Pseudohomozygous dysfibrinogenemia

Abstract

Essentials• Hypodysfibrinogenaemia (HD) can cause bleeding or thrombosis and is usually monoallelic.• A new case report and database search identifes a genetically distinct subtype of recessive HD.• Cases inherit qualitative and quantitative fibrinogen gene variants that are biallelic.• This disorder is better classified as pseudohomozygous dysfibrinogenemia.Heritable fibrinogen disorders have variable and overlapping clinical manifestations and are by convention subclassified according to the results of quantitative and qualitative fibrinogen testing of plasma. 1,2 According to this classification, a concordant reduction of plasma fibrinogen antigen and function indicates the disorders afibrinogenemia and hypofibrinogenemia (Online Mendelian Inheritance in Man [OMIM] No. 202400) in which there are reduced circulating levels of fibrinogen.These disorders are usually associated with variants in the fibrinogen genes FGA, FGB, or FGG that predict failure of expression or secretion of the fibrinogen polypeptide and which are usually biallelic in afibrinogenemia and monoallelic in hypofibrinogenemia. 3 In dysfibrinogenemia (OMIM No. 616004) plasma fibrinogen antigen is normal but function is reduced, usually because of an underlying monoallelic missense variant disrupting a functionally critical region of the fibrinogen polypeptide. 3,4 A further disorder termed hypodysfibrinogenemia (OMIM No. 616004) is characterized by reduced fibrinogen function but also a less marked reduction of plasma fibrinogen antigen that may arise from abnormal assembly, secretion, or increased clearance of the fibrinogen chains. 5 Here, we report a new case with a severe heritable fibrinogen disorder and review the literature to highlight that hypodysfibrinogenemia is genetically heterogeneous and includes a distinct subset of cases better classified as pseudohomozygous dysfibrinogenemia.

Diagnosis and classification of hereditary fibrinogen disorders

“…In hypodysfibrinogenemia, a single mutation can affect both the secretion and the function of the fibrinogen molecule. In alternative, a compound mutation can confer a concomitant "hypofibrinogenemia" and "dysfibrinogenemia" trait 4 .…”

“…Clinical features vary according to the fibrinogen level and the subtype of HFDs. Afibrinogenemia, characterised by the complete absence of fibrinogen, is typically associated with a severe bleeding phenotype and a paradoxical thrombotic tendency 3,4 . Hypofibrinogenemia, defined by decreased levels of fibrinogen activity and antigen, is associated with a bleeding risk dependent on the fibrinogen concentration 5,6 .…”

“…In dysfibrinogenemia, normal levels of dysfunctional fibrinogen lead to highly heterogenous clinical features, from mild to life-threatening bleeding to recurrent thrombotic events, even though most patients are asymptomatic at time of diagnosis 7 . Hypodysfibrinogenemia, in which both activity and antigen fibrinogen levels are decreased, is often marked by a strong tendency to bleeding and thrombosis 4,8 . A recent classification identified several sub-types of HFDs considering fibrinogen activity and antigen levels, genotype, and clinical phenotype.…”

Two Novel Heterozygous Mutations (p.γPhe230Val and p.AαAsn839Thr) Cause Hereditary Hypodysfibrinogenemia in Two Chinese Independent Families

“…Type I defects include hereditary afibrinogenemia and hereditary hypofibrinogenemia; type II defects include dysfibrinogenemia or hypodysfibrinogenemia [2]. There are few reports of hypodysfibrinogenemia, which is characterized by varying degrees of reduced fibrinogen levels and abnormal function, and the pathogenic mechanism may be caused by abnormal assembly, secretion, or increased degradation of fibrinogen chain [3]. Most patients are asymptomatic, with a few spontaneous bleeding or thrombosis [4].…”