Case Report

Clinical, Genetic, and Biochemical Findings in Two SiblingsWith Papillon-Lefevre Syndrome

N. Arzu Cagli,* Sema S. Hakki,* Recep Dursun,† Hatice Toy,‡ Alparslan Gokalp,§

Ok Hee Ryu,i P. Suzanne Hart,¶ and Thomas C. Harti

Background: Papillon-Lefevre Syndrome (PLS) is anautosomal recessive disease characterized by palmoplan-tar hyperkeratosis and severe periodontitis affecting bothprimary and secondary dentitions. Cathepsin C (CTSC)gene mutations are etiologic for PLS. The resultant lossof CTSC function is responsible for the severe periodontaldestruction seen clinically.

Methods: A 4-year-old female (case 1) and her 10-year-old sister (case 2) presented with palmoplantar skinlesions, toothmobility, and advanced periodontitis. Basedon clinical findings, the cases were diagnosed with PLS.Mutational screening of the CTSC gene was conductedfor the cases, and their clinically unaffected parents andbrother. Biochemical analysis was performed for CTSC,cathepsin G (CTSG), and elastase activity in neutrophilsfor all members of the nuclear family. The initial treatmentincluded oral hygiene instruction, scaling and root plan-ing, and systemic amoxicillin-metronidazole therapy.

Results: CTSC mutational screening identified ac.415G>A transition mutation. In the homozygous state,this mutation was associated with an almost completeloss of activity of CTSC, CTSG, and elastase. Althoughmonthly visits, including scaling, polishing, and 0.2%chlorhexidine digluconate irrigation were performed tostabilize the periodontal condition, case 1 lost all her pri-mary teeth. In case 2, some of the permanent teeth couldbe maintained.

Conclusions: This reportdescribestwosiblingswithaca-thepsin C genemutation that is associatedwith the inactiv-ity of cathepsin C and several neutrophil serine proteases.The failure of patients to respond to periodontal treatmentis discussed in the context of these biological findings.J Periodontol 2005;76:2322-2329.

KEY WORDS

Cathepsin C; cathepsin G; elastase; gene mutation;Papillon-Lefevre syndrome.

Papillon-Lefevre syndrome (PLS) was firstdescribed in 1924 by Papillon and Lefevre.1

It is a rare heritable disorder with clinicalonset usually apparent by 2 to 3 years of age.The two cardinal diagnostic features of PLS arepalmoplanter keratosis and an early-onset formof generalized aggressive periodontitis manifest-ing severely inflamed gingiva, deep periodontalprobing depths, severe resorption of alveolarbone, and spontaneous exfoliation of teeth.2,3

Gorlin et al.4 have suggested that calcification ofthe dura mater may be a third component of thesyndrome, but this may reflect the increased rateof parental consanguinity observed for patientswith this condition. The prevalence of PLS isreported to be one to four per million of the pop-ulation. Males and females are equally affected,and no racial predominance seems to exist.2

Palmoplantar keratosis, varying from mild psor-iasiform scaly skin to overt hyperkeratosis, ischaracteristic, but keratosis frequently also af-fects other sites such as the elbows and knees.

Periodontitis affects both the primary and sec-ondary dentitions, resulting in premature toothloss of both dentitions. The primary teeth eruptat the expected age and in the normal sequence.The teeth are typically of normal form and struc-ture. Eruption of the primary dentition into theoral cavity is typically accompanied by severegingival inflammation and generalized aggres-sive periodontitis. Chewing can be painful dueto tooth mobility. The primary teeth frequentlybecome loose and exfoliate by age 5. With lossof the primary dentition, gingival inflammationresolves. After the eruption of secondary teeth,the same cycle of events begins and, withouttreatment, most of the secondary teeth may alsobe lost by ;17 years of age.5 Most PLS patientsdisplay both periodontitis and hyperkeratosis,1

although some cases have only one of these clin-ical findings, and the periodontitis is mild or of lateonset in rare individuals.6-8

PLS is transmitted as an autosomal recessivegenetic trait. Genetic mutations of the cathepsin

* Department of Periodontology, Faculty of Dentistry, Selcuk University, Konya,Turkey.

