Hepatic Fibrinogen Storage Disease in a Patient with Hypofibrinogenemia: Report of a Case with a Missense Mutation of the FGA Gene

Abstract

We report a 9-year-old patient with abnormal liver tests found incidentally during routine bloodwork as part of a preoperative evaluation for excision of a benign cyst. A liver biopsy demonstrated hepatocytes to have pale and expanded cytoplasm that contained multiple vague globular eosinophilic inclusions. Electron microscopy showed fingerprint-like structures in the dilated cisternae of the rough endoplasmic reticulum, characteristic of fibrinogen. Whole exome sequencing identified a heterozygous missense mutation at codon 35 of the fibrinogen α (FGA) gene. No mutation was identified in the β or γ chains. His plasma fibrinogen levels were found to be decreased to 85 mg/dL (normal range 215-464). His family history was pertinent for his mother and maternal grandfather with hypofibrinogenemia. He had not had any significant bleeding episodes except for minor bruising over the shins. This case illustrates a rare etiology of storage disease that causes abnormal liver function tests.

Hepatic and Extrahepatic Sources and Manifestations in Endoplasmic Reticulum Storage Diseases

“…Interestingly most cases of either a-or hypofibrinogenemia are not associated with fibrinogen accumulation in hepatocytes. Apparent exceptions are missense mutations or a single large deletion in the fibrinogen gamma chains [89,90] and in a single case report a missense mutation of the FGA gene [91] previously documented to be associated with dysfibrinogenemia but not with hypofibrinogenemia [92].…”

Hereditary Hypofibrinogenemia with Hepatic Storage

“…Finally, we have to mention the p.Arg35Cys missense mutation located in exon 2 of the FGA gene [ 45 ], which was described in a young hypofibrinogenemic patient with mild hepatomegaly and only slightly increased transaminase levels. Importantly, it has to be underlined that the identified mutation was reported in the literature as one of the most frequent cause of dysfibrinogenemia world-wide [ 46 ], directly involving the thrombin cleavage site of fibrinopeptide A, and often associated with hemorrhagic or thrombotic manifestations.…”

“…Importantly, it has to be underlined that the identified mutation was reported in the literature as one of the most frequent cause of dysfibrinogenemia world-wide [ 46 ], directly involving the thrombin cleavage site of fibrinopeptide A, and often associated with hemorrhagic or thrombotic manifestations. Indeed, Lee and colleagues [ 45 ] claimed that they were reporting the p.Arg35Cys mutation as associated with hypofibrinogenemia for the first time (rather than with dysfibrinogenemia), but failed to report the measurement method used to evaluate fibrinogen levels in their patient. In addition, morphologic analyses were not performed with the use of specific antihuman-fibrinogen IgG, so that we are tempted to consider this specific case as a storage disorder of unknown nature, with the concomitant presence of a coagulation defect (either hypofibrinogenemia or dysfibrinogenemia).…”

Fibrinogen as a Pleiotropic Protein Causing Human Diseases: The Mutational Burden of Aα, Bβ, and γ Chains

“…This condition is called fibrinogen storage disease (FSD), and is generally caused by heterozygous mutations, leading to an impaired secretion of the abnormal fibrinogen, which however maintains its capacity for polymerization and spontaneously aggregates in hepatocellular ER. In the vast majority of cases, mutations leading to FSD are missense variants that are located in a defined region of the C-terminal γ chain (residues 284–375) [ 18 , 19 ]. FSD-causing mutation carriers show a great variability in the severity of liver injury, going from the lack of symptoms to severe liver fibrosis/cirrhosis; more severe manifestations can be secondary to xenobiotic intake (e.g., estrogen therapy, alcohol abuse), to viral infections, or even to cancer [ 18 , 20 ].…”