What clotting factor deficiency is inherited in an X-linked manner?

Factor IX Deficiency is the X-linked Inherited Clotting Factor Deficiency

Factor IX deficiency (Hemophilia B) is the correct answer as it is the only clotting factor deficiency that is inherited in an X-linked manner among the options provided. 1, 2, 3

Genetics of Hemophilia B

Hemophilia B is characterized by:

• X-linked recessive inheritance pattern, primarily affecting males 1
• Caused by pathogenic variants in the F9 gene located on the X chromosome 3
• Over 1,000 known pathogenic variants have been identified, with missense and frameshift mutations predominating 3
• Males with the mutation are hemizygous (have only one X chromosome) and manifest the disease 3
• Females are typically carriers but may experience bleeding symptoms due to:
  • Random or non-random X chromosome inactivation
  • Rare cases of homozygosity, compound heterozygosity, or hemizygosity 3

Distinguishing from Other Clotting Disorders

Factor IX Deficiency (Hemophilia B)

• Inheritance pattern: X-linked recessive 1, 3
• Prevalence: Approximately 5.0 cases per 100,000 males at birth 1
• Laboratory findings: Prolonged aPTT with normal PT 2
• Severity classification: Based on factor IX levels 2
  • Severe: <1% of normal
  • Moderate: 1-5% of normal
  • Mild: 5-40% of normal

Von Willebrand Disease (Option B)

• Inheritance pattern: Primarily autosomal dominant (not X-linked) 4
• Prevalence: Most common inherited bleeding disorder
• Laboratory findings: Variable aPTT, abnormal platelet function tests

DIC (Option D)

• Inheritance pattern: Not inherited; acquired condition
• Laboratory findings: Prolonged PT, aPTT, thrombocytopenia, elevated D-dimer

Clinical Implications of X-linked Inheritance in Hemophilia B

The X-linked inheritance pattern of hemophilia B has important clinical implications:

• Males with the mutation will develop the disease 3
• Female carriers typically have approximately 50% factor IX activity and are usually asymptomatic 3
• Sons of affected males will not inherit the disease (receive Y chromosome)
• All daughters of affected males will be carriers (receive X chromosome with mutation)
• Sons of carrier females have a 50% chance of inheriting the disease
• Daughters of carrier females have a 50% chance of being carriers

Diagnostic Approach

Diagnosis of hemophilia B involves:

1. Prolonged aPTT with normal PT 2
2. Normal mixing studies (suggesting factor deficiency rather than inhibitor) 2
3. Specific factor IX activity assay showing reduced levels 2
4. Genetic testing to identify the specific F9 mutation 3, 4

Management Considerations

Treatment of hemophilia B includes:

• Replacement therapy with factor IX concentrates (plasma-derived or recombinant) 2
• Prophylactic regimens (25-40 IU/kg twice weekly) for severe cases 2
• Target factor IX levels based on bleeding severity:
  • Minor bleeding: 30-50 IU/dL
  • Major bleeding: 50-100 IU/dL
  • Surgery: 70-90 IU/dL preoperatively, >50 IU/dL postoperatively 2

The International Society on Thrombosis and Haemostasis strongly recommends prophylaxis over episodic treatment for individuals with severe and moderately severe hemophilia B 1.