OBJECTIVE: The oral microbiota composition of patients diagnosed with Papillon-Lefèvre-syndrome and treated for several years were compared to those existing in the oral cavity of the clinically healthy family members and a cohort of patients having various stages of chronic periodontitis.
METHODS: A family with two sisters affected with severe periodontitis and with the typical skin symptoms of Papillon-Lefèvre-syndrome, and symptomless parents and third sibling were investigated. The Patients received periodontal treatment for several years and their oral microbiome was analysed by amplicon sequencing. Data were evaluated by microbial cluster analysis.
RESULTS: The microbiome of the patients with Papillon-Lefèvre-syndrome was predominated with Aggregatibacter actinomycetemcomitans and associated oral periodontopathogens. Although the clinically healthy family members showed no oral disorder, their microbiome resembled that of subjects having mild periodontitis.
CONCLUSIONS: Predominance of A. actinomycetemcomitans in the subgingival microbiome of patients with Papillon-Lefèvre-syndrome suggests that specific treatment strategies directed against this pathobiont may improve the oral health status of the affected individuals.
BACKGROUND: The study was conducted in accordance with the Declaration of Helsinki and the ethical permission has been issued by the Human Investigation Review Board of the University of Szeged, Albert Szent-Györgyi Clinical Centre (Permission No. 63/2017-SZTE). September 19, 2017.  https://u-szeged.hu/klinikaikutatas/rkeb-altal-jovahagyott/rkeb-2017 .

This report details the successful prosthetic rehabilitation of a 25-year-old male patient with Papillon Lefèvre Syndrome (PLS) using an implant-supported hybrid prosthesis. Six implants were placed in the maxilla, and four were placed in the mandibular arch. All implants were inserted axially (non-tilted) and were planned to be loaded after a healing period of 6 months. One implant failed due to graft loss during the healing phase, which was removed and the remaining implants were restored with a hybrid prosthesis after 6 months, using the delayed loading protocol. The patient was followed-up for four years and all the remaining implants successfully integrated and remained fully functional during this period. The prosthesis significantly improved the functional, aesthetic, and psychological well-being of the patient. This case report is the first of its kind to use only four axially placed implants for rehabilitation of a PLS patient with a successful four-year follow-up.

Papillon-Lefevre syndrome (PLS) is a rare autosomal recessive syndrome, and consanguinity has been reported in 20%-40% of cases. It is characterised by palmoplantar hyperkeratosis associated with severe early-onset periodontitis and premature loss of primary and permanent teeth. This report describes a case of PLS in a female patient with consanguineously married parents. The patient reported mobile upper front teeth. Clinical examination revealed presence of marked palmoplantar hyperkeratosis.Symmetric, well-demarcated, yellowish, keratotic and confluent plaques were seen on the skin of her palms and soles. Intraoral periodontal examination revealed erythematous gingiva with generalised periodontal pockets. Generalised mobility of teeth was present with clinically missing lower anterior teeth. Based on clinical and radiographic feature and the patient\'s medical, dental and family history, a diagnosis of PLS was made.

