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Papillon-Lefèvre syndrome (PLS) is a rare autosomal disorder characterized by severe periodontitis and palmar plantar hyperkeratosis (PPK). PLS is caused by mutations in the cathepsin C (CTSC) gene. Dipeptidyl peptidase I (DPPI) encoded by the CTSC locus removes dipeptides from the amino terminus of the protein substrate and mainly plays an important role in immune and inflammatory processes. Several mutations have been reported in this gene in patients with PLS. This study reports two novel deletion mutation of the CTSC gene in two Indian families with PLS.Peripheral blood samples were obtained for genomic DNA isolation from individuals belonging to two Indian families. Exon-specific intronic primers were used to amplify DNA from all individuals, and the PCR products were subsequently sequenced to detect the mutations. Heteroduplex analysis (HDA) was used to confirm heterozygosity and to determine the presence of mutations in control individuals.All patients from both families had a classic PLS phenotype, which included PPK and severe periodontitis. Sequence analysis of the CTSC gene revealed two novel deletion mutations, one (1213-1215delCAT) in exon 7 and the other (629-630delGA) in exon 4 of the CTSC gene. For both mutations, the patients were homozygous, whereas the parents were heterozygous.This study reports two novel deletion mutations in two Indian families with PLS. One of the mutations introduces a premature stop codon, thereby producing a truncated protein. In the other case, the mutation observed leads to the loss of a highly conserved histidine molecule that is present in the active site of the enzyme. In both cases, mutations may result in a conformation change, causing loss of the enzymatic activity.

Activation of granzyme B, a key cytolytic effector molecule of natural killer (NK) cells, requires removal of an N-terminal pro-domain. In mice, cathepsin C is required for granzyme processing and normal NK cell cytolytic function, whereas in patients with Papillon-Lefèvre syndrome (PLS), loss-of-function mutations in cathepsin C do not affect lymphokine activated killer (LAK) cell function. Here we demonstrate that resting PLS NK cells do have a cytolytic defect and fail to induce the caspase cascade in target cells. NK cells from these patients contain inactive granzyme B, indicating that cathepsin C is required for granzyme B activation in unstimulated human NK cells. However, in vitro activation of PLS NK cells with interleukin-2 restores cytolytic function and granzyme B activity by a cathepsin C-independent mechanism. This is the first documented example of a human mutation affecting granzyme B activity and highlights the importance of cathepsin C in human NK cell function.

The purpose of this study was to evaluate the effect of a comprehensive preventive program, based on mechanical plaque control and local and systemic antibacterial measures, on periodontal health and preservation of permanent teeth in patients with Papillon-Lefèvre syndrome (PLS).Thirty-five consecutive PLS patients (median age=7 years; range=3-19 years) were treated and followed every third month over 3 to 7 years. Visible plaque, bleeding on probing, periodontal pocketsor = 5 mm, and number of lost permanent teeth were registered at the first visit and during the follow-up period. Due to severe periodontal inflammation, all primary teeth were extracted prior to the eruption of the first permanent tooth. Tooth-brushing was supported by comprehensive periodontal care and local and systemic chemotherapeutics (chlorhexidine and amoxicillin/metronidazole) on individual indications.Subjects treated strictly according to the program from their early years showed significantly fewer signs of periodontal disease and lost fewer permanent teeth than patients who started the program at an older age (P.05). This was especially true if signs of periodontal disease had emerged when the treatment started. Compliance with the treatment protocol had a significant impact on the presence of plaque, bleeding surfaces, periodontal pockets, and number of lost permanent teeth.Early treatment and compliance with the preventive program were the major determinants for preserving permanent teeth in young PLS patients.

A 9 year old male presented with keratotic plaques over the skin of his palms and soles extending onto the dorsal surface and swollen gums since the age of 4 with subsequent loss of most of his permanent dentition. These findings are consistent with Papillon-Lefèvre syndrome.

A 7-year-old boy born to consanguineous parents had suffered from palmoplantar keratoderma and chronic gingivitis since the age of 3 months. He was diagnosed with Papillon-Lefevre syndrome. Genetic testing confirmed that he was homozygous with a point mutation in exon 6 of the cathepsin C gene. One year after initiating treatment with acitretin 10 mg oral daily and trimethoprim-sulfamethoxazole, the patient's skin remains almost lesion-free, and he has new teeth that erupted during treatment and are free of periodontal disease.

Papillon-Lefevre syndrome (PLS) is a rare autosomal recessive disorder characterized by palmar- plantar hyperkeratosis and rapid periodontal destruction of both primary and permanent dentitions. It has been shown that the disease is caused by cathepsin C gene (CTSC) mutation leading to the deficiency of cathepsin C enzymatic activity. This study demonstrates the clinical manifestations and CTSC mutational and enzymatic activity analyses in a 5-year-old Thai male PLS patient and his parents.Peripheral blood samples were obtained for genomic DNA isolation. All exons of the CTSC gene were amplified by polymerase chain reaction (PCR) using specific primers. Mutations were identified by DNA sequencing. Verification of the mutation was performed by digestion of PCR products by restriction endonucleases. The cathepsin C enzymatic activity was determined using the synthetic substrate glycyl- L-arginine-7-amino-4-methylcoumarin.The patient demonstrated classical characteristics of PLS, including hyperkeratotic skin lesions. By the age of 5, all of his primary teeth were extracted due to severe periodontal infection. The parents had no physical abnormalities. The periodontal examination revealed localized mild periodontal destruction. Sequence analysis showed a nucleotide change at position 90 from CA (c.90CA) which resulted in a change from cysteine residue to a premature stop codon at the amino acid position 30 in the exon 1. The HpyCH4V digestion revealed that the patient was homozygous, whereas both the father and mother were heterozygous carriers of this mutation. The cathepsin C activity was reduced in the patient's mother, and the activity in the patient was almost completely lost.This is the first study to demonstrate a CTSC gene mutation in a Thai family with PLS. The identified mutation is novel and potentially leads to the drastic reduction of the cathepsin C enzymatic activity. This suggests that the mutation is pathogenetic, causing the PLS. Mutational analysis in more members of the family is warranted to identify whether the mutation is inherited from a common ancestor.

