical care. The symptoms of beta thalassemia intermedia are widely variable and severity falls in the broad range between the two extremes of the major and minor forms. The characteristic finding of beta thalassemia is anemia, which is caused because red blood cells are abnormally small (microcytic), are not produced at the normal amounts, and do not contain enough functional hemoglobin. Consequently, affected individuals do not receive enough oxygen-rich blood (microcytic anemia) throughout the body. Affected individuals may experience classic signs of anemia including fatigue, weakness, shortness of breath, dizziness or headaches. Severe anemia can cause serious, even life-threatening complications if left untreated. Affected individuals are usually treated by regular blood transfusions. Individuals with beta thalassemia major and intermedia may develop excess levels of iron in the body (iron overload), which primarily results from repeated blood transfusions. Iron overload can potentially cause a variety of symptoms affecting multiple systems of the body, but can be treated by specific medications. Beta thalassemia is caused by mutations in the hemoglobin beta (HBB) gene. Individuals with beta thalassemia minor have a mutation in one HBB gene, while individuals with the intermediate and major forms have mutations in both HBB genes.
Thalassemia is a general term for a group of disorders in which there is reduced levels of hemoglobin, decreased red blood cell production and anemia. There are two main forms – alpha thalassemia and beta thalassemia, each with various subtypes. Beta thalassemia minor, also known as beta thalassemia trait, is a common condition. Beta thalassemia major was first described in the medical literature in 1925 by an American physician named Thomas Cooley. Beta thalassemia major is also known as Cooley’s anemia. Today, the classic clinical picture of beta thalassemia major is primarily seen in countries with insufficient resources to provide affected individuals with proper treatment (e.g. regular transfusions and iron-lowering medications).
The specific symptoms and severity of beta thalassemia varies greatly from one person to another. Individuals with beta thalassemia minor do not develop any symptoms of the disorder or only a very mild anemia. Many individuals with beta thalassemia minor go through life never knowing they carry an altered gene for the disorder.
A diagnosis of beta thalassemia major is usually made during the first two years of life and individuals often require regular blood transfusions and lifelong medical care to survive. When the disorder develops later during life, a diagnosis of beta thalassemia intermedia is given; individuals may only require blood transfusions on rare, specific instances.
BETA THALASSEMIA MAJOR
Beta thalassemia major, also known as Cooley’s anemia, is the most severe form of beta thalassemia. Affected infants exhibit symptoms within the first two years of life, often between 3 and 6 months after birth. The full or classic “description” of beta thalassemia major tends to primarily occur in developing countries. Most individuals will not develop the severe symptoms discussed below. Although beta thalassemia major is a chronic, lifelong illness, if individuals follow the current recommended treatments, most individuals can live happy, fulfilling lives.
Severe anemia develops and is associated with fatigue, weakness, shortness of breath, dizziness, headaches, and yellowing of the skin, mucous membranes and whites of the eyes (jaundice). Affected infants often fail to grow and gain weight as expected based upon age and gender (failure to thrive). Some infants become progressively pale (pallor). Feeding problems, diarrhea, irritability or fussiness, recurrent fevers, abnormal enlargement of the liver (hepatomegaly), and the abnormal enlargement of the spleen (splenomegaly) may also occur.
Splenomegaly may cause enlargement or swelling of the abdomen. Splenomegaly may be associated with an overactive spleen (hypersplenism), a condition that can develops because too many blood cells build up and are destroyed within the spleen. Hypersplenism can contribute to anemia in individuals with beta thalassemia and cause low levels of white blood cells, increasing the risk of infection, and low levels of platelets, which can lead to prolonged bleeding.
If untreated, additional complications can develop. Beta thalassemia major can cause the bone marrow, the spongy material within certain bones, to expand. Bone marrow is where most of the blood cells in the body are produced. The bone marrow expands because it is trying to compensate for chronic anemia. This abnormal expansion causes bones to become thinner, wider and brittle. Affected bones may grow abnormally (bone deformities), particularly the long bones of the arms and legs and certain bones of the face. When facial bones are affected it can result in distinctive facial features including an abnormally prominent forehead (frontal bossing), full cheek bones (prominent malar eminence), a depressed bridge of the nose, and overgrowth (hypertrophy) of the upper jaw (maxillae), exposing the upper teeth. There is an increased risk of fracture of affected bones, particularly the long bones of the arms and legs. Some individuals may develop ‘knock knees’ (genu valgum), a condition in which the legs bend inward so that when a person is standing the knees will touch even if the ankles and feet are not.