The ANCA autoantigens proteinase 3 (PR3) and myeloperoxidase (MPO) are exclusively expressed by neutrophils and monocytes. ANCA-mediated activation of these cells is the key driver of the vascular injury process in ANCA-associated vasculitis (AAV), and neutrophil serine proteases (NSPs) are disease mediators. Cathepsin C (CatC) from zymogens activates the proteolytic function of NSPs, including PR3. Lack of NSP zymogen activation results in neutrophils with strongly reduced NSP proteins.
To explore AAV-relevant consequences of blocking NSP zymogen activation by CatC, we used myeloid cells from patients with Papillon-Lefèvre syndrome, a genetic deficiency of CatC, to assess NSPs and NSP-mediated endothelial cell injury. We also examined pharmacologic CatC inhibition in neutrophil-differentiated human hematopoietic stem cells, primary human umbilical vein cells, and primary glomerular microvascular endothelial cells.
Patients with Papillon-Lefèvre syndrome showed strongly reduced NSPs in neutrophils and monocytes. Neutrophils from these patients produced a negative PR3-ANCA test, presented less PR3 on the surface of viable and apoptotic cells, and caused significantly less damage in human umbilical vein cells. These findings were recapitulated in human stem cells, in which a highly specific CatC inhibitor, but not prednisolone, reduced NSPs without affecting neutrophil differentiation, reduced membrane PR3, and diminished neutrophil activation upon PR3-ANCA but not MPO-ANCA stimulation. Compared with healthy controls, neutrophils from patients with Papillon-Lefèvre syndrome transferred less proteolytically active NSPs to glomerular microvascular endothelial cells, the cell type targeted in ANCA-induced necrotizing crescentic glomerulonephritis. Finally, both genetic CatC deficiency and pharmacologic inhibition, but not prednisolone, reduced neutrophil-induced glomerular microvascular endothelial cell damage.
These findings may offer encouragement for clinical studies of adjunctive CatC inhibitor in patients with PR3-AAV.

Papillon-Lefèvre syndrome (PLS) is an autosomal recessive rare disease, main characteristics of which include palmoplantar hyperkeratosis and premature edentulism due to advanced periodontitis (formerly aggressive periodontitis). This study aimed to characterize the oral phenotype, including salivary parameters, and the salivary microbiome of three PLS sisters, comparatively. Two sisters were toothless (PLSTL1 and PLSTL2), and one sister had most of the teeth in the oral cavity (PLST). Total DNA was extracted from the unstimulated saliva, and the amplicon sequencing of the 16S rRNA gene fragment was performed in an Ion PGM platform. The amplicon sequence variants (ASVs) were obtained using the DADA2 pipeline, and the taxonomy was assigned using the SILVA v.138. The main phenotypic characteristics of PLS were bone loss and premature loss of primary and permanent dentition. The PLST sister presented advanced periodontitis with gingival bleeding and suppuration, corresponding to the advanced periodontitis as a manifestation of systemic disease, stage IV, grade C. All three PLS sisters presented hyposalivation as a possible secondary outcome of the syndrome. Interestingly, PLST salivary microbiota was dominated by the uncultured bacteria Bacterioidales (F0058), Fusobacterium, Treponema, and Sulfophobococcus (Archaea domain). Streptococcus, Haemophilus, and Caldivirga (Archaea) dominated the microbiome of the PLSTL1 sister, while the PLSTL2 had higher abundances of Lactobacillus and Porphyromonas. This study was the first to show a high abundance of organisms belonging to the Archaea domain comprising a core microbiome in human saliva. In conclusion, a PLST individual does have a microbiota different from that of the periodontitis\' aggressiveness previously recognized. Due to an ineffective cathepsin C, the impairment of neutrophils probably provided a favorable environment for the PLS microbiome. The interactions of Bacteroidales F0058, Caldivirga, and Sulfophobococcus with the microbial consortium of PLS deserves future investigation. Traditional periodontal therapy is not efficient in PLS patients. Unraveling the PLS microbiome is essential in searching for appropriate treatment and avoiding early tooth loss.

Cathepsin C, an important lysosomal cysteine protease, mediates the maturation process of neutrophil serine proteases, and participates in the inflammation and immune regulation process associated with polymorphonuclear neutrophils. Therefore, cathepsin C is considered to be an attractive target for treating inflammatory diseases. With INS1007 (trade name: brensocatib) being granted a breakthrough drug designation by FDA for the treatment of Adult Non-cystic Fibrosis Bronchiectasis and Coronavirus Disease 2019, the development of cathepsin C inhibitor will attract attentions from medicinal chemists in the future soon. Here, we summarized the research results of cathepsin C as a therapeutic target, focusing on the development of cathepsin C inhibitor, and provided guidance and reference opinions for the upcoming development boom of cathepsin C inhibitor.