† Department of Dermatology, Faculty of Medicine, Selcuk University.‡ Department of Pathology, Faculty of Medicine, Selcuk University.§ Department of Pedodontics, Faculty of Dentistry, Selcuk University.i Human Craniofacial Genetics Section, National Institute of Dental and

Craniofacial Research, National Institutes of Health, Bethesda, MD.¶ Office of the Clinical Director, National Human Genome Research Institute,

National Institutes of Health.

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C gene (CTSC) are etiologic for PLS, as well as the re-lated condition Haim-Munk syndrome and somecases of prepubertal periodontitis.9-13 CTSC muta-tions have been shown to result in a loss of functionof the cathepsin C enzyme.12,13 The cathepsin C pro-tein encoded by the CTSC gene, a member of the pep-tidase C1 family, is a lysosomal cysteine proteinasethat appears to be a central coordinator for activationof many serine proteinases in immune/inflammatorycells, including the neutrophil serine proteases ca-thepsin G (CTSG), elastase, and proteinase 3.14 Ryuet al.15 recently proposed that the loss of CTSC func-tion and subsequent inactivity of neutrophil serineproteases may cause dysregulation of the localizedpolymorphonuclear leukocyte (PMN) response in in-flamed periodontal tissues, leading to the severe tis-sue destruction seen in PLS cases.

We report clinical, molecular, and biological find-ings in two cases with PLS. These findings suggest thata localized dysregulation of the immune response isetiologic for the treatment response observed.

METHODS

AscertainmentThe proband, a 4-year-old female, was brought to theDepartment of Periodontology, Faculty of Dentistry,Selcuk University in May 2000 by her mother becauseof concern about tooth mobility, pain when chewing,and premature tooth exfoliation. Palmar-plantar skinlesions were evident (Fig. 1), suggesting the possibil-ity of Papillon-Lefevre syndrome. A medical historywas taken for the patient and her nuclear family.Available family members also received an oral ex-amination that included conventional periodontalmeasurements (plaque assessment,16 bleeding onprobing, gingival assessment,17 and periodontal

probing depth) and analysis of radiographs. Chestand skull radiographs as well as hematologic evalua-tions including peripheral smear and completed bloodcount were performed for the proband and her sisterwho had similar clinical findings.

Mutational Analysis of Cathepsin C GenePeripheral blood samples were obtained by standardvenepuncture from the PLS affected cases, their unaf-fected brother, and parents after signing a consentformapprovedby theEthicsCommitteeofSelcukUni-versity. Genomic DNA was isolated from whole blood,and all exons, including intron/exon boundaries of theCTSCgene,wereamplifiedandpurifiedasdescribed.18

The purified products were analyzed by agarose gelelectrophoresis prior to sequencing.# Automated DNAsequencing was performed using a DNA analyzer.**The sequences were aligned with published CTSCsequences (accession #1947070) using the NationalCenter for Biotechnology Information Basic LocalAlignment Search Tool (NCBI BLAST).

Preparation of Neutrophil Cell LysatesHuman neutrophils and mononuclear cells were iso-lated fromtheperipheral bloodof study participants.††

Neutrophils were treated with cold NH4Cl buffer tolyse contaminating erythrocytes and washed withPBS. Neutrophils and mononuclear cells were as-sessed by light microscopy with Giemsa staining,and cells were counted using a hemacytometer. Cellswere suspended at a concentration of 1 · 106 cells/mlin Hank’s balanced salt solution (HBSS) and soni-cated for 30 seconds. After centrifugation at 4�C for5 minutes at 13,000 rpm, the supernatants were usedas the cell lysate.

Determination of Cathepsin C, Cathepsin G,and Elastase ActivitiesCTSC enzyme activity was assayed as previously de-scribed.18 Cathepsin G and elastase activities weredetermined by measuring the amount of p-nitroani-lide (pNA) released by the hydrolysis of the syntheticsubstrates N-succinyl-Ala-Ala-Pro-Phe-pNA‡‡ andN-succinyl-Ala-Ala-Val-pNA,§§ respectively. A totalof 10 ml 5 mM substrate, 10 ml neutrophil lysate, and200ml 50 mM sodium acetate buffer (pH 5.5) contain-ing 150 mM NaCl were mixed (water was added toa total volume of 240 ml) and incubated with agitationat room temperature. The amount of released pNAwas measured at 405 nm using a microplate reader.kk

Figure 1.Extraoral appearance of 4-year-old girl (case 1) with PLS at firstappointment. Note hyperkeratosis of the palms (left) and soles (right).

