Vitamin K-Dependent Clotting Factors, Combined Deficiency Of, 2

A number sign (#) is used with this entry because VKCFD2 is caused by homozygous mutation in the VKORC1 gene (608547), which encodes vitamin K epoxide reductase, on chromosome 16p11.

For a general phenotypic description and a discussion of genetic heterogeneity of combined deficiency of vitamin K-dependent clotting factors, see VKCFD1 (277450).

Description

Deficiency of all vitamin K-dependent clotting factors leads to a bleeding tendency that is usually reversed by oral administration of vitamin K. Familial multiple coagulation factor deficiency is rare. Clinical symptoms of the disease include episodes of intracranial hemorrhage in the first weeks of life, sometimes leading to a fatal outcome (Fregin et al., 2002).

Clinical Features

Oldenburg et al. (2000) described 2 pedigrees showing an autosomal recessive transmission of familial multiple coagulation factor deficiency. The first pedigree was a consanguineous kindred of Lebanese origin with 8 children alive. There were 2 further children who died, one on day 3 after birth from intracranial hemorrhage, and the other during the first year of life. Four sibs had experienced severe bleeding previously. The second family, of German origin, was apparently nonconsanguineous; however, distant consanguinity could not be ruled out, since both maternal and paternal grandparents originated from neighboring villages. Internal hydrocephalus caused by intracranial bleeding had been diagnosed in 1 child. Oldenburg et al. (2000) excluded mutations in the GGCX gene in these families.

Mapping

Fregin et al. (2002) excluded mutations in the genes encoding microsomal epoxide hydrolase (EPHX1; 132810) and DT-diaphorase (NQO1; 125860) in the families with multiple coagulation factor deficiency reported by Oldenburg et al. (2000). They performed a genomewide linkage analysis in these 2 pedigrees and found a total maximum 2-point lod score of 3.4 at theta of 0.0 in the interval between markers D16S3131 on chromosome 16p12 and D16S419 on chromosome 16q21. In both families, patients were autozygous for 26 and 28 markers, respectively, in an interval of 3 cM. Thus, Fregin et al. (2002) assigned a second locus for combined multiple coagulation factor deficiency, VKCFD2, to chromosome 16p12-q21. They suggested that the warfarin resistance phenotype in mice and rats (see 122700) and familial combined deficiency of vitamin K-dependent clotting factors in humans may be allelic mutations, and, assuming a single gene for both phenotypes, mouse-human homology maps would restrict the candidate gene region to the short arm of chromosome 16.

Molecular Genetics

In 2 unrelated index patients with VKCFD2 and their affected sibs, Rost et al. (2004) identified an arg98-to-trp mutation in vitamin K epoxide reductase (608547.0001).