Heterozygous pathogenic variants in the central region (exon 23-34) of FBN2 cause a hereditary connective tissue disorder named congenital contractural arachnodactyly, which presents with obligatory skeletal features but rarely with vascular manifestations. Scarce data exist on the association between FBN2 variants and aortic disease. This study aimed to investigate whether the location of FBN2 variants correlates with distinct clinical features, including aortic disease. In this case-controlled cohort study, we ascertained clinical features, sequenced 62 (candidate) disease genes, and classified variants according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines in 392 patients with suspected connective tissue or thoracic aortic diseases. We summarized our results and published data and compared clinical manifestations between patients with variants outside and within the central region of FBN2. Heterozygous FBN2 variants outside the central region were identified in 10 patients from 5 families. Two variants were of uncertain significance, 1 was likely pathogenic, and 2 were pathogenic. A total of 60% of these patients had thoracic aortic disease, but only 20% were diagnosed with congenital contractural arachnodactyly according to an established clinical scoring system. Combined data from the literature and this study revealed that patients with FBN2 variants outside the central region presented with aortic dilatation (55.0% versus 9.9%; P<0.001) more often and had less pronounced musculoskeletal manifestations (congenital contractural arachnodactyly score, 5.6±5.1 versus 9.8±3.6; P=0.011) compared with those with central region variants. Our results suggest that heterozygous FBN2 variants outside the central region predispose individuals to thoracic aortic disease and are less associated with the typical clinical presentation of congenital contractural arachnodactyly than pathogenic variants in the FBN2 central region.

Beals-Hecht (BH) syndrome is a rare autosomal dominant disorder caused by a mutation of the FBN-2 gene that codifies for fibrillin-2 (FBN-2). Its nosology includes congenital contractural arachnodactyly. The aim of this study was to evaluate the possible breakdown of redox homeostasis in the thoracic aortic aneurysm (TAA) from patients with BH. We determined OS markers such as malondialdehyde (MDA), total antioxidant capacity (TAC), carbonyl groups, glutathione (GSH), thiols the nitrate/nitrite ratio (NO3-/NO2-) and super oxide radical (O2-) by spectrophotometry in homogenized TAA from BH and the ascending fragment of the thoracic aorta (AFTA) from control subjects (CS). We also measured the activities of some of antioxidant enzymes such as GST, GPx, GR and TrxR. The super oxide dismutase (SOD) isoforms, catalase and peroxidase activities were evaluated by native polyacrylamide gels. The activities of the antioxidant enzymes GPx, TrxR, SOD isoforms, catalase and peroxidases were decreased in the TAA from patients with BH (p ≤ 0.04) and the OS markers NO3-/NO2-, TAC and thiols were decreased(p ≤ 0.04). In addition, O2- was increased in patients with BH (p = 0.02). The results suggest a possible loss of redox homeostasis; this loss could be due to the decrease of some of the enzymatic antioxidant system´s enzymes and some antioxidants of the non-enzymatic system. In addition, the decrease in TrxR activity and the concentration of thiol groups could contribute to the alteration and instability of the FBN-2 protein.

Fibrillinopathies comprise allelic disorders with opposing phenotypes. Pathogenic variants in fibrillin-2, encoded by FBN2, have mainly been associated with congenital contractural arachnodactyly but in a few cases also with brachydactyly. We recruited two families with index patients presenting with short stature (heights ≤3 SD scores), brachydactyly, joint contractures and facial dysmorphism as major features. In Family 2, the proband and father also had carpal tunnel syndrome. Radiographs showed signs of mild skeletal dysplasia with short long bones, brachydactyly and mild metaphyseal and vertebral irregularity. Whole genome sequencing revealed novel variants in the FBN2 gene that segregated with the phenotype: in Family 1, a novel heterozygous missense variant c.4862G>A, p.(Cys1621Tyr) and in Family 2, a novel heterozygous deletion of exons 9-11. The missense variant affects a highly conserved residue and is predicted to be deleterious by most in silico tools. The FBN2 deletion affects a well-conserved region and leads to loss of the transforming growth factor β binding-like 2 domain and part of the calcium-binding epidermal growth factor-like domain. Our findings suggest that short stature and mild skeletal dysplasia might be part of the spectrum of FBN2-related phenotypes. The study supports the role of FBN2 variants in growth failure and expands the molecular spectrum of FBN2 variants.

Beals syndrome, also known as Beals-Hetch syndrome or congenital contractural arachnodactyly, is an autosomal dominantly inherited, rare connective tissue disorder characterized by flexion contractures, arachnodactyly, camptodactyly, severe kyphoscoliosis, and, less frequently, cardiovascular features. We describe the successful management of labor analgesia in a pregnant woman with Beals syndrome. During labor, a combined spinal/epidural technique was performed uneventfully, and intermittent top-ups were administered as needed at lower-than-usual volumes. Eutocic delivery occurred without complications, and both mother and baby were discharged three days later. Given the sparse literature about obstetric patients with Beals syndrome, we summarize the main anesthetic challenges and suggested approaches.

Congenital contractural arachnodactyly (CCA) is a rare autosomal dominant connective tissue disorder caused by mutations in the fibrillin-2 (FBN2) gene, characterized by crumpled ears, arachnodactyly, camptodactyly, dolichostenomelia, large-joint contractures and thoracolumbar scoliosis. Variations in the FBN2 gene primarily include missense mutations and splice sites mutations. It is crucial to clarify whether missense mutations in the FBN2 gene affect mRNA splicing. We identified a novel pathogenic missense variant (c.3472G > C, p.Asp1158His) in exon 26 of the FBN2 gene using whole-exome sequencing (WES) and Sanger sequencing. In vitro, both the wild-type and mutant minigenes were successfully inserted into the pcMINI and pcMINI-C vectors to verify the impact of this variant on FBN2 mRNA splicing. We utilized CLUSTALW to perform multiple sequence alignment to compare the evolutionary conservation of this variant and employed AlphaFold2 to predict the protein structure of the mutant. The likely pathogenic missense mutation (c.3472G > C) results in the amino acid at position 1158 of the FBN2 changing from aspartic acid (Asp) to histidine (His). Furthermore, DNA multiple sequence alignment indicates that this site is highly evolutionarily conserved. Functional assays and structure prediction indicated that the missense variant located at the edge of exon 26 of FBN2 does not affect RNA splicing, instead, it changes the structure and function of the protein by altering the amino acid sequence. This study enriches the pathogenic spectrum of CCA. Our research provides new insights for the diagnosis of CCA and may have an impact on genetic counseling.