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

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

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.

Related collections

Most cited references 19

Record: found
Abstract: found
Article: not found

The 2017 international classification of the Ehlers-Danlos syndromes.

Fransiska Malfait, Clair Francomano, Peter K. Byers … (2017)

The Ehlers-Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs) characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Over the past two decades, the Villefranche Nosology, which delineated six subtypes, has been widely used as the standard for clinical diagnosis of EDS. For most of these subtypes, mutations had been identified in collagen-encoding genes, or in genes encoding collagen-modifying enzymes. Since its publication in 1998, a whole spectrum of novel EDS subtypes has been described, and mutations have been identified in an array of novel genes. The International EDS Consortium proposes a revised EDS classification, which recognizes 13 subtypes. For each of the subtypes, we propose a set of clinical criteria that are suggestive for the diagnosis. However, in view of the vast genetic heterogeneity and phenotypic variability of the EDS subtypes, and the clinical overlap between EDS subtypes, but also with other HCTDs, the definite diagnosis of all EDS subtypes, except for the hypermobile type, relies on molecular confirmation with identification of (a) causative genetic variant(s). We also revised the clinical criteria for hypermobile EDS in order to allow for a better distinction from other joint hypermobility disorders. To satisfy research needs, we also propose a pathogenetic scheme, that regroups EDS subtypes for which the causative proteins function within the same pathway. We hope that the revised International EDS Classification will serve as a new standard for the diagnosis of EDS and will provide a framework for future research purposes. © 2017 Wiley Periodicals, Inc.

0 comments Cited 490 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Comprehensive molecular analysis demonstrates type V collagen mutations in over 90% of patients with classic EDS and allows to refine diagnostic criteria.

Fransiska Malfait, Bert Callewaert, Anne Paepe … (2012)

Type V collagen mutations are associated with classic Ehlers-Danlos Syndrome (EDS), but it is unknown for which proportion they account and to what extent other genes are involved. We analyzed COL5A1 and COL5A2 in 126 patients with a diagnosis or suspicion of classic EDS. In 93 patients, a type V collagen defect was found, of which 73 were COL5A1 mutations, 13 were COL5A2 mutations and seven were COL5A1 null-alleles with mutation unknown. The majority of the 73 COL5A1 mutations generated a COL5A1 null-allele, whereas one-third were structural mutations, scattered throughout COL5A1. All COL5A2 mutations were structural mutations. Reduced availability of type V collagen appeared to be the major disease-causing mechanism, besides other intra- and extracellular contributing factors. All type V collagen defects were identified within a group of 102 patients fulfilling all major clinical Villefranche criteria, that is, skin hyperextensibility, dystrophic scarring and joint hypermobility. No COL5A1/COL5A2 mutation was detected in 24 patients who displayed skin and joint hyperextensibility but lacked dystrophic scarring. Overall, over 90% of patients fulfilling all major Villefranche criteria for classic EDS were shown to harbor a type V collagen defect, which indicates that this is the major--if not only--cause of classic EDS. © 2012 Wiley Periodicals, Inc.

0 comments Cited 45 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Ehlers-Danlos syndrome, classical type.

Nigel P. Burrows, Glenda J Sobey, Jessica M Bowen … (2017)

Classical EDS is a heritable disorder of connective tissue. Patients are affected with joint hypermobility, skin hyperextensibilty, and skin fragility leading to atrophic scarring and significant bruising. These clinical features suggest consideration of the diagnosis which then needs to be confirmed, preferably by genetic testing. The most recent criteria for the diagnosis of EDS were devised in Villefranche in 1997. [Beighton et al. (1998); Am J Med Genet 77:31-37]. The aims set out in the Villefranche Criteria were: to enable diagnostic uniformity for clinical and research purposes, to understand the natural history of each subtype of EDS, to inform management and genetic counselling, and to identify potential areas of research. The authors recognized that the criteria would need updating, but viewed the Villefranche nosology as a good starting point. Since 1997, there have been major advances in the molecular understanding of classical EDS. Previous question marks over genetic heterogeneity have been largely surpassed by evidence that abnormalities in type V collagen are the cause. Advances in molecular testing have made it possible to identify the causative mutation in the majority of patients. This has aided the further clarification of this diagnosis. The aim of this literature review is to summarize the current knowledge and highlight areas for future research. © 2017 Wiley Periodicals, Inc.

0 comments Cited 44 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): Genes (Basel)

Journal ID (iso-abbrev): Genes (Basel)

Journal ID (publisher-id): genes

Title: Genes

Publisher: MDPI

ISSN (Electronic): 2073-4425

Publication date (Electronic): 27 September 2019

Publication date Collection: October 2019

Volume: 10

Issue: 10

Electronic Location Identifier: 762

Affiliations

[1 ]National Complex Ehlers-Danlos Syndrome Service London, North West Health Care NHS Trust, Harrow HA1 3UJ, UK; chloeangwin@ 123456nhs.net (C.A.); angela.brady@ 123456nhs.net (A.F.B.); neeti.ghali@ 123456nhs.net (N.G.)

[2 ]Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; marina.colombi@ 123456unibs.it (M.C.); marco.ritelli@ 123456unibs.it (M.R.)

[3 ]Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK; david.ferguson@ 123456ndcls.ox.ac.uk

[4 ]Department Biological & Medical Sciences, Oxford Brookes University, Oxford OX3 0BP, UK

[5 ]Connective Tissue Disorders Service, Sheffield Diagnostic Genetics Service, Sheffield S10 2TQ, UK; rebeccapollitt@ 123456nhs.net

[6 ]Department of Dermatology, Chelsea and Westminster Hospital, London, SW10 9NH UK; fmandhpope@ 123456googlemail.com

[7 ]Center for Medical Genetics, Ghent University Hospital, B-9000 Ghent, Belgium; Sofie.Symoens@ 123456UGent.be

Author notes

[* ]Correspondence: email: fleur.dijk@ 123456nhs.net ; Tel.: +44-208-869-3166; Fax: +44-208-869-3106

Author information

Marina Colombi https://orcid.org/0000-0002-3105-5990

David J. P. Ferguson https://orcid.org/0000-0001-5045-819X

Marco Ritelli https://orcid.org/0000-0002-7025-2495

Neeti Ghali https://orcid.org/0000-0003-2847-1376

Article

Publisher ID: genes-10-00762

DOI: 10.3390/genes10100762

PMC ID: 6826538

PubMed ID: 31569816

SO-VID: 3540ffa7-f8c0-4989-91ae-1e2e37e05f39

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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

Read this article at

Abstract

Related collections

Electron Channelling Contrast Imaging (ECCI)

Most cited references 19

The 2017 international classification of the Ehlers-Danlos syndromes.

Comprehensive molecular analysis demonstrates type V collagen mutations in over 90% of patients with classic EDS and allows to refine diagnostic criteria.

Ehlers-Danlos syndrome, classical type.

Author and article information

Journal

Affiliations

Author notes

Author information

Article

History

Categories

Comments

Comment on this article

Similar content 483

Cited by 6

Most referenced authors 325