Ann Periodontol

Early-Onset Periodontitis
Maurizio S. Tonetti* and Andrea Mombelli
*Previously, Department of Periodontology and Fixed Prosthodontics, University of Bern, Switzerland; currently, Department of Periodontology, Eastman Dental Institute and Hospital, University College, London, United Kingdom. Department of Periodontology and Oral Pathophysiology, University of Geneva, Switzerland.

In 1993, the 1st European Workshop on Periodontology explicitly recognized that there was insufcient knowledge to differentiate truly different forms of periodontal disease from differences in the presentation/severity of the same disease. In spite of recent progress in our understanding of periodontal diseases, the issue is far from having been resolved. Classication of periodontal diseases, therefore, remains based upon the denition of specic clinical syndromes. Early-onset periodontitis (EOP) is one such syndrome and comprises a group of pathological conditions leading to loss of periodontal tissues early in life. The notion that classies periodontitis syndromes as early-onset or adult is primarily epidemiological in nature and is based on the observation that periodontitis is rather infrequent in children and young adults. Nevertheless, considerable epidemiological evidence indicates that periodontitis does affect children and young adults to a level of severity that may lead to premature exfoliation of primary and/or permanent teeth. Clinical presentation of periodontitis early in the life of an individual is thought to indicate that the etiologic agents have been able to cause considerable tissue damage over a relatively short period of time. It also implies either infection with highly virulent bacteria and/or a highly susceptible subject. The purpose of this review is to discuss the criteria generally utilized to classify EOP, provide the rationale to designate EOP as a distinct disease entity, and to review the evidence justifying a subclassication into particular subgroups of EOP. Ann Periodontol 1999;4:39-52. KEY WORDS Periodontitis/classication; periodontitis/aggressive (earlyonset)/classication.
Editors note: this review reects the terminology in use prior to the Disease Classication Workshop and that is most commonly seen in the literature.

CLASSIFICATION CRITERIA The criteria available to classify periodontal diseases will be discussed at the syndromic, etiologic, and genetic levels of understanding. The Workshop participants have proposed the term Aggressive Periodontitis to replace Early-Onset Periodontitis; please see page 53 for further information. Syndromic Criteria EOP syndromes have been primarily dened using the following criteria:1-13 1) relationship to systemic conditions; 2) age of onset and reference to puberty; 3) involvement of primary/permanent dentition; 4) distribution of lesions; 5) severity of destruction; 6) rate of progression; and 7) response to therapy. Relationship to systemic conditions. It has long been recognized that periodontal diseases in children and young adults may represent an oral manifestation of a systemic condition (see reference 14 for review). A variety of host defense disorders, in particular, may lead to destruction of the periodontal attachment apparatus and eventually premature exfoliation of primary and/or permanent teeth. The most recent version of the International Classication of Disease (ICD10) by the World Health Organization15 and its application to dentistry and stomatology (ICD-DA)16 has dened a specic disease entity (code: K08.0) to designate periodontal destruction and exfoliation of teeth due to systemic causes. Such coding is completely different from that used to classify periodontal diseases which are not oral manifestations of other systemic conditions (code K05). On the other hand, it is also clear that EOP may be present in children and
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Volume 4 Number 1 December 1999

young adults in the absence of obvious systemic conditions. Given the different relevance and prognosis of periodontal destruction in the two clinical situations it would seem appropriate that EOP syndromes be classied according to their relationship to a systemic condition, or lack thereof. With regards to the pathophysiology of attachment loss in the presence of systemic conditions, little is known about its etiology, inammatory mediators, and tissue destruction mechanisms. In particular, it is unclear whether or not the pathogenesis of attachment loss in such conditions would share the key features that have been established for periodontitis. It would seem that, at least in several diseases, the underlying systemic condition should play a dominant role in the process leading to attachment loss. Furthermore, extreme heterogeneity is expected in the molecular mechanisms leading to attachment loss; as an example, ulcerative forms of periodontitis, such as those observed in HIV infected individuals, may be radically different from the attachment loss and tooth exfoliation associated with specic collagen diseases such as some of the forms of Ehlers-Danlos syndrome. The critical question from a classication standpoint is whether or not attachment loss and tooth exfoliation associated with systemic conditions should be classied as a form of periodontitis (i.e., as EOP modied by a systemic disease) or as a local complication of a systemic condition (i.e., as a periodontal manifestation of a systemic disease). No direct evidence is available on this issue and the answer is likely to be disease dependent. Age of onset and puberty. Age of the subject represents the primary descriptor used in differentiating between EOP and adult forms of periodontitis (AP). One rationale for using age as a discriminator is the potential to discriminate highly susceptible individuals or individuals infected by a highly virulent agent. Age would also be a very valuable discriminator if there were evidence to support a hypothesis for an agedependent window of susceptibility. In the absence of proof for an age-dependent modulation of susceptibility, however, patients diagnosed on the basis of an agedependent classication will change diagnosis as they grow older, although they still suffer from the same disease as viewed from etiology and susceptibility points of view. In addition, using age as a classication criterion is limited by the fact that age of diagnosis does not necessarily mean age of onset of the disease. Current classication schemes of EOP make further reference to puberty to dene early-onset periodontal syndromes occurring before or after this physiologic, age-related event. Rationale for this classication criterion comes from the fact that it is readily identiable and from the fact that puberty-associated hormonal changes may change the microora and/or the indi40

