Vitamin K1 and K2 supplementation in VKCFD1 patients

Introduction Vitamin K dependent clotting factor deficiency type1 (VKCFD1) is a rare congenital disorder caused by mutations in the γ-glutamyl carboxylase ( GGCX ) gene. VKCFD1 patients are homozygous or compound heterozygous. GGCX is essential for the post-translational activation of all vitamin K–dependent proteins (VKDPs), including the coagulation factors II, VII, IX, and X, as well as proteins C, S and Z. In addition, GGCX is required for the activation of VKDPs unrelated to coagulation, such as matrix Gla protein (MGP) and osteocalcin (OC), whose impairment contributes to severe phenotypes, including midfacial hypoplasia and hearing loss. Treatment strategies for VKCFD1 have primarily focused on correcting the coagulation defects through the daily supplementation of phylloquinone (vitamin K₁). Here, we present a therapeutic protocol with supplementation of Vitamin K1 and MK-4, addressing both clotting- and non–clotting-related manifestations in 2 children with VKCFD1. Method Patient 1 is a 3-year-old girl compound heterozygous forc.944G>A (p.Trp315Ter) and c.1A>G, (p.Ala2_Met75del). At 31 weeks of gestation, midface hypoplasia, polyhydramnios and micromelia were noted. Soon after birth, she developed extensive subdural, subarachnoid, and epidural hemorrhages with impending herniation. She has spinal punctiform calcifications. Her atlas arch is hypoplastic without brain stem compression. She shows mild vertebral anomalies. She has hearing loss and relevant pulmonary artery stenosis. Patient 2 is a 4-year-old girl compound heterozygous for c.1616dup (p.His539GlnfsTer8); c.1790C>A (p.Ser597Tyr) and c.1822G>C (p.Glu608Gln). At 32 weeks of gestation, amniocentesis was performed because of facial dysplasia and polyhydramnios. She has a small nasal bridge, hypoplastic alae nasi, protruding forehead, shortned limbs, fingers, atlas arch with narrowing of the craniocervical junction without brainstem compression, mild vertebral anomalies, hearing loss and asymptomatic pulmonary artery stenosis. Plasma uncarboxylated OC (ucOC) was measured using the ELISA kit from Takara (#MK118). Plasma ucMGP levels were determined using the CE-marked chemiluminescent InaKtif MGP assay on the IDS-iSYS system (IDS, Boldon, UK). Results Supplementation with vitamin K₁ (K₁) (10 mg/day) improved activities of vitamin K–dependent (VKD) clotting factors. However, for the non-hematological VKDPs, markedly elevated pathological levels of ucOC and ucMGP were detected in plasma. Therefore, a stepwise increase in the concentration of the vitamin K₂ derivative menaquinone-4 (MK-4) was considered as an adjunct therapy. Following MK-4 supplementation, both patients exhibited improved carboxylation of the non-hepatic VKD proteins MGP and OC ([ Fig. 1 ]). Fig. 1 Patient data Conclusion Here, for the first time we present a treatment protocol for VKCFD1 patients that includes supplementation of Vitamin K1 and additionally MK-4 that improves both, the activity of VKD clotting factors and the γ-carboxylation of non-hematological VKDPs. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany