J Clin Periodontol 2002; 29: 370–374 Copyright C Blackwell Munksgaard 2002Printed in Denmark . All rights reserved

ISSN 0303-6979

Case ReportJ. J. Pacheco 1, C. Coelho 2,F. Salazar1, A. Contreras 3,4, J. Slots 3Treatment of Papillon-Lefevreand C. H. Velazco 2

1Department of Periodontology, School ofDentistry, Instituto Superior de Ciencias dasyndrome periodontitis Saude-Norte, Paredes, Portugal; 2Departmentof Microbiology, Instituto Superior de Cienciasda Saude-Norte, Paredes, Portugal;3Department of Periodontology, School ofDentistry, University of Southern California,Los Angeles, USA; 4Department ofPeriodontology, School of Dentistry,Universidad del Valle, Cali, Colombia

Pacheco JJ, Coelho C, Salazar F, Contreras A, Slots J, Velazco CH: Treatmentof Papillon-Lefevre syndrome periodontitis. J Clin Periodontol 2002; 29: 370–374. C Blackwell Munksgaard, 2002.

AbstractBackground, aims: Conventional mechanical treatment of Papillon-Lefevre syn-drome periodontitis has a poor prognosis. This report describes an effectiveantimicrobial treatment of rapidly progressing periodontitis in an 11-year old girlhaving Papillon-Lefevre syndrome.Method: Clinical examination included conventional periodontal measurementsand radiographic analysis. Occurrence of major suspected periodontopathicbacteria was determined by selective and non-selective culture and by polymerasechain reaction (PCR) identification. Presence of cytomegalovirus and Epstein-Barr type 1 virus was determined by a nested-PCR detection method. Therapyincluded scaling and root planing, oral hygiene instruction, and systemic amoxi-cillin-metronidazole therapy (250 mg of each/3 times daily/10 days) which, basedon follow-up microbiological testing, was repeated after 4 months. Supportiveperiodontal therapy took place at 2 visits during a 16-month period.Results: At baseline, 10 of 22 available teeth demonstrated severe periodontalbreakdown. At 16 months, probing and radiographic measurements revealedno teeth with additional attachment loss, and several teeth exhibited significantreduction in gingivitis and pocket depth, increase in radiographic alveolar boneheight and clinical attachment level, and radiographic evidence of crestal laminadura. Baseline subgingival microbiota included Actinobacillus actinomycetem-comitans (3.4% of total isolates), Prevotella nigrescens (16.4%), Fusobacteriumnucleatum (14.3%) and Peptostreptococcus micros (10.6%), as well as cytomeg-alovirus and Epstein-Barr type 1 virus. At termination of the study, culture and Key words: Papillon-Lefevre syndrome;PCR examinations showed absence of A. actinomycetemcomitans, P. micros and periodontitis; periodontal treatment;herpesviruses, and P. nigrescens and F. nucleatum each comprised less than 0.1 Actinobacillus actinomycetemcomitans;

amoxicillin, metronidazole; human% of subgingival isolates.cytomegalovirus; Epstein-Barr virus;Conclusion: This study suggests that controlling the periodontopathic microbiota polymerase chain reaction

by appropriate antibiotic and conventional periodontal therapy can arrest Papil-lon-Lefevre syndrome periodontitis. Accepted for publication 13 March 2001

Papillon-Lefevre syndrome is an auto-somal recessive trait in which the mainfeatures are hyperkeratosis of the palmsand the soles and severe early-onsetperiodontitis (Hart et al. 1999, Nitta et

al. 2000). Possible mechanisms relatinggenetics and periodontal disease includevirulent infection, altered immune re-sponse and underlying tissue pathology(Hart & Shapira 1994). Velazco et al.

(1999) suggested that Actinobacillusactinomycetemcomitans in concert withhuman herpesviruses play importantroles in the development of Papillon-Lefevre syndrome periodontitis.

