Abstract
Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder. Diagnostic criteria of neonatal MFS (nMFS), the most severe form, are still debated. The aim of our study was to search for clinical and molecular prognostic factors that could be associated with length of survival. Probands ascertained via the framework of the Universal Marfan database-FBN1, diagnosed before the age of 1 y and presenting with cardiovascular features (aortic root dilatation or valvular insufficiency) were included in this study. Clinical and molecular data were correlated to survival. Among the 60 individuals, 38 had died, 82% died before the age of 1 y, mostly because of congestive heart failure. Three probands reached adulthood. Valvular insufficiencies and diaphragmatic hernia were predictive of shorter life expectancy. Two FBN1 mutations were found outside of the exon 24–32 region (in exons 4 and 21). Mutations in exons 25–26 were overrepresented and were associated with shorter survival (p = 0.03). We report the largest genotyped series of probands with MFS diagnosed before 1 y of life. In this population, factors significantly associated with shorter survival are presence of valvular insufficiencies or diaphragmatic hernia in addition to a mutation in exons 25 or 26.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- IQR:
-
interquartile ratio
- MFS:
-
Marfan syndrome
- nMFS:
-
neonatal MFS
References
Marfan A 1896 [A case of congenital deformation of four members more pronounced in the extremities characterized by the elongation of bones with a certain degree of thinning down]. French. Bull Mem Soc Med Hop Paris 13: 220–226
De Paepe A, Devereux RB, Dietz HC, Hennekam RC, Pyeritz RE 1996 Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 62: 417–426
Judge DP, Dietz HC 2005 Marfan's syndrome. Lancet 366: 1965–1976
Booms P, Cisler J, Mathews KR, Godfrey M, Tiecke F, Kaufmann UC, Vetter U, Hagemeier C, Robinson PN 1999 Novel exon skipping mutation in the fibrillin-1 gene: two ‘hot spots' for the neonatal Marfan syndrome. Clin Genet 55: 110–117
Putnam EA, Cho M, Zinn AB, Towbin JA, Byers PH, Milewicz DM 1996 Delineation of the Marfan phenotype associated with mutations in exons 23–32 of the FBN1 gene. Am J Med Genet 62: 233–242
Tiecke F, Katzke S, Booms P, Robinson PN, Neumann L, Godfrey M, Mathews KR, Scheuner M, Hinkel GK, Brenner RE, Hovels-Gurich HH, Hagemeier C, Fuchs J, Skovby F, Rosenberg T 2001 Classic, atypically severe and neonatal Marfan syndrome: twelve mutations and genotype-phenotype correlations in FBN1 exons 24–40. Eur J Hum Genet 9: 13–21
Hennekam RC 2005 Severe infantile Marfan syndrome versus neonatal Marfan syndrome. Am J Med Genet A 139: 1
Collod-Béroud G, Le Bourdelles S, Ades L, Ala-Kokko L, Booms P, Boxer M, Child A, Comeglio P, De Paepe A, Hyland JC, Holman K, Kaitila I, Loeys B, Matyas G, Nuytinck L, Peltonen L, Rantamaki T, Robinson P, Steinmann B, Junien C, Béroud C, Boileau C 2003 Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. Hum Mutat 22: 199–208
Frédéric MY, Boileau C, Hamroun D, Claustres M, Béroud C, Collod-Béroud G 2009 UMD-predictor, a new prediction tool for nucleotide substitution pathogenicity—application to four genes: FBN1, FBN2, TGFBR1, and TGFBR2. Hum Mutat 30: 952–959
Desmet FO, Hamroun D, Lalande M, Collod-Beroud G, Claustres M, Beroud C 2009 Human splicing finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 37: e67
Faivre L, Masurel-Paulet A, Collod-Beroud G, Callewaert BL, Child AH, Stheneur C, Binquet C, Gautier E, Chevallier B, Huet F, Loeys BL, Arbustini E, Mayer K, Arslan-Kirchner M, Kiotsekoglou A, Comeglio P, Grasso M, Halliday DJ, Beroud C, Bonithon-Kopp C, Claustres M, Robinson PN, Ades L, De Backer J, Coucke P, Francke U, De Paepe A, Boileau C, Jondeau G 2009 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. Pediatrics 123: 391–398
Kaplan EM 1958 Non parametric estimation from incomplete observations. J Am Stat Assoc 53: 457–481
Tekin M, Cengiz FB, Ayberkin E, Kendirli T, Fitoz S, Tutar E, Ciftci E, Conba A 2007 Familial neonatal Marfan syndrome due to parental mosaicism of a missense mutation in the FBN1 gene. Am J Med Genet A 143A: 875–880