vidual susceptibility of the subject. Using puberty as a classication criterion to differentiate among EOP syndromes, however, has been shown to have the same limitations of using age to classify EOP and AP syndromes. Involvement of primary/permanent dentition. The justication for the use of this criterion would require evidence indicating that primary teeth have a different susceptibility to certain forms of EOP than the permanent dentition. Substantial evidence, however, indicates that early-onset periodontal destruction may affect both the deciduous and the permanent dentition.17,18 The possibility of a sequential involvement of the primary and the permanent dentition in the same individual decreases the value of this criterion. Distribution of lesions. Since the early identication of a specific molar-incisor pattern of occurrence of periodontal lesions in adolescents, disease distribution within the dentition has represented an important criterion for the classication of EOP syndromes. Terms such as localized or generalized have therefore been widely employed to describe specic patterns of disease presentation. Evidence indicating that specic teeth have an increased susceptibility to certain forms of EOP than others would enhance the value of this criterion. Clinical observations in some patients, however, have indicated that localized distribution patterns may convert to generalized patterns of disease if proper periodontal treatment is not provided. Furthermore, in localized juvenile periodontitis patients, an association between the number of lesions and the age of the subject has been described, suggesting an age-dependent shift from localized to generalized forms of EOP.3,6 It has been suggested that progression from a localized to a more generalized form of disease may happen in distinct patient subsets characterized by either infection with specific pathogens and/or by an increased environmentally or genetically based susceptibility.11,12 Severity of destruction. The level of periodontal destruction in the dentition of the affected individual has been used as a primary classification criterion. The rationale for using severity of lesions is based upon the concept that, at any specic age, the level of periodontal destruction may give an estimate of the virulence of the etiologic agents and the susceptibility of the individual. As compared to similar estimates of virulence and susceptibility based on the rate of disease progression, severity provides an appraisal without needing a longitudinal observation. The problem with severity as a criterion for classication is related to the lack of evidence indicating that periodontal diseases progress continuously (i.e., a disease process may be resting at the moment of clinical diagnosis). Rate of progression. Some authors and classication systems have placed considerable emphasis on the

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Tonetti, Mombelli

rate of destruction of the periodontium. With reference to including severity of the lesions, the rate of progression criterion is aimed at identifying subjects characterized by high virulence of the microora and/or high levels of susceptibility. Correct application of this criterion requires availability of clinical or radiographic data from more than one time point. Response to therapy. Introduction of this element in a classification scheme recognizes the fact that response to previously rendered treatment may provide useful information by specically identifying nonresponding, so-called refractory subjects. The major criticism for this criterion comes from the need to establish that the lack of treatment response should not be due to improper or inadequate therapy. On the other hand, lack of response to properly rendered treatment represents the most important rationale to subdivide a specic syndrome. In summary, it is apparent that the syndromic criteria that have been used to distinguish between EOP and AP and to classify different forms of EOP represent a heterogeneous group of descriptors of the clinical presentation of periodontal disease. Furthermore, when multiple classication criteria are applied to the description of a specic case, considerable overlap among disease categories occurs. These limitations have been recognized by participants in both the 1989 World Workshop on Clinical Periodontology19 and the 1st European Workshop in Periodontology20 held in 1993 in which only a few classication criteria (primarily age and distribution of the lesions) were suggested. These should be supplemented by the use of disease descriptors whenever the information is available. It should, however, be clearly understood that a syndromic classication of disease is only justied in the early stages of understanding of a morbid condition. It plays a fundamental role in identifying homogeneous cases that, by virtue of a similar clinical presentation, have a reasonably high probability of representing a true disease entity and therefore be the basis for the necessary research aimed at the identification of the etiologic agents and individual susceptibility traits. A classication scheme limited to the syndromic description of the disease does not address the fundamental questions related to true disease heterogeneity and to phenotypic variation of disease presentation. Etiologic Criteria Classication based on etiology may be very meaningful, if etiologic agents can be identied and therapy can be directed towards suppression or elimination of these agents. Today there is little doubt that periodontitis is an infection caused by bacterial pathogens. In particular, in 1996 the World Workshop on Clinical Periodontology21 deliberated that sufficient experimental evidence has been gathered to designate at

least 3 bacterial species; i.e., Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, and Bacteroides forsythus, as etiologic agents of periodontitis in susceptible hosts. This section reviews the specic information available for the role of specic pathogens in EOP. The most abundant evidence regarding a specic bacterial etiology of EOP comes from studies of a specific clinical periodontal syndrome affecting adolescents with a molar-incisor pattern of distribution of lesions termed localized juvenile periodontitis (LJP). Early studies demonstrated the presence of a layer of bacterial deposits on the root surface of advanced EOP lesions.22,23Attempts were made using culture techniques to identify the involved bacteria.24-26 In these studies, Gram-negative organisms comprised approximately two-thirds of the isolates from deep periodontal pockets. In contrast, these organisms averaged only about one-third of the isolates in control sites with normal gingiva. The most frequently detected microorganisms in LJP included A. actinomycetemcomitans, Capnocytophaga sp., Eikenella corrodens, Prevotella intermedia, and motile anaerobic rods, such as Campylobacter rectus. Gram-positive isolates were mostly streptococci, actinomycetes, and peptostreptococci. One of these organisms, A. actinomycetemcomitans, received particular attention. Based on the following lines of evidence, it has been regarded as a key etiologic agent in LJP: 1. Association studies, linking the organism to the disease: classical studies reported frequencies around 90% for A. actinomycetemcomitans in periodontal lesions of LJP patients.27-34 2. Association studies, linking the organism to disease progression: in some studies it was possible to demonstrate elevated levels of A. actinomycetemcomitans in sites showing evidence of recent or ongoing periodontal tissue destruction.29,33,34 3. Findings of immune responses towards this bacterium: investigators repeatedly reported signicantly elevated levels of serum antibodies to A. actinomycetemcomitans in LJP patients.34-42 LJP patients also locally produced antibodies against A. actinomycetemcomitans at diseased sites.43-45 4. Clinical studies showing a signicant correlation between treatment outcomes and levels of A. actinomycetemcomitans after therapy: unsuccessful treatment outcomes could be linked to the failure to reduce the subgingival load of A. actinomycetemcomitans.33,34,46-56 5. Demonstration of virulence factors: A. actinomycetemcomitans produces several potentially pathogenic substances, including a leukotoxin, and is capable of inducing disease in experimental animals at non-oral sites, and can translocate across epithelial membranes.
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Volume 4 Number 1 December 1999