Report of a combined periodontal and orthodontic treatment in a patient with Papillon-Lefevre Syndrome (PLS).A patient with PLS was treated orthodontically 26 months after the start of a combined mechanical and antibiotic therapy. Clinical periodontal parameters were obtained 26 (t1), 60 (t2), and 79 (t3) months after anti-infective therapy. The deepest site of each tooth was sampled for microbiological analysis at 26 and 60 months. Periodontal maintenance therapy was provided every 6 weeks. After a stable periodontal situation was achieved, orthodontic treatment, consisting of space opening for the upper canines with a multibracket appliance and coil springs, was carried out. In the lower jaw, crowding was resolved by an orthodontic mesialization of the canines.Twenty-six months (t1) after the beginning of the combined mechanical and antibiotic therapy, 6% of the sites exhibited 4 mm probing depth (PD) with bleeding on probing (BOP) or PDor =5 mm. Sixty months (t2) after therapy the number of sites with 4 mm PD with BOP or PDor =5 mm had increased to 17%, and 79 months after therapy (t3) 13% of all sites were similarly affected. From 26 to 60 months, a slight mean clinical attachment level (CAL) gain was observed, whereas the mean PD increased. From 60 to 79 months, there was a mean PD reduction. However, a significant mean attachment loss was also noted. After 26 months (t1), RNA probes failed to detect A. actinomycetemcomitans, P. gingivalis, or T. forsythensis from any site. Thirty-four months later (t2), subgingival recolonization was observed. A. actinomycetemcomitans was detected by RNA probes at three sites. At 26 and 60 months (t1, t2), trypticase-soy with serum, bacitracin, and vancomycin (TSBV) culture failed to detect A. actinomycetemcomitans at any of the sampled sites. Eighty-two months after the beginning of therapy (t4), none of the applied methods could detect A. actinomycetemcomitans from the pooled samples from the deepest pockets of each quadrant or the oral mucosa. In the present case, concomitant orthodontic treatment with a fixed appliance could be performed without further pronounced periodontal deterioration. Space for eruption of the canines and premolars was created, in addition to an alignment of the teeth.After a successful combined mechanical and antibiotic periodontal therapy of the PLS periodontitis, moderate orthodontic tooth movements may be possible within a complex interdisciplinary treatment regimen.

The term periodontitis is used to describe a group of multifactorial diseases that result in the progressive destruction of the structures that support the teeth within the jaws, the so-called attachment apparatus, which includes the periodontal ligament, cementum and alveolar bone. If left untreated, this process can ultimately lead to tooth loss. The pathogenesis of these diseases involves the initial colonization of the gingival microenvironment of a susceptible host by pathogenic bacteria found in dental plaque. Subsequently, much of the tissue destruction characteristic of periodontitis is a , by-product, of the host response directed against these organisms. One of the major factors that appear to modulate disease severity is systemic health. Severe periodontitis in young individuals can therefore be a manifestation of an underlying systemic disease. In this review we will discuss the most important systemic diseases that should be considered in a differential diagnosis when evaluating a pediatric patient presenting with periodontitis.

Summary Haim–Munk syndrome (HMS) is a rare autosomal recessive disorder characterized clinically by abnormal palmoplantar hyperkeratosis and destruction of the periodontium, with hallmarks of onychogryphosis and arachnodactyly. Germline mutations in the lysosomal protease cathepsin C gene (CTSC) have been described in a single patient with HMS and in several individuals with the clinically related disorder Papillon–Lefevre syndrome (PLS). We describe a patient with HMS. We have analysed the cathepsin C gene in the proband and her mother. Sequence analysis of CTSC in the proband revealed a homozygous mutation at codon 196 (587TC) within exon 4 that altered the conserved leucine to proline (Leu196Pro), whereas the patient's mother was heterozygous for that mutation. The same mutation has previously been described in an unrelated Brazilian family with PLS. An identical single missense mutation in the cathepsin C gene may underlie both PLS and HMS. These findings confirm that HMS and PLS are allelic variants of cathepsin C gene mutations and suggest that other factors (environmental or genetic) may be important determinants of the clinical phenotype of HMS and PLS.

Microbiological and serological (enzyme linked immunosorbent assay) investigations were carried out, including karyotyping, on two Asian children with Papillon-Lefèvre syndrome. In case 1, a girl aged four years, the most prevalent putative periodontopathogens were Eikenella corrodens, Fusobacterium nucleatum, Porphyromonas gingivalis, Prevotella intermedia (deciduous dentition) and Bacteroides gracilis, E corrodens and F nucleatum (permanent dentition). In case 2, a boy aged nine years, they were F nucleatum, P intermedia and P loeschii and E corrodens. Serum from case 2 showed a raised specific IgG antibody response to Actinomyces actino-mycetemcomitans serotype b. Thus, a wider range of species than hitherto reported may be associated with Papillon-Lefèvre syndrome, including A actino-mycetemcomitans and F nucleatum.

