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CASE REPORT
Year : 2013  |  Volume : 17  |  Issue : 6  |  Page : 806-811  

Papillon-lefevre syndrome: Case series and review of literature


1 Department of Periodontology, Government Dental College and Hospital, Ahmedabad, Gujarat, India
2 Department of Periodontology, Faculty of Dental Science, Dharmsinh Desai University, Nadiad, Gujarat, India

Date of Submission01-Feb-2013
Date of Acceptance04-Jun-2013
Date of Web Publication7-Jan-2014

Correspondence Address:
Nilam A Brahmbhatt
Department of Periodontology, Government Dental College and Hospital, New Civil Hospital Campus, Asarva, Ahmedabad 380 016, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-124X.124530

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   Abstract 

Papillon-lefevre syndrome (PLS) belongs to a heterogeneous group of skin diseases that are characterized by hyperkeratosis of palms and soles. It is a type IV palmoplantar keratosis (PPK) while the palmoplantar keratodermas share some features of PPK, they are etiologically heterogeneous. PLS differs from other types of PPK by the presence of severe and early onset periodontitis. Genetic studies have shown that mutation in the major gene locus of chromosome 11q14 with the loss of function of cathepsin-C (CTSC) gene is responsible for PLS. CTSC gene mutations are causative for PLS. The resultant loss of CTSC function is responsible for the severe periodontal destruction seen clinically. This report represents two siblings with classical signs and symptoms of PLS.

Keywords: Aggressive periodontitis, cathepsin-C gene, Papillon-lefevre syndrome


How to cite this article:
Bhavsar MV, Brahmbhatt NA, Sahayata VN, Bhavsar NV. Papillon-lefevre syndrome: Case series and review of literature. J Indian Soc Periodontol 2013;17:806-11

How to cite this URL:
Bhavsar MV, Brahmbhatt NA, Sahayata VN, Bhavsar NV. Papillon-lefevre syndrome: Case series and review of literature. J Indian Soc Periodontol [serial online] 2013 [cited 2019 Feb 18];17:806-11. Available from: http://www.jisponline.com/text.asp?2013/17/6/806/124530


   Introduction Top


Papillon-lefevre syndrome (PLS) was first described in 1924 by Papillon and Lefevre. [1] It is a rare heritable, autosomal recessive disorder [2] caused by the deficiency in cathepsin-C (CTSC), [3],[4] characterized by hyperkeratosis of palms and soles and severe destructive periodontal disease affecting both the primary and permanent teeth. It has prevalence of 1-4 cases per million persons, [5] without sex and racial predominance. [6],[7] The sharply demarcated erythomatous keratotic plaque may occur focally, but usually involve the entire surface of the palms and soles, sometimes extending on to the dorsal surfaces. Often, there is associated hyperhidrosis of the palms and soles resulting in a foul-smelling odor. [5] The genetic basis for most PLS cases appears to be mutation affecting both alleles of the CTSC gene, located on chromosome 11q14.1-q14.3. [8],[9] Biochemical assays of CTSC indicated that CTSC mutation associated with PLS and related conditions dramatically reduces its enzymatic activity. Heterozygous carriers of the mutation have approximately 50% of enzymatic activity, while subjects in whom both CTSC alleles are mutated show lesser than 10% of normal activity in hydrolysis of the synthetic substrate glycyl-L-arginin-7-amino-4-methylcoumarin. [9],[10]

Coming to oral changes, following the eruption of primary teeth gingiva becomes inflamed, followed by rapid destruction of periodontium and premature loss of primary teeth. Gingiva appears normal after exfoliation of primary teeth. The aggressive periodontal destruction repeats after the eruption of permanent teeth and most of the permanent dentition is lost during teenage years. [8],[10]

Conventional periodontal treatment usually fails in patients with PLS and the rapid progression of periodontitis results in the severe loss of alveolar bone. [2],[9],[11] To preserve the alveolar bone early extraction of periodontally involved permanent teeth and replacing them with titanium implants has been considered a mode of treatment. [12]

This paper presents the etiology, clinical features and highlights different treatment modalities, which can be used to rehabilitate oral cavity in patients with PLS.

