Recent developments in the diagnosis, treatment, and management of Papillon-Lefèvre Syndrome.

DATA SOURCES: A systematic search of PubMed, LIVIVO, and Ovid was conducted up to March 2021. These databases were searched for relevant clinical studies on periodontal treatment success in individuals with Papillon-Lefèvre syndrome (PLS). STUDY SELECTION: Clinical studies reporting successful treatment outcomes defined as the loss of four or fewer permanent teeth due to periodontitis and the arrest of periodontitis or probing depths of 5 mm or less in individuals with PLS followed up for ≥24 months were included, and data extracted. DATA EXTRACTION AND SYNTHESIS: Twelve studies reporting on nine PLS patients met the inclusion criteria. The extracted main outcomes in the studies reporting successful periodontal treatment in PLS were as follows: (1) clinical and genetic diagnosis of PLS; (2) age at baseline; (3) initial dental, periodontal parameters, and microbiological assessment, if available; (4) description of disease progression and applied therapies; and (5) outcome and follow-up. RESULTS: Twelve studies reporting nine individuals were included. The timely extraction of affected or all primary teeth, compliance with oral hygiene instructions, supra- and subgingival debridement within frequent supportive periodontal care intervals, and adjunctive systemic antibiotic therapy in most patients affected a halt in disease progression. Suppression of Aggregatibacter actinomycetemcomitans below detection limits was associated with periodontal stabilization. CONCLUSIONS: An intensive, multidisciplinary approach with strict compliance may enable the decelerated progression of PLS-associated periodontitis. The early diagnosis of PLS and the suppression of A. actinomycetemcomitans below the detection level might be critical factors for treatment success. It required significant effort and patient compliance. The study emphasized the importance of timely interventions, oral hygiene maintenance, regular professional dental care, and, in some cases, systemic antibiotics.

Multidisciplinary management of Papillon-Lefevre syndrome as a result of consanguineous marriage.

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.

Abnormal profiles of cathepsin C secreted in urine of Papillon Lefevre syndrome patients.

BACKGROUND: Papillon Lefevre syndrome (PLS) is an autosomal recessive disorder that results from a mutated gene that encodes a lysosomal peptidase known as cathepsin C (CTSC). The clinical presentation of PLS involves mainly palmoplantar keratosis and periodontitis with a variable degree of severity. SUBJECTS: and methods: Our study included ten patients with a broad spectrum of palmoplantar keratosis and periodontitis severity. CTSC variants were detected by Sanger sequencing. CTSC protein secreted in urine was detected by western blotting. RESULTS: Five patients have missense variants, Four have nonsense variants, and one has splice variants in CTSC. The activation products of cathepsin C protein (Heavy and light chains) were absent in all patients' urine samples except one with a significantly reduced level compared to the controls. The dimeric form of CTSC protein was found in all the studied cases. The monomeric form was found in five cases. The products of proteolytic activation of CTSC by other cathepsins (L and S) were found in the urine samples of five of the patients. Each patient had a characteristic pattern of accumulated CTSC protein maturation/activation substrates, intermediates, and products. 40% of the patients had the activation products of other lysosomal cathepsins. CONCLUSION: Urinary CTSC in PLS patients could be used as a diagnostic biomarker for the biochemical screening of the disease. Different variants in CTSC result in different profiles of CTSC secreted in the urine of PLS patients. The profiles of secreted CTSC in urine could be correlated to the severity of palmoplantar keratosis.

"Oral Manifestations of Patients with Inherited Defect in Phagocyte Number or Function" a systematic review.

INTRODUCTION: Inherited phagocyte defects are one of the subgroups of primary immunodeficiency diseases (PIDs) with various clinical manifestations. As oral manifestations are common at the early ages, oral practitioners can have a special role in the early diagnosis. MATERIALS AND METHODS: A comprehensive search was conducted in this systematic review study and data of included studies were categorized into four subgroups of phagocyte defects, including congenital neutropenia, defects of motility, defects of respiratory burst, and other non-lymphoid defects. RESULTS: Among all phagocyte defects, 12 disorders had reported data for oral manifestations in published articles. A total of 987 cases were included in this study. Periodontitis is one of the most common oral manifestations. CONCLUSION: There is a need to organize better collaboration between medical doctors and dentists to diagnose and treat patients with phagocyte defects. Regular dental visits and professional oral health care are recommended from the time of the first primary teeth eruption in newborns.

Two patients with Papillon-Lefèvre syndrome without periodontal involvement of the permanent dentition.

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.

Papillon-Lefèvre syndrome: Oral aspects and treatment.

Papillon-Lefèvre syndrome (PLS) is a rare disorder characterized by diffuse palmoplantar erythematous, fissured hyperkeratosis, and aggressive periodontal disease that starts in the early periods of childhood. Periodontal disease occurs with the early loss of deciduous teeth at the age of 2 to 4 years, followed by the loss of permanent teeth during adolescence. Prosthodontics management of PLS patients is very complex and sometimes requires invasive therapeutic treatments. Early diagnosis is essential for correct treatment management avoiding the possibility that patients are early edentulous. Management could be a conventional periodontal treatment and pharmacological therapy but in severe cases, digital techniques, could be help the clinician for increased patient comfort and minimized tissue damage.

A new terminal nonsense mutation of the cathepsin C gene in a patient with atypical Papillon-Lefèvre syndrome

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CTSC compound heterozygous mutations in two Chinese patients with Papillon-Lefèvre syndrome.

