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Treatment of in a Patient With Ehlers- Danlos Syndrome. A Case Report and Literature Review*

Luis A. Perez, Khalaf F. Al-Shammari, William V. Giannobile, and Hom-Lay Wang

Background: Ehlers-Danlos syndrome (EDS) des- Ehlers-Danlos syndrome (EDS) is a group of con- ignates a heterogeneous group of connective tissue nective tissue disorders that is characterized by skin disorders characterized by skin elasticity, tissue extensibility, joint hypermobility, and tissue fragility.1-4 fragility, and chronic joint pain. Dental findings have EDS affects all races and ethnic groups without sex been reported with some types of EDS. This case predominance.1,2 Other features may include mitral report describes the periodontal findings in a patient valve prolapse, bruising and hematomas, and chronic with a previously undiagnosed EDS type VIII. joint and limb pain.1,4 Oral and dental findings have also Methods: Diagnostic aids utilized included micro- been reported.1,5-10 The prevalence of EDS has been bial testing, histological examination, gingival crevic- estimated to be between 1 in 5,000 to 1 in 10,000.1,4,11 ular fluid (GCF) analysis for the levels of C-telopep- The diagnosis of EDS is first made on the basis of clin- tide pyridinoline cross-links (ICTP), and genetic ical findings. Skin hyperelasticity, easy bruising, dys- counseling. Periodontal treatment consisted of trophic scarring, and joint hypermobility are the car- mechanical and adjunctive antibiotic dinal signs of the syndrome and may be present in therapy. different combinations and with variable severity.1,2,12 Results: Genetic counseling and clinical presen- CASE REPORT tation confirmed the diagnosis of EDS type VIII. Peri- odontal treatment led to marked clinical improve- A 48-year old Caucasian female was referred to the ments and GCF levels of the bone resorptive marker Graduate Periodontics clinic at the University of Michi- ICTP were significantly reduced. The patient and her gan, School of for the evaluation and treat- siblings are currently pursuing appropriate medical ment of persistent hyperplastic despite care and genetic counseling. repeated treatment efforts that included several ses- Conclusion: Periodontal involvement may lead to sions of in combination with the diagnosis of an underlying systemic condition. several regimens of anti-inflammatory and antimi- † Identification of suspected etiological factors of peri- crobial agents, including dexamethasone, nystatin, ‡ odontal disease may prove critical for the general well- and diphenhydramine HCl rinses, and systemic being of some patients. J Periodontol 2002;73:564- courses of amoxicillin trihydrate, amoxicillin/clavu- § 570. lanate potassium, and doxycycline hyclate. The referring periodontist had also ordered allergy testing KEYWORDS for nickel and penicillin with negative results. Blood Cross-linking; Ehlers-Danlos syndrome; genetic tests ordered prior to referral revealed normal values counseling; gingival crevicular fluid/analysis; except for the erythrocyte sedimentation rate (ESR) periodontal diseases/etiology. that was elevated to approximately twice the normal value (46 mm/hour versus NV: 0 to 20 mm/hour), and elevated serum IgG levels (2090 mg/dl versus NV: 723 to 1685 mg/dl). Review of the patient’s medical records showed a history of mitral valve prolapse, depression, and chronic joint pain. The patient was a former smoker, and reported smoking cessation 20 years ago. Cur- rent medications at the time of examination included sertraline and lorazepam¶ for the treatment of depres-

† Ligand Pharmaceuticals, San Diego, CA. ‡ Benadryl, Warner-Lambert, Morris Plains, NJ. § Augmentin, SmithKline Beecham, Philadelphia, PA. * Department of Periodontics/Prevention/Geriatrics, University of Michigan Zoloft, Pfizer Inc., New York, NY. School of Dentistry, Ann Arbor, MI. ¶ Ativan, Wyeth-Ayerst, Philadelphia, PA.

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sion, celecoxib# for the control of joint pain, pre- scribed by her physicians, and a 6-month suban- timicrobial doxycycline regimen ordered by her refer- ring periodontist. Intraoral examination revealed good with minimal plaque, and mild to mod- erate subgingival deposits throughout the dentition. The gingival tissues exhibited generalized mild to moderate hyperplasia and were generally ery- thematous with rolled contours of the free (Fig. 1). Probing depths ranged between 2 and 6 mm, with localized areas of moderate attach- ment and alveolar bone loss (maxillary first and sec- ond molars). Bleeding upon probing was noted in 100% of examined sites. A full-mouth radiographic survey revealed the presence of pulp stones in the maxillary molars (Fig. 2). Given the history and clinical presentation of the patient, efforts were focused on the identification of possible etiological factors. Plaque samples were col- lected from 4 sites with the deepest probing depths using paper points and submitted for bacterial DNA analysis prior to treatment. A gingival biopsy was also taken from the upper anterior region and sub- mitted for histological examination to rule out the presence of a form of . The patient was also referred for a medical evaluation and genetic counseling, since a connective tissue disor- der was suspected. Additionally, gingival crevicular fluid (GCF) samples were collected from 3 deep and 3 shallow sites after the initial phase of therapy and again after completion of the surgical phase of treat- ment and analyzed in the laboratory for the total