Etiology

Genetic etiology

CTSC involvement in the etiology of PLS

cause of PLS is not well-understood, but recently, two research groups have reported that loss of function mutations affecting both alleles of the CTSC gene, located on chromosome 11q14.1-q14.3, [8],[9] were associated with PLS. The CTSC gene encodes a cysteine-lysosomal protease also known as dipeptidyl-peptidase I, which functions to remove dipeptides from the amino terminus of the protein substrate. It also has endopeptidase activity. The CTSC gene is expressed in epithelial regions commonly affected by PLS such as palms, soles, knees and keratinized oral gingiva. It is also expressed at a high level in various immune cells including polymorphonuclear leukocytes, macrophages and their precursors. Several mutations have been reported in the CTSC gene in individuals from diverse ethnic groups. [9],[13]

Immunological defects

CTSC is involved in a wide variety of immune and inflammatory responses. It plays an essential role in activating serine proteinases expressed in the granules of bone marrow derived cells from both the myeloid and lymphoid series. The serine proteinases are implicated in a variety of inflammatory and immune processes, including phagocytic destruction of bacteria and activation of phagocytic cells and T-lymphocytes. Therefore, deficiency of CTSC function will result in loss of immunological response, leading to liability of infection. Recently, impairment of natural killer ( NK) cell cytotoxic function is the first consistent immune dysfunction reported in PLS. This suggests that the impaired NK cell cytotoxicity might contribute to the pathogenesis of PLS associated periodontitis. [14] A defect that principally interferes in phagocytic function is likely to give rise to aggressive periodontitis of PLS since nearly identical features occur in other defects of phagocytic function. The loss of CTSC function and subsequent inactivity of neutrophil serine proteinases may cause deregulation of localized polymorphonuclears response in inflamed periodontal tissues, leading to the severe tissue destruction in PLS. [15],[16]

Microbial defects

In PLS, neutrophil function test showed reduced response to staphylococcus spp. and Actinobacillus actinomycetemcomitans. There is a hypothesis that herpes viruses together with pathogenic bacteria, including A. actinomycetemcomitans and underlying host defense disorders, participate in the development of PLS periodontitis. [15],[16],[17],[18] Presence of numerous virulence factors such as leukotoxin, collagenase, endotoxin, epitheliotoxins and fibroblast-inhibiting factor, suggests that PLS is mediated bacteriologically and therefore could be treated to some improvement with antibiotics. [19] The serum of the patients showed high immunoglobulin G (IgG) titer against A. actinomycetemcomitans. Moreover, A. actinomycetemcomitans colonies were cultured in high percentages from the pocket samples. Antibiotic therapy was associated with elimination of A. actinomycetemcomitans from the periodontal pockets and serum IgG titers against A. actinomycetemcomitans decreased in the patients. [20]


   Case Reports Top


Case 1

A 14-year-old girl, visited to outpatient Department of Periodontia, Government Dental College and Hospital, Ahmedabad, India with chief complain of premature loss of deciduous and permanent teeth and mobility in remaining teeth.

She was the first child born to apparently healthy non-consanguineous parents. History revealed that her deciduous teeth had erupted normally, but exfoliated gradually by the age of 4-5 years. Similarly, her permanent teeth were lost prematurely after erupting normally. Patient was having complained of mobility and bleeding gum before 2 years, visited a periodontist and undergone treatment in the form of periodontal flap surgery. After one and half year, patient was having same complain and came to Government Dental College and Hospital, Ahmedabad.

There was no family history of ichthyosis or hereditary or acquired palmoplanter keratodermas. The patient also gave a history of development of fissures, thickening and flaking in the skin of palms and soles that resulted in peeling off of skin leaving red thin area underneath since age of 3-4 years. She had exacerbation and remissions of the skin lesions since early childhood, visiting dermatologist regularly, but no improvement was seen. She repeatedly contracted systemic infections.