A. actinomycetemcomitans, Capnocytophaga sp., and P. intermedia have also been detected frequently in the subgingival microbiota of periodontitis affecting the primary dentition of children.57-62 The microbial patterns observed in periodontal lesions of the primary dentition, however, seem to be more complex than the ones detected in LJP patients. Generalized early-onset periodontitis (G-EOP) and rapidly progressive periodontitis (RPP) have been frequently associated with the detection of P. gingivalis, B. forsythus, and A. actinomycetemcomitans.45,55,63-68 High local and systemic immune responses against P. gingivalis have been demonstrated in patients with G-EOP.41,68-71 The view of a specic role of some bacteria is challenged using the following arguments: Several reports have not conrmed the association between A. actinomycetemcomitans and LJP: A. actinomycetemcomitans was not detected in any affected subject.65,72,73 In other studies it was not possible to reproduce the previously reported frequencies of A. actinomycetemcomitans in the range of 90%.54,63,74 In one study,75 the subgingival ora of affected juvenile periodontitis sites were not signicantly different from the ora of sites with gingival index scores of 1 or 2 in adults with developing (experimental) gingivitis. In another study,76 high levels and proportions were found for P. gingivalis, P. intermedia, Fusobacterium nucleatum, C. rectus, and T. denticola. A. actinomycetemcomitans, however, was not significantly associated with EOP (generalized, localized, or incidental). It has been reported that A. actinomycetemcomitans can also be detected with considerable frequency in subjects without clinical evidence of periodontal disease.28,77-82 High general prevalence in several nondiseased cohorts suggested that A. actinomycetemcomitans might be a common constituent of the normal ora in many populations. If a putative pathogen can be detected frequently in healthy subjects, this indicates that not all humans are equally susceptible and/or that there is variation in virulence and pathogenic potential. Evidence for serotype-dependent variance in virulence has indeed been presented for A. actinomycetemcomitans. In the United States, serotype b strains were more often isolated from patients with localized juvenile periodontitis than from other subjects.83,84 A higher frequency of serotype b strains was also reported from Finnish subjects with periodontitis.85,86 Differing results were, however, reported from other parts of the world, suggesting that there may be specic distribution patterns in ethnically distinct populations.87-89 Leukotoxin production, a factor considered important for virulence of A. actinomycetemcomitans, varies signicantly among strains of this species.90-93 The strain-specific difference in leukotoxin production
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seems to be regulated at the level of transcription.92 Brogan et al.93 detected a 530 bp deletion in the promoter region of the leukotoxin operon and found that strains with this feature produced 10 to 20 times more leukotoxin. A subsequent study in the United States indicated a higher occurrence of such highly toxigenic strains in patients with localized juvenile periodontitis than in adult periodontitis patients or healthy subjects.84 Another group investigated a collection of 88 clinical isolates from 81 periodontally healthy and diseased Finnish individuals and over 60 strains from an additional northern European population. In these samples the deletion of the 530 bp sequence could not be demonstrated.94 However, a single clone of highly toxigenic A. actinomycetemcomitans was isolated from multiple patients with juvenile periodontitis in members of families of African origin, living in geographically widespread areas.95,96 This has suggested that juvenile periodontitis may be associated with a disseminating clone of A. actinomycetemcomitans in some adolescents of African origin. Several association studies indicate that the role of some periodontal microorganisms may change with advancing age. The prevalence of A. actinomycetemcomitans, and the relative numbers of this organism in positive sites, appear to decrease with age.97-104 The presence of A. actinomycetemcomitans seems to be a major problem for a small number of subjects, who develop severe periodontal tissue breakdown early in life. On the other hand, if it is true that young people generally have more A. actinomycetemcomitans, higher frequencies of this organism in EOP than in AP could be interpreted as a simple reection of age. In summary, although several studies have established a link between specic components of the subgingival microora and at least one clinical presentation of EOP, there is not enough evidence to suggest that current clinical classication schemes discriminate between disease entities with a specic microbial cause. In other words, A. actinomycetemcomitansassociated periodontal disease is not a synonym of LJP. Conversely, EOP does not seem to be synonymous of infection with A. actinomycetemcomitans. On the other hand, since clinical studies of A. actinomycetemcomitans-associated periodontal disease are showing a significant correlation between treatment outcomes and levels of A. actinomycetemcomitans after therapy, inclusion of a microbiologic diagnosis of LJP and possibly EOP appears meaningful from a therapeutic point of view. In fact, there is evidence showing that A. actinomycetemcomitans is suppressed more effectively with mechanical treatment plus adjunctive antibiotic therapy than with mechanical instrumentation alone. In this respect, once diagnosis of EOP has been established, additional knowledge regarding the