Figure 2. Periapical radiographs of the right (A) and left (B) maxillary molars illustrating the pulp stones.

amounts of a bone-specific degradation product, the pyridinoline carboxyterminal telopeptide of type I col- lagen (ICTP). DNA probe analysis** revealed negative results for 7ofthe 8 evaluated periodontal pathogens (Acti- nobacillus actinomycetemcomitans, Prevotella inter- media, P. gingivalis, E. corrodens, C. rectus, B. forsythus, and T. denticola). However, high levels of F. nucleatum (>105 cells) were present. The gingival biopsy report indicated the presence of chronic inflam- mation, with no specific histological features unique to the patient’s medical history (Fig. 3). GCF sample Figure 1. Erythematous, hyperplastic appearance of the gingival tissues at initial presentation. # Celebrix, Pfizer Inc. ** DMDx, MicroDentex, Mandeville, LA.

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Figure 4. Improved tissue tone noted after initial therapy. However, signs of inflammation are still present.

Figure 3. Gingival biopsy section. Non-specific chronic inflammation and plasma cells are noted (Original magnification:A, ×4; B, ×40).

Figure 5. analysis revealed elevated levels of ICTP in both deep Marked clinical improvement and reduced signs of inflammation and shallow sites (mean level 197.78 pg/site for all noted. sites). Genetic counseling results suggested a diag- nosis of Ehlers-Danlos syndrome type VII or VIII based on the patient’s medical and family history. Based on intervention was deemed necessary in the maxillary combined clinical findings and associated diagnostic molar regions. The surgical phase of therapy was tests, the patient’s profile was consistent with Ehlers- completed 2 months after initial therapy, with contin- Danlos syndrome type VIII. ued improvements of tissue tone observed during Atreatment plan was formulated based on these active treatment. A 6-month post-treatment evalua- findings, aiming at control of the microbial compo- tion (Fig. 5) indicated improved gingival contours and nent through mechanical and chemical means. Scal- resolution of the initial inflammation. Bleeding score ing and root planing was performed in localized areas at the 6-month examination was 4% (only 6/144 and the patient was given a prescription for metro- sites). GCF ICTP levels after treatment were also sig- nidazole (250 mg t.i.d. × 10 days) and amoxicillin nificantly reduced to a mean level of 12.26 pg/site (500 mg t.i.d. × 10 days). Reevaluation of the initial (Fig. 6). ICTP was undetectable in 5 of the 6 initially phase of therapy was performed after 4 weeks, at evaluated sites. The patient has been entered into the which time the gingival tissues appeared to respond maintenance phase of therapy and is being monitored favorably in most areas (Fig. 4). However, surgical for any relapse or exacerbations of her periodontal

