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Congenital factor VII deficiency
A rare, genetic, congenital vitamin K-dependant coagulation factor deficiency disorder characterized by decreased levels or absence of coagulation factor VII (FVII), resulting in bleeding diathesis of variable severity.
ORPHA:327Classification level: Disorder
European point prevalence appears to be close to 1/300,000, but may be markedly higher in countries where consanguineous marriage is frequent.
Clinical expression of this disorder is highly variable and no consistent relationship has been found between the severity of the hemorrhagic syndrome and the residual levels of FVII activity. The clinical picture can be very severe, with early occurrence of intracerebral hemorrhages or repeated hemarthroses, or, in contrast, may be moderate with cutaneous/mucosal hemorrhages (epistaxis, menorrhagia) or hemorrhages provoked by surgery or trauma. Finally, numerous subjects are completely asymptomatic despite a very low FVII level.
FVII deficiency is caused by mutations in the F7 gene (13q34) coding for FVII. Typically, only homozygotes or compound heterozygotes develop a hemorrhagic syndrome; heterozygotes are usually asymptomatic. More than 250 mutations and six common variants are known to be associated with increased or decreased FVII plasma levels. Large genomic rearrangements have been reported in the literature and in the different locus-specific databases but they are rare. Genetic rearrangements have also been demonstrated, resulting in total or partial deletion of the F7 gene. The proximity and implication with the F10 gene (13q34) might also be the cause of combined deficits.
Diagnosis is suspected with isolated prothrombin time and further confirmed by chronometric assays revealing a FVII activity level below that of pooled normal plasma (with values usually being between 70 and 140%). The deficiency is usually symptomatic only for values below 30%.
Differential diagnoses include hepatocellular insufficiency, hypoavitaminosis K, acquired FVII deficiency associated with severe sepsis and, more rarely, the presence of autoantibodies against FVII.
Due to the marked heterogeneity of the phenotypes (including asymptomatic individuals), access to prenatal diagnosis depends on the clinical repercussions of the disease in the family being considered. Only the existence of a first child with the very severe form may lead the medical team to propose prenatal diagnosis at the time of a subsequent pregnancy.
The disease is transmitted in an autosomal recessive manner. Due to the wide phenotypic heterogeneity of the disorder, with many asymptomatic patients, genetic counseling tends to differ depending on the clinical features specific to a family.
Management and treatment
At present, the main treatment consists of recombinant activated FVII (eptacog alfa). Concentrated prothrombinic or plasmatic Factor VII may be used as a second choice and frozen plasma as a last resort. However, indications remain difficult to establish prior to surgery in subjects with few or no symptoms. In 2008, recombinant coagulation factor VIIa (rFVIIa) got an Orphan designation in the USA.
Congenital FVII deficiency usually has good prognosis. Nevertheless, disease remains very disabling, or even fatal, in patients who cannot benefit from long-term replacement prophylaxis and which present the most severe forms (intracerebral hemorrhage and repeated hemarthroses).
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