Variable severity of cardiovascular phenotypes in patients with an early-onset form of Marfan syndrome harboring FBN1 mutations in exons 24–32

Abstract

A subgroup of patients with Marfan syndrome (MFS) who have mutations in exons 24-32 of the FBN1 gene manifests severe atrioventricular valve insufficiency and skeletal problems as early as the neonatal period. These patients usually die in the first 2 years of life, thus a region between exons 24 and 32 of FBN1 is recognized as a critical region for this neonatal form of MFS (nMFS). Here, we report five consecutive patients who manifested a cardiovascular phenotype until infancy with mutations in the critical region for nMFS. Although three of these patients showed severe mitral regurgitation and died before reaching 1 year of age, the remaining two patients survived for over 5 years under medical and/or surgical interventions. Two splicing mutations and one missense mutation were identified in the three deceased patients, whereas two missense mutations were found in the two survivors. Currently, the clinical severity of patients with early-onset MFS harboring mutations in the critical region for nMFS seem to be more variable than ever thought, and intensive treatments are recommended even in this subgroup of patients with MFS.

Differences in manifestations of Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome

“…The previously socalled neonatal form of MFS (nMFS) is typically caused by mutations in the middle part of the FBN1 gene, exons 24-32, comprising transforming growth factor beta binding protein-like domain 3 until calcium-binding epidermal growth factor-like domain 18. Although this neonatal form of MFS was considered as a separate entity in the past, it is now considered as the most severe end of the MFS spectrum, associated childhood mortality (6,7).…”

“…Neonatal MFS is typically characterized by early onset severe tricuspid and mitral valve regurgitation, which can lead to heart failure, a frequent cause of death in patients with nMFS (7). The valve insufficiencies do occur without significant aortic dilatation.…”

Early-Onset Marfan Syndrome: A Case Series

“…2 The primary cause of death in classical MFS is aortic root disease in the form of aortic dissection or rupture of an ascending aortic aneurysm, 16 but the predominant mode of death in the early-onset form is cardiac failure secondary to a severely regurgitant mitral valve. [17][18][19] With adequate monitoring and timely interventions along with advances in the surgical management techniques, more patients with earlyonset MFS live longer. The prognosis of early-onset MFS is historically poor.…”

A case of G1013R FBN1 mutation: A potential genotype–phenotype correlation in severe Marfan syndrome

“…There has been a heated debate about diagnostic criteria for “neonatal Marfan syndrome”, with some groups rejecting the use of this subtype outright (Meester et al, ). However, regardless of this debate, mutations in the region of exon 24–32 have been consistently found to be associated with a severe cardiovascular phenotype of MFS (Maeda et al, ). A clinical and molecular study of 320 MFS patients found a significantly higher proportion of both the neonatal, defined as diagnosis of type I fibrillinopathy with severe valvular involvement before 4 weeks of age, and severe MFS patients, defined by the diagnosis of MFS according to international criteria before 10 years of age, to have mutations between exons 24–32 as compared to adults with classical MFS, defined as meeting international criteria (Faivre et al, ).…”