Faivre L, Collod-Beroud G, Callewaert B, Child A, Binquet C, Gautier E, Loeys BL, Arbustini E, Mayer K, Arslan-Kirchner M, Stheneur C, Kiotsekoglou A, Comeglio P, Marziliano N, Wolf JE, Bouchot O, Khau-Van-Kien P, Beroud C, Claustres M, Bonithon-Kopp C, Robinson PN, Ades L, De Backer J, Coucke P, Francke U, De Paepe A, Jondeau G, Boileau C 2009 Clinical and mutation-type analysis from an international series of 198 probands with a pathogenic FBN1 exons 24–32 mutation. Eur J Hum Genet 17: 491–501
Frédéric MY, Monino C, Marschall C, Hamroun D, Faivre L, Jondeau G, Klein HG, Neumann L, Gautier E, Binquet C, Maslen C, Godfrey M, Gupta P, Milewicz D, Boileau C, Claustres M, Béroud C, Collod-Béroud G 2009 The FBN2 gene: new mutations, locus-specific database (Universal Mutation Database FBN2), and genotype-phenotype correlations. Hum Mutat 30: 181–190
Frederic MY, Hamroun D, Faivre L, Boileau C, Jondeau G, Claustres M, Beroud C, Collod-Beroud G 2008 A new locus-specific database (LSDB) for mutations in the TGFBR2 gene: UMD-TGFBR2. Hum Mutat 29: 33–38
Mizuguchi T, Collod-Beroud G, Akiyama T, Abifadel M, Harada N, Morisaki T, Allard D, Varret M, Claustres M, Morisaki H, Ihara M, Kinoshita A, Yoshiura K, Junien C, Kajii T, Jondeau G, Ohta T, Kishino T, Furukawa Y, Nakamura Y, Niikawa N, Boileau C, Matsumoto N 2004 Heterozygous TGFBR2 mutations in Marfan syndrome. Nat Genet 36: 855–860
Loeys BL, Chen J, Neptune ER, Judge DP, Podowski M, Holm T, Meyers J, Leitch CC, Katsanis N, Sharifi N, Xu FL, Myers LA, Spevak PJ, Cameron DE, De Backer J, Hellemans J, Chen Y, Davis EC, Webb CL, Kress W, Coucke P, Rifkin DB, De Paepe AM, Dietz HC 2005 A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 37: 275–281
Morse RP, Rockenmacher S, Pyeritz RE, Sanders SP, Bieber FR, Lin A, MacLeod P, Hall B, Graham JM Jr 1990 Diagnosis and management of infantile marfan syndrome. Pediatrics 86: 888–895
Faivre L, Collod-Beroud G, Loeys BL, Child A, Binquet C, Gautier E, Callewaert B, Arbustini E, Mayer K, Arslan-Kirchner M, Kiotsekoglou A, Comeglio P, Marziliano N, Dietz HC, Halliday D, Beroud C, Bonithon-Kopp C, Claustres M, Muti C, Plauchu H, Robinson PN, Ades LC, Biggin A, Benetts B, Brett M, Holman KJ, De Backer J, Coucke P, Francke U, De Paepe A, Jondeau G, Boileau C 2007 Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. Am J Hum Genet 81: 454–466
Stheneur C, Collod-Beroud G, Faivre L, Buyck JF, Gouya L, Le Parc JM, Moura B, Muti C, Grandchamp B, Sultan G, Claustres M, Aegerter P, Chevallier B, Jondeau G, Boileau C 2009 Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet 17: 1121–1128
Schrijver I, Liu W, Odom R, Brenn T, Oefner P, Furthmayr H, Francke U 2002 Premature termination mutations in FBN1: distinct effects on differential allelic expression and on protein and clinical phenotypes. Am J Hum Genet 71: 223–237
Schrijver I, Liu W, Brenn T, Furthmayr H, Francke U 1999 Cysteine substitutions in epidermal growth factor-like domains of fibrillin-1: distinct effects on biochemical and clinical phenotypes. Am J Hum Genet 65: 1007–1020
Author information
Authors and Affiliations
Corresponding author
Additional information
Supported by a Grant from the French Ministry of Health (PHRC 2004), GIS maladies rares 2004, Bourse de la Société Française de Cardiologie, Fédération Française de Cardiologie 2005, Assistance Publique Hôpitaux de Paris (CIRC 2007), and ANR-05-PCOD-014.
Rights and permissions
About this article
Cite this article
Stheneur, C., Faivre, L., Collod-Béroud, G. et al. Prognosis Factors in Probands With an FBN1 Mutation Diagnosed Before the Age of 1 Year. Pediatr Res 69, 265–270 (2011). https://doi.org/10.1203/PDR.0b013e3182097219
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/PDR.0b013e3182097219
This article is cited by
-
Ocular, cardiovascular, and genetic characteristics and their associations in children with Marfan syndrome and related fibrillinopathies
Graefe's Archive for Clinical and Experimental Ophthalmology (2023)
-
Marfan syndrome
Nature Reviews Disease Primers (2021)
-
Aggressive Aortopathy in neonatal Marfan syndrome
Journal of Congenital Cardiology (2019)
-
A novel fibrillin-1 gene missense mutation associated with neonatal Marfan syndrome: a case report and review of the mutation spectrum
BMC Pediatrics (2016)
-
Variable severity of cardiovascular phenotypes in patients with an early-onset form of Marfan syndrome harboring FBN1 mutations in exons 24–32
Heart and Vessels (2016)
