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

摘要

The occurrence of point mutation alpha-thalassaemia and of complex combinations of haemoglobin defects is underestimated. Haemoglobinopathies, the most frequent monogenic recessive autosomal disorder in man, occur predominantly in Mediterranean, African and Asiatic populations. However, countries of immigration with a low incidence in the indigenous population, are now confronted with a highly heterogeneous array of imported defects. Furthermore, the occurrence of severe phenotypes is bound to increase in the near future 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 consanguineous relationship are carriers of a beta- as well as an alpha-thalassaemia 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 Mediterranean beta zero-thalassaemia mutation, and the alpha 2(zero/+)-thalassaemia AATA(-AA) polyadenylation defect. The alpha-thalassemia defect is a rare RNA-processing mutant described only twice before in heterozygous form in Asian-Indian patients. The mutation suppresses the expression of a alpha 2 gene and reduces the expression of the less efficient, 3' located alpha 1 gene as well, inducing a near alpha zero-thalassaemia phenotype. This defect is now described for the first time in the homozygous condition in one of the children who, in addition to being homozygous for the alpha-thalassaemia point mutation, is also a carrier of the beta zero-thalassaemia defect. A previously described homozygous case of the alpha (zero/+)-thalassaemia condition, caused by a similar polyadenylation defect, was characterised by 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 hepatosplenomegaly, haemolysis or severe anaemia. The haematological analysis revealed 9.5 g/dl Hb; 5.4 x 10(12)/I RBC; 0.33 I/I PCV; 61 fl MCV; 17.6 pg MCH and 6.2% of HbA2. The biosynthetic ratio beta:alpha was 1.6 and no HbH fraction was detectable either on electrophoresis or as inclusion bodies. The parents reported no complications during pregnancy, at birth, or in the neonatal period in rural Afghanistan. We presume therefore that the counterbalancing effect induced by the co-existing beta-thalassaemia defect could have modified a potentially severe perinatal HbH disease into a strongly hypochromic but well compensated 'alpha zero-like heterozygous' thalassaemia phenotype. The risk of a severe HbH disease, could have been easily missed in this family which was referred because of a child affected with beta-thalassaemia major.