Vitamin K-Dependent Clotting Factors, Combined Deficiency Of, 1

A number sign (#) is used with this entry because combined deficiency of vitamin K-dependent clotting factors-1 (VKCFD1) is caused by homozygous or compound heterozygous mutation in the gene encoding gamma-glutamyl carboxylase (GGCX; 137167) on chromosome 2p11.

Description

Deficiency of all vitamin K-dependent clotting factors leads to a bleeding tendency that is usually reversed by oral administration of vitamin K. Acquired forms of the disorder can be caused by intestinal malabsorption 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. The pathomechanism is based on a reduced hepatic gamma-carboxylation of glutamic acid residues of all vitamin K-dependent blood coagulation factors, as well as the anticoagulant factors protein C (612283) and protein S (176880). Posttranslational gamma-carboxylation of proteins enables the calcium-dependent attachment of the proteins to the phospholipid bilayer of membranes, an essential prerequisite for blood coagulation. Vitamin K1 acts as a cofactor for the vitamin K-dependent carboxylase in liver microsomes, GGCX.

Genetic Heterogeneity of Combined Deficiency of Vitamin K-Dependent Clotting Factors

Combined deficiency of vitamin K-dependent clotting factors-2 (VKFCD2; 607473) is caused by mutation in the gene encoding vitamin K epoxide reductase (VKORC1; 608547) on chromosome 16p11.

Clinical Features

Factor II (176930), factor X (613872), factor VII (613878), and factor IX (300746) all require vitamin K for their synthesis. It is theoretically possible that a genetic disorder of the metabolism of vitamin K might lead to a congenital combined deficiency of these 4 clotting factors. (In a review of the molecular basis of vitamin K-dependent gamma-carboxylation, Furie and Furie (1990) pointed out that 2 other blood clotting and regulatory proteins, namely protein C and protein S, require vitamin K-dependent posttranslational modification to yield the biologically active form.) Although combined deficiency had been reported several times, in nearly every instance the patient had access to coumarin-like drugs. A more convincing case was reported by McMillan and Roberts (1966). An infant girl had had bleeding from the first week of life. No evidence of hepatic damage or of malabsorption was found but the patient responded to the administration of vitamin K. Clotting factors were normal in both parents. Chung et al. (1979) restudied the patient of McMillan and Roberts (1966) after a follow-up of 15 years. High doses of vitamin K returned the clotting factors (II, VII, IX, and X) toward but not to normal and prevented bleeding. Immunologic tests showed higher levels of these clotting factors than did clotting tests, thus suggesting that the factors were present in abnormal form. Two-dimensional crossed immunoelectrophoresis showed that prothrombin was present in at least 2 forms, 1 normal and 1 with the mobility of acarboxyprothrombin. The latter form was shown to lack gammacarboxyglutamate. The defect was postulated to be either in the gamma-carboxylation mechanism in the hepatocyte or in transport of vitamin K. Vitamin K promotes conversion of amino-terminal glutamic acid residues to gamma-carboxyglutamic acid residues. Defective gamma-carboxylation of glutamic acid residues occurs after ingestion of coumarin drugs. Prothrombin (factor II) with the electrophoretic mobility of the acarboxyprothrombin found in warfarin-treated patients is demonstrable in patients with the genetic disorder (Chung et al., 1979). Other cases were reported by Johnson et al. (1980) and Newcomb et al. (1956). An uncle and first cousin of the patient of Newcomb et al. (1956) died of hemorrhage. Parents have been normal.

In the 2 sibs reported by Goldsmith et al. (1982), prothrombin and factor X were most severely affected. The defect was totally corrected by administration, orally or parenterally, of vitamin K1.

Pauli et al. (1985, 1987) described a patient with congenital deficiency of multiple vitamin K-dependent coagulation factors and a mild form of chondrodysplasia punctata. The patient had features of warfarin embryopathy (Hall et al., 1980), namely, nasal hypoplasia, distal phalangeal hypoplasia and, in infancy, stippled epiphyses. These observations appear to establish that the mechanism of warfarin embryopathy is inhibition of carboxylation of osteocalcins and/or other vitamin K-dependent bone proteins. Pauli et al. (1987) concluded that the findings were consistent with decreased posttranslational carboxylation secondary to an inborn deficiency of vitamin K epoxide reductase. The disorder might be called pseudowarfarin embryopathy.