Clinical examination

Extra-oral examination

extra-oral examination, patient presented with well-demarcated, yellowish, keratotic plaques over the skin of palms and soles extending on to the dorsal surfaces. Skin of both palms and soles was peeling off leaving underlying red shiny area suggestive of keratoderma [Figure 1]. Well circumscribed, psoriasiform, erythematous, scaly plaques were also present on the elbows and knees bilaterally along with dystrophy and transverse grooving of the nails. The fingers were pointed giving clawed appearance.
Figure 1: Case-1 - Palm and sole

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oral examination

oral examination revealed edentulous area between teeth 44 and 33 and 11, 21 and 22 were also missing. Edentulous maxillary and mandibular ridges were covered with normal mucosa. The teeth present were 12, 13, 14, 15, 16, 22, 24, 25, 26, 33, 34, 35, 36, 44, 45 and 46 covered with soft deposits and band of subgingival calculus. Gingiva was fiery red in color with inflammatory gingival enlargement Iva Ingle Classification grade II. Pathological migration was associated with 12, 14, 23, 24, 33 and 34. On assessment grade III mobility was present in relation with 14, grade II in relation with 24, 25, 33, 34, 36 and 44. Remaining teeth were present with grade I mobility. There was the presence of recession grade III in relation with 14 and 33 [Figure 2], [Figure 3], [Figure 4].
Figure 2: Case-1 - Anterior view

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Figure 3: Case-1 eft posterior view

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Figure 4: Case-1 - Right posterior view

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Radiographic findings

Orthopantogram showed extensive alveolar bone loss in all remaining teeth. The alveolar bone around the mobile teeth was devoid of definable lamina dura. An extensive alveolar bone loss was noted, giving the teeth 31, 41 and 43 a "floating in air appearance," which were extracted afterwards [Figure 5].
Figure 5: Case-1 - Orthopantogram

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Case 2

Second patient was a 6-year-old sister of the above patient. She was asymptomatic before 2 years. Her father noticed mobility in relation with some of her deciduous teeth and then early exfoliation of same. Her elder sister had same complain, so he brought her also for a checkup and treatment at Government Dental College and Hospital, Ahmadabad.

Clinical examination

Extra-oral examination

complained about dry scaly skin of palms and soles like her sister, but she has not taken any dermatological treatment for that. On examination, well-demarcated keratotic plaques over the skin of her palms and soles, extending on to dorsal surfaces were present [Figure 6] and [Figure 7].
Figure 6: Case-2 - Palm

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Figure 7: Case-2 - Sole

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oral examination

showed the presence of 16, 26, 31, 36, 46, 41 and 53 in the oral cavity. There is grade III recession and grade II mobility in 53. Remaining teeth revealed the presence of soft deposits and grade I mobility [Figure 8].
Figure 8: Case-2 - Anterior view

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Radiographic findings

Radiographically, right and left lateral oblique radiographs show angular bone loss and periodontal widening present in relation with 36 and 46. There are developing tooth germs of permanent tooth are also seen [Figure 9].
Figure 9: Case-2 - Right and left lateral cephalogram

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Investigations

  • Radiographic analysis
  • Complete blood count
  • Liver function transaminase levels
  • Total bilirubin
  • Alkaline phosphatase
  • Urine analysis.



   Discussion Top


Several case reports in literature showed phenotypic variation among patients affected by this syndrome. The oral feature of this syndrome is severe periodontitis, which starts at the age of 3-4 years affecting both primary and permanent dentition.

CTSC gene mutation affects onset, progression and severity of periodontitis, as it is required for proteolytic activation of neutrophil serine protease, cathepsin G, elastase and proteinase 3, resulting in deregulation of the host immune response to microbial infection. [7],[8] In addition to the skin and oral findings, patients may have decreased neutrophil, lymphocyte or monocyte functions and an increased susceptibility to bacterial infection. [21]

Increase in the percentage of gram negative microorganisms is recognized to be the primary factor in the etiology of periodontitis. In case of PLS, the inflammatory infiltrate at the sites of periodontal infection is not under regulatory control. Increase neutrophil influx and retention of inflammatory infiltrate and their proteases play a significant role in continued periodontal destruction. It makes difficult to control and limit periodontitis once lesions are established and disease becomes unresponsive to traditional periodontal treatment.

