Patients with Bernard-Soulier syndrome and different severity of the bleeding phenotype

Abstract

Bernard-Soulier syndrome is a rare (1:1million), hereditary bleeding disorder caused by defects of the platelet GPIb-IX-V complex. Patients suffer from mucocutaneous bleedings. Typical are thrombocytopenia, giant platelets and impaired agglutination after stimulation with ristocetin. In populations in which consanguineous marriages are common the frequency of the disorder is increased because Bernard-Soulier syndrome is mostly inherited autosomal recessively. Genetic analyses of the disease-related genes may help to gain more insights regarding the phenotype/genotype correlation. Here, we investigated several patients with Bernard-Soulier syndrome from different families. We analyzed two patients with severe bleeding symptoms from one family of middle east origin and confirmed the diagnosis by identifying a pathogenic variant in GP1BB. We compared phenotype/genotype correlation of this GP1BB mutation with the GP9 (p.Asn61Ser) European founder mutation present in 9 patients out of 4 families for whom we also performed molecular genetic analysis.

Introduction

Bernard-Soulier syndrome (BSS) is an inherited disease characterized by macrothrombocytopenia and impaired platelet function. The receptor defects lead to an impaired binding to von Willebrand factor [1], [2]. These patients typically present with epistaxis, petechial or gingival bleeding with onset already in infancy. Symptoms include genitourinary or gastrointestinal bleeding and menorrhagia. Trauma or surgery, especially in mucosal regions, may also lead to excessive bleeding. Nevertheless, the severity of bleeding symptoms varies substantially among patients [3].

To form the GPIb-IX-V complex, the products of four genes (GP1BA, GP1BB, GP9 and GP5) assemble within maturing megakaryocytes in the bone marrow [4]. Different mutations (deletions, insertions and nonsense mutations) in GP1BA, GP1BB or GP9 cause BSS and are distributed over these entire genes [1], [2], [5]. However, so far, mutations in GP5 causing BSS have not been reported. Most of the mutations prevent the formation or trafficking of the complex through the endoplasmic reticulum and Golgi apparatus and alter receptor expression [6], [7], [8]. The mature glycoproteins of all three genes consist of a short cytoplasmic tail, a transmembrane helix and an N-terminal extracellular domain, containing leucine-rich repeats (LRRs) [9], [10], [11]. Most cases of BSS are inherited as an autosomal recessive (bialletic) genetic trait. However, autosomal dominant inheritance for missense mutations has also been reported [12]. Mutations which affect VWF-binding domains at the N-terminal domain of the GPIb alpha chain may change receptor function but not expression [13], [14].

The International Consortium for the study of BSS collected data from 211 unrelated families with the autosomal recessive form of BSS because a comprehensive database had been lacking. They described 60 mutations in GP1BA (28%), 59 (28%) in GP1BB and 92 (44%) in GP9, respectively [15]. Cases with more than one variant per allele were also reported [16], [17]. The majority (85%) of the cases were homozygous for the mutation. More than 50% of the families derived from consanguine marriages (mostly first cousins). Family members with only one mutant allele (BSS carriers) are usually asymptomatic with normal platelet counts; however, they may sometimes show slightly enlarged platelets and decreased GPIb-IX-V complex expression, as well as a moderately reduced response to ristocetin [18]. The incidence of BSS is probably higher than 1 per 1 million because it may be often misdiagnosed if the patient does not present with the typical clinical or laboratory results [8], [19].

As we describe in this paper, bleeding symptoms of BSS patients may differ in their severity. Therefore, differential diagnoses should be considered in patients with chronic immunothrombocytopenia (ITP) and BSS should be investigated using platelet function analyses and molecular genotyping.