Papillon-Lefevre syndrome periodontitis 371

Previous treatment of Papillon-Le-fevre syndrome periodontitis amountedmainly to extraction of severely affectedteeth (Rosenthal 1951, Preus & Gjermo1987). To prevent periodontal break-down of permanent teeth, Coccia et al.(1966) and Baer & McDonald (1981)extracted all primary teeth at a youngage. Tinanoff et al. (1986) extracted allerupted permanent teeth of a Papillon-Lefevre syndrome patient 9-years of ageafter unsuccessful clinical treatmentwith erythromycin and found normalperiodontal conditions at age 16-years.In 2 Papillon-Lefevre syndrome pa-tients, Preus & Gjermo (1987) pre-vented further loss of alveolar bone andperiodontal attachment by extractinghopeless teeth and prescribing systemictetracycline. However, some Papillon-Lefevre syndrome patients have experi-enced continued periodontal break-down following tetracycline therapy(Van Dyke et al. 1984, Lu et al. 1987,Bullon et al. 1993). Glenwright (1990)treated Papillon-Lefevre syndrome peri-odontitis with penicillin, tetracyclineand metronidazole at different timesbut did not arrest bone destructionaround primary or permanent teeth.Eronat et al. (1993) were successful intreating Papillon-Lefevre syndromeperiodontitis with amoxicillin/clavulan-ic acid but Bullon et al. (1993) were not.Umeda et al. (1990) used systemicofloxacin to eliminate A. actinomyce-temcomitans from a patient with Papil-lon-Lefevre syndrome periodontitis andobtained reduction in gingivitis andpocket depth. However, antimicrobialagents of the quinolone group are notrecommended for children and adoles-cents. Rüdiger et al. (1999) prescribedsystemic amoxicillin and metronidazoleto 4 Papillon-Lefevre syndrome pa-tients, which resolved the periodontalA. actinomycetemcomitans infectionand destructive disease in 3 patients but

Table 1. Clinical findings in an 11-year old girl with Papillon-Lefevre syndrome periodontitis

Antibiotic therapy Antibiotic therapyBaseline 4 months 8 months 16 months

Items (6 study sites per tooth, totally 20 teeth) (%) (%) (%) (%)

% sites with visible plaque 100 100 83 67% teeth with >3 sites bleeding on probing 65 65 20 15% teeth with at least 1 sitde bleeding on probing 65 65 45 30% sites with >5 mm pocket depth 16 16 9 1% sites with 4 mm pocket depth 84 84 13 12% sites with <3 mm pocket depth 0 0 78 87% teeth with mobility >1 mm in horizontal direction 20 20 10 10

did not control A. actinomycetemcomit-ans or the disease in one patient.

Since A. actinomycetemcomitansseems to be an important pathogen inPapillon-Lefevre syndrome peri-odontitis (Van Dyke et al. 1984, Preus1988, Bimstein et al. 1990, Umeda et al.1990, Eronat et al. 1993, Ishikawa et al.1994, Stabholz et al. 1995, Kleinfelderet al. 1996, Lundgren et al. 1998, Velaz-co et al. 1999, Rüdiger et al. 1999, DeVree et al. 2000), it is rational to employantimicrobials effective against the or-ganism in treatment of the disease.

The present report describes clinicaland microbiological features of an 11-year old girl suffering from Papillon-Lefevre syndrome periodontitis whowas treated with systemic amoxicillin-metronidazole, an antimicrobial drugcombination with proven effectivenessagainst A. actinomycetemcomitans peri-odontal infection (Pavicic et al. 1994).The therapy rendered was able to pre-vent further periodontal disease pro-gression throughout the 16 months ob-servation period.

Material and Methods

Baseline clinical and microbiologicalfeatures of the 11-year old girl with Pa-pillon-Lefevre syndrome have been de-scribed previously (Velazco et al. 1999).

Clinical examination included con-ventional periodontal measurementsand radiographic analysis. In eachtooth, mesio-facial, mid-facial, disto-fa-cial, mesio-lingual, mid-lingual and dis-to-lingual sites were evaluated for pres-ence of visible plaque, bleeding onprobing and probing pocket depth.

