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    • Image copyright Whitaker JK, Alexander P, Chau DY, Tint NL, BMC Ophthalmology. Creative Commons Attribution 2.5 Generic.
    Figure 1: (left) depicts the elasticity of the skin with profound flexibility; (right) demonstrates joint mobility.
    1. Pathology

    Recognizing the clinical signs of Ehlers-Danlos syndrome

    Feb. 1, 2021
    Nancy W. Burkhart, EdD, MEd, BSDH, AAFAAOM, and Carol Perkins, BA, AS, RDH, review the clinical signs of Ehlers-Danlos syndrome, an inherited connective tissue disorder, and suggest ways to make dental appointments for EDS patients go more smoothly.
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    Ehlers-Danlos syndrome (EDS) is a diverse group of connective tissue disorders that usually follows an autosomal dominant inheritance pattern, but there are some autosomal recessive forms. Essentially, the individual produces abnormal or defective collagen, the main structural protein of the body. EDS is an inherited disorder of the connective tissue matrix that results in skin and blood vessel abnormalities. Depending upon which type of collagen is defective, the extent of the structures affected is determined, and this may be in a mild or severe state. When the collagen is defective but incorporated into bodily structures, the poor quality causes severe weakness, and lack of support and strength in the structures.1 Blood vessel walls and organs, such as the heart, may be greatly affected. There may be an increase in the risk of aortic aneurysm formation and mitral valve prolapse due to deformed heart valves.2 The patient exhibits bruising, hypermobility, and elasticity with fragility of the skin (figure 1).

    Collagen exists in many different forms, and each has a unique function within our bodies. For example, collagen type I forms the scaffolds for mineralized tissues and is the major component in all connective tissue. A good example would be the periodontal ligament (PDL) that is comprised of collagen type I (80%) and type III (20%), with lesser amounts of several other types of collagen.3 When there is disruption in collagen formation or when it is poorly synthesized, the bones, teeth, and various structures are weakened and the structural foundation is impaired.

    EDS type VIII is associated with periodontal disease/variable connective tissue features and is designated a periodontitis form.4 This form is characteristic of tooth loss, periodontal disease, and periodontal ligament destruction along with alveolar bone destruction. Tooth loss may occur in the early teen years of patients who have this type of EDS.5

    Specifically, EDS results because of genetic defects on chromosomes 1, 2, 5, 6, 7, 9, 12q, 13, and 17. Any one of the genes can cause varying degrees of defective collagen. The Ehlers-Danlos Society also has a genetic classification structure of EDS, listing groups according to similarities in the way the responsible genes affect the body.1,3,4

    Image courtesy of Carol Jin, DDS, in San Ramon, California, and Carol Perkins, BA, AS, RDH.
    Figure 2: Depicts the image of a mother and daughter both missing teeth nos. 7 and 10. Both have a form of EDS.
    Figure 2: Depicts the image of a mother and daughter both missing teeth nos. 7 and 10. Both have a form of EDS.
    According to the Ehlers-Danlos Society, the classic form of EDS may have both mild and severe features.3 The three most common types of EDS are estimated at one in every 5,000–10,000 births. There is equal distribution among males and females without any ethnic propensity.2 It is estimated that there may be 25,000–50,000 patients with EDS in North America, but many more unreported cases may exist. Clinical findings and a family history are crucial in rendering a diagnosis, although genetic testing and other specific tests may be needed as well. Depending upon the abnormalities in the collagen fibrils, the skin, vascular, and dental structures may be altered. Congenitally missing teeth are a feature, with other noticeable dental features such as early periodontal disease type VIII (figure 2). Ocular signs, such as blue sclera and conjunctivochalasis, are reported. There are also some rare types, such as kyphoscoliosis and vascular types.6
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    The skin may feel soft, rubbery, and have abnormal skin elasticity with noticeable bruising. The skin exhibits hyperextensibility. Elastin fibers can be noted on biopsy with histological examination by using certain stains. These fibers continue to expand, giving the skin a rubbery, stretchy consistency (figure 3).7 Varicose veins may be noticeable due to the vascular component, and pretibial discoloration and ecchymosis may be common. EDS may be found in some individuals
    Image copyright the Indian Journal of Dermatology. Creative Commons Attribution 2.0 Generic.
    Figure 3: Elastin fibers in the dermis continue to grow and expand. Stain is Verhoeff-Van Gieson. The altered elastin fibers (black) in the image are likely from a hypermobility type of EDS, with the TNX mutation. The enlarged/thickened elastin is believed to alter anesthesia and promote the elastic quality of the skin.
    Figure 3: Elastin fibers in the dermis continue to grow and expand. Stain is Verhoeff-Van Gieson. The altered elastin fibers (black) in the image are likely from a hypermobility type of EDS, with the TNX mutation. The enlarged/thickened elastin is believed to alter anesthesia and promote the elastic quality of the skin.

    who show little or no obvious signs, but it is called into question when the characteristics of the disorder are more noticeable and the patient seeks a diagnosis for related issues. In other patients who have been diagnosed with EDS, even minor trauma can cause large hematomas and gaping wounds.

    Studies show that pain is felt in the peripheral neurons in mice and has been noted as a genetic mutation in the matrix protein layer. Consequently, local anesthesia is a case-by-case decision. One theory as to why anesthesia is less effective in some patients is that the connective tissue is broken down and has a looseness that acts as a barrier.8-10

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    Depending upon the type of EDS, patients may present with subtle signs at one end of the spectrum or more pronounced signs at the other. Dental professionals may be the first to piece together the subtle signs that arise over time, such as early-onset periodontal disease, missing teeth, and the failure to react in a normal fashion to local anesthesia. Many dental practices see entire families, thereby giving them an opportunity to link genetic and clinical/dental signs in EDS patients. When specific signs seem to indicate the presence of the disorder, referral to specialists who diagnose and treat EDS is warranted. This is especially true when early periodontal disease is diagnosed.

