Early-onset Periodontitis Research Articles

Papillon-Lefèvre Syndrome: Detrimental Periodontal Condition in the Affected Individuals

This paper aims to highlight the detrimental periodontal condition in patients with Papillon-Lefèvre syndrome (PLS) and the pivotal role of a Periodontist in the diagnosis of the condition. PLS is also known as palmo-plantar keratosis (PPK) with an unusual periodontal status. Uncontrolled early-onset periodontitis, which affects both primary and permanent dentitions alike, is a hallmark of the syndrome. PLS patients’ exhibit defected neutrophil chemotactic function due to substandard activity of Cathepsin C (CTSC) gene. The result is the failure of elimination of periodontal pathogens that leads to severe periodontal destruction. We reported a case of an 11 years old Pakistani girl affected with PLS whose parents are consanguineously married. Since PLS is a rare autosomal recessive disorder and multiple consanguinity in a family, increases the risk of the occurrence of the syndrome in the off springs, the case report also highlights the importance of pre-marital genetic mapping and conception counseling for the families.

Palmoplantar keratoderma, oral involvement, and homozygous CTSC mutation in two brothers from Cambodia

Haim-Munk syndrome (HMS) and Papillon-Lefevre syndrome (PLS) are phenotypic variants of palmoplantar keratoderma (PPK) with progressive early-onset periodontitis and dental caries. HMS and PLS have been associated with homozygous or compound heterozygous mutations in the lysosomal protease gene Cathepsin C (CTSC). There have been only a few documented cases of CTSC mutations in patients from South-East Asia. We report the clinical findings of two Cambodian brothers who presented with diffuse, demarcated PPK with transgrediens extending to the elbows and knees, as well as pachyonychia and dental caries. Arachnodactyly and periodontitis were also found in the older brother. Next-generation sequencing unveiled a homozygous missense variant in CTSC (NM_001814.5: c.1337AC: p.(Asp446Ala)) in both brothers. Both parents were heterozygous for the variant, while an unaffected older brother was homozygous for the wild-type allele. Our study adds to the spectrum of mutations and associated clinical presentations for this rare genodermatosis.

ORAL MANIFESTATIONS OF KOSTMANN SYNDROME: CASE REPORT

Kostmann syndrome (KS), or severe congenital neutropenia, is a rare autosomal recessive genetic disorder with a mutation in the HAX1 gene, located on chromosome 1 q21.3. The typical symptoms are abscesses located on various parts of the body: ear, cutis, lung, and oral cavity. The decrease in the number of neutrophils alters the host defense capacity, causing periodontal disease to manifest at an early age, with gingival inflammation, aggressive periodontal destruction, edema, periodontal pouches, and tooth mobility. The aim of this report is to describe the most typical signs of this pathology in the oral cavity presenting the case of a 15-year-old adolescent girl diagnosed as having congenital neutropenia with generalized early-onset periodontitis aggravated by this systemic condition and recurrent oral infections, generalized bleeding, and early dental loss.

Smoking Modifies the Genetic Risk for Early-Onset Periodontitis

Periodontitis has low-prevalence, highly severe disease manifestations with an early onset and rapid progression. The diagnosis is based on severe destruction of the alveolar bone in adolescents and young adults. Genetic susceptibility variants and smoking are well-established risk factors, but their interactions in modifying disease susceptibility have not been studied. We aimed to identify genetic risk variants of early-onset periodontitis that unmask their effects on tobacco smoke exposure. To this end, we analyzed 79,780,573 common variants in 741 northwest Europeans diagnosed to have >30% bone loss at >2 teeth before 35 y of age, using imputed genotypes of the OmniExpress BeadChip. Never versus ever smokers were compared in a logistic regression analysis via a case-only approach. To explore the effect of tobacco smoke on the expression of the G×S-associated genes, cultures of primary gingival fibroblasts (n = 9) were exposed to cigarette smoke extract, and transcripts were quantified by reverse transcription polymerase chain reaction. We identified 16 loci for which our analysis suggested an association with G×S increased disease risk (P < 5 × 10−5). Nine loci had previously been reported to be associated with spirometric measures of pulmonary function by an earlier G×S genome-wide association study. Genome-wide significant cis expression quantitative trait loci were reported for G×S-associated single-nucleotide polymorphisms at ST8SIA1 and SOST, indicating a causal role of these genes in tobacco-related etiopathology. Notably, SOST is a negative regulator of bone growth, and ST8SIA1 has a role in tissue remodeling. Cigarette smoke extract significantly altered the expression of 2 associated genes: SSH1 (P = 5 × 10−07), which is required for NF-κB activation and innate immune responses to bacterial invasion, and ST8SIA1 (P = 0.0048). We conclude that the genetic predisposition to early-onset periodontitis is in part triggered by smoking and that tobacco smoke directly affects the expression of genes involved in bone homeostasis, tissue repair, and immune response.