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implication of A. actinomycetemcomitans in the disease process is justied. Susceptibility Criteria The marked contrast between clinical appearance of AP and EOP, with EOP often showing a marked disproportion between the amount of bacterial deposits and the severity of periodontal destruction, has led to a general acceptance of a hypothesis that EOP patients have high susceptibility to periodontal infections. Over the years many investigations have demonstrated the association of both environmental (external) and endogenous (internal) host response modifiers with early-onset forms of periodontitis. An important aspect in the initial understanding of host susceptibility towards EOP has been the decreased migration and antibacterial functions of the polymorphonuclear leukocytes (PMN) detected in some LJP and G-EOP patients.105-110 These abnormalities are frequently minor in the sense that they are usually not associated with infections other than periodontitis. Interestingly, the reports of neutrophil abnormalities associated with EOP have not been conrmed in a European population.111,112 This may indicate heterogeneity in host susceptibility to EOP in different populations. A key report in North American populations has indicated that PMN abnormalities in LJP patients seem to cluster in families in much the same way as EOP does.113 This evidence has been interpreted as a suggestion that the LJP-associated PMN defect(s) may be inherited. Other recent reports have indicated that PMN abnormalities in LJP patients may be, at least in part, the result of a hyper-inammatory state resulting in the presence of pro-inammatory cytokines in the serum of some EOP patients.114,115 In EOP, local inflammatory responses have been characterized by high levels of inammatory mediators such as prostaglandin E2, interleukin-1 (IL) and interleukin-1 in both crevicular fluid and tissue.116,117 Prostaglandin E2 production, in particular, has been shown to be highly elevated in EOP subjects when compared to periodontally healthy individuals and adult periodontitis patients.118 Of key importance was the observation that the increased local concentrations of inammatory mediators in EOP were associated with increased responsiveness of circulating monocytes to bacterial challenges.118,119 The relative contribution of genetic and environmental factors to the detected hyper-inammatory phenotype in EOP subjects, however, remains to be determined. In recent years the level of genetic susceptibility for EOP has received increasing attention. Several family studies have indicated that the prevalence of EOP is disproportionately high among certain families, where the percentage of affected siblings may reach 40% to 50%.120-124 Such a dramatic familial aggregation of

cases indicates that genetic factors may be important in susceptibility to EOP. Genetic studies in these families suggest that the pattern of disease transmission is consistent with Mendelian inheritance of a gene of major effect.120-125 This means that the observed familial pattern can be partly accounted for by one or more genes that could predispose individuals to develop EOP. Segregation analyses have indicated that the likely mode of inheritance is autosomal dominant.120,121,124,125 Most of these investigations, however, were carried out in African-American populations; it is therefore possible that other modes of inheritance may exist in different populations. Segregation analysis can provide information about the mode of inheritance of a genetic trait but does not provide information about the specic gene(s) involved. The chromosomal location of a gene of major effect for a trait such as EOP susceptibility can be determined by linkage analysis. An investigation utilizing this methodology reported linkage of LJP to the vitamin D binding locus on region q of chromosome 4 in a large family of the Brandywine population.126 These results, however, were not conrmed in a subsequent study in a different population.127 Allelic variations in the Fc receptor for IgG2 immunoglobulins have also been suggested to play a role in suboptimal handling of A. actinomycetemcomitans infections in susceptible subjects. PMNs of subjects expressing the R131 allotype of FcRIIa (i.e., a Fc receptor containing an arginine instead of a histidine at amino acid 131) show decreased phagocytosis of A. actinomycetemcomitans.128 Furthermore, a heterogeneous group of periodontitis patients (aged 20 years) who did not respond to treatment (refractory periodontitis) has been shown to display a somewhat higher prevalence of homozygosity in the R131 allelic variant.129 Of interest are also recent investigations130-132 indicating that EOP subjects do not seem to share an increased prevalence of a specific polymorphism in the IL-1 gene complex with non-smoking AP subjects.133 In addition, genes of major effect that may determine susceptibility to EOP, it has been proposed that other genes may act as modifying genes and inuence clinical expression of the disease. In this respect, special interest has been focused upon the impact of genetic control on antibody responses against specic EOPassociated bacteria and against A. actinomycetemcomitans in particular. These studies have indicated that the ability to mount high titers of specic antibodies is race-dependent and probably protective.134,135 This has been shown to be under genetic control as a co-dominant trait, independent of the risk for EOP. In individuals susceptible to EOP, therefore, the ability to mount high titers of antibodies (IgG2 in particular) may
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Volume 4 Number 1 December 1999

