Thalassemia

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Basics

Description

  • A group of inherited hematologic disorders that affect the synthesis of adult hemoglobin tetramer (HbA) (1,2)[C]
  • α-Thalassemia is due to a deficient synthesis of α-globin chain, whereas β-thalassemia is due to a deficient synthesis of β-globin chain:
    • The synthesis of the unaffected globin chain proceeds normally.
    • This unbalanced globin chain production causes unstable hemoglobin tetramers, which leads to hypochromic, microcytic red blood cells (RBCs), and hemolytic anemia.
  • α-Thalassemia is more common in persons of Mediterranean, African, and Southeast Asian descent, whereas β-thalassemia is more common in patients of African and Southeast Asian descent.
  • Types
    • Thalassemia (minor) trait (α or β): absent or mild anemia with microcytosis and hypochromia
    • α-Thalassemia major with hemoglobin Bart usually results in fatal hydrops fetalis (fluid in ≥2 fetal compartments secondary to anemia and fetal heart failure).
    • α-Thalassemia intermedia with hemoglobin H (hemoglobin H disease): results in moderate hemolytic anemia and splenomegaly
    • β-Thalassemia major: results in severe anemia, growth retardation, hepatosplenomegaly, bone marrow expansion, and bone deformities. Transfusion therapy is necessary to sustain life.
    • β-Thalassemia intermedia: milder disease; transfusion therapy may not be needed or may be needed later in life.
  • Other variants include hemoglobin E/β-thalassemia in Southeast Asians, which often mimics the severity of α-thalassemia major; δ-thalassemia; hemoglobin H Constant Spring
  • System(s) affected: hematologic/lymphatic/immunologic, cardiac, hepatic
  • Synonym(s): Mediterranean anemia; hereditary leptocytosis; Cooley anemia
Pediatric Considerations
  • β-Thalassemia major causes symptoms during early childhood, usually starting at 6 months of age, and requires periodic transfusions to sustain life.
  • Newborn’s cord blood or heel stick should be screened for hemoglobinopathies with hemoglobin electrophoresis or comparably accurate test, although this primarily detects sickle cell disease.
Pregnancy Considerations
  • Preconception genetic counseling is advised for couples at risk for having a child with thalassemia and for parents or other relatives of a child with thalassemia (3)[A].
  • Once pregnant, a chorionic villus sample at 10 to 11 weeks’ gestation or an amniocentesis at 15 weeks’ gestation can be done to detect point mutations or deletions with polymerase chain reaction (PCR) technology.

Epidemiology

Incidence
  • Occurs in ~4.4/10,000 live births
  • Predominant age: Symptoms start to appear 6 months after birth with β-thalassemia major.
  • Predominant sex: male = female

Prevalence
  • Worldwide, ~200,000 people are alive with β-thalassemia major and <1,000 patients are in the United States.
  • In the worldwide population, an estimated 1.5% are β-thalassemia carriers and 5% α-thalassemia carriers (4).

Etiology and Pathophysiology

Unknown; it is unclear how the imbalance of β-globulin in α-thalassemia and α-globin in β-thalassemia results in ineffective RBC genesis and hemolysis.

Genetics
  • Inherited in an autosomal recessive pattern
  • α-Thalassemia results from a deletion of ≥1 of the 4 genes, 2 on each chromosome 16, responsible for α-globin synthesis. 1-gene deletion is a silent carrier state, 2-gene deletion is the trait, 3-gene deletion results in hemoglobin H, and 4-gene deletion results in hemoglobin Bart, causing fatal hydrops fetalis.
  • Nondeletional forms do occur rarely. Hemoglobin H Constant Spring is the most common nondeletional form.
  • β-Thalassemia is caused by any of >200-point mutations and, very rarely, deletions on chromosome 11; 20 alleles account for >80% of the mutations.
  • Significantly disparate phenotype with the same genotype occurs because β-globin chain production can range from near-normal to absent.

Risk Factors

Family history of thalassemia

General Prevention

  • Prenatal information: genetic counseling regarding partner selection and information on the availability of diagnostic tests during the pregnancy
  • Complication prevention
    • For offspring of adult thalassemia patients, an evaluation for thalassemia by 1 year of age
    • Severe forms
      • Avoid exposure to sick contacts.
      • Keep immunizations up to date.
    • Promptly treat bacterial infections. (After splenectomy, patients should maintain a supply of an appropriate antibiotic to take at the onset of symptoms of a bacterial infection.)
    • Dental checkups every 6 months
    • Avoid activities that could increase the risk of bone fractures.

Commonly Associated Conditions

See “Complications.”

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