Clinical Syndromes.

The clinical syndromes are determined and classified by the number of -globin genes that are deleted. Each of the four -globin genes normally contributes 25% of the total -globin chains. -Thalassemia syndromes stem from combinations of deletions that remove one to four -globin genes. Not surprisingly, the severity of the clinical syndrome is proportional to the number of -globin genes that are deleted. The different types of -thalassemia and their salient clinical features are listed in Table 143. TABLE 14-3 -- Clinical and Genetic Classification of Thalassemias Clinical Syndromes

Genotype

Clinical Features

Molecular Genetics

-THALASSEMIAS -Thalassemia Homozygous Severe; requires blood Mainly point mutations that major thalassemia (0/0, transfusions lead to defects in the + + 0 + / , / ) transcription, splicing, or translation of -globin -Thalassemia Variable (0/+, Severe but does not mRNA + + 0 + intermedia / , /, /) require regular blood transfusions -Thalassemia Heterozygous Asymptomatic with minor thalassemia (0/, mild or absent anemia; +/) red cell abnormalities seen -THALASSEMIAS Silent carrier -/ / Asymptomatic; no red cell abnormality Asymptomatic, like thalassemia minor Severe; resembles thalassemia intermedia Lethal in utero without transfusions Mainly gene deletions

-Thalassemia -/- / (Asian) trait -/ -/ (black African, Asian) HbH disease Hydrops fetalis -/- -/ -/- -/-

Silent Carrier State This is associated with the deletion of a single -globin gene, which causes a barely detectable reduction in -globin chain synthesis. These individuals are completely asymptomatic, but they have slight microcytosis.

-Thalassemia Trait. This is caused by the deletion of two -globin genes from a single chromosome (/ /), or the deletion of one -globin gene from each of the two chromosomes (/ /) (see Table 14-3 ). The former genotype is more common in Asian populations, the latter in regions of Africa. Both genotypes produce similar quantitative deficiencies of -globin and are clinically identical, but have different implications for the children of affected individuals, who are at risk of clinically significant -thalassemia (HbH disease or hydrops fetalis) only when at least one parent has the / haplotype. As a result, symptomatic -thalassemia is relatively common in Asian populations and rare in black African populations. The clinical picture in -thalassemia trait is identical to that described for -thalassemia minor, that is, small red cells (microcytosis), minimal or no anemia, and no abnormal physical signs. HbA2 levels are normal or low. Hemoglobin H Disease. This is caused by deletion of three -globin genes. As already discussed, HbH disease is most common in Asian populations. With only one normal -globin gene, the synthesis of chains is markedly reduced, and tetramers of -globin, called HbH, form. HbH has an extremely high affinity for oxygen and therefore is not useful for oxygen delivery, leading to tissue hypoxia disproportionate to the level of hemoglobin. Additionally, HbH is prone to oxidation, which causes it to precipitate out and form intracellular inclusions that promote red cell sequestration and phagocytosis in the spleen. The result is a moderately severe anemia resembling -thalassemia intermedia. Hydrops Fetalis This most severe form of -thalassemia is caused by deletion of all four -globin genes. In the fetus, excess -globin chains form tetramers (hemoglobin Barts) that have such a high affinity for oxygen that they deliver little to tissues. Survival in early development is due to the expression of chains, an embryonic globin that pairs with chains to form a functional 22 Hb tetramer. Signs of fetal distress usually become evident by the third trimester of pregnancy. In the past, severe tissue anoxia led to death in utero or shortly after birth; with intrauterine transfusion many such infants are now saved. The fetus shows severe pallor, generalized edema, and massive hepatosplenomegaly similar to that seen in hemolytic disease of the newborn. There is

a lifelong dependence on blood transfusions for survival, with the associated risk of iron overload. Bone marrow transplantation can be curative