Prognosis Factors in Probands With an FBN1 Mutation Diagnosed Before the Age of 1 Year

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 ϭ 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. (Pediatr Res 69: 265-270, 2011)

Study of phenotype evolution during childhood in Marfan syndrome to improve clinical recognition

“…Neonatal forms of Marfan syndrome were not included because they have a different prognosis and clinical picture. 8 In our center, patients were evaluated by a geneticist, an ophthalmologist, a cardiologist, and a pediatrician. Physical findings included skeletal features used for the diagnosis of Marfan syndrome: scoliosis, pectus deformity, pes planus, arm span/ height ratio, and positive thumb-and-wrist sign.…”

The translational science of Marfan syndrome

“…The main phenotype/genotype correlation observed is that of a severe phenotype associated with mutations located within exons 24–32 (‘neonatal region of the gene’), which are more frequent in children than in adults10 32: it includes not only neonatal forms of MFS but also more severe phenotypes than that of MFS patients carrying a mutation in another region of the FBN1 gene even in non-neonatal forms 10. Interestingly, when a premature termination codon is present in this region (probably with no synthesis of abnormal fibrillin 1 protein, leading to haplo-insufficiency), the clinical spectrum is less severe, but this type of mutation is under-represented in this region 33.…”

Neonatal Marfan Syndrome: Report of a Case with an Inherited Splicing Mutation outside the Neonatal Domain

“…Life expectancy seems to be the central issue when managing a patient with early diagnosed Marfan syndrome with cardiovascular involvement. Some prognostic factors associated with early death have been pointed out from a retrospective cohort of 60 probands carrying mutations in the FBN1 gene and with cardiovascular involvement before 1 year of age [Stheneur et al, 2011]. Factors significantly associated with shorter survival are presence of valvular insufficiencies, diaphragmatic hernia and a mutation in exons 25 or 26 [Stheneur et al, 2011].…”

“…Some prognostic factors associated with early death have been pointed out from a retrospective cohort of 60 probands carrying mutations in the FBN1 gene and with cardiovascular involvement before 1 year of age [Stheneur et al, 2011]. Factors significantly associated with shorter survival are presence of valvular insufficiencies, diaphragmatic hernia and a mutation in exons 25 or 26 [Stheneur et al, 2011]. However, several cases of neonatal Marfan syndromes with favorable outcome, up to 9 years after cardiac surgical management, have nonetheless been reported, but their initial presentations were less severe than our case [Rozendaal et al, 2011;Brito-Filho et al, 2013].…”