J Clin Feriodomot 1996: 23: 764-769Primed in Denmark . ,4ti rights reserved

Copyright C Munk.tgaard 1996

ISSN 0303-6979

Partial expression of thePapillon-Lefevre syndrome in 2unrelated families

W, Aubrey Soskolne\Ayala Stabholz',Thomas E, van Dyke ,̂Thomas C. Hart= and Joerg Meyle"^Hebrew Universify-IHadassah Faculty of Dentalfufedicine. Jerusalem 91t20, Israel. ^EastmanDenial Center. Rochester, HY, 14620. USA.^Department of Dentisfry. Bowman Gray Schoolof Medicine. Winston-Salem. NC 271S7-1093.USA. "Universitat Giessen, Department ofPeriodontics. Schlangenzahl 14. Giessen 34392.Germany

Aubrey Soskolne W, Stabhoh A, Van Dyke TE, Hart TC, Meyie J: Partialexpression of the Papillon-Lefevre syndrome in 2 unrelated families, J ClinPeriodontol 1996: 23: 764-769, © Munksgaard, 1996.

Abstract, The Papillon-Lefevre syndrome (PLS) is a rare, autosomal recessivetrait that is characterized by palmar plantar keratosis (PPK) and severe, early onsetperiodontitis, affecting both deciduous and permanent dentitions. The clinicalpresentation of PLS is variable; the disease occurs so infrequently as to limitclinical cases for study. The exception is a few families with extensive consanguin-ity in which numerous cases occur. Of particular interest to mapping the geneticorigin of the syndrome is the co-expression of the major traits of hyperkeratosisand periodontitis, and their severity. In this paper, we report 2 families withmultiple affected individuals from geographically remote areas. A large extendedfamily, from the Cochin region of India, currently residing in Israel, in which thereis documented consanguinity and a family from the southwest region of Ger-many. In each family, I individual presents with hyperkeratotic lesions with thecomplete absence of periodontal lesions. Further, the difference in severity of thehyperkeratotic lesions between families is marked, and one sibling in the Ger-man family expressed rapid, early onset periodontitis in the absence of PPK. Thegenetic nature and penetrance of the genetic defect are discussed.

Key words: Papillon Lefevre syndrome; palmarplantar hyperkerafosis; periodontal disease;genetics; variable expression

Accepted for publication 16 October 1995

The Papillon Lefevre syndrome (PLS)is characterized by periodontal diseaseaffecting both the deciduous as well asthe permanent dentition and hyperkera-tosis of the hands and feet (palmarplantar keratosis, PPK) (Papillon & Le-fevre 1924). The syndrome is thoughtto be the homozygous expression of anautosomal recessive trait transmittedwith an estimated frequency of 1-2 per-sons per million (Gorlin et al. 1964).The 2 major components of the syn-drome are known to occur as distinctdisease entities. Dermatological lesionssimilar to those seen in the syndromeare fairly commonly found as a separ-ate, genetically transmitted trait (Gold-smith & Thomas 1992), suggesting amultigenetic etiology for PLS (Hart &Shapira 1994). Destructive adult typeperiodontitis is a relatively common

disease, affecting approximately 30% ofthe working adult American population(Miller et al. 1987). Periodontitis is farrarer in the younger population whereit occurs as Early Onset Periodontitis ofthe localized or generalized form affect-ing approximately 0.6% of the popula-tion (Loe & Brown 1991). Destructiveperiodontal disease affectmg the de-ciduous dentition has otily been de-scribed in a few isolated case reports.(Page et al. 1983, Spector et al. 1985,Page et al. 1985). While there is someevidence for a genetic component toadult periodontitis, a form of early on-set periodontitis. Juvenile Periodontitis,has been shown to likely be inherited asan autosoma! dominant trait (VanDyke et al. 1985, Hart et al. 1992, Mar-azita et al. 1994). Certain forms of pre-pubertal periodontitis (leukocyte adher-

ence deficiency) are autosomal recessivedefects of integrin expression (Springeret al. 1987).

