Von Willebrand disease type 2M: Correlation between genotype and phenotype.

BACKGROUND: An appropriate clinical diagnosis of von Willebrand disease (VWD) can be challenging because of a variable bleeding pattern and laboratory phenotype. Genotyping is a powerful diagnostic tool and may have an essential role in the diagnostic field of VWD. OBJECTIVES: To unravel the clinical and laboratory heterogeneity of genetically confirmed VWD type 2M patients and to investigate their relationship. METHODS: Patients with a confirmed VWD type 2M genetic variant in the A1 or A3 domain of von Willebrand factor (VWF) and normal or only slightly aberrant VWF multimers were selected from all subjects genotyped at the Radboud university medical center because of a high suspicion of VWD. Bleeding scores and laboratory results were analyzed. RESULTS: Fifty patients had a clinically relevant genetic variant in the A1 domain. Median bleeding score was 5. Compared with the nationwide Willebrand in the Netherlands study type 2 cohort, bleeding after surgery or delivery was reported more frequently and mucocutaneous bleedings less frequently. Median VWF activity/VWF antigen (VWF:Act/VWF:Ag) ratio was 0.32, whereas VWF collagen binding activity/VWF antigen (VWF:CB/VWF:Ag) ratio was 0.80. Variants in the A3 domain were only found in two patients with low to normal VWF:Act/VWF:Ag ratios (0.45, 1.03) and low VWF:CB/VWF:Ag ratios (0.45, 0.63). CONCLUSION: Genetically confirmed VWD type 2M patients have a relatively mild clinical phenotype, except for bleeding after surgery and delivery. Laboratory phenotype is variable and depends on the underlying genetic variant. Addition of genotyping to the current phenotypic characterization may improve diagnosis and classification of VWD.

Thirteen novel mutations in the factor VIII gene in the Nijmegen haemophilia A patient population.

The development of neutralising antibodies to factor VIII (FVIII) is a major complication of haemophilia A (HA) therapy. We aimed to construct an individual risk profile for the development of inhibitors in HA and started by screening for the causative mutation in our HA patient population. A total of 109 patients and 28 carriers were screened. The analysis revealed 38 different mutations in the FVIII gene, of which 13 have not been described on the Haemophilia A Mutation, Search, Test and Resource Site (HAMSTeRS). Twenty-five mutations have been reported previously and all except two had a similar phenotype to what has been described. Three novel mutations were associated with severe HA: one non-missense mutation, a small insertion in the A2 domain, and two missense mutations, a H256R mutation in the A1 domain and a L2025P substitution in the C1 domain. One novel mutation, Y156C, was associated with moderate HA. Nine novel mutations caused mild HA. The P130R, D167E and V278M mutations are located in the A1 domain. R439C, Y511H, A544G and Q645H in the A2 domain, L1758F in the A3 domain and a S2157R mutation in the C1 domain. In conclusion, the genotypic profile of our HA population was not different from others described and is suitable to study inhibitor formation.