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Identification of three novel plasminogen (PLG) gene mutations in a series of 23 patients with low PLG activity

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
DOI: http://dx.doi.org/10.1160/TH10-04-0216
Issue: 2011: 105/3 (Mar) pp. 387-570
Pages: 454-460

Identification of three novel plasminogen (PLG) gene mutations in a series of 23 patients with low PLG activity

J. Klammt (1), L. Kobelt (1), D. Aktas (2), I. Durak (3), A. Gokbuget (4), Q. Hughes (5), M. Irkec (6), I. Kurtulus (4), E. Lapi (7), H. Mechoulam (8), R. Mendoza-Londono (9), J. S. Palumbo (10), H. Steitzer (11), K. F. Tabbara (12), Z. Ozbek (3), N. Pucci (7), T. Sotomayor (13), M. Sturm (14), T. Drogies (15), M. Ziegler (1), V. Schuster (1)

(1) Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany; (2) Hacettepe University Medical School, Department of Genetics, Ankara, Turkey; (3) Department of Ophthalmology, Dokuz Eylul University School of Medicine, Izmir, Turkey; (4) Istanbul University, Faculty of Dentistry, Dept. of Periodontology, Capa, Istanbul; (5) School of Surgery and Pathology, University of Western Australia, Perth, Australia; (6) Department of Ophthalmology, Hacettepe University School of Medicine, Ankara, Turkey; (7) Children's Hospital “Anna Meyer”, Florence, Italy; (8) Department of Ophthalmology, Hadassah Medical Center, Jerusalem, Israel; (9) Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, Canada; (10) Division of Hematology/Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, USA; (11) Austrian Red Cross, Transfusion Service for Upper Austria, Linz, Austria; (12) The Eye Center and The Eye Foundation for Research in Ophthalmology, Riyadh, Saudi Arabia; (13) Pediatric Pulmonary Medicine, WVU Children's Hospital; (14) Division of Laboratory Medicine, Royal Perth Hospital, Perth, Australia; (15) Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Leipzig, Germany

Keywords

Inherited hypoplasminogenaemia, clinical heterogeneity, PLG gene mutations

Summary

Inherited severe hypoplasminogenaemia is a multisystemic disorder leading to deficient extravascular fibrinolysis. As a clinical consequence wound healing capacity of mucous membranes is markedly impaired leading to ligneous conjunctivitis and several other manifestations. Here we report the molecular genetic and clinical findings on 23 new cases with severe hypoplasminogenaemia. Homozygous or compound-heterozygous mutations in the plasminogen (PLG) gene were found in 16 of 23 patients (70%), three of which were novel mutations reported here for the first time (C166Y, Y264S, IVS10–7T/G). Compared to 79 previously published cases, clinical manifestations of the current group of patients showed higher percentages of ligneous periodontitis, congenital hydrocephalus, and involvement of the female genital tract. In contrast, involvement of the gastrointestinal or urogenital tract was not observed in any of the cases. Patients originated to a large extent (61%) from Turkey and the Middle East, and showed a comparably frequent occurrence of consanguinity of affected families and a greater female to male ratio than was derived from previous reports in the literature. Individual treatment of ligneous conjunctivitis included topical plasminogen or heparin eye drops, topical or systemic fresh frozen plasma, and surgical removal of ligneous pseudomembranes, mostly with modest or transient efficacy. In conclusion, the present study underscores the broad range of clinical manifestations in PLG-deficient patients with a trend to regional differences. Transmission of genetic and clinical data to the recently established Plasminogen Deficiency Registry should help to determine the prevalence of the disease and to develop more efficient treatment strategies.