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

Abstract

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.

Multisystemic manifestations in a cohort of 75 classical Ehlers-Danlos syndrome patients: natural history and nosological perspectives

“…TNXB deficiency [51], and the recently defined clEDS type 2 caused by biallelic variants in AEBP1 [52]. The clEDS type 1 is generally distinguishable from cEDS for the absence of atrophic scarring [28,45,[53][54][55][56][57], whereas a more severe multisystemic presentation in clEDS type 2 should assist the differential diagnosis with cEDS [43,52,[58][59][60]. The dermatosparaxis (ADAMTS2) [61], cardiac-valvular (COL1A2) [62][63][64], kyphoscoliotic (PLOD1, FKBP14) [65,66], and arthrochalasia (COL1A1, COL1A2) [67,68] EDS subtypes, also sharing with cEDS several cutaneous and articular issues, are mostly distinguishable for the presence of specific hallmarks [1,9,16].…”

COL1-Related Disorders: Case Report and Review of Overlapping Syndromes

“…Due to the complex structure of the TNXB locus, EDS molecular diagnostic workflow should include NGS for the non-homologous TNXB sequence, long PCR/Sanger sequencing for the TNXA/TNXB homology region and TNXB deletion/duplication analysis (Demirdas et al, 2017;Micale et al, 2019). The last two molecular diagnostic steps have not been performed because TNXB-related classical-like EDS (TNXB-clEDS), the ultrarare type of EDS due to biallelic null variants in TNXB, has been excluded by the proband's physical examination that revealed the presence of atrophic scarring.…”

Hypermobile Ehlers‐Danlos syndromes: Complex phenotypes, challenging diagnoses, and poorly understood causes

“…229 The Tenascin X deficient patients were found to have truncating mutations or deletions in TNXB. 229,230 This has since been reclassified as classic-like EDS, a rare, autosomal recessive type of EDS. 231 Some other point mutations in TNXB have also been suggested to cause hEDS or classiclike EDS (clEDS).…”

“…Tenascin X deficiency has been indicated in a recessive form of EDS in which patients meet major and minor diagnostic criteria of classical EDS 229 . The Tenascin X deficient patients were found to have truncating mutations or deletions in TNXB 229,230 . This has since been reclassified as classic‐like EDS, a rare, autosomal recessive type of EDS 231 .…”