Congenital deficiency of vitamin K dependent coagulation factors in two families presents as a genetic defect of the vitamin K-epoxide-reductase-complex

Hereditary combined deficiency of the vitamin K dependent coagulation facto rs is a rare bleeding disorder. To date, only eleven families have been rep orted in the literature. The phenotype varies considerably with respect to bleeding tendency, response to vitamin K substitution and the presence of s keletal abnormalities, suggesting genetic heterogeneity. In only two of the reported families the cause of the disease has been elucidated as either a defect in the gamma -carboxylase enzyme (1) or in a protein of the vitamin K 2,3-epoxide reductase (VKOR) complex (2). Here we present a detailed phenotypic description of two new families with an autosomal recessive deficiency of all vitamin K dependent coagulation fa ctors. In both families offspring had experienced severe or even fatal peri natal intracerebral haemorrhage. The affected children exhibit a mild defic iency of the vitamin K dependent coagulation factors that could be complete ly corrected by oral substitution of vitamin K. Sequencing and haplotype an alysis excluded a defect within the gamma -carboxylase gene. The finding of highly increased amounts of vitamin K epoxide in all affected members of b oth families indicated a defect in a protein of the VKOR-multienzyme-comple x. Further genetic analysis of such families will provide the basis for a m ore detailed understanding of the structure-function relation of the enzyme s involved in vitamin K metabolism.