The co-occurrence of two rare recessive genetic conditions in apparently unrelated individuals or families is extremely rare. Two geographically distant and apparently unrelated families were identified in which individuals were simultaneously affected by two rare recessive mendelian syndromes, Papillon-Lefevre syndrome and type 1 oculocutaneous albinism. The families were tested for mutations in the causative genes, cathepsin C (CTSC) and tyrosinase (TYR), respectively, by direct sequencing. To assess the relationship of the two families, both families were tested for polymorphisms at eight microsatellite markers spanning both CTSC and TYR loci. Independent mutations (c.318-1G-->A and c.817G-->C/p.W272C) were identified in CTSC and TYR, respectively, that were shared by the affected individuals in both families. The two affected genes lie close together on chromosome bands 11q14.2-14.3, and studies with linked genetic markers suggested that the families shared a small chromosomal segment carrying both mutations that had been transmitted intact from a remote common ancestor. The co-occurrence of the two rare diseases in multiple families depends on their shared chromosomal location, but not on any shared pathogenic mechanism.

A 15-year-old boy presented with symmetric, well-demarcated, yellowish, keratotic plaques over the skin of his palms and soles extending onto the dorsal surfaces. Well-circumscribed, psoriasiform, erythematous, scaly plaques were also present on the elbows and knees bilaterally along with dystrophy an transverse grooving of the nails. He also had swollen and friable gums since the age of 3 with subsequent loss of most of his permanent dentition. These findings are consistent with Papillon-Lefèvre syndrome. The clinical presentation, differential diagnosis, complications and management of this syndrome are discussed.

Summary. Papillon–Lefevre syndrome is a rare disease characterized by skin lesions caused by palmar-plantar hyperkeratosis, and severe periodontal destruction involving both the primary and permanent dentitions. It is transmitted as an autosomal recessive condition and consanguinity of parents is evident in about one-third of cases. This paper describes two preschool children who presented at the Paediatric Dentistry Department, Sheffield, UK, with progressively loosening teeth and discomfort during eating. The medical history revealed scaling on the hands and feet, which had been medically diagnosed as eczema. Papillon–Lefevre syndrome was diagnosed in both cases.

Papillon-Lefevre syndrome is a very rare autosomal recessive condition characterised by pronounced palmoplantar hyperkeratosis and severe early onset periodontitis, leading to early loss of teeth. Here, we report a case of Papillon-Lefevre syndrome with a brief discussion on treatment aspect.

Papillon-Lefèvre syndrome (PLS) is a rare autosomal recessive disease that involves severe periodontitis and hyperkeratosis of the hand palms and foot soles. Recently it was found that PLS patients carry loss-of-function mutations in the gene encoding cathepsin C (CTSC). In the present study we have analyzed the CTSC gene in two unrelated families with PLS. In the first non-consanguineous family, mutation analysis revealed the previously reported c.815GC/p.R272P mutation. The second consanguineous family displayed a c.1213CA mutation which resulted in the novel mutation p.H405N and is the first mutation described in the active site of the enzyme. The PLS patients had, next to the absence of cathepsin C activity in polymorphonuclear leukocytes (PMNs), no activity of the three serine proteinases elastase, cathepsin G and proteinase 3. Serine proteinases are supposed to be important in both the innate and adaptive immune systems. Their absence in PLS patients could explain the inadequate defense to periodontal infection.

Background Papillon-Lefevre syndrome (PLS) is a very rare autosomal recessive disorder characterized by palmoplantar hyperkeratosis and severe early onset of destructive periodontitis leading to premature loss of both primary and permanent dentitions. The etiopathogenesis of the condition suggests that there is a genetic basis for susceptibility to specific virulent pathogens. Variation in the clinical presentation of PLS has recently been observed. Objective The objective was to present the first report, which describes the concurrence of PLS and albinism. The etiology, pathology, and management of the condition were reviewed and genetic analysis was performed. Subjects and clinical presentation The probands are Jordanian brothers aged 13 and 20 years on their initial presentation. The parents were second cousins and not affected. The patients exhibited the typical clinical features of PLS with type 1 oculocutaneous albinism (OCA1). They also had increased susceptibility to infection manifested in recurrent tonsillitis, respiratory tract infection, pyoderma, onychogryphosis, and other pathosis. Skin biopsy demonstrated hyperkeratosis, focal parakeratosis, hypergranulosis, and acanthosis. Ectopic calcification of the dura was noticed in one of the probands. Hematological parameters tested were within the normal limits. The probands were tested for mutations in the causative genes of PLS and OCA1, cathepsin C (CTSC), and tyrosinase, respectively. Independent mutations (c.318-1G>A and c.817G>C/p.W272C) were identified in CTSC and tyrosinase, respectively. The probands were homozygous and their sister who had only PLS was homozygous for the same (CTSC) mutation but heterozygous for tyrosinase gene. Conclusion We hope that this report of coinheritance PLS and albinism will initiate further investigations to disclose other possible variations that may enhance our knowledge on gene mutations of this intriguing syndrome.