In classical descriptions of PLS, der-matological symptoms begin prior toage 2 years and continue throughoutlife. The periodontal disease componentof the syndrome affects the deciduousdentition causing destruction of theperiodontium and early tooth loss fol-lowed by similar rapid destruction ofthe support of the permanent dentitionand edentulism by the 15th year. Theremay or may not be a history of consan-guinity between the parents. However,the literature describes a number ofvariants of this clinical presentationunder the heading of PLS. A number ofcases have been described where there isno history of the deciduous teeth beingaffected (Brown et al. 1993, BuUon et

Partial expression of Papillon-Lefevre 765

II

IIIKey: O=female

D=male|]=edenlulous permanent dentition with a history of severe, early onset periodontitis(Eden)[I = palmar plantar keratosis (PPK)•=PPK, edentulous

Fig, I. The nuclear family of the individual from Israel affected by paltnar plantar hyperkera-tosis only (PPK).

al, 1993, Willet et al. 1985, Schroeder et keratosis (PPK) within the first 2-3al, 1983), Of these cases, some showed years of life (BuUon et al. 1993, Schro-early onset of palmar plantar hyper- eder et al 1983), while in the others, the

dermatological symptoms startedaround the 3rd decade (Brown et al,1993), The nature of the periodontaldisease affecting the permanent teethalso varies from an acute fulminatingtype infection affecting the teeth ontheir eruption and resulting in theirearly loss m spite of treatment (Shamset al. 1984, Celenligil et al. 1992, Hane-ke et al 1975, Preus 1988, Van Dyke etai. 1984, Schroeder etal. 1983), to a dis-ease recognized only later in life aroundthe 3rd decade and which has a moresubdued clinical presentation (Brown etal, 1993, Willet et al. 1985). There arealso those cases which appear to re-spond to periodontai therapy haltingthe disease progression (Tinanoff et al.1986, Preus & Gjermo 1987, Ishikawaet al. 1994).

These descriptions of the syndrometogether with the fact that the twomajor manifestations of disease (PPKand periodontal disease) occur as inde-pendent diseases raise the difficulty ofhaving to differentiate between a rare

Fig, 2, Extensive hyperkeratosis of the sole of the foot (A) and the palm of the hand (B) of the Israeli individtial affected by the dermatologicalsigns only.

Fig, 3, Radiological status of the Israeli individual showing the presence of all teeth and no periodontal destruction at 19 years of age.

766 So.skolne et al.

II1

Key: O=femalen=maleI]=edenlulous permanent dentition with a history of severe, early onset periodontitis(Eden)[I=palmar plantar keratosis (PPK)•=PPK. edentulous

Fig. 4. The German nuclear family showing the members affected by Papillon-Lefevre syn-drome.

genetic syndrome and the possible se-rendipitous association of 2 separatedisease entities. The purpose of this re-port is to present two unrelated familieswith PLS in which there is partial ex-pression of the cardinal features of thesyndrome.

Case ReportsCase no. 1

A large family of Jews from Cochin, In-dia with 15 members affected by Papil-lon-Lefevre syndrome has been exten-sively studied over the years (Shoshanet al. 1970, Hacham-Zadeh et al. 1979,Shapira et ai. 1985). Because of the geo-graphical and religious isolation of thiscommunity in India prior to their immi-gration to Israel, extensive intermar-riage amongst the family members was

culturally acceptable. Fig. 1 illustratesthe pedegree of the nuclear family re-ported here.

One member of the family, a 19-year-old male (IL-9). expresses only the der-matological lesions without any peri-odontal involvement. The 1st signs ofthe disease occurred on the soles of thefeet at approximately 3 months of ageas single small maccular lesions whichspread to involve the entire plantar sur-face. At approximateiy 3-4 years of age,the paimar surfaces became involvedand to date the disease involves the dor-sum of the hands and feet as weil asother skin surfaces including the eibowsand the knees (Fig. 2). The 30 teethpresent in his mouth have intact peri-odontium with pocket probing depthsthat do not exceed 4 mm and no attach-ment loss (Fig. 3). He has a mild gingi-

Fig. 5. intraoral photograph of one of theGerman individuals with Papillon-Lefevresyndrome at the age of 2.5 years old showingsevere gingival inflammation and early lossof the deciduous incisor. This patient is nowcompletely edentulous.

vitis. Of the remaining 5 siblings. 1brother, now deceased, suffered fromboth dermatological and periodontallesions and had lost his teeth by the ageof 13 years. A sister had lost her teethby the age of 15 years and has hyper-keratosis affecting only the plantar sur-faces of her feet.

