Dysfibrinogenemia, Congenital

A number sign (#) is used with this entry because congenital dysfibrinogenemia is caused by mutation in one of the fibrinogen genes: alpha (FGA; 134820), beta (FGB; 134830), or gamma (FGG; 134850). It is most often caused by heterozygous mutation, but can also be caused by homozygous or compound heterozygous mutation.

Congenital hypodysfibrinogenemia is caused by heterozygous, homozygous, or compound heterozygous mutation in one of the fibrinogen genes.

Description

Inherited disorders of fibrinogen affect either the quantity (afibrinogenemia and hypofibrinogenemia; 202400) or the quality (dysfibrinogenemia) of the circulating fibrinogen, or both (hypodysfibrinogenemia). Patients with dysfibrinogenemia are frequently asymptomatic, but some patients have bleeding diathesis, thromboembolic complications, or both (summary by de Moerloose and Neerman-Arbez, 2009). Reports (e.g., Haverkate and Samama, 1995) on approximately 350 families with dysfibrinogenemia revealed that approximately half of cases are clinically silent, a quarter show a tendency toward bleeding, and another quarter show a predisposition for thrombosis with or without bleeding (summary by Lefebvre et al., 2004).

Inheritance

Dominant inheritance of dysfibrinogenemia and hypofibrinogenemia is indicated by the pedigree patterns of many families. Dysfibrinogenemia may exemplify one mechanism for dominant inheritance: the mutant polypeptide may not participate normally as a subunit in the aggregate that is fibrinogen (Vogel and Motulsky, 1979). An unstable aggregate molecule results.

Dysfibrinogenemia is in most cases an autosomal dominant disorder (Asselta et al., 2006).

Recessive inheritance of dysfibrinogenemia has also been reported (e.g., Soria et al., 1972 and Blomback et al., 1968).

Pathogenesis

Mutations in the fibrinogen genes that cause dysfibrinogenemia affect any one of the functional properties of fibrinogen, including absence or delayed release of fibrinopeptides A and B, delayed or enhanced polymerization, defective cross-linking, decreased thrombin binding, and delayed plasmin digestion (summary by Asselta et al., 2006).

Molecular Genetics

Henschen et al. (1981) identified a missense mutation in the FGA gene as a cause of dysfibrinogenemia (R16C; 134820.0003). Flood et al. (2006) stated that the FGA R16C mutation is the most common fibrinogen mutation in humans. Although about 30% of the reported cases of the R16C mutation in humans are associated with hemorrhage, some 15% of reported cases are associated with thrombosis (Hanss and Biot, 2001).

In 3 Italian sibs with dysfibrinogenemia with thrombosis, Koopman et al. (1992) identified a homozygous mutation in the FGB gene (A68T; 134830.0007).

In affected members of a family with increased tendency to thrombosis and a mild hemorrhagic diathesis originally reported by Beck et al. (1965), Bantia et al. (1990) identified a heterozygous missense mutation in the FGG gene (G292V; 134850.0003).

Lefebvre et al. (2004) described a nonconsanguineous American family of European descent in which 2 sibs with hypodysfibrinogenemia had lifelong trauma-related bleeding. The brother had recurrent thrombosis after cryoprecipitate infusions following surgery. The sister had 6 miscarriages. The sibs were found to be compound heterozygous for a truncating and a splice site mutation in the FGA gene (134820.0024-134820.0025).

In affected members of a family with hypodysfibrinogenemia, originally described by Martinez et al. (1974), Keller et al. (2005) identified a heterozygous missense mutation in the FGG gene (S378P; 134850.0022).