Papillon-Lefèvre syndrome (PLS) is a rare autosomal recessive genodermatosis characterized by palmoplantar keratoderma and severe periodontitis leading to premature loss of primary and permanent teeth. PLS is caused by loss-of-function mutations in CTSC, lacking functional cathepsin C, which impairs the activation of neutrophil serine proteases. Precise pathogenesis of periodontal damage is unknown. Patient 1 presented with well-demarcated, transgredient, diffuse, palmoplantar keratoderma and psoriasiform lesions from the age of 2 years. Based on severe and recurrent periodontal inflammation, his dentist had diagnosed PLS at the age of 3 years and provided a strict oral hygiene regimen with repeated adjunct antibiotic therapies. Oral acitretin 10 mg/day along with tretinoin ointment at the age of 9 greatly improved palmoplantar keratoderma. Aged 18 years, the patient exhibited an intact permanent dentition and absence of periodontal disease. Patient 2, a 30-year-old man, suffered from transgredient, diffuse, palmoplantar keratoderma with fissuring from the age of 2 months, marked psoriasiform plaques on elbows and knees, and nail dystrophy. Intriguingly, without specific dental treatment, teeth and dental records were unremarkable. He was referred with a suspected diagnosis of psoriasis. Both patients were otherwise healthy, blood tests and sonography of internal organs were within normal limits. Panel sequencing revealed loss-of-function mutations in CTSC, c.322A>T (p.Lys108Ter) and c.504C>G (p.Tyr168Ter) in patient 1 and homozygous c.415G>T (p.Gly139Ter) in patient 2. The final diagnosis of unusual PLS was made. PLS should be considered in palmoplantar keratoderma lacking periodontitis or tooth loss.

The field of primary immunodeficiencies (PIDs) is rapidly evolving. Indeed, the number of described diseases is constantly increasing thanks to the rapid identification of novel genetic defects by next-generation sequencing. PIDs are now rather referred to as \"inborn errors of immunity\" due to the association between a wide range of immune dysregulation-related clinical features and the \"prototypic\" increased infection susceptibility. The phenotypic spectrum of PIDs is therefore very large and includes several orofacial features. However, the latter are often overshadowed by severe systemic manifestations and remain underdiagnosed. Patients with impaired innate immunity are predisposed to a variety of oral manifestations including oral infections (e.g., candidiasis, herpes gingivostomatitis), aphthous ulcers, and severe periodontal diseases. Although less frequently, they can also show orofacial developmental abnormalities. Oral lesions can even represent the main clinical manifestation of some PIDs or be inaugural, being therefore one of the first features indicating the existence of an underlying immune defect. The aim of this review is to describe the orofacial features associated with the different PIDs of innate immunity based on the new 2019 classification from the International Union of Immunological Societies (IUIS) expert committee. This review highlights the important role played by the dentist, in close collaboration with the multidisciplinary medical team, in the management and the diagnostic of these conditions.

Papillon Lefevre syndrome (PLS) manifests with palmoplantar keratoderma, combined with a rapidly progressive periodontitis associated with mutations in Cathepsin C (CTSC) gene. This article reports a 15-year old male proband with typical PLS traits having a novel compound heterozygote with p.Q49X mutation in exon 1 and p.Y259C missense mutation in exon 6 of CTSC gene respectively. The exon 1 mutation, p.Q49X, (found in proband\'s mother) was located in exclusion domain and exon 6 mutation, p.Y259C (found in proband\'s father), was present in peptidase C1A, papain C-terminal domain. Interestingly, missense mutation p.Y259C identified in this study was found to be not reported so far. Upon computational analysis, this missense mutation was found to be lethal. Moreover, our protein modelling approach using mutant protein revealed the presence of monomeric structure on contrary to the tetrameric structure of the wild type protein. In addition, in vitro functional characterization of mutant p.Y259C expressed in HEK293 cells showed a significant reduction in CTSC activity (0.015 ± 0.009 mU/ml) when compared with wild type protein (0.21 ± 0.008 mU/ml). Thus, in this study, we have demonstrated that the pathogenic missense mutant p.Y259C might cause PLS by impaired CTSC function.

暂无摘要。