Microbiological examination wascarried out on pooled samples of sub-gingival plaque obtained from the me-sial surfaces of teeth number 16, 26, 32and 42. Selective and nonselective cul-ture and polymerase chain reaction

(PCR) identification were used to deter-mine the occurrence of major suspectedperiodontopathic bacteria, and nested-PCR detection to determine the pres-ence of cytomegalovirus and Epstein-Barr type 1 virus.

Treatment included scaling and rootplaning, oral hygiene instruction, andsystemic amoxicillin-metronidazoletherapy (250 mg of each/3 times daily/10 days) which, based upon follow-upmicrobiological testing, was repeatedafter 4 months. Supportive periodontaltherapy was performed at months 4, 8and 16.

Results

The 11-year old girl exhibited hyper-keratosis on her palms and soles. Thepatient showed no other signs of der-matological disorders.

At initial examination, teeth number16 to 26, 32 to 36 and 42 to 46 werepresent. Teeth number 31 and 41 werepreviously lost due to excessive mo-bility. Teeth number 11, 21, 32 and 42showed radiographic evidence of peri-odontitis that affected virtually the en-tire root surface. Teeth number 11 and21 exhibited mobility in an incisal-api-cal direction and were extracted.

At baseline, 100% of tooth surfacesrevealed visible plaque and 65% of theteeth demonstrated bleeding on probingin at least 3 sites (Table 1). All teeth ex-hibited pocket depths of 4 mm or moreand 20% of the teeth showed horizontalmobility of 1 mm or more (Table 1). Noteeth showed evidence of calculus.

Following the second course of anti-biotic therapy, proportions of teethshowing multiple sites with bleeding onprobing decreased about 4-fold (Table1). Also, most teeth exhibited reducedpocket depth and only one tooth had 5mm or more in probing depth at the

372 Pacheco et al.

Fig. 1. Radiographic examination at 16-months posttreatment of an 11-year old girl havingPapillon-Lefevre syndrome periodontitis. Several deep periodontal sites show radiographicevidence of crestal lamina dura.

end of the observation period (Table1).

The 4 tooth surfaces that were exam-ined microbiologically exhibited at base-line an average pocket depth of 5.8 mm(range, 4–8 mm) and an average gingivalrecession of 3.0 mm (range, 2–4 mm). At16 months, pocket depth averaged 3.5mm (range, 2–4 mm) and gingival re-cession 5.0 mm (range, 3–6 mm).

No further loss in radiographic al-veolar bone height was evident frombaseline to 16 months posttreatment.At the end of the observation period,periodontal lesions around teeth No.24, 25, 33, 34, 35, 36, 43, 44, 45 and 46revealed radiographic evidence ofcrestal lamina dura (Fig. 1).

Table 2 lists the subgingival micro-biota of the patient. At baseline, A.actinomycetemcomitans comprised3.4%, and Prevotella nigrescens, Fuso-bacterium nucleatum and Peptostreptoc-

Table 2. Subgingival microbial agents in an 11-year-old girl with Papillon-Lefevre syndrome periodontitisa)

Antibiotic Antibiotictherapy therapy

Baseline 2 months 6 months 13 months 16 months

pooled pooled sample sample sample samplesample sample 1 2 1 2 pooled sample 1 sample 2

Microbial agents culture PCR culture culture culture culture culture PCR culture PCR culture PCR

A. actinomycetemcomitans 3.4 π 3.0 0 0 0 0 0 0 0 0 0P. nigrescens 16.4 π 7.2 0 0 0.08 0.07 π 0 π 0.08 πF. nucleatum 14.3 not done 3.4 0.03 0 0.08 0.04 not done 0.1 not done 0.08 not doneP. micros 10.6 not done 8.5 0 0 0 0 not done 0 not done 0 not doneE. corrodens 0.8 π 0 0.06 10.8 0 0 π 0 π 0 πP. gingivalis 0 π 0 0 0 0 0 π 0 π 0 0Cytomegalovirus π π 0 0 0Epstein-Barr type 1 virus π 0 0 0 0a Pooled sample from 16 mesial, 32 mesial and 42 mesial. Sample 1 from 16 mesial and 26 mesial. Sample 2 from 32 mesial and 42 mesial.

occus micros combined made up 40% ofcultivable microorganisms. Subgingivalcytomegalovirus and Epstein-Barr type1 virus were detected as well.

