Dominant inheritance of hemophilia A in three generations of women
JB Graham, ES Barrow, HR Roberts, WP Webster, PM Blatt, P Buchanan, AI Cederbaum, JP Allain, DA Barrett and HR Gralnick
A bleeding diathesis is described which is phenotypically indistinguishable
from hemophilia A and which has been transmitted as a dominant trait in
three generations of women in a North Carolina kindred. The abnormal
phenotype is characterized by clinical mildness and slightly abnormal
clotting time, prothrombin consumption, and partial thromboplastin time.
Bleeding time, platelet count, clot retraction, tourniquet test, and
prothrombin time are normal. Concentration of factors I, II, V, VII, IX, X,
and XII are normal, while factor VIII activity is reduced to 2%-5% of
control values. De novo synthesis of factor VIII does not occur after
transfusion; factor VIII-related antigen is normal; patients' plasmas
aggregate platelets normally in the presence of ristocetin, and a typical
protein pattern is seen when a chymotryptic digest of cryoprecipitate of
the proband is examined by SDS-polyacrylamide gel electrophoresis. Six
possible genetic explanations are entertained. Balanced X-autosomal
translocation of hemophilia A heterozygotes has been excluded by
cytogenetic analysis of metaphase chromosomes. Classes von Willebrand's
disease (vWd) is 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 fourth locus involved in factor VIII synthesis and control.
Volume 46,
Issue 2,
pp. 175-188,
08/01/1975
Copyright © 1975 by The American Society of Hematology
