Afibrinogenemia, Congenital

A number sign (#) is used with this entry because afibrinogenemia is caused by homozygous or compound heterozygous mutation in one or another of the 3 fibrinogen genes: alpha (FGA; 134820), beta (FGB; 134830), or gamma (FGG; 134850).

Hypofibrinogenemia is most often caused by heterozygous mutation, but also by homozygous or compound heterozygous mutation, in one of these genes.

Description

Inherited disorders of fibrinogen affect either the quantity (afibrinogenemia and hypofibrinogenemia; 202400) or the quality (dysfibrinogenemia; 616004) of the circulating fibrinogen or both (hypodysfibrinogenemia; see 616004). Afibrinogenemia is characterized by the complete absence of immunoreactive fibrinogen. Bleeding due to afibrinogenemia usually manifests in the neonatal period, with 85% of cases presenting umbilical cord bleeding, but a later age of onst is not unusual. Bleeding may occur in the skin, gastrointestinal tract, genitourinary tract, or the central nervous system, with intracranial hemorrhage being reported as the major cause of death. Patients are susceptible to spontaneous rupture of the spleen. Menstruating women may experience menometrorrhagia. First-trimester abortion is common. Both arterial and venous thromboembolic complications have been reported (summary by de Moerloose and Neerman-Arbez, 2009).

Hypofibrinogenemia is characterized by reduced amounts of immunoreactive fibrinogen. Patients are often heterozygous carriers of afibrinogenemia mutations and are usually asymptomatic. However, they may bleed when exposed to trauma or if they have a second associated hemostatic abnormality. Women may experience miscarriages. Liver disease occurs in rare cases (summary by de Moerloose and Neerman-Arbez, 2009).

Clinical Features

In 2 brothers reported by Lemoine et al. (1963) congenital afibrinogenemia was associated with osseous and hepatic lesions, thought to be of hemorrhagic origin.

Fried and Kaufman (1980) studied an Iraqi Jewish sibship and a Moroccan Jewish kindred in which 10 of 27 sibs had congenital afibrinogenemia. Death occurred in 6 in childhood. Two affected sibs were young women. Two died as neonates from uncontrollable bleeding. Two of the survivors had suffered spontaneous rupture of the spleen. Fitness seemed to be close to zero.

Inheritance

Fried and Kaufman (1980) noted that consanguinity had been reported in 31 of 56 families with congenital afibrinogenemia, supporting autosomal recessive inheritance.

Clinical Management

Neerman-Arbez et al. (1999) reported that patients with afibrinogenemia respond well to fibrinogen replacement therapy, either prophylactically or on demand.

Population Genetics

De Moerloose and Neerman-Arbez (2009) stated that the estimated prevalence of afibrinogenemia is 1 in 1 million. They noted that the prevalence of hypofibrinogenemia and dysfibrinogenemia is difficult to establish because of the large number of asymptomatic cases.

Molecular Genetics

Complete absence of detectable fibrinogen was first demonstrated to be due to an 11-kb deletion in the FGA gene (134820.0019). The phenotype has also been associated with missense mutations in the FGB gene (134830.0009, 134830.0010) that result in impaired fibrinogen secretion and with mutations in the FGG gene (134850.0016-134850.0017).

Neerman-Arbez et al. (2000) pointed out that the overwhelming majority of cases of afibrinogenemia are due to truncating mutations of the FGA gene. Some of these are recurrent mutations, including the FGA 11-kb deletion and the FGA donor splice site mutation at intron 4 (134820.0020).

De Moerloose and Neerman-Arbez (2009) noted that missense mutations in the highly conserved C-terminal globular domains of the FGB and FGG genes lead to afibrinogenemia. Functional studies of these mutations in transfected cells have shown either impaired assembly or impaired secretion of the fibrinogen hexamer, demonstrating the importance of these globular structures in the quality control of fibrinogen biosynthesis.

In a patient with severe hypofibrinogenemia, Asselta et al. (2004) identified compound heterozygous mutations in the FGB gene (134830.0015; 134830.0016).