Clinical findings such as liver abscesses [21],[22] and cranial calcifications [23] have been reported in many cases, were absent in current cases. Given the high rate of parental consanguinity reported for PLS cases, it is possible these rarer findings are the result of the high degree of homozygosity of another alleles in addition to the CTSC locus.

It may be possible to prevent inflammation related destruction of permanent teeth by the combination of more intense conventional mechanical and antimicrobial therapy at younger age. [24] Good dental care and use of antibiotics to eradicate A. actinomycetemcomitans minimizes periodontitis and loss of teeth. A course of antibiotics should be tried to control the active periodontitis on an effort to preserve the teeth and to prevent bacteremia and subsequently pyogenic liver abscess. The risk of pyogenic liver abscess should be kept in mind in evaluating these patients when they present with fever of unknown origin.

Following extraction or exfoliation of all teeth, healing is uneventful suggesting that microbial challenge is requisite for inflammatory response. Several reports have documented successful osseointegration and function of dental implants in PLS cases. [12],[25],[26]

Treatment

A multidisciplinary approach involving the Dermatologist, Periodontist, Pedodontist and Pediatrician is important for the overall care of patient with PLS.

Periodontal treatment

Aim of periodontal treatment is to eliminate the reservoir of causative organisms. It is generally agreed that the response to local debridement or to systemic antibiotic alone or in combination provide at best a transitory response. [24],[27],[28],[29]

Ullbro et al. [2] proposed a mode of periodontal therapy for patients with PLS as shown in [Table 1].
Table 1: Dental treatment protocol for patients with Papillon-lefevre syndrome


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In this two cases:

  • Conventional periodontal treatment in the form of scaling and root planning
  • 0.2% chlorhexidine gluconate mouthwash and oral hygiene instruction was employed to control disease activity
  • Systemic antibiotic treatment was given for 4 weeks amoxicillin (20-50 mg/kg/d) + metronidazole (15-35 mg/kg/d) in divided doses every 8 h as an adjunctive with conventional treatment
  • Teeth with hopeless prognosis were extracted
  • In teeth having deep periodontal pockets, periodontal flap surgery was done
  • To restore masticatory function, partial dentures were inserted
  • On maintenance visits of 3 months, mobility of 25 and 36 was markedly increased, we planned to extract them. As we were unable to prevent periodontal disease activity, we are planning to extract remaining teeth gradually and replacing them with dental implants.


In recent years, dental implant offers not only considerable better stability and retention of prosthesis, but also improved comfort, masticatory efficiency and esthetics. There is data available that dental implants are successful mode of rehabilitation in patients with PLS. [12],[25],[26] We have planned for implant supported prosthesis in patients after growth period is over.

Dermatological treatment

The skin manifestations of PLS are usually treated with emollients. Salicylic acid and urea may be added to enhance their effect. Oral retinoids including acitretin, etretinate and isotretinoin are the mainstay of the treatment of both the keratoderma and periodontitis associated with PLS. [30] After 8 weeks of oral acitretin, there was a dramatic improvement with marked reduction of keratodermas.

Treatment may be more beneficial if it is started during the eruption and maintained during the development of the permanent teeth.


   Conclusion Top


In summary, PLS is a rare autosomal recessive disorder. The conflicting findings of PLS management could be related to the severity of the condition, the age at which treatment was instituted, timing and duration of antibiotic therapy, professional supervision, supportive treatment plan and home care. The complex etiopathogenesis of PLS means that successful treatment of the periodontal component of this syndrome remains challenging. It is hoped that with identification of the gene defect, better treatment modalities can be developed. In cases where patient reports late or not responding to periodontal treatment, dental implants are successfully advised.

