A complex haemoglobinopathy diagnosis in a family with both beta(0)- and alpha(0/+)-thalassaemia homozygosity

The occurrence of point mutation alpha-thalassaemia and of complex combinat ions of haemoglobin defects is underestimated. Haemoglobinopathies, the mos t frequent monogenic recessive autosomal disorder in man, occur predominant ly in Mediterranean, African and Asiatic populations. However, countries of immigration with a low incidence in the indigenous population, are now con fronted,vith a highly heterogeneous array of imported defects. Furthermore, the occurrence of severe phenotypes is bound to increase in the near futur e because of the endogamous growth of the ethnical minorities and the lack of prevention. We describe an Afghan family in which both partners of a con sanguineous relationship are carriers of a beta- as well as an alpha-thalas saemia determinant. The combination of defects was revealed by the in vitro measurement of the beta/alpha biosynthetic ratio and was characterised at the DNA level. The molecular defects involved are the Cd5(-CT), a Mediterra nean beta degrees-thalassaemia mutation, and the alpha(2)(o/+)-thalassaemia AATA(-AA) polyadenylation defect. The alpha-thalassemia defect is a rare R NA-processing mutant described only twice before in heterozygous form in As ian-Indian patients. The mutation suppresses the expression of a a, gene an d reduces the expression of the less efficient, 3' located alpha(1) gene as well, inducing a near alpha(o)-thalassaemia phenotype. This defect is now described for the first time in the homozygous condition in one of the chil dren who, in addition to being homozygous for the alpha-thalassaemia point mutation, is also a carrier of the beta(o)-thalassaemia defect. A previousl y described homozygous case of the alpha(o/+)-thalassaemia condition, cause d by a similar polyadenylation defect, was characterised by a a severe HbH disease. However, the patient described here present at 7 years of age with severe caries, like his beta-thalassaemia homozygous brother but without h epatosplenomegaly, haemolysis or severe anaemia. The haematological analysi s revealed 9.5 g/dl Hb; 5.4 x 10(12)/I RBC; 0.33 I/I PCV; 61 fl MCV; 17.6 p g MCH and 6.2% of HbA(2), The biosynthetic ratio beta:alpha was 1.6 and no HbH fraction was detectable either on electrophoresis or as inclusion bodie s. The parents reported no complications during pregnancy, at birth, or in the neonatal period its rural Afghanistan, We presume therefore that the co unterbalancing effect induced by the co-existing beta-thalassaemia defect c ould have modified a potentially severe perinatal HbH disease into a strong ly hypochromic but well compensated 'alpha(o)-like heterozygous' thalassaem ia phenotype, The risk of a severe HbH disease, could have been easily miss ed in this family which was referred because of a child affected with beta- thalassaemia major.