Papillon-Lefevre syndrome: clinical presentation and a brief review

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<ul><li><p>Pa esen</p><p>c, FR</p><p>ribedrec hyperkpe t dentC rief revSu 1-e7)</p><p>Thscr</p><p>au</p><p>paand devastating periodontitis, affecting the primary aswell as the permanent dentition, attributed to a pointmutation of the cathepsin C gene.2-6</p><p>The syndrome is estimated to have frequency of 1-4pewiisthieo</p><p>cidare</p><p>bedeex</p><p>givatima</p><p>eru</p><p>mo</p><p>tee</p><p>patients 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 teeth</p><p>OraRe200107 2doi</p><p>Vol. 108 No. 1 July 2009</p><p>NDEditor million and 300 cases have been reported world-de.7 It seems that the incidence in the Saudi Arabiahigher compared with other parts of the world, ands may be attributed to cluster marriages (consanguin-us marriages).8,9 The onset of disease usually coin-es with the eruption of primary teeth. Boys and girlsequally affected, with no racial predominance.</p><p>Following eruption of primary teeth, the gingivaecome inflamed. This is generally followed by a rapidstruction of periodontium and most affected childrenperience premature loss of their primary teeth. Gin-</p><p>has been considered to be a mode of treatment.20-25For many years, clinicians have been aware of the</p><p>prosthetic problems posed by severely atrophic thinalveolar ridges, and this has constantly motivated cli-nicians to develop new methods of treatment.</p><p>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</p><p>This paper presents the etiology and clinical features,and highlights different treatment modalities used topillon-Lefevre syndrome: clinical prreview</p><p>Parmanand J. Dhanrajani, BDS, MDS, MSc, MSSydney, AustraliaHCF DENTAL CENTRE</p><p>The Papillon-Lefevre syndrome (PLS) was first descessive disorder characterized by a diffuse palmoplanterriodontitis, affecting the primary as well as the permanengene. This paper presents a clinical presentation and a brg Oral Med Oral Pathol Oral Radiol Endod 2009;108:e</p><p>e Papillon-Lefevre syndrome (PLS) was first de-ibed by Papillon and Lefevre in 1924.1 It is antosomal recessive disorder characterized by a diffuselmoplanter hyperkeratosis and rapidly progressive</p><p>MEDICAL MANAGEMENT Aa seems to resume normal appearance after exfoli-on of the primary dentition.9 The aggressive inflam-tory periodontal process then repeats itself after the</p><p>rehLe</p><p>ET</p><p>intso</p><p>ordas</p><p>l &amp; Maxillofacial Surgeon.ceived for publication Sep 12, 2008; returned for revision Mar 7,9; accepted for publication Mar 9, 2009.9-2104/$ - see front matter009 Mosby, Inc. All rights reserved.</p><p>:10.1016/j.tripleo.2009.03.016tation and a brief</p><p>ACDS, FDSRCS, FFDRCSI,</p><p>by Papillon and Lefevre in 1924. It is an autosomaleratosis and rapidly progressive and devastatingition, attributed to a point mutation of the cathepsiniew of its etiology and treatment modalities. (Oral</p><p>ption of the permanent teeth, and in general all orst of the permanent dentition is lost during thenage years.10-13Conventional periodontal treatment usually fails in</p><p>PHARMACOLOGY UPDATErs: F. John Firriolo and Nelson I. Rhodusabilitate the oral cavity in patients with Papillon-fevre syndrome.</p><p>IOLOGY AND PATHOGENESISExact etiology and pathogenesis is unknown, butensive work during the last decade has revealedme important factors in the development of the dis-er. In recent years, three main factors are suggested</p><p>responsible for the initiation and progression of PLS.