Mercedeh Tajdar1, Christelle Orlando2, Alessandro Casini3, Margaux Herpol2, Barbara De Bisschop4, Paul Govaert4, Marguerite Neerman-Arbez5, Kristin Jochmans2. 1. Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of Haematology, Laarbeeklaan 101, 1090 Brussels, Belgium. Electronic address: mercedeh.tajdar@azsintjan.be. 2. Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of Haematology, Laarbeeklaan 101, 1090 Brussels, Belgium. 3. University Hospitals of Geneva, Division of Angiology-Haemostasis, Rue Michel Servet 1, 1211 Geneva 4, Switzerland. 4. Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of Neonatology, Laarbeeklaan 101, 1090 Brussels, Belgium. 5. University of Geneva, Department of Genetic Medicine and Development, Rue Michel Servet 1, 1211 Geneva 4, Switzerland.
Abstract
INTRODUCTION: The propositus - a two-week-old boy - was transferred to our university hospital for investigation of increased head circumference and full fontanel. On ultrasound, thrombosis of the right internal cerebral vein and intraventricular haemorrhage was diagnosed, confirmed by MRI. Family history revealed a bleeding history in the mother. A haemostatic work-up in both mother and child was performed in order to rule out congenital coagulopathy. AIM: We document a clinical case of congenital dysfibrinogenemia, caused by heterozygosity for the mutation FGA p.Asp473Ter, previously reported as fibrinogen Nieuwegein in homozygosity in an asymptomatic patient. METHODS: Fibrinogen activity in plasma was determined by functional Clauss assay, and immunological fibrinogen concentration by nephelometry. In vitro fibrin clot investigations and genetic analysis of the fibrinogen gene were performed. Complete haemostatic work-up was done by conventional methods. RESULTS AND DISCUSSION: After full laboratory work-up, dysfibrinogenemia was diagnosed, based on fibrinogen activity:antigen ratio, thrombin time, and reptilase time. Molecular analysis showed a frameshift mutation in exon 5 of FGA: c.1415_1416 insC, leading to a termination codon immediately after the insertion (CCT GAT>CCC TGA) and resulting in a truncated αC-domain. This mutation has been reported earlier as fibrinogen Nieuwegein. Further in vitro investigations revealed an abnormally tight clot structure, prolonged clot lysis time and affected polymerization, suggesting a thrombotic phenotype. Cerebral imaging revealed thrombosis, most likely developed in the antenatal period, leading to extensive intraventricular haemorrhage and posthaemorrhagic ventricular dilatation. CONCLUSION: We highlight the combined thrombotic and haemorrhagic phenotype linked to heterozygous fibrinogen Nieuwegein, in contrast to the previously reported asymptomatic homozygous case.
INTRODUCTION: The propositus - a two-week-old boy - was transferred to our university hospital for investigation of increased head circumference and full fontanel. On ultrasound, thrombosis of the right internal cerebral vein and intraventricular haemorrhage was diagnosed, confirmed by MRI. Family history revealed a bleeding history in the mother. A haemostatic work-up in both mother and child was performed in order to rule out congenital coagulopathy. AIM: We document a clinical case of congenital dysfibrinogenemia, caused by heterozygosity for the mutation FGA p.Asp473Ter, previously reported as fibrinogen Nieuwegein in homozygosity in an asymptomatic patient. METHODS:Fibrinogen activity in plasma was determined by functional Clauss assay, and immunological fibrinogen concentration by nephelometry. In vitro fibrin clot investigations and genetic analysis of the fibrinogen gene were performed. Complete haemostatic work-up was done by conventional methods. RESULTS AND DISCUSSION: After full laboratory work-up, dysfibrinogenemia was diagnosed, based on fibrinogen activity:antigen ratio, thrombin time, and reptilase time. Molecular analysis showed a frameshift mutation in exon 5 of FGA: c.1415_1416 insC, leading to a termination codon immediately after the insertion (CCT GAT>CCC TGA) and resulting in a truncated αC-domain. This mutation has been reported earlier as fibrinogen Nieuwegein. Further in vitro investigations revealed an abnormally tight clot structure, prolonged clot lysis time and affected polymerization, suggesting a thrombotic phenotype. Cerebral imaging revealed thrombosis, most likely developed in the antenatal period, leading to extensive intraventricular haemorrhage and posthaemorrhagic ventricular dilatation. CONCLUSION: We highlight the combined thrombotic and haemorrhagic phenotype linked to heterozygous fibrinogen Nieuwegein, in contrast to the previously reported asymptomatic homozygous case.