Mapping of Papillon-Lefevre syndrome to the chromosome 11q14 region.

Papillon-Lefevre syndrome (PLS) is an autosomal recessive disease which belongs to the palmo-plantar keratoderma (PPK) group. It is characterized by a premature loss of primary and permanent teeth and early onset periodontitis. High consanguinity has been observed in over one-third of PLS families. No candidate genes or gene localizations have been described to date for this disorder. A primary genome-wide search by homozygosity mapping using samples from a large consanguineous family in which 4 siblings were affected by the disease showed homozygosity and linkage in the region of 11q14. Linkage was confirmed in 4 additional families with diverse ethnic and geographic backgrounds, 2 of which were consanguineous. A maximum two-point lod score of 8.19 was obtained for the marker AFM063yg1 (D11S901= for theta = 0. Analysis of recombination events places the gene within a 7-cM interval between AFM063yg1 and AFM269yg9 (D11S4175). No shared haplotype was found for the 5 families analysed.

Autophagic dysfunction in patients with Papillon-Lefèvre syndrome is restored by recombinant cathepsin C treatment

Cathepsin C (CatC) is a lysosomal enzyme involved in activation of serine proteases from immune and inflammatory cells. Several loss-of-function mutations in the CatC gene have been shown to be the genetic mark of Papillon-Lefèvre syndrome (PLS), a rare autosomal recessive disease characterized by severe early-onset periodontitis, palmoplantar hyperkeratosis, and increased susceptibility to infections. Deficiencies or dysfunction in other cathepsin family proteins, such as cathepsin B or D, have been associated with autophagic and lysosomal disorders. Here we characterized the basis for autophagic dysfunction in patients with PLS by analyzing skin fibroblasts derived from patients with several mutations in the CatC gene and reduced enzymatic activity. Skin fibroblasts were isolated from patients with PLS assessed by using genetic analysis. Authophagic flux dysfunction was evaluated by examining accumulation of p62/SQSTM1 and a bafilomycin assay. Ultrastructural analysis further confirmed abnormal accumulation of autophagic vesicles in mutant cells. Arecombinant CatC protein was produced by a baculovirus system in insect cell cultures. Mutant fibroblasts from patients with PLS showed alterations in oxidative/antioxidative status, reduced oxygen consumption, and a marked autophagic dysfunction associated with autophagosome accumulation. These alterations were accompanied by lysosomal permeabilization, cathepsin Brelease, and NLR family pyrin domain containing 3 (NLRP3) inflammasome activation. Treatment of mutant fibroblasts with recombinant CatC improved cell growth and autophagic flux and partially restored lysosomal permeabilization. Our data provide a novel molecular mechanism underlying PLS. Impaired autophagy caused by insufficient lysosomal function might represent a new therapeutic target for PLS.

Reduced salivary flow rate and high levels of oxidative stress in whole saliva of children with Down syndrome.