The antibiotic therapy prescribed atbaseline had little or no effect upon thecomposition of the subgingival micro-biota, as revealed by the 4-month fol-low-up microbiological sample (Table2). However, the second course of anti-biotic therapy caused a marked changein the subgingival microbiota. Micro-biological sampling at 5, 8 and 16months showed absence of A. actino-mycetemcomitans and P. micros, and P.nigrescens and F. nucleatum each com-prised less than 0.1 % of subgingivalisolates (Table 2). Porphyromonas gingi-valis was identified by PCR at baselineand at 16 months but was present inlevels too low to be detected by culture(Table 2). Subgingival cytomegaloviruswas detected at 8 months but not at 16

months, and Epstein-Barr virus was notidentified at 8 or 16 months (Table 2).

Discussion

Appreciating the etio-pathology of Pa-pillon-Lefevre syndrome periodontitis isa prerequisite for successful treatment.The apparent involvement of A. actino-mycetemcomitans in many cases of thedisease may have significant therapeuticimplication. Amoxicillin-metronidazolecombination drug therapy that is effec-tive in treating A. actinomycetemcomit-ans-associated periodontitis (Van Wink-elhoff et al. 1996), may be employed inthe treatment of Papillon-Lefevre syn-drome periodontitis.

The combined mechanical andamoxicillin-metronidazole antibiotictherapy caused a marked change in theperiodontal status of the 11-year oldPapillon-Lefevre syndrome patientstudied. No teeth at baseline but 87% ofall teeth posttreatment showed probingdepths of 3 mm or less, and the pro-portion of teeth with multiple bleedingsites decreased by more than 4-fold.Baseline examination revealed no peri-odontal lesion with radiographic evi-dence of crestal lamina dura whereasposttreatment radiographs showed evi-dence of crestal lamina dura in all man-dibular teeth and in some advancedlesions in the maxilla. As demonstratedby Rams et al. (1994), presence ofradiographic crestal lamina durastrongly suggests periodontal stabilitywhereas absence of radiographic crestallamina dura can be due to either radio-graphic angulation difficulties orfurther disease progression and is ofless diagnostic significance.

The present findings demonstrated

Papillon-Lefevre syndrome periodontitis 373

the efficacy of systemic amoxicillin-me-tronidazole to eradicate A. actinomyce-temcomitans from Papillon-Lefevre syn-drome periodontitis lesions. Rüdiger etal. (1999) and De Vree et al. (2000) usedsimilar antibiotic therapy to success-fully treat A. actinomycetemcomitans-associated Papillon-Lefevre syndromeperiodontitis. That eradication of A.actinomycetemcomitans was associatedwith arrest of periodontal destructionlends credence to the notion that the or-ganism is an important pathogen in Pa-pillon-Lefevre syndrome periodontitis.

This report also illustrated the valueof microbiological examination in treat-ment of periodontal disease. First, thebaseline microbiological examinationidentified relatively high proportions ofA. actinomycetemcomitans, which thenbecame the main target of the anti-microbial therapy. Second, the follow-upmicrobiological examination showedthat the first course of systemic anti-microbial therapy failed to eradicate theorganism, but that the second course ofantibiotics was successful. A. actino-mycetemcomitans isolates from this pa-tient were susceptible in vitro to the com-bination antibiotic therapy and the inef-fectiveness of the initial therapy mayhave been related to lack of patient com-pliance. In any event, the microbiologi-cal monitoring identified the persistentA. actinomycetemcomitans infection andprompted repeat antimicrobial therapy,which then was effective in eradicatingthe organism. Arguably, without themicrobiological follow-up examination,A. actinomycetemcomitans might havesurvived in the periodontal lesions andcaused further periodontal destruction.De Vree et al. (2000) also emphasized thevalue of microbiological guidance in thetreatment of Papillon-Lefevre syndromeperiodontitis.

