Background. Bernard-Soulier syndrome is a severe bleeding disease due to a defect of GPIb/IX/V, a platelet complex that binds the von Willebrand factor. Due to the rarity of the disease, there are reports only on a few cases preventing any attemptable correlations between genotype and phenotype. In order to reveal any associations, we described the largest case series ever reported, which was evaluated systematically at the same centre. Design and Methods. Thirteen patients with the disease and seven obligate carriers were enrolled. We collect clinical aspects and determined platelet features, including number and size, expression of membrane glycoproteins, and ristocetin induced platelet aggregation. Mutations were identified by directly sequencing of the GP1BA, GP1BB, and GP9 genes and their effect revealed by molecular modelling analyses. Results. Patients had all a moderate thrombocytopenia with giant platelets and a bleeding tendency whose severity varied among individuals. Consistent with an expression levels of GPIbα always lower than 10% of control values, platelet aggregation was absent or severely reduced. Homozygous mutations were identified in the GP1BA, GP1BB and GP9 gene. Six were novel alterations expected to destabilize the conformation of the respective protein. Except for obligate carriers of a GP9 mutation with a reduced GPIb/IX/V expression and defective aggregation, all the others had any obvious anomalies. Conclusions. Regardless of mutations identified, the patients' bleeding diathesis did not correlate with thrombocytopenia, which was always moderate, and platelet GPIbα expression, which was always severely impaired. Obligate carriers had features similar to controls though their GPIb/IX/V expression showed discrepancies. Aware of the limitations of our cohort, we cannot define any correlations. However, further investigations are should be encouraged to better understand the causes of this rare and underestimated disease.
