Factor X Deficiency

A number sign (#) is used with this entry because factor X deficiency is caused by homozygous or compound heterozygous mutation in the gene encoding coagulation factor X (F10; 613872) on chromosome 13q34.

Description

Factor X deficiency is a rare autosomal recessive bleeding disorder showing variable phenotypic severity. Affected individuals can manifest prolonged nasal and mucosal hemorrhage, menorrhagia, hematuria, and occasionally hemarthrosis. The disorder can be caused either by reduced levels of the factor X protein or by synthesis of a dysfunctional factor X protein (summary by Millar et al., 2000).

Clinical Features

Girolami et al. (1970) described a congenital haemorrhagic condition due to the presence of an abnormal factor X in a large kindred from Friuli, a remote valley in northeastern Italy. Girolami et al. (1971) reported another family from Friuli with a bleeding disorder due to an abnormal factor X. The proposita was a 43-year-old woman with a history of bleeding since early childhood. She had had epistaxis, menorrhagia, bleeding after tooth extractions, gum bleeding, postpartum hemorrhage, posttraumatic hemarthroses, and hematuria. Laboratory studies showed prolonged prothrombin time (PT), prolonged partial thromboplastin time (PTT), and correction with Russell viper venom. Factor X activity was significantly decreased (6 to 9% of normal), but antigen levels were normal; however, an abnormal factor X protein was identified immunologically, indicating a qualitative deficiency. The patient's 2 children and mother had 38 to 48% activity levels, consistent with the heterozygous state.

Sumer et al. (1986) reported a Saudi Arabian infant with severe factor X deficiency who had had 2 intracranial hemorrhages.

De Stefano et al. (1988) reported a 13-year-old girl, born of consanguineous parents, with defective factor X. Laboratory studies showed normal factor X antigen levels, but the protein was severely impaired in activation via the intrinsic pathway (3% of normal) and partially defective in activation via the extrinsic pathway (30-50% of normal). The variant protein, termed factor X Roma, was activated by Russell viper venom. The parents of the proposita showed factor X functional levels compatible with heterozygosity for the abnormality. Millar et al. (2000) determined that the Roma variant results from a T318M substitution (613872.0015) in the F10 gene.

Peyvandi et al. (1998) studied 32 Iranian patients with congenital factor X deficiency. The most frequent symptom was epistaxis, which occurred in 72% of patients, with all degrees of deficiency. Other mucosal hemorrhages (e.g., hematuria, gastrointestinal bleeding) were less frequent and occurred mainly in patients with unmeasurable factor X. Menorrhagia occurred in half of the women of reproductive age. Soft tissue bleeding occurred in two-thirds of the patients; spontaneous hematomas and hemarthroses led to severe arthropathy in 5 patients. Bleeding from the umbilical stump was an unexpected finding in 9 patients. The study demonstrated that the bleeding tendency of factor X deficiency can be severe and correlates with factor levels.

Acquired Factor X Deficiency

Furie et al. (1977) presented evidence that the acquired deficiency of factor X associated with systemic amyloidosis is caused by binding of the factor X protein to amyloid.

Ashrani et al. (2003) described factor X deficiency associated with lupus anticoagulant and a bleeding diathesis. They reported 2 patients in whom severe bleeding developed after a respiratory infection. Both the factor X deficiency and lupus anticoagulant were transient. Deficiency of factor X may be another mechanism whereby patients with antiphospholipid antibodies present with bleeding complications.

Other Features

Endo (1981) observed spontaneously developing hematomyelia with incomplete transverse paralysis in a 17-year-old patient with factor X deficiency.

Pregnancy in women with congenital deficiencies of coagulation factors such as factor X is often associated with adverse fetal outcomes. Recurrent spontaneous abortions, placental abruptions, and premature births are reported. Kumar and Mehta (1994) reviewed the outcome of 4 pregnancies in a patient with factor X deficiency. The first 2 pregnancies resulted in the birth of premature babies at 21 and 25 weeks of gestation, both of whom died in the neonatal period. The patient had been treated with fresh frozen plasma for acute bleeding episodes during these pregnancies. In addition, during the second conception she was given factor IX complex prophylactically during the latter half of her pregnancy. During her next 2 pregnancies, she was treated early in pregnancy with prophylactic replacement of factor X. She delivered healthy babies at 34 and 32 weeks of gestation and both babies thrived.

Inheritance

Factor X deficiency is usually inherited in an autosomal recessive pattern (Cooper et al., 1997).

However, Millar et al. (2000) reported a family manifesting an autosomal dominant pattern of inheritance for factor X deficiency. There were 3 clinically affected members who were heterozygous for a splice site mutation that was predicted to lead to the production of a truncated protein product (613872.0012). Millar et al. (2000) presented a model that accounted for the dominant-negative effect of this lesion.

Cytogenetics

Stoll and Roth (1980) described a girl with a duplication-deficiency syndrome involving chromosomes 4 and 13. The mother had a balanced translocation t(4;13)(q26;q34). The child had partial trisomy of 4q and partial monosomy of 13q. Factor X level was half normal.

