Oral Medicine

Papillon-Lefvre syndrome-Successful treatment with a combination of retinoid and concurrent systematic periodontai therapy: Case reports
Stephati Kressin*/Artnin Herforth*/Sabine Preis**/V. Wahn**/H. G. Lenard** Papillon-Lefvre syndrome is a rare autosomal-recessive congenital differentiation disorder: the external signs are hyperkeratosis of the palms and soles. Intraorally, the most salient manifestations aie dystrophic periodontai problems that affect both the primary and permanent dentitions and frequently lead to premature tooth loss. Two children were treated with acitretin 0.5 mg/kg of body weight per day from November 1992 to November 1993, and another child since October 1993. Concurrently, the children receivedprofe.fsional oral hygiene care (scaling, root planing, and curettage). The combination of retinoid therapy and periodontai treatment improved the dermatologie and periodontal conditions. (Quintessence Int 1995:26.795-803.)

Introduction The symptom complex that includes hyperkeratosis of the internal surfaces ofthe hands and the soles ofthe feel; and concurrent serious periodontai problems in children and youths was described by Papillon and Lefevre in 1924. Sitice then, more than 200 cases of this autosomal-recessive differentiation disorder have been reported. Its frequency is reported to be 1 to 5 per million.' Apparently there is no gender preference.Changes ofthe skin are observed electron microscopically, with diminution of the tonofibrils. Alterations of the keratohyalin granules are found, as is acanthosis in the stratum spinosum. Additionai. irregular findings include a variety of disturbances ofthe

' Dcparlmeni of Period onto logy. Heinrich Heme University Dusseldorf. Center of Dentistry, Dsseldorf. Germary. *' Department of Pdiatrie Dentistry, Heinricli Heine University Dsseldorf. Center of Dentistr>', Dsseldorf, Germany. Reprint recjuests; Dr Stephan Kressln. Dorfplalz 6, D-12526 Berlin. Germany. TTiis article was previously published in German as .Das PapillonLefvre-Synd rom ; Erfolge bei der Therapie durch Kombination von Retlnoidgabe und gleichzeitiger systematischer Parodontalbeliandlung" (Pamdoiilohgie 1994;4;305-314l.

immune system (in approximateiy 20%},--' ectopic intracranial calcifications (in about 6%), mental retardation, and acro-osteolysis.' Intraorally. periodontai symptoms may arise soon after the beginning of eruption ofthe primary teeth. The first signs are inflammatory changes ofthe gingiva. The teeth become mobile soon after eruption; tooth movement and tilting follow, and the teeth are lost spontaneously. The continuously progressive process of periodontai destruction affects the primary and the permanent dentitions, so that the tbrmcr may be lost by the age of 4 or 5 years and the latter by the age of 13 to 15 years, depending on the severity of the disease."* Once the teeth are lost, the gingiva shows no further signs of periodontai alteration. It has been reponed that the third molars are protected from the continuously progressing tooth ioss.^'^ Some reports have described a reciprocal relationship between the intensity of the kratoses and inflammatory episodes of tooth-supporting apparatus.*'' It seems remarkable that the cutaneous changes rarely lead to consultation with a dermatologist, but the early loss of teeth or extensive tooth mobility often is the reason for consuitation with a dentist.'

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Case reports Case reports involving two siblings; aged 5 and 8 years, are presented together with that of an unrelated child, aged 4 years. All three are children of healthy, consanguineous Turkish parents.'" Concurrently to this therapy, the patient was prepared for systematic periodontal therapy. Two preliminary appointments in which the periodontal status was recorded (Fig Id) and periodontitis marker organisms were demonstrated through the DMDPathotek test, were completed. Evaluation ofthat test, however, revealed only a low to average number of organisms (between 2 x 10' and 4 x lC*), The organisms found (Actinobacillus actinomycetes concotnitans, Porphyromonas ginglvalis, and Prevotelk intermedia) corresponded to those found in adult periodontitis. The 10 permanent teeth were treated through scaling, root planing, and curettage until January 1993; no antibiotic therapy was provided. The first recall examination took place in April 1993, when the patient reported a subjective feeling of improvement, particularly with respect to the maxillary incisors. Tiie proximal Plaque Index was 82%; oniy two teeth were free of plaque. The Suicular Bleedii^ Index was 100%, Measurement of probing depth showed improvement for five teeth, no change for one, and increased probing depths around four teeth (Fig le). Orthodontic treatment, originally planned to retrude the tnaxillary incisors, was deemed inappropriate at that time because of insufficient oral bygiene and significant mobiiity (grade II), Acitretin therapy was interrupted in November 1993 so that the course of the periodontal disease with and without the medicament could be observed. At recall appointments in September and December 1993, oral hygiene conrinued to be poor. Progressive periodontal destruction was comparatively more rapid after discontinuation of tbe medicament than before. Probing depths increased by I to 4 mm on seven teeth; no change was recorded on five other teeth. Three teeth were atfected by increased mobility. Four months after cessation of acitretin therapy, the periodontai condition had worsened substantially (Fig IQ.