We have previously reported that loss-of-function mutations in the cathepsin C gene (CTSC) result in Papillon-Lefèvre syndrome, an autosomal recessive condition characterized by palmoplantar keratosis and early-onset, severe periodontitis. Others have also reported CTSC mutations in patients with severe prepubertal periodontitis, but without any skin manifestations. The possible role of CTSC variants in more common types of non-mendelian, early-onset, severe periodontitis ("aggressive periodontitis") has not been investigated. In this study, we have investigated the role of CTSC in all three conditions. We demonstrate that PLS is genetically homogeneous and the mutation spectrum that includes three novel mutations (c.386TA/p.V129E, c.935AG/p.Q312R, and c.1235AG/p.Y412C) in 21 PLS families (including eight from our previous study) provides an insight into structure-function relationships of CTSC. Our data also suggest that a complete loss-of-function appears to be necessary for the manifestation of the phenotype, making it unlikely that weak CTSC mutations are a cause of aggressive periodontitis. This was confirmed by analyses of the CTSC activity in 30 subjects with aggressive periodontitis and age-sex matched controls, which demonstrated that there was no significant difference between these two groups (1,728.7 +/- SD 576.8 micro moles/mg/min vs. 1,678.7 +/- SD 527.2 micro moles/mg/min, respectively, p = 0.73). CTSC mutations were detected in only one of two families with prepubertal periodontitis; these did not form a separate functional class with respect to those observed in classical PLS. The affected individuals in the other prepubertal periodontitis family not only lacked CTSC mutations, but in addition did not share the haplotypes at the CTSC locus. These data suggest that prepubertal periodontitis is a genetically heterogeneous disease that, in some families, just represents a partially penetrant PLS.

Papillon- Lefèvre syndrome (PLS) is a rare autosomal recessive disorder of keratinization characterized by palmoplantar hyperkeratosis, periodontopathy and precocious loss of dentition. The exact pathomechanism of these clinical events mainly remains speculative. This paper describes two cases of PLS with classic clinical features and briefly review the relevant literature.

Mutations in the cathepsin C gene have recently been detected in Papillon-Lefevre syndrome (PLS). Until now, 5 cases with the late-onset variation of this disease have been reported in the literature. The genetic background of this type of PLS is still unknown. We describe a 46-year-old woman with late-onset transgredient palmar hyperkeratosis and a 10-year history of severe periodontal disease. Histology of skin biopsy specimens revealed a psoriasiform pattern. Dental examination showed severe gingival inflammation with loss of alveolar bone. Dental plaque investigated by a polymerase chain reaction method revealed DNA signals of 5 different dental bacteria. DNA from EDTA blood was investigated for mutations in the cathepsin C gene by polymerase chain reaction analysis and direct sequencing. A silent variation in the codon for proline-459 was detected but interpreted as a polymorphism of this gene. All genetic linkage and mutation studies for PLS performed so far have shown that PLS is genetically homogeneous. Our patient with late-onset variation of PLS, however, did not show a mutation in the cathepsin C gene. Thus, we suspect that there is another genetic cause for the late-onset forms of PLS.

Papillon-Lefèvre syndrome (PLS) is an uncommon disease. Less than 300 cases have been described. PLS is characterized by the association between palmar plantar hyperkeratosis (PPK) and severe precocious periodontitis that results in the premature loss of both the primary and secondary dentitions. It is known that periodontitis (PE), the destructive phase of periodontal disease, is a multifactor phenomenon involving a variety of molecular species, among them free radicals and reactive oxygen species (ROS). Antioxidants have been shown to play a critical role in modulating ROS-induced damages during PE. We wondered if patients belonging to a family group with different grades of PLS severity may present altered plasma concentrations of oxidation products as well as of lipophilic antioxidants, like Coenzyme Q or vitamin E, which are molecules that possess well-known antioxidant properties and could play a role in PE processes. We also wondered about the actual plasma total antioxidant capacity of these subjects as well as a complete identification of their plasma fatty acids features, which have been never investigated before. The results we obtained indicate an impairment in the antioxidant capacity of the subjects characterized by abnormally high hydroperoxide levels and, in some cases, by altered CoQ and vitamin E contents. Moreover, an essential fatty acid deficiency (EFAD) was registered on the basis of the peculiar plasma fatty acid patterns found (i.e. low PUFA, high MUFA and high delta-9 desaturase activity). This finding would support the hypothesisby Gutteridge and co-workers (Free Radic. Res. 1998, 28: 109-114) that conditions exist in which some forms of oxidative stress can lead to changes characteristic of EFAD.

Background PLS is a rare autosomal recessive disorder characterized by early onset periodontopathia and palmar plantar keratosis. PLS is caused by mutations in the cathepsin C (CTSC) gene. Dipeptidyl-peptidase I encoded by the CTSC gene removes dipeptides from the amino-terminus of protein substrates and mainly plays an immune and inflammatory role. Several mutations have been reported in this gene in patients from several ethnic groups. We report here mutation analysis of the CTSC gene in three Indian families with PLS. Methods Peripheral blood samples were obtained from individuals belonging to three Indian families with PLS for genomic DNA isolation. Exon-specific intronic primers were used to amplify DNA samples from individuals. PCR products were subsequently sequenced to detect mutations. PCR-SCCP and ASOH analyses were used to determine if mutations were present in normal control individuals. Results All patients from three families had a classic PLS phenotype, which included palmoplantar keratosis and early-onset severe periodontitis. Sequence analysis of the CTSC gene showed three novel nonsense mutations (viz., p.Q49X, p.Q69X and p.Y304X) in homozygous state in affected individuals from these Indian families. Conclusions This study reported three novel nonsense mutations in three Indian families. These novel nonsense mutations are predicted to produce truncated dipeptidyl-peptidase I causing PLS phenotype in these families. A review of the literature along with three novel mutations reported here showed that the total number of mutations in the CTSC gene described to date is 41 with 17 mutations being located in exon 7.

