Electron microscopy in the diagnosis of Ehlers–Danlos syndromes: correlation with clinical and genetic investigations

Abstract

Summary Background The Ehlers–Danlos syndromes (EDS) consist of 13 subtypes with overlapping features including joint hypermobility, skin and vascular fragility and generalized connective tissue friability. As DNA analysis has become the gold standard for investigation of EDS, transmission electron microscopy (TEM) in clinical practice is decreasing. However, owing to the use of next‐generation sequencing, the frequency of variants of uncertain significance (VUS) identified using DNA analysis is increasing. We hypothesized that TEM can provide evidence for or against pathogenicity of VUS. Objectives The aim of this study was to evaluate the role of TEM in the diagnosis of EDS subtypes. Methods Data were collected from patients who underwent a skin biopsy between October 2012 and March 2017 at the London EDS National Diagnostic Service. TEM biopsies were categorized as ‘normal’ or ‘abnormal’ according to the description and conclusion in the TEM reports. Definitive diagnoses were reached via a combination of clinical features, structural and functional studies and DNA investigations. Results The analysis included 177 patients, comprising 30 abnormal and 147 normal TEM reports. A definitive diagnosis of monogenic EDS subtypes was made in 24 patients. Overall, 17 of these 24 patients (71%) had an abnormal biopsy report and seven (29%) had a normal biopsy report. No TEM findings were specifically associated with any EDS subtype, although collagen flowers were present in most patients with a genetically confirmed diagnosis of classical EDS. Conclusions TEM analysis of collagen structure may have the potential to provide evidence for or against the pathogenicity of a VUS, but more work is needed to establish a clear role for TEM in this process. What's already known about this topic? Collagen fibril abnormalities can be seen in several Ehlers–Danlos syndrome (EDS) subtypes. What does this study add? This study provides clinical data, transmission electron microscopy (TEM) data and molecular data of one of the largest groups of patients suspected to have a monogenetic EDS subtype. No TEM findings were specifically associated with an EDS subtype. There was a higher percentage (71%) of abnormal biopsy findings in patients with a definitive diagnosis of a monogenetic EDS subtype and where a class 4/5 genetic variant was present.

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

“…246,247,249 Angwin et al, recently published transmission electron microscopy findings that revealed no specific collagen abnormalities associated with any subtype of EDS, except collagen flowers in most patients with cEDS. 250 Eighty-six of ninety patients diagnosed with hEDS had what were considered normal biopsy appearance by transmission electron microscopy (TEM), despite some variations in collagen and elastin, possibly due to age variation of the patients evaluated. 250 To date, collagen structure analysis is mostly outdated and provides limited information on the pathophysiology of hEDS.…”

“…250 Eighty-six of ninety patients diagnosed with hEDS had what were considered normal biopsy appearance by transmission electron microscopy (TEM), despite some variations in collagen and elastin, possibly due to age variation of the patients evaluated. 250 To date, collagen structure analysis is mostly outdated and provides limited information on the pathophysiology of hEDS. Additionally, most of the studies investigating extracellular matrix structure have focused only on collagen and elastin structure, specifically by TEM.…”

Biomarkers for Ehlers-Danlos Syndromes: There Is a Role?

“…An electron microscope (TEM) study recently conducted by Angwin and colleagues showed no specific correlation between collagen abnormalities and the different EDS subtypes, other than the presence of collagen flowers in many cEDS patients. In particular, many of the patients suffering from hEDS presented normal biopsies on TEM despite the presence of anomalies justifiable as age-related variants [ 69 ].…”

Pachyonychia congenita, a paradigm for rare skin disorders

“…In this issue of the BJD, collaboration is used to report on rare cohorts, providing new insights in larger groups of patients. From national collaboration or centralization, we learn about the impact of epidermolysis bullosa on the quality of life and mental health of 81 children 7 For some rare disorders, cohorts will be small, even with national collaboration. Global registries have been proposed as a solution 8 and can create an infrastructure that facilitates education, understanding, research and ultimately outcome improvement.…”