Case I An 8-year-old boy had suffered gingival infiammation since the eruption of his primaty teeth, which showed increased mobility and began to fall otit during bis fourth year of life. Medical examination revealed tbalassemia minor. Results of neurologic and radiograpbic studies of the skeletal system (witb the exception of the jaws) and computerized tomography of the skull were all noncontributory. Computer-assisted tomographic studies of the maxilla and mandible indicated well-advanced vertical and horizontal bone rsorption Tbe cusp tips of the second molars of the maxilla and mandible had erupted passively as a result of the bone loss, despite tbe absence of any root growth (Fig la). Dermatologically, the patient showed palmoplantar hyperkeratosis (Fig lb). Immunologie studies revealed no significant cbanges in surface markers (CD2, CD3, CD4, CD8, CD18, CDlla, CD3-CD56+), lymphocyte transformation test with pbytohemagglutinin A, pokeweed mitogen, StaphylococcusaureusCowanl(SAC).OKT3(Ortho Pharmaceuticai), and tetanus toxoid. Among normal mmunoglobulin in serum, immunoglobulin synthesis in vitro to SAC and SAC-i-II-2 was missing; in vivo it was missing to pokeweed mitogen. The number of polymorpbonuclear granulocytes in blood and the oxygen production per 10* granulocytes were within normal limits. Intraorally. the gingiva was chronically inflamed, edematous, swollen, and partially hyperplastic (Fig lc). Only two primary teeth (75 and 85) remained in the mixed dentition. The permanent teeth had probing depths of up to 10 mm and were mobile to grade II. The anterior teeth were decidedly protruded. Pus extruded from the pockets in response to pressure. Oral hygiene was entirely inadequate; the proximal space Plaque Index was 100%," and the modified Sulcular Bleeding Index also was lOOii.'^ The boy was treated for 1 year (November 1992 to November 1993) with 0.5 mg/kg of body weight per day of acitretin. This therapy, including laboratory, clinical, and radiographie checkups, was tolerated without any problems.

Case 2 In addition to palmoplantar hyperkeratosis (Fig 2a), both of this 5-year-old girl's lower legs showed subpatellar hyperkeratosis (Fig 2b), The child had a prematurely reduced (loss of all leeth from 64 to 74) and severely carious primary dentition (carious lesions on teeth 53, 63, 75, 73, 83, and S5). Tbe marginalgingiva was chronically inflamed and hyp erp la s tie in part. The mandibuiar centrai incisors and the 6-year molars were in eruption (Fig
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Figs la to If Case 1. Papillon-Lefvre syndrome in an 8-year-old boy Fig la (Leltj Panoramic view of the maxiila and mandible at initial examination

Fig Ib

(Seton'^Hyperkeratotic soies of the feet

Fig 1c

Intraoral appearance

Fig Id

Periodontal status at the beginning of treatment.

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Fig le

Perjodontal status 3 months after initiation of treatment.

Fig If Panoramic radiograph ol tfie maxilla and mandible 4 months after cessation ot acitretin therapy.

2c). Her poor oral hygiene was reflected by a proximal Plaque Index of more than 80%) and a Sulcular Bleeding Index of 83%. Radiographic findings, similar to those of her older brother, showed extensive horizontal and vertical bone loss in the maxilla and the mandible (Fig 2d). Treatment, begun in September 1992, included professional tooth cleaning and motivation of the child, who was required to rinse twice daily at home with Meridol solution. Acitretin therapy, provided from November 1992 to November 1993, was tolerated well, according to clinical, laboratory, and radiographie follow-ups.

In January 1993, the child's oral hygiene had decidedly improved; the proximal Plaque Index was only 10%, and the Sulcular Bleeding Index was 17%. Signs of inflammation were found around only one tooth. Recall examinations in April, September, and December 1993 indicated the situation to be stable; both index values were under 10%. The child was free of complaints. Case 3 A 4-year-old boy was referred by his physician for treatment because of severe tooth tnobility. The child's
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Figs 2a to 2d Case 2. Papillon-Lefvre syndrome in a 5-year-old girl (sister of boy in case 1).

Fig 2a Hyperkeratolic soles of the feet.

Fig 2b

Hyperkeratosis over the tibial tuberosity.

Fig 2c

Initial intraorai appearance.

Fig 2d Panoramic radiographie appearance ol the maxiila and mandibie before treatment.

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Figs 3a to 3f Papi i ion-Lefevre syndrome in a 4-year-oid boy.

Fig 3a

Hyper<eratotic nands.

Fig 3b

Hyperkeratolic elbows.

Fig 3c

Hyperkeratotic knees.