Subgingival cytomegalovirus andEpstein-Barr type 1 virus that were pres-ent at baseline were not detected at 16months posttreatment. Previously, Preuset al. (1987) described 4 morphologicallydistinct viruses in actively progressingbut not in arrested periodontitis lesionsor in healthy periodontal sites of two Pa-pillon-Lefevre syndrome patients. Preuset al. (1987) characterized the observedviruses as A. actinomycetemcomitansbacteriophages but some might indeedhave been herpesvirus virions. Activeherpesvirus infections may contribute tothe pathogenesis of Papillon-Lefevresyndrome periodontitis by several mech-anisms, as discussed by Velazco et al.

(1999). Systemic amoxicillin-metronida-zole therapy exerts no direct anti-viral ef-fect. However, the antibacterial therapymight reduce levels of gingivitis andthereby limit entrance into gingiva ofcytomegalovirus residing in monocytes/macrophages and T-lymphocytes and ofEpstein-Barr virus residing in B-lymphocytes (Contreras et al. 1999). De-creased gingival presence of herpesvi-ruses has also been observed after treat-ment of Trisomy 21 periodontitis(Hanookai et al. 2000). Conceivably,little or no occurrence of herpesvirusesin treated Papillon-Lefevre syndromeperiodontal lesions would minimize therisk of experiencing herpesvirus acti-vation and associated pathology(Slots & Contreras 2000).

In conclusion, the present reportfound scaling and root planing togetherwith systemic amoxicillin-metronidazoletherapy to be effective in halting peri-odontal disease progression in an 11-year old girl suffering from Papillon-Le-fevre syndrome. The therapeutic out-come might be due to marked reductionor elimination of periodontal A. actino-mycetemcomitans and possibly of cyto-megalovirus and Epstein-Barr virus.Early diagnosis and institution of appro-priate systemic antibiotic therapy in Pa-pillon-Lefevre syndrome patients mightpreserve teeth that otherwise would ex-foliate spontaneously or be extracted.

Acknowledgement

The authors thank Dr. Mario Machadofor referring the Papillon–Lefevre pa-tient to our clinics for diagnosis andtreatment.

Zusammenfassung

Parodontitistherapie bei Papillon-LefevreSyndromHintergrund: Konventionelle mechanischeParodontitistherapie bei Papillon-LefevreSyndrom (PLS) hat eine schlechte Prognose.Zielsetzung: Dieser Bericht stellt eine wir-kungsvolle antimikrobielle Therapie beirasch fortschreitender Parodontitis im Falleines 11-jahrigen Madchens mit PLS dar.Material und Methoden: Die klinische Unter-suchungen umfassten konventionelle paro-dontale Parameter und die Anfertigung vonRontgenbildern. Das Vorkommen der wich-tigsten putativen Parodontalpathogene wur-de mittels Kultur auf selektiven und nicht-selektiven Medien sowie mittels Polymerase-Ketten-Reaktion (PCR) untersucht. Das Vor-handensein des Zytomegalie- und des Ep-steion-Barr-Virus Typ 1 wurde mit einer spe-ziellen PCR-Methode bestimmt. Die Thera-