Even when treated, severe complications may develop, specifically the buildup of iron in the body (iron overload). Iron overload results from the blood transfusions required to treat individuals with beta thalassemia major. In addition, affected individuals experience greater absorption of iron in the gastrointestinal tract, which contributes to iron overload (although this primarily occurs in untreated individuals). Iron overload can cause tissue damage and impaired function of affected organs such as the heart, liver and endocrine glands. Iron overload can damage the heart causing abnormal heart rhythms, inflammation of the membrane (pericardium) that lines the heart (pericarditis), and enlargement of the heart and disease of the heart muscle (dilated cardiomyopathy). Heart involvement can eventually progress to life-threatening complications such as heart failure. Involvement of the liver can cause scarring and inflammation of the liver (cirrhosis) and high blood pressure of the main vein of the liver (portal hypertension). Involvement of the endocrine glands can cause insufficiency of certain glands such as the thyroid (hypothyroidism) and, in rare cases, diabetes mellitus. Iron overload can also be associated with growth retardation and the failure or delay of sexual maturation.
Additional symptoms that may occur include masses that form because of blood cell production outside of the bone marrow (extramedullary hematopoiesis). These masses primarily form in the spleen, liver, lymph nodes, chest, and spine. These masses can potentially cause compression of nearby structures and a variety of symptoms. Affected individuals may also exhibit leg ulcers, an increased risk of developing blood clots within a vein (venous thrombosis) and decreased mineralization of bone resulting in brittle bones that are prone to fracture (osteoporosis).
BETA THALASSEMIA INTERMEDIA
Individuals diagnosed with beta thalassemia intermedia have a widely varied expression of the disorder. Moderately severe anemia is common and affected individuals may require periodic blood transfusions. Each individual case is unique. Common symptoms include pallor, jaundice, leg ulcers, gallstones (cholelithiasis), and abnormal enlargement of the liver and spleen. Moderate to severe skeletal malformations (as described in beta thalassemia major) may also occur.
DOMINANT BETA THALASSEMIA
Dominant beta thalassemia is an extremely rare form in which individuals who have one mutated HBB gene develop certain symptoms associated with beta thalassemia. Affected individuals may develop mild to moderate anemia, jaundice, and an abnormally enlarged spleen (splenomegaly).
Most cases of beta thalassemia are caused by a mutation in the HBB gene. In extremely rare cases, a loss of genetic material (deletion) that includes the HBB gene causes the disorder. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. Individuals with beta thalassemia minor have a mutation in one HBB gene and are carriers for the disorder. Individuals with beta thalassemia intermedia or major have mutations in both HBB genes. These mutations are inherited in an autosomal recessive manner.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms (beta thalassemia minor). The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Investigators have determined that the HBB gene is located on the short arm (p) of chromosome 11 (11p15.4). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p15.4” refers to band 15.4 on the short arm of chromosome 11.
Normal hemoglobin is made up of specialized proteins called globins, specifically two alpha chains and two beta chain proteins attached to a central heme ring. The HBB gene creates (encodes) beta globin protein chains. A mutation in one HBB gene results in either reduced production of beta chains or no production of beta chains from that gene. Regardless, the second (unaffected) copy of the HBB gene functions normally and produces enough beta chain protein to avoid symptoms, although red blood cells are still abnormally small and mild anemia can still develop. A mutation in two HBB genes results in either significantly reduced levels of beta chains (beta thalassemia intermedia) or an almost complete lack of beta chains (beta thalassemia major). The reduction or lack of beta globin protein chains leads to an imbalance with the normally-produced alpha globin protein chains and, ultimately, the defective formation of red blood cells, a lack of functional hemoglobin, and the failure to deliver sufficient amounts of oxygen to the body.
In individuals with dominant beta thalassemia, the mutated HBB gene creates (synthesizes) an extremely unstable type of hemoglobin. Affected individuals also have ineffective red blood cell formation (erythropoiesis). Dominant beta thalassemia may be suspected in individuals with beta thalassemia intermedia with parents who are hematologically normal or in families who display an autosomal dominant pattern of inheritance of the disorder.
Researchers believe that additional factors influence the severity of beta thalassemia major and intermedia including modifier genes. Modifier genes, unlike the gene that causes beta thalassemia, affect the clinical severity of the disorder. More research is necessary to discover the various modifier genes associated with beta thalassemia and their exact role in the development of the disorder.
