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PeriodontalEhlers-Danlos Syndrome

Johannes Zschocke, Rebekka Gröbner, Human Genetics

Ines Kapferer-Seebacher, Dental Hospital

Medical University Innsbruck

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• Increased inflammatory response to periopathogenic bacteria

• Hyperreactive immune defense connective tissue/bone loss

• Genetic modifying factors; also as part of systemic diseases

Chronic infectious inflammatory disease destruction of the tooth-supporting structures

Periodontitis

Periodontal pocketing, bone loss

Environmental factors, „Lifestyle“

Genetic factors

Prevalence: 0.1 - 5% -------------------------------------------- >70 %

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McKusick 1972: ‘‘A condition unique in my experience, and apparently in the literature as well... lesions on the shins ... skin is not generally fragile, no unusual bruisability or stretchability... joints are not hyperextensible ... periodontitis, with early loss of the teeth.“

Periodontal EDS (pEDS, previously EDS VIII)

Stewart and Hollister 1977: patient at age 21 yrs

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pEDS is caused by mutations in C1R or C1S

17 families, 93 affected individuals

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• C1 complex circulating as zymogen in serumC1r/C1s tetramer (CUB domains) bound to C1q at collagen-like stem

• Activation of the classical complement pathway:C1q binds to targets conformational change C1r autoactivation C1s activation C4/C2 cleavage C3 convertase (C4b2a)

• C1R or C1S homozygous null mutations: SLE-like syndrome, ↑ suscep�bility to infec�ons /autoimmune disease; heterozygotes asymptomatic

Classical complement pathway

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• n = 93

• Molecular confirmation:C1S/C1R mutations

• Retrospective questionnaire study

• different clinicians

• Some published data only

Clinical features

Kapferer-Seebacher et al. AJHG 2016

Oral features Prevalence

Early severe periodontitis 99%

Gingival recession 98%

Lack of attached gingiva 93%

Skin features Prevalence

Easy bruising 95%

Pretibial discoloration 80%

(Mild) skin fragility 80%

Prominent vasculature 50%

Abnormal scarring 50%

Joint features Prevalence

Joint hypermobility 44%

Joint pain 31%

Flat feet 30%

Scoliosis 22%

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• Age of first tooth loss: 2-30 years

• complete tooth loss: 14-48 years

• prepubertal periodontitis (age < 10 years): 16 %

Periodontitis

Kapferer-Seebacher et al. AJHG 2016

Oral features Prevalence

Early severe periodontitis 99%

Gingival recession 98%

Lack of attached gingiva 93%

Skin features Prevalence

Easy bruising 95%

Pretibial discoloration 80%

(Mild) skin fragility 80%

Prominent vasculature 50%

Abnormal scarring 50%

Joint features Prevalence

Joint hypermobility 44%

Joint pain 31%

Flat feet 30%

Scoliosis 22%

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• Ferré et al. 2012:

– Case-control study: 17 vEDS, 46 age-matched controls

– Periodontitis: 23.5% in vEDS, 45% in controls

• De Coster et al. 2005:

– Cross-sectional study: 31 EDS patients, 6 vEDS

– No individual with periodontitis

Periodontitis is no feature of EDS except pEDS

Ferré FC et al. BMJ Open 2012;2:e000705.

Kapferer-Seebacher et al., J Clin Periodontol. 2017;44:1088-1100

De Coster et al. J Oral Pathol Med 2005; 34: 298–307.

Published patients with „vEDS“ and periodontitismay have had pEDS

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• 3 Individuals: primary implant success

• Peri-implant disease with highly inflamed tissues, receding gums and progressive bone loss

• Explantation necessary after 5-10 years

Peri-implant disease in pEDS

Rinner et al., Clin Oral Implants Res. 2018

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• Receding gums with visible dental roots

• Due to gum fragility and gingival thinning, with/without destruction of the underlying periodontal bone; no pocketing

Gingival recessions

Kapferer-Seebacher et al. AJHG 2016

Oral features Prevalence

Early severe periodontitis 99%

Gingival recession 98%

Lack of attached gingiva 93%

Skin features Prevalence

Easy bruising 95%

Pretibial discoloration 80%

(Mild) skin fragility 80%

Prominent vasculature 50%

Abnormal scarring 50%

Joint features Prevalence

Joint hypermobility 44%

Joint pain 31%

Flat feet 30%

Scoliosis 22%

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11 Kapferer-Seebacher et al. AJHG 2016

