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Sequential Manifestation of DifferentForms of Early-Onset Periodontitis.A Case ReportLior Shapira, *f Ami Smidt,* Thomas E. Van Dyke/ Vivian Barak,1Aubrey W. Soskolne, * Chaim Brautbar,11 Michael N. Sela/ and Enrique Bimstein*

Pathogenic bacteria constitute the primary extrinsic agent in the etiology ofearly onset Periodontitis. However, the risk of developing periodontal disease is not equalfor all individuals, suggesting host factors are involved in determining an individual'sdisease susceptibility. In this report, a case of an otherwise healthy female, who exhibitedprepubertal Periodontitis (PPP) at age 10, juvenile Periodontitis (JP) at age 13, and rapidlyprogressive Periodontitis (RPP) at age 29 years, is presented. Microbial, immunological,and genetic features of the case are presented. PPP, JP, and RPP are considered distinctdisease entities, albeit with similar pathology and pathogenesis, yet all were manifestsequentially in the same individual. This report presents the idea that certain individualsare predisposed to early-onset periodontal diseases and the early identification of riskfactors is important in the management of these individuals. J Periodontol 1994;65:631-635.

Key Words: Host factors; Periodontitis, early-onset, etiology; Periodontitis, prepubertal/etiology; Periodontitis, juvenile/etiology; Periodontitis, rapidly progressive/etiology.

Although periodontal diseases are infectious in nature witha specific pathogenic flora,1 recent evidence has indicatedthat disease susceptibility and individual variability in thehost-response plays a major role in the disease process.2'3Alveolar bone loss may already be evident in children4'5and may be indicative of an inherent susceptibility to furtherperiodontal breakdown in the permanent dentition.6 There-fore, the early diagnosis and treatment of individuals at riskfor periodontal diseases in childhood should be considereda goal in clinical dentistry. The establishment of risk factorsand risk indicators will help to achieve this goal. In thispaper, we present a longitudinal clinical report of a medi-cally healthy female, with sequential periodontal diagnosesof pre-pubertal Periodontitis (PPP) at age 10, juvenile Peri-odontitis (JP) as a young adult, and rapidly progressivePeriodontitis (RPP) at age 29 years. This case emphasizes'Department of Periodontics, The Hebrew University, Hadassah Schoolof Medicine, Jerusalem, Israel. Department of Periodontology, Eastman Dental Center, Rochester, NY. Department of Prosthodontics, The Hebrew University, Hadassah Schoolof Dental Medicine, Jerusalem, Israel.«Department of Oncology, Hadassah University Hospital."Tissue Typing Unit, the Lautenberg Center for Immunology, HadassahUniversity Hospital.'Department of Oral Biology, The Hebrew University-Hadassah Schoolof Dental Medicine.'Department of Pediatrie Dentistry.

the need for early detection of individuals at risk for peri-odontal breakdown.

CASE REPORTA 29-year-old female was referred to the Department ofPeriodontics of the Hadassah Faculty of Dental Medicineof Jerusalem for treatment of severe Periodontitis. The pa-tient had no history of systemic disease and since she pre-viously attended the Hadassah Faculty of Dental Medicine,past dental records were available. Comprehensive dentaltreatment plans were done at ages 10, 13, and 22 years.However, due to compliance difficulties, the treatments werenever completed. At age 10 years, enamel hypoplasia ofthe permanent first molars and central incisors, gingivalinflammation and alveolar bone loss (Fig. 1) characteristicof idiopathic PPP were recorded. Differential diagnosis ofother systemic diseases were excluded by laboratory tests.At age 13 years, shedding of the primary teeth and eruptionof the premolars apparently resulted in an improvement ofthe alveolar bone status (Fig. 2). In contrast, incipient signsof alveolar bone loss on the mesial surfaces of the firstpermanent molars could be seen, typical of localized ju-venile Periodontitis (LJP), but the presence of stainless steelcrowns could be the possible reason for this process. How-ever, at age 22 years, alveolar bone loss was evident aroundall the first permanent molars and the mandibular and max-

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Figure 1. Bite-wing radiographs at age 10 years. Note the alveolar bone loss, characteristic ofprepubertalPeriodontitis, affecting the primary dentition. Enamel hypoplasia on the first permanent molars is also evident.

Figure 2. Radiographs at age 13 years. Incipient alveolar bone loss is evident at the alveolar bone locatedmesial to the first permanent molars.