To investigate salivary parameters between children with Down Syndrome (DS) and without DS. Stimulated whole saliva was collected from 18 children with DS and 23 without DS. Salivary flow rate, pH, and salivary buffering capacity were determined. Cariogenic microorganisms were quantified by culture, and periodontopathogens by quantitative real-time polymerase chain reaction. The antioxidant profile was quantified spectrophotometrically, while malondialdehyde (MDA) was quantified by high-performance liquid chromatography. Data were analyzed by Mann-Whitney test and Spearman correlation (α = 0.05). Salivary flow rate was significantly lower in DS than in controls (p < 0.0001). Significant higher difference was observed for total protein dosage (p < 0.0001), superoxide dismutase activity (SOD) (p = 0.0002), and MDA (p < 0.001) in DS group. Reduced salivary flow rate might be an important factor in oral diseases development.High salivary levels of SOD and MDA show the significant influence of the oxidative stress and the early-onset periodontal disease in DS people.

Further evidence for specific IFIH1 mutation as a cause of Singleton-Merten syndrome with phenotypic heterogeneity.

Singleton-Merten syndrome (MIM 182250) is an autosomal dominant inherited disorder characterized by early onset periodontitis, root resorption, osteopenia, osteoporosis, and aortic valve or thoracic aorta calcification. The disorder can have significant intrafamilial phenotypic variability. Here, we present a mother and daughter with Singleton-Merten syndrome harboring a previously described pathogenic missense mutation, c.2465G>A p.(Arg822Gln), in IFIH1 (interferon induced with helicase C domain 1), encoding MDA5 (Melanoma Differentiation-Associated protein 5). These data confirm the pathogenicity of IFIH1 c.2465G>A p.(Arg822Gln) for Singleton-Merten syndrome and affirm the striking phenotypic heterogeneity of this disorder. In addition, we expand the Singleton-Merten phenotype by adding severe systemic lupus erythematosus (SLE) to the clinical picture. Investigations of known SLE genes as well as a single nucleotide polymorphism suggested to be involved in development of SLE were normal.

Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement

Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis.

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.

Maresin 1 Biosynthesis and Proresolving Anti-infective Functions with Human-Localized Aggressive Periodontitis Leukocytes.

Localized aggressive periodontitis (LAP) is a distinct form of early-onset periodontitis linked to periodontal infection with uncontrolled inflammation and leukocyte-mediated tissue destruction. The resolution of inflammation is an active process orchestrated by specialized proresolving lipid mediators (SPMs). Since the level of the Maresin pathway marker 14-hydroxy-docosahexaenoic acid (14-HDHA) was lower in activated peripheral blood from LAP patients, we investigated the Maresin 1 (MaR1) biosynthetic pathway in these subjects and its role in regulating phagocyte functions. Macrophages from LAP patients had a lower level of expression of 12-lipoxygenase (∼30%) and reduced MaR1 (LAP versus healthy controls [HC], 87.8 ± 50 pg/10(6) cells versus 239.1 ± 32 pg/10(6) cells). Phagocytosis by LAP macrophages was reduced ∼40% compared to that of HC, and killing of periodontal pathogens, including Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, were similarly reduced. LAP neutrophils also displayed slower kinetics (∼30%) and decreased maximal phagocytosis (∼20% lower) with these pathogens than those of HC. The administration of MaR1 at 1 nM enhanced phagocytosis (31 to 65% increase), intracellular antimicrobial reactive oxygen species production (26 to 71% increase), bacterial killing of these periodontal pathogens (22 to 38% reduction of bacterial titers), and restored impairment of LAP phagocytes. Together, these results suggest that therapeutics targeting the Maresin pathway have clinical utility in treating LAP and other oral diseases associated with infection, inflammation, and altered phagocyte functions.

A novel large deletion combined with a nonsense mutation in a Chinese child with Papillon-Lefèvre syndrome

Papillon-Lefèvre Syndrome (PLS) is a rare autosomal recessive hereditary disease (MIM245000). The syndrome is characterized by palmoplantar keratoderma and early onset periodontitis, caused by CTSC gene mutation. The mutation in CTSC previously reported is mainly point mutations. Large deletion in the CTSC gene has not yet been reported. We collected 5 mL peripheral blood from a patient with PLS and her family members and used the direct sequencing method to perform CTSC bidirectional sequencing. We also used FISH to analyze the approximate locations of the ends of the missing fragment and then determined the fragment sequence through direct sequencing. The result demonstrated that the patient have a 110 kb deletion (Chr11: 88032292: 88142997(NC_000011)) combined with a nonsense mutation (Gln182Ter) in this gene. Our study reveals a compound mutation consisting of a large deletion and a nonsense mutation, which provides a new insight in the mutation type of CTSC gene.