</p><p>e1</p></li><li><p>Ge</p><p>sivrepma</p><p>as</p><p>isfectinex</p><p>cluan</p><p>toass</p><p>Im</p><p>thephcygecen</p><p>ase</p><p>phtasma</p><p>res</p><p>milostroizepesee</p><p>M</p><p>geogfuncu</p><p>Prwe</p><p>etsspppathaicahypataninrio</p><p>su</p><p>toxthaco</p><p>potitina</p><p>phmiinmy</p><p>zyagma</p><p>tioua</p><p>wa</p><p>pro</p><p>duhefunera</p><p>co</p><p>me</p><p>PL</p><p>me</p><p>ind</p><p>inoftumhyno</p><p>for</p><p>PLno</p><p>ne</p><p>na</p><p>lesme</p><p>an</p><p>attno</p><p>fre</p><p>CL</p><p>demo</p><p>OOOOEe2 Dhanrajani July 2009neticPapillon-Lefevre syndrome is an autosomal reces-e disorder. Recently, a few research groups haveorted that loss-of-function mutations of the lysoso-l protease cathepsin C gene are associated with PLSwell as related conditions.14-18 The cathepsin C geneexpressed in the epithelial regions commonly af-ted by PLS, such as palms, soles, knees, and kera-ized oral gingiva. The cathepsin C gene is alsopressed at high levels in various immune cells, in-ding polymorphonuclear leukocytes, macrophages,</p><p>d their precursors. This discovery will certainly leadbetter understanding of the signs and symptomsociated with PLS.3,4,20,21</p><p>munologicAnother important etiologic factor is an alteration of</p><p>host defense owing to decreased function of lym-ocytes,26 polymorphonuclear leucocytes, or mono-tes.27 The cathepsin C protein encoded by the CTSCne is a lysosomal cysteine proteinase that appears to betral coordinator for activation of many serine protein-s in immune/inflammatory cells, including the neutro-</p><p>il serine proteases (NPS) (cathepsin G [CTSG], elas-e, and proteinase 3).28 The inactivation of these NPSsy have multiple downstream effects that ultimatelyult in desregulation of the host immune response tocrobial infection. Ryu et al.26 recently proposed that thes of CTSC function and subsequent inactivity of neu-phil serine proteases may cause dysregulation of local-d polymorphonuclear leucocyte response in inflamedriodontal tissues, leading to the severe tissue destructionn in PLS.29</p><p>icrobialGram-negative microbial polysaccharides (LPS) arenerally recognized to be primary factors in the etiol-y of periodontitis, including PLS.19,22 Neutrophilction test showed reduced response to Staphylococ-</p><p>s spp. and Actinobacillus actinomycetecomitans.esence of virulent gram-negative anaerobic pathogensre found at the site of lesion (plaque/periodontal pock-), such as Bacteroides gingivalis, Capnocytophagas., spirochetes, and A. actinomycetemcomitans. Of the</p><p>thogens, A. actinomycetemcomitans constituted moren 50% of the total colony-forming units,20 and clin-l improvement followed its eradication. There is apothesis that periodontal herpes viruses together withthogenic bacteria, including A. actinomycetemcomi-s, and underlying host defense disorders, participatethe development of Papillon-Lefevre syndrome pe-dontitis.23,24There are also numerous virulence factors present,ch as leukotoxin, collagenase, endotoxin, epithelio-ins, and a fibroblast-inhibiting factor, suggestingt PLS is mediated bacteriologically and therefore</p><p>uld be treated to some improvement with antibiotics.24The subgingival plaque found in the periodontalckets of PLS patients resembles a typical periodon-s-associated microflora and has shown a predomi-nce of gram-negative anaerobic rods, including Por-yromonas gingivalis and spirochetes.28,30 Recentcrobiologic studies have revealed that periodontitisPLS patients may also be associated with A. actino-cetemcomitans.7,31,32Human keratinocytes in culture normally secrete gran-me B with antimicrobial activity that is able to protectainst invading pathogens. The activation of granzyme By thus provide protection against dermal inflamma-n.33,34 The failing activation of granzyme B in individ-ls with PLS might weaken the epithelial response to-rd bacterial infection and contribute to the individualpensity to develop gingival inflammation.</p><p>Defect of immune-mediated mechanisms, including re-ced lymphocyte response to pathogens, depression oflper-to-suppressor T-cell ratio, deficient monocyticction, elevation of serum immunoglobulin, and degen-tive changes of plasma cells,35 have been reported.The elevated antibody titers to A. actinomycetem-mitans support the microbial findings of the involve-nt of this bacteria in periodontopathy associated withS.36There are investigations carried out to check urinetabolism and serum vitamin C and zinc levels in PLSividuals in literature that were insignificant.