title: Bleeding and non-bleeding phenotypes in patients with GGCX gene mutations.
abstract: Functional limitations for the vitamin K cycle, caused either by mutations in gamma-glutamyl carboxylase or vitamin K epoxide reductase genes, result in hereditary deficiency of vitamin K-dependent coagulation factors (VKCFD1 and VKCFD2, respectively). Patients suffering from VKCFD often share several other anatomical irregularities which are not related to haemostasis. Here we report on nine patients, eight of them previously unreported, who presented with VKCFD1. All were examined with special attention to vitamin K-dependent coagulation factors as well as to bone and heart development and to other anatomical signs of embryonal vitamin K deficiency. In total, we detected ten mutations in the gamma-glutamyl carboxylase gene of which seven have not been previously reported. Most interestingly, additional non-bleeding phenotypes were observed in all patients including midfacial hypoplasia, premature osteoporosis, cochlear hearing loss, heart valve defects, pulmonary stenosis, or pseudoxanthoma elasticum-like phenotype. Undercarboxylated matrix Gla protein, osteocalcin, and periostin appear to be responsible for these defects which are also observed in cases of fetal warfarin syndrome.
authors.affiliation: Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, 53105 Bonn, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Watzka
authors.affiliation: Institute of Transfusion Medicine and Immunohaematology, DRK Blood Donor Service Baden-Württemberg-Hessen, 60526 Frankfurt/Main, Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: Geisen
authors.affiliation: Pediatrics 5 (Oncology, Hematology, Immunology), Klinikum Stuttgart, Olgahospital, 70176 Stuttgart, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Scheer
authors.affiliation: Department of Paediatric Haematology and Oncology, Children's Hospital, University of Essen, 45122 Essen, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Wieland
authors.affiliation: Department of Paediatric Haematology, Oncology, Paediatric Stem Cell Transplantation Program, University Children's Hospital Würzburg, 97080 Würzburg, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Wiegering
authors.affiliation: Department of Medicine/ Rheumatology and Clinical Immunology, Clinical Hemostaseology, Charité University Medicine Berlin, 10098 Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dörner
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Center of Child and Adolescent Health, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Laws
authors.affiliation: Division of Pediatric Hematology, Faculty of Medicine, Hacettepe University, 06100 Sihhiye/Ankara, Turkey.
authors.forename: Fatma
authors.initials: F
authors.lastname: Gümrük
authors.affiliation: Division of Pediatric Hematology, Faculty of Medicine, Hacettepe University, 06100 Sihhiye/Ankara, Turkey.
authors.forename: Sahin
authors.initials: S
authors.lastname: Hanalioglu
authors.affiliation: Division of Pediatric Hematology, Faculty of Medicine, Hacettepe University, 06100 Sihhiye/Ankara, Turkey.
authors.forename: Sule
authors.initials: S
authors.lastname: Unal
authors.affiliation: Department of Pediatric Hematology, Ondokuz Mayis University, 55139 Samsun, Turkey.
authors.forename: Davut
authors.initials: D
authors.lastname: Albayrak
authors.affiliation: Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, 53105 Bonn, Germany. Electronic address: johannes.oldenburg@ukb.uni-bonn.de.
authors.forename: Johannes
authors.initials: J
authors.lastname: Oldenburg
mesh_terms: D000293:Adolescent; D000328:Adult; D025861:Blood Coagulation Disorders, Inherited / Q000150:complications* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001779:Blood Coagulation Factors / Q000378:metabolism; D015519:Bone Density; D019735:Carbon-Carbon Ligases / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D006470:Hemorrhage / Q000150:complications* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015675:Osteocalcin / Q000032:analysis / Q000097:blood / Q000378:metabolism; D010641:Phenotype; D055815:Young Adult
chemical_list: D001779:Blood Coagulation Factors; D015675:Osteocalcin; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase
keywords: Bone; GGCX; MGP; Mutation; Osteocalcin