# BigDye automated DNA sequencing kit, Applied Biosystems,Foster City, CA.

** 3100 DNA analyzer, Applied Biosystems.†† Histopaque-1119-1 and Histopaque-1077-1 as described in

Sigma procedure no. 1119, Sigma, St. Louis, MO.‡‡ Sigma.§§ Sigma.kk Molecular Devices, Sunnyvale, CA.

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RESULTS

The parents of the proband (case 1) were first cousinswho reported that pregnancy, labor, and delivery werenormal for all three children (Fig. 2).

Proband Case 1Oral findings. The chief complaints of the 4-year-oldproband included tooth mobility and pain on chewing.Clinical examination revealed primary teeth presentincluded: A, C, H, J, K, M, N, O, Q, R, and T. Therewere marked flaring and mobility, severe gingival re-cession, and inflammation associated with heavy pla-que accumulation of all teeth (Fig. 3). Periodontalindices are summarized in Table 1. Tooth mobilityranged from grade 2 to 3. The majority of sites bledon probing and presented supurrative discharge.The oral mucosa, including that covering the edentu-lous area, was normal in color and consistency.

Radiographs, which included a panoramic radio-graph, revealed severe bone resorption around allteeth, widening of periodontal ligament spaces, andincomplete formation of root apices. No ectopic calci-fications were found (Fig. 4).

Skin findings. The proband exhibited hyperkerato-sis of the palms and soles (Fig. 1). She was reported tohave beenhealthy and developednormally through thefirst 4 months of age, at which time skin lesions startedto appear. There was no history of other serious illnessor susceptibility to infection in areas other than the oralcavity. The patient received topical keratolytic andanti-inflammatoryointmentsandcreams fromherphy-sician for her skin lesions without significant improve-ment. Cutaneous examination revealed palmoplantarkeratoderma transgradiens extending up to dorsolat-eralaspectsand tendo-Achillesarea.Thedermatologic

lesions were diffuse and mild on soles and palms.Elbows, knees, hair, nails, and sweating of case 1 werenormal.Histologicexaminationofa palmarskin biopsydisplayed hyperkeratosis, acanthosis, and tortuouscapillaries in thinned dermal papillae and a sparse,superficial, perivascular lymphocytic infiltrate (Fig. 5).

Systemic examination and routine laboratoryinvestigation. Hematologic results of case 1 are shownin Table 2. Creatine, uric acid, glucose, cholesterol,triglycerides, phosphorus, calcium, sodium, potas-sium, zinc, total protein, albumin, alkaline phosphatase,thyroid hormones, parathyroid hormon, immunoglob-ulins, C3,C4, antistreptolysin O (ASO), rheumatoidfactor (RF), C-reactive protein (CRP), and urine anal-ysis were at normal limits. Anti-human immunodefi-ciency virus (HIV), hepatitis B markers, and VenerealDisease Research Laboratory-rapid plasma reagin(VDRL-RPR) were negative. Chest and skull x-rayfilms were normal. Candidal infection was found inthe gingival culture.

Table 1.

Mean Values of Clinical MeasurementsBefore Periodontal Treatment

Case 1 Case 2

Number of teeth present 11 10

Plaque index (0 to 3) 3 3

Gingival index (0 to 3) 2.5 3

Probing depth (mm), mean – SD 6.69 – 1.80 6.73 – 2.63

Clinical attachment loss (mm),mean – SD

8.01 – 2.03 7.20 – 4.94Figure 2.Pedigree chart of the consanguineous family (circles: females;squares: males).

Figure 3.Intraoral appearance of 4-year-old girl (case 1). Note gingivalinflammation and severe recession.

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Case 2The 10-year-old female sibling of the proband pre-sented with tooth mobility and gingival inflammation.Medical and dental histories were similar to case 1.

