Combined deficiency of vitamin K–dependent clotting factors II, VII, IX, and X (and proteins C, S, and Z) is usually an acquired clinical problem, often resulting from liver disease, malabsorption, or warfarin overdose. A rare inherited form of defective γ-carboxylation resulting in early onset of bleeding was first described by McMillan and Roberts in 1966 and subsequently has been termed vitamin K–dependent clotting factor deficiency (VKCFD). Biochemical and molecular studies identify 2 variants of this autosomal recessive disorder: VKCFD1, which is associated with point mutations in the γ-glutamylcarboxylase gene (GGCX), and VKCFD2, which results from point mutations in the vitamin K epoxide reductase gene (VKOR). Bleeding ranges in severity from mild to severe. Therapy includes high oral doses of vitamin K for prophylaxis, usually resulting in partial correction of factor deficiency, and episodic use of plasma infusions. Recent molecular studies have the potential to further our understanding of vitamin K metabolism, γ-carboxylation, and the functional role this posttranslational modification has for other proteins. The results may also provide potential targets for molecular therapeutics and pharmacogenetics.

All current publications in PubMed and other scientific databases were searched. Approximately 300 articles pertaining to the subject were reviewed in detail. Original studies published in the past 3 years were chosen for additional analysis. Polymorphisms in GGCX and VKOR were reviewed in standard genome databases and registries. Selected investigators working in this area were also contacted. Several recent reviews and perspectives are also recommended [20–24].

VKCFD1 and VKCFD2 are extremely rare autosomal recessive disorders with fewer than 30 cases reported. Carrier incidence, racial distribution, and ethnic predilections are not known. Cases and pedigrees have been reported in Africa, Asia, Europe, and North America. As mentioned previously (19), SNP frequencies in the GGCX and VKOR genes in several large population-based studies have been reported, but obviously these rarely result in the clinical syndrome VKCFD.

These rare autosomal disorders arise from point mutations in either the GGCX or VKOR genes. Several compound heterozygous cases and pedigrees have been described [5, 7, 15]. Carriers are asymptomatic. As Ginsberg notes [23], the rarity of VKCFD and the fact that only missense mutations have been identified suggest embryonic lethality with complete deficiency of either enzyme in humans; this is supported by knockout mice results [23].

Prenatal diagnosis is possible if both alleles are sequenced and familial SNPs are defined. Prognosis of VKCFD can be guarded based on the propensity for perinatal intracranial hemorrhage, which can result in permanent neurological damage and developmental disabilities [8]. Other cases, however, have been milder and have favorable outcomes over time. Early intervention with appropriate treatment and prevention modalities would likely improve the prognosis, as with any coagulation disorder. As noted previously, factor levels partially improve with vitamin K therapy, and regular vitamin K dosing may maintain hemostasis, though not preventing all complications.

Future areas of potential clinical relevance resulting from this work include prediction of warfarin dose using SNPs in VKOR and other genes, design of new small molecule inhibitors of VKOR and GGCX, and further definition of defective carboxylation of nonhematologic proteins.