Vol. 108 No. 1 July 2009
MEDICAL MANAGEMENT AND PHARMACOLOGY UPDATEEditors: F. John Firriolo and Nelson I. Rhodus
Papillon-Lefevre syndrome: clinical presentation and a briefreview
Parmanand J. Dhanrajani, BDS, MDS, MSc, MSc, FRACDS, FDSRCS, FFDRCSI,Sydney, AustraliaHCF DENTAL CENTRE
The Papillon-Lefevre syndrome (PLS) was first described by Papillon and Lefevre in 1924. It is an autosomalrecessive disorder characterized by a diffuse palmoplanter hyperkeratosis and rapidly progressive and devastatingperiodontitis, affecting the primary as well as the permanent dentition, attributed to a point mutation of the cathepsinC gene. This paper presents a clinical presentation and a brief review of its etiology and treatment modalities. (Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 2009;108:e1-e7)The Papillon-Lefevre syndrome (PLS) was first de-scribed by Papillon and Lefevre in 1924.1 It is anautosomal recessive disorder characterized by a diffusepalmoplanter hyperkeratosis and rapidly progressiveand devastating periodontitis, affecting the primary aswell as the permanent dentition, attributed to a pointmutation of the cathepsin C gene.2-6
The syndrome is estimated to have frequency of 1-4per million and �300 cases have been reported world-wide.7 It seems that the incidence in the Saudi Arabiais higher compared with other parts of the world, andthis may be attributed to cluster marriages (consanguin-eous marriages).8,9 The onset of disease usually coin-cides with the eruption of primary teeth. Boys and girlsare equally affected, with no racial predominance.
Following eruption of primary teeth, the gingivaebecome inflamed. This is generally followed by a rapiddestruction of periodontium and most affected childrenexperience premature loss of their primary teeth. Gin-giva seems to resume normal appearance after exfoli-ation of the primary dentition.9 The aggressive inflam-matory periodontal process then repeats itself after the
Oral & Maxillofacial Surgeon.Received for publication Sep 12, 2008; returned for revision Mar 7,2009; accepted for publication Mar 9, 2009.1079-2104/$ - see front matter© 2009 Mosby, Inc. All rights reserved.
doi:10.1016/j.tripleo.2009.03.016eruption of the permanent teeth, and in general all ormost of the permanent dentition is lost during theteenage years.10-13
Conventional periodontal treatment usually fails inpatients with Papillon-Lefevre syndrome, and the rapidprogression of periodontitis results in severe loss ofalveolar bone.14-19 To preserve alveolar bone, earlyextraction of periodontally involved permanent teethhas been considered to be a mode of treatment.20-25
For many years, clinicians have been aware of theprosthetic problems posed by severely atrophic thinalveolar ridges, and this has constantly motivated cli-nicians to develop new methods of treatment.
In recent years, titanium implants have become animportant treatment alternative to replace missing teeth,and the present author was the first to experience suc-cessful use of them as a mode to rehabilitate patientswith Papillon-Lefevre syndrome.8
This paper presents the etiology and clinical features,and highlights different treatment modalities used torehabilitate the oral cavity in patients with Papillon-Lefevre syndrome.
ETIOLOGY AND PATHOGENESISExact etiology and pathogenesis is unknown, but
intensive work during the last decade has revealedsome important factors in the development of the dis-order. In recent years, three main factors are suggested
as responsible for the initiation and progression of PLS.e1
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GeneticPapillon-Lefevre syndrome is an autosomal reces-
sive disorder. Recently, a few research groups havereported that loss-of-function mutations of the lysoso-mal protease cathepsin C gene are associated with PLSas well as related conditions.14-18 The cathepsin C geneis expressed in the epithelial regions commonly af-fected by PLS, such as palms, soles, knees, and kera-tinized oral gingiva. The cathepsin C gene is alsoexpressed at high levels in various immune cells, in-cluding polymorphonuclear leukocytes, macrophages,and their precursors. This discovery will certainly leadto better understanding of the signs and symptomsassociated with PLS.3,4,20,21
ImmunologicAnother important etiologic factor is an alteration of
the host defense owing to decreased function of lym-phocytes,26 polymorphonuclear leucocytes, or mono-cytes.27 The cathepsin C protein encoded by the CTSCgene is a lysosomal cysteine proteinase that appears to becentral coordinator for activation of many serine protein-ases in immune/inflammatory cells, including the neutro-phil serine proteases (NPS) (cathepsin G [CTSG], elas-tase, and proteinase 3).28 The inactivation of these NPSsmay have multiple downstream effects that ultimatelyresult in desregulation of the host immune response tomicrobial infection. Ryu et al.26 recently proposed that theloss of CTSC function and subsequent inactivity of neu-trophil serine proteases may cause dysregulation of local-ized polymorphonuclear leucocyte response in inflamedperiodontal tissues, leading to the severe tissue destructionseen in PLS.29
MicrobialGram-negative microbial polysaccharides (LPS) are
