Type 2B von Willebrand's disease due to Val1316Met mutation. Heterogeneityin the same sibship

An analysis was conducted in four members of the same family, two of whom h ad a history of severe bleeding associated with type 2B von Willebrand's di sease (VWD) which. although found to be due to the same mutation, neverthel ess exhibited different phenotype patterns in the two subjects involved. Vo n Willebrand's factor (VWF) multimers were assayed with high- and low-resol ution sodium dodecyl sulfate (SDS) agarose gels. The patients were studied before and after intravenous administration of desmopressin (DDAVP) at dose s of 0.4 mug/kg body weight. Automatic sequencing techniques were used to a nalyze VWF gene exon 28. The propositus presented with mild basal thrombocy topenia with ristocetin-induced platelet aggregation (RIPA) at low concentr ations of ristocetin. He had a very prolonged bleeding time (BT), and his p lasma VWF was found to be lacking in large and intermediate multimers. Thro mbocytopenia was observed to intensify transiently after the administration of DDAVP. The propositus' mother, in contrast, presented reduced RIPA whil e in a basal state, with only partial loss of the high molecular weight VWF multimers. Although she had a very prolonged BT, her platelet count was bo rderline. Transient correction of BT and a decrease in the platelet count w ere observed after administration of DDAVP and RIPA was observed at low con centrations of ristocetin. Exon 28 sequencing revealed a G4196A --> Val1316 Met mutation in both patients. No other abnormality was detected within thi s exon. Val1316Met has been reported in type 2B VWD. In conclusion, in the family presented here, the phenotype pattern in one patient was typical of type 2B VWD, whereas the pattern in his mother was closer to type 2A VWD. A fter administration of DDAVP, however, a type 2B phenotype could be clearly attributed to both, indicating that this drug can be a useful tool for elu cidating ambiguous phenotypes.