What causes factor IX deficiency (FIX) (hemophilia B)?

Updated: Mar 09, 2021
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Srikanth Nagalla, MD, MS, FACP  more...
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The gene for FIX is on the distal region of the long arm of the X chromosome, bands q27.1-q27.2. The gene is reported to be approximately 34 kilobases long with 8 exons and 7 introns and is located close to the fragile X site. The FIX gene has been studied extensively. Structural and functional defects in FIX are due to gene alterations, including large or small deletions, insertions or splice junction alterations, single base substitutions, or nonsense mutations. Similar to hemophilia A, approximately 30% of cases represent a de novo mutation. Extensive homologies exist between the gene and protein structures of all of the vitamin K–dependent factors. The introns occur in identical positions in FIX, FVII, FX, and protein C, suggesting evolution from a common ancestral gene.

Most patients deficient in FIX have point mutations; the nature of the mutation determines the level of FIX activity. More than one third of the mutations affect critical arginine residues (cytosine-guanine dinucleotide site mutations) resulting in a dysfunctional molecule.

Variability in clinical bleeding manifestations is due to heterogeneity of the molecular defects found in this disorder, with each mutation resulting in a specific pattern of alteration of FIX activity. Baseline levels of FIX and the severity of bleeding tend to be similar in members of a family, who have inherited the same specific defect.

Many mutations in the FIX gene cause hemophilia B. The mutations provide an understanding of structure-activity relationships. Three groups of mutations are particularly instructive and have important clinical consequences.

The first group consists of gross FIX gene deletions and gene rearrangements causing severe deficiency of FIX, which results in a severe bleeding diathesis. These patients are prone to developing severe anaphylactic reactions when factor replacement therapy is started. Allergic/anaphylactic reactions are associated with development of a specific FIX inhibitor.

New patients with severe FIX deficiency should be screened for such large gene defects, which can alert the clinician prior to development of life-threatening anaphylaxis in patients. Patients with large gene defects should be selected to receive initial FIX product infusions under well-supervised conditions that will allow prompt attention to serious complications.

The second group consists of the FIX Leyden phenotype, which is caused by several different mutations in the FIX promoter region. The patients may have a spontaneous increase in basal FIX levels during and after puberty. Anabolic steroids also can raise the level of FIX in patients. In the FIX Leyden phenotype, baseline FIX levels are in the 1-13% range, and FIX levels can rise to approximately 30% in childhood (age 4-5 y) and to approximately 70% with the onset of puberty and testosterone production.

The third group involves missense mutations in the propeptide sequence of FIX, resulting in a markedly decreased affinity of abnormal FIX for vitamin K–dependent carboxylase. Patients have normal baseline levels of FIX, but because of increased sensitivity to vitamin K antagonists, they develop unexpected and severe reductions in FIX following administration of oral anticoagulants, which then predisposes patients to an increased risk of bleeding. Identification of mutations in families is feasible because of the small size of the gene, and it is useful for carrier detection. The different types of intragenic polymorphisms vary with the ethnic group. These are useful in counseling families with unknown mutations.

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