Marfan syndrome: Progress report Romy Franken a, b , Alexander W. den Hartog a, b , Michael Singh c , Gerard Pals d , Aeilko H. Zwinderman e , Maarten Groenink a, b, f , Barbara J.M. Mulder a, b, ⁎ a Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands b Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands c Department of Cardiology, Children's Hospital, Boston, MA, United States d Department of Clinical Genetics and DNA diagnostics, VU University Medical Center, Amsterdam, The Netherlands e Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Amsterdam, The Netherlands f Department of Radiology, Academic Medical Center, Amsterdam, The Netherlands abstract article info Keywords: Aortic root dilatation Clinical implications Ghent criteria Losartan therapy Marfan syndrome Revised Ghent criteria Marfan syndrome is a multi-system connective tissue disorder, with primary involvement of the cardiovas- cular, ocular and skeletal systems. This autosomal heritable disease is mainly attributable to a defect in the FBN1 gene. Until 2010, the clinical diagnosis of Marfan syndrome was based on the Ghent criteria of 1996. Recently, the Ghent criteria have been revised. The revised guidelines of 2010 place more emphasis on aortic root dilatation, ectopia lentis and FBN1 mutation testing in the diagnostic assessment of Marfan syndrome. Although the revised Ghent criteria of 2010 are easier to apply, they do raise some issues that need to be addressed. In addition to adjustments in the diagnosis of Marfan syndrome, there is progress in the understanding of the pathophysiology in Marfan syndrome, leading to new treatment strategies. Losartan, an angiotensin II recep- tor type 1 blocker, has been shown to inhibit transforming growth factor beta signal transduction and there- by prevent aortic root aneurysms in a mouse model of Marfan syndrome. This article will provide a critical appraisal of the revised Ghent nosology in 2010 and will highlight future perspectives regarding the treat- ment of Marfan syndrome. © 2012 Elsevier Ireland Ltd. All rights reserved. 1. Introduction 1.1. Diagnosis Marfan syndrome (MFS) is a multi-system autosomal dominant her- itable disorder of the connective tissue with a prevalence of 1 per 5000 individuals [1]. MFS is mainly caused by mutations in the fibrillin-1 gene (FBN1) encoding for extracellular matrix protein fibrillin-1. Pa- tients with MFS may present with aortic dilatation, ectopia lentis, dural ectasia and skeletal features [2–8]. Aortic dilatation is present in the vast majority of the patients with MFS and is the most important cause for morbidity and mortality in MFS (Fig. 1) [9–12]. The diagnosis MFS is based on the Ghent criteria of 1996 in which the features have been divided into major and minor clinical criteria based on their frequency in MFS, in other conditions and in the general population (Table 1) [13]. In the revised Ghent criteria more weight has been given to aortic root dilatation, FBN1 testing and ectopia lentis (Table 2) [14]. In this article we will discuss the historical evolution of MFS and provide a critical appraisal of the revised Ghent nosology of 2010. 1.2. Treatment Treatment of MFS consists mainly of prophylactic surgical replace- ment of aortic root aneurysms (or other dilated parts of the aorta). These procedures have resulted in an increased life expectancy in MFS [15]. Before the aortic aneurysm reaches dimensions which will justify surgical prophylactic intervention, beta-blocking agents are commonly used to lower aneurysm expansion rate [16]. Recently, new possibilities for medical therapies have emerged from animal experiments. MFS has recently been associated with increased Transforming Growth Factor (TGF)-β signalling [17,18]. TGF-β is a cytokine with diverse cellular functions, including cell proliferation and differentiation. It is involved in cancer pathogenesis, immunity, tissue fibrosis and many other pro- cesses [19]. In addition to the role of fibrillin-1 as a structural compo- nent of the extracellular matrix, it regulates TGF-β activation through interactions with TGF-β precursors, keeping it in its inactive form. Due to defective or deficient fibrillin-1, increased sequestration and activa- tion of TGF-β occurs, causing most of the disease features in a well- Progress in Pediatric Cardiology 34 (2012) 9–14 ⁎ Corresponding author at: Academic Medical Center, Department of Cardiology, B2- 240, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel.: +31 20 566 2193; fax: +31 20 697 1385. E-mail addresses: r.franken@amc.uva.nl (R. Franken), a.w.denhartog@amc.uva.nl (A.W. den Hartog), michael.singh@cardio.chboston.org (M. Singh), g.pals@vumc.nl (G. Pals), a.h.zwinderman@amc.uva.nl (A.H. Zwinderman), m.groenink@amc.uva.nl (M. Groenink), b.j.mulder@amc.uva.nl (B.JM. Mulder). 1058-9813/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ppedcard.2012.05.003 Contents lists available at SciVerse ScienceDirect Progress in Pediatric Cardiology journal homepage: www.elsevier.com/locate/ppedcard