Figure 3." Radiographs at age 22years. Alveolar bone loss, characteristic ofgeneralizedjuvenile PeriodontitisIrapidly progressive Periodontitis, affecting the first permanenet molars, mandibular and maxillary incisors,lower canine, and second molars and second premolars is evident.

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Figure 4. Radiographs at age 29 years. Generalized severe bone loss, characteristic of rapidly progresivePeriodontitis is evident.

Table 1. Percentage of Colony Forming Units of Black-PigmentdBacteroides (BPB) and Actinobacillus actinomycetemcomitans (Aa)Tooth %BPB %AaMaxillary right lateral incisor 1.18 0.0Maxillary right first bicuspid 1.33 0.0Maxillary left lateral incisor 1.91 0.0Maxillary left first bicuspid 0.49 0.12

illar incisor areas, including teeth with no restorations (Fig.3). In addition, some bone loss also occured around lowercanines, second molars and second premolars. At age 29years further deterioration of the periodontium was evidentwith the radiographie image of RPP (Fig. 4).

Microbial ExaminationAt the latest examination carried out at age 29, four siteswith probing depths of > 6 mm were chosen for sampling(maxillary first premolars and lateral incisors). Briefly, su-

pragingival plaque was removed and 3 sterile paper pointswere inserted into the periodontal pocket. The samples werediluted in reduced transport media,7 and plated in duplicatewith an automated spiral platter8 on enriched trypticase soyagar (ETSA) and onto selective media for Actinobacillusactinomycetemcomitans.9 The plates were incubated in ananaerobic chamber for 8 days.10 Following incubation, thetotal number of colony forming units, black-pigmented bac-teroides (BPB), and Aa were counted and identified bymeans of colony morphology and biochemistry.9'11 Thefindings of the microbiologie examination are presented inTable 1. All four sites were positive to BPB, while onlyone site was positive for A. actinomycetemcomitans.

HLA TypingSeveral studies have found an association between HLAphenotypes and periodontal disease (for review see refer-ence 12). Our aim was to find if the present case had anyHLA markers which might serve as a risk indicator fordisease suceptibility. Peripheral blood lymphocytes of thepatient, drawn at age 29, were used for HLA class I (ABC)and class II (DR, DQ) typing by the microlymphocytotox-icity method.13 The HLA phenotype of the patient was A2,A23 (9), B7, B44 (12), Cw5, DR4, DQ8 (3), DRw53.

Monocyte FunctionsMonocytes can respond to bacterial stimuli by secretion ofinflammatory mediators. Some of these mediators, such astumor necrosis factor alpha (TNFa,), interleukin-lß (IL-lß), interleukin-6 (IL-6), and Prostaglandin E2 (PG-E2) areknown to have bone resorptive potential.2,14 Due to the factthat the monocyte response to bacterial components is ge-netically determined,15 we examined the patient monocyteresponse to lipopolysaccharide (LPS).

At the same time of HLA typing, adherence-purifiedmonocytes of the patient were cultured in serum-free RPMI1640 for 24 hours in the presence of 30 µg/ml Escherichiacoli LPS.** The media was analyzed for TNFa by ELISA,IL-lß, IL-6, and PG-E2 by radioimmunoassay. DNA con-tent of the cultures was determined according to Shapira etal.16 Fourteen healthy age-matched controls were also stud-ied for comparison.17 Secretion of TNFa by the patientmonocytes was higher than mean control level + 2 standarddeviations. In contrast IL-lß secretion was lower than the

"Sigma Chemical Co., St. Louis, MO.

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Table 2. Secretion of TNF- , IL-lß, IL-6, and PG-E2 byAdherence-Purified Monocytes

Patient Controls ( +SD)TNF- 1065 432 (±223)IL-lß 376 1071 (±485)IL-6 752 881 (±576)PG-E2 135 123 (±65)Values are in picograms per µg DNA. Values of the controls (n = 14)are mean ± standard deviation (± SD), and the patient mean of dupli-cates.

controls. IL-6 and PG-E2 secretion between the patient andthe control group did not differ (Table 2).

