Clinical characteristics: Beta-thalassemia (β-thalassemia) has two clinically significant forms, β-thalassemia major and β-thalassemia intermedia, caused by absent or reduced synthesis of the hemoglobin subunit beta (beta globin chain).
Individuals with β-thalassemia major present between ages six and 24 months with pallor due to severe anemia, poor weight gain, stunted growth, mild jaundice, and hepatosplenomegaly. Feeding problems, diarrhea, irritability, and recurrent bouts of fever may occur. Treatment with regular red blood cell transfusions and iron chelation therapy allows for normal growth and development and improves prognosis. Long-term complications associated with iron overload include stunted growth, dilated cardiomyopathy, liver disease, and endocrinopathies.
Individuals with β-thalassemia intermedia have a more variable age of presentation due to milder anemia that does not require regular red blood cell transfusions from early childhood. Additional clinical features may include jaundice, cholelithiasis, hepatosplenomegaly, skeletal changes (long bone deformities, characteristic craniofacial features, and osteoporosis), leg ulcers, pulmonary hypertension, extramedullary masses of hyperplastic erythroid marrow, and increased risk of thrombotic complications. Individuals with β-thalassemia intermedia are at risk for iron overload secondary to increased intestinal absorption of iron as a result of dysregulation of iron metabolism caused by ineffective erythropoiesis.
Diagnosis/testing: The diagnosis of β-thalassemia is established in a proband older than age 12 months by identification of microcytic hypochromic anemia, absence of iron deficiency, anisopoikilocytosis with nucleated red blood cells on peripheral blood smear, and decreased or complete absence of hemoglobin A (HbA) and increased hemoglobin A2 (HbA2) and often hemoglobin F (HbF) on hemoglobin analysis. Identification of biallelic pathogenic variants in HBB on molecular genetic testing can establish the diagnosis in individuals younger than age 12 months who have a positive or suggestive newborn screening result and/or unexplained microcytic hypochromic anemia with anisopoikilocytosis and nucleated red blood cells on peripheral blood smear.
Management: Targeted therapies: For β-thalassemia major, hematopoietic stem cell transplantation (HSCT), cord blood transplantation from a related donor, or autologous HSCT with gene therapy.
Supportive care: For β-thalassemia major, regular red blood cell transfusions with iron chelation therapy (e.g., deferoxamine B, deferiprone, deferasirox). Transfusion requirements may be reduced with the use of luspatercept. Anticoagulation for unprovoked venous thromboembolism; cholecystectomy for biliary colic; additional treatments for osteoporosis include hormone replacement therapy, vitamin D supplementation, regular physical activity, and bisphosphonates.
For β-thalassemia intermedia, splenectomy, folic acid supplementation, red blood cell transfusions as needed, and iron chelation. Some individuals can benefit from HbF induction with hydroxyurea. Luspatercept may also be used to ameliorate anemia with variable efficacy. Cholecystectomy for biliary colic; vitamin D supplementation, regular physical activity, and bisphosphonates for osteoporosis; referral for treatment of pulmonary hypertension; anticoagulation for unprovoked venous thromboembolism.
Surveillance: For β-thalassemia major, complete blood count every three to four weeks and with illnesses. For β-thalassemia intermedia, complete blood count every three to four months and with illnesses. Additional surveillance in individuals with β-thalassemia major and β-thalassemia intermedia: monitor efficacy and side effects of transfusion therapy and chelation therapy with monthly physical examination; evaluation of growth and development every three months during childhood; ALT and serum ferritin every three months; annual evaluation of eyes, hearing, heart, endocrine function (thyroid, endocrine pancreas, parathyroid, adrenal, pituitary), and myocardial and liver MRI. In adults: bone densitometry to assess for osteoporosis; serum alpha-fetoprotein concentration for early detection of hepatocarcinoma in those with hepatitis C and iron overload.
Agents/circumstances to avoid: Alcohol consumption if there is history of liver damage, iron-containing preparations, and exposure to infection.
Evaluation of relatives at risk: If the pathogenic variants have been identified in an affected family member, molecular genetic testing of at-risk sibs should be offered to allow for early diagnosis and treatment. Hematologic testing can be used if the pathogenic variants in the family are not known.
Pregnancy management: Individuals with β-thalassemia major often require increased red blood cell transfusions during pregnancy. Individuals with β-thalassemia intermedia often have a significant drop in hemoglobin necessitating regular red blood cell transfusions during pregnancy, and those who have never received a red blood cell transfusion or who received minimal transfusions are at risk for severe alloimmune anemia if red blood cell transfusions are required during pregnancy. Iron chelation should not be given during fetal organogenesis and may be started in the second trimester if necessary due to extent of maternal iron overload. Cardiac evaluation including pulmonary hypertension screening is recommended prior to conception.
Genetic counseling: Beta-thalassemia major and β-thalassemia intermedia are inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an HBB pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a (typically) asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. If one parent is known to be heterozygous for an HBB pathogenic variant and the other parent is affected with β-thalassemia, each sib of an affected individual has a 50% chance of inheriting biallelic HBB pathogenic variants and being affected and a 50% chance of inheriting one HBB pathogenic variant and being a (typically) asymptomatic carrier. Carrier testing for at-risk relatives can be done by hematologic and/or molecular genetic testing (if the familial pathogenic variants are known). Once both HBB pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
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