Beta thalassemia is relatively rare in the United States, but is one of the most common autosomal recessive disorders in the world. The incidence of symptomatic cases is estimated to be approximately 1 in 100,000 individuals in the general population. The disorder is particularly prevalent in the Mediterranean, Middle East, Africa, central Asia, the Indian subcontinent, and the Far East. Individuals in other parts of the world whose families are from these regions carry a greater risk of having beta thalassemia.
A diagnosis of beta thalassemia is based upon identification of characteristic symptoms, a patient history, a clinical evaluation and a variety of specialized tests. With beta thalassemia major, initial symptoms often become apparent during the first two years of life and can include failure to thrive, a swollen abdomen, and symptoms of anemia. Beta thalassemia intermedia may be suspected in individuals who present with similar (yet milder) symptoms, but at a later age.
In the United States, in many states, infants are diagnosed with a hemoglobin disorder through newborn screening. Newborn screening is a public health program that tests newborn infants for a variety of disorders that are treatable, but not readily apparent at birth. Each state’s newborn screening program (and the specific disorders tested for) is different. Most states do not routinely test for thalassemia. Further testing is required to determine the exact hemoglobin disorder present.
Clinical Testing and Workup
Physicians will take a blood sample from individuals suspected of having beta thalassemia. Several different tests can be performed on a single blood sample. Individuals suspected of having beta thalassemia will undergo blood tests such as a complete blood count (CBC). A CBC measures several components and aspects of blood including the number, concentration, size, shape, and maturity of blood cells. A specialized blood test known as hemoglobin electrophoresis measures the different types of hemoglobin found in blood.
With beta thalassemia, a CBC is given to measure the amount of hemoglobin and the number and the size and shape of red blood cells, which are fewer in number and smaller in size than in individuals with beta thalassemia. Red blood cells may also be pale in color (hypochromic) and of varying shapes. The distribution of hemoglobin in red blood cells in individuals with beta thalassemia is uneven, giving the cells a distinctive “bull’s eye” appearance when viewed under a microscope. A blood sample can also be tested to measure the amount of iron in the blood, which is often elevated in individuals with beta thalassemia.
Molecular genetic testing can confirm a diagnosis of beta thalassemia. Molecular genetic testing can detect mutations in the HBB gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories. Molecular genetic testing is not necessary to confirm a diagnosis of beta thalassemia and is generally used to identify at-risk, unsymptomatic relatives, to aid prenatal diagnosis, and to attempt to predict the progression or severity of the disease in specific cases.
Prenatal diagnosis in pregnancies with an increased risk of beta thalassemia is possible by amniocentesis or chorionic villus sampling (CVS) if the specific gene mutation has been identified in a family member. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta.
Individuals with beta thalassemia major and intermedia will benefit from referral to a thalassemia treatment center. These specialized centers can provide comprehensive care for individuals with beta thalassemia including the development of specific treatment plans, monitoring and follow up of affected individuals, and state-of-the-art medical care. Treatment at such a center ensures that individuals and their family members will be cared for by a professional healthcare team (physicians, nurses, physical therapists, social workers and genetic counselors) experienced in the treatment of individuals with beta thalassemia. Genetic counseling will be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as the specific type of beta thalassemia; the progression of the disease; the presence or absence of certain symptoms; severity of the disease upon diagnosis; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
Individuals with beta thalassemia minor usually do not develop symptoms and do not require treatment. It is important that individuals with beta thalassemia minor be correctly diagnosed, however, in order to avoid unnecessary treatments for similarly-appearing conditions such as iron deficiency anemia.
Physicians may recommend folic acid supplementation in individuals with mild cases of anemia. Supplementation with folic acid, a B vitamin, boosts the production of red blood cells in certain individuals. Along with blood transfusions, folic acid may be given and medications to lower iron levels.
Individuals with beta thalassemia major require regular blood transfusions. A blood transfusion is a common procedure in which affected individuals receive donated blood in order to restore the levels of healthy, functioning hemoglobin to their blood. During this procedure, donated blood is delivered to the body through a small, plastic tube inserted into a blood vessel (intravenously). The procedure may take anywhere from 1-4 hours. Individuals with beta thalassemia major require regular blood transfusions, as frequently as every 2-4 weeks in severe cases. Individuals with beta thalassemia intermedia occasionally require blood transfusions such as when suffering from an illness or infection or when planning to undergo surgery.