OBJECTIVES: To identify the molecular basis of Papillon-Lefèvre syndrome in two Chinese families. METHODS: Peripheral blood and mouth swab samples were obtained, from which genomic DNA and RNA were isolated. Sanger sequencing was employed to identify the mutations. mRNA expression was tested by real-time quantitative PCR. Evolutionary conservation, pathogenicity prediction and impact of protein structures of the mutations were conducted with bioinformatics tools and homology modelling. HEK293 cells were transfected with plasmids expressing wild-type or mutated CTSC. CTSC protein expression level and enzyme activity were explored. RESULTS: Mutation analysis revealed two novel compound heterozygous mutations, the c.190-191insA and c.1211-1212delA in patient 1 and the c.716A>G and c.757+1G>A in patient 2. In both patients, the levels of CTSC mRNA were significantly lower than in their relatives. Homology modelling analysis predicted that the mutations affect the structure and stability of the protein, and in vitro study showed that the CTSC proteins containing the mutations c.190-191insA and c.1211-1212delA, which result in truncated versions of protein, display impaired enzyme activity. The protein containing c.716A>G mutation showed quite similar enzyme activity compared to wild-type CTSC. CONCLUSION: Our data support the molecular mechanism of PLS and enlarge the scope of CTSC gene mutations related to PLS.

Papillon-Lefevre Syndrome: A case report / Síndrome de Papillon-Lefevre: descripción de un caso

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Papillon-Lefèvre syndrome: A series of three cases in the same family and a literature review.

Papillon-Lefèvre syndrome (PLS) is a rare autosomal recessive disorder that exhibits palmoplantar keratosis and early severe periodontitis. The oral disease affects both the primary and permanent dentitions leading to premature exfoliation of teeth. Various etiologic factors, such as genetic mutations, immunologic alterations, and bacteria have been implicated in PLS. Genetic mutations leading to the loss of function of cathepsin C (CTSC) gene, located on chromosome 11q14, is considered pivotal in this condition. The present case series describes PLS in three siblings, with consanguineously married parents, who live in a remote area of Yemen. The affected children presented with prominent palmoplantar keratosis and early periodontitis with only a few remaining teeth. The severity of skin lesions in all patients exhibited seasonal variations. Based on their clinical findings, a diagnosis of PLS was made. Dentists have a significant role in the early diagnosis and management of PLS patients.

[Papillon-Lefèvre syndrome: A new case]. / Le syndrome de Papillon-Lefèvre, à propos d'une nouvelle observation.

Papillon-Lefèvre syndrome (PLS) is a rare primary immunodeficiency, which combines severe periodontal disease with edentulism and palmoplantar keratosis (PPK). PLS is inherited as an autosomal recessive trait and is due to mutations in the cathepsin C gene. The biological properties of the neutrophils (PN) are altered, leading to a gingival dysbiosis and bacterial overgrowth, with intense inflammation of the periodontium. We report the observation of a 4-year-old girl who presented to the clinic with gingivitis, partial edentulism, and PPK, whose diagnosis, raised after a long delay, was suggested by null cathepsin C activity and confirmed by the presence of heterozygous mutations in exon 4: c.628C>T, pArg210* and in exon 7: c.1286G>A, p.Trp429*. A multidisciplinary approach transformed the functional and esthetic prognosis and psychological behavior of this child. This classical observation describes this poorly known phenotype.

Papillon-Lefèvre syndrome: report of six patients and identification of a novel mutation.

Papillon-Lefèvre syndrome is an autosomal recessive genodermatosis typically manifesting with the constellation of palmoplantar keratoderma and progressive early-onset periodontitis. The cutaneous phenotype can be strikingly psoriasiform, possibly posing a diagnostic challenge. This rare disorder is caused by loss-of-function mutations in the CTSC gene, which encodes cathepsin C. We report six patients with Papillon-Lefèvre syndrome from five consanguineous Turkish families, in whom genetic analysis of the CTSC gene revealed four recurrent mutations (c.415G>A; c.1015C>T; c.1019A>G; and c.103-105delCTG) and a novel missense mutation (c.117G>T) in the homozygous state.

Analysis of urinary cathepsin C for diagnosing Papillon-Lefèvre syndrome.

Papillon-Lefèvre syndrome (PLS) (OMIM: 245000) is a rare disease characterized by severe periodontitis and palmoplantar keratoderma. It is caused by mutations in both alleles of the cathepsin C (CatC) gene CTSC that completely abrogate the proteolytic activity of this cysteine proteinase. Most often, a genetic analysis to enable early and rapid diagnosis of PLS is unaffordable or unavailable. In this study, we tested the hypothesis that active CatC is constitutively excreted and can be easily traced in the urine of normal subjects. If this is true, determining its absence in the urine of patients would be an early, simple, reliable, low-cost and easy diagnostic technique. All 75 urine samples from healthy control subjects (aged 3 months to 80 years) contained proteolytically active CatC and its proform, as revealed by kinetic analysis and immunochemical detection. Of the urine samples of 31 patients with a PLS phenotype, 29 contained neither proteolytically active CatC nor the CatC antigen, so that the PLS diagnosis was confirmed. CatC was detected in the urine of the other two patients, and genetic analysis revealed no loss-of-function mutation in CTSC, indicating that they suffer from a PLS-like condition but not from PLS. Screening for the absence of urinary CatC activity soon after birth and early treatment before the onset of PLS manifestations will help to prevent aggressive periodontitis and loss of many teeth, and should considerably improve the quality of life of PLS patients.