 
   References Top

1.Papillon MM, Lefèvre P. Two cases of family symmetrical keratoderma palmar and plantar (disease of Meleda) in the brother and the sister. Coexistence in both cases of serious dental deteriorations. Bull Soc Fr Dermatol Syphiligr 1924;31:82-7.  Back to cited text no. 1
    
2.Ullbro C, Crossner CG, Nederfors T, Alfadley A, Thestrup-Pedersen K. Dermatologic and oral findings in a cohort of 47 patients with Papillon-Lefèvre syndrome. J Am Acad Dermatol 2003;48:345-51.  Back to cited text no. 2
[PUBMED]    
3.Wani AA, Devkar N, Patole MS, Shouche YS. Description of two new cathepsin C gene mutations in patients with Papillon-Lefèvre syndrome. J Periodontol 2006;77:233-7.  Back to cited text no. 3
[PUBMED]    
4.James WD, Berger T, Elston D. Andrews' Diseases of the Skin: Clinical Dermatology. 10 th ed. Philadelphia: Saunders; 2006. p. 214.  Back to cited text no. 4
    
5.Gorlin RJ, Sedano H, Anderson VE. The syndrome of palmar-plantar hyperkeratosis and premature periodontal destruction of the teeth. A clinical and genetic analysis of the Papillon-Lef'evre syndrome. J Pediatr 1964;65:895-908.  Back to cited text no. 5
[PUBMED]    
6.Haneke E. The Papillon-Lefèvre syndrome: Keratosis palmoplantaris with periodontopathy. Report of a case and review of the cases in the literature. Hum Genet 1979;51:1-35.  Back to cited text no. 6
[PUBMED]    
7.Cury VF, Costa JE, Gomez RS, Boson WL, Loures CG, De ML. A novel mutation of the cathepsin C gene in Papillon-Lefèvre syndrome. J Periodontol 2002;73:307-12.  Back to cited text no. 7
[PUBMED]    
8.Hart TC, Hart PS, Bowden DW, Michalec MD, Callison SA, Walker SJ, et al. Mutations of the cathepsin C gene are responsible for Papillon-Lefèvre syndrome. J Med Genet 1999;36:881-7.  Back to cited text no. 8
[PUBMED]    
9.Toomes C, James J, Wood AJ, Wu CL, McCormick D, Lench N, et al. Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. Nat Genet 1999;23:421-4.  Back to cited text no. 9
[PUBMED]    
10.Hart PS, Zhang Y, Firatli E, Uygur C, Lotfazar M, Michalec MD, et al. Identification of cathepsin C mutations in ethnically diverse Papillon-Lefèvre syndrome patients. J Med Genet 2000;37:927-32.  Back to cited text no. 10
[PUBMED]    
11.Cagli NA, Hakki SS, Dursun R, Toy H, Gokalp A, Ryu OH, et al. Clinical, genetic, and biochemical findings in two siblings with Papillon-Lefèvre Syndrome. J Periodontol 2005;76:2322-9.  Back to cited text no. 11
[PUBMED]    
12.Ullbro C, Crossner CG, Lundgren T, Stålblad PA, Renvert S. Osseointegrated implants in a patient with Papillon-Lefèvre syndrome. A 4 1/2-year follow up. J Clin Periodontol 2000;27:951-4.  Back to cited text no. 12
    