American Academy of Periodontology Task Force Report on the Update to the 1999 Classification of Periodontal Diseases and Conditions.

American Academy of Periodontology Task Force Report on the Update to the 1999 Classification of Periodontal Diseases and Conditions.

Proxy molecular diagnosis from whole-exome sequencing reveals Papillon-Lefevre syndrome caused by a missense mutation in CTSC.

Papillon-Lefevre syndrome (PLS) is an autosomal recessive disorder characterised by severe early onset periodontitis and palmoplantar hyperkeratosis. A previously reported missense mutation in the CTSC gene (NM_001814.4:c.899G>A:p.(G300D)) was identified in a homozygous state in two siblings diagnosed with PLS in a consanguineous family of Arabic ancestry. The variant was initially identified in a heterozygous state in a PLS unaffected sibling whose whole exome had been sequenced as part of a previous Primary ciliary dyskinesia study. Using this information, a proxy molecular diagnosis was made on the PLS affected siblings after consent was given to study this second disorder found to be segregating within the family. The prevalence of the mutation was then assayed in the local population using a representative sample of 256 unrelated individuals. The variant was absent in all subjects indicating that the variant is rare in Saudi Arabia. This family study illustrates how whole-exome sequencing can generate findings and inferences beyond its primary goal.

A Specific IFIH1 Gain-of-Function Mutation Causes Singleton-Merten Syndrome

Singleton-Merten syndrome (SMS) is an infrequently described autosomal-dominant disorder characterized by early and extreme aortic and valvular calcification, dental anomalies (early-onset periodontitis and root resorption), osteopenia, and acro-osteolysis. To determine the molecular etiology of this disease, we performed whole-exome sequencing and targeted Sanger sequencing. We identified a common missense mutation, c.2465G>A (p.Arg822Gln), in interferon induced with helicase C domain 1 (IFIH1, encoding melanoma differentiation-associated protein 5 [MDA5]) in four SMS subjects from two families and a simplex case. IFIH1 has been linked to a number of autoimmune disorders, including Aicardi-Goutières syndrome. Immunohistochemistry demonstrated the localization of MDA5 in all affected target tissues. Invitro functional analysis revealed that the IFIH1 c.2465G>A mutation enhanced MDA5 function in interferon beta induction. Interferon signature genes were upregulated in SMS individuals' blood and dental cells. Our data identify a gain-of-function IFIH1 mutation as causing SMS and leading to early arterial calcification and dental inflammation and resorption.

English

Papillon-Lefevre syndrome (PLS) is a very rare syndrome of autosomal recessive inheritance characterized by progressive palmar-plantar keratoderma and early onset periodontitis, leading to premature loss of both primary and permanent dentitions and recurrent pyogenic infections. Patient Presented with a chief complaint of thickening of palms and soles extending on to knees and elbows.. On intraoral examination there is loss of both temporary and permanent teeth. Patient had recurrent pyogenic infections involving face and nose leading to nasal destruction. Histopathological examination of the specimen taken from the thickened skin was reported to be consistent with PLS1,2,3

Singleton-Merten Syndrome: a rare autoimmune disorder caused by a specific IFIH1 mutation

