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

Abstract

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 mRNA). Reports on severe recessive 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 FVIII and 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 D2 domains, 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 1 both 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 type 1 VWD in OC.

Keywords: Autosomal recessive von Willebrand disease type 3 and 1; Molecular etiology; Carrier of von Willebrand disease null or missense allele; Desmopressin acetate responses

Core tip: The novel lethal bleeding disorder described as “Hereditary Pseudohemophilia by von Willebrand (VW) in 1926 is caused by a homozygous nonsense mutation (one nucleotide deletion in exon 18) of the VW-factor gene consistent with autosomal recessive VW disease (VWD) type 3. Heterozygous carriers presented with VWD type 1 with variable penetrance of mild mucocutaneous bleeding manifestations. The present editorial reviews the clinical, laboratory and molecular features of severe recessive type 1 and 3 VWD and obligate heterozygous carriers of VWF nonsense and missense mutations.