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in the proa1(III) chain of collagen type III produced by fibroblasts encoded by COL3A1.17 The EDS type VI diagnostic test measures the total amounts of uri- nary hydroxylysyl pyridinoline and lysyl pyridinoline crosslinks after hydrolysis by high performance liq- uid chromatography (HPLC).20 EDS type VII is con- firmed by electrophoretic demonstration of pNa1(I) and pNa2(I) chains from collagen type I extracted from the dermis in presence of protease inhibitors or obtained from fibroblasts.23 EDS types I, II, III, V, and VIII have no biochemical markers, and a diagnosis must be made on the basis of symptoms and family history alone. Electron microscopic examination of a skin biopsy may reveal changes in the structure of collagen fibers that are not specific, but can be used Figure 6. as diagnostic criteria for EDS in the absence of a bio- Gingival crevicular fluid ICTP levels at baseline (4 weeks after initial chemical marker. In some patients, an unequivocal therapy) and at the 6-month post-treatment evaluation of 3 deep classification cannot be made.1,2 ≥ ≤ ( 5 mm PD) and 3 shallow ( 3 mm PD) sites. Periodontal conditions have been reported with EDS * Significant reductions in mean GCF ICTP levels noted post-therapy. types I, VII, and VIII. Type I is autosomal dominant, characterized by prominent skin hyperextensibility; fragility and easy bruisability; “cigarette paper” scars, condition. She is also being closely observed by her molluscoid psuedotumours (swellings in the skin), and physician for any systemic complications related to subcutaneous spheroids (soft accumulations of tissue the diagnosis of Ehlers-Danlos syndrome and her sib- under the skin which cause soft non-malignant lumps); lings have been contacted for genetic counseling. large and small joint hypermobility; and frequent vari- cose veins.1 Premature birth due to early rupture of LITERATURE REVIEW membranes is also common.2 Pope et al. reported Up to 11 types of EDS have been described.13 Ehlers- defective dentinogenesis, resulting in aplasia or Danlos Syndrome types I, II, and III comprise 90% of hypoplasia of root development affecting the mandibu- all cases1,2,4,11 and their pathogenesis is not known, lar incisors, and predisposition for localized periodon- although recent data suggest a role for type V colla- tal disease in EDS type I.8 The authors described a gen.14 The etiologies of EDS types IV, VI, and VII, radiographic appearance of a bulbous enlargement of however, have been established. EDS-type IV is the roots together with pulp stones at the other teeth.8 caused by a mutation in the collagen III gene;15-18 EDS type VII is an autosomal dominant/recessive dis- EDS-type VI occurs when a mutation in the lysyl ease. It is characterized by soft skin with relatively hydroxylase gene is present;19-21 and in EDS type normal scarring, marked joint hypermobility, marked VII, the underlying defect is a mutation in the colla- hypotonia, congenital hip dislocation, and short gen I gene.22,23 EDS types V, VII, and X are very rare, stature.1 Part of one or more of the collagen genes has but their symptoms resemble those of EDS-type II.2 been shown to be faulty in 5 different type VII fami- The nosology of the EDS was reviewed and sim- lies.23,24 Genetic prenatal diagnosis can be offered to plified by the Ehlers-Danlos Foundation (USA) and this particular subgroup of Type VII.20 Caries, but not the Ehlers-Danlos Support Group (UK).1 The pro- periodontal disease, has been reported to be associ- posed classification included the use of major and ated with this type. Poor healing after extractions, a minor criteria for the classification of 6 types: 1) clas- radiographic evidence of pulp stones, and/or mal- sical type (I and II); 2) hypermobility type (III); 3) formed teeth have also been described.7 EDS type VIII vascular type (IV); 4) kyphoscoliosis type (VI); 5) is an autosomal dominant form characterized by frag- arthrochalasia type (VIIA and VIIB); and 6) other ile skin, abnormal scarring, and early onset of peri- types (V, VIII, IX, X, and XI). odontal disease, with premature loss of the perma- Laboratory testing may be performed for the diag- nent teeth.25,26 Fragility of the alveolar mucosa and nosis of EDS types IV, VI, and VII. EDS type IV is blood vessels and increased bleeding tendencies have confirmed by the identification of a structural defect also been suggested.27,28

