Papillon-Lefèvre SyndromePapillon-Lefèvre Syndrome

Ashley L. Paulus, DDSPediatric Dentistry ResidentApril 13, 2009

Papillon-Lefèvre SyndromePapillon-Lefèvre Syndrome

First described by two French physicians, Papillon and Lefèvre, in 1924

Prevalence of 1-4 cases per million persons Consanguinity between parents in 1/3 of casesMales and females are equally affected with no

racial predominanceRare genetic disorder Autosomal recessive

Papillon-Lefèvre SyndromePapillon-Lefèvre Syndrome

1. Rapid generalized periodontal destruction of alveolar bone (primary and secondary dentition)

1. Palmar-plantar hyperkeratosis

CTSC geneCTSC geneIn humans, Cathepsin C is coded

by the CTSC geneLocated on chromosome 11q14-

q21Encodes a cysteine-lysosomal

protease known as dipeptidyl-peptidase I or Cathepsin C◦Appears to be a central coordinator

for activation of many serine proteinases in immune/inflammatory cells

Cathepsin CCathepsin CFound in PMN and leukocyte granules,

important in protein degradation and proenzyme activation in PMNs and T-cells◦ CTSC required for processing and activation of

the T-lymphocyte granzymes A and B, the key agents of T cell-mediated cell killing

◦ Activator of the PMN-derived serine proteinases elastase, cathepin G, and proteinase 3 These serine proteases are implicated in a wide variety

of immune and inflammatory processes A lack of functional cathepsin C may be

associated with a reduced host response against plaque bacteria

Papillon-Lefèvre SyndromePapillon-Lefèvre SyndromeThe exact cause of periodontal

disease in PLS has not been found but it has been attributed to:◦Neutrophil defects:

Decreased neutrophil chemotaxis and phagocytosis

◦Bacterial infection A. actinomycetemcomitans

◦Natural killer cell defect: Cytotoxicity

ImmunologyImmunology

Neutrophils create a barrier along the junctional epithelium and within the gingival crevice

Neutrophils are the first line of defense against dental plaque microorganisms

Neutrophils and Periodontal Neutrophils and Periodontal DiseaseDisease

Evidence that neutrophils are protective against periodontal destruction:◦ First, primary neutrophil or myeloid

abnormalities have been associated with severe periodontal destruction.

◦ Second, otherwise healthy individuals with severe periodontal problems appear to have subtle defects in their neutrophils.

◦ Third, experimental neutropenia in animals leads to rapid periodontal infection.

Papillon-Lefèvre SyndromePapillon-Lefèvre Syndrome

A. A. actinomycetemcomitactinomycetemcomitansansFacultatively anaerobic nonmotile

gram-negative rodProduces virulence factors to

promote its colonization and survival◦Leukotoxin is the prime virulence factor

of A.a.Five distinct serotypes of A.a.

◦Serotype B most commonly associated with diseased sites

A. a. A. a. LeukotoxinLeukotoxin

116-kDa pore-forming leukotoxin belonging to the repeat-in-toxins (RTX)◦Effects myeloid cells, such as PMNs and

monocytes, and causes degranulationCathepsin G and elastase from PMNs

degrade this toxin extracellulary ◦Cathepsin C activates the PMN-derived

serine proteinases elastase and cathepsin G◦Decreases PMN ability to neutralize

leukotoxin

IgG2IgG2Alteration in immunoglobins present in PLSElevated levels of salivary and serum IgG2

antibody to A.a. in PLS◦Serum antibody IgG2 = weak complement

fixation activity and poor opsonization compared to other IgG subclasses

IgG2 production dependant upon Th1

Name Percent Crosses placenta easily

Complement activator

Binds to Fc receptor on phagocytic cells

IgG1 70% Y second highest high affinity

IgG2 20% N third highest extremely low affinity

IgG3 8% Y highest high affinity

IgG4 2% Y N intermediate affinity

PLS vs Haim-Munk Syndrome PLS vs Haim-Munk Syndrome

PLS HMSCathepsin C gene mutation 2126CT substitution 2127AG substitution

Palmoplantar keratosis Y Y

Progressive periodontal disease

Y (more severe) Y

Arachnodactyly N Y

acroosteolysis N Y

Abnormal changes of the nails N Y

A claw-like deformity of the hands

N Y

Haim-Munk SyndromeHaim-Munk Syndrome

PLS vs Non-Syndromic PLS vs Non-Syndromic Prepubertal Periodontitis Prepubertal Periodontitis

