Type 2 von Willebrand Disease is Inherited in an Autosomal Dominant Pattern
Type 2 von Willebrand disease (VWD) is inherited in an autosomal dominant pattern. 1, 2
Understanding Type 2 VWD Inheritance
Type 2 VWD represents a qualitative defect in von Willebrand factor (VWF) and is further classified into four subtypes (2A, 2B, 2M, 2N) based on specific functional abnormalities. The inheritance pattern for Type 2 VWD has important implications for genetic counseling and family screening:
- Type 2 VWD (including subtypes 2A, 2B, 2M, and 2N) follows an autosomal dominant inheritance pattern 1
- This means that affected individuals have a 50% chance of passing the disorder to each of their children
- The mutations responsible for Type 2 VWD are typically missense mutations affecting specific functional domains of VWF 2
Genetic Basis of Type 2 VWD
The genetic characteristics of Type 2 VWD help explain its inheritance pattern:
- Type 2 VWD mutations are localized to specific regions of the VWF gene, particularly exons 18-28 1
- These mutations affect critical functional domains of VWF including:
- Platelet-binding regions (Types 2A, 2B, 2M)
- Factor VIII-binding regions (Type 2N)
- Unlike Type 3 VWD (which is autosomal recessive), Type 2 VWD results from mutations that create dysfunctional VWF rather than absent VWF 2
Clinical Implications of Autosomal Dominant Inheritance
The autosomal dominant inheritance pattern of Type 2 VWD has several important clinical implications:
- Family screening is essential when a Type 2 VWD diagnosis is made
- First-degree relatives have a 50% chance of inheriting the mutation
- Women with Type 2 VWD may be more symptomatic than men despite the autosomal inheritance pattern 1, 3
- The severity of bleeding symptoms can vary within families sharing the same mutation, suggesting additional genetic or environmental factors influence clinical expression
Distinguishing from Other VWD Types
It's important to distinguish Type 2 VWD's inheritance pattern from other VWD types:
- Type 1 VWD: Also autosomal dominant, but represents a quantitative deficiency of VWF
- Type 3 VWD: Autosomal recessive inheritance, requiring mutations in both VWF alleles, resulting in virtually complete absence of VWF 4
Diagnostic Considerations
When evaluating patients for possible Type 2 VWD:
- Family history should reveal a pattern consistent with autosomal dominant inheritance
- Laboratory testing should focus on both quantitative and qualitative aspects of VWF function
- Ristocetin cofactor activity (VWF:RCo) is particularly useful for diagnosing Type 2 VWD as it reveals functional defects in VWF 1
- Genetic testing can confirm the diagnosis and identify the specific mutation, which may help predict clinical severity and response to treatments
Understanding the autosomal dominant inheritance pattern of Type 2 VWD is crucial for proper genetic counseling, family screening, and clinical management of affected individuals.