Pediatric Clinics of North America - CIPERJ

384 ROBERTSON et al
of considering a diagnosis carefully. Assigning an incorrect diagnostic label of
VWD to patients can be difficult to revise subsequently and may lead to confusion
and inappropriate management. In addition, the wider implications of
this diagnosis, including the potential social stigma and health insurance implications,
should be considered carefully before making a diagnosis. In contrast,
underdiagnosis of type 1 VWD can be a concern in young children who
may not have been subjected to a sufficient hemostatic challenge to manifest
a bleeding tendency that would lead to consideration of a diagnosis of VWD.
Taking all of these factors into consideration, a suggested definition of type 1
VWD in children could include both definite (for children with excessive mucocutaneous
bleeding and low VWF levels) and possible (for children with
low VWF levels but no history of excessive mucocutaneous bleeding potentially
because of the lack of opportunity).
The genetic basis of type 1 VWD has been the focus of much recent investigation,
and two large multicenter trials have reported consistent results
[37,38]. Mutations throughout the VWF gene were identified in approximately
65% of index cases and the majority of these were missense mutations.
Mutations were identified more frequently in cases of lower VWF
levels and more highly penetrant in those cases. The genetic variation
reported most frequently identified in both studies was a missense mutation
resulting in an AA substitution of tyrosine to cysteine at codon 1584
(Y1584C), identified in 10% to 20% of patients who had type 1 VWD
[39]. In both studies, however, some patients who had type 1 VWD had
no obvious VWF mutation identified, and in these (often milder) cases,
the genetic determinants likely are more complex and could involve other
genetic loci. At this time, genetic testing for type 1 VWD generally is neither
available nor required for establishing the diagnosis.
Type 2 von Willebrand disease
Type 2 VWD is characterized by a qualitative deficiency of VWF activity
and is classified further into the qualitative variants that affect VWF-platelet
interactions (2A, 2B, and 2M) and the rare type 2N characterized by defective
VWF binding to FVIII. The clinical presentation of type 2 VWD is
similar to type 1 VWD in that patients present with excessive mucocutaneous
bleeding; however, in contrast to the variably positive family histories in
type 1 VWD, patients who have type 2 VWD usually present with a clearly
positive family history.
Type 2A
Type 2A VWD accounts for approximately 10% of all VWD cases and is
characterized by the loss of HMW and intermediate-molecular-weight multimers.
This is the result of a defect in the synthesis of the higher-molecularweight
multimers (group 1 mutations) or the synthesis of multimers that are
more susceptible to cleavage by ADAMTS-13 (group 2 mutations) [40].
Type 2A can be suspected because of disproportionately low functional