Variant Bernard-Soulier syndrome due to homozygous Asn45Ser mutation in the platelet glycoprotein (GP) IX in seven patients of five unrelated Finnishfamilies

Bernard-Soulier syndrome (BSS), a rare bleeding disorder with macrothromboc ytopenia, is caused by a defect of the platelet glycoprotein (GP) Ib/IX/V c omplex. Here we report a variant form of BSS in eleven patients of five unr elated families who originate from a particular area of Finland. The differ ential diagnosis from idiopathic thrombocytopenic purpura was difficult. Bl eeding symptoms were epistaxis and haematomas debuting in childhood, but no spontaneous, severe bleeding episodes were reported. The platelet count va ried from 43 to 81 x 10(9)/l. Screening the entire GP Ib alpha, GP Ib beta, GP IX and GP V genes revealed a recurrent homozygous Asn45Ser mutation in GP TX in all probands. Flow cytometry showed markedly reduced expression of GP Ib (<10%), and only moderately reduced expression of GP IX (24-36%) and GP V (35-49%). The expression of subunits seemed to vary independently fro m the normal polymorphisms. Heterozygotes did not differ significantly from controls by their GP Ib/IX/V expression. Since the Asn45Ser mutation has a lso been reported in three other kindreds of northern and central European origin, this study reveals that instead of being a mutation hot spot, it ma y be ancient and scattered in Europe. Moderate, chronic thrombocytopenia sh ould be carefully studied to diagnose variant BSS correctly from treatment resistant idiopathic thrombocytopenia.