Bacteroides forsythus is an important pathogen in periodontal diseases and has been associated with advanced and refractory periodontitis. The difficulties associated with culturing this species have meant that the distribution and pathogenic mechanisms of B. forsythus remain unclear. In this study, the arbitrarily primed polymerase chain reaction (AP-PCR) method was used to investigate the genotype distribution of B. forsythus in a Japanese periodontitis population, as well as the relationship between AP-PCR genotypes and periodontal status. B. forsythus reference strain, ATCC 43037T and 137 clinical bacterial isolates from 64 subjects were separated into 11 distinct AP-PCR genotypes using a single randomly-sequenced primer, 5'-CCGGCGGCG-3' (A-05). The majority (80.9%) of B. forsythus strains examined belonged to AP-PCR genotypes I, II, III and IV (accounting for 39.7%, 20.6%, 10.3% and 10.3%, respectively). Types I and III primarily consisted of isolates from chronic periodontitis subjects (80.8% and 85.7%, respectively), while Types II and IV consisted mainly of isolates from aggressive periodontitis subjects (85.7% and 100%, respectively). Except for three subjects who harbored two different B. forsythus genotypes in the oral cavity, all subjects only infected with one genotype intraindividually. These results demonstrate that the AP-PCR method is useful for genotypic analysis of B. forsythus. This species showed a genetic diversity among the investigated population. A clonal nature of B. forsythus infection is suggested. Furthermore, different AP-PCR genotypes of B. forsythus appear to be associated with different types of periodontitis.

Papillon-Lefevre syndrome is an autosomal recessive disorder characterized by palmoplantar hyperkeratosis and early development of aggressive periodontal infection. The aims of this study were to rank the severity of dermatologic and oral affections using a semiquantitative scoring system, and to evaluate whether the severity of the dermatologic changes were correlated to age, degree of periodontal infection, or both. The study included 47 patients with Papillon-Lefevre syndrome. With no exception both skin and oral changes developed early in life. The dermatologic involvement showed no correlation with age, whereas the periodontal infection was significantly worse in young children with deciduous teeth. A strong correlation was found between the condition of feet and hands, although the scores for the feet were significantly higher. No significant correlation could be demonstrated between the level of periodontal infection and severity of skin affections, supporting the concept that these 2 major components of Papillon-Lefevre syndrome are unrelated to each other. (J Am Acad Dermatol 2003;48:345-51.)

Papillon-Lefevre syndrome is a rare autosomal recessive disease comprising palmoplantar keratoderma and periodontitis. Palmoplantar keratoderma can be severe, necessitating systemic treatment. Different systemic retinoids were found to be highly efficacious. We describe the successful use of acitretin in one patient who had severe palmoplantar keratoderma, with maintenance of the improvement using topical treatment.

Papillon-Lefevre Syndrome (PLS) is an inherited autosomal recessive disorder presenting with Palmar plantar Keratoderma and Juvenile Periodontitis leading to early loss of both the dentitions. Two cases of PLS in a family with a history of consanguineous descent are presented.

The Papillon-Lefevre syndrome is a rare genetic disorder with a predisposition to severe infections. We describe Papillon-Lefevre syndrome in a 17 year old boy from a family where four out of eight siblings were affected with this disease and who presented with recurrent pyogenic liver abscesses over a period of 9 years, an association never previously reported.

We report the first diagnosed case of Papillon-Lefevre syndrome in Thailand. The patient is the youngest child of consanguinous parents, and she has had symmetrical hyperkeratotic plaques on both plantar surfaces since birth with a history of chronic gingivitis, periodontitis, and premature loss of primary dentition. The histologic study revealed compact hyperkeratosis with epidermal acanthosis. Radiologic studies of the skull were normal. The radiographic panoramic view of the oral cavity revealed generalized severe vertical and horizontal alveolar bone loss. The immunologic analysis of polymorphonuclear leukocyte phagocytic function by nitrobluetetrazolium test (NBT test) showed decreasing response to latex stimulation. Serum parathyroid hormone, calcium, phosphate, and alkaline phosphatase levels were within normal limits. The skin lesions were temporary relieved with topical keratolytic agents. The oral lesions were improved by the extraction of hopeless teeth and conventional periodontal treatments.

Papillon Lefèvre syndrome (PLS) is an autosomal recessive disorder characterized by palmoplantar hyperkeratosis and severe periodontitis. The disease is caused by mutations in the cathepsin C gene (CTSC) that maps to chromosome 11q14. CTSC gene mutations associated with PLS have been correlated with significantly decreased enzyme activity. Mutational analysis of the CTSC gene in three North American families segregating PLS identified four mutations, including a novel mutation p.G139R. All mutations were associated with dramatically reduced CTSC protease enzyme activity. A homozygous c.96TG transversion resulting in a p.Y32X change was present in a Mexican PLS proband, while one Caucasian PLS proband was a compound heterozygote for the p.Y32X and p.R272P (c.815GC) mutations. The other Caucasian PLS proband was a compound heterozygote for c.415GA transition and c.1141delC mutations that resulted in a p.G139R and a frameshift and premature termination (p.L381fsX393), respectively. The c.415GA was not present in more than 300 controls, suggesting it is not a CTSC polymorphism. Biochemical analysis demonstrated almost no detectable CTSC activity in leukocytes of all three probands. These mutations altered restriction enzyme sites in the highly conserved CTSC gene. Sequence analysis of CTSC exon 3 confirmed the previously reported p.T153I polymorphism in 4 of the 5 ethnically diverse populations studied.

