Non-oral manifestations in adults with a clinical and molecularly confirmed diagnosis of periodontal Ehlers-Danlos syndrome

C Angwin; J Zschocke; T Kammin; E Björck; J Bowen; A F Brady; H Burns; C Cummings; R Gardner; N Ghali; R Gröbner; J Harris; M Higgins; D Johnson; U Lepperdinger; D Milnes; F M Pope; R Sehra; I Kapferer-Seebacher; G Sobey; F S Van Dijk

doi:10.3389/fgene.2023.1136339

Non-oral manifestations in adults with a clinical and molecularly confirmed diagnosis of periodontal Ehlers-Danlos syndrome

Front Genet. 2023 May 31:14:1136339. doi: 10.3389/fgene.2023.1136339. eCollection 2023.

Authors

C Angwin^{1

2}, J Zschocke³, T Kammin⁴, E Björck⁵, J Bowen⁴, A F Brady^{1

2}, H Burns^{6

7}, C Cummings¹, R Gardner⁸, N Ghali^{1

2}, R Gröbner³, J Harris¹, M Higgins⁸, D Johnson⁴, U Lepperdinger⁹, D Milnes⁸, F M Pope^{1

10}, R Sehra¹, I Kapferer-Seebacher⁹, G Sobey⁴, F S Van Dijk^{1

2}

Affiliations

¹ National EDS Service, London North West University Healthcare NHS Trust, London, United Kingdom.
² Department of Metabolism, Digestion and Reproduction, Section of Genetics and Genomics, Imperial College London, London, United Kingdom.
³ Institute of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
⁴ National EDS Diagnostic Service, Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom.
⁵ Clinical Genetics, Karolinska University Hospital, Solna, Sweden.
⁶ Department Otolaryngology Head and Neck Surgery, Children's Health QLD, Brisbane, QLD, Australia.
⁷ School of Medicine, University of Queensland, Brisbane, QLD, Australia.
⁸ Clinical Genetics, Genetic Health Queensland, Brisbane, QLD, Australia.
⁹ Department of Operative and Restorative Dentistry, Medical University of Innsbruck, Innsbruck, Austria.
¹⁰ Department of Dermatology, Chelsea and Westminster Hospital NHS Foundation Trust, London, United Kingdom.

Abstract

Introduction: Periodontal Ehlers-Danlos Syndrome (pEDS) is a rare autosomal dominant type of EDS characterised by severe early-onset periodontitis, lack of attached gingiva, pretibial plaques, joint hypermobility and skin hyperextensibility as per the 2017 International EDS Classification. In 2016, deleterious pathogenic heterozygous variants were identified in C1R and C1S, which encode components of the complement system. Materials and Methods: Individuals with a clinical suspicion of pEDS were clinically and molecularly assessed through the National EDS Service in London and Sheffield and in genetic services in Austria, Sweden and Australia. Transmission electron microscopy and fibroblast studies were performed in a small subset of patients. Results: A total of 21 adults from 12 families were clinically and molecularly diagnosed with pEDS, with C1R variants in all families. The age at molecular diagnosis ranged from 21-73 years (mean 45 years), male: female ratio 5:16. Features of easy bruising (90%), pretibial plaques (81%), skin fragility (71%), joint hypermobility (24%) and vocal changes (38%) were identified as well as leukodystrophy in 89% of those imaged. Discussion: This cohort highlights the clinical features of pEDS in adults and contributes several important additional clinical features as well as novel deleterious variants to current knowledge. Hypothetical pathogenic mechanisms which may help to progress understanding and management of pEDS are also discussed.

Keywords: Ehlers-Danlos syndrome; complement; genetics; non-oral; periodontitis.

Copyright © 2023 Angwin, Zschocke, Kammin, Björck, Bowen, Brady, Burns, Cummings, Gardner, Ghali, Gröbner, Harris, Higgins, Johnson, Lepperdinger, Milnes, Pope, Sehra, Kapferer-Seebacher, Sobey and Van Dijk.

Grants and funding

This work was supported by a grant from the Ehlers-Danlos Syndrome Society (grant number 2019.02.PRO05). Imperial College London Biomedical Research Centre provided funding for a Clinical Research Fellowship. Funding was also provided for publication in an open access journal, (Imperial College London, PO number 4550141).