A large Swiss family with Bernard-Soulier syndrome

Summary

Bernard-Soulier syndrome (BSS) is a rare, autosomal recessive inherited bleeding disorder associated with thrombocytopenia, thrombocytopathy and giant platelets. BSS is caused by genetic alterations of the glycoprotein (GP) Ib/V/IX complex.

We report on a large Swiss family of whom four family members suffer from BSS. Here, a homozygous missense mutation in position 1829 (A→G) of the GPIX gene constituting a N45S substitution is the cause for the bleeding symptoms. A totalof 38 family members within two generations were analyzed regarding the N45S mutation by DNA sequencing and restriction fragment length polymorphism. The laboratory parameters which are characteristically for BSS such as platelet count, platelet volume and the expression of CD42a (GPIX), CD42b (GPIbα) and CD41 (GPIIb) were measured for all 38 individuals. The four homozygous patients showed bleeding symptoms, thrombocytopenia and giant platelets. In these patients, the expression of CD42a (GPIX), CD42b (GPIbα) was diminished. Interestingly, the intensity of the bleeding symptoms of the 4 homozygous family members seemed to vary although they carry the same mutation. The 24 heterozygous carriers did not differ significantly from their 10 wildtype family members regarding bleeding symptoms and laboratory analysis.

Zusammenfassung

Bernard-Soulier Syndrom (BSS) ist eine seltene, autosomal rezessiv vererbte Erkrankung, die mit Thrombozytopenie, -pathie und Riesenthrombozyten assoziiert ist. BSS wird durch Mutationen des Glykoprotein (GP) Ib/V/IXKomplexes verursacht. Wir berichten über eine große Schweizer Familie, in der 4 Familienmitglieder an BSS erkrankt sind. Eine homozygote Missense-Mutation an Position 1829 (A→G) des GPIX Gens, die zu einer N45S Substitution führt, wurde als Ursache für die Blutungssymptome identifiziert. Insgesamt wurden 38 Familienmitglieder in 2 Generationen bzgl. der N45S Mutation mittels Sequenzierung und Restriktionsfragmentlängen-Polymorphismus untersucht. Die für Bernard-Soulier Syndrom charakteristischen Laborparameter wie z.B Thrombozytenzahl, -volumen und Expression von CD42a (GPIX), CD42b (GPIbα) und CD41 (GPIIb) wurden bei 38 Familienmitgliedern untersucht. Die vier homozygoten Patienten zeigten vermehrt Blutungsymptome, Thrombozytopenie und Riesenthrombozyten. Die Expression von CD42a (GPIX) und CD42b(GPIbα) war bei diesen Patienten reduziert. Interessanterweise variierte die Intensität der Blutungssymptome bei den 4 Familienmitglieder, obwohl sie die gleiche Mutation tragen. Die 24 heterozygoten Träger unterschieden sich nicht signifikant von den 10 gesunden Familienmitgliedern bzgl. der Blutungssymptome oder der Thrombozytenparameter.

Keywords

Bernard-Soulier syndrome - bleeding symptoms - glycoprotein Ib/V/IX - missense mutation

Schlüsselwörter

Bernard-Soulier Syndrom - Blutungssymptome - Glykoprotein Ib/V/IX - Missense-Mutation

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