Clinical characteristics.

Periodontal Ehlers-Danlos syndrome (pEDS) is characterized by distinct oral manifestations. Periodontal tissue breakdown beginning in the teens results in premature loss of teeth. Lack of attached gingiva and thin and fragile gums lead to gingival recession. Connective tissue abnormalities of pEDS typically include easy bruising, pretibial plaques, distal joint hypermobility, hoarse voice, and less commonly manifestations such as organ or vessel rupture. Since the first descriptions of pEDS in the 1970s, 148 individuals have been reported in the literature; however, future in-depth descriptions of non-oral manifestations in newly diagnosed individuals with a molecularly confirmed diagnosis of pEDS will be important to further define the clinical features.

Diagnosis/testing.

The diagnosis of pEDS is established in a proband with suggestive clinical findings and a heterozygous pathogenic gain-of-function variant in either C1R or C1S identified by molecular genetic testing.

Management.

Treatment of manifestations: Treatment is individualized based on the clinical manifestations present. Due to the characteristic features of early and severe periodontitis, all individuals should be regularly seen by a periodontist beginning in early childhood. Excellent oral hygiene is also a major element of the treatment of existing periodontitis. Prosthetic rehabilitation after tooth loss is challenging as most of the alveolar bone is destroyed. Joint hypermobility may benefit from physiotherapy, occupational therapy, pain management, and appropriate exercise.

Surveillance: Due to high risk of progression of the periodontal disease, supportive periodontal care including reevaluation of periodontal parameters, oral hygiene instructions (e.g., use of interdental cleaning devices and electric toothbrushes), and supra- and sub-gingival debridement is recommended every three to six months, according to the needs of the individual. Complications of joint hypermobility addressed by consultant rheumatologist, physical therapist, and occupational therapist as needed.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of preventive dental hygiene and routine dental care and surveillance.

Genetic counseling.

Periodontal EDS is inherited in an autosomal dominant manner. Most individuals with pEDS have the disorder as the result of a C1R or C1S pathogenic variant inherited from an affected parent. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant and developing the disorder. Once the pEDS-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are technically possible.

Suggestive Findings

Periodontal Ehlers-Danlos syndrome (pEDS) should be suspected in adults with a combination of the following major and minor criteria and family history [Malfait et al 2017].

Clinical Findings

Major criteria

• Severe periodontitis of early onset (childhood or adolescence)
• Generalized lack of attached gingiva (Figure 1) (Complete lack of attached gingiva is considered pathognomonic for pEDS [Kapferer-Seebacher et al 2021].)
• Pretibial plaques (i.e., hemosiderin deposition) (Figure 2)
• Family history of a first-degree relative who meets diagnostic criteria (Absence of a known family history does not preclude the diagnosis.)

Figure 1.

Generalized lack of attached gingiva is a major criterion of periodontal Ehlers-Danlos syndrome. A. In healthy individuals a band of thick and keratinized gingiva (*) provides mechanical protection. It is tightly and unmovably bound to the periosteum (more...)

Figure 2.

Pretibial plaques have been described in 83% of individuals with periodontal EDS [Kapferer-Seebacher et al 2016]. Histologic analysis from brownish pretibial skin demonstrated dermal fibrosis and hemosiderin deposition [Ronceray et al 2013]. Some affected (more...)

Minor criteria

• Easy bruising
• Prominent vasculature
• Joint hypermobility, mostly distal joints
• Hernias
• Marfanoid facial features
• Acrogeria
• Skin hyperextensibility and fragility, abnormal scarring (wide or atrophic)
• Increased rate of infections

Minimal criteria suggestive for pEDS

• EITHER of the following major criteria:
  • Severe and intractable periodontitis of early onset (childhood or adolescence)
  • Lack of attached gingiva
• Plus BOTH of the following:
  • At least two other major criteria
  • One minor criterion

Since the publication of the diagnostic criteria for pEDS [Malfait et al 2017] hoarse, high-pitched voice has also been reported in individuals with pEDS [George et al 2016].

Generalized lack of attached gingiva is the only clinical finding consistently present in affected children younger than age ten years. As such, the current combination of criteria will not be suitable to make a diagnosis in children. Other clinical manifestations apart from easy bruising and gum bleeding are mild or absent in early childhood. Lack of attached gingiva in combination with family history of a first-degree relative would be suggestive of a diagnosis of pEDS [Kapferer-Seebacher et al 2021].

Establishing the Diagnosis

The diagnosis of periodontal Ehlers-Danlos syndrome is established in a proband with suggestive findings and a heterozygous pathogenic gain-of-function variant in either C1R or C1S identified by sequence analysis (see Table 1).