Case no. 2

A German family consisting of bothparents and 5 children has been fol-lowed over the past 15-20 years. (Fig.4). There was no history of consanguin-ity between the parents. According tothe family dentist, although both par-ents are edentulous they had not shownsigns of an aggressive form of peri-odontitis and had lost their teeth be-cause of severe caries. The mothershowed signs of abnormal keratiniz-ation of her skin from childhood. Ofthe 5 children, 4 had lost their teeth al-most immediately after eruption of thepermanent dentition (Fig. 5). 3 of these

Fig. 6. Mild hyperkeratosis affecting the iiel (A) and the palm of the hand (B) of the same individual seen in fig. 5 in his late teens.

Partial expre,ssion of Papillon-Lefevre 767

Fig. 7. Intraoral photograph showing healthyperiodontiutn of the German individualaffected by palmar plantar hyperkeratosisonly.

4 siblings also showed signs of palmar-plantar-hyperkeratosis (Eig. 6|. The 4thchild was free of any signs of hyperkera-tinization at the time of the clinicalexamination. The 5th child expressedonly the dermatological symptomswithout periodontitis (Eig. 7). Com-pared to other reports of PLS, thehyperkeratinization of this Germanfamily was mild. Eig. 8 follows the pro-gression of the syndrome radiographi-cally, in the youngest member of thefamily, over a 16-year period. Of inter-

est to us in this report are the 2 siblingswith discordant expression of the cardi-nal features of PLS. In one, only thePPK. symptoms are present, while inthe other, only the periodontal symp-toms are present.

Discussion

The 2 families described illustrate bothvariable and discordant expression ofthe two cardinal features of PLS. Thefindings corroborate previous reports ofpartial expression of periodonta! anddermatological manifestations of PLS(Bullon et al. 1993. Shams el din et al.1984). The discordant expression ob-served suggests several possible geneticetiologies for PLS. Does PLS representthe variable clinical expression of asingle gene defect or is PLS a multi gen-etic disease representing co-expressionof two closely linked loci. Both hall-marks of PLS (severe onset peri-odontitis leading to edentulism and pal-mar plantar hyperkeratosis) are knownto exist as independent traits, yet bothare uncommon. Severe early onset peri-odontitis leading to premature edentul-

ism of both dentitions is particularelyrare. This suggests that the chance oc-currence of these two traits in the nu-merous families reported to date is un-likely (Goriin et al. 1964, Haneke 1979),and argues for another explanation.PLS is an autosomai recessive trait, pre-sumed to result in individuals homo-zygous for the disease locus. However.the disease alleles may not be identical.Allelic heterozygosity could account forsome of the clinical variability observedparticularely in cases where consan-guinity is absent. In the case of theCochin family, the disease alleles are be-lieved to be identical by descent. An-other possibility is that of manifestationof heterozygosity. Kotzot & Pfeiffer(1993) noted that occasional manifes-tation of heterozygosity for autosomalrecessive disorders has been reported.They presented a case of a presumedheterozygous parent of PLS affected in-dividuals presenting with eariy toothloss. The reported abnormal keratiniz-ation of the probands mother in theGerman family (Eig. 2) is interesting inthis regard and may represent a mani-festation of heterozygosity in PLS.

Fig. 8. Panoramic radiographs following the progression of the periodontal disease in the youngest member of the German family. (A) Theindividual at 2.5 years of age with severe periodonta! destruction in the deciduous incisor and molar regions. (B) The same individual at theage of 5.5 years shows loss of all deciduous teeth. (C) At age 8 years, bone loss is already apparent around the erupted permanent incisorsand first molars. (D) At 18 years of age. the patient was edentulous.

