Fetal erythropoiesis and the diagnosis and treatment of hemoglobin disorders in the fetus and child

Although synthesis of adult hemoglobin (α2β2) is reduced or absent in both α and β thalassemias, these disorders differ in their clinical significance to the fetus and neonate. α-Globin synthesis is observated in the yolk sac by 3 weeks of gestation and, by 9 weeks of gestation, α-globin represents the main α-like hemoglobin in the fetus. By contrast, the switch to β-globin chain synthesis usually remains incomplete until 1 year after birth. Therefore, the clinical manifestations of homozygous β-thalassemia may be ameliorated by sustained synthesis of fetal hemoglobin during the first 6 months of life, whereas up until 10 years ago, homozygous α-thalassemia was invariably associated with death in utero. More recently, reports of infants with homozygous α-thalassemia surviving the neonatal period have emerged, observations particularly relevant to large numbers of immigrants to Morth America from Southeast Asia, where α-thalassemia is common. Studies of patients with the β-globin disorders thalassemia and sickle cell disease showed that the severity of both disorders is ameliorated by sustained synthesis of fetal hemoglobin into adult life. Hence, treatment for both these disorders has focused on the pharmacological manipulation of fetal hemoglobin. Studies in vitro, in animal models, and in affected patients have shown that several compounds stimulate γ-globin synthesis and fetal hemoglobin production through a variety of proposed mechanisms. Some of the successes in human trials are outlined herein.