Oral features Prevalence

Early severe periodontitis 99%

Gingival recession 98%

Lack of attached gingiva 93%

Skin features Prevalence

Easy bruising 95%

Pretibial discoloration 80%

(Mild) skin fragility 80%

Prominent vasculature 50%

Abnormal scarring 50%

Joint features Prevalence

Joint hypermobility 44%

Joint pain 31%

Flat feet 30%

Scoliosis 22%

Child with pEDS

HealthyChild

Lack of attached gingiva

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• Nonspecific dermal fibrosisconsistent with trauma andhemosiderin deposition

• Without evidence of necrobiosis lipoidica orvasculitis

• Increased fragility of dermisand small blood vessels extensive bruising andconfluent atrophic scars

Pretibial discoloration

Kapferer-Seebacher et al. AJHG 2016

Oral features Prevalence

Early severe periodontitis 99%

Gingival recession 98%

Lack of attached gingiva 93%

Skin features Prevalence

Easy bruising 95%

Pretibial discoloration 80%

(Mild) skin fragility 80%

Prominent vasculature 50%

Abnormal scarring 50%

Joint features Prevalence

Joint hypermobility 44%

Joint pain 31%

Flat feet 30%

Scoliosis 22%

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• Nonspecific dermal fibrosis consistent with trauma and hemosiderin deposition

• Without evidence of necrobiosis lipoidica or vasculitis

• Increased fragility of dermis and small blood vessels extensive bruising and confluent atrophic scars

Lesions on the shins - pretibial discolorations

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• Fingers 30 %

• Elbows 19 %

• Knees 11 %

• Hips, wrist, and ankles 3 %

Joint hypermobility

Kapferer-Seebacher et al. AJHG 2016

Oral features Prevalence

Early severe periodontitis 99%

Gingival recession 98%

Lack of attached gingiva 93%

Skin features Prevalence

Easy bruising 95%

Pretibial discoloration 80%

(Mild) skin fragility 80%

Prominent vasculature 50%

Abnormal scarring 50%

Joint features Prevalence

Joint hypermobility 44%

Joint pain 31%

Flat feet 30%

Scoliosis 22%

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• Recurrent infections 40 %

(e.g. bladder/kidney, zoster, otitis media, wounds, etc.)

• Hernia 25 %

(Inguinal, umbilical, hiatal, abdominal, surgical)

• Aneurysms 16 %

(3 families: 4x cerebral, 2x aortic)

• Autoimmune disorder

(only in 1 family: Crohn’s, Sjögren)

• Organ rupture

(3 times in individual 1:III-10)

Other features

Kapferer-Seebacher et al. AJHG 2016

Oral features Prevalence

Early severe periodontitis 99%

Gingival recession 98%

Lack of attached gingiva 93%

Skin features Prevalence

Easy bruising 95%

Pretibial discoloration 80%

(Mild) skin fragility 80%

Prominent vasculature 50%

Abnormal scarring 50%

Joint features Prevalence

Joint hypermobility 44%

Joint pain 31%

Flat feet 30%

Scoliosis 22%

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• First described by Spranger et al. 1996 (1 case)

• Present in all studied adult individuals with pEDS

• Suggestive of small vessel disease, progressing with age

• Extent disproportionate to neurologic features

– recurrent headaches or depression in some cases

– one individual mild cognitive decline, ataxia, single seizure

Leukoencephalopathy in pEDS

Kapferer-Seebacher et al., Neurogenetics. 2019;20:1-8

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• Missense or in-frame indel variants

• Mostly C1R, all domains except serine proteaseonly 2 C1S mutations, CCP1 domain

pEDS mutations in C1R and C1S

C1s

C1r

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• A specific EDS subtype

– Oral features: Early-onset periodontitis, absence of attached gingiva

– Pre-tibial plaques

– Mild connective tissue features: easy brusing, mildly hyperelastic and fragile skin

– Variable other features

• Caused by dominant gain of function mutations in C1R or C1S

– Adjacent genes on chromosome 12p13

• All mutations cause abnormal extracellular presence of activated C1s

C1s non-complement proteolytic hyperactivity as pEDS pathomechanism?

Conclusion: Periodontal EDS

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Medical University Innsbruck

• Human Genetics– Rebekka Gröbner– Albert Amberger– Roland Werner– Rita Redolfi– Markus Keller– Katharina Lackner– Johannes Zschocke

• Dentistry– Ines Kapferer-Seebacher

• Virology– Heribert Stoiber,

Brigitte Müllauer

• Neuroanatomy– Lars Klimaschewski

Acknowledgements

International collaboration partners

• Inst. de Biol. Struct., Grenoble, France: Nicole Thielens, Christine Gaboriaud

• Univ. Washington, Seattle, USA: Peter Byers, Melanie Pepin

• Children’s Hospital, Zürich, Switzerland: Cecilia Giunta, Marianne Rohrbach

• NHS EDS service London: Fleur Van Dijk