768 So.ikolne et al

Variable clinical expression of singlegene mutations is known to occur, forexample, in ectodermal dysplasia, Du-cijenne muscular dystrophy and cysticfibrosis. In the case of Duchenne mus-cuiar dystrophy, it is beheved that amajor iocus gene (unlinked to the dis-ease gene) influences dystropin ex-pression. Such epistatic interactions be-tween a disease gene and other (notnecessariiy iinked) modifying genescould be present in PLS. and result invariable clinical expression of the syn-drome. Olher possible modifying infiu-ences include genetic imprinting, partic-ularely in cases of somatic heterozygos-ity of the mutative aliele. Genetic

''imprinting has nol been evaluated inPLS. but differential methylation pat-terns of disease and modifying alielescould influence disease expression. Weare currently conducting genetic linkageanalyses for these families. Resuits ofthese studies may allow us to determinethe genetic etiology of PLS.

Zusammenfassung

Teilweiser Ausbruch des Papillon Lefevre Svn-droms hei 2 verwandten FamilienDas Papillon-Lefevre-Syndrom (PLS) ist eineseltene autosomal rezessive Erkrankung, diecharakterisiert ist durch eine Keratosis pal-mo-plantare (KPP) und eine schwere friiheinsetzende Parodontitis. die sowohl die Mil-ch- als auch die bleibenden Zahne befallt.Das klinische Erscheinungsbild des PLS istveriabel. Diese Erkrankung ist so seiten. dal3die klinjschen Falle fdr eine Studie sehr limit-iliert sind. Die Ausnahme sind einige Famili-en mit intensiver Blutsverwandtschaft. in de-nen zahlreiche Falle vorkommen. Von beson-derem Interesse bei der Dokumentation desgenetischen Ursprungs des Syndroms ist dieKo-Expression der Hauptcharakteristika derHyperkeratose und Parodontitis und derenSchwere. In dieser Verdffentlichung berichtenwir ulier zwei Familien mit multibel befalle-nen Individuen aus geografisch enfferntenGebieten. Eine stark verbreitete Familie ausder Cochin Region in Indien, die zur Zeit inIsrael wohnt und in der es eine dokumentier-te Blutsverwandtschaft gibt und einer Fami-lie aus dem Stidwesten Deutschlands. In je-der Familie gibt es eine Person mit hyperke-ratotischen Lasionen bei gleichzeitigerAbwesenheit von parodontalen Lasionen.Deshveiteren besteht ein deutlieher Unter-schied zwischen den Familien in der (:chwereder hyperkeratotischen Lasionen und ein Ge-schwister aus der deutschen Famiiie zeigteeine rasche frijh beginnende Parodontitis beiAbwesenheit von KPP Die genetische Naturund das Eindringen von genetischen Defek-ten wird diskutiert.

Resume

Expression partielle du syndrome de Papillon-Lefevre dans deux families entre lesquvlles itn 'existe pas de liens de parentcLe syndrome de Papillon-Lefevre (PLS) estun trait recessif autosomique rare, caracterisepar une keratose palmo-plantaire (PKK) etune parodontite severe a debut precoce. af-fectant la denture lacteaie et la denture pier-manente. Cliniquement. PLS se presente defapons diverses: la rarete de cette maladie li-mite le nombre des cas cliniques pouvant etreetudies. Cependant. queiques families a forteconsanguinite au sein desquelles se produi-sent de nombreux cas constituent I'exception,La co-expression des traits principaux. I'by-perkeratose et la parodontite. et Ieur severitesont d'un interet particulier pour etablir lacarte de I'origine genetique du syndrome.Nous decrivons dans le present article deuxfamilies dans lesquelles de nombreux indivi-dus originaires de regions geographiqueseloignees sont atteints: une familie comptantde nombreux membres. originaire de la re-gion de Cochin en Inde. habitant actuelle-ment en Israel et pour laquelle il existe unedocumentation de consanguinite. et une fa-milie du sud-ouest de r.A!lemagne. Dans cha-cune des families, on constate chez un dessujets des lesions d'hyperkeratose en l'absen-ce totale de lesions parodontales. De plus, ilexiste une difference marquee entre la severi-te des lesions d'hyperkeratose observees dansles 2 families: dans la familie allemande. undes membres de la fratrie exprimait une pa-rodontite rapide a debut precoce. en l'absen-ce de PPK. La nature du defaut genetique etsa penetrance font Tobjet d'une discussion.