PLS NS-PPP

Cathepsin C gene mutation

2126CT substitution 1040AG substitution

Palmoplantar keratosis Y N

Progressive periodontal disease

Y Y

Teeth effected Generalized Generalized or Localized

Patterns of familial transmission

AR AD and AR

PLS vs LJPPLS vs LJP

PLS LJPCTSC gene defect Y N

A. a. Y Y

Reduced chemotaxis Y Y

PMN defect Y Y

Teeth effected Generalized Localized

Hyperkeratosis of the palms Hyperkeratosis of the palms of the hands and soles of the of the hands and soles of the feet feet

Dermatologic Dermatologic Treatment Treatment

A multidisciplinary approach is important for the care of patients with PLS, skin manifestations are usually treated with emollients

Salicylic acid and urea may be added to enhance their effects

Oral retinoids including acitretin, etretinate, and isotretinoin are used in treatment of both the keratoderma and periodontitis associated with PLS

Aggressive Periodontits in Aggressive Periodontits in PLSPLS

Periodontal TreatmentPeriodontal Treatment

Periodontal TreatmentPeriodontal TreatmentEarly treatment and compliance with the

prevention program are the major determinants for preserving permanent teeth in young PLS patients

By extracting all primary teeth and eradicating periodontal pathogens the patients adult teeth can erupt into a safe environment

Pyogenic Liver Abscess in Pyogenic Liver Abscess in PLSPLS

ReferencesReferences Ullbro C, Brown A, Twetman S. Preventive Periodontal Regimen in Papillon-Lefèvre

Syndrome. Pediatric Dentistry 27:3, pages 226-231, 2005. Yang, H. W., Asikainen, S., Dogan, B., Suda, R., Lai, C. H. Relationship of Actinobacillus

actinomycetemcomitans serotype b to aggressive periodontitis: frequency in pure cultured isolates. Journal of Periodontology, Taichung, Taiwan. www.pubmedcentral.nih.gov/articlerender.fcgi?artid=88070

Burne R, Lamont R, Lantz M, LeBlanc D. Oral Microbiology and Immunology. ASM Press. Washington, DC. 2006.

Hart TC, Shapira L. Papillon-Lefèvre syndrome. Periodontol 2000. 1994 Oct;6:88-100. Gorlin RJ, Sedano H, Anderson VE. The syndrome of palmar-plantar hyperkeratosis and

premature periodontal destruction of the teeth. J Pediatr 1964;65:895-908. Rudiger S, Petersika G, Fleming F. Combined systemic and local antimicrobial therapy of

periodontal disease in Papillon-Lefevre syndrome. A report of 4 cases. J Clin Periodontol1999;26:847-54.

Cury VF, Costa JE, Gomez RS, Boson WL, Loures CG, De ML. A Novel Mutation of the Cathepsin C Gene in Papillon-Lefevre syndrome. J Periodontol 2002;73:307-12.

Lundgren, T., Parhar, R.S., Renvert, S., Tatakis, D.N. (2005). Impaired Cytotoxicity in Papillon-Lefevre Syndrome. JDR 84: 414-417

Moore SW, Millar AJW, Cywes S. Conservative initial treatment for liver abscesses in children. Br J Surg.1994; 81 :872 –874

Noack, B., Gorgens, H., Hoffmann, Th., Fanghanel, J., Kocher, Th., Eickholz, P., Schackert, H.K. (2004). Novel Mutations in the Cathepsin C Gene in Patients with Pre-pubertal Aggressive Periodontitis and Papillon-Lefevre Syndrome. JDR 83: 368-370