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Beta-Thalassemia.

Authors

Origa R1.

Source

GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.
2000 Sep 28 [updated 2018 Jan 25].

Author information

1
Dipartimento di Scienze Mediche e Sanità Pubblica, Università degli Studi di Cagliari, Ospedale Pediatrico Microcitemico Antonio Cao, Cagliari, Italy

Excerpt

CLINICAL CHARACTERISTICS:

Beta-thalassemia (β-thalassemia) is characterized by reduced synthesis of the hemoglobin subunit beta (hemoglobin beta chain) that results in microcytic hypochromic anemia, an abnormal peripheral blood smear with nucleated red blood cells, and reduced amounts of hemoglobin A (HbA) on hemoglobin analysis. Individuals with thalassemia major have severe anemia and hepatosplenomegaly; they usually come to medical attention within the first two years of life. Without treatment, affected children have severe failure to thrive and shortened life expectancy. Treatment with a regular transfusion program and chelation therapy, aimed at reducing transfusion iron overload, allows for normal growth and development and may improve the overall prognosis. Individuals with thalassemia intermedia present later and have milder anemia that does not require regular treatment with blood transfusion. These individuals are at risk for iron overload secondary to increased intestinal absorption of iron as a result of ineffective erythropoiesis.

DIAGNOSIS/TESTING:

The diagnosis of β-thalassemia relies on measuring red blood cell indices that reveal microcytic hypochromic anemia, nucleated red blood cells on peripheral blood smear, hemoglobin analysis that reveals decreased amounts of HbA and increased amounts of hemoglobin F (HbF) after age 12 months, and the clinical severity of anemia. Identification of biallelic pathogenic variants in HBB (the gene encoding the hemoglobin subunit beta) on molecular genetic testing may be useful for diagnosis in at-risk individuals under 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:

Treatment of manifestations: Thalassemia major. Regular transfusions correct the anemia, suppress erythropoiesis, and inhibit increased gastrointestinal absorption of iron. Bone marrow transplantation (BMT) from an HLA-identical sib represents an alternative to traditional transfusion and chelation therapy. Cord blood transplantation from a related donor offers a good probability of a successful cure and is associated with a low risk for graft-vs-host disease. Thalassemia intermedia. Symptomatic therapy based on splenectomy in most affected individuals, sporadic red cell transfusions in some, folic acid supplementation, and iron chelation. Prevention of secondary complications: Assessment of iron overload through one or more of the following: serum ferritin concentration, liver biopsy, magnetic biosusceptometry, and MRI techniques; prevention of transfusional iron overload with adequate iron chelation therapy (i.e., desferroxamine B, deferiprone, deferasirox); assessment of myocardial siderosis by MRI and monitoring of cardiac function; treatment of osteoporosis, including consideration of bisphosphonate therapy. Surveillance: Thalassemia major: monitoring of the effectiveness/side effects of transfusion therapy and chelation therapy in affected individuals of all ages by monthly physical examination; trimonthly assessment of liver function tests, determination of serum ferritin concentration, and evaluation of growth and development (during childhood); annual evaluation of eyes, hearing, heart, endocrine function (thyroid, endocrine pancreas, parathyroid, adrenal, pituitary), liver (ultrasound examination), 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; regular gallbladder echography for early detection of cholelithiasis for those at risk. Agents/circumstances to avoid: Alcohol consumption, iron-containing preparations. 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 appropriate treatment. Hematologic testing can be used if the pathogenic variants in the family are not known. Pregnancy management: Women with thalassemia intermedia who have never received a blood transfusion or who received a minimal quantity of blood are at risk for severe alloimmune anemia if blood transfusions are required during pregnancy.

GENETIC COUNSELING:

The β-thalassemias are inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (i.e., carriers) may be slightly anemic but are clinically asymptomatic. Carriers are often referred to as having thalassemia minor (or β-thalassemia minor). Carrier testing for individuals at risk (including family members, gamete donors, and members of at-risk ethnic groups) is possible. Once both HBB pathogenic variants have been identified in a couple at risk, prenatal testing and preimplantation genetic diagnosis are possible.

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