There are hundreds of mutations within the beta globin gene, but approximately 20 different alleles comprise 80% of the mutations found world wide. Within each geographic population there are unique mutations. Individuals who have beta thalassemia major are usually homozygous for one of the common mutations, or heterozygous for one of the common mutations and one of the geographically-unique mutations. Both lead to absence of beta globin chain production.
Splice site mutations also occur and are of clinical consequence, when combined with a
thalassemia mutation. Three splice site mutations occur in exon 1 of the beta globin gene.
These mutations result in three different abnormal hemoglobins: Malay, E, and Knossos.
Individuals who have
Infants born in 42 of the 50 states in the United States with newborn screening programs will be diagnosed as having a hemoglobin disorder. In states without newborn screening for hemoglobinopathies and in recent immigrants to this country, affected children are frequently identified outside the newborn period, and the evaluation of their microcytic anemia includes differentiation between iron deficiency and beta thalassemia trait. The red blood cell indices can be helpful in this differentiation, as the hemoglobin concentration and the red cell count will generally be lower in iron deficiency. The distinguishing finding in beta thalassemia is a hemoglobin electrophoresis with the finding of elevated Hgb A2 and F. Both will be increased in beta thalassemia trait without iron deficiency, and will be normal or decreased in alpha thalassemia and isolated iron deficiency anemia. There are several formulas to help in office screening, but they are also based on the assumption that the child is not iron deficient. Usually iron deficiency can be ruled out using free erythrocyte protoporphyrin (FEP), transferrin saturation or ferritin as a screening test in children who have a hypochromic microcytic anemia. The least expensive test is a trial of iron and a repeated hemogram after a month. A lead level should be obtained if there is an index of suspicion for lead toxicity.
Diagnostic challenges can still arise: if both alpha and beta thalassemia coexist, the changes in Hgb A2 and F will not be apparent, and as noted above, there are instances of normal or elevated levels of Hgb A2 and F in beta thalassemia trait. Family studies and, if warranted, DNA analysis can be used to make a definitive diagnosis.
Children who are diagnosed with
Children who can not maintain a hemoglobin between 6 and 7 gm/dl should have an alternative diagnosis considered. If thalassemia is the cause of the anemia, transfusion and/or splenectomy should be considered. Frequently, adolescents and adults are unable to tolerate the degree of anemia that is seen in thalassemia intermedia. Hypersplenism, splenic pain, congestive heart failure secondary to anemia, severe exercise intolerance, thrombocytopenia and leukopenia should be considered indications for beginning transfusion therapy or for splenectomy in the child who has severe hemolytic anemia.
Children who have untreated thalassemia generally die in the first decade of life from anemia and septicemia, and may suffer from pathologic fractures. When palliative transfusions are introduced, children live into their late teens, but eventually succumb to heart failure if iron overload is not treated. But with the introduction of frequent chronic transfusion and the use of chelation therapy, many patients who are compliant with chelation are entering their 50th decade and later. However, those not compliant will have a much shortened lifespan. Bone marrow transplantation has the potential for a permanent cure, though there are significant risks.
Listed below is common terminology that you may find in textbooks which describe beta thalassemia.
Beta thalassemia disorders result from decreased production of beta globin chains, resulting in relative excess of alpha globin chains. The degree of excess nonfunctional alpha chains is the major predictor of disease severity.
Beta-0 thalassemia refers to the absence of production of beta globin. When patients are homozygous for a beta0 thalassemia gene, they cannot make any normal beta chains (hemoglobin A).
Beta + thalassemia indicates a mutation that presents decreased but not absent production of beta globin. Thalassemia patients in which one or both of their beta thalassemia mutations are beta+ mutations make some hemoglobin A, and the disorder may be less severe.
Thalassemia trait, also called thalassemia minor, is when a person carries the trait for thalassemia major – there is no clinical significance when a person carries the trait.
Beta thalassemia major is a clinical diagnosis referring to a patient who has a severe form of the disease and requires chronic transfusions early in life.
Beta thalassemia intermedia is a clinical diagnosis of a patient characterized by a less severe chronic anemia and a more variable clinical phenotype.