</p><p>A dysplasia of the root cementum has been reportedPLS by Page and Baab,37 suggesting the possibilityabnormal deposition or maintenance of root cemen-, similar to that observed in less severe cases of</p><p>pophosphatasia. However, in that study the roots didt show any structural alterations that could accountthe severity of the periodontal lesions.38,39</p><p>It has been suggested that palmoplantar keratoses inS predispose to high incidences of malignant mela-ma. Nakajima et al.40 reported a 51-year-old Japa-se woman with PLS associated with recurrent malig-nt melanoma arising from hyperkeratotic cutaneousions. They also reported 4 other cases of malignantlanoma in PLS patients: Out of 4, 3 were Japanese,</p><p>d the authors suggested that this tendency might beributed to high frequency of acral lentiginous mela-ma in Japanese populations, in contrast to a lowquency of this subtype in caucasians.41</p><p>INICAL PRESENTATIONSThe onset of the cutaneous lesion of PLS (kerato-rma) may appear at birth or 1 to 2 months of age, butst commonly appears between the ages of 6 months</p></li><li><p>an</p><p>tee</p><p>so</p><p>thefreineex</p><p>invan</p><p>(F</p><p>reddefec</p><p>ne</p><p>Thno</p><p>an</p><p>an</p><p>ca</p><p>theed</p><p>wipoprethepreser</p><p>Figpal Fig</p><p>invB,ext</p><p>Fig</p><p>OOOOEVolume 108, Number 1 Dhanrajani e3d 4 years, coinciding with the eruption of primaryth.8The severity of keratoderma is variable, with theles being prominently more involved. The margins of</p><p>keratoderma are well defined and erythematous,quently extending to the thenar and hypothenar em-nces of the palms and to the Achilles tendon and</p><p>ternal malleoli of feet (Figs. 1 and 2). Other sites ofolvement include the dorsal surface of the fingers</p><p>d toes, elbows, legs, thighs, and rarely the trunk42ig. 3).Skin lesions appear as white, light yellow, brown, or</p><p>plaques, which undergo crustation, cracking, andep fissuring. Infection may superimpose on the de-tive skin, resulting in the formation of abscesses.Oral manifestations of PLS appear almost simulta-ously with the onset of palmoplantar hyperkeratosis.e primary teeth erupt at the expected age and inrmal sequence. Usually, the teeth are of normal formd structure, although microdontia, root resorption,d incomplete root formation are reported in a fewses. Rapidly progressing periodontitis ensues, once</p><p>primary dentition are erupted, manifested by mark-ly reddened, inflamed and swollen gingiva associated</p><p>. 1. A, B, Photograph showing kyperkeratosis of thems extending to thenar and hypothenar eminences.th extensive bone resorption and deep periodontalckets from which pus exudes in response to slightssure (Fig. 4). Chewing is very painful because ofmobility of the teeth. Fetid mouth odor is usually</p><p>sent. Regional lymphadenopathy has also been ob-ved.5,43</p><p>. 2. A, Photograph showing hyperkeratosis of the feetolving external malleoli of feet and Achilles tendon.Photograph showing hyperkeratosis of the feet involvingernal malleoli of feet and Achilles tendon.</p><p>. 3. Photograph showing hyperkeratosis involving knees.</p></li><li><p>looliaagex</p><p>wiAfev</p><p>ofex</p><p>theairgradiaon</p><p>boab</p><p>sev</p><p>ne</p><p>de</p><p>inghacel</p><p>chThsu</p><p>kidres</p><p>in</p><p>Figsyn</p><p>Figalv</p><p>Figsw</p><p>OOOOEe4 Dhanrajani July 2009The pathognomic dental features of PLS are theseness, hypermobility, drifting, migration and exfo-</p><p>tion of teeth without signs of root resorption. At thee of 4-5 years, the primary teeth are exfoliated ortracted and the child becomes completely edentulousth the gingiva returning to its normal healthy state.ter the eruption of permanent teeth, the same cycle ofents begins again, and by the age of 13-15 years allthe permanent teeth are lost (Fig. 