Thoracic Aortic Disease in Patients with Heterozygous Variants Outside the Central Region of FBN2

Background: Heterozygous pathogenic variants in the central region (exons 23–34) of FBN2 cause a hereditary connective tissue disorder named Congenital Contractural Arachnodactyly (CCA), which presents with obligatory skeletal features but very rarely with vascular manifestations. Limited data exist on the association between FBN2 variants and aortic disease. This study aimed to investigate whether the location of FBN2 variants correlates with aortic disease.

Background: We evaluated the clinical features of connective tissue diseases, including aortic manifestations, and screened for genetic variants in FBN2 among 392 patients with suspected connective tissue or thoracic aortic diseases. We then summarized our results alongside published data, comparing clinical manifestations between patients with genetic variants located outside and within the central region of FBN2. The CCA Score published by Meerschaut et al (2020) was used to evaluate the diagnosis of CCA based on the following criteria: crumpled ears, arachnodactyly, camptodactyly, contractures of large joints, pectus deformity, dolichostenomelia, kyphoscoliosis, muscle hypoplasia, highly arched palate, and micrognathia.

Background: Within the cohort of 392 patients, heterozygous FBN2 variants outside the central region were identified in 10 patients (2.6%) from five families. The mean age of the cohort was 41.9 ± 22.8 years, consisting of 6 females, with a mean CCA score of 3.8 ± 3.0. Sixty percent of these patients had thoracic aortic disease, but only 20% were diagnosed with CCA as they showed a CCA score ≥7. In case of musculoskeletal features, the patients predominantly exhibited contractures of large joints, spinal deformity, and pectus deformans. Two genetic variants were classified as of uncertain significance, one was likely pathogenic, and two were pathogenic. Combined data from 26 published papers and this study, totaling 123 patients, revealed that patients with FBN2 variants outside the central region more often present with aortic dilatation (55.0% versus 9.9%, p < 0.001) and have less pronounced musculoskeletal manifestations (i.e., arachnodactyly, camptodactyly, contractures of the large joints, and highly arched palate; CCA score 5.6 ± 5.1 versus 9.89 ± 3.63, p < 0.001) compared with those with central region variants.

Conclusion: Our results suggest that heterozygous FBN2 variants outside the central region predispose individuals to thoracic aortic disease and are less associated with the typical musculoskeletal features of CCA than pathogenic variants in the FBN2 central region.

Publication History

Article published online:
11 February 2025