generally recognized to be primary factors in the etiol-ogy of periodontitis, including PLS.19,22 Neutrophilfunction test showed reduced response to Staphylococ-cus spp. and Actinobacillus actinomycetecomitans.Presence of virulent gram-negative anaerobic pathogenswere found at the site of lesion (plaque/periodontal pock-ets), such as Bacteroides gingivalis, Capnocytophagasspp., spirochetes, and A. actinomycetemcomitans. Of thepathogens, A. actinomycetemcomitans constituted morethan 50% of the total colony-forming units,20 and clin-ical improvement followed its eradication. There is ahypothesis that periodontal herpes viruses together withpathogenic bacteria, including A. actinomycetemcomi-tans, and underlying host defense disorders, participatein the development of Papillon-Lefevre syndrome pe-riodontitis.23,24
There are also numerous virulence factors present,
such as leukotoxin, collagenase, endotoxin, epithelio-toxins, and a fibroblast-inhibiting factor, suggestingthat PLS is mediated bacteriologically and thereforecould be treated to some improvement with antibiotics.24
The subgingival plaque found in the periodontalpockets of PLS patients resembles a typical periodon-titis-associated microflora and has shown a predomi-nance of gram-negative anaerobic rods, including Por-phyromonas gingivalis and spirochetes.28,30 Recentmicrobiologic studies have revealed that periodontitisin PLS patients may also be associated with A. actino-mycetemcomitans.7,31,32
Human keratinocytes in culture normally secrete gran-zyme B with antimicrobial activity that is able to protectagainst invading pathogens. The activation of granzyme Bmay thus provide protection against dermal inflamma-tion.33,34 The failing activation of granzyme B in individ-uals with PLS might weaken the epithelial response to-ward bacterial infection and contribute to the individualpropensity to develop gingival inflammation.
Defect of immune-mediated mechanisms, including re-duced lymphocyte response to pathogens, depression ofhelper-to-suppressor T-cell ratio, deficient monocyticfunction, elevation of serum immunoglobulin, and degen-erative changes of plasma cells,35 have been reported.
The elevated antibody titers to A. actinomycetem-comitans support the microbial findings of the involve-ment of this bacteria in periodontopathy associated withPLS.36
There are investigations carried out to check urinemetabolism and serum vitamin C and zinc levels in PLSindividuals in literature that were insignificant.
A dysplasia of the root cementum has been reportedin PLS by Page and Baab,37 suggesting the possibilityof abnormal deposition or maintenance of root cemen-tum, similar to that observed in less severe cases ofhypophosphatasia. However, in that study the roots didnot show any structural alterations that could accountfor the severity of the periodontal lesions.38,39
It has been suggested that palmoplantar keratoses inPLS predispose to high incidences of malignant mela-noma. Nakajima et al.40 reported a 51-year-old Japa-nese woman with PLS associated with recurrent malig-nant melanoma arising from hyperkeratotic cutaneouslesions. They also reported 4 other cases of malignantmelanoma in PLS patients: Out of 4, 3 were Japanese,and the authors suggested that this tendency might beattributed to high frequency of acral lentiginous mela-noma in Japanese populations, in contrast to a lowfrequency of this subtype in caucasians.41
CLINICAL PRESENTATIONSThe onset of the cutaneous lesion of PLS (kerato-
derma) may appear at birth or 1 to 2 months of age, but
most commonly appears between the ages of 6 months
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and 4 years, coinciding with the eruption of primaryteeth.8
The severity of keratoderma is variable, with thesoles being prominently more involved. The margins ofthe keratoderma are well defined and erythematous,frequently extending to the thenar and hypothenar em-inences of the palms and to the Achilles tendon andexternal malleoli of feet (Figs. 1 and 2). Other sites ofinvolvement include the dorsal surface of the fingersand toes, elbows, legs, thighs, and rarely the trunk42
(Fig. 3).Skin lesions appear as white, light yellow, brown, or
red plaques, which undergo crustation, cracking, anddeep fissuring. Infection may superimpose on the de-fective skin, resulting in the formation of abscesses.
Oral manifestations of PLS appear almost simulta-neously with the onset of palmoplantar hyperkeratosis.The primary teeth erupt at the expected age and innormal sequence. Usually, the teeth are of normal formand structure, although microdontia, root resorption,and incomplete root formation are reported in a fewcases. Rapidly progressing periodontitis ensues, oncethe primary dentition are erupted, manifested by mark-
Fig. 1. A, B, Photograph showing kyperkeratosis of thepalms extending to thenar and hypothenar eminences.
edly reddened, inflamed and swollen gingiva associated
with extensive bone resorption and deep periodontalpockets from which pus exudes in response to slightpressure (Fig. 4). Chewing is very painful because ofthe mobility of the teeth. Fetid mouth odor is usuallypresent. Regional lymphadenopathy has also been ob-
Fig. 2. A, Photograph showing hyperkeratosis of the feetinvolving external malleoli of feet and Achilles tendon.B, Photograph showing hyperkeratosis of the feet involvingexternal malleoli of feet and Achilles tendon.