s of the 51st Workshop for Pediatric Research 51st Workshop for Pediatric Research Gottingen, Germany 16-17 April 2015 This supplement has not been sponsored. Meeting abstracts Meeting abstract Singleton-Merten Syndrome (SMS) is a rare autosomal-dominant disorder characterized by a variety of symptoms including extreme calcifications of the ascending aorta and cardiac valves, dental anomalies (early onset periodontitis, root resorption), psoriasis and widened medullary cavities of the phalanges with focal osteoporosis. Employing whole exome sequencing of five SMS individuals of three families we identified the missense mutation, c.2465G>A (p.Arg822Gln) in the interferon induced with helicase C domain 1 (IFIH1) gene. Additional Sanger sequencing confirmed co-segregation of the mutation with the disorder. IFIH1, encoding melanoma differentiation-associated protein 5 (MDA5), is a member of the RIG-I-like receptor family and functions as a cytoplasmic pattern recognition receptor recognizing viral double stranded RNA (dsRNA). Immunohistochemistry demonstrated the localization of MDA5 in all affected target tissues including heart, skin and cartilage. Functional analysis revealed that the IFIH1 c.2465G>A mutation enhanced MDA5 function in interferon beta induction after polyinosinic:polycytidylic acid (poly (I:C)) stimulation in vitro. This indicates that SMS-MDA5 is hyperactive to non-self dsRNA. According to additional in vitro studies, interferon signature genes including SIGLEC1 were upregulated in blood and dental cells derived from SMS individuals. Taken together, our data demonstrate that the MDA5 gain-of-function mutation p.Arg822Gln causes the autosomal dominant disorder SMS through dysregulation of the human innate immune response.

Papillon-Lefèvre syndrome: Clinical presentation and literature review

Background: Papillon-Lefevre syndrome (PLS) is a rare autosomal recessive genodermatosis characterized by a diffused palmoplantar hyperkeratosis and severe early-onset periodontitis. Although the exact pathogenesis of this syndrome is still unknown, however, it has been linked to mutations in the cathepsin C gene. Case report: This paper is a clinical presentation of a 12-year-old male with severe periodontitis and characteristic palmoplantar hyperkeratosis diagnosed as PLS. Conclusion: An early diagnosis of the syndrome can help preserve the teeth by the early institution of treatment, using a multidisciplinary approach. Thereby, sparing the patients increase the risk of social, psychological, and economical stigma. Owing to the vast degree of periodontal breakdown involved at such an early age. Incidentally, the dentist is might often be the first to encounter such patients.

PO-0653 The Periodontal Pathogens In The Saliva Of One-year-old Infants Delivered With Very Low Birth Weight

Aim The aim of this study is to identify the presence of main periodontal pathogens in the oral cavity of 12-month-old infants and compared the occurrence of these microbes between a cohort of very low birth weight infants and a control cohort. Methods The research cohort was composed of 69 one-year-old infants, 24 of whom were born prematurely with very low birth weight and 45 of whom were born at term. At 12 months of age, both groups of infants were examined, and unstimulated saliva samples from the dorsum of the tongue and dental plaque samples were collected. The periodontal pathogens Aggregatibacter actinomycetemcomitans , Porphyromonas gingivalis , Tannerella Forsythensis , Treponema denticola , Peptostreptococcus micros , Prevotella intermedia and Fusobacterium nucleatum were identified using a PCR-based method. Chi-square and Fisher´s factorial tests were used for the statistical evaluation. Results Periodontal pathogens were present in 83% of the pre-term infants and 96% of full-term infants. Aggregatibacter actinomycetemcomitans was the most common periodontal pathogen found in the oral cavities of the infants enrolled in our study. No statistically significant differences between the pre-term infants and the full-term infants were found regarding the presence of periodontal pathogens. Conclusions The study confirmed the early transmission of periodontal pathogens to the oral cavity of one-year-old infants. Future research should focus on establishing the clinical importance of periodontal pathogens in the saliva of infants and their role in the aetiology of early onset periodontal disease. The study was supported by grant IGA of Ministry of Health Czech Republic, NT 14336–3.

CR0291 Chédiak-Higashi syndrome: an atypical phenotype case

Chédiak-Higashi syndrome (CHS) is an autosomal recessive disorder usually caused by a mutation in the gene LYST (lysosomal trafficking regulator) resulting in systemic neutrophil abnormalities and characterized by cutaneous, ocular, neurologic, and hematologic abnormalities. CHS usually manifests early in life in the form of partial oculocutaneous albinism (OCA), frequent infections (mostly skin and upper respiratory tract), and lymphadenopathy. Reported oral findings include ulcerations and early-onset periodontitis occurring in childhood.