Note: Identification of a heterozygous variant of uncertain significance in either C1R or C1S does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of pEDS has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Periodontal EDS (pEDS) is characterized by distinct oral manifestations. Early and severe breakdown of the tooth-supporting tissues (i.e., alveolar bone, periodontal ligament, root cementum, and gingival attachment) result in premature loss of teeth. Lack of attached gingiva and thin and fragile gums lead to gingival recession. Connective tissue abnormalities of pEDS typically include easy bruising, pretibial plaques, distal joint hypermobility, hoarse voice, and less commonly manifestations such as organ or vessel rupture (see Table 2).

Since the first descriptions of pEDS in the 1970s [McKusick 1972, Stewart et al 1977], 148 individuals have been described in 34 case reports, seven pedigree analyses, and two cohort studies [Kapferer-Seebacher et al 2017, Wu et al 2018, Kapferer-Seebacher et al 2019, Cortés-Bretón Brinkmann et al 2021, Kapferer-Seebacher et al 2021]. The following description of the phenotypic features associated with this condition is based on these reports. However, in-depth description of non-oral manifestations in newly diagnosed individuals with a molecularly confirmed diagnosis of pEDS will be important to further define the clinical features.

Genotype-Phenotype Correlations

No genotype-phenotype correlations in pEDs have been identified.

Penetrance

The penetrance in affected individuals identified to date is 100%. However, it is age-related: periodontitis may be absent in young individuals, particularly those with good dental hygiene [Kapferer-Seebacher et al 2021].

Nomenclature

Periodontal EDS was originally referred to as Ehlers Danlos syndrome type VIII [Stewart et al [1977]. The term EDS periodontitis was introduced by the Villefranche nomenclature [Beighton et al 1998].

Prevalence

There are no estimates of the prevalence of pEDS in any population.

To date, 148 individuals with pEDS have been described in 34 case reports, seven pedigree analyses, and two cohort studies [Kapferer-Seebacher et al 2017, Wu et al 2018, Kapferer-Seebacher et al 2019, Cortés-Bretón Brinkmann et al 2021, Kapferer-Seebacher et al 2021].

Due to the high prevalence of periodontitis in the general population [Chen et al 2021] and the sometimes only mild connective tissue manifestations of pEDS, this disorder is likely underdiagnosed.

Genetic Disorders

In addition to the disorders summarized in Table 3, pEDS shares limited phenotypic overlap with other forms of EDS and disorders associated with vascular disease that can be clinically distinguished from pEDS by the absence of prominent oral manifestations. These disorders include the following:

• Classic EDS, Ehlers-Danlos classic/vascular type [Nuytinck et al 2000, Malfait et al 2007], kyphoscoliotic EDS (See FKBP14-kEDS & PLOD1-kEDS.)
• Nonsyndromic aortopathy (See Heritable Thoracic Aortic Disease Overview.)
• Loeys-Dietz syndrome
• Polycystic kidney disease, autosomal dominant
• Marfan syndrome

Periodontitis is a multifactorial disorder caused by complex interactions between various pathogenic environmental and genetic factors that in combination are thought to determine the variability of disease onset, progression, and severity. Periodontitis is triggered by bacterial microorganisms and characterized by a chronic inflammatory destruction of the tooth-supporting tissues (alveolar bone, periodontal ligament, root cementum, and gingival attachment) in progredient cases leading to tooth loss. Key to periodontitis case definition is the notion of interdental clinical attachment loss [Tonetti et al 2018]. The typical individual with periodontitis is older than age 30 years and the amount of bone destruction is consistent with the presence of plaque and calculus. The rate of disease progression can be modified by local factors, systemic diseases, and extrinsic factors such as smoking or emotional stress.

According to the current classification of periodontal and peri-implant diseases and conditions, "periodontitis" is distinguished from "necrotizing periodontal diseases" and "periodontitis as a manifestation of systemic disease," the latter including rare systemic disorders like pEDS [Caton et al 2018].

In contrast to periodontitis as a manifestation of a rare disorder, periodontitis in general is a highly prevalent disease. In population-based studies periodontitis was diagnosed in up to 72.4% of individuals, with severe periodontitis (corresponding to stage III and IV) in up to 17.5% [Germen et al 2021, Stødle et al 2021]. Prevalence estimates for periodontitis in young individuals range from 0.1% (individuals of northern and central European origin) to 5% (individuals of African origin) [Albandar 2014]. In comparison, 98% of adults with pEDS present with periodontitis, clinical/radiologic attachment loss mainly according to stage III and IV periodontitis [Kapferer-Seebacher et al 2016, Kapferer-Seebacher et al 2017].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with periodontal Ehlers-Danlos syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Preventive Measures

Periodontal breakdown with pEDS is most likely caused by a hyperinflammatory reaction [Gröbner et al 2019].

• Early severe periodontitis may be ameliorated with strict oral hygiene measures starting in early childhood.
• Professional tooth cleaning approximately every three months and frequent oral hygiene instructions to achieve livelong excellent personal oral hygiene appear to be essential.
• Soft toothbrushes are recommended because of sensitive gums.

