Absence of Collagen Flowers on Electron Microscopy and Identification of (Likely) Pathogenic COL5A1 Variants in Two Patients

Abstract

Two probands are reported with pathogenic and likely pathogenic COL5A1 variants (frameshift and splice site) in whom no collagen flowers have been identified with transmission electron microscopy (TEM). One proband fulfils the clinical criteria for classical Ehlers-Danlos syndrome (cEDS) while the other does not and presents with a vascular complication. This case report highlights the significant intrafamilial variability within the cEDS phenotype and demonstrates that patients with pathogenic COL5A1 variants can have an absence of collagen flowers on TEM skin biopsy analysis. This has not been previously reported in the literature and is important when evaluating the significance of a TEM result in patients with clinically suspected cEDS and underscores the relevance of molecular analysis.

The Role of Cell Adhesion and Cytoskeleton Dynamics in the Pathogenesis of the Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders

“…Further studies have shown that patients can present with no significant collagen abnormalities, despite a clinical presentation and/or confirmation of genetic disorder. In 2019, one study reported two individuals with a likely pathogenic variant of the COL5A1 gene that did not present with the typical collagen flowers expected ( Angwin et al, 2019 ), contradicting a consensus previously reached by the EDS committee in 2017 ( Bowen et al, 2017 ). Another study in vEDS patients found that the size of collagen fibers and bundle characteristics did not discriminate between vEDS and control participants, nor did all vEDS participants present with abnormal fibril diameters ( Ong et al, 2012 ).…”

Mechanobiology in the Comorbidities of Ehlers Danlos Syndrome

“…Since defected genes are related to collagen formation, it has been assumed that microarchitectural changes due to those genetic defects can give rise to clinical abnormality exhibited in the EDS patients ( Kobayasi, 2004 ). However, recent evidence shows that the structure alone is not a sole factor that determines clinical severity ( Proske et al, 2006 ; Hermanns-Lê et al, 2012 ; Angwin et al, 2019 ). As an alternative, mechanobiological factors appear to be a key player that induces the EDS symptoms.…”

“… Collagen in EDS is irregular in microarchitecture, softer in mechanical behavior, and might induce mast cell degranulation. (A) Transmission electron microscopy images of normal skin biopsy (A1) , adapted from ( Malfait et al, 2013 ), cEDS skin biopsy (A2) , adapted from ( Angwin et al, 219 ), and hEDS skin biopsy (A3), adapted from ( Hermanns-Lê et al, 2012 ). Note that collagen fibrils are enlarged (black arrowheads) and have irregular shapes in (A2) , and that occasional irregular fibrils depicted by black arrowheads in (A3) .…”

3d phase‐contrast nanotomography of unstained human skin biopsies may identify morphological differences in the dermis and epidermis between subjects

“…Recently, gastrointestinal dysmotility and peripheral neuropathy have been described as well 15 . Abnormal wider collagen fibrils with irregular patterns have previously been described in the reticular dermis by transmission electron microscopy in some patients with Ehlers‐Danlos syndrome 16‐18 . From a 3d analysis, the organization of collagen fibrils along with the neuropathy might be further visualized.…”