Alpha Thalassemia Clinical Presentation

Clinical courses and physical findings are different for each of the 4 genotypes. Concomitant beta chain hemoglobinopathies and beta thalassemia alter the clinical course.

• Silent carrier/alpha thalassemia-2 trait: Patients are essentially asymptomatic and the CBC, hemoglobin electrophoresis, and peripheral smear are usually normal. Slight hypochromia and microcytosis may be evident by microscopic evaluation. The silent carrier state becomes apparent in families when related carriers of this allele mate and have children with HbH disease.
• Homozygous alpha (+) thalassemia: The peripheral blood smear typically shows hypochromia, microcytosis, and target cells. The MCV is frequently less than 80 fL, and the MCH is always below 27 pg. RBC counts are usually higher than normal. Hemoglobin electrophoresis is normal. Although elevation of hemoglobin A2 does not occur, elevations of hemoglobin F have been reported. Individuals of African origin usually carry a homozygous state of the alpha-2 allele, and deletion usually involves the less active of 2 normal alleles. Alpha thalassemia-2 and alpha thalassemia-1 tend to be milder in this population.

In Asia, the cis deletion is common, and subpopulations exhibit more dramatic features of thalassemia trait. If patients have the hemoglobin CS mutation, a slowly migrating abnormal hemoglobin band is present on hemoglobin electrophoresis. Clinical symptoms do not exist. The condition is diagnosed as a result of incidental laboratory abnormalities and family studies to characterize a relative.

• Hemoglobin H disease: Marked impairment of α-globin production results in accumulation of excess beta globin chains that are soluble enough to form the homotetrameric HbH. This form of hemoglobin has a dramatically left-shifted oxygen dissociation curve that renders it of no value in oxygen transportation. In addition, it is structurally unstable during the later stages of erythropoiesis and during the circulating lifespan of the red blood cell. As HbH precipitates, it forms inclusion bodies within the red blood cell, thereby causing chronic hemolytic anemia.

  • Patients are often symptomatic at birth; many others present with neonatal jaundice or anemia, and some others have hydrops fetalis. Indirect hyperbilirubinemia, elevated lactate dehydrogenase levels, and reduced haptoglobin are all consistently seen with hemolytic anemia. Exacerbations of hemolysis may occur when patients are exposed to oxidant stressors such as infections or oxidizing drugs.
  • Other complications occur in varying degrees and include the following:
    • Hepatosplenomegaly
    • Leg ulcers
    • Gallstones
    • Aplastic or hypoplastic crises
    • Skeletal, developmental, and metabolic changes due to ineffective erythropoiesis (These resemble beta thalassemia intermedia or beta thalassemia major.)
    • Prominent frontal bossing (due to bone marrow expansion)
    • Delayed pneumatization of sinuses
    • Marked overgrowth of the maxillae
    • Ribs and long bones become box-like and convex
    • Premature closure of epiphyses resulting in shortened limbs
    • Compression fracture of the spine (which may result in cord compression or other neurological deficits)
    • Osteopenia and fractures
  • Splenectomy or transfusional support is often necessary in the second or third decade of life. Iron overload may also occur due to increased iron absorption and frequent transfusions.
  • Acquired cases are observed in myeloproliferative diseases (eg, acute myelogenous leukemia, erythroleukemia, refractory sideroblastic anemia, acute lymphocytic leukemia).
• Hemoglobin Bart or hydrops fetalis (--/--): This disease affects individuals with no functional α-globin genes (--/--). Infants with hemoglobin Bart/hydrops fetalis syndrome usually die in utero.

  • They have massive total body edema due to high output heart failure, pallor, massive hepatomegaly secondary to extramedullary hematopoiesis, and edematous friable placenta.
  • There have now been several case reports of individuals with Hb Bart’s that have survived for variable amounts of time, but many have developmental abnormalities, and all have required regular blood transfusion and chelation therapy.
• Alpha thalassemia with mental retardation syndromes: There are 2 clinical entities described in which patients are noted to have both mild forms of alpha thalassemia and mental retardation. ATR-16 is characterized by large chromosomal rearrangements that cause deletions of many genes from the short arm of chromosome 16. The second form, ATR-X, results from mutations in an X-chromosome encoded gene that acts (in trans) as a regulator of expression of the α-globin genes. Thus these patients have normal α-globin genes; however, expression of α-globin proteins is down-regulated.
• Alpha thalassemia myelodysplastic syndrome: This disease is characterized by marked hypochromic microcytic anemia and presence of HbH demonstrated by hemoglobin electrophoresis and supravital staining. These patients are also found to have a very low α/β globin chain ratio (often < 0.2). This is less than expected for patients with a single functioning α-globin gene (--/-α), which suggests down-regulation of all four α-globin genes by a trans acting mutation. Analysis of archival blood and bone marrow from the ATMDS registry has revealed acquired ATR-X mutations in the majority of these patients.

See History.

See Pathophysiology.