Cysteine peptidases (CPs) are phylogenetically ubiquitous enzymes that can be classified into clans of evolutionarily independent proteins based on the structural organization of the active site. In mammals, two of the major clans represented in the genome are: the CA clan, whose members share a structure and evolutionary history with papain; and the CD clan, which includes the legumains and caspases. This review focuses on the properties of these enzymes, with an emphasis on their potential roles in the oral cavity. The human genome encodes at least (but possibly no more than) 11 distinct enzymes, called cathepsins, that are members of the papain family C1A. Ten of these are present in rodents, which also carry additional genes encoding other cathepsins and cathepsin-like proteins. Human cathepsins are best known from the ubiquitously expressed lysosomal cathepsins B, H, and L, and dipeptidyl peptidase I (DPP I), which until recently were considered to mediate primarily "housekeeping" functions in the cell. However, mutations in DPP I have now been shown to underlie Papillon-Lefevre syndrome and pre-pubertal periodontitis. Other cathepsins are involved in tissue-specific functions such as bone remodeling, but relatively little is known about the functions of several recently discovered enzymes. Collectively, CPs participate in multiple host systems that are active in health and in disease. They are involved in tissue remodeling and turnover of the extracellular matrix, immune system function, and modulation and alteration of cell function. Intracellularly, CPs function in diverse processes including normal protein turnover, antigen and proprotein processing, and apoptosis. Extracellularly, they can contribute directly to the degradation of foreign proteins and the extracellular matrix. However, CPs can also participate in proteolytic cascades that amplify the degradative capacity, potentially leading to pathological damage, and facilitating the penetration of tissues by cancer cells. We know relatively little regarding the role of human CPs in the oral cavity in health or disease. Most studies to date have focused on the potential use of the lysosomal enzymes as markers for periodontal disease activity. Human saliva contains high levels of cystatins, which are potent CP inhibitors. Although these proteins are presumed to serve a protective function, their in vivo targets are unknown, and it remains to be discovered whether they serve to control any human CP activity.

Made available in DSpace on 2019-09-12T16:53:44Z (GMT). No. of bitstreams: 0 Previous issue date: 2002 Papillon-Lefevre syndrome (PLS) is an autosomal recessive palmoplantar keratoderma caused by cathepsin C (CTSC) gene mutations. This study reports CTSC mutational and enzyme analyses in a consanguineous Brazilian family with PLS, representing the first enzymatic analysis of a Brazilian kinship with PLS. This family segregates a novel PLS-related mutation, p.W185X, that is associated with a complete loss of enzymatic activity. (C) 2002 Elsevier Science (USA). All rights reserved. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA; Universidade de Taubaté (Unitau), Sch Dent, Dept Periodont, Sao Paulo, Brazil; Univ Pittsburgh, Sch Dent Med, Ctr Craniofacial & Dent Genet, Pittsburgh, PA 15261 USA; Univ Fed Sao Paulo, Ctr Genet Med, Sao Paulo, Brazil

Conventional mechanical treatment of Papillon-Lefèvre syndrome periodontitis has a poor prognosis. This report describes an effective antimicrobial treatment of rapidly progressing periodontitis in an 11-year old girl having Papillon-Lefèvre syndrome.Clinical examination included conventional periodontal measurements and radiographic analysis. Occurrence of major suspected periodontopathic bacteria was determined by selective and non-selective culture and by polymerase chain reaction (PCR) identification. Presence of cytomegalovirus and Epstein-Barr type 1 virus was determined by a nested-PCR detection method. Therapy included scaling and root planing, oral hygiene instruction, and systemic amoxicillin-metronidazole therapy (250 mg of each/3 times daily/10 days) which, based on follow-up microbiological testing, was repeated after 4 months. Supportive periodontal therapy took place at 2 visits during a 16-month period.At baseline, 10 of 22 available teeth demonstrated severe periodontal breakdown. At 16 months, probing and radiographic measurements revealed no teeth with additional attachment loss, and several teeth exhibited significant reduction in gingivitis and pocket depth, increase in radiographic alveolar bone height and clinical attachment level, and radiographic evidence of crestal lamina dura. Baseline subgingival microbiota included Actinobacillus actinomycetemcomitans (3.4% of total isolates), Prevotella nigrescens (16.4%), Fusobacteriumnucleatum (14.3%) and Peptostreptococcus micros (10.6%), as well as cytomegalovirus and Epstein-Barr type 1 virus. At termination of the study, culture and PCR examinations showed absence of A. actinomycetemcomitans, P. micros and herpesviruses, and P. nigrescens and F.nucleatum each comprised less than 0.1 % of subgingival isolates.This study suggests that controlling the periodontopathic microbiota by appropriate antibiotic and conventional periodontal therapy can arrest Papillon-Lefèvre syndrome periodontitis.

