Ehlers –Danlos Syndrome Caused by Biallelic TNXB Variants in Patients with Congenital Adrenal Hyperplasia

We present here three patients with biallelic CAH‐X and identify a novel dominant‐negative chimera termed CAH‐X CH‐3. Compared with monoallelic CAH‐X, biallelic CAH‐X results in a more severe phenotype with skin features characteristic of classical EDS. We present evidence for disrupted tenascin‐X function and computational data linking the type of TNXB variant to disease severity. Biallelic TNXB variants in patients with congenital adrenal hyperplasia due to CYP21A2 deletions result in a classical Ehlers‐Danlos syndrome phenotype with skin hyperextensibility, widened atrophic scars and joint hypermobility. Reduced elastic fiber formation, shortened and disorganized fibrillin‐1 fibers and reduced collagen density are observed in dermal tissue. Modeling reveals that the TNXB variants interfere with the tenascin‐X fibrinogen‐like domain stability. The expansion of TNXB findings in patients with CAH widens our understanding of connective tissue dysplasias.
Source: Human Mutation - Category: Genetics & Stem Cells Authors: Tags: Brief Report Source Type: research