Prospective clinical investigations of children with periodontal Ehlers–Danlos syndrome identify generalized lack of attached gingiva as a pathognomonic feature



We report prospective clinical investigations of children affected with periodontal Ehlers–Danlos syndrome (pEDS). The main clinical features of pEDS in adults are early severe periodontitis, generalized lack of attached gingiva, and pretibial hemosiderin plaques due to dominant pathogenic variants in the C1R or C1S genes.


Nineteen children with a parent diagnosed with molecularly confirmed pEDS underwent physical examination including oral and radiological investigations followed by genetic testing.


The only consistent manifestation of pEDS in childhood was a characteristic gingival phenotype: generalized lack of attached gingiva. All children with this gingival phenotype had inherited the familial pathogenic variant (n = 12) whereas the gingival phenotype was absent in children without the familial pathogenic variant (n = 7). Easy bruising was reported in eight affected and zero unaffected children. Other manifestations of pEDS were rarely present in children. Only 2/12 affected children aged 8 and 13 years fulfilled the clinical criteria for pEDS.


Generalized lack of attached gingiva is a pathognomonic feature of pEDS and the only clinical finding that is consistently present in affected adults and children. This is important because an early diagnosis may facilitate better dental hygiene in childhood, which may be essential to prevent early dental loss.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Dental and periodontal tissues in health and disease.
Fig. 2: Healthy children with attached gingiva.
Fig. 3: Lack of attached gingiva is pathognomonic for periodontal Ehlers–Danlos syndrome (pEDS) in young children.
Fig. 4: Pretibial findings.


  1. 1.

    Morlino S, Micale L, Ritelli M, et al. COL1-related overlap disorder: a novel connective tissue disorder incorporating the osteogenesis imperfecta/Ehlers–Danlos syndrome overlap. Clin Genet. 2020;97:396–406.

    CAS  Article  Google Scholar 

  2. 2.

    Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers–Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175:8–26.

    Article  Google Scholar 

  3. 3.

    Blackburn PR, Xu Z, Tumelty KE, et al. Bi-allelic alterations in AEBP1 lead to defective collagen assembly and connective tissue structure resulting in a variant of Ehlers–Danlos syndrome. Am J Hum Genet. 2018;102:696–705.

    CAS  Article  Google Scholar 

  4. 4.

    Malfait F. Vascular aspects of the Ehlers–Danlos syndromes. Matrix Biol. 2018;71-72:380–395.

    CAS  Article  Google Scholar 

  5. 5.

    Grobner R, Kapferer-Seebacher I, Amberger A, et al. C1R mutations trigger constitutive complement 1 activation in periodontal Ehlers–Danlos syndrome. Front Immunol. 2019;10:2537.

    Article  Google Scholar 

  6. 6.

    Bally I, Dalonneau F, Chouquet A, et al. Two different missense C1S mutations, associated to periodontal Ehlers–Danlos syndrome, lead to identical molecular outcomes. Front Immunol. 2019;10:2962.

    CAS  Article  Google Scholar 

  7. 7.

    Papapanou PN, Sanz M, Buduneli N, et al. Periodontitis: consensus report of workgroup 2 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions. J Periodontol. 2018;89 Suppl 1:S173–S182.

    Article  Google Scholar 

  8. 8.

    Jepsen S, Caton JG, Albandar JM, et al. Periodontal manifestations of systemic diseases and developmental and acquired conditions: consensus report of workgroup 3 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions. J Clin Periodontol. 2018;45 Suppl 20:S219–S229.

    Article  Google Scholar 

  9. 9.

    Kapferer-Seebacher I, Lundberg P, Malfait F, Zschocke J. Periodontal manifestations of Ehlers–Danlos syndromes: a systematic review. J Clin Periodontol. 2017;44:1088–1100.

    CAS  Article  Google Scholar 

  10. 10.

    Mataix J, Banuls J, Munoz C, Bermejo A, Climent JM. Periodontal Ehlers–Danlos syndrome associated with type III and I collagen deficiencies. Br J Dermatol. 2008;158:825–830.

    CAS  Article  Google Scholar 

  11. 11.

    Cunniff C, Williamson-Kruse L. Ehlers–Danlos syndrome, type VIII presenting with periodontitis and prolonged bleeding time. Clin Dysmorphol. 1995;4:145–149.

    CAS  Article  Google Scholar 

  12. 12.

    Kapferer-Seebacher I, Pepin M, Werner R, et al. Periodontal Ehlers–Danlos syndrome is caused by mutations in C1R and C1S, which encode subcomponents C1r and C1s of complement. Am J Hum Genet. 2016;99:1005–1014.

    CAS  Article  Google Scholar 

  13. 13.

    Ainamo J, Barmes D, Beagrie G, Cutress T, Martin J, Sardo-Infirri J. Development of the World Health Organization (WHO) community periodontal index of treatment needs (CPITN). Int Dent J. 1982;32:281–291.

    CAS  PubMed  Google Scholar 

  14. 14.

    Ainamo J, Talari A. The increase with age of the width of attached gingiva. J Periodontal Res. 1976;11:182–188.

    CAS  Article  Google Scholar 

  15. 15.

    Vandana KL, Shivani S, Savitha B, Vivek HP. Assessment of gingival sulcus depth, width of attached gingiva, and gingival thickness in primary, mixed, and permanent dentition. J Dent Res Rev. 2017;4:8.

    Article  Google Scholar 

  16. 16.

    Armitage GC. Development of a classification system for periodontal diseases and conditions. Ann Periodontol. 1999;4:1–6.

    CAS  Article  Google Scholar 

  17. 17.

    Nanci A. Structure of the oral tissues. In: Ten Cate´s Histology. 7th ed. St. Louis: Mosby Elsevier; 2008. p. 3.

  18. 18.

    Linde A. The extracellular matrix of the dental pulp and dentin. J Dent Res. 1985;64:523–529.

    Article  Google Scholar 

  19. 19.

    Tsuzaki M, Yamauchi M, Mechanic GL. Bovine dental pulp collagens: characterization of types III and V collagen. Arch Oral Biol. 1990;35:195–200.

    CAS  Article  Google Scholar 

Download references


We thank the families with periodontal EDS for their kind cooperation. We grateful to J. Leary for recontacting families with a (suspected) diagnosis of pEDS in the South of the UK, and to A. Rinner for providing X-rays and photographs of some Austrian patients.

Author information



Corresponding authors

Correspondence to Ines Kapferer-Seebacher DMD, MSc or Fleur S. van Dijk MD, PhD.

Ethics declarations


The authors declare no conflicts of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kapferer-Seebacher, I., Oakley-Hannibal, E., Lepperdinger, U. et al. Prospective clinical investigations of children with periodontal Ehlers–Danlos syndrome identify generalized lack of attached gingiva as a pathognomonic feature. Genet Med (2020).

Download citation


  • Ehlers–Danlos syndrome
  • complement system
  • C1R
  • C1S
  • attached gingiva