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DISCUSSION toid arthritis, Paget’s disease, and hyperparathy- The association between Ehlers-Danlos syndrome roidism.40-43 Gingival crevicular fluid levels of ICTP and dental and/or periodontal involvement has been have also been correlated with disease activity in reported in several case studies.27-33 EDS type VIII experimental periodontitis44 and with several puta- has been more closely associated with periodontal tive periodontal pathogens, including, Fusobacterium findings than the other types.27,28,31,33 Although the nucleatum subspecies.45 Although a study evaluat- exact mechanism of the reported periodontal involve- ing serum ICTP levels in pediatric EDS reported its ment in EDS patients has not yet been established, inability to differentiate EDS patients from those with the suggested defects in type III collagen may under- osteogenesis imperfecta,46 no reports evaluating the mine the integrity of the periodontal attachment appa- levels of ICTP in adult EDS patients are available. ratus since type III collagen comprises approximately Elevated levels of ICTP in the GCF of the sampled 16% to 18% of the total collagen in the periodontal sites were found and the levels were significantly ligament.34 Currently, no diagnostic markers are avail- reduced after completion of active periodontal ther- able to identify EDS type VIII.1 A diagnosis was there- apy (Fig. 6). Similar reductions were reported after fore made based on the clinical findings and reported treatment of periodontal patients with scaling and medical history of the patient and her siblings. root planing and low-dose doxycycline.47 ICTP lev- The patient presented in this report was suspected els in this patient were similar in deep and shallow of having a systemic predisposing etiologic factor sites. In contrast, higher ICTP levels were reported in based on the medical history findings and the his- deep sites than in shallow sites in periodontal tory of the previous periodontal treatment. Although patients.48 This may indicate that in the presence of the long-term periodontal history of the patient was EDS, both deep and shallow sites may be equally not available, recent therapeutic interventions by her susceptible to periodontal involvement. In addition, referring dentist were well documented. The resistant the baseline GCF samples were collected 4 weeks nature of the patient’s periodontal condition to all after completion of the initial phase of therapy, yet previous antimicrobial treatment efforts mandated ICTP levels were not reduced until after the comple- careful appraisal of all potential contributing factors. tion of active treatment. A recent study has also An array of diagnostic aids were therefore utilized. reported no significant reductions in ICTP levels after An elevated erythrocyte sedimentation rate, as scaling and root planing in periodontal patients.48 revealed in the patient’s blood test, is suggestive of The reduced marker levels after completion of active infection or inflammation.35,36 Bacterial DNA testing treatment in this case may reflect a greater GCF was performed to evaluate the bacterial profile of the mediator response to surgical intervention. Studies subgingival microflora and to estimate the severity in progress are currently evaluating this hypothesis of the periodontal infection. The sampled sites were (unpublished data). negative for most of the examined pathogens except This case report presents an example of how peri- F. nucleatum, which has been reported to be present odontal involvement may lead to the diagnosis of in periodontally active sites, but is also frequently an underlying systemic condition. The patient was detected in inactive sites.37,38 A gingival biopsy was referred for the evaluation and treatment of persis- also taken and submitted for histological examination tent gingival inflammation and hyperplasia that were to exclude the possible differential diagnosis of a form refractory to repeated attempts for control. A sys- of desquamative gingivitis. The pathology report, tematic approach and close cooperation with other however, indicated chronically inflamed gingival tis- health care providers involved in the patient’s care sue and no suggestion of desquamative gingivitis. allowed the identification of a possible etiological Gingival crevicular fluid samples were collected factor for the patient’s periodontal condition. and evaluated for the levels of the bone-specific Although no direct correlations were obtained in this degradation product ICTP. The pyridinoline cross- case to suggest a cause-effect relationship between linked carboxyterminal telopeptide of type I collagen the diagnosis of Ehlers-Danlos syndrome and the (ICTP) is a 12-20 kD fragment of bone type I colla- extent of periodontal involvement, such diagnosis gen released by digestion with trypsin or bacterial aided in the better understanding of the patient’s collagenase.39 Elevated serum ICTP and other pyridi- periodontal disease and in the establishment of real- noline cross-links levels have been shown to corre- istic treatment objectives. Furthermore, the diagno- late with the bone resorptive rate in several bone sis of systemic conditions previously unknown to metabolic diseases, including osteoporosis, rheuma- patients allows them to seek appropriate medical