Fig 3d

Hyperkeratotic soles of fhe feef.

extensive palmoplantar hyperkeratoses (Figs 3a to 3d) all had been treated as psoriasis. Medical examinations revealed no pathoiogic findings. Intraoral examination revealed premature loss of the maxiiiary and mandibular incisors (teeth 52 to 62
800

and 72 to 82). Carious lesions were present on all remaining teeth. His marginal gingiva was reddened and thickened (Fig 3e). The panoramic radiograph of the maxilia and mandible indicated notable horizontal and vertical bone loss (Fig 3f).
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Fig 3e

Intraoral condition.

Fig 3f Panoramic radiograph of tbe maxilla and mandible.

In addition to acitretin therapy, oral bygiene appointments were provided and restorations were placed to tbe extent that the severe tooth mobility permitted. Tbe brief period of treatment that has elapsed precludes any dependable conclusion about the success of the combination therapy provided. None of the parents gave permission for taking of photographs at the conclusion of treatment. For that reason, it has been impossible to provide complete documentarion of these three cases.

Discussion These three case reports illustrate the chief characteristics of the PapiUon-Lefvre syndrome; palmoplantar hyperkeratosis and periodontal disease.''''^""^ Additional characteristics, such as intracranial calcification, psychomotor retardation, or aero-osteolysis, were not found. Various authors have described immune system defects that are associated with a variety of fianctJonal disturbances.''"'' Krekeler, in particular, pointed to

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defects of granulocyte adherence and chemotaxis-^" The extent to which immunologie disturbances can be considered the cause of recurrent inflatnmatory processes is not yet clean"^' The immunologie parameters ofthe 5-year-old giri and the 4-year-old boy were not unusual; those ofthe 8-year-old boy show only a few nonspecific changesThe chief problem of these patients related to their periodontal conditions. For the girl and the 4-year-old boy. chronic gingivitis was the main concern; for the 8-year-o!d boy, this condition was complicated by tooth mobility (lack of comfort during chewing and pain when brushing the teeth), and protrusion ofthe maxillary incisors. The latter condition made him an object of ridicule at school. Numerous views about treatment have been expressed in the literature. D'Angelo et al" described a 6.6-year-old boy in whom local therapy (extraction of teeth with mobility grade III, scaling, root planing, and subgingival irrigation with chlorhexidine) sufficed to reduce periodoncitis. Other authors beheve such attempts at local therapy to hold liule promise.-'' ''^^ As an alternative, a series of reports have recommended retinoid therapy for retention of teeth-'''*''^'^'' This type of therapy has found broad application in dermatology since the early 1980s for the treatment of kratoses. In long-term therapy, the bone toxicity of this preparation can lead to problems.'^"'' Disturbances of growth in children, premature closure of epiphyses, and traumatic fractures have been described in case reports.^^'^^ Because long-term treatment should be avoided in children before epiphyseal closure,^" treatment was paused after 12 months in these patients. The extreme worsening of the periodontal situation, which was particularly evident in the 8-year-old boy (see Eig If) about 4 months after cessation of the medicament, tends to support the argument in favor of continuation of the acitretin therapy.
Conclusion

the relative short duration of therapy However, the results observed in the 8-year-old boy indicate the need for long-term treatment with acitretin m association with continuous dental care.