be protective and prevent extension of disease to a generalized form.12 It should, however, also be emphasized that environmental factors such as cigarette smoking have also been associated with changes in the capability to produce IgG2.136 Complex eco-genetic interactions may, therefore, be the basis of patient susceptibility to EOP. Such data are currently considered to support the existence of genetic heterogeneity in host susceptibility between EOP and AP, and among distinct forms of EOP. Therefore, it is currently maintained that although formal genetic studies of EOP support the existence of a gene of major effect, it is unlikely that all EOP clinical syndromes are associated with the same genetic defect.137 This idea is consistent with the fact that numerous diseases and syndromes with similar clinical appearance are known to be associated with different genetic susceptibility traits. It also represents the most convincing data suggesting that AP and EOP syndromes comprise different disease entities, and that the same may be true for the various EOP syndromes. Among environmental factors, particular emphasis is currently placed upon cigarette smoking. It has been shown that cigarette smoking is associated with signicant increases in the odds of EOP and that such increase is dose-dependent. Furthermore, cigarette smoking has been associated with an increase in both the severity and the extent (distribution of lesions) of periodontal destruction in young adults.12 In taking into account the role of both genetic and environmental susceptibility factors, it should be emphasized that host susceptibility to periodontitis (and possibly to EOP) is currently considered to be a complex trait. The combination of multiple endogenous and exogenous factors, in fact, is thought to determine the susceptibility level of the individual subject.138-140 Very little evidence, however, is available on the signicance, relative impact, and interaction of the different factors. At the present stage of knowledge, these concepts further limit the incorporation of host susceptibility factors into a classication. In particular, proposing a classication scheme in which EOP associated with various susceptibility traits or systemic conditions would each be listed as unique disease entities would be misleading since it will not account for the multifactorial nature of EOP susceptibility. As an example, attachment loss in a young subject with diabetes, who smokes cigarettes, and is HIV-positive could not be adequately performed. In summary, it seems that EOP susceptibility has a tendency to run in families. At least in some ethnic groups, this is probably due to Mendelian gene(s) inherited according to an autosomal dominant pattern. It seems that the specic genes may be different in various populations and/or ethnic groups and that
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therefore true heterogeneity in disease susceptibility may be present. The role of specic genes remains to be elucidated. Environmental factors, such as cigarette smoking, have also been shown to be able to affect disease presentation and gene expression, suggesting that disease susceptibility may in fact be regulated by complex eco-genetic interactions. In spite of the great progress in the understanding of EOP susceptibility, it seems that, to date, there is insufcient knowledge to implicate genetic and/or environmental factors in the classification of these syndromes. At the present state of imperfect knowledge, the evidence that has been reviewed in these sections indicates that a classication scheme needs to be based on syndromic criteria and possibly integrated with etiologic information. EPIDEMIOLOGICAL CONSIDERATIONS Relatively few investigations employing different epidemiological techniques have estimated the prevalence and the progression of EOP in the primary and permanent dentition(s) of children and young adults. All available investigations, however, indicate that early-onset forms of periodontal diseases are detectable in all age and ethnic groups.141 Wide variation in prevalence, however, has been reported; with some studies showing up to 51.5% of individuals affected. These differences are probably due to differences in the employed epidemiological methodologies and denition of EOP. Little evidence is available concerning the prevalence of EOP affecting the primary dentition. In the few studies from industrialized countries, alveolar bone loss has been found to affect the primary dentition of 5- to 11-year-olds with frequencies ranging from 0.9 to 4.5% of subjects.142-144 Permanent Dentition In the permanent dentition of 13 to 20 year-old individuals, the majority of studies have reported a prevalence of EOP of less than 1% (usually 0.1 to 0.2% in Caucasian populations).145 The risk of developing EOP, however, does not seem to be shared equally in the population: among U.S. schoolchildren 5 to 17 years of age, the prevalence of EOP has been estimated to range from about 0.2% for Caucasians to about 2.6% for African-Americans.9 Furthermore, a higher prevalence of EOP has been reported in studies from some developing countries.145 A synopsis of Community Periodontal Index of Treatment Needs (CPITN) data from the WHO global oral health bank including 103 surveys of 15- to 19-year-old individuals from 60 countries indicated that, in this age group, deep periodontal pockets are a rare occurrence.146 In a recently reported study involving a representative sample of

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18- to 34-year-old people in the U.S. population, the observed EOP prevalence was 3.6%.147 Longitudinal studies of disease progression in adolescents indicate that subjects with signs of destructive periodontitis at a young age are prone to further deterioration. Such deterioration appears to be more pronounced at initially affected sites and in individuals diagnosed with juvenile periodontitis and from low socio-economic levels. Deterioration of the periodontal status involves both an increase in extent (prevalence of lesions within the dentition) and an increase in severity of lesions.148-153 RATIONALE TO DIFFERENTIATE AP AND EOP AND DISTINCT FORMS OF EOP The following justify discriminating between EOP and AP clinical syndromes: 1. Epidemiologically, EOP is an infrequent condition, whereas AP is a common disease. 2. In contrast to adult periodontitis, there is often a marked disproportion between the amount of periodontal tissue destruction and the amount of plaque and calculus in EOP. 3. There is evidence for a specic role of some bacterial pathogens. The differential element of treatment of EOP relates to specic efforts to affect the composition, not only the quantity, of the subgingival microbiota. 4. Genetic studies support the existence of differential genetic predisposition to the two clinical entities. The following diagnostic problems are not resolved by proposing EOP as a distinct disease entity based on age as the primary criterion: 1. Unless age at onset is considered, patients diagnosed on the basis of an age-dependent classication will change their diagnosis, as they grow older, even if there is no evidence for a change in etiology and susceptibility. 2. The age criterion to differentiate the two syndromes (currently 35 years of age147) is, to a large extent, arbitrary and largely based upon epidemiological considerations. 3. Differential diagnosis of EOP and AP may be problematic in cases displaying documented discrepancy between age of onset and age of detection. 4. The same etiologic agents can cause EOP and AP. The following observations justify the need for a subclassication of EOP: 1. Recognition that periodontal disease in children and young adults may represent an oral manifestation of a systemic disease. 2. Existence of phenotypic variation in disease presentation that has led, over the years, to the identication of specic EOP syndromes. 3. General clinical consensus of differential prognosis and the need for specic treatment approaches for the various syndromes.

