Novel mutation in the γ-glutamyl carboxylase gene resulting in congenital combined deficiency of all vitamin K–dependent blood coagulation factors

Abstract

A mutation in the γ-glutamyl carboxylase gene leading to a combined congenital deficiency of all vitamin K-dependent coagulation factors was identified in a Lebanese boy. He is the first offspring of consanguineous parents and was homozygous for a unique point mutation in exon 11, resulting in the conversion of a tryptophan codon (TGG) to a serine codon (TCG) at amino acid residue 501. Oral vitamin K1 administration resulted in resolution of the clinical symptoms. Screening of several family members on this mutation with an RFLP technique revealed 10 asymptomatic members who were heterozygous for the mutation, confirming the autosomal recessive pattern of inheritance of this disease. In 50 nonrelated normal subjects, the mutation was not found. This is the second time a missense mutation in the γ-glutamyl carboxylase gene is described that has serious impact on normal hemostasis.

The rare coagulation disorders – review with guidelines for management from the United Kingdom Haemophilia Centre Doctors' Organisation

“…There is wide variation in phenotype in the reported kindreds with VKCFD. Severely affected individuals may present at birth with spontaneous intracranial haemorrhage or umbilical stump bleeding [125][126][127] or in infancy and childhood with spontaneous haemarthroses and retroperitoneal, soft tissue or gastrointestinal bleeds. Otherwise, presentation may be later in life with easy bruising and mucocutaneous or postsurgical bleeding [128][129][130].…”

Guideline for the diagnosis and management of the rare coagulation disorders

“…VKDCFD may present at birth with intracranial or umbilical bleeding (Oldenburg et al, 2000;Spronk et al, 2000) or in infancy or childhood with joint, mucocutaneous, soft tissue or gastrointestinal bleeding (Brenner et al, 1998). Less commonly, VKDCFD presents with bleeding in early adulthood (Lunghi et al, 2011) or is an incidental laboratory finding (Rost et al, 2004b).…”

“…VKCDFD typically manifests as prolongation of the PT and APTT and approximately parallel reductions in the activities of FII, FVII, FIX and FX. Factor activities may be <0Á1 iu/ml at presentation (Brenner et al, 1998;Spronk et al, 2000) but more typically are 0Á2-0Á6 iu/ml (Oldenburg et al, 2000;Rost et al, 2004b;Lunghi et al, 2011).…”

“…Most reported cases with VKDCFD show partial or complete long term restoration of coagulation factor activities with oral (Oldenburg et al, 2000;Spronk et al, 2000;Rost et al, 2004b) or parenteral (Brenner et al, 1998;McMahon & James, 2001;Marchetti et al, 2008) vitamin K 1 (phytomenadione). In a minority of cases, vitamin K 1 was ineffective (Lunghi et al, 2011).…”

Familial multiple coagulation factor deficiencies: new biologic insight from rare genetic bleeding disorders

“…High doses of vitamin K partially restored the clotting factors (FII, FVII, FIX, and FX) in this patient toward normal and prevented bleeding [76]. Only a few additional cases of VKCFD2 have been reported since [77][78][79][80][81][82][83][84][85][86][87][88]. Clinical symptoms of VKCFD vary in accordance with procoagulant protein levels [87].…”