TNXB-related classical-like Ehlers-Danlos syndrome (
TNXB-clEDS) is an ultrarare type of Ehlers-Danlos syndrome due to biallelic
null variants in
TNXB, 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.
TNXB-clEDS is likely underdiagnosed due to the complex structure of the
TNXB locus, a fact that complicates diagnostic molecular testing. Here, we report two unrelated Italian women with
TNXB-clEDS due to compound heterozygosity for
null alleles in
TNXB. 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
null alleles in
TNXB, and adds three novel variants to its mutational repertoire. Unusual digital anomalies seem confirmed as possibly peculiar of
TNXB-clEDS, while vascular fragility could be more than a chance association also in this Ehlers-Danlos syndrome type.
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