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

Jürgen Klammt; Louise Kobelt; Dilek Aktas; Ismet Durak; Aslan Gokbuget; Quintin Hughes; Murat Irkec; Idil Kurtulus; Elisabetta Lapi; Hadas Mechoulam; Roberto Mendoza-Londono; Joseph S. Palumbo; Hansjörg Steitzer; Khalid F. Tabbara; Zeynep Ozbek; Neri Pucci; Talia Sotomayor; Marian Sturm; Tim Drogies; Maike Ziegler; Volker Schuster

doi:10.1160/TH10-04-0216

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2011; 105(03): 454-460
DOI: 10.1160/TH10-04-0216

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

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

Jürgen Klammt

¹Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany

,

Louise Kobelt

¹Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany

,

Dilek Aktas

²Hacettepe University Medical School, Department of Genetics, Ankara, Turkey

,

Ismet Durak

³Department of Ophthalmology, Dokuz Eylul University School of Medicine, Izmir, Turkey

,

Aslan Gokbuget

⁴Istanbul University, Faculty of Dentistry, Dept. of Periodontology, Capa, Istanbul

,

Quintin Hughes

⁵School of Surgery and Pathology, University of Western Australia, Perth, Australia

,

Murat Irkec

⁶Department of Ophthalmology, Hacettepe University School of Medicine, Ankara, Turkey

,

Idil Kurtulus

⁴Istanbul University, Faculty of Dentistry, Dept. of Periodontology, Capa, Istanbul

,

Elisabetta Lapi

⁷Children’s Hospital “Anna Meyer”, Florence, Italy

,

Hadas Mechoulam

⁸Department of Ophthalmology, Hadassah Medical Center, Jerusalem, Israel

,

Roberto Mendoza-Londono

⁹Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, Canada

,

Joseph S. Palumbo

¹⁰Division of Hematology/Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, USA

,

Hansjörg Steitzer

¹¹Austrian Red Cross, Transfusion Service for Upper Austria, Linz, Austria

,

Khalid F. Tabbara

¹²The Eye Center and The Eye Foundation for Research in Ophthalmology, Riyadh, Saudi Arabia

,

Zeynep Ozbek

³Department of Ophthalmology, Dokuz Eylul University School of Medicine, Izmir, Turkey

,

Neri Pucci

⁷Children’s Hospital “Anna Meyer”, Florence, Italy

,

Talia Sotomayor

¹³Pediatric Pulmonary Medicine, WVU Children‘s Hospital; Morgantown, USA

,

Marian Sturm

¹⁴Division of Laboratory Medicine, Royal Perth Hospital, Perth, Australia

,

Tim Drogies

¹⁵Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Leipzig, Germany

,

Maike Ziegler

¹Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany

,

Volker Schuster

¹Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany

› Author Affiliations

Abstract

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.

Keywords

Inherited hypoplasminogenaemia - clinical heterogeneity - PLG gene mutations

Full Text

References

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