Genotype–Phenotype Correlations in Pediatric Patients with a Heterozygous Pathogenic FBN1 Variant

Background: Marfan's syndrome (MFS) is an inherited connective tissue disorder caused by heterozygous FBN1 pathogenic variants. Currently, genotype–phenotype correlations of pediatric patients with MFS for daily clinical use are missing.

Method: Between 2008 and 2021, we included 131 FBN1-positive pediatric patients (12.08 ± 5.89 years, male: 51.1%) and investigated correlations of FBN1 variants with prevalence and age of onset of Marfan's symptoms according to the Ghent criteria. We distinguished the following variant groups: Missense/inframe, splicing, and nonsense/frameshift variants. In addition, we distinguished missense variants affecting a cysteine residue (cysmissense) and changes not affecting a cysteine residue (noncysmissense). We also compared patients with FBN1 variants that occurred in exons 24 to 32 with the patients of the other variant groups as a whole.

Results: Patients with cysmissense variants were more likely to develop aortic dilatation requiring medication (p < 0.05), mitral valve prolapse (p < 0.05), and earlier onset of pectus carinatum (p < 0.01) than patients with noncysmissense variants. Missense/inframe variants correlated with an earlier occurrence of pulmonary artery dilatation (p < 0.05) than nonsense/frameshift. Dilatations of the sinus valsalva (SV; p < 0.05) occurred more frequently in patients with splicing compared with missense/inframe variants, aside from skeletal manifestations such as thumb or wrist signs (p < 0.05) or arm span to body length ratio greater than 1.05 of (p < 0.01). Patients with an FBN1 variant in exons 24 to 32 were more likely to have SV (p < 0.001) and pulmonary artery dilatation (p < 0.001). They had a higher prevalence of mitral valve (p < 0.05) and aortic valve regurgitation (p < 0.05) which they also developed at a younger age (p < 0.01), and they more often required aortic root replacement (p < 0.05). In case of a pectus excavatum, the age at onset was earlier than in the other FBN1 variants (p < 0.05).

Conclusion: Interdisciplinary therapy may improve with knowledge of genotype–phenotype correlations in MFS-affected children. In patients with cysmissense variants, early drug treatment of aortic dilatation and closer echocardiographic monitoring seem to be beneficial. In patients with nonsense/frameshift and splicing variants, early involvement of orthopedists is useful to observe skeletal phenotypes and to treat if necessary. Especially patients with a suspicion of neonatal MFS should be monitored early and closely by a cardiologist.

Publication History

Article published online:
12 February 2022