4. Heterogeneity in etiology with possible therapeutic implications. 5. Heterogeneity in genetic and environmental susceptibility. 6. Possibility of forms affecting only the permanent or the primary dentition. The following criteria may be useful in differentiating among EOP syndromes: 1. Association with medical conditions. 2. Involvement limited to the primary dentition or affecting also permanent teeth. 3. Distribution of lesions within the dentition. 4. Additional criteria which include severity of lesions, rate of progression, and response to therapy. 5. Etiology, particularly an association with A. actinomycetemcomitans. CLASSIFICATION OF EOP CLINICAL SYNDROMES In the current classication schemes, early-onset forms of periodontal disease have been grouped based on the fundamental criterion of being an oral manifestation of a systemic disease or being a primarily periodontal condition. This fundamental subdivision has been also recognized by the International Classication of Disease that has assigned a specic code to periodontal disease and premature tooth exfoliation resulting from a systemic condition (Code K08.0) as opposed to primarily periodontal infections that are described in the K05 family of codes. A compilation of the systemic disorders associated with periodontal destruction early in life was provided in the 1996 World Workshop.154 Another criterion comes from the description of the lesions being limited to the primary dentition or extending to the permanent dentition. Since detection of EOP affecting the primary dentition usually occurs before puberty, these forms have frequently been called prepubertal. Conversely, EOP forms involving the permanent dentition have been classically diagnosed after puberty and have been termed juvenile. Two broad groups of EOP have therefore been identied: prepubertal forms affecting mainly the primary dentition and juvenile or young adult forms involving the permanent dentition. Because primary teeth are shed and because of the infrequent documented occurrence of periodontal disease in the primary dentition, it appears reasonable to use involvement of the primary dentition as an additional classification criterion. However, because the primary and permanent dentition may be simultaneously or sequentially affected in the same subject, this subclassication may not be based on a unique etiology and susceptibility of the primary dentition. Disease severity and distribution within the dentition are the secondary criteria that have been
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employed for the current classication of early-onset forms of periodontal disease. The following syndromes have thus been recognized: localized and generalized forms of prepubertal periodontitis (PPP);6,8 localized juvenile periodontitis (LJP);1-3,7,9-13 and generalized early-onset periodontitis (G-EOP),9,12 also referred to as generalized juvenile periodontitis (GJP),3,6,7,13 severe periodontitis (SP),6 or rapidly progressing periodontitis (RPP).5 Discriminating between localized and generalized EOP appears justied on the basis of the fact that some forms of EOP characterized by localized lesions do not seem to spread to the entire dentition. These forms are generally considered to have a better prognosis than those where the disease produces lesions throughout the dentition. On the other hand, it has been documented that localized forms often progress to a generalized pattern. Diagnosis of EOP requires exclusion of the presence of systemic diseases that may severely impair host defenses and lead to premature tooth loss. In such instances the clinical diagnosis may be attachment loss and premature exfoliation of teeth associated with systemic diseases.16 Often adolescents and young adults present with attachment loss that does not t the specic diagnostic criteria established for EOP; this occurrence has been recently termed incidental attachment loss in children and young adults.9 Current clinical and anamnestic criteria for diagnosis and case denition of the different forms of EOP are dened below.1-13 Attachment Loss and Premature Exfoliation of Teeth Associated With Systemic Diseases (ICD-DA K08.0) 1. Advanced attachment loss frequently leading to premature tooth exfoliation (primary and/or permanent) in children, adolescents, and young adults. 2. Association with severe systemic conditions (frequently with genetic basis) leading to impaired host defense against bacterial infections. 3. Age of onset: variable and dependent upon nature of systemic condition. 4. Distribution: most of the dentition (both primary and permanent). 5. Severe inflammation of both marginal and attached gingiva. This condition17 is generally considered to include the generalized forms of prepubertal periodontitis. In fact, just one single case of generalized prepubertal periodontitis in the absence of obvious systemic conditions has been described.155 It has been shown that various systemic conditions may be associated with an increased incidence of periodontitis. For some of these, development of attachment loss and tooth exfoliation can be con46

sidered to be a periodontal manifestation of the systemic condition. Typical examples will include rare leukocyte deciencies such as the type 1 leukocyte adhesion deciency, Jobs syndrome, Chediak-Higashi syndrome, Papillon-Lefvre syndrome, neutropenias, aplastic anemias, leukemias, and rare collagen diseases such as some forms of the Ehlers-Danlos syndrome. The association between other diseases and EOP, however, may be more complex. Taking diabetes as an example, in an affected subject, periodontitis may be considered to be primarily a rather infrequent complication of poor glycemic control.138 In the specic case of diabetes, the majority of the evidence reports an increase in the prevalence of gingivitis but no increase in the prevalence or incidence of attachment loss and/or bone loss in well controlled juvenile diabetics.156-165 Increased incidence of attachment loss and bone loss, on the other hand, has been observed in young adults affected with non-insulin-dependent diabetes in specific populations such as the Pima and Popago Indian tribes.160 These forms may represent either periodontal manifestation of a systemic disease or an early-onset form of periodontitis associated with the presence of a systemic disease acting as a modifying factor. Prepubertal Periodontitis (PPP, Localized Form) 1. Attachment alveolar bone loss evident only in the primary dentition (more frequently primary molars). 2. Age of onset: currently unknown but probably as early as 4 years of age and as late as the late mixed dentition. 3. Distribution: primary molars and incisors. 4. Moderate accumulation of plaque and calculus. 5. Moderate signs of gingival inammation; bleeding on probing, however, is present at diseased sites. 6. Presence of gingival clefts and localized ulceration of the gingival margin. 7. Absence of systemic conditions and no history of recurrent infections. 8. Absence of local factors (e.g., subgingival decay or llings) at the areas of periodontal destruction. Localized Juvenile Periodontitis (LJP) 1. Attachment loss of 4 mm or more on at least 2 permanent rst molars and incisors (at least one rst molar must be affected). 2. Distribution: attachment loss of 4 mm or more in no more than two teeth other than rst molars or incisors. 3. Age of onset: between puberty and 25 to 30 years of age. 4. Tendency of cases to aggregate in families.

