SG08 Cutaneous features in classical Ehlers–Danlos syndrome: an update

Abstract Classical Ehlers–Danlos syndrome (cEDS) is a rare, monogenic EDS type with clinical features of skin hyperextensibility and skin fragility with distinctive atrophic scarring. Heterozygous (likely) pathogenic variants in COL5A1 and COL5A2 have been reported to account for approximately 90% of cases of clinically diagnosed cEDS. The COL5A1 and COL5A2 genes encode procollagen chains alpha-1(V) and alpha-2(V), respectively, which combine and are further processed to form type V collagen. Our aim was to describe a large cohort of individuals with clinically and genetically diagnosed cEDS in order to develop a clearer understanding of the natural history and pathogenic mechanisms of disease with a focus on the skin and clinical presentation in children vs. adults. A cohort of individuals with clinically and genetically confirmed cEDS, diagnosed through a national centre, underwent retrospective analysis of medical history, examinations, clinical photographs and biochemical and molecular studies as part of the NEEDS study (Natural History Exploration of rare EDS types). NEEDS was approved by the Health Research Authority and Research Ethics Committee. Analysis of clinical data focused on cutaneous features. Statistical analysis was carried out using χ2-tests with Yeats correction to compare clinical presentations of children (≤ 18 years) vs. adults with cEDS. In total, 179 individuals with genetically confirmed cEDS from 146 families have been identified (122 adults; 104 female; mean age at last assessment 32 years, range 1–83). Epicanthal folds were noted in 17 children and eight adults (P < 0.001). Presence of skin hyperextensibility (109 adults, 53 children, P = 0.25) and skin fragility (98 adults, 44 children, P = 0.78) were not statistically significant. In the adult cohort, individuals reported a clear decrease in frequency of skin injuries in adulthood, with some individuals able to report definite ages of last event. A cohort of 21 individuals did not develop atrophic scarring (10 children, 11 adults), with (likely) pathogenic COL5A1 (n = 18) and COL5A2 (n = 3) variants, the majority of which are predicted to lead to loss of function but with no apparent genotype–phenotype association. There is a paucity of published data regarding the natural history and pathogenic mechanism of cEDS. These data appear to show a clinically heterogeneous condition, with both progressive changes from childhood to adulthood and constitutive changes that remain consistent throughout life. The reduction in skin injury frequency in adulthood may be explained by behavioural changes; however, a change in the biochemical processes and components of the extracellular matrix at different ages should be considered.