Oral findings. Intraoral examination revealed thatthe teeth were normal in size and shape, with general-ized severe periodontitis. Gingival recession andheavy plaque accumulation were also noted. Teethclinically present included the following: #7, #8, #9,#10, #22, #23, #24, #25, #26, #27, and #30. A mesio-dens was radiographically evident between the max-illary central incisors. Significant periodontal probingdepths were noted, and purulent exudates were freelyexpressed around mandibular right molars. The teethwere mobile, with evidence of drift and extrusion (Fig.6). The patient reported difficulty in chewing. Peri-odontal indices, probing depth, and attachment levelare shown in Table 1. Tooth mobility ranged fromgrade 2 to 3.

Radiographs revealed gen-eralized severe, vertical, andhorizontal alveolar bone lossassociated with all eruptedteeth. The maxillary anteriorteeth and mandibular right mo-lar were almost entirely withoutbone support with no evidenceof root resorption.Theuneruptedteeth were in normal stages ofdevelopment (Fig. 7).

Skin examination. Moder-ate, diffuse palmoplantar kerato-derma was evident on thepalms and soles, with transgra-diens extending up to dorsolat-eral aspects and tendo-Achillesarea. Mild psoriasiform plaqueswere also seen on elbows and

knees. Slight onychodystrophy and transverse groov-ing were evident on the fingernails. No other cutane-ous lesions, hair, or sweating anomalies were noted.Histologic examination of a palmar biopsy revealedhyperkeratosis, acanthosis, tortuous capillaries inthinned dermal papillae, and a sparse, superficial,perivascular lymphocytic infiltrate.

Systemic examination and routine laboratory in-vestigation. Hematologic results for case 2 are shownin Table 2. Anti-HIV, hepatitis B markers, and VDRL-RPR were negative. Chest and skull x-ray films werenormal. Cognitive, visual, and cardiovascular prob-lems were not present.

Clinical Findings in the Parents and BrotherThe parents and 1-year-old brother were free fromperiodontitis and palmar-plantar skin lesions. Based

Figure 4.Panoramic radiograph of case 1. Note severe bone loss around the deciduous teeth.

Figure 5.Histologic examination of a palmar skin biopsy (hematoxylin andeosin stain; original magnification ·10).

Table 2.

Results of Peripheral Blood Tests

Case 1 Case 2

Reference Range

(4 to 10 years old)

WBC (·109/l) 9.9 7.3 4.0 to 11.0

RBC (·1012/l) 4.08 4.19 3.8 to 5.4

Hb (g/dl) 10.6 11.0 10 to 16.0

Hct (%) 33.3 32.6 / 33 to 42

Ferritin (ng/ml) 5.2 Y 22.0 7 to 140

Iron (mg/dl) 23 Y 101 30 to 170

Copper (mmol/l) 3.4 Y 18.8 11.0 to 24.0

WBC = white blood cells; RBC = red blood cells; Hb = hemoglobin;Hct = hematocrit; Y = low; / = borderline low.

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on clinical findings, our preliminary diagnosis wasPapillon-Lefevre syndrome in cases 1 and 2.

Cathepsin C Mutational AnalysisThe affected individuals are homozygous for ac.415G>A mutation in exon 3 of the cathepsin C gene.This mutation changes a highly conserved amino acid(#139) from a glycine to an arginine (p.G139R). Theclinically unaffected brother and parents are also car-riers of the same mutation. This mutation was notpresent in 100 chromosomes from unaffected Turkishcontrols. The affected individuals are also homozy-gous for the T153I polymorphism, a polymorphismpresent in 19% of the Turkish population.

Cathepsin C, Cathepsin G, and Elastase ActivityCTSC activity was undetectable in the PLS-affectedindividuals. CTSC activity in the brother and parents,all carriers of the c.415G>A mutation, ranged between25% and 50% of normal control values (Table 3). Ca-thepsin G and elastase activity was undetectable inthe PLS-affected individuals. Cathepsin G and elas-tase activity in the brother and parents ranged from

25% to 75% and >95% of normal control values, re-spectively.

