Variable Clinical Phenotype in 5 Patients with the Same VKORC1 Gene Mutation

The first patient presented at the age of 14 weeks. Ten days after her first vaccination in both thighs she was admitted because of an anemia of 6 g/dl. Unfortunately the blood for coagulation analysis was coagulated. The next day, swelling of her right thigh and bleeding from the blood collection site were noted. Coagulation analysis showed a PT of 5%, aPTT of >160 seconds, Factor II <4%, Factor VII <5%, Factor IX <3.4%, Factor X <6.1% and normal Factors V, VIII, XI und von Willebrand parameters. She had complete lack of Vitamin K dependent factors despite of having received regular prophylaxis with vitamin K at U1, U2 and U3. Liver function tests were normal and abdominal ultrasound showed a normal gallbladder without sings of atresia. In the right thigh, ultrasound revealed a 8 × 3 cm large bleeding. The patient was treated with FFP, intravenous Vitamin K (5 mg) and blood transfusions. And coagulation normalized. She was discharges with the recommendation for substitution with Vitamin K. After 2 weeks PT was reduced to 11% again, because substitution did not take place. Family history revealed that the mother suffered from severe bleedings 3 days after delivery with a PT of 15%. The bleeding stopped after several doses of Vitamin K. The sister of the mother has iron deficiency from bleedings. Starting with a substitution of Vitamin K the factors normalized very quickly. Because of the response to low vitamin K doses we suspected VKCFD2, a deficiency of the VKORC1 gene. The genetic analysis confirmed a homozygous missense mutation c.[292>];[292>T] p. (Arg98Trp) of the VKORC1 gene. The mother and the younger newborn brother have the same homozygous mutation. The father has PT and Vitamin K dependent factors in the normal range. We have two other not related patients with the VKCFD2, and the same homozygous missense mutation c.[292>];[292>T] p.(Arg98Trp), but without bleeding history. One boy was diagnosed in the age of 17 years and one girl with 15 years. The PT at diagnosis was 38–44% Because of the VKCFD2 a life-long substitution with Vitamin K is necessary. The recommended dose for adult is 3–5 mg per day. Since γ-carboxylated proteins, including osteocalcin and matrix-GLA-protein, are involved in the calcium homeostasis of vessels and bone, patients with VKCFD2 have an increased risk for osteoporosis. It is unclear at this time whether higher doses of vitamin K1 or the addition of Vitamin K2 are helpful to prevent osteoporosis.

No conflict of interest has been declared by the author(s).