CASE REPORT Haemoglobin Lepore in a Malay family: a ... - MJPath

Malaysian J Pathol June 2005A diagnosis of heterozygous haemoglobinLepore was made for both parents. The parentsare first degree relatives. The patient’s andparents’ samples were sent for DNA sequencingwhich confirmed this unknown haemoglobin tobe Hb Lepore Washington Boston. The patientis on regular follow-up and has received 3 bloodtransfusions at 4 -5 monthly intervals since thetime of diagnosis.DISCUSSIONHb Lepore is a common abnormal haemoglobinseen in the Mediterranean region. It is the mostcommon abnormal haemoglobin in Caucasiansin Central Portugal and in the Spanish AltaExtremadura. 1 It is a variant form of humanhaemoglobin that contains delta beta hybridchains or a fused globin chain, from the productof a hybrid gene: the unequal crossing overbetween the delta and beta globin genes resultingin a deletion of 7.4kb in the beta globin genecluster. 1,2Three different types of Hb Lepore have beendescribed so far, each with a different crossoverbreakpoint: Hb Lepore Washington Boston, HbLepore Baltimore and Hb Hollandia. 1,2,4 Thebasic defect in all the Hb Lepore disorders is theinefficient synthesis of the delta beta fusionchains of Hb Lepore, which leads to a variabledegree of globin imbalance, excess alpha chainproduction and the clinical phenotype of betathalassaemia. The ineffective erythropoiesis andthe shortened red cell survival results from thedeleterious effects of excess alpha chains. Theselection of cells which are synthesizingrelatively more gamma chains follow the samemechanism as occurs in beta thalassemia. 5 It hasbeen postulated that the deletion which resultedin the delta beta fusion is somehow responsiblefor increasing the absolute output of gammachains. 6 This is compatible with the observationthat Hb Lepore heterozygotes producesignificantly more Hb F than beta thalassaemiaheterozygotes.The Hb Lepore heterozygotes are usuallyasymptomatic. In a large Italian series noabnormal physical signs were reported, but afew of the Greek and Yugoslavian heterozygoteshad mild splenomegaly. 7,8 Heterozyogotes aretherefore healthy individuals with only a slightdecrease in haemoglobin levels, but with adistinct microcytosis and hypochromia of theirred blood cells. The mean cell haemoglobin(MCH) is thought to be the most reliableparameter that is altered in the Hb Leporeheterozygotes (range 20-25 pg). 9 In this series,the red cell indicies and morphologicalappearances of the blood film of betathalassaemic carriers were compared with thatof heterozygous Hb Lepore. It was found to besimilar in both conditions. Studies suggest thatthere are no major differences in thehaematological findings between carriers of thedifferent molecular varieties of Hb Lepore. 1 Redcell survival and ferrokinetic data available revealred cell survival is slightly shortened and Fe 59utilization is increased. 10The Hb Lepore homozygotes vary in theseverity of their clinical manifestations. 6,7,8 Atone end of the spectrum are patients who presentwithin the first 5 years of life with severe anaemiawith haemoglobin values ranging from 4 to 7 g/dl. Significant splenomegaly, hepatomegaly, andskeletal abnormalities indistinguishable fromthose of homozygous beta thalassaemia are seen.These patients require regular blood transfusionand exhibit shortened life span. At the other endof the spectrum are patients who have a milderdisorder indistinguishable from beta thalassemiaintermedia, who are anaemic throughoutchildhood and require only occasional bloodtransfusions. The homozygous state for HbLepore therefore varies from a transfusiondependent disease like beta thalassaemia majorthrough the milder spectrum of thalasaemiaintermedia that appears to be compatible withlongevity of life. 5 The haematological findingsin these patients are peripheral blood film featuresindistinguishable from the severe forms of betathalassaemia. Bone marrow smears show markederythroid hyperplasia due to high level oferythropoietin production in response to theanaemia. 6The multifaceted approach for thepresumptive identification of haemoglobinvariants includes a scrutiny of blood counts/redcell indices and haemoglobin analysis. Thisapproach easily identifies Hb Lepore. Oncellulose acetate electrophoresis at alkaline pH,Hb Lepore shows electrophoretic mobilitysimilar to Hb S. 5 The other haemoglobins thatrun in this position are Hb D and Hb G, whichare differentiated from Hb S by sickle solubilitytest and electrophoresis at acid pH. Hb Leporehas a similar retention time (RT) value as Hb A2on high performance liquid chromatography(HPLC) analysis with the Bio-Rad VariantHaemoglobin testing system. 2 Values greaterthan 10% suggest the presence of variant36