Fig. 3. Photograph showing hyperkeratosis involving knees.
served.5,43
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The pathognomic dental features of PLS are thelooseness, hypermobility, drifting, migration and exfo-liation of teeth without signs of root resorption. At theage of 4-5 years, the primary teeth are exfoliated orextracted and the child becomes completely edentulouswith the gingiva returning to its normal healthy state.After the eruption of permanent teeth, the same cycle ofevents begins again, and by the age of 13-15 years allof the permanent teeth are lost (Fig. 5). Radiographicexamination of advanced cases reveals severe loss ofthe alveolar bone, and teeth appear to be “floating inair” (Fig. 6). Differential diagnoses considering radio-graphic findings include Haim-Munk syndrome, Che-diak-Higashi syndrome, juvenile periodontitis, and soon. Unerupted teeth tend to develop normally in theirbony crypts, although in some cases they assume anabnormal position and have incompletely formed roots.
The histopathology of the PLS periodontitis shows asevere inflammatory infiltration of the subepithelial con-nective tissue, leaving only a few collagen fibres.43,44 The
Fig. 4. A, B, Photographs showing marked red inflamed andswollen gingivae.
dense infiltration mainly consists of plasma cells dominat-
ing the entire gingiva in certain area. Electron microscopyhas also revealed degenerative alterations of plasmacells.34
Asymptomatic calcification of the falx cerebri andchoroid plexus have been noted in many PLS patients.These patients have been reported to have increasedsusceptibility to other infections, such as of liver, lung,kidney, etc. It is possible that these rare findings are theresult of a high degree of homozygosity at other alleles
Fig. 5. Flow chart of oral manifestations of Papillon-Lefevresyndrome.
Fig. 6. A, B, Orthopantomograph showing severe loss ofalveolar bone and teeth appear to be “floating in air.”
in addition to cathepsin C locus.
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The mechanism underlying periodontal disease indifferent genetic conditions as characterized by connec-tive tissue alterations is explained by the fact thatanomalies at this level generate increased susceptibilityto periodontal inflammation and bone resorption. De-spite the existence of a common background alteration,the manifestations of periodontal disease may differ ineach of the syndromes.
In case of Marfan syndrome, periodontitis manifestsin a chronic and severe form, with patterns of bothhorizontal and vertical bone resorption, according tothe presence of bacterial plaque. In Ehler-Danlos syn-drome, periodontal disease can be associated with typeI, VII, III, or IV. The postulated mechanism is a defectin type III collagen, present in 16% of total collagen ofthe periodontal ligament, affecting the integrity of theperiodontal junction.39,45
In severe congenital neutropenia and infantile ge-netic agranulocytosis, the decrease in number of neutro-phils alters the host defense capacity, causing periodontaldisease to manifest at an early age, with gingival inflam-mation, aggressive periodontal destruction, edema, peri-odontal pouches, and tooth mobility. This is similar toprepubertal or rapidly progressive periodontitis.42,46,47
There is early-onset periodontitis with premature ex-foliation of both dentitions in Chediak-Higashi syn-drome.48 The pattern of bone resorption may be localizedor generalized and is related to gingival inflammation. Thedisorder is associated with anaerobic infection due to theabundant presence of purulent processes. In addition,lysosomal alterations and defective chemotaxis in neu-trophils give rise to aggressive periodontitis that tendsto be recurrent and refractory to antibiotic treatment.48
Down syndrome associated with mental retardationand systemic alterations is characterized by aggressiveand generalized periodontitis, with the subsequent de-struction of the supporting tissues and loss of the teethat early age. To these factors we must also add immunedeficiency, inadequate control of bacterial plaque, de-ficient masticatory function, early aging, and alterationin dental anatomy.49
Papillon-Lefevre syndrome can also be distinguishedfrom palmoplantar keratoderma of Unna-Thost, mal deMeleda, Howel-Evans syndrome, keratosis punctata,keratoderma hereditarium mutilans (Vohwinkel syn-drome), and Greither syndrome, because these entitiesare not associated with periodontopathy.
MANAGEMENTA multidisciplinary approach involving the derma-
tologist, pediatrician, and pediatric dentist is importantfor the overall care of patient with PLS.
