Interaction of β-thalassaemia and Hereditary Persistence of Foetal Haemoglobin

Hereditary persistence of foetal haemoglobin (HPFH) is a term used to describe an inherited high level of Hb-F which is present throughout life and is not associated with anaemia. In that respect and by showing interaction with the S and C variants of adult haemoglobin, it resembles ,3-thalassaemia, and at one time it was described as 'non-microcythaemic thalassaemia'. There are, however, 3 fundamental differences from p-thalassaemia: (i) absence of any haematological and clinical abnormality (Edington and Lehmann, I955 a, b), (2) presence of foetal haemoglobin in all red cells rather than in separate clones (Bradley, Brawner, and Conley, i96i), and (3) in contrast to ,B-thalassaemia, Hb-A2 is never raised in the heterozygote, and in the one homozygote described so far by Wheeler and Krevans (I96I) HbA2 was as completely absent as Hb-A. Whereas 13-thalassaemia may be considered as a specific defect in the gene controlling the formation of the ,B-chain, HPFH is thought to be due to a failure of switching on the ,B-chain production necessary for the transition from foetal haemoglobin (ex2y2) to adult haemoglobin (M2132). The gene for the 13-chain would be affected therefore only indirectly by a failure at the controller locus. The fact that Hb-A2 (a2 82) as well as Hb-A (O2 132) are missing in the homozygote for the HPFH has been interpreted as indicating that the genes for the 13 and the 8 chains are close neighbours on the chromosome and are 'switched on' by the same operon, which seems to be absent in HPFH (Wheeler and Krevans, I96I; Neel, I96I; Motulsky, I963; Ceppellini, I963). The simple heterozygote for HPFH has now been widely seen, and in a recent review, Conley, Weatherall, Richardson, Shepard, and Charache (I963) quote references to iio persons so affected including 64 seen by them at The Johns Hopkins Hospital in Baltimore. To these can be added 13 more reported since by Sukumaran, Randelia, Sanghvi, and Merchant (i96i), Brumpt, de Traverse, and Coquelet (i96i), Barkhan and Adinoffi (I962), and Thompson and Lehmann (I962). Unpublished observations have also been made in Nigeria by G. M. Edington and E. J. WatsonWilliams. In addition to this large number of persons with the phenotype A + F, Conley et al. (I963) refer tO 20 with the phenotype S + F and 9 with the phenotype C + F; again i each has been seen additionally by Thompson and Lehmann (I962). Though the haemoglobin composition of the blood as a whole is the same as in homozygous sickle-cell anaemia, namely some 80-90% Hb-S with the rest Hb-F and a trace of Hb-A2, those subjects with a combination of sickling and HPFH are clinically well. The presence of foetal haemoglobin in all red cells counteracts the sickling tendency (Bradley et al. I96I; Mitchener, Thompson, and Huisman, I96I). Conley et al. (I963) have pointed out that in the light of present-day knowledge some of the cases described as S + F or C + F are more likely to be instances of sicklecell thalassaemia or Hb-C thalassaemia. The Hb-F level was too low in some, and Hb-A was present in others; also some were clinically affected. Double heterozygosity for (-thalassaemia and HPFH has so far been described in 5 families. Kraus, Koch, and Burckett (I96I) and Wheeler and Krevans (I96I) saw it in American Negroes, Sukumaran et al. (I96I) saw it in an Indian Christian family; Fessas (I962) reported it from Greece, where he also observed the combination of HPFH with ex-thalassaemia, and Barkhan and Adinolfi (I962) described it in a family of mixed Indian and Portuguese origin. The affected individuals were on the whole well, but there was a mild haemolytic disorder, presumably due to thalassaemia. We have seen again a family showing interaction between (-thalassaemia and HPFH, and it is of interest in view of the previous reports from India (Sukumaran et al., I96I) and from a part-Indian family (Barkhan and Adinolfi, I962) that this family is of pure Indian stock.