5). Radiographic</p><p>amination of advanced cases reveals severe loss ofalveolar bone, and teeth appear to be floating in</p><p> (Fig. 6). Differential diagnoses considering radio-phic findings include Haim-Munk syndrome, Che-k-Higashi syndrome, juvenile periodontitis, and so. Unerupted teeth tend to develop normally in theirny crypts, although in some cases they assume annormal position and have incompletely formed roots.The histopathology of the PLS periodontitis shows aere inflammatory infiltration of the subepithelial con-</p><p>ctive tissue, leaving only a few collagen fibres.43,44 Thense infiltration mainly consists of plasma cells dominat-</p><p>. 4. A, B, Photographs showing marked red inflamed andollen gingivae.the entire gingiva in certain area. Electron microscopys also revealed degenerative alterations of plasmals.34Asymptomatic calcification of the falx cerebri andoroid plexus have been noted in many PLS patients.ese patients have been reported to have increasedsceptibility to other infections, such as of liver, lung,ney, etc. It is possible that these rare findings are theult of a high degree of homozygosity at other allelesaddition to cathepsin C locus.</p><p>. 5. Flow chart of oral manifestations of Papillon-Lefevredrome.</p><p>. 6. A, B, Orthopantomograph showing severe loss ofeolar bone and teeth appear to be floating in air.</p></li><li><p>diftivan</p><p>tosptheea</p><p>inhothedroI, Vinthepe</p><p>ne</p><p>phdisma</p><p>odpre</p><p>foldroor</p><p>disablystroto</p><p>an</p><p>an</p><p>stratdeficin</p><p>froMkedroare</p><p>M</p><p>tolfor</p><p>be</p><p>thaan</p><p>tra</p><p>aimErplaTrstr</p><p>atSotraso</p><p>me</p><p>puproPL</p><p>bioi.eredmo</p><p>Thinflon</p><p>an</p><p>proalvve</p><p>tec</p><p>TaPaDeOraTeeAll</p><p>PerOraMoTee</p><p>DPA</p><p>Tee</p><p>OOOOEVolume 108, Number 1 Dhanrajani e5The mechanism underlying periodontal disease inferent genetic conditions as characterized by connec-e tissue alterations is explained by the fact thatomalies at this level generate increased susceptibilityperiodontal inflammation and bone resorption. De-</p><p>ite the existence of a common background alteration,manifestations of periodontal disease may differ in</p><p>ch of the syndromes.In case of Marfan syndrome, periodontitis manifestsa chronic and severe form, with patterns of bothrizontal and vertical bone resorption, according to</p><p>presence of bacterial plaque. In Ehler-Danlos syn-me, periodontal disease can be associated with typeII, III, or IV. The postulated mechanism is a defect</p><p>type III collagen, present in 16% of total collagen ofperiodontal ligament, affecting the integrity of the</p><p>riodontal junction.39,45In severe congenital neutropenia and infantile ge-tic agranulocytosis, the decrease in number of neutro-ils alters the host defense capacity, causing periodontalease to manifest at an early age, with gingival inflam-tion, aggressive periodontal destruction, edema, peri-ontal pouches, and tooth mobility. This is similar topubertal or rapidly progressive periodontitis.42,46,47</p><p>There is early-onset periodontitis with premature ex-iation of both dentitions in Chediak-Higashi syn-me.48 The pattern of bone resorption may be localized</p><p>generalized and is related to gingival inflammation. Theorder is associated with anaerobic infection due to theundant presence of purulent processes. In addition,osomal alterations and defective chemotaxis in neu-phils give rise to aggressive periodontitis that tendsbe recurrent and refractory to antibiotic treatment.48Down syndrome associated with mental retardationd systemic alterations is characterized by aggressived generalized periodontitis, with the subsequent de-uction of the supporting tissues and loss of the teethearly age. To these factors we must also add immuneficiency, inadequate control of bacterial plaque, de-ient masticatory function, early aging, and alterationdental anatomy...</p></li></ul>

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