Dental treatment efforts other than extraction have
been attempted in PLS patients. It is generally agreedthat the response to local debridement or to systemicantibiotics alone or in combination provides at best atransitory response.29,37,42,44,50-52
Good dental care and use of prophylactic antibioticsaims to minimize periodontitis and the loss of teeth.Eradication of A. actinomycetecomitans has shown toplay a role in the successful treatment of periodontitis.Trimethoprim and sulfamethoxazole has been demon-strated to be effective against the organism.
Treatment of the dental component of PLS is aimedat eliminating the reservoir of causative organisms.Some authors have claimed good results after the ex-traction of all the deciduous teeth. Permanent succes-sors then erupt to an altered microbiologic environ-ment.47,48
During the past decades, several articles have beenpublished on the treatment of PLS.53 Ullbro et al.21
proposed a mode of periodontal therapy of patients withPLS as shown in Table I.
Many other studies showed that the use of an anti-biotic adjunct with conventional periodontal therapy,i.e., plaque control, scaling and root planing, pocketreduction, oral hygiene instructions, and chlorhexidinemouth rinses, were of marginal benefit or ineffective.The use of tetracycline to stabilize the periodontalinflammation and destructive periodontitis was basedon its effectiveness against A. actinomycetemcomitansand Capnocytophaga.21,22
For many years, clinicians have been aware of theprosthetic problems posed by severely atrophic thinalveolar ridges and have constantly endeavored to de-velop new methods of treatment. Preprosthetic surgical
Table I. Dental treatment protocol for patients withPapillon-Lefevre syndromeDeciduous dentitionOral hygiene instructions and prophylaxis every third monthTeeth with advanced periodontal disease: extractionAll teeth should be extracted at least 6 months before eruption of
the first permanent tooth; antibiotics should be given for 2weeks after extraction. Recommended antibiotics: amoxillin �clavularic acid, 20-40 mg/kg/d, in divided doses every 8 hours
Permanent dentitionOral hygiene instructions and prophylaxis every third monthMouth rinses twice daily with chlorhexidine gluconate 0.2%Teeth with moderate periodontal disease (bone loss �30% of the
root length, probing pocket depths �5 mm):Dental scalingProphylaxis once every monthAntibiotic treatment for 4 weeks; recommended antibiotics:
amoxilin (20-50 mg/kg/d) � metronidazole (15-35 mg/kg/d)in divided doses every 8 hours
Teeth with advanced periodontal disease (bone less �30% of theroot length, probing pocket depth �6 mm): extraction
techniques have been introduced as aids to retention
OOOOEe6 Dhanrajani July 2009
and stability of dentures. Modern dental implants areavailable that offer not only considerably better stabil-ity and retention of prosthesis but also improved com-fort and masticatory efficiency and esthetics.
Titanium implants have become an important treat-ment alternative to replace missing teeth. The use ofimplants in patients with severe periodontitis has beenreported, and the results indicate that periodontallycompromised patients can be successfully treated withimplants.37,53,54
The conventional treatment of keratoderma wasbased on administration of antiinflammatory emollientsand keratolytic agents, such as topical steroids andsalicylic acid. It was not until the development ofretinoids in the early 1970s that the control of PLSbecame promising. Etretinate is the ethyl ester of aci-tretin, an aromatic retinoid related to both retinoic acidand retinal, and was reported to be effective in thetreatment of some kinds of palmoplantar keratoderma,such as Haim-Munk syndrome, Unna-Thost disease,mal de Meleda, mutilating palmoplantar keratoderma,and progressive palmoplantar keratoderma.8 Lee et al.reported a successful treatment of skin lesions of PLSusing acitretin 10mg oral daily and trimethoprim-sulf-methoxazole.14,55-57
The use of oral retinoids has been reported to beeffective in patients with PLS. After 8 weeks of oralacitretin (10 mg), there was a dramatic improvementwith marked reduction of keratoderma.57-60 Side effectsencountered due to prolonged administration of etreti-nate are angular cheilitis, dryness of the lips, hair loss,arthralgias, tendinous and ligamentous calcifications,and teratogenicity.
In summary, PLS is a very rare autosomal recessivedisorder characterized by palmoplantar hyperkeratosisand severe early onset of destructive periodontitis lead-ing to premature loss of both primary and permanentdentitions. The etiopathogenesis of the condition sug-gests that there is a genetic basis for susceptibility tospecific virulent pathogens.
The conflicting findings on PLS management couldbe related to the severity of the condition, the age atwhich treatment was instituted, timing and duration ofantibiotic therapy, professional supervision, follow-upsupportive treatment, and home care. The complexetiopathogenesis of PLS means that successful treat-ment of the periodontal component of this syndromeremains challenging.
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Reprint requests:
Dr. P. J. DhanrajaniOral, Maxillofacial SurgeonHCF Dental CentreSydney, NSWAustralia
[email protected]