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and genetic counseling that may prove critical for 15. Smith LT, Schwarze U, Goldstein J, Byers PH. Muta- their general well-being. The diagnosis of EDS in tions in the COL3A1 gene result in the Ehlers-Danlos this case has prompted the patient to seek genetic syndrome type IV and alterations in the size and dis- tribution of the major collagen fibrils of the dermis. J counseling for herself and her siblings and to exam- Invest Dermatol 1997;108:241-247. ine her previous symptoms associated with the dis- 16. Steinmann BU, Abe S, Martin GR. Modulation of type order (i.e., muscle weakness, chronic joint pain) I and type III collagen production in normal and mutant more thoroughly. human skin fibroblasts by cell density, prostaglandin E2 and epidermal growth factor. Coll Relat Res 1982;2: ACKNOWLEDGMENTS 185-195. This work was partially supported by the University 17. Steinmann B, Superti-Furga A, Joller-Jemelka HI, Cetta G, Byers PH. Ehlers-Danlos syndrome type IV: A sub- of Michigan Periodontal Graduate Student Research set of patients distinguished by low serum levels of the Fund. amino-terminal propeptide of type III procollagen. Am J Med Genet 1989;34:68-71. REFERENCES 18. Superti-Furga A, Gugler E, Gitzelmann R, Steinmann 1. Beighton P, De Paepe A, Steinmann B, Tsipouras P, B. Ehlers-Danlos syndrome type IV: A multi-exon dele- Wenstrup RJ. for the Ehlers-Danlos National Founda- tion in one of the two COL3A1 alleles affecting struc- tion (USA) and Ehlers-Danlos Support Group (UK) ture, stability, and processing of type III procollagen. J Ehlers-Danlos Syndromes: Revised nosology. Am J Biol Chem 1988;263:6226-6232. Med Genet 1998;77:31-77. 19. Brinckmann J, Acil Y, Feshchenko S, et al. Ehlers- 2. Brinckmann J, Behrens P, Brenner R, Batge B, Tron- Danlos syndrome type VI: Lysyl hydroxylase deficiency nier M, Wolff HH. Ehlers-Danlos syndrome (in Ger- due to a novel point mutation (W612C). Arch Derma- man). 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435. 45. Palys MD, Haffajee AD, Socransky SS, Giannobile WV. 31. Karrer S, Landthaler M, Schmalz G. Ehlers-Danlos type Relationship between C-telopeptide pyridinoline cross- VIII. Review of the literature. Clin Oral Invest 2000;4: links (ICTP) and putative periodontal pathogens in peri- 66-69. odontitis. J Clin Periodontol 1998;25:865-871. 32. Seki M, Iwasaki M, Takei K, Maeda T. A case of Ehlers- 46. Proszynska K, Wieczorek E, Olszaniecka M, Lorenc Danlos syndrome (in Japanese). Shoni Shikagaku RS. Collagen peptides in osteogenesis imperfecta, idio- Zasshi 1989;27:208-219. pathic juvenile osteoporosis and Ehlers-Danlos syn- 33. Serman NJ, Albert DA. Ehlers-Danlos syndrome: A drome. Acta Paediatr 1996;85:688-691. case report. Ann Dent 1992;51:6-9. 47. Golub LM, Lee HM, Greenwald RA, et al. A matrix met- 34. Hartsfield JK, Kousseff BG. Phenotypic overlap of alloproteinase inhibitor reduces bone-type collagen Ehlers-Danlos syndrome types IV and VIII. Am J Med degradation fragments and specific collagenases in Genet 1990;37:465-470. gingival crevicular fluid during adult periodontitis. 35. Kamme C, Lindberg L. Aerobic and anaerobic bacte- Inflamm Res 1997;46:310-319. ria in deep infections after total hip arthroplasty: Dif- 48. Al-Shammari KF, Giannobile WV, Aldredge WA, et al. ferential diagnosis between infectious and non-infec- Effect of non-surgical periodontal therapy on C-telopep- tious loosening. Clin Orthop 1981:201-207. tide pyridinoline cross-links (ICTP) and interleukin-1 36. McCain GA, Harth M, Bell DA, Disney TF, Austin T, levels. J Periodontol 2001;72:1045-1051. Ralph E. Septic discitis. J Rheumatol 1981;8:100-109. 37. Dzink JL, Tanner AC, Haffajee AD, Socransky SS. Accepted for publication December 3, 2001. Gram-negative species associated with active destruc- tive periodontal lesions. J Clin Periodontol 1985;12: 648-659. 38. Dzink JL, Socransky SS, Haffajee AD. The predomi- nant cultivable microbiota of active and inactive lesions of destructive periodontal diseases. J Clin Periodontol 1988;15:316-323. 39. Risteli J, Elomaa I, Niemi S, Novamo A, Risteli L. Radioimmunoassay for the pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen: A new serum marker of bone collagen degradation. Clin Chem 1993;39:635-640. 40. Black D, Marabani M, Sturrock RD, Robins SP. Urinary excretion of the hydroxypyridinium cross links of col- lagen in patients with rheumatoid arthritis. Ann Rheum Dis 1989;48:641-644. 41. Eastell R, Robins SP, Colwell T, Assiri AM, Riggs BL, Russell RG. Evaluation of bone turnover in type I osteo- porosis using biochemical markers specific for both bone formation and bone resorption. Osteoporos Int 1993;3:255-260. 42. Katagiri M, Ohtawa T, Fukunaga M, Harada T. Evalu- ation of bone loss and the serum markers of bone metabolism in patients with hyperparathyroidism. Surg Today 1995;25:598-604. 43. Uebelhart D, Gineyts E, Chapuy MC, Delmas PD. Uri- nary excretion of pyridinium crosslinks: A new marker of bone resorption in metabolic bone disease. Bone Miner 1990;8:87-96. 44. Giannobile WV, Lynch SE, Denmark RG, Paquette DW, Fiorellini JP, Williams RC. Crevicular fluid osteocalcin and pyridinoline cross-linked carboxyterminal telopep- tide of type I collagen (ICTP) as markers of rapid bone turnover in periodontitis. A pilot study in beagle dogs. J Clin Periodontol 1995;22:903-910.

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