    As always, continue to ask good questions and always listen to your patients. 

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    References
    1. EDS Types. The Ehlers-Danlos Society. https://www.ehlers-danlos.com/eds-types/
    2. Delong L, Burkhart NW. General and Oral Pathology for the Dental Hygienist. Enhanced 3rd ed. Jones & Bartlett Learning; 2019.
    3. Kaur P, Kakar V. Collagen: role in oral tissues: a review. Int J Sci Res. 2014;3(5):273-276. https://www.ijsr.net/archive/v3i5/MDIwMTMxNjg2.pdf
    4. Ehlers-Danlos syndromes. The Medical Biochemistry Page. https://themedicalbiochemistrypage.org/ehlers-danlos-syndromes/
    5. Reinstein E, DeLozier CD, Simon Z, Bannykh S, Rimoin DL, Curry CJ. Ehlers-Danlos syndrome type VIII is clinically heterogeneous disorder associated primarily with periodontal disease, and variable connective tissue features. Eur J Hum Genet. 2013;21(2):233-236. doi:10.1038/ejhg.2012.132
    6. Whitaker JK, Alexander P, Chau DYS, Tint NL. Severe conjunctivochalasis in association with classic type Ehlers-Danlos syndrome. BMC Ophthalmol. 2012;12:47. doi:10.1186/1471-2415-12-47
    7. Premalatha S, Sarveswari KN, Lahiri K. Reverse-namaskar: a new sign in Ehlers-Danlos syndrome: a family pedigree study of four generations. Indian J Dermatol. 2010;55(1):86-91. doi:10.4103/0019-5154.60360
    8. Schubart JR, Schaefer E, Janicki P, et al. Resistance to local anesthesia in people with the Ehlers-Danlos syndromes presenting for dental surgery. J Dent Anesth Pain Med. 2019;19(5):261-270. doi:10.17245/jdapm.2019.19.5.261
    9. Wiesmann T, Castori M, Malfait F, Wulf H. Recommendations for anesthesia and perioperative management in patients with Ehlers-Danlos syndrome(s). Orphanet J Rare Dis. 2014;9:109. doi:10.1186/s13023-014-0109-5
    10. Calcaterra N. Dental local anesthesia and Ehlers Danlos Syndrome. Directions in Dentistry. April 24, 2016. http://directionsindentistry.net/dental-local-anesthesia-ehler-danlos-syndrome/
    11. Glick M. Burket’s Oral Medicine. 12th ed. People’s Medical Publishing House; 2015.
    12. James WD, Berger TG, Elston DM, Neuhaus IM. Andrews’ Diseases of the Skin. Clinical Dermatology. 12th ed. Elsevier; 2016:502-505.
    13. Younger DS. The Autoimmune Brain. A Five-Step Plan for Treating Chronic Pain, Depression, Anxiety, Fatigue, and Attention Disorders. Rowman & Littlefield; 2019:47, 205, 223.

    Nancy W. Burkhart, EdD, MEd, BS, RDH, AAFAAOM, is an adjunct professor in the department of periodontics-stomatology at Texas A&M University College of Dentistry. Dr. Burkhart is founder and cohost of the International Oral Lichen Planus Support Group (dentistry.tamhsc.edu/olp) and coauthor of General and Oral Pathology for the Dental Hygienist, in its third edition. She was awarded an affiliate fellow status in the American Academy of Oral Medicine in 2016. She received the Dental Professional of the Year award in 2017 through the International Pemphigus and Pemphigoid Foundation and is a 2017 Sunstar/Award of Distinction recipient. She can be contacted at [email protected].

    Carol Perkins, BA, AS, RDH, has worked as a dental hygienist for 45 years in private practice in California. She was presented the Leadership & Professionalism Award by the Fresno Madera Dental Society at her dental hygiene graduation ceremony in 1975 at Fresno City College. She has been published in Access Magazine by the American Dental Hygiene Association and has contributed to RDH magazine. She frequently does outreach to children by teaching hygiene in grammar and special needs schools. Contact her at [email protected].

    About the Author

    Nancy W. Burkhart, EdD, MEd, BSDH, AAFAAOM

    NANCY W. BURKHART, EdD, MEd, BSDH, AAFAAOM, is an adjunct professor in the Department of Periodontics-Stomatology, College of Dentistry, Texas A&M University, Dallas, Texas. She is founder and cohost of the International Oral Lichen Planus Support Group (dentistry.tamhsc.edu/olp/) and coauthor of General and Oral Pathology for the Dental Hygienist, now in its third edition. Dr. Burkhart is an academic affiliate fellow with the American Academy of Oral Medicine, where she also serves as chair of the Affiliate Fellowship Program Committee. She was awarded the Dental Professional of the Year in 2017 through the International Pemphigus and Pemphigoid Foundation, and she is a 2017 Sunstar/RDH Award of Distinction recipient. Her professional interests are in the areas of oral medicine and the relationship between oral and whole-body health, with a focus on mucosal disease and early oral cancer detection. Contact her at [email protected].

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    About the Author

    Carol Perkins, BA, AS, RDH

    Carol Perkins, BA, AS, RDH, has worked as a dental hygienist for 44 years in private practice in California. She was presented the Leadership & Professionalism Award by the Fresno Madera Dental Society at her dental hygiene graduation ceremony in 1975 at Fresno City College. She has been published in Access Magazine by the American Dental Hygiene Association and has contributed to RDH magazine. She frequently does outreach to children by teaching hygiene in grammar and special needs schools. Contact her at [email protected].

    Updated February 1, 2020