Thalassemia Syndromes

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Chapter 13 Thalassemia Syndromes

Patricia J. Giardina, Stefano Rivella

Table 13-1 Common β-Thalassemia Mutations in Different Racial Groups

Racial Group	Description
Mediterranean	IVS-1, position 110 (G → A)
	Codon 39, nonsense (CAG → TAG)
	IVS-1, position 1 (G → A)
	IVS-2, position 745 (C → G)
	IVS-1, position 6 (T → C)
	IVS-2, position 1 (G → A)
Black	-34 (A → G)
	-88, (C → T)
	Poly(A), (AATAAA → AACAAA)
Southeast Asian	Codons 41/42, frameshift (-CTTT)
	IVS-2, position 654 (C → T)
	-28 (A → T)
Asian Indian	IVS-1, position 5 (G → C)
	619-bp deletion
	Codons 8/9, frameshift (++G)
	Codons 41/42, frameshift (–CTTT)
	IVS-1, position 1 (G → T)

Data from Kazazian HH Jr, Boehm CD: Molecular basis and prenatal diagnosis of beta-thalassemia. Blood 72(4):1107, 1988; and Kazazian HH Jr, Boehm CD: personal communication, 1993.

Figure 13-1 PATHOPHYSIOLOGY OF SEVERE FORMS OF β-THALASSEMIA.

The diagram outlines the pathogenesis of clinical abnormalities resulting from the primary defect in β-globin chain synthesis. RBC, Red blood cell.

Clinical Heterogeneity of Thalassemia

The severity of β-thalassemia is remarkable for its variability in different patients. Two siblings inheriting identical thalassemia mutations sometimes exhibit markedly different degrees of anemia and erythroid hyperplasia. Many factors contribute to this clinical heterogeneity. Individual alleles vary with respect to severity of the biosynthetic lesion. Other modifying factors ameliorate the burden of unpaired α-globin. High levels of Hb F expression persist to widely various degrees in β-thalassemia. Because γ-globin can substitute for β-globin, simultaneously generating more functional hemoglobins and reducing the α-globin inclusion burden, this is a powerful modulating factor. Theoretically, patients may also vary in their ability to solubilize unpaired globin chains by proteolysis. Occasional heterozygous patients have had more severe anemia than expected, possibly because of defects in these proteolytic systems or because of the type of thalassemic mutation. Inheritance of more than the usual complement of α-globin genes may also increase with severity of β-thalassemia because of additional production of unpaired α-globin chains. All of these factors emphasize the essential role of α-globin inclusions in the pathophysiology of β-thalassemia.

Figure 13-2 MORPHOLOGIC APPEARANCE OF THE PERIPHERAL BLOOD FILM IN A CASE OF SEVERE β-THALASSEMIA.

Note the many bizarre cells, the hypochromia, nucleated red blood cells, target cells, and leptocytes.

(From Pearson HA, Benz EJ Jr: Thalassemia syndromes. In Miller DR, Baehner RL, McMillan CW, editors: Smith’s blood diseases of infancy and childhood, ed 5, St. Louis, 1984, CV Mosby, p 439.)