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5. Absence of local factors (e.g., subgingival decay or llings) at the areas of periodontal destruction. Generalized Early-Onset Periodontitis (G-EOP) 1. Attachment loss of 4 mm or more affecting at least 8 teeth. 2. Distribution: at least 3 affected teeth other than molars and incisors. 3. Age of onset: before age 35. G-EOP represents the most heterogeneous group and includes the most severe forms of periodontitis, comprising forms originally described as generalized juvenile periodontitis (emphasis on a possible relationship with LJP), severe periodontitis (emphasis on the advanced destruction in a young subject), or rapidly progressing periodontitis (emphasis on the high rate of progression of lesions in these forms). Each of these G-EOP forms, however, remains highly heterogeneous in terms of clinical presentation and response to therapy. Incidental Attachment Loss Isolated areas of attachment loss in otherwise healthy dentitions, including recessions associated with traumatic injuries and/or tooth position, attachment loss associated with impacted third molars, with endodontic infection, root fractures, subgingival caries,and/or with restorations have been termed incidental attachment loss.10 Since isolated areas of attachment loss may also represent initial clinical presentations of localized forms of EOP, patients with this clinical diagnosis should be considered as a high-risk group for EOP. In fact, in one study, one fourth of patients classied as having incidental attachment loss experienced moderate/rapid disease progression.13 Relationship Among Recognized EOP Clinical Syndromes Case reports have indicated that some subjects may, at different ages, be classied as having experienced PPP, followed by LJP, and later by G-EOP.166 One investigation has indicated that the primary dentition of LJP patients presented bone loss at primary molars in 20% to 52% of the cases. This suggested that at least some of the studied LJP cases may have started as PPP.17,18 Furthermore, in LJP subjects an association between the number of lesions and the age of the subject has been described, suggesting an age-dependent shift from localized to generalized forms of EOP.3,6 This evidence underlines the limitations of a classication based upon syndromic criteria only and age in particular. CONCLUSIONS The points discussed above support the following conclusions: 1. The emerging evidence of genetic heterogeneity in the susceptibility prole to AP and EOP support the

case for differentiating between adult and early-onset periodontitis syndromes. 2. There seems to be evidence of disease heterogeneity among different forms of EOP; this supports differentiating among different EOP syndromes. 3. A case can be made to differentiate early-onset periodontitis from attachment loss and tooth exfoliation observed in children and young adults affected with systemic conditions. 4. An ideal classication of EOP should be based on etiology and individual susceptibility and provide the basis to implement focused, predictable therapy. In the light of the present level of knowledge, such a classication cannot be proposed. A practical classication needs to be based upon imperfect syndromic criteria. 5. Syndromic classication(s) should be designed to cluster similar disease phenotypes in more homogeneous syndromes. This is the prerequisite to establish etiology and susceptibility traits and thus separate truly different forms of disease (disease heterogeneity) or conversely link different phenotypic variations to the same underlying disease. 6. Using the patients age as the major classication criterion has important limitations since clinical conditions with the same underlying etiology and susceptibility may be classified differently only on the basis of the patients age. In addition, given the lack of evidence of a discrete age-dependent window of susceptibility, the use of a specic age to discriminate among different conditions has to be arbitrary and, therefore, subject to criticism. 7. Besides age, distribution of lesions has been the other key classication criterion. In this respect, the number and the location of the lesions along with their involvement of the primary and/or permanent dentition has been widely used in case denition. This strategy has proven successful in establishing the association between LJP and A. actinomycetemcomitans infection with PMN abnormalities in specic subpopulations. 8. Several classification systems have included response to therapy or lack thereof as an additional criterion. As discussed, lack of treatment response represents the major clinical rationale for subclassication of a syndrome. On the other hand, at the present time, insufcient documentation of treatment outcomes seems to warrant including lack of response to treatment as a major classication parameter. Classications based on syndromic criteria should be as simple as possible and offer the possibility of describing the specic case with additional descriptors. These descriptors could include information on the microbiological, genetic, or environmental risk factor prole of the case. As suggested by the Consensus Report of the 1st European Workshop on Periodontology, each of the
47