References

Loe, H. & Brown. L.J, (1991) Early onsetperiodontitis in the USA, Journal of Peri-odontology 62. 608-616,

Brown. R.S., Hays, G. L.. Flaitz, C. M.,O'Neil, P A.. Abramowitch. K. & White,R. R. (1993) A possible late onset vari-ation of Papillon Lefevre syndrome: reportof 3 cases. Journal of Periodontoiogy 64,379-386.

Bullon. P., Pascual, A.. Fernandez-Novoa.M. C , Borobio, M. V., Muniain, M. A. &Camacho. F. (1993) Late onset PapillonLefevre syndrome? A chromosomic, neu-trophil function and microbiologicalstudy. Journal of Clinical Periodontology20, 662-667.

Celenligil. H., Ruacan, K. E. & Eratalay. K.(1992) Papillon-Lefevre syndrome. Char-acterization of peripheral blood and gingi-val lymphocytes with monoclonal anti-bodies. Journal of Clinical Periodontology19. 392-397.

Goldsmith, L. A. & Thomas, N. E. (1992)Disorders of cornification. chapter 55. In:Dermatology. 3rd edition. Moschella, S.L. & Hurley, H. J. (eds.) W. B. SaundersCo., Philadelphia, pp. 1383-1417.

Gorlin, R. J.. Sedano. H. & Anderson, V F.(1964) The syndrome of palmar-plantarhyperkeratosis and premature periodontaldestruction of the teeth. Journal of Pedi-atrics 65. 985-907.

Hacham-Zadeh. S., Schaap, T. & Cohen, M.M. (1979) A genetic analysis of the Papil-lon Lefevre syndrome in a Jewish familyfrom Cochin. American Journal of MedicalGenetics 2. 153-157.

Hart. T .C . Marazitta. M. L.. Schenkein. H..A. & Diehl. S. R. (1992) Re-mterpretationof the evidence for X-linked dominant in-heritance of juvenile periodontitis. Journalof Periodontology 63. 169-173.

Hart. T. C. & Shapira. L. (1994) Papillon-Lefevre syndrome. Periodontology 2000 6.88-100.

Haneke. E.. Horstein. P O. & Lex. C. (1975)Increased susceptibility to infections in thePapillon-Lefevre syndrome. Derniatologica150. 283-286.

Haneke E. (1979) The Papillon-Lefevre syn-drome: keratosis palmoplantaris with peri-odontopathy. Report of a case and reviewof the cases in the Ijterature. Human Gen-erics 51. 1-35.

Ishikawa. I.. Umeda. M, & Laosrisin. N.(1994) Clinical, bacteriological, and im-munological examinations and the treat-ment process of 2 Papillon-Lefevre syn-drome patients. Journal of Periodontology65.364-371,

Kotzot. D, & Pfeifer. R. A. (1993) Manifes-tation of heterozygosity in Papillon-Lefev-re syndrome? Letter to the Editor Atner-ican Journal of Medical Genetics 46. 247.

Marazitta. M, .. Burmeister, J. A., Gunsolley,J. C . Koertge, T. E., Lake, K. & Schenk-ein, H. A. (1994) Evidence for autosomaldominant inheritance and race-specificheterogeneity m early-onset periodontitis.Journal of Periodontology 65, 623-630.

Miller, A. J., Brunelle. J. L., Carlos, J. R,Brown, L. J. & Loe, H. (1987) Oral healthof USA adults. Bethesda. Maryland: Na-tional Institute of Dental Research. NIHpublication no, 97-2868.