Treatment of Manifestations

Treatment is individualized based on the clinical manifestations present.

Given the characteristic features of early and severe periodontitis, all individuals should be regularly seen by a periodontist beginning in early childhood. Excellent oral hygiene is also a major element of the treatment of existing periodontitis. For example, affected individuals must be instructed frequently in order to achieve excellent personal oral hygiene with interdental cleaning devices and (electric) toothbrushes (see Surveillance).

Dental implants are often used to replace lost teeth. With pEDS there appears to be a high risk of peri-implantitis and consequently implant failure [Rinner et al 2018]. Dental implants affected by peri-implantitis clinically present with progressive inflammatory peri-implant bone loss representing a clinical phenotype similar to periodontitis.

Therefore, the primary objective in the oral treatment of pEDS is to help affected individuals retain their own teeth for as long as possible [Kapferer-Seebacher et al 2021].

Surveillance

Agents/Circumstances to Avoid

Currently, evidence does not support a general recommendation that persons with pEDS avoid any specific activities/treatment/medications. However, this may vary on an individual basis; for example, in an individual with pEDS and arterial aneurysms, activities such as high-impact sports and weight lifting would be actively discouraged.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of preventive dental hygiene and routine dental care and surveillance.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Periodontal Ehlers-Danlos syndrome (pEDS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most probands reported to date have pEDS as the result of a C1R or C1S pathogenic variant inherited from a heterozygous, affected parent.
• Some individuals with pEDS may have the disorder as the result of a de novo C1R or C1S pathogenic variant; the relative frequency of de novo occurrence of pEDS is unknown.
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
    A parent with somatic and germline mosaicism for a C1R or C1S pathogenic variant may in theory be mildly/minimally affected.
• The family history of some individuals diagnosed with pEDS may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. All sibs who inherit a pEDS-related pathogenic variant are expected to develop manifestations of pEDS, although the age of onset may vary between heterozygous family members (see Penetrance).
• If the proband has a known pEDS-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the C1R or C1S pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for pEDS because of the possibility of failure to diagnose pEDS in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with pEDS has a 50% chance of inheriting the C1R or C1S pathogenic variant and being affected by pEDS.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the C1R or C1S pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the pEDS-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are technically possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Periodontal Ehlers-Danlos syndrome (pEDS) results from specific heterozygous variants in C1R and C1S.

The central element in the pathogenesis of pEDS is the intracellular activation of C1r and/or C1s, and extracellular presence of activated C1s that – independent of microbial triggers – can activate the classic complement cascade. This mechanism is triggered by specific gain-of-function variants [Bally et al 2019, Gröbner et al 2019].

Mechanism of disease causation. The mechanism of pathogenesis of these variants differs from homozygous loss of function of these genes and from loss of the C1 esterase inhibitor.

Functional studies in transfected HEK cells and fibroblasts from affected individuals revealed that all 16 pEDS variants studied prevented normal integration into the C1 complex and caused abnormal extracellular C1r/C1s serine protease activation. C1R variants pathogenic for pEDS showed different, domain-specific abnormalities of intracellular processing and secretion such as retention of C1r fragments inside the cell, secretion of aggregates, or a new C1r cleavage site. One variant disabled a C1q binding site. All available fibroblasts from affected individuals exhibited activated C1s and activation of externally added C4 in the supernatant in contrast to control cell lines which secreted proenzyme C1s without C4 activation [Gröbner et al 2019]. Similarly, functional studies in C1S-related pEDS showed trypsin-like or C1s-like enzymatic cleavage at the end of the CCP1 domain of the C1s protein in both C1S pathogenic variants known at the time of study [Bally et al 2019].

Variants that remove C1r or C1s serine protease function – such as large genomic rearrangements, out-of-frame deletions or duplications, or nonsense variants – are not expected to cause pEDS. However, pEDS causation cannot be fully excluded for in-frame deletions or duplication.

Gene-specific laboratory technical considerations. The range of variants that cause pEDS is greater for C1R than C1S. This appears to be due to the autocatalytic activity of native C1r in the absence of C1 esterase inhibitor. C1R variants may be causative for pEDS when they interfere with the inhibition of autoactivation, whereas C1S variants may be causative for pEDS only if they trigger autoactivation. This is relevant for the interpretation of variants of uncertain significance in both genes. These considerations also explain why null variants in C1R or C1S are not associated with pEDS.

Author Notes

Further information is available at the dedicated website www.p-eds.org.

Acknowledgments

The authors wish to thank the affected individuals and their families who supported the detailed clinical characterization of the condition. The assistance of the many collaborative partners listed in the various publications is gratefully acknowledged.

Revision History

• 29 July 2021 (bp) Review posted live
• 5 May 2021 (jz) Original submission

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