Pfeiffer et al. (1982) presented evidence suggesting that factors VII (F7; 613878) and X may be encoded by genes on chromosome 13q34. They found deficiency of the 2 factors in 2 cases with 46,XY,t(13;Y)(q11;q34) including probable deletion of a terminal segment of 13q. A prolonged prothrombin time was found before surgery in the first case, leading to studies of coagulation; neither patient had clinical abnormality of coagulation. In 1 case, factor VII was measured as 42%, 40%, and 45% and factor X as 59%, 44%, and 60% of normal, in 2 different laboratories; in the second case, factor VII was 55% and 54% of normal and factor X was 25% and 62%. These values were normal in all 4 parents.

Scambler and Williamson (1985) studied a female monosomic for 13q34 and deficient in clotting factors VII and X, as well as her brother, who was trisomic for 13q34 and had elevated levels of these factors. These persons suffered the effects of segregation from a reciprocal translocation in the mother involving the tip of chromosome 13 (13q34) and 6q24-6q26. DNA dosage studies with a cloned human factor X gene showed that the low levels of factor X expression were due to absence of one copy of the factor X structural gene.

Molecular Genetics

In a patient with a bleeding disorder due to factor X deficiency, Reddy et al. (1989) identified compound heterozygosity for 2 mutations in the F10 gene (613872.0001 and 613872.0002). The patient had prolonged bleeding after surgery, and laboratory studies showed that factor X activity and antigen were 14% and 36% of normal, respectively. This was the first characterization of factor X deficiency at the molecular level.

Bernardi et al. (1989) found that a patient with factor X deficiency was a genetic compound for 2 mutations affecting the F10 gene: the maternal allele contained a partially deleted gene missing the 3-prime portion coding for the catalytic domain of the factor; the defect on the paternal F10 allele was not determined.

James et al. (1991) demonstrated that factor X Friuli is caused by a homozygous mutation in the F10 gene (P343S; 613872.0004).

Wieland et al. (1991) identified an instance of germline mosaicism for deletion of exons 7 and 8 of factor X. One offspring had this deletion and a different deletion inherited from the mother, i.e., she was a compound heterozygote.

Millar et al. (2000) sequenced the F10 genes of 14 unrelated individuals with factor X deficiency, including 12 familial and 2 sporadic cases, and found a total of 13 novel mutations (see, e.g., 613872.0012-612872.0014). Missense mutations were studied by means of molecular modeling, whereas single basepair substitutions in splice sites and the 5-prime flanking region were examined by in vitro splicing assay and luciferase reporter gene assay, respectively. The deletion allele of a novel 6-nucleotide insertion/deletion polymorphism in the F10 gene promoter region was shown by reporter gene assay to reduce promoter activity by approximately 20%. Variation in the antigen level of heterozygous relatives of probands was found to be significantly higher between families than within families, consistent with the view that the nature of the F10 lesion(s) segregating in a given family is a prime determinant of the laboratory phenotype.

Millar et al. (2000) commented that the complete absence of nonsense mutations in the F10 mutational spectrum is highly unusual. The ratio of nonsense to missense mutations is normally approximately 1 in 4. The observed lack of nonsense mutations was statistically significant. Assuming that the relative rate of single basepair substitutions in the F10 gene is similar to the overall mutational spectrum of human genes, this discrepancy would be explicable only in terms of a reduced relative likelihoods of clinical observation (RCOL; Krawczak et al., 1998) of nonsense versus missense mutations as compared with other genes. The reasons for this reduction were not clear.

Peyvandi et al. (2002) analyzed the phenotype and genotype of 15 Iranian patients with factor X deficiency from 13 unrelated families with a high frequency of consanguinity. Nine different homozygous candidate mutations were identified, of which 8 were novel.

Population Genetics

Factor X deficiency has an estimated prevalence of 1 in 500,000 individuals (summary by Millar et al., 2000).

History

Giangrande (2003) gave an account, with photograph, of Miss Audrey Prower, who was 22 years old when she was admitted to University College Hospital of London in 1956 for investigation of a bleeding tendency prior to a dental extraction (Telfer et al., 1956; Denson, 1957). She had had significant bleeding after 2 previous dental extractions and after tonsillectomy. A brother had died of postoperative bleeding after tonsillectomy when he was 5 years old.

Lewis et al. (1953) described a North Carolina patient seemingly similar to Audrey Prower. Hougie et al. (1957) tracked the patient down and confirmed that the defect was the same. As recounted by Giangrande (2003), Rufus Stuart was a 36-year-old farmer and lay-Baptist preacher, a member of a large and interrelated kindred living in the Blue Ridge Mountains of the northwestern corner of North Carolina and neighboring Virginia. He was born of an aunt-nephew mating. His principal problems had been recurrent epistaxis and significant bruising as well as hemarthrosis. Graham et al. (1957) provided a pedigree and showed that the inheritance pattern of the bleeding disorder was clearly autosomal recessive. Giangrande (2003) provided a photograph of Rufus Stuart with 3 of his physicians, Drs. Hougie, Barrow, and Graham.