Expanded phenotype-genotype correlations in a pediatric population with type 1 von Willebrand disease.

BACKGROUND: Recent phenotype-genotype studies have provided valuable insights into the pathophysiology of type 1 von Willebrand disease (VWD); however, no study has examined an exclusively pediatric cohort.
OBJECTIVES: To describe phenotype-genotype correlations in a selected pediatric cohort with a historical diagnosis of type 1 VWD, using first-degree family members as controls.
METHODS: Comprehensive phenotypic assessment included standard assays of von Willebrand factor (VWF) level and function, bleeding score, desmopressin response, VWF propeptide (VWFpp) level, and platelet-derived VWF mRNA level.
RESULTS: Fourteen VWF mutations were identified in 17 of 23 index cases (ICs) (aged 5-17 years), including four that were previously unreported (L60P, nt1658 insT, Q1388X, and C2237F). VWFpp levels were lower in ICs than in unaffected controls (median 49 vs. 86 U dL(-1) , P < 0.0001). A VWFpp/VWF antigen ratio of > 1.6 was observed in eight of nine ICs with a suboptimal response to desmopressin, including four of four with the R1205H (Vicenza) mutation (median 7.9), and three of four IC with the R1315C mutation (median 1.9). The R1315C mutation was also associated with a reduced absolute VWFpp level (median 32 U dL(-1) ), a previously unreported finding. The amount of platelet-derived VWF mRNA was significantly reduced in individuals with nonsense mutations.
CONCLUSIONS: Increased VWF clearance and intracellular retention are important mechanisms underlying type 1 VWD in pediatric patients, concordant with the observations of larger, predominantly adult, cohort studies. Additionally, in some patients, nonsense-mediated decay of mutant mRNA transcripts may be contributory. Several mechanisms underlie the variable phenotype associated with the R1315C mutation. The potential utility of VWFpp as an independent marker of VWF biosynthesis and release warrants further research.