Pseudohemophilia of Erik von Willebrand caused by homozygous one nucleotide deletion in exon 18 of the VW-factor gene

The original description of a novel severe bleeding disorder as"Hereditary Pseudohemophilia"by Erik von Willebrand can currently be labelled as von Willebrand disease(VWD)type 3.VWD type 3 is autosomal recessive caused by homozygous or double heterozygous null mutations in the von Willebrand factor(VWF)gene and typically characterized by prolonged bleeding time and APTT,FⅧ:C levels below 2%,undetectable VWF:Ag,VWF:RCo and VWF:CB and absence of ristocetin induced platelet aggregation(RIPA).Autosomal recessive von Willebrand disease type 3 VWD with virtual complete VWF deficiency are homozygous or compound heterozygous for two null alleles(gene deletions,stop codons,frame shift mutations,splice site mutations,and absence of m RNA).Reports on severerecessive VWD compound heterozygous for a null allele and a missense mutation and homozygous or double heterozygous for missense mutations are associated with very low but measurable FⅧand VWF:Ag and should be reclassified as severe recessive type 1 VWD.Homozygous missense or compound missense/null mutations related to recessive severe type 1 VWD have been indentified in the VWF prosequence D1 and D2domains,the D4,B1-3,C1-2 domains,and only a very few in the dimmerization site(D3 domain).The detection of even tiny amounts of VWF:Ag after desmopressin acetate(DDAVP)or in hidden sites like platelets allows the differentiation between patients with VWD type 3 and homozygous or double heterozygous recessive severe type 1.Carriers of a null allele related to VWD type 3 or a missense mutation related with severe recessive type 1 VWD may present with mild VWD with low penetrance of bleeding in particular when associated with blood group O.Heterozygous obligatory carriers(OC)of a null mutation or a missense mutation related to recessive VWD type 3 or severe type 1both present with asymptomatic or mild VWD type 1 in particular when associated with blood group O.The response to DDAVP of OC of either a nonsense or a missense mutation appears to be abnormal and diagnostic with a 3-times higher response of FⅧ:C as compared to VWF:Ag.In contrast,the responses to DDAVP of FⅧ:C and VWF:Ag are equally good in individuals with low VWF levels related to blood group O and a normal VWF gene and protein(pseudo-VWD).These observations are completely in line with and extend the original observations of von Willebrand in a large family with VWD type 3 and asymptomatic or mild true type1 VWD in OC.