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above conditions should be further described using secondary descriptors.21 These include relationship to specic systemic modifying factors, presence of specic etiologic agents, and response to treatment. REFERENCES
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titis. J Periodontol 1996;67:355-366. 138. Le H. Periodontal disease. The sixth complication of diabetes mellitus. Diabetes Care 1993;16(Suppl.1): 329-334. 139. Genco RJ. Current view of risk factors for periodontal diseases. J Periodontol 1996;67:1041-1049. 140. Tonetti MS. Cigarette smoking and periodontal diseases: Etiology and management of disease. Ann Periodontol 1998;3:88-101. 141. Papapanou PN. Periodontal diseases: Epidemiology. Ann Periodontol 1996;1:1-36. 142. Sweeney EA, Alcoforado GAP, Nyman S, Slots J. Prevalence and microbiology of localized prepubertal periodontitis. Oral Microbiol Immunol 1987;2:65-70. 143. Sjdin B, Matsson L. Marginal bone loss in the primary dentition. A survey of 79-year-old children in Sweden. J Clin Periodontol 1994;21:313-319. 144. Bimstein E, Treasure ET, Williams SM, Dever JG. Alveolar bone loss in 5-year-old New Zealand children: its prevalence and relationship to caries prevalence, socioeconomic status and ethnic origin. J Clin Periodontol 1994;21:447-450. 145. Papapanou P, Lindhe J. Epidemiology of periodontal disease. In: Lindhe J, Karring T, Lang N, eds. Clinical Periodontology and Implant Dentistry. Copenhagen: Munksgaard; 1997:69-101. 146. Miyazaki H, Pilot T, Leclercq M-H, Barnes DE. Proles of periodontal conditions in adolescents measured by CPITN. Int Dent J 1991;41:67-73. 147. Oliver RC, Brown LJ, Le H. Periodontal disease in the United States population. J Periodontol 1998;69:269278. 148. Albandar JM, Buischi YAP, Barbosa MFZ. Destructive forms of periodontal disease in adolescents. A 3-year longitudinal study. J Periodontol 1991;62:370-376. 149. Albandar JM, Baghdady VS, Ghose LJ. Periodontal disease progression in teenagers with no preventive dental care provisions. J Clin Periodontol 1991;18:300304. 150. Albandar JM. Juvenile periodontitispattern of progression and relationship to clinical periodontal parameters. Community Dent Oral Epidemiol 1993;21:185189. 151. Aass AM, Tollefsen T, Gjermo P. A cohort study of radiographic alveolar bone loss during adolescence. J Clin Periodontol 1994;21:133-138. 152. Clerehugh V, Lennon MA, Worthington HV. 5-year results of a longitudinal study of early onset periodontitis in 14- to 19-year-old adolescents. J Clin Periodontol 1990;17:702-708. 153. Lissau I, Holst D, Friis-Hasch E. Dental health behaviors and periodontal disease indicators in Danish youths. A 10-year epidemiologic follow-up. J Clin Periodontol 1990;17:42-47. 154. Mealey BL. Periodontal implications: Medically compromised patients. Ann Periodontol 1996;1:256-321. 155. Bimstein E, Sela MN, Shapira L. Clinical and microbial considerations for the treatment of an extended kindred with seven cases of prepubertal periodontitis: a 2-

year follow-up. Pediatric Dent 1997;19:396-403. 156. Barnett ML, Baker RL, Yancey JM, MacMillan DR, Kotoyan M. Absence of periodontitis in a population of insulin-dependent diabetes mellitus (IDDM) patients. J Periodontol 1984;55:402-405. 157. Rylander H, Ramberg P, Blohm G, Lindhe J. Prevalence of periodontal disease in young diabetics. J Clin Periodontol 1987;14:38-43. 158. Rosenthal IM, Abrams H, Kopczyk RA. The relationship of inammatory periodontal disease to diabetic status in insulin-dependent diabetes mellitus. J Clin Periodontol 1988;15:425-429. 159. Sandholm L, Swanljung O, Rytmaa I, Kaprio EA, Menp J. Periodontal status of Finnish adolescents with insulin-dependent diabetes mellitus. J Clin Periodontol 1989;16:617-620. 160. Emrich LJ, Shlossman M, Genco RJ. Periodontal disease in non-insulin-dependent diabetes mellitus. J Periodontol 1991;62:123-130. 161. De Pommereau V, Dargent-Par C, Robert JJ, Brion M. Periodontal status in insulin-dependent diabetic adolescents. J Clin Periodontol 1992;19:628-632. 162. Firalti E, Yilmaz O, Onan U. The relationship between clinical attachment loss and the duration of insulindependent diabetes mellitus (IDDM) in children and adolescents. J Clin Periodontol 1996;23:362-366. 163. Pinson M, Hoffman WH, Garnick JJ, Litaker MS. Periodontal disease and type 1 diabetes mellitus in children and adolescents. J Clin Periodontol 1995;22:118-123. 164. Novaes AB Jr., Silva MAP, Batista EL Jr., des Anjos BA, Novaes AB, Pereira ALA. Manifestations of insulindependent diabetes mellitus in the periodontium of young Brazilian patients. A 10-year follow-up study. J Periodontol 1997;68:328-334. 165. Sbordone L, Ramaglia L, Barone A, Ciaglia RN, Iacono VJ. Periodontal status and subgingival microbiota of insulin-dependent juvenile diabetics: A 3-year longitudinal study. J Periodontol 1998;69:120-128. 166. Shapira L, Smidt A, Van Dyke TE, et al. Sequential manifestation of different forms of early-onset periodontitis. A case report. J Periodontol 1994;65:631635. Send reprint requests to: Dr. Maurizio Tonetti, Department of Periodontology, Eastman Dental Institute and Hospital, University College London, 256 Grays Inn Road, London WC1X 8LD UK. E-mail: M.Tonetti@eastman.ucl.ac.uk

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