Alpha-thalassemia (alpha-thalassemia) has two clinically significant forms: hemoglobin Bart hydrops fetalis (Hb Bart) syndrome and hemoglobin H (HbH) disease. Hb Bart syndrome, the most severe form, is characterized by fetal onset of generalized edema, pleural and pericardial effusions, and severe hypochromic anemia, in the absence of ABO or Rh blood group incompatibility. Clinical features include: hepatosplenomegaly, extramedullary erythropoiesis, hydrocephaly, and cardiac and urogenital defects. Death usually occurs in the neonatal period. HbH disease is characterized by microcytic hypochromic hemolytic anemia, hepatosplenomegaly, mild jaundice, and sometimes thalassemia-like bone changes. Carriers of alpha masculine-thalassemia (alpha-thalassemia trait) show microcytosis, hypochromia, and normal percentages of HbA2 and HbF. Carriers of alpha(+)-thalassemia (alpha-thalassemia silent carrier) have either a silent hematologic phenotype or present with a moderate thalassemia-like hematologic picture. Homozygosity for alpha(+)-thalassemia results in an alpha masculine-thalassemia (alpha-thalassemia trait) hematologic phenotype.
All four alpha-globin alleles are deleted or inactivated in Hb Bart syndrome. Deletion or dysfunction of three alleles results in HbH disease. Alpha masculine-thalassemia results from deletion or dysfunction of two alleles, and alpha(+)-thalassemia results from deletion or dysfunction of one allele. Testing for alpha-thalassemia includes: hematologic testing of red blood cell indices, peripheral blood smear, supravital stain to detect RBC inclusion bodies, and qualitative and quantitative hemoglobin analysis. HBA1, the gene encoding alpha1-globin, and HBA2, the gene encoding alpha2-globin, are the two genes most commonly associated with alpha-thalassemia. Molecular genetic testing of HBA1 and HBA2 detects deletions in about 90% and point mutations in about 10% of affected individuals.
Alpha-thalassemia is usually inherited in an autosomal recessive manner. At conception, each sib of an individual with Hb Bart syndrome has a 25% chance of having Hb Bart syndrome, a 50% chance of having alpha masculine-thalassemia (alpha-thalassemia trait), and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her having alpha masculine-thalassemia (alpha-thalassemia trait) is 2/3. At conception, if one parent has alpha degrees -thalassemia and the other is an alpha(+)-thalassemia silent carrier, each sib of an individual with HbH disease has a 25% chance of having HbH disease, a 25% chance of having alpha masculine-thalassemia (alpha-thalassemia trait), a 25% chance of having alpha(+)-thalassemia (alpha-thalassemia silent carrier), and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her having either alpha masculine-thalassemia (alpha-thalassemia trait) or alpha(+)-thalassemia (alpha-thalassemia silent carrier) is 2/3. Each child of an individual with HbH disease inherits the mutation for either alpha masculine-thalassemia or alpha(+)-thalassemia and is thus an obligate heterozygote; risk to the child for disease depends on the allele inherited from the other parent. Family members, members of ethnic groups at risk, and gamete donors should be considered for carrier testing. Couples who are members of populations at risk for alpha masculine-thalassemia carrier status can be identified prior to pregnancy to identify those at risk of conceiving a fetus with Hb Bart syndrome. Prenatal testing may be carried out for couples who are at high risk of having a fetus with Hb Bart syndrome or for a pregnancy in which one parent is a known alpha masculine-thalassemia carrier and it is unknown whether the other parent has the mutation.