A common mutation 4247T ® A (I1416N) causing type 2M von Willebrand disease in patients from three unrelated families previously diagnosed as severe type 1 VWD

Abstract number: P0098

Lester W. A., Jones N. L., Guilliatt A. M., Surdhar G. K., Enayat M. S., Hill F. G. H.

Birmingham Childrens Hospital, UK

Many patients previously diagnosed with type 1 VWD have underlying mutations which have both a dominant negative quantitative effect on total VWF plasma levels in addition to causing a qualitative defect in the secreted VWF and should be classified as type 2M VWD. Such accurate subclassification can be difficult in patients with low plasma VWF:Ag and VWF:RiCof due to current diagnostic limitations. We describe three unrelated families with 16 affected members previously classified as having moderately severe autosomal dominant type 1 VWD. Clinically, affected members from all three families have had either moderate to severe mucocutaneous bleeding, occasional suspected hemarthrosis or post surgical and dental bleeding requiring plasma product support. All the affected members show a similar laboratory phenotype with low VWF:Ag (0.09–0.30 U mL^-1) VWF:RiCof (<0.02–0.13) VIIIc (0.12–0.48) and virtually absent RIPA at 1.25 and 1.5 mg mL^-1 final ristocetin concentration. Multimeric distribution of VWF:Ag is normal in all cases. Clinical response to desmopressin infusion has been suboptimal in patients from two of the families even requiring salvage treatment with intermediate purity factor VIII concentrate for post surgical bleeding. A missense mutation 4247T ® A (I1416N) was found in all affected members of each of the three unrelated families but not in 50 controls thereby authenticating it as the causative mutation. This mutation is located in a highly conserved area of the A1 domain in proximity to the GP1b and ristocetin binding sites. In addition, this mutation has also been found in a patient with type 3 VWD. This patient is being further investigated as we suspect a compound heterozygote state. Although the four families are unrelated, the same VWF haplotype has been identified in all affected individuals suggesting a common genetic origin. In summary, I1416N is a previously unreported mutation producing a marked quantitative and qualitative defect in VWF. Molecular studies and careful review of phenotypic data has helped reclassification of individuals from type 1 to type 2M VWD, aiding effective counseling and appropriate treatment.