[en] We report a 16-year-old girl with neonatal progeroid features and congenital lipodystrophy who was considered at birth as a possible variant of Wiedemann-Rautenstrauch syndrome. The emergence of additional clinical signs (marfanoid habitus, severe myopia and dilatation of the aortic bulb) lead to consider the diagnosis of the progeroid variant of Marfan syndrome. A de novo donor splice-site mutation (c.8226+1G>A) was identified in FBN1. We show that this mutation leads to exon 64 skipping and to the production of a stable mRNA that should allow synthesis of a truncated profibrillin-1, in which the C-terminal furin cleavage site is altered. FBN1 mutations associated with a similar phenotype have only been reported in four other patients. We confirm the correlation between marfanoid phenotype with congenital lipodystrophy and neonatal progeroid features (marfanoid-progeroid-lipodystrophy syndrome) and frameshift mutations at the 3' end of FBN1. This syndrome should be considered in differential diagnosis of neonatal progeroid syndromes.
Arbustini E., Grasso M., Ansaldi S., Malattia C., Pilotto A., Porcu E., et al. Identification of sixty-two novel and twelve known FBN1 mutations in eighty-one unrelated probands with Marfan syndrome and other fibrillinopathies. Hum Mutat 2005, 26(5):494.
Attanasio M., Lapini I., Evangelisti L., Lucarini L., Giusti B., Porciani M., et al. FBN1 mutation screening of patients with Marfan syndrome and related disorders: detection of 46 novel FBN1 mutations. Clin Genet 2008, 74(1):39-46.
Callier P., Aral B., Hanna N., Lambert S., Dindy H., Ragon C., et al. Systematic molecular and cytogenetic screening of 100 patients with marfanoid syndromes and intellectual disability. Clin Genet 2013, 84(6):507-521.
Collod-Béroud G., Le Bourdelles S., Ades L., Ala-Kokko L., Booms P., Boxer M., et al. Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. Hum Mutat 2003, 22(3):199-208.
Comeglio P., Johnson P., Arno G., Brice G., Evans A., Aragon-Martin J., et al. The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. Hum Mutat Sept 2007, 28(9):928.
Davis M.R., Summers K.M. Structure and function of the mammalian fibrillin gene family: implications for human connective tissue diseases. Mol Genet Metab 2012, 107(4):635-647.
Faivre L., Collod-Beroud G., Loeys B.L., Child A., Binquet C., Gautier E., et al. 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 2007, 81(3):454-466.
Goldblatt J., Hyatt J., Edwards C., Walpole I. Further evidence for a marfanoid syndrome with neonatal progeroid features and severe generalized lipodystrophy due to frameshift mutations near the 3' end of the FBN1 gene. Am J Med Genet A 2011, 155A(4):717-720.
Graul-Neumann L.M., Kienitz T., Robinson P.N., Baasanjav S., Karow B., Gillessen-Kaesbach G., et al. Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3' terminus of the FBN1-gene. Am J Med Genet A 2010, 152A(11):2749-2755.
Horn D., Robinson P.N. Progeroid facial features and lipodystrophy associated with a novel splice site mutation in the final intron of the FBN1 gene. Am J Med Genet A 2011, 155A(4):721-724.
Kudlow B.A., Kennedy B.K., Monnat R.J. Werner and Hutchinson-Gilford progeria syndromes: mechanistic basis of human progeroid diseases. Nat Rev Mol Cell Biol 2007, 8(5):394-404.
Loeys B.L., Dietz H.C., Braverman A.C., Callewaert B.L., De Backer J., Devereux R.B., et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010, 47(7):476-485.
Milewicz D.M., Pyeritz R.E., Crawford E.S., Byers P.H. Marfan syndrome: defective synthesis, secretion, and extracellular matrix formation of fibrillin by cultured dermal fibroblasts. J Clin Invest 1992, 89(1):79-86.
Milewicz D.M., Grossfield J., Cao S.N., Kielty C., Covitz W., Jewett T. A mutation in FBN1 disrupts profibrillin processing and results in isolated skeletal features of the Marfan syndrome. J Clin Invest 1995, 95(5):2373-2378.
Nagy E., Maquat L.E. A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance. Trends Biochem Sci 1998, 23(6):198-199.
Passos J.F., Nelson G., Wang C., Richter T., Simillion C., Proctor C.J., et al. Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol Syst Biol 2010, 6:347.
Piha-Gossack A., Sossin W., Reinhardt D.P. The evolution of extracellular fibrillins and their functional domains. PloS One 2012, 7(3):e33560.
Raghunath M., Putnam E.A., Ritty T., Hamstra D., Park E.S., Tschodrich-Rotter M., et al. Carboxy-terminal conversion of profibrillin to fibrillin at a basic site by PACE/furin-like activity required for incorporation in the matrix. J Cell Sci 4 janv 1999, 112(7):1093-1100.
Takenouchi T., Hida M., Sakamoto Y., Torii C., Kosaki R., Takahashi T., et al. Severe congenital lipodystrophy and a progeroid appearance: mutation in the penultimate exon of FBN1 causing a recognizable phenotype. Am J Med Genet A 2013, 161:3057-3062.
Verloes A., Pierard G., Lombet J., de Paepe A. Congenital progeroid-marfanoid syndrome: variant of Wiedemann-Rautenstrauch or new syndrome?. Proc Greenwood Genet Cent 1998, 17(103).
Wallis D.D., Putnam E.A., Cretoiu J.S., Carmical S.G., Cao S.-N., Thomas G., et al. Profibrillin-1 maturation by human dermal fibroblasts: proteolytic processing and molecular chaperones. J Cell Biochem 2003, 90(3):641-652.
Yoo E.-H., Woo H., Ki C.-S., Lee H.J., Kim D.-K., Kang I.-S., et al. Clinical and genetic analysis of Korean patients with Marfan syndrome: possible ethnic differences in clinical manifestation. Clin Genet 2010, 77(2):177-182.