References
1. Naiaro V Blanchet-Bardon C. Mimoz C, Revuz I. Puissant A. Papillon-Lefevre syndrome. Uttrastructural study of successful treaiment with adtretin. Arch Dermalol \9SS:\2A:533-^39. 2. Hanekc E. Panillon-Lefevre syndrome. In: Urabe H. Kimura M, Yamamoto K. Ogaiva H leds). Pdiatrie Dermatology. Tokyo: University of Tokyo Press 1979^93-99. 3. Bergmann R, Friedmann-Bimbaum R. Papilton-Lefevre syndrome: A study of the long-term clinical course of recurrent pyogenic infections and the effects of etrinitate ireatment. Br J Dermatol 1988;119i731-736. 4. Herforth A, Knoile G. Strassburg M. Juvenile Parodontopathien und Hauterkrankungen. Dtsch Zahnarzt! Z 1973:28:243-246. 5. Galanter DR, Bradford S. Hyperkeratosis paimo-plantans and periodontosis. The Papillun-Lefvre syndrome. J Periodontol 1969; 40;40. 6. Gorlin KS, Sedao H. Andersen VE. The syndrome of palmarplantar hyperkeratosis and premature periodontal destruction ofthe teeth. J Pediatr I964;65;895. 7. Greither A. Keratosis palmo-plantaris mit Periodontopothie (Papilion-Lefevre). Dermatolgica 1959:119:248. 8. Jansen LH, Dekker G. Hyperkeratosis palmo-plantaris with periodontitis (Papillon-Lefevre). Dermatolgica 1965;133r207. 9. Rink B, Stoelu" K.. Parodontopathien im Kindesalter und Keiatoma palmare et plantare Dtsch Stomatol I971;21:917. 10. Preis S, Wahn Y Kressin S, Herforth A, Lenard HG. PapillonLcfcvrc-Syndrom. Eine a kroek to dermale Ditferen zierung sstrung mit vorzeitigem Zahnverlust, die mit Retinoiden therapierbar ist? Monatsschr Kinderheilkd i994;142:93-96. 11. Lange DE, Plagmann H-C, Eenboom A. Prommesberger A. Klinische Bewertungsyerfahren zur Objektivierung der Mundhygiene. Dtsch Zahnrztl Z 1977;32:44. 12. Mhlemann HR. Praxis der Zahnheilkunde. Vol 4. Munich: Llrban & Schwa ri enberg, I99O;69-7O. 13. Bravo-Piris i, Aparicio M. Moran M. Armjjo M. Papillon-Lefvre syndrome. Report of a case treated with oral retinoid Ro 10-9359. Dermatolgica 1983;I66:97-1O3. 14. Driban NE. Jung JR. Papillon-Lefvre syndrome. A clinical and therapeutical contribution. Dermatolgica 19S2il65:653-659. 15. GelmettiC.Na^iaroVCerriD.hracassoI. Long-term preservation of permanent teeth in a patient witb Papillon-Lefevre syndrome treated with etretinate. Pediatr Dermatol 1989:6:222-225. 16. Nguyen TQ, Greer KE. Fisher GB. Cooper PH. Papiilon-Lefvre sryndrome. Report uf two patients treated successfully with isotretinoin. J Am Acad Dermatol 1986;15:-46-49. 17. Bimstein E, Lustmann J, Sela MN, Neriah ZB, Soskolne WA. Periodontitis associated with Papillon-Lefevre syndrome. J Periodontoi 1990;61:373-377. 18. van Dyke TE, Taubman MA, Ebersole JL, HafTajee AD, Socransky SS, Smith DJ, Genco RJ. The Papillon-Lefevre syndrome: Neutrophil dysfunction with severe periodontat disease. Clin Immunol Immunopathol 1984:31:419-429. 9. Stalder JF. Torres M. Taraud D. Hakim J. Delaire J. Barriere H, Anomaiies fonctionelles des polynuclaires dans la maladie de Papiilon-Lefevre. Nouv Presse Med i9S2:i 1:2135-2138. 20. Krekeler G. Parodontalbehandlung beim Risikopatienten. In: Deutseher Zahnrztekaiender 993. Munich: Hanser, t993:120.

The results in these three children have demonstrated that eifective treatment of the Papillon-Lefvre syndrome is possible. The combination of retinoid and periodontal therapy appears to be more effective than either alone. The cutaneous changes were influenced more than the periodontal ones, because the latter can be stabilized or retarded only with very good oral hygiene (strict recall). Nothing can be said dependably about the longterm prognosis for the teeth from this study, because of

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21. Posteraro AF. Papillon-Lefvre syndrome. NY State Dem J 1991; 57-,49-50. 32. D'AngeloM.MargiottaV.AmmatumaP.SainmartanoF. Treatment of preptibertal period o ntitjs, J Clin Periodontol I992i 19i2l4-219, 2}. Rateitsehak-Plss EM, Schroeder HE. Histori'of periodontitis in a ehild with Paplllon-Lefvre-syndrome. A case report. J Periodontol 1984:55:35-46. 24, Wehrmann W, Traupe H, Happle R, Papillon-Lefevre Syndrom (Keratosis palnioplantaris mit Periodontopathie). Behardiung mit Etretinat. Hautarzt 1985^36 17,1-175, 25. Kaplan G, Haettieh B. Rheumatologicai symptoms due to retinoids. Baiire's Clin Rheumatol 199l;5;77-97, 26. Kilcoyne RF. EllecLs of retinoids in bone. J Am Acad Dermatol 27. Tatnayo L, Ruiz-Ma I dona do R, Long-term follow-up ofJO children under oral retinoid Ro 10-9359. In: Orfanos CE, Braun-Faleo O, Frber EM, Grupper C. Polano MK. .Sclmppli R leds). Retinoids. Berlin: Springer. 1981:387-294. 28. MilstoneLM.McGuireJ.AblowRC. Premature epiphyseal closure in a ciiiid receiving oral -cis-retinoic acid. J Am Acad Dermatol 1982;7:663-666, 29. Prcndiville J, Binghatn EA, Burrows D. Premature epiphyseal closureA complication of ettetinate therapy in children. J Am AcadDermatol 1986:13:1259-1262. 30. Vahiquist A, Long-term safety of retinoit therapy. J An Acad Dermatol 1992:27(suppll:29-33, D

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