13.Angel TA, Hsu S, Kornbleuth SI, Kornbleuth J, Kramer EM. Papillon-Lefevre syndrome: A case report of four affected siblings. J Am Acad Dermatol 2002;46:S8-10.  Back to cited text no. 13
[PUBMED]    
14.Lundgren T, Parhar RS, Renvert S, Tatakis DN. Impaired cytotoxicity in Papillon-Lefèvre syndrome. J Dent Res 2005;84:414-7.  Back to cited text no. 14
[PUBMED]    
15.Ryu OH, Choi SJ, Firatli E, Choi SW, Hart PS, Shen RF, et al. Proteolysis of macrophage inflammatory protein-1alpha isoforms LD78beta and LD78alpha by neutrophil-derived serine proteases. J Biol Chem 2005;280:17415-21.  Back to cited text no. 15
[PUBMED]    
16.de Haar SF, Hiemstra PS, van Steenbergen MT, Everts V, Beertsen W. Role of polymorphonuclear leukocyte-derived serine proteinases in defense against Actinobacillus actinomycetemcomitans. Infect Immun 2006;74:5284-91.  Back to cited text no. 16
[PUBMED]    
17.Umeda M, Zhang VJ, Koseki T, Ishikawa I. Clinical, bacteriological and immunological examination and treatment of two Papillon-Lefevre patients. J Oral Pathol 1990;65:364-71.  Back to cited text no. 17
    
18.Albandar JM, Khattab R, Monem F, Barbuto SM, Paster BJ. The subgingival microbiota of Papillon-Lefèvre syndrome. J Periodontol 2012;83:902-8.  Back to cited text no. 18
[PUBMED]    
19.Preus HR. Treatment of rapidly destructive periodontitis in Papillon-Lefèvre syndrome. Laboratory and clinical observations. J Clin Periodontol 1988;15:639-43.  Back to cited text no. 19
[PUBMED]    
20.Ishikawa I, Umeda M, Laosrisin N. Clinical, bacteriological, and immunological examinations and the treatment process of two Papillon-Lefèvre syndrome patients. J Periodontol 1994;65:364-71.  Back to cited text no. 20
[PUBMED]    
21.Almuneef M, Al Khenaizan S, Al Ajaji S, Al-Anazi A. Pyogenic liver abscess and Papillon-Lefèvre syndrome: Not a rare association. Pediatrics 2003;111:e85-8.  Back to cited text no. 21
[PUBMED]    
22.Dalgic B, Bukulmez A, Sari S. Pyogenic liver abscess and peritonitis due to Rhizopus oryzae in a child with Papillon-Lefevre syndrome. Eur J Pediatr 2011;170:803-5.  Back to cited text no. 22
[PUBMED]    
23.Reyes VO, King-Ismael D, Abad-Venida L. Papillon-Lefèvre syndrome. Int J Dermatol 1998;37:268-70.  Back to cited text no. 23
[PUBMED]    
24.Ashri NY. Early diagnosis and treatment options for the periodontal problems in Papillon-Lefèvre syndrome: A literature review. J Int Acad Periodontol 2008;10:81-6.  Back to cited text no. 24
[PUBMED]    
25.Woo I, Brunner DP, Yamashita DD, Le BT. Dental implants in a young patient with Papillon-Lefevre syndrome: A case report. Implant Dent 2003;12:140-4.  Back to cited text no. 25
[PUBMED]    
26.Etöz OA, Ulu M, Kesim B. Treatment of patient with Papillon-Lefevre syndrome with short dental implants: A case report. Implant Dent 2010;19:394-9.  Back to cited text no. 26
    
27.Rateitschak-Plüss EM, Schroeder HE. History of periodontitis in a child with Papillon-Lefèvre syndrome: A case report. J Periodontol 1984;55:35-46.  Back to cited text no. 27
    
28.Shapira J, Eidelman E, Fuks A, Hacham-Zadeh S. Treatment of Papillon-Lefevre syndrome with chemotherapy: Report of cases. Spec Care Dentist 1985;5:71-4.  Back to cited text no. 28
[PUBMED]    
29.Lundgren T, Renvert S. Periodontal treatment of patients with Papillon-Lefèvre syndrome: A 3-year follow-up. J Clin Periodontol 2004;31:933-8.  Back to cited text no. 29
[PUBMED]    
30.Gelmetti C, Nazzaro V, Cerri D, Fracasso L. Long-term preservation of permanent teeth in a patient with Papillon-Lefèvre syndrome treated with etretinate. Pediatr Dermatol 1989;6:222-5.  Back to cited text no. 30
[PUBMED]    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]
 
 
    Tables

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