Published online December 29, 2008
PEDIATRICS Vol. 123 No. 1 January 2009, pp. 391-398 (doi:10.1542/peds.2008-0703)

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SPECIAL ARTICLE

Clinical and Molecular Study of 320 Children With Marfan Syndrome and Related Type I Fibrillinopathies in a Series of 1009 Probands With Pathogenic FBN1 Mutations

Laurence Faivre, MD, PhD^a,b, Alice Masurel-Paulet, MD^a, Gwenaëlle Collod-Béroud, PhD^c,d, Bert L. Callewaert, MD^e, Anne H. Child, MD, FRCP^f, Chantal Stheneur, MD, PhD^g, Christine Binquet, MD, PhD^b,h, Elodie Gautier, MSc^b,h, Bertrand Chevallier, MD^g, Frédéric Huet, MD, PhD^a, Bart L. Loeys, MD, PhD^e,i,j, Eloisa Arbustini, MD^k, Karin Mayer, PhD^l, Mine Arslan-Kirchner, MD^m, Anatoli Kiotsekoglou, MD^g, Paolo Comeglio, PhD^g, Maurizia Grasso, PhD^k, Dorothy J. Halliday, BSc, MBBS, MRCP, PhDⁿ, Christophe Béroud, MD, PhD^c,d,o, Claire Bonithon-Kopp, MD, PhD^b,h, Mireille Claustres, MD, PhD^c,d,o, Peter N. Robinson, MD, MSc^p, Lesley Adès, MBBS, FRACP, MD, CG^q,r,s, Julie De Backer, MD, PhD^e, Paul Coucke, PhD^e, Uta Francke, MD, PhD^t, Anne De Paepe, MD, PhD^e, Catherine Boileau, PharmD, PhD^u and Guillaume Jondeau, MD, PhD^v

^a Genetic Center
^b Center of Clinical Investigation, Epidemiological/Clinical Trials, Centre Hospitalier Universitaire Dijon, Dijon, France
^c Institut National de la Santé et de la Recherche Médicale (INSERM) U827, Montpellier, France
^d Montpellier University I, Montpellier, France
^e Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
^f Department of Cardiological Sciences, St George's Hospital, London, England
^g Pediatric Service
^u Laboratory of Molecular Genetics, Ambroise Paré Hospital, Assistance Publique-Hôpitaux de Paris, Université Versailles-Saint Quentin en Yvelines, Boulogne, France
^h Institut National de la Santé et de la Recherche Médicale Centre d’Investigation Epidémiologique, Dijon, France
ⁱ Institute of Genetic Medicine
^j Howard Hughes Medical Institute, School of Medicine, Johns Hopkins University, Baltimore, Maryland
^k Center for Inherited Cardiovascular Diseases, Foundation Instituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy
^l Center for Human Genetics and Laboratory Medicine, Martinsried, Germany
^m Institute for Human Genetics, Hannover, Germany
ⁿ Department of Biochemistry, University of Oxford, Oxford, England
^o Centre Hospitalier Universitaire Montpellier, Laboratory of Molecular Genetics, Arnault de Villeneuve Hospital, Montpellier, France
^p Insitute for Genetic Medicine, Universitätsmedizin Charité, Berlin, Germany
^q Marfan Research Group
^r Department of Clinical Genetics, Children's Hospital at Westmead, Sydney, Australia
^s Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia
^t Department of Genetics and Pediatrics, Stanford University Medical Center, Stanford, California
^v Multidisciplinary Marfan Consultation, Bichat Hospital, AP-HP, Paris, France

From a large series of 1009 probands with pathogenic FBN1 mutations, data for 320 patients <18 years of age at the last follow-up evaluation were analyzed (32%). At the time of diagnosis, the median age was 6.5 years. At the last examination, the population was classified as follows: neonatal Marfan syndrome, 14%; severe Marfan syndrome, 19%; classic Marfan syndrome, 32%; probable Marfan syndrome, 35%. Seventy-one percent had ascending aortic dilation, 55% ectopia lentis, and 28% major skeletal system involvement. Even when aortic complications existed in childhood, the rates of aortic surgery and aortic dissection remained low (5% and 1%, respectively). Some diagnostic features (major skeletal system involvement, striae, dural ectasia, and family history) were more frequent in the 10- to <18-year age group, whereas others (ascending aortic dilation and mitral abnormalities) were more frequent in the population with neonatal Marfan syndrome. Only 56% of children could be classified as having Marfan syndrome, according to international criteria, at their last follow-up evaluation when the presence of a FBN1 mutation was not considered as a major feature, with increasing frequency in the older age groups. Eighty-five percent of child probands fulfilled international criteria after molecular studies, which indicates that the discovery of a FBN1 mutation can be a valuable diagnostic aid in uncertain cases. The distributions of mutation types and locations in this pediatric series revealed large proportions of probands carrying mutations located in exons 24 to 32 (33%) and in-frame mutations (75%). Apart from lethal neonatal Marfan syndrome, we confirm that the majority of clinical manifestations of Marfan syndrome increase with age, which emphasizes the poor applicability of the international criteria to this diagnosis in childhood and the need for follow-up monitoring in cases of clinical suspicion of Marfan syndrome.

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Key Words: Marfan syndrome • FBN1 • childhood • international criteria

Abbreviations: AAD—ascending aortic dilation • CI—confidence interval • EL—ectopia lentis • MFS—Marfan syndrome • PTC—premature termination codon

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Accepted Apr 23, 2008.

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