pie bestand aus Mundhygieneunterwei-sungen, Scaling und Wurzelglattung sowieder systemischen Gabe von Amoxicillin undMetronidazol (jeweils 250 mg 3 mal taglichfur 10 Tage). 2 Schneidezahne mussten ent-fernt werden. Nachdem sich die Zusammen-setzung der subgingivalen Plaque kaum ver-andert hatte, wurde die Antibiotikagabe 4Monate spater wiederholt. UnterstutzendeParodontitistherapie fand wahrend des 16-monatigen Untersuchungszeitraumes in 2Sitzungen statt.Ergebnisse: Vor der Therapie zeigten 10 von22 vorhandenen Zahnen schwere parodonta-le Destruktionen. 16 Monate spater ergabendie klinischen und rontgenologischen Unter-suchungen keine zusatzlichen Attachment-verluste. Einige Zahne zeigten eine deutlicheReduktion der Gingivitis, der Sondierungs-tiefen und klinische Attachmentgewinne so-wie eine Zunahme der rontgenologischenHohe des Limbus alveolaris, rontegenologi-sche Hinweise auf eine krestale Lamina dura.Vor Therapie konnten Actinobacillus actino-mycetemcomitans (3.4% aller Isolate), Prevo-tella nigrescens (16.4%), Fusobacterium nucle-atum (14.3%), Peptostreptococcus micros(10.6%) sowie Zytomegalie- und Epstein-Barr-Virus Typ 1 nachgewiesen werden. BeiAbschluss der Studie konnten A. actinomyce-temcomitans, P. micros sowie Herpesvirennicht mehr nachgewiesen werden. P. nigres-cens und F. nucleatum machten weniger als0.1% der subgingivalen Isolate aus.Schlussfolgerungen: Diese Studie legt denSchluss nahe, dass PLS-Parodontitis durchBeeinflussung der subgingivalen Mikrofloramittels geeignerter antimikrobieller und kon-ventioneller Parodontitistherapie zum Still-stand gebracht werden kann.

Resume

Traitement de la parodontite associee au syn-drome de Papillon-LefevreOrigine, but: Le traitement mecaniqueconventionnel de la parodontite associee ausyndrome de Papillon-Lefevre a un faiblepronostic. Ce rapport decrit un traitementantimicrobien efficace d’une parodontite pro-gressant rapidement chez une fille de 11 anspresentant un syndrome de Papillon-Lefevre.Methode: L’examen clinique comprenait lesmesures parodontales traditionnelles et uneanalyse radiographique. La presence des bac-teries parodontopathogenes potentielles ma-jeures fut determinee par culture selective etnon-selective et par identificatioin par reac-tion de polymerase en chaine (PCR). La pre-sence du cytomegalovirus et du virusd’Epstein-Barr de type 1 a ete determinee parune methode de detection de PCR nidifiee.Le traitement comprenait le detartrage et lesurfacage radicultare, des instructions d’hy-giene orale, et la prise par voie systemiqued’amoxicilline et de metronidazole (250 mgde chaque, 3¿ par jour pendant 10 jours),qui fut repetee apres 4 mois en fonction desexamens microbiologiques de suivi. Un trai-tement parodontal de soutien fut mis en pla-

374 Pacheco et al.

ce sur 2 visites pendant une periode de 16mois.Resultats: Initialement, 10 des 22 dents enplace montraient un effondrement parodon-tal severe. A 16 mois, le sondage et la radione donnaient pas de dents ayant connu uneperte d’attache supplementaire et plusieursdents presentaient une reduction significativede la gingivite et de la profondeur de poche,et une augmentation de la hauteur osseusealveolaire radiographique et du niveau d’at-tache, ainsi qu’une preuve radiographique dela lamina dura crestale. La microflore initialecomprenait Actinobacillus actinomycetemco-mitans (3.4% des isolats totaux), Prevotellanigrescens (16.4%), Fusobacterium nucleatum(14.3%), et Peptostreptococcus micros(10.6%), mais aussi le cytomegalovirus et levirus d’Epstein-Barr de type 1. A la fin del’etude, les cultures et la PCR montraient uneabsence de Actinobacillus actinomycetemco-mitans, P. micros, et des virus herpetiques, etP. nigrescens et F. nucleatum chacun a moinsde 0.1% des isolats sous-gingivaux.Conclusion: Cette etude suggere que lecontrole de la microflore parodontopatho-gene par un antibiotique approprie et un trai-tement parodontal conventionnel peut arre-ter une parodontite associee au syndrome dePapillon-Lefevre.

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Address:

Corsina H. VelazcoInstituto Superior de Ciencias da Saude-Norte

Rua Central de Gandra, 13174580 Gandra, ParedesPortugal

Fax: π351 (22) 4155954e-mail: cespu.porto/mail.telepac.pt