Periodontal TreatmentInitially, conventional periodontal treatment includ-ing scaling and root planing, and oral hygiene instruc-tion was employed to control the progression ofperiodontal destruction. Chlorohexidine digluconatemouthrinse (0.2%) and systemic antibiotic therapy(amoxicillin and metronidazole, 250 mg of each, threetimes daily, for10 days) were also prescribed as an ad-junctive regimen to treat the generalized periodontalinfection. All hopeless teeth were extracted. To re-store masticatory function, partial dentures wereinserted 3 months after the patient’s periodontal con-dition improved. At a 2-month maintenance visit, themobility of remaining teeth increased significantly,and a periodontal abscess was noted in the maxillarysecond molar. As we were unable to prevent peri-odontal disease progression, and the patient was un-able to functionwith thedentalprosthesis, the remainingteeth were extracted and complete dentures were fab-ricated for case 1. In case 2, tooth #30 was extracteddue to severe mobility, and a space maintainer wasmade (Fig. 8). Radiographs of cases 1 and 2 weretaken to evaluate permanent teeth eruption after den-tures and space maintainer were performed (Figs. 9Aand 9B). Regular maintenance therapy was per-formed at 2-month intervals to stabilize the health oforal tissues (Table 4).

DISCUSSION

Gram-negative microbial lipopolysaccharides (LPS)are generally recognized to be primary factors in theetiology of periodontitis, including PLS.19-24 In PLS,the onset, severity, and progression of periodontitis

Figure 6.Intraoral appearance of 10-year-old girl (case 2). Note poor oralhygiene, pathologic migration of teeth, and severe gingivalinflammation.

Figure 7.Panoramic radiograph of case 2. Note severe bone loss around theteeth. The mandibular right first molar was almost entirely withoutbone support.

Table 3.

Evaluation of Cathepsin C, Cathepsin G,and Elastase Activity

Enzyme Sample* Cathepsin C† Cathepsin G† Elastase†

Father (unaffected, +/-) ++ ++ ++++

Mother (unaffected, +/-) ++ +++ ++++

Child 1 (affected, -/-) – – –

Child 2 (affected, -/-) – – –

Child 3 (unaffected, +/-) + ++ ++++

Control (unaffected, +/+) ++++ ++++ ++++

* +/- = heterozygous carrier of CTSC mutation; -/- = homozygous for CTSCmutation; +/+ = no CTSC mutation.

† Control activity: – = complete loss; + = between 5% and 25%; ++ = between25% and 50%; +++ = between 50% and 75%; ++++ = >75%. Enzymeactivities were calculated by normalizing the control activity at 100%.

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are greatly increased due to cathepsin C gene muta-tions.10 Cathepsin C functions to activate other pro-teases that modulate the immune response tomicrobial infection.14 The c.415G>A/p.G139R ca-thepsin C mutation identified in the current caseshas been previously reported in the compound het-erozygous state in two different families.25,26 Al-though this mutation is associated with the loss ofcathepsin C activity,27 the downstream consequence

of this mutation has not been evaluated. The currentreport is the first to show this mutation in the homozy-gous state, and confirms that in the homozygousstate, this mutation is associated with almost com-plete loss of cathepsin C activity. Cathepsin C muta-tions associated with PLS, Haim-Munk syndrome, andprepubertal periodontitis are associated with the lossof cathepsin C enzyme activity.12,14,27-29 Cathepsin Cactivity is required for proteolytic activation of neutro-phil serine proteases (NSP) cathepsin G, elastase, andproteinase 3. The inactivation of these NSPs mayhave multiple downstream effects that ultimately re-sult in a dysregulation of the host immune responseto microbial infection. The accumulation of inflamma-tory infiltrate at sites of infection may exacerbate localtissue destruction.

Our findings confirm that the inactivity of cathepsinC in PLS is associated with failure of the activation ofneutrophil serine proteases.29 These neutrophil serineproteases are able to proteolytically degrade the mac-rophage inflammatory protein (MIP)-1a isoformsLD78b and LD78a.15 Findings of recent biochemicalstudies suggest that the cathepsin C mutation is re-sponsible for a localized dysregulation of the micro-bial-induced inflammatory response.15 As a result,it is likely that inflammatory infiltrate at local sites ofperiodontal infection is not under normal regulatorycontrol, and accentuated influx of neutrophils and re-tention of inflammatory infiltrate and their proteasesmay play a significant role in continued periodontaldestruction. It may be for this reason that it is difficultto control and limit periodontitis once lesions are es-tablished in PLS cases.

