Background

Beta-thalassemia is characterized by a reduced or absent synthesis of the β-globin chain of hemoglobin. It is an autosomal recessive disorder in Southern China with an incidence rate of 2.54% in Guangdong [1] and 6.78% in Guangxi provinces [9]. However, the proband had a normal Hb A2 level (3.2%) and high Hb F level (35.1%) but no Hb H peaks on CE electrophoregram and severe microcythemia and hypochromia, which are consistent with a previous study [10]. The genotype of this patient was not consistent with phenotype, as β-thalassemia usually has a high HbA2 level [11]. The discrepancy between the genotype and phenotype made us to explore the potential reasons. A previous report about a case of the co-existence of Hb H disease (−-SEA/−α4.2) and β-thalassemia major (βCD17A > T/βIVS2-654C > T) [7], gave us a clue that our case may also have Hb H disease, which could ameliorate the phenotype of β-thalassemia via decreasing the amount of HbA2 (α2δ2). The level of HbA2 globin (3.2%) was supportive of our hypothesis. Then, Hb H disease (−α3.7/−-SEA) was verified by gap-PCR which usually screens three common α-globin deletions in south China. As a result, our patient was finally diagnosed with a compound heterozygous thalassemia [Hb H (−-SEA/−α3.7) and β0/β+ (βCD41–42/βIVS-II-654)], which is very rare in the Chinese population.

Although the patient had deletional Hb H (−-SEA/−α3.7) disease, neither Hb Bart’s nor Hb H peaks were found on the CE electropherogram. The absence of Hb H might be due to the reduction of the β-globin chain from the affected β-globin allele, leading to a less excessive β-globin chain and hence the homotetramer of the β-globin chain is minimal [9], and the absence of Hb Bart’s might be owing to increased level of Hb F. Co-inheritance of α- thalassemia could modify the phenotypes of homozygous or compound heterozygous states for β-thalassemia. The patient had low Hb levels (57 g/L), and microcythemia, hypochromia [MCV (48.8 fL) and MCH (15.7 pg)].This was consistent with a previous study, which showed that the heterozygous β- thalassemia patients who co-inherited Hb H disease, had an obvious reduction in these three hematological parameters [12]. Moreover, it had been reported that the homozygous β0-thal [13] and β0/β+-thal patients [14] who also had Hb H disease, had similar severe clinical manifestations when compared with those who did not have Hb H disease. Although, the ratio of α-globin and non-α-globin chain biosynthesis were completely balanced, a striking hypochromia (MCH15.0 pg) and a marked reduction of MCV (55.0 fL) were found in these patients [14, 15]. Hb H disease usually results in severe anemia and the formation of inclusion bodies and the malfunction of globins. In our report, the phenotype of Hb H disease was ameliorated by the decreasing of Hb H, as a consequence of the heterozygous β-thalassemia (β0/β+), which could decrease the Hb H inclusion bodies and hemolytic by balancing the ratio of α-globin and of β-globin. In other words, though the amount of the globins was reduced, its function was normal. We would like to speculate on the phenomena regarding the “teeter- totter” paradigm: the α-globin gene and of β-globin gene can be regarded as both ends of the “teeter-totter”. Malfunction of either of these genes would result in severe changes in the phenotype, while the malfunction of the rest of genes could rebalance the “teeter-totter”. However, re-balancing the “teeter-totter” may obscure the diagnosis of the underlying Hb H disease by reducing the phenotype on the anemia, which may increase the genetic load.

Co-inheritance of a β-thalassemia defect with a single functional α-globin gene is rare. There were reports that co-inheritance of β-thalassemia trait in the Hb H disease could reduce the level of excess β-globin chains, resulting in less severe imbalance of α/β-globin chain synthesis. But if patients with β-thalassemia co-inherited HbH disease had increased hemolysis secondary to infections or fever, blood transfusion therapy may be necessary [16]. Our report was just consistent with this reference. Co-inheritance of α-thalassemia can lead to a reduction in the level of Hb A2; this does not interfere with the diagnosis of β-thalassemia carriers as the Hb A2 level in these double heterozygotes was still higher than the normal level. However, concurrent heterozygous β-thalassemia and Hb H disease could show a normal level of Hb A2 [17], and our case was consistent with this report. The diagnosis of β- thalassemia cannot be totally excluded in patients who have a normal HbA2 level, as the HbA2 level can be normal in a patient with co-inheritance of both α and β thalassemia [18]. Hb analysis alone may not be a reliable diagnostic tool, especially in patients who had concurrent Hb H disease and heterozygous β-thalassemia. Genetic analysis therefore serves as an important mean to identify patients with Hb H disease, especially in those who have unexplained phenotypes [17]. A better understanding of the interactions of β and alpha globin chains and the resulting phenotypes will help the diagnosis, prevention and controlling program of β-TM. It is also essential to design an appropriate screening strategy to detect complex mutation carriers, including those who co-inherited α- and β-globin gene defects. Together with previous reports [12,13,14] and our case, a valuable strategy for the diagnosis of a compound heterozygous thalassemia (Hb H disease and β0/β+) was proposed (Fig. 4).

Fig. 4
figure 4

Framework for the diagnosis of a compound heterozygous thalassemia (Hb H disease and β0/β+)

Full size image

In conclusion, we report a case who inherited the compound heterozygosity of (β+) IVS-II-654 and (β0) codons 41-42 mutations and the Hb H (--SEA/-α3.7) disease. Our examinations showed that the co-inheritance of Hb H disease could affect not only the hematological parameters (Hb, MCV and MCH) but also the HbA2 levels.