Key Points
Disease summary:
Alpha-thalassemia is one of the most common hemoglobin (Hb) genetic disorder, characterized by reduced or absent production of the alpha-globin chains, especially frequent in Mediterranean, South East Asia, Africa, India, and the Middle East.
Four main conditions resulting from deletion or inactivation (nondeletion mutants) of one, two, three, or all four alpha-globin genes are recognized. Carriers of alpha0-thalassemia (two deleted alpha-globin genes, ie, alpha-thalassemia trait) show microcytosis, hypochromia, and normal percentages of HbA2 and HbF, carriers of alpha+-thalassemia (one deleted or nonfunctional alpha-globin gene, ie, alpha-thalassemia silent carrier) have either a silent hematologic phenotype or present with a moderate thalassemia-like hematologic picture. Two are the alpha-thalassemia clinically significant forms: Hb Bart hydrops fetalis syndrome and HbH disease (four and three deleted or nonfunctional alpha-globin genes, respectively). Hb Bart hydrops fetalis syndrome is the most severe form, 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. 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. Detection of red blood cell inclusion bodies (precipitated HbH) with supravital stain and HbH by hemoglobin analysis with high-performance liquid chromatography (HPLC) or electrophoresis is diagnostic for HbH disease. Genetic testing is used to confirm hematologic and clinical diagnosis and is useful in carriers for genetic counseling. If both parents carry an alpha0 mutation, they have a risk of 25% of having an offspring with Hb Bart syndrome at each conception. In patients with HbH, genetic testing has a prognostic value, as interactions between nondeletional molecular defects or between deletional and nondeletional defects result in more severe phenotypes than interactions with deletional molecular defects.
Hereditary basis:
Alpha-thalassemia follows an autosomal recessive inheritance pattern.
Differential diagnosis (see Table 38-1):
Hydrops fetalis is associated with many other conditions, including immune-related disorders, fetal cardiac anomalies, chromosomal abnormalities, fetal infections, genetic disorders, and maternal and placental disorders. However, the combination of a hydropic fetus with a very high Hb Bart, is not found in other conditions.
HbH disease may be distinguished from other hemolytic anemias by (1) microcytosis, which is uncommon in other forms of hemolytic anemia, (2) the fast-moving band (HbH) on Hb qualitative or quantitative analysis, (3) the presence of inclusion bodies (precipitated HbH) in red blood cells after vital stain, and (4) absence of morphologic or enzymatic changes characteristic of other forms of inherited hemolytic anemia (eg, hereditary spherocytosis or elliptocytosis, glucose-6-phosphate dehydrogenase deficiency [G6PD] deficiency, 5-pyridin-dinucleotidase deficiency).
Alpha+-, alpha0-thalassemia carriers and beta-thalassemia carriers both show microcytosis and hypochromia, but beta-thalassemia carriers are distinguished by increased HbA2 (>4%). Iron status determination (serum iron, transferrin, and sometimes serum ferritin) is used to identify the presence of iron deficiency anemia which is also characterized by microcytosis and hypochromia.
| Syndrome | Gene Symbol | Associated Findings |
|---|---|---|
| Beta-thalassemia carrier | HBB | Clinically asymptomatic, reduced MCV and MCH with increased HbA2 level, microcytosis, hypochromia, anisocytosis, and poikilocytosis in peripheral blood smear. |
| X-linked mental retardation syndrome associated with alpha-thalassemia | ATRX | Distinctive craniofacial features, genital anomalies, and severe developmental delays with hypotonia and intellectual disability. Hematologic picture of a mild alpha-thalassemia trait. An acquired form is associated with myelodysplasia. |
| Alpha- thalassemia or mental retardation 16 syndrome | ATR16 | Relatively mild mental retardation, variety of facial and skeletal abnormalities and developmental delay. Hematologic picture of an alpha-thalassemia trait. |
Diagnostic Criteria and Clinical Characteristics
Very severe fetal macrocytic anemia
Hb Bart (85%-90%)
Absence of HbF and HbA at Hb analysis with electrophoresis or HPLC
Molecular analysis (see Genetic Testing paragraph)
Microcytic hypochromic anemia and reduced (<2%) HbA2
Presence of variable amounts (up to 30%) of HbH
In the neonatal period, approximately 25% of Hb Bart
Molecular analysis (see Genetic Testing paragraph)
Reduced mean corpuscular volume (MCV) and mean cell volume (MCH) in –alpha/–alpha and – –/alpha alpha carriers
Normal red cell indices or only slightly reduced MCV and MCH in −alpha/alpha alpha carriers
Normal or slightly reduced HbA2, normal HbF
Inclusion bodies (precipitated beta-4 tetramers) after incubation of erythrocytes with 1% brilliant cresyl blue supravital stain
Reduced alpha- or beta-globin chain ratio in vitro
Molecular analysis (see Genetic Testing paragraph)
Marked hepatosplenomegaly, diffuse edema, heart failure, and extramedullary erythropoiesis
Hydropic fetus
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