Abstract
Currently, no reliable genotype–phenotype correlation is available for pediatric Marfan patients in everyday clinical practice. We investigated correlations of FBN1 variants with the prevalence and age of onset of Marfan manifestations in childhood and differentiated three groups: missense/in-frame, splice, and nonsense/frameshift variants. In addition, we differentiated missense variants destroying or generating a cysteine (cys-missense) and alterations not affecting cysteine. We categorized 105 FBN1-positive pediatric patients. Patients with cys-missense more frequently developed aortic dilatation (p = 0.03) requiring medication (p = 0.003), tricuspid valve prolapse (p = 0.03), and earlier onset of myopia (p = 0.02) than those with other missense variants. Missense variants correlated with a higher prevalence of ectopia lentis (p = 0.002) and earlier onset of pulmonary artery dilatation (p = 0.03) than nonsense/frameshift, and dural ectasia was more common in the latter (p = 0.005). Pectus excavatum (p = 0.007) appeared more often in patients with splice compared with missense/in-frame variants, while hernia (p = 0.04) appeared earlier in the latter. Findings on genotype–phenotype correlations in Marfan-affected children can improve interdisciplinary therapy. In patients with cys-missense variants, early medical treatment of aortic dilatation seems reasonable and early regular ophthalmologic follow-up essential. Patients with nonsense/frameshift and splice variants require early involvement of orthopedic specialists to support the growing child.
Highlights
Marfan syndrome (MFS) is a genetic disorder with a wide clinical phenotype and a reported prevalence of 6.5/100,000 [1]
FBN1 variants in 131 of them; 202 of the 327 children had a clinical diagnosis of MFS according to revised Ghent Criteria (RGC)
Even though the genotype–phenotype correlation for MFS is still lacking, we can use some consistent findings on this condition in everyday clinical practice
Summary
Marfan syndrome (MFS) is a genetic disorder with a wide clinical phenotype and a reported prevalence of 6.5/100,000 [1]. It is inherited in an autosomal dominant manner. There are some rare cases with compound heterozygous and homozygous FBN1 variants. Whether patients with biallelic FBN1 variants are more disease affected than heterozygous cases remains unclear and has been regarded controversial [2]. MFS was diagnosed using the combination of manifestations presenting in different organ systems [3]. Since Dietz et al revealed the correlation of FBN1 mutation with this disease, the “modern” diagnosis of MFS based on the Ghent criteria and the later revised
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