Some individuals may be treated by the surgical removal of the spleen (splenectomy). An abnormally enlarged spleen can cause severe pain and contribute to anemia. It can also cause low levels of the blood cells (platelets) that allow the blood to clot. An enlarged spleen in individuals with beta thalassemia may occur due to increased destruction of red blood cells, the formation of blood cells outside of the bone marrow (extramedullary hematopoiesis), repeated blood transfusions, and iron overload. If other forms of therapy fail, removal the spleen may be considered. Splenectomy has led to improvement in certain symptoms associated with beta thalassemia. However, this surgical procedure carries risks, which are weighed against benefits in each individual case. If a splenectomy is required, one month before the surgery pneumococcal conjugate vaccine should be given. In addition, antibiotic prophylaxis, usually penicillin 250 mg twice a day, is given the first two years after surgery and for children younger than 16 years. Because of advances in the treatment of beta thalassemia in the past several years, splenectomy is rarely necessary as a treatment for affected individuals.
Individuals with beta thalassemia major and intermedia may develop iron overload, which occurs because of two reasons. First, blood transfusions cause the accumulation or excess iron in the body. Second, beta thalassemia can cause increased absorption of dietary iron within the gastrointestinal tract. The body has no normal way to remove excess iron. In individuals who receive regular blood transfusions, iron overload primarily occurs because of treatment. Iron overload can cause a variety of symptoms affecting various organ systems of the body. Iron overload is treated by medications that remove excess iron from the body such as deferoxamine. Deferoxamine is an iron chelator, a drug that binds to iron in the body allowing it to be dissolved in water and excreted from the body through the kidneys. Other oral iron chelators, such as deferiprone and deferasirox, have also been used to lower iron levels.
Treatment of additional complications of beta thalassemia or iron overload is symptomatic and supportive. Special attention is recommended for the early diagnosis and prompt treatment of heart (cardiac) disease potentially associated with iron overload. Cardiac disease is the main cause of life-threatening complications in individuals with beta thalassemia.
Some affected individuals may be candidates for a hematopoietic stem cell transplantation, which can potentially cure the disorder. However, because of the risk of morbidity and mortality, it is reserved for individuals with serious complications who have not responded to other therapies. Hematopoietic stem cells are special cells found in bone marrow that manufacture different types of blood cells (e.g., red blood cells, platelets). Individuals with beta thalassemia are treated with allogeneic stem cell transplantation. During this type of transplant, an affected individual’s bone marrow cells are eradicated by chemotherapy or radiation and replaced with healthy marrow from a donor, usually from a closely matched family member. However, only about 20% of affected individuals will have a fully compatible family member or unrelated donor. A hematopoietic stem cell transplant has the potential to correct the underlying abnormality that causes beta thalassemia. Ideally, a hematopoietic stem cell transplant should be done before the age of 16 and before the onset of hepatomegaly, portal fibrosis, or iron overload.
Gene therapy is also being studied as another approach to therapy for individuals with beta thalassemia major. In gene therapy, the defective gene present in a patient is replaced with a normal gene to enable the production of the active enzyme and prevent the development and progression of the disease in question. Given the permanent transfer of the normal gene, which can produce active enzyme at all sites of disease, this therapy can, theoretically, lead to a “cure.” However, at this time, there remain some technical difficulties to resolve before gene therapy can be advocated as a viable alternative approach.
Certain drugs such as 5-azacytidine, decytabine and butyrate derivatives are being studied as potential treatments for individuals with beta thalassemia. These drugs induce the creation (synthesis) of fetal hemoglobin, which is produced in the developing fetus and newborn infants (before the body begins to produce adult hemoglobin). These drugs bind with the excess alpha protein chains thereby reducing the imbalance between alpha protein chains and beta protein chains. More research is necessary to determine the long-term safety and effectiveness of these medications in treating individuals with beta thalassemia.
Hydroxyurea is another drug that helps to stimulate the production of fetal hemoglobin. This drug has been studied as a treatment for individuals with beta thalassemia intermedia to increase hemoglobin levels, reduce the size of extramedullary masses, and improve leg ulcers. Further studies such as controlled, randomized clinical trials would be beneficial to determine what role, if any, hydroxyurea can play in the treatment of beta thalassemia.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
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