Page, R. C . Sims. T. J.. Geissler. F . Altman,L. C. & Baab, D A, (1985) Defective neu-trophil and monocyte mobiiity in patientswith early-onset periodontitis. Infectionat}d Immunity 41. 169-175.

Page, R. C . Brown, X, Altman, L. C . Vand-esteen, E., Ochs, H.. Mackenzie, P, Oster-berg, S.. Engel, D. L. & Williams, B. L.(1983) Prepubertal periodoniitis (1), Defi-nition of a clinical entity. Journal of Peri-odontology 54. 257-271.

Papillon, M. N. & Lefevre, B, (1924) Deuxcas de kertodermie palmaire et plantairesymetrique familiale (Maladie de Maleda)chez le frere et la soeur. Cexistance dans ledeux cas d' alteration. Bulletin de la Socie-te Francaise de Dermatologie et de Syphili-graphieil. 81-84.

Preus. H. R. (1988) Treatment of rapidly de-structive periodontitis in P^apillon-Lefevresyndrome. Journal of Clinical Periodonto-logy 15, 639-643.

Partial expression of Papillon-Lefevre 769

Preus, H. & Gjermo. P (1987) Clinical man-agement of prepuberta! periodontitis in 2siblings with Papillon-Lefevre syndrome.Journal of Clinical Periodontoiogy 14. 156-160.

Schroeder, H. E., Seger, R. A.. Keller, H.U & Rateitschak-Pluss, E. M. (1983) Be-havioui; of neutrophilic granulocytes in acase of Papillon-Lefevre syndrome.Journal of Clinical Periodontology 10, 618-635.

Shams. .El Din A., Benton. R., Bottomley, W.K., Hoy, G. R.. Wientzerg, R. L., Zeligs,B. & Bellanti. J. A. (1984) Hyperkeratosis.periodontosis, and chronic pyogenic infec-tions in a 15 year-old boy. Annals of Al-lergy 53, 11-14.

Shapira. J.. Eidelman, E.. Euks, A. & Hach-am-Zadeh. S. (1985) Treatment of PapillonLefevre syndrome with chemotherapy: re-port of cases. Special Care in Dentistry xx,71-74.

Shoshan, S., Finkelstein, S. & Rosenzweig,

K. A. (1970) Disc electrophorethic patternof gingival collagen isolated from a patientwith palmoplantar hyperkeratosis. Journalof Periodontal Research 5, 255-258.

Spector. M. D.. Vandesteen. G. E. & Page.R. C. (1985) Clinical studies of one familymanifesting rapidly progressive, juvenileand pre-pubertal periodontitis. Journal ofPeriodontology 56. 9J-101.

Springer. T. A.. Dustin, M. L., Kishimoto, T.K. & Marlin. S. D. (1987) The lymphocytefunction-associated LFA-1. CD2 andLFA-3 molecules. Cell adhesion receptorsof the immune system. Annual Reviews ofImmunology 5. 223-252.

TinanofT. N., Tanzer, J. M.. Kornman. K.S. & Maderazo, G. E. (1986) Treatment ofperiodontal component of Papillon-Lefev-re syndrome. Journal of Clinical Periodon-tohgy 13, 6-10.

Van Dyke, T E., Schweinebraten, M., Cianci-ola, L. J., Offenbacher, S. & Genco, R. J.(1985) Neutrophil chemotaxis in families

with localized juvenile periodontitis.Jourtuil of Periodontat Research 20, 503-514.

Van Dyke. T. E., Taubman. M. A.. Ebersole,J. L., Haffajee, A. D.. Socransky, S. S.,Smith, D. J. & Genco, R. J. (1984) The Pa-pillon-Lefevre syndrome: neutrophii dys-function with severe periodontal disease.Clinical Immunology and Immunopathol-ogy3l, 419^29.

Willett, L. M., Gabriel, S. A.. Kozma. C &Bottomley. W. K. (1985) Papillon Lefevresyndrome. Journal of Oral Medicine 40,43^5.

Address:

W. A. SoskolneDepartment of PeriodonticsHebrew University-Hadassah Faculty of

Denial MedicineP.O.Box 12272Jerusalem 91120Israel