Background: Papillon-Lefevre syndrome (PLS) is a disorder that involves destruction of the periodontium and abnormal hyperkeratosis of the palms of the hands and soles of the feet. Mutations of the lysosomal protease cathepsin C gene (CTSC) have been associated with PLS. However, genotypic and phenotypic correlation has not been established. In the present study we investigated the CTSC gene in a Brazilian cohort affected by PLS. Methods: Eight consanguineous members of a kindred with PLS were studied. DNA was extracted and all exons of the gene amplified by the polymerase chain reaction (PCR) using specific primers. Mutations were identified by DNA sequencing of the coding region and introns of the CTSC gene. Results: Sequence analysis of CTSC from subjects affected by PLS identified a novel mutation (587T → C) in exon 4, predicted to cause a Leu196Pro amino acid substitution. Three of 3 subjects were homozygous for cathepsin C mutations inherited from a common ancestor. One patient was heterozygous and showed plantar hyperkeratosis without periodontal disease. Two other family members were also heterozygous but did not present palmoplantar hyperkeratosis and/or periodontal disease. Conclusions: This study describes a novel mutation of the cathepsin C gene in a Brazilian kindred with Papillon-Lefevre syndrome. J Periodontol 2002;73:307-312.

Papillon-Lefevre syndrome is an autosomal recessive palmoplantar keratoderma caused by cathepsin C gene mutations. We present the second family segregating the IVS3-1G → A mutation and demonstrate for the first time that altered splicing and decreased enzymatic activity occur. RNA analysis revealed two species in carriers, corresponding to wild-type and mutant transcripts, and only the mutant transcript in affected individuals. Sequencing of the mutant transcript revealed that it lacked exon 3, resulting in a frameshift and introduction of a premature termination codon.

Papillon–Lefevre syndrome is an autosomal recessive disorder characterized by palmoplantar keratoderma, periodontitis, and premature loss of dentition. Mutations in the CTSC gene that encodes cathepsin C have been described in families affected with Papillon–Lefevre syndrome. Cathepsin C is the least understood of the lysosomal cysteine proteases; it has been reported to participate in both intracellular and extracellular cleavage of proteins and activation of serine proteases in immune and inflammatory cells. We report here eight new mutations in Papillon–Lefevre syndrome families: four deletions and four point mutations, including a missense mutation in the propeptide chain that could help elucidate structure-function relationships in this protein. We also found that the 458C > T mutation, first reported in two families by Hart et al (2000c), was a neutral polymorphism in our families, as suggested by Allende et al (Cathepsin C gene: first compound heterozygous patient with Papillon–Lefevre syndrome and novel symptomless mutation. Hum Mutat 17:152–153, 2001).

Papillon Lefevre Syndrome is a rare syndrome autosomal recessive in nature, manifesting as keratosis palmoplantaris with periodontitis. A case of Papillon Lefevre Syndrome present in a 12 year old boy is presented. Only the permanent maxillary canines were present in the oral cavity when the patient was first seen, and despite efforts towards preservation, they had to be extracted. (complete dentures were made and the patient was followed up for 26 months.

Systemic diseases affecting the host response as primary immunodeficiencies or secondary defects caused by lack of nutrients or changes in the local tissues are very often accompanied by early-onset prepubertal periodontitis. Local treatment in combination with systemic antibiotics may in milder forms improve the situation, but in many cases the success is questionable and premature loss of teeth occurs. Since the genetic basis of many of the diseases has been identified, future developments permit the correction of at least some of these defects by gene therapy.

Papillon Lefèvre syndrome (PLS) is a rare entity and, as such, it is almost impossible to evaluate an effective therapy in a randomized controlled study. The amount of success reported after therapy for prepubertal periodontitis (PP) in PLS is highly variable from case to case. The goal of this case report is to evaluate the effects of a combined mechanical and antibiotic periodontal therapy regimen in the management of PLS.A male patient was diagnosed as suffering from PP associated with PLS at the age of 7 years. He showed hyperkeratosis of the palms and soles, as well as advanced periodontal disease already affecting permanent teeth with maximal probing depth and vertical attachment loss of 12 mm and 11 mm, respectively. Subgingival debridement was performed with simultaneous administration of oral 250 mg amoxicillin 3 times daily and 250 mg metronidazole twice daily for one week. Clinical parameters were assessed and subgingival plaque was collected from all teeth prior to therapy and 7 and 26 months after treatment. Selective cultures for A. actinomycetemcomitans were incubated for each individual tooth and DNA probe analysis was performed for various periodontal pathogens.Prior to combined mechanical and antibiotic treatment, all teeth but one harbored Actinobacillus actinomycetemcomitans subgingivally. However, at 7 and 26 months after therapy A. actinomycetemcomitans could be detected neither by culture nor by DNA probes. Clinical parameters improved markedly and teeth erupting after therapy did not exhibit attachment loss of more than 1.5 mm during the observation period.Eradication (suppression beneath detection levels) of A. actinomycetemcomitans seems to play a significant role in the successful treatment of localized prepubertal periodontitis in PLS.

