A Novel GeneticVariant in Siblings with von Willebrand Disease Type 2N: A Case Report
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
Abstract Introduction von Willebrand disease (vWD) type 2N is a hereditary bleeding disorder based on a structural defect in the region of the von Willebrand factor (vWF) that binds to coagulation factor VIII with high affinity. The underlying mutations cause impaired adhesion of vWF to coagulation factor VIII, which becomes prematurely degraded in the blood circulation, resulting in a coagulation factor VIII deficiency that can only be distinguished from mild hemophilia A using specialized assays. Therefore, the diagnosis of vWD type 2N can be challenging. Case Presentation We report on two sisters with reduced coagulation factor VIII activities of 20–30% and a mild bleeding tendency. While both siblings presented with normal vWF activity and antigen, they were each diagnosed with a decreased vWF:FVIIIC binding activity. Subsequent genetic testing revealed the same two heterozygous variants of thegene in each of the sisters, namely, the common vWD type 2N mutation p.R854Q and a variant of uncertain significance p.S801N, both located in exon 18–20. The mother was heterozygous for the p.R854Q variant but did not carry the p.S801N variant while none of the 2 genetic variants were detectable in a third sister. Notably, both the mother and the third sister presented with a normal coagulation factor VIII activity. Conclusion Our case report suggests a novel compound heterozygous form of vWD type 2N in two sisters based on a pathologic vWF:FVIIIC binding assay in combination with g
Abstract
Abstract Introduction von Willebrand disease (vWD) type 2N is a hereditary bleeding disorder based on a structural defect in the region of the von Willebrand factor (vWF) that binds to coagulation factor VIII with high affinity. The underlying mutations cause impaired adhesion of vWF to coagulation factor VIII, which becomes prematurely degraded in the blood circulation, resulting in a coagulation factor VIII deficiency that can only be distinguished from mild hemophilia A using specialized assays. Therefore, the diagnosis of vWD type 2N can be challenging. Case Presentation We report on two sisters with reduced coagulation factor VIII activities of 20–30% and a mild bleeding tendency. While both siblings presented with normal vWF activity and antigen, they were each diagnosed with a decreased vWF:FVIIIC binding activity. Subsequent genetic testing revealed the same two heterozygous variants of thegene in each of the sisters, namely, the common vWD type 2N mutation p.R854Q and a variant of uncertain significance p.S801N, both located in exon 18–20. The mother was heterozygous for the p.R854Q variant but did not carry the p.S801N variant while none of the 2 genetic variants were detectable in a third sister. Notably, both the mother and the third sister presented with a normal coagulation factor VIII activity. Conclusion Our case report suggests a novel compound heterozygous form of vWD type 2N in two sisters based on a pathologic vWF:FVIIIC binding assay in combination with genetic testing that yielded the common p.R854Q variant as well as a novel genetic variant p.S801N.