DISCUSSIONThe observation that children with periodontal diseases in-volving the primary dentition may develop advanced peri-odontal diseases involving their permanent dentition cor-

responds with the observation that there are inherent hostfactors which make certain individuals more susceptible toperiodontal breakdown. Sjödin et al.6 reported 17 cases ofUP, in which all but one showed some evidence of boneloss in radiographs of their primary dentition examined ret-rospectively. Therefore, periodontal diseases in a child shouldbe considered a sign of susceptibility to further periodontalbreakdown. Furthermore, a connection between periodontaldiseases in the primary and permanent dentitions is feasiblesince, in the mixed dentition, the pathogenic flora associ-ated with the primary teeth may facilitate the establishmentof periodontal diseases in the adjacent permanent teeth. Thefact that, in the present case, at age 10 years, the alveolarbone located between the second primary and first perma-nent molars was affected, suggests the possibility that thepathogenic bacteria from the primary teeth accelerated thedisease process associated with the first molars.

The predominant microorganisms found in the affectedpockets at age 29 years were BPB species. No attempt was

made to differentiate between the BPB species. On the otherhand, only one site was found to be positive for low numberof A. actinomycetemcomitans colonies. Although many re-

ports have implicated A. actinomycetemcomitans as theprincipal pathogen at least in UP,18 other studies have shownthat A actinomycetemcomitans is not always detected.19'20The flora at an earlier age of this patient could have beenmuch different, contributing to the evidence that diseasesusceptibility is the major factor in early onset Periodontitis.

Today, subclassification of EOP diseases is not com-

plete. UP and PPP are relatively well defined according tothe clinical manifestations of the periodontal lesions.21However, the borderline between UP and generalized ju-venile Periodontitis (GJP) is not clear. Furthermore, RPPand GJP are frequently used for similar cases. The distinc-tion between GJP and RPP21 may be arbitrary, and may beconfusing the laboratory data involved in studies lookingfor disease markers or disease pathogenesis. In the presentcase, the patient showed signs of UP at age 13, which

developed to GJP or RPP at age 22. Better definition ofEOP diseases are needed for the understanding the patho-genesis of these conditions and for the development of treat-ment strategies.

The association between HLA and antigens and peri-odontal susceptibility have been recently reviewed byWilton12 and Page.22 Katz et al.13 found in a study of 10patients with rapidly progressive Periodontitis (RPP), that8 patients exhibited HLA-DR4 antigen, compared to 38%in the control group. Other studies found increased fre-quency of HLA-A9 in RPP patients.23 25 In the present case,the patient had both antigens HLA-A9 and DR4, raisingthe possibility that these associations may be used as a riskmarkers. More studies are needed to verify those HLA as-sociations with EOP, and to try to explore the nature of thisprocess. However, one working hypothesis can be sug-gested from this patient monocyte function data (Table 2).The in culture monocyte studies revealed that the patientcells are "high producers" of TNFa as compared to thecontrol group. Molvig et al.15 showed that monocytes fromDR4 positive individuals are "high producers" of TNFain response to bacterial lipopolysaccharide. The TNFa geneis located on chromosome 6, in close proximity to the HLAcluster. There is also evidence today that overproduction ofTNFa in periodontal breakdown is important.26'27 The re-

lationship between periodontal diseases, hyper-secretion ofTNFa and HLA phenotype are interesting and need furtherinvestigation.

The case reported here clearly represents a person whois at high risk for periodontal disease. However, had we

been able to address the primary causative agent, plaque,when the disease was initially detected we probably wouldhave been able to prevent or, at least diminish, the advancedpathology seen at age 29 years. Future use of markers fordisease susceptibility can be an effective tool for preventiveregimens.

AcknowledgmentThe authors thank Mrs. Ronit Naor and Ina Kalishman fortheir excellent technical assistance.

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matory periodontal disease. In: Periodontal Diseases, 2nd ed. Phil-adelphia: Lea & Febiger; 1990:89-124.

2. Genco RJ. Host responses in periodontal diseases. Current concepts.J Periodontol 1992; 63:338-355.

3. Johnson NW, Griffiths GS, Wilton JMA et al. Detection of high riskgroups and individuals for periodontal disease: Evidence for existenceof high risk groups and approaches to their detection. / Clin Perio-dontol 1988; 15:276-288.

4. Bimstein E, Delaney JE, Sweeney EA. Radiographic assessment ofthe alveolar bone height in children and adolescents. Ped Dent 1988;10:199-204.

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6. Sjödin , Crossner C-G, Unell L, Östlund P. A retrospective radio-

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graphic study of alveolar bone loss in the primary dentition in patientswith localized juvenile Periodontitis. / Clin Periodontol 1989; 16:124—127.