A number of clinical findings have been reported forPLS cases including liver abscesses and cranial calci-fications. These were not present in the current cases.Given the high rate of parental consanguinity reportedfor PLS cases, it is possible these rarer findings are theresult of the high degree of homozygosity at other al-leles in addition to the cathepsin C locus. In hemato-logic examination of the cases, case 1 was found tohave ferritin levels at the lower normal range. Ferritinfunctions to bind iron in the blood and provides an in-dication of stored iron. The low ferritin levels may ac-count in part for the low levels of iron found. Case 1also had low copper levels, but there were no apparentsystemic findings noted. Low socioeconomic condi-tions are reported to contribute to anemia and iron de-ficiency.30,31 These abnormalities may be explainedby low socioeconomic conditions and difficulties inmastication due to severe tooth mobility and recurrentabscess formation in PLS cases. The periodontal se-quela of the two cases presented is typical of Papil-lon-Lefevre syndrome. The clinical course involvessevere gingival inflammation and rapid periodontaldestruction in conjunction with palmar-plantar

Figure 8.The appearance of case 2 after periodontal treatment withmaintainers. Although oral hygiene was not satisfactory, reducedinflammation and improved clinical features of the gingiva werenoted.

Figure 9.Panoramic radiographs of cases 1 (A) and 2 (B) after periodontaltreatments. The teeth of case 1 could not be saved due to severemobility and periodontal abscess.

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hyperkeratosis. Although there have been reports ofPLS-affected individuals responding to periodontaltherapy, many PLS patients do not respond effectivelyto conventional periodontal treatment.25,26,32-34

Following extraction or exfoliation of all teeth, the gin-gival tissues typically heal without signs of inflamma-tion, suggesting that a focus of microbial challenge isrequisite for the characteristic severe inflammatoryresponse.2 Several reports have documented suc-cessful osseointegration and function of dental im-plants in PLS cases following tooth removal.35,36 Luet al.37 reported that the progression of periodontalbreakdown was completely stopped by removingthe dentogingival junctions around the remaining per-manent teeth and submerging them beneath the oralmucoperiosteum. This treatment may have been ef-fective because it removed local microbial sites ofinfection, eliminating the cycle of PMN recruit-ment. Another approach that has been used to limitperiodontal destruction in PLS is to remove se-verely infected primary teeth that have advancedperiodontitis-associated destruction.32 It is hoped thatby eliminating the infection, the oral cavity can be pre-pared for eruption of the secondary dentition. It maythen be possible to prevent inflammatory-related de-struction of the secondary dentition by a combinationof more intense conventional therapy, including a morefrequent maintenance program incorporating antimi-crobial agents such as chlorhexidine, together with apharmacologic approach such as systemic amoxicil-lin-metronidazole therapy.25,26,33

In the present study, cases 1 and 2 initially re-sponded to scaling and root planing combined withsystemic amoxicillin-metronidazole therapy. Afterantibiotic therapy, proportions of teeth showing mul-tiple sites with bleeding on probing and purulent exu-dates decreased. In case 2, some teeth with advancedmobility and severe alveolar bone loss could not besaved due to the delay in diagnosis and treatment in-

tervention. The roots of the remaining erupted perma-nent teeth of case 2 will be maintained with vitalsubmerging surgery if possible. However, clinical re-sults of the present cases illustrate the need for moreeffective treatment alternatives for PLS. It is hopedthat with the identification of the underlying gene de-fect and a greater understanding of the biological con-sequence of cathepsin C inactivity, better treatmentscan be developed. Until such treatments are devel-oped, the treatment of periodontal manifestations ofPLS will be problematic.

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familiary palmar and plantar hyperkeratosis (Meledadisease) within brother and sister combined withsevere dental alterations in both cases (in French).Bull Soc Fr Dermatol Syphilis 1924;31:82-87.

