Novel Variants in Two Italian Patients with Classical-Like Ehlers-Danlos Syndrome.

-related classical-like Ehlers-Danlos syndrome (-clEDS) is an ultrarare type of Ehlers-Danlos syndrome due to biallelic variants in , encoding tenascin-X. Less than 30 individuals have been reported to date, mostly of Dutch origin and showing a phenotype resembling classical Ehlers-Danlos syndrome without atrophic scarring. -clEDS is likely underdiagnosed due to the complex structure of the locus, a fact that complicates diagnostic molecular testing. Here, we report two unrelated Italian women with -clEDS due to compound heterozygosity for alleles in . Both presented soft and hyperextensible skin, generalized joint hypermobility and related musculoskeletal complications, and chronic constipation. In addition, individual 1 showed progressive finger contractures and shortened metatarsals, while individual 2 manifested recurrent subconjunctival hemorrhages and an event of spontaneous rupture of the brachial vein. Molecular testing found the two previously unreported c.8278C > T p.(Gln2760*) and the c.(2358 + 1_2359 - 1)(2779 + 1_2780 - 1)del variants in Individual 1, and the novel c.1150dupG p.(Glu384Glyfs*57) and the recurrent c.11435_11524+30del variants in Individual 2. mRNA analysis confirmed that the c.(2358 + 1_2359 - 1)(2779 + 1_2780 - 1)del variant causes a frameshift leading to a predicted truncated protein [p.(Thr787Glyfs*40)]. This study refines the phenotype recently delineated in association with biallelic alleles in , and adds three novel variants to its mutational repertoire. Unusual digital anomalies seem confirmed as possibly peculiar of -clEDS, while vascular fragility could be more than a chance association also in this Ehlers-Danlos syndrome type.