consistent with a post-Golgi defect in the packaging and/or secretion of mutant FV protein.In conclusion, the Y478 deletion in the A2 domain of FV results in a conformational change of the protein, a 50% decrease in the level of intracellular FV, and a near total failure of secretion. In the heterozygous state with the T2952del-induced premature termination codon, these findings account for the severe bleeding phenotype of this patient.
AcknowledgementsWe thank J. C. Christianson for his advice on immunofluorescent subcellular localization and the Beckman Cell Sciences Imaging Facility at Stanford.
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A girl with severe pre- and post-natal short stature, low-pitched voice, retinitis pigmentosa, photophobia, short neck, broad thorax, platyspondyly, rhizomelic shortening of the long bones, bilateral subluxation of the hips, advanced maturation of the epiphyses, and apparently normal intellectual development is described. The girl's parents are first cousins. Two subsequent pregnancies had ended in spontaneous abortion with polyhydramnios and severe growth retardation. To the best of our knowledge, this association had not been previously reported, and may be considered a newly recognized syndrome.
Factor VII deficiency is a rare inherited bleeding disorder. Intracranial hemorrhage can occur in approximately 1 to 10% of the cases. We report the case of a one month old girl from Lebanon who presented with vomiting, abnormal cry, lethargy and partial seizures. She was diagnosed prenatally with severe factor VII deficiency after detection of a splice-site mutation in exon 2 of the FVII gene (IVS2+1 G→C) that was described previously in her sister who died at the age of 4 months from severe intracranial hemorrhage. The parents are first degree cousins and are both heterozygous. She has a healthy heterozygous two year old sister.
An emergency head CT Scan showed intra ventricular and right hemispheric intra parenchymal hemorrhage, peri-hemorrhage edema and minimal midline shift. The patient was placed immediately on mechanical ventilation and anti-epileptics and activated recombinant factor VII (rFVIIa, NovoSeven) was administered intra-venously at 60 ug/kg for the first dose then 30 ug/kg/dose every 4 to 6 hours for 10 days then once a day for 5 days. She was treated conservatively with no surgery. Stabilization of the hematoma was observed with gradual improvement of her neurological condition. Communicating hydrocephalus developed later and a ventriculo-peritoneal shunt was placed on day 16 post-hemorrhage. Subsequently, she received weekly infusions of rFVIIa at 30 ug/kg/dose for 4 weeks after this episode and showed no bleeding symptoms. Follow-up two months later showed axial hypotonia and a mild left sided spasticity. Auditory evoked potentials were normal. However, afte prophylactic rFVIIa was dicontinued, the patient developed sub-arachnoid hemorrhage and was placed again on weekly prophylactic infusions of rFVIIa at 30 ug/kg/dose. The patient tolerated the infusions very well. No side-effects were observed.
Conclusion: rFVIIa is safe and effective in Factor VII deficient newborns with intracranial hemorrhage. Rapid treatment at the onset of hemorrhage is critical to reduce mortality and improve the outcome. Prophylactic factor VII infusions can be proposed in this setting to minimize the risk of subsequent bleeding episodes. The ideal dosing and schedule for treatment and/or prophylaxis will have to be defined. Despite the short half-life of rFVIIa, weekly infusions in our experience seemed safe and effective in reducing the incidence of further bleeding episodes.
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