title: Fibrinogen gamma375 arg-->trp mutation (fibrinogen aguadilla) causes hereditary hypofibrinogenemia, hepatic endoplasmic reticulum storage disease and cirrhosis.
abstract: Hypofibrinogenemia is a rare inherited disorder characterized by low levels of circulating fibrinogen, caused by mutations within 1 of the 3 fibrinogen genes. We report here the case of a 61-year-old man with chronic liver function test alterations. Liver biopsy examination revealed chronic hepatitis complicated by cirrhosis and weakly eosinophilic globular cytoplasmic inclusions within the hepatocytes, faintly stained with PAS-diastase. On immunohistochemistry, the inclusions reacted strongly with human antifibrinogen antibodies. Coagulation investigations of the propositus and his 2 sons showed low functional and antigenic fibrinogen concentrations that were indicative of hypofibrinogenemia. A liver biopsy performed on the 28-year-old son demonstrated the same globular cytoplasmic inclusions, albeit without associated chronic liver disease. PCR amplification followed by sequencing showed that all 3 were heterozygous for a CGG>TGG mutation at codon 375 of the fibrinogen gamma-chain gene (FGG), corresponding to an Arg>Trp substitution. This is the first in an adult male and the second published case with a discernible hepatic fibrinogen endoplasmic reticulum storage disease due to an FGG Arg375Trp (fibrinogen Aguadilla) mutation. Our results suggest that familial hypofibrinogenemia should be considered in the differential diagnosis of a progressive liver disease associated to hepatocellular intracytoplasmic globular inclusions.
authors.affiliation: Gastrointestinal and Liver Pathology Unit, University Hospital, 24 rue Micheli-du-Crest, 1211 Geneva 14, Switzerland. laura.rubbia-brandt@hcuge.ch
authors.forename: Laura
authors.initials: L
authors.lastname: Rubbia-Brandt
authors.forename: Marguerite
authors.initials: M
authors.lastname: Neerman-Arbez
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Rougemont
authors.forename: Pierre-Jean
authors.initials: PJ
authors.lastname: Malé
authors.forename: Laurent
authors.initials: L
authors.lastname: Spahr
mesh_terms: D000328:Adult; D000347:Afibrinogenemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001120:Arginine / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005192:Family Health; D005340:Fibrinogen / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017354:Point Mutation; D014364:Tryptophan / Q000235:genetics / Q000378:metabolism
chemical_list: D014364:Tryptophan; D005340:Fibrinogen; D001120:Arginine