'Dominant' inheritance of hemophilia A in three generations of women

Abstract

A bleeding diathesis is described which is phenotypically indistinguishable from hemophilia A but which has been transmitted as a 'dominant' trait in 3 generations of women. The studies performed included a genetic, cytogenic, and coagulation evaluation. The pertinent data include the facts that the affected females are cytogenetically normal. The abnormal phenotype is characterized by clinical mildness, and by slightly abnormal clotting time, prothrombin consumption and partial thromboplastin time. Bleeding time, platelet count, clot retraction, tourniquet test, and prothrombin time are normal. Factor VIII activity is reduced to 2-5% of control values while concentrations of the other factors are normal. De novo synthesis of Factor VIII does not occur after transfusion; Factor VIII related antigen is normal; patient's plasma aggregate platelets normally in the presence of Ristocetin. Six possible genetic explanations are entertained. 'Balanced' X autosomal translocation of hemophilia A heterozygotes has been excluded by cytogenetic analysis of metaphase chromosomes. Classical von Willebrand's disease (vWD) is most probably excluded on the basis of the laboratory data and 'extreme lyonization' of hemophilia A heterozygotes on probabilistic grounds. The genetic possibilities which cannot be excluded include a previously unrecognized variant mutation at the vWD locus, a 'dominant' mutation at the hemophilia A locus on the X chromosome and 'dominant' mutation at a hypothetical 4th locus involved in Factor VIII synthesis and control.