Human cytomegalovirus and Epstein-Barr virus type 1 are discussed in this review as they relate to destructive periodontal disease in humans. Genomes of the two herpesviruses occur frequently in severe adult periodontitis, localized and generalized juvenile periodontitis, Papillon-Lefèvre syndrome periodontitis, Down's syndrome periodontitis, HIV-associated periodontitis and acute necrotizing ulcerative gingivitis. Herpesvirus infections generally involve a mild or asymptomatic primary phase followed by an asymptomatic latent phase interrupted sporadically by periods of activation, where viral replication and possibly clinical disease become manifest. Herpesvirus reactivation is triggered by a number of immunosuppressing factors, some of which have also been shown to be risk indicators of periodontal disease. Available evidence argues for the involvement of active cytomegalovirus infection in the initiation and progression of localized juvenile periodontitis and possibly other types of periodontal disease. In periodontal disease, herpesviruses may cause release of tissue-destructive cytokines, overgrowth of pathogenic periodontal bacteria, and initiation of cytotoxic or immunopathogenic events. Understanding the significance of herpesviruses in the causation and pathogenesis of destructive periodontal diseases may have important implications in future prevention and treatment of the diseases.

The Saudi female reported in this study was diagnosed with Papillon-Lefèvre syndrome. She had lost all her teeth, including third molars, at the age of 18 years.She was wearing full dentures for 7 years, before 5 titanium implants were installed in the mandible.4 1/2 years after the implant installation, the treatment was clinically and radiographically successful. Neither A. actinomycetemcomitans nor P. gingivalis were detected at any of the implants. This very encouraging result does not differ from what is generally reported in edentulous medically healthy patients.The use of implants could considerably enhance future therapeutic options for the severely dentally compromised patients with Papillon-Lefèvre syndrome.

Papillon-Lefèvre syndrome (PLS) is a rare disease associated with prepubertal periodontitis. Our previous studies demonstrated that three unrelated patients with PLS showed the similar antigen-specific immune responses to Actinobacillus actinomycetemcomitans. The initiation of antigen-specific immune responses was involved with human leukocyte antigens (HLA) on antigen-presenting cells. The aim of this study was to examine HLA haplotypes in the three patients with PLS.The three PLS patients, their mothers and the father of one patient participated in this study. HLA class I and class II antigens were determined serologically and DNA typing for DRB1 and DQB1 was performed using the restriction fragment length polymorphism-polymerase chain reaction method.The distribution of serologic HLA haplotypes, in two of three patients, was found to be quite similar. The DNA typing revealed that DRB1*0406, DRB1*08032, DQB1*0302, DQB1*06011 genotypes were shared in the two patients. The probability of sharing these four DNA types in unrelated individuals was nearly 1:40,000 in the Japanese population.Our results suggest that HLA antigen may be included as a possible host factor in the pathogenesis of PLS and that a genetically controlled immune response may account for an increased susceptibility to periodontal infection.

Aims: This paper reports the treatment of the periodontal component of the Papillon-Lefevre syndrome in 2 siblings (case A, born 1974; case B, born 1976). Method: The initial treatment, in 1982, consisted of extraction of all primary teeth, scaling and rootplaning of the erupted permanent teeth and systemic antibiotic therapy. During 15 years, continuous and intensive periodontal treatment consisted of chlorhexidine 0.2% rinses, bi-weekly professional prophylaxis, scaling and rootplaning or surgery if indicated. Systemic antibiotics often accompanied mechanical therapy after bacteriological analysis. Results: In case A, a favourable number of permanent teeth could be maintained, but in case B, all permanent teeth were lost in spite of the intensive treatment. Darkfield microscopy at different intervals revealed high numbers of spirochetes and motile rods in both siblings. Only in case A were they temporarily reduced to zero after scaling and rootplaning combined with metronidazole. Anaerobic cultering revealed high numbers of Actinobacillus actinomycetemcomitans (A.a) in both patients. In 1994, 2 years after combined amoxicillin/metronidazole therapy, no A.a could be detected in case A. In case B, A.a could still be detected and was found to be resistant to metronidazole. One year after extraction of all permanent teeth, could no A.a be detected in case B. Conclusion: Intensive periodontal treatment combined with antibiotic therapy was not able to prevent complete tooth loss in case B. In case A, the treatment was more effective, resulting in preserving a number of permanent teeth in a stable clinical situation. In these 2 cases, no attempt was made to create an edentulous period between the periodontally-diseased mixed dentition and the eruption of the remaining teeth, which may have contributed to treatment failure.

Papillon-Lefèvre syndrome is characterized by the association of palmoplantar hyperkeratosis, severe periodontitis, and early loss of deciduous and permanent teeth. We report two patients from the same family, aged 21 and 30 years, who were unaware of their pathology; one was successfully treated with etretinate.

4 patients, 2 pairs of siblings, suffering from Papillon-Lefèvre syndrome were treated for periodontal disease. Following extraction of hopeless teeth, the children received scaling and adjunctive systemic antibiotics (metronidazole and amoxicillin for 7 to 10 days). In addition, they performed supragingival pulsated jet irrigation with 0.06% chlorhexidine digluconate 1 x daily. In 2 siblings, A. actinomycetemcomitans was suppressed subgingivally below detectable levels, pocket probing depths were reduced to 4 mm or less, and plaque and bleeding indices were low. No further disease progression was seen over a 3-year-period. Another female patient also showed clinical improvement and suppression of subgingival A. actinomycetemcomitans and B. forsythus up to the 9-month-follow-up, while her sister showed further attachment loss over the course of 4 years. The present case reports indicated that in some patients suffering from Papillon-Lefèvre syndrome periodontal disease may be arrested by means of (i) oral hygiene instruction, (ii) extraction of severely diseased teeth, (iii) scaling, (iv) systemic antibiotics and (v) long-term antimicrobial irrigation.