Bernard-Soulier syndrome (BSS; 2019 ICD-10-GM: D69.1) is a rare inherited bleeding disorder characterised by abnormal platelet morphology, count and function. First characterised by Jean Bernard and Jean Pierre Soulier in 1948, BSS has a prevalence of approximately 1:1,000,000 population irrespective of sex, although BSS may be underreported and often misdiagnosed. Thus, the actual prevalence is likely higher. There have been reports of BSS in various populations worldwide.1,2
The glycoprotein (GP) Ib-IX-V complex is a large protein complex located on the surface of platelets and assembled from four subunits: GPIX, GPIbα, GPIbβ and GPV. Among other interactions, the GPIb-IX-V complex mediates platelet binding to von Willebrand factor (vWF) on the subendothelium during clotting. Mutations in the GP9 (chromosome 3), GPIBA (chromosome 17), and GPIBB (chromosome 22) genes (corresponding to the GPIX, GPIbα and GPIbβ proteins, respectively) affect assembly of the GPIb-IX-V complex on the cell surface through various mechanisms, causing dysfunction in platelet binding to vWF.
BSS is often inherited in an autosomal recessive manner, with causal mutations largely missense, nonsense or frame-shifts that result in decreased expression or truncation of one of the GPI-IX-V complex subunits. Specific mutations, such as a single nucleotide polymorphism in the GPIBA gene (the Bolzano mutation) behave in an autosomal dominant manner. Patients with autosomal dominant BSS typically present with a mild bleeding phenotype, although low platelet counts with corresponding severe bleeding can occur.1-4
The GPIb-IX-V complex is hypothesised to have multiple functions in the platelet, including regulating platelet adhesion to the subendothelium and interacting with the cytoskeleton. In short, the GPIb-IX-V complex interacts with filamin-A, a protein that links the cytoskeleton to the plasma membrane. Disruption of this interaction causes large platelets that easily disintegrate and are cleared from the plasma. Thus defects in the GPIb-IX-V complex not only cause reduced platelet/subendothelium adhesion, but also low platelet counts and the presence of large platelets.2,4,5
Patients with BSS present with common bleeding symptoms such as epistaxis, ecchymosis and gingival bleeding in early life. However, the severity of bleeds can range for mild to life-threating and the age at presentation can vary. Less commonly, patients present with menometrorrhagia, haematuria, gastrointestinal bleeding or severe haemorrhage during an injury or surgery. Individuals heterozygous for GPIb-IX-V mutations can present with mild symptoms. Furthermore, symptoms of BSS may decrease over time, becoming less severe as a patient enters adulthood.1,2,4
Patients with autosomal dominant forms of BSS, such as the Bolzano mutation, often present with mild to moderate bleeding symptoms and only a mild reduction in GPIb-IX-V levels. Patients with the Bolzano mutation or their ancestors often originate from Italy, although emigration has led to the identification of this mutation in other populations.3,6
Initial laboratory analyses of patients with BSS typically reveals low platelet counts (<30–200x103 /µL) and a proportion of large platelets reaching approximately 3.5 µm. Patents heterozygous for autosomal recessive BSS can present with a limited number of large platelets during routine blood tests.2,4,6
1. Lanza F. Bernard-Soulier syndrome (hemorrhagiparous thrombocytic dystrophy). Orphanet J Rare Dis 2006;1:46.
2. Pham A, Wang J. Bernard-Soulier syndrome: an inherited platelet disorder. Arch Pathol Lab Med 2007;131:1834-6.
3. Balduini CL, Savoia A, Seri M. Inherited thrombocytopenias frequently diagnosed in adults. J Thromb Haemost 2013;11:1006-19.
4. Andrews RK, Berndt MC. Bernard-Soulier syndrome: an update. Semin Thromb Hemost 2013;39:656-62.
5. Kanaji T, Ware J, Okamura T, Newman PJ. GPIbalpha regulates platelet size by controlling the subcellular localization of filamin. Blood 2012;119:2906-13.
6. Diz-Kucukkaya R. Inherited platelet disorders including Glanzmann thrombasthenia and Bernard-Soulier syndrome. Hematology Am Soc Hematol Educ Program 2013;2013:268-75.