Abstract
Congenital contractural arachnodactyly (CCA) is a rare autosomal dominant disorder of connective tissue characterized by crumpled ears, arachnodactyly, camptodactyly, large joint contracture, and kyphoscoliosis. The nature course of CCA has not been well-described. We aim to decipher the genetic and phenotypic spectrum of CCA. The cohort was enrolled in Beijing Jishuitan Hospital and Peking Union Medical College Hospital, Beijing, China, based on Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study (http://www.discostudy.org/). Exome sequencing was performed on patients’ blood DNA. A recent published CCA scoring system was validated in our cohort. Seven novel variants and three previously reported FBN2 variants were identified through exome sequencing. Two variants outside of the neonatal region of FBN2 gene were found. The phenotypes were comparable between patients in our cohort and previous literature, with arachnodactyly, camptodactyly and large joints contractures found in almost all patients. All patients eligible for analysis were successfully classified into likely CCA based on the CCA scoring system. Furthermore, we found a double disease-causing heterozygous variant of FBN2 and ANKRD11 in a patient with blended phenotypes consisting of CCA and KBG syndrome. The identification of seven novel variants broadens the mutational and phenotypic spectrum of CCA and may provide implications for genetic counseling and clinical management.
Highlights
Congenital contractural arachnodactyly (CCA), known as Beals syndrome, is an autosomal dominantly inherited connective tissue disorder with an unknown prevalence (Putnam et al, 1995)
We investigated 10 families with 27 patients diagnosed with CCA, based on their clinical and molecular profiles
We identified seven novel variants and three previously reported variants in FBN2 gene
Summary
Congenital contractural arachnodactyly (CCA), known as Beals syndrome, is an autosomal dominantly inherited connective tissue disorder with an unknown prevalence (Putnam et al, 1995). The clinical manifestations of CCA primarily include arachnodactyly, congenital joint contractures, crumpled ears, kyphoscoliosis, chest deformity, dolichostenomelia, muscle hypoplasia, micrognathia. CCA is caused by variants in fibrillin-2 (FBN2) gene. Fibrinllin-2 is an integral component of elastin fibers in extracellular matrix (ECM), which provides supporting structure for tissues and scaffolds for physiological processes (Olivieri et al, 2010). Fibrillin-2 mediates signaling molecules on cell surfaces, including transforming growth factor β(TGF-β), bone morphogenetic proteins (BMPs), integrins and controls ECM formation and remodeling. Pathogenic variants in FBN2 may weaken microfibril structure or disrupt binding capability, subsequently weaken the elastic fiber and perturbate ECMmediated signaling, which leads to the anomalies of CCA (Ratnapriya et al, 2014)
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