title: Clinical phenotype in heterozygote and biallelic Bernard-Soulier syndrome--a case control study.
abstract: Bernard-Soulier syndrome (BSS) is a rare severe autosomal recessive bleeding disorder. To date heterozygous carriers of BSS mutations have not been shown to have bleeding symptoms. We assessed bleeding using a semi-quantitative questionnaire, platelet parameters, PFA-100 closure times, ristocetin response, GP Ib/IX expression and VWF antigen in 14 BSS patients, 30 heterozygote carriers for related mutations and 29 controls. Eight mutations in GP1BA, GP1BB or GP9 were identified including four previously unknown pathogenic mutations. Subjects with BSS reported markedly more mucocutaneous bleeding than controls. Increased bleeding was also observed in heterozygotes. Compared to controls, patients with BSS had lower optical platelet counts (P < 0.001), CD61-platelet counts (P < 0.001) and higher mean platelet volume (17.7 vs. 7.8 fL, P < 0.001) and ristocetin response and closure times were unmeasurable. Heterozygotes had higher MPV (9.7 fL, P < 0.001) and lower platelet counts (P < 0.001) than controls but response to ristocetin and closure times were normal. The VWF was elevated in both BSS and in heterozygotes (P = 0.005). We conclude that heterozygotes for BSS mutations have lower platelet counts than controls and show a bleeding phenotype albeit much milder than in BSS. Both patients with BSS and heterozygote carriers of pathogenic mutations have raised VWF.
authors.affiliation: Laboratory Hematology and Coagulation Disorder Unit, Central Laboratory, Landspitali University Hospital, Reykjavik, Iceland.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Bragadottir
authors.forename: Elisabet R
authors.initials: ER
authors.lastname: Birgisdottir
authors.forename: Brynja R
authors.initials: BR
authors.lastname: Gudmundsdottir
authors.forename: Bylgja
authors.initials: B
authors.lastname: Hilmarsdottir
authors.forename: Brynjar
authors.initials: B
authors.lastname: Vidarsson
authors.forename: Magnus K
authors.initials: MK
authors.lastname: Magnusson
authors.forename: Ole Halfdan
authors.initials: OH
authors.lastname: Larsen
authors.forename: Benny
authors.initials: B
authors.lastname: Sorensen
authors.forename: Jorgen
authors.initials: J
authors.lastname: Ingerslev
authors.forename: Pall T
authors.initials: PT
authors.lastname: Onundarson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001606:Bernard-Soulier Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D001777:Blood Coagulation; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002648:Child; D003029:Coagulants / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D010976:Platelet Count; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000235:genetics*; D012310:Ristocetin / Q000494:pharmacology; D012720:Severity of Illness Index; D011795:Surveys and Questionnaires; D014841:von Willebrand Factor / Q000235:genetics*
chemical_list: D003029:Coagulants; D019038:Platelet Glycoprotein GPIb-IX Complex; C094990:adhesion receptor; D014841:von Willebrand Factor; D012310:Ristocetin