7. Syed SA, Loesche WJ. Survivial of human dental plaque flora invarious transport media. Appi Microbiol 1972; 24:638-644.

8. Jarvis B, Lach VH, Wood JKM. Evaluation of the spiral plate markerfor the enumeration of microorganisms in food. JApp Bacteriol 1977;43:149-157.

9. Slots J. Selective medium for isolation of Actinobacillus actinomy-cetemcomitans. J Clin Microbial 1982; 15:606-609.

10. Aranki A, Syed SA, Kennedy EB, Fréter R. Isolatoion of anaerobicbacteria from gingiva and mouse caecum by means of a simplifiedglove box procedure. Appi Microbiol 1969; 17:568-576.

11. Hunt DE, Jones JV, Dowell VR: Selective medium of the isolationof Bacteroides gingivalis. J Clin Microbiol 1986; 23:441^145.

12. Wilton JMA. Unchanging, subject-based risk factors for destructive Peri-odontitis; race, sex, genetic, congenital and childhood systemic diseases.In: Johnson NW, ed. Risk Markers for Oral Diseases, vol 3. Periodontaldiseases. Cambridge: Cambridge University Press; 1991:109-138.

13. Katz J, Goultschin J, Benoliel R, Brautbar C. Human leukocyte an-

tigen (HLA) DR4: Positive association with rapidly progressive Peri-odontitis. / Periodontol 1987; 58:607-610.

14. Mundy GR. Inflammâtory mediators and the destruction of bone. JPeriodont Res 1991; 26:213-217.

15. Molvig J, Baek P, Christensen , et al. Endotoxin stimulated humanmonocyte secretion of interleukin-1, tumor necrosis factor a, andProstaglandin E2 shows stable inter-individual differences. Scand JImmunol 1988; 27:707-716.

16. Shapira L, Takashiba S, Kalmar JR, Barak V, Van Dyke TE, Sos-kolne WA. Rapid fluorometric quantification of monocyte attachmentin tissue culture wells. J Immunol Methods 1993; 165:93-98.

17. Shapira L, Soskolne WA, Sela MN, Offenbacher S, Barak V. Thesecretion of PGE2 IL-lß, IL-6, and TNFa by adherent mononuclearcells from early onset Periodontitis patients. JPeriodontol 1994; 65:139-146.

18. Zambón JJ. Actinobacillus actinomycetemcomitans in human peri-odontal disease. / Clin Periodontol 1985; 12:1-20.

19. Loesche WJ, Syed E, Schmidt E, Morrison EC. Bacterial profiles ofsubgingival plaque in Periodontitis. J Periodontol 1985; 56:447-456.

20. Moore WEC, Holdeman LV, Cato EP, et al. Comparative bacteri-ology of juvenile Periodontitis. Infect Immun 1985; 48:507-519.

21. The American Academy of Periodontology. Proceedings of the WorldWorkshop in Clinical Periodontics. Chicago: The American Academyof Periodontology 1989; I-23/I-31.

22. Page RC. Risk factors involving host defense mechanism. In: BaderGD, Risk Assessment in Dentistry. Chapel Hill: University of NorthCarolina, Dental Ecology; 1990; 94-104.

23. Amer A, Singh G, Darke C, Dolby AE. Association between HLAantigens and periodontal disease. Tissue Antigens 1988; 31:53-58.

24. Klouda PT, Porter SR, Scully C, et al. Association between HLA-A9 and rapidly progressive Periodontitis. Tissue Antigens 1986; 28:146-149.

25. Shapira L, Eizenberg S, Sela MN, Soskolne WA, Brautbar H. HLAA9 and B15 are associated with the generalized form, but not thelocalized form, of early onset periodontal disease. JPeriodontol 1994;65:219-224.

26. McFarlane CG, Reynolds JJ, Meikle MC. The release of interleukin-lß, tumor necrosis factor- , and interferon-y by cultured peripheralmononuclear cells from patients with Periodontitis. / Periodont Res1990; 25:207-214.

27. Matsuki Y, Yamamoto J, Hará . Detection of inflammatory cytokinemessenger RNA (mRNA)- expressing cells in human inflammed gin-giva by in situ hybridization and immunohistochemistry. Immunology1992; 76:42-47.

Send reprint requests to: Dr. Lior Shapira, Department of Periodontics,Hebrew University, Hadassah Faculty of Dental Medicine, P.O. Box 12272,Jerusalem 91120, Israel.

Accepted for publication November 17, 1993.