Beta thalassemia variants that may present as symptomatic non-transfusion-dependent thalassemia (NTDT)

General principles: The pathophysiology of beta (β) thalassemia depends on the amount of excess unpaired alpha globin chains. Therefore, any genetic variant that increases or decreases the amount of these unpaired alpha chains (eg, by altering the rate of alpha or beta chain production or by substituting for the missing beta chains) will modify the phenotype. Disorders that typically present as non-transfusion-dependent thalassemia with some degree of anemia include:

Homozygosity for mild β+ thalassemia variants

Compound heterozygosity for β⁺/βº thalassemia variants

Compound heterozygosity for β thalassemia and another beta chain variant (eg, β-thal/Hb E)

Coinheritance of homozygosity for β thalassemia with variants that increase gamma chain synthesis (ie, HPFH)

Coinheritance of homozygosity for β⁺ thalassemia with alpha thalassemia (eg, β⁺/β⁺ with –a/–a, ––/aa, –a/aa, or ––/–a)

Coinheritance of heterozygosity for β thalassemia and triplicated or quadruplicated alpha genes (eg, aa/aaa or aa/aaaa)

Dominantly acting β thalassemia variants ^[1,2]

These variants were previously called beta thalassemia intermedia.

β⁺ thalassemia: reduced production of beta chains (may be mild, moderate, or severely reduced); βº thalassemia: no production of beta chains; Hb E: hemoglobin E; HPFH: hereditary persistence of fetal hemoglobin.

References:

Thein SL. Is it dominantly inherited beta thalassemia or just a beta-chain variant that is highly unstable. Br J Haematol 1999; 107:12.
Thein SL. Structural Variants with a β thalassemia phenotype. In: Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management, Steinberg MH, Forget BG, Higgs DR, Nagel RL (Eds), Cambridge University Press, Cambridge 2001.

Courtesy of Stanley L. Schrier, MD.

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Beta thalassemia variants that may present as symptomatic non-transfusion-dependent thalassemia (NTDT)