Brenner et al. (1990) described a case of this disorder in a 7-year-old Arab girl who was the tenth offspring of a first-cousin marriage. The child showed deficiency of the procoagulant factors II, VII, IX, and X and also the natural anticoagulant proteins C and S. The child presented at 6 weeks of age with spontaneous intracerebral hemorrhage. A sib had died at 5 days from uncontrollable umbilical bleeding. In another branch of the proband's kindred, a 7-month-old female with hemarthrosis was observed as the first offspring of a consanguineous marriage.

Menger et al. (1997) pointed out another mechanism by which a phenocopy of the warfarin embryopathy due to a disorder of embryonic vitamin K metabolism is produced by maternal vitamin K deficiency. They described 3 unrelated infants who presented with radiographic punctate calcifications, nasal hypoplasia, and abnormalities of the spine. Additional anomalies included cupped ears in 2 patients and 1 each with Dandy-Walker malformation with hydrocephaly, congenital cataracts, and peripheral pulmonary artery stenosis. The mothers of these 3 infants had chronic conditions associated with intestinal malabsorption requiring total parenteral nutrition for varying periods of time. The underlying causes of malabsorption were celiac disease, short bowel syndrome secondary to surgical resection, and jejuno-ileal bypass, respectively. Bleeding diathesis occurred in one mother requiring vitamin K supplementation during the second and third trimesters of pregnancy. Menger et al. (1997) speculated that the chondrodysplasia punctata and other abnormalities in these children were caused by an acquired maternal vitamin K deficiency manifested during early pregnancy; however, the involvement of other vitamin deficiencies could not be excluded. Thus, maternal malabsorption is added to warfarin embryopathy and epoxide reductase deficiency (pseudowarfarin embryopathy) as a cause of this phenotype.

Khau Van Kien et al. (1998) also observed pseudowarfarin embryopathy in a fetus of a 25-year-old woman with deficiency of vitamin K-dependent coagulation factors. She had undergone several abdominal operations for idiopathic chronic intestinal obstruction and had been treated with erythromycin which was thought to have been an aggravating factor in malabsorption of vitamin K caused by surgery, because it alters the bacterial intestinal flora that produces menaquinones (vitamin K2). The pregnancy ended spontaneously at 18 weeks and 3 days. The fetus showed pronounced frontonasal hypoplasia, a cystic hygroma, and metaphyseal spicules visible on radiographs, as well as abdominal calcification. Frontonasal ossification was very deficient, and long bones were abnormally short for gestational age. Osseous trabeculae of the metaphyses were abnormally wide on microscopy.

Howe et al. (1997) described an infant who was exposed to warfarin throughout pregnancy and had warfarin embryopathy. When the child was examined radiologically at 20 months of age, areas of calcification were visible in the septal and alar cartilages of the small external part of the nose. The authors noted that the location of this ectopic calcification was consistent with that seen in an animal model of warfarin embryopathy. The findings supported the hypothesis that warfarin interferes with the prenatal growth of the cartilaginous nasal septum by inhibiting the normal formation of a vitamin K-dependent protein that prevents calcification of cartilage. The child also had severe abnormalities of the cervical vertebrae and secondary damage to the spinal cord. Cervical vertebral anomalies are a relatively common finding in warfarin embryopathy and in the related Binder syndrome (155050).

Molecular Genetics

In an editorial on variants of vitamin K-dependent coagulation factors, Bertina et al. (1979) stated that 9 defective variants of factor II, 5 variants of factor X, and many variants (about 180 pedigrees) of factor IX had been identified. At least one variant of factor VII (Padua) is also known.

A homozygous mutation in the GGCX gene (137167.0001) was identified in 4 affected members of an Arab family with combined deficiency of vitamin K-dependent clotting factors by Brenner et al. (1998).