2. Haneke E. The Papillon-Lefevre syndrome: Keratosispalmoplantaris with periodontopathy: Report of a caseand review of the cases in the literature. Hum Genet1979;51:1-35.

3. Hart TC, Shapira L. Papillon- Lefevre syndrome. Peri-odontol 2000 1994;6:88-100.

4. Gorlin RJ, Sedano H, Anderson VE. The syndrome ofpalmar-plantar hyperkeratosis and premature peri-odontal destruction of the teeth: A clinical and geneticanalysis of the Papillon-Lefevre syndrome. J Pediatr1964;65:895-908.

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6. Soskolne WA, Stabholz A, van Dyke TE, Hart TC,Meyle J. Partial expression of the Papillon-Lefevresyndrome in 2 unrelated families. J Clin Periodontol1996;23:764-769.

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8. Pilger U, Hennies HC, Truschnegg A, Aberer E. Late-onset Papillon-Lefevre syndrome without alterationof the cathepsin C gene. J Am Acad Dermatol 2003;49(5 Suppl.):S240-243.

9. Hart TC, Hart PS, Michalec MD, et al. Haim-Munksyndrome and Papillon-Lefevre syndrome are allelicmutations in cathepsin C. J Med Genet 2000;37:88-94.

10. Hart TC, Hart PS, Bowden DW, et al. Mutations of thecathepsin C gene are responsible for Papillon-Lefevresyndrome. J Med Genet 1999;36:881-887.

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Table 4.

Mean Values of Clinical Measurementsof Case 2 After Periodontal Treatment*

Case 2

Number of teeth present 7

Plaque index (0 to 3) 2

Gingival index (0 to 3) 2

Probing depth (mm), mean – SD 2.50 – 0.91

Clinical attachment loss (mm), mean – SD 2.98 – 1.52

* Because case 1 lost all of her teeth, periodontal records were notprovided.

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14. de Haar SF, Jansen DC, Schoenmaker T, de Vree H,Everts V, Beertsen W. Loss-of-function mutations incathepsin C in two families with Papillon-Lefevresyndrome are associated with deficiency of serineproteinases in PMNs. Hum Mutat 2004;23:524.

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19. Van Dyke TE, Taubman MA, Ebersole JL, et al. ThePapillon-Lefevre syndrome: Neutrophil dysfunctionwith severe periodontal disease. Clin Immunol Immu-nopathol 1984;31:419-429.

20. Preus HR. Treatment of rapidly destructive periodonti-tis in Papillon-Lefevre syndrome. Laboratory andclinical observations. J Clin Periodontol 1988;15:639-643.

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23. Velazco CH, Coelho C, Salazar F, Contreras A, Slots J,Pacheco JJ. Microbiological features of Papillon-Lefe-vre syndrome periodontitis. J Clin Periodontol 1999;26:622-627.

24. Eickholz P, Kugel B, Pohl S, Naher H, Staehle HJ.Combined mechanical and antibiotic periodontal ther-apy in a case of Papillon-Lefevre syndrome. J Peri-odontol 2001;72:542-549.

25. Rudiger S, Petersilka G, Flemmig TF. Combinedsystemic and local antimicrobial therapy of periodon-tal disease in Papillon-Lefevre syndrome. A report of 4cases. J Clin Periodontol 1999;26:847-854.

26. De Vree H, Steenackers K, De Boever JA. Periodontaltreatment of rapid progressive periodontitis in 2 sib-lings with Papillon-Lefevre syndrome: 15-year follow-up. J Clin Periodontol 2000;27:354-360.

27. Zhang Y, Hart PS, Moretti AJ, et al. Biochemical andmutational analyses of the cathepsin c gene (CTSC) inthree North American families with Papillon-Lefevresyndrome. Hum Mutat 2002;20:75.

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Correspondence: Dr. Sema S. Hakki, Department ofPeriodontology, Faculty of Dentistry, Selcuk University,42079 Konya, Turkey. Fax: 90-332-241-0062; e-mail:sshakki@selcuk.edu.tr.

Accepted for publication May 4, 2005.

J Periodontol • December 2005 Cagli, Hakki, Dursun, et al.

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