Hydrops Fetalis Caused by α-Thalassemia: An Emerging Health Care Problem

This paper reviews 47 series of hydrops fetalis (804 cases) and 610 individual cases published since 1980. From this large number of cases, guidelines are derived for prenatal diagnosis and management.

Hydrops revisited: literature review of 1,414 cases published in the 1980s.

A rapid and inexpensive polymerase chain reaction (PCR) based strategy is described which detects the three common, severe α thalassaemia determinants observed in southeast Asia (——SEA) and the Mediterranean (——MED and —(α)20.5). Oligonucleotide primers have been chosen which allow specific identification of both normal (αα) and abnormal (——) chromosomes using identical conditions in either the same or parallel PCR reactions. This strategy should be useful in the development of screening programmes to identify carriers of α thalassaemia (——/αα) and prenatal diagnosis of the Hb Bart's hydrops fetalis syndrome (——/——) for those populations in which this represents a major cause of perinatal death.

A PCR-based strategy to detect the common severe determinants of alpha thalassaemia.

Identification of the molecular basis of the β-thalassaemias and sickle cell disease (SCD) has made it clear that patients with the same β-globin genotypes can have very variable patterns of clinical expression. Extensive biochemical and pathophysiological studies over the last 50 years have derived two major modifiers - innate ability to produce fetal haemoglobin and co-inheritance of α-thalassaemia, subsequently validated by family and population studies. However, these two modifiers do not explain the full clinical spectrum. Genetic studies have been successful in identifying modifiers if the loci have a major clinical effect and if the genetic variants are common. It is possible that additional modifiers could be uncovered using genetic approaches but success will depend on large sample sizes of well-characterised patients with well-defined phenotypes. Since some of the complications, such as overt stroke in SCD, are relatively rare events, intermediate end-points that contribute to the phenotype, such as Transcranial Doppler velocity (a major predictor of stroke in SCD), could be integrated within the genetic analysis. Integrating multiplex genetic testing with clinical and laboratory data to generate predictive models shows potential, but such genetic approaches also require large datasets.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2141.2008.07084.x

Genetic modifiers of the beta-haemoglobinopathies.

A study of the molecular pathology of beta thalassaemia in the Asian Indian immigrant population in the U.K. included 37 patients with thalassaemia major and 14 with thalassaemia intermedia. Using a combination of oligonucleotide probe hybridization and restriction endonuclease analysis the mutations in 100/102 (98%) of the beta thalassaemia genes were characterized. Nine different types were found, of which six are associated with beta zero, one with severe beta+ and two with mild beta+ thalassaemia. Comparison of the beta-globin gene cluster haplotypes, alpha globin genotypes and beta gene mutations of the thalassaemia major group with the thalassaemia intermedia group suggests that the co-inheritance of a high Hb F determinant associated with the - + - + + 5' beta haplotype and the inheritance of a mild beta-thalassaemia mutation are the major ameliorating factors of disease severity in Asian Indians. In comparison with other population groups. beta thalassaemia in Asian Indians is not associated with one or two predominant mutations. Despite this, prenatal diagnosis by direct detection is possible in the majority of families by restriction analysis and a limited number of oligonucleotide probes since the majority of severely affected individuals are homozygous for a single mutation. The characterization of these mutations should be useful for the planning of prenatal diagnosis programmes for beta thalassaemia in other Asian Indian communities.

The molecular basis of thalassaemia major and thalassaemia intermedia in Asian Indians: application to prenatal diagnosis

The alpha globin genotypes of 55 beta thalassaemia heterozygotes have been determined by restriction endonuclease analysis to identify those with interacting alpha thalassaemia genes. A comparison of the haematological and haemoglobin synthesis findings of individuals with normal alpha genotypes (alpha alpha/alpha alpha) with those with one (-alpha/alpha alpha) or two (-alpha/-alpha) alpha genes deleted shows that the latter two groups have more balanced globin chain synthesis ratios, higher haemoglobin levels, and larger, better haemoglobinized red cells. This suggests that the degree of globin chain imbalance is a significant factor in determining the red cell characteristics in heterozygous beta thalassaemia. Screening programmes for thalassaemia, based on the detection of low MCVs, could miss cases of the interaction of alpha and beta thalassaemia.

The interaction of alpha thalassaemia with heterozygous beta thalassaemia.

The haemoglobin Bart’s hydrops fetalis syndrome is a common cause of fetal loss in South-East Asia. It results from the homozygous state for an a thalassaemia determinant in which there is a deletion of both of the a globin genes which are closely linked on chromosome 16 (reviewed by Weatherall &. Clegg, 1979). Affected fetuses produce no a globin chains and therefore make no fetal haemoglobin (a2+): the resulting excess of y chains form haemoglobin Bart’s (y4) which is ineffective as an oxygen carrier. Hence they die from severe hypoxia and anaemia either in utero or immediately after delivery. It has been known for some time that a thalassaemia occurs in the Cypriot population (reviewed by Weatherall & Clegg, 1972). Although the overall incidence of a thalassaemia in Cyprus is not known, limited surveys have shown that approximately 10% of Greek Cypriot newborns have elevated levels of Hb Bart’s, which may indicate the presence of a thalassaemia, in this population (Ashiotis et al, 1973; Hadjiminas et al, 1979). Recently Hunt et al(1980) have shown that the clinical and haematological features of Cypriots with a thalassaemia are similar to those seen in other populations. Despite this, unlike in South-East Asia, the haemoglobin Bart’s hydrops fetalis syndrome is not regarded as a common cause of fetal loss in Cyprus; indeed only a single case of the syndrome has been reported in a Greek Cypriot family in London (Diamond et al, 1965). We report here the first fully characterized case of the haemoglobin Bart’s hydrops fetalis syndrome from Cyprus. The molecular defect is identical to that recently reported in a Greek fetus with this syndrome (Pressley et a / , 1980; Kattamis et al , 1980) and involves a deletion of both a globin genes and one of the embryonic [ globin genes. Table I summarizes the haematological and biosynthetic findings in the parents which are consistent with both of them having a severe C( thalassaemia determinant. In addition the raised level of Hb Ar in the father suggests that he might also have /? thalassaemia. The present

T. Sophocleous

Papers

The interaction of alpha thalassaemia with heterozygous beta thalassaemia.

The molecular basis for the haemoglobin bart's hydrops fetalis syndrome in cyprus