Dental management of a pediatric patient with Kohlschutter-Tonz syndrome: A case report.

INTRODUCTION: Kohlschutter-Tonz syndrome (KTS) is a rare, genetic condition, which typically manifests as a triad of symptoms: 1) amelogenesis imperfecta, 2) infantile onset epilepsy, and 3) intellectual disability. The condition poses dental treatment challenges given the manifestation of amelogenesis imperfecta. Additional considerations are needed to medically manage these patients who present with epilepsy and intellectual disability. CASE REPORT: Our patient presented with multiple restorative needs, was treated under general anesthesia, and maintained good oral outcomes with close follow-up. DISCUSSION: To the best of our knowledge, this is the first case report which documents comprehensive dental management of a pediatric patient with KTS.

Multiple Idiopathic Cervical Root Resorption: A Challenge for a Transdisciplinary Medical-Dental Team.

The goal of this perspective article is to use multiple idiopathic cervical root resorption (MICRR) as a model to demonstrate the need for transdisciplinary collaborations, from basic science to treatment planning, to improve the quality of health care for all. This is not a review of the literature on the current state of MICRR. Tooth root resorption is a normal physiological process required for resorption and exfoliation of primary teeth; however, root resorption of adult teeth is largely pathological. MICRR is an aggressive form of external root resorption, which occurs near the cemento-enamel junction (CEJ). The cause of MICRR remains elusive, however, it is mediated primarily by osteoclasts/odontoclasts. Accumulating case studies and experiments in animal models have provided insights into defining the etiologies and pathophysiological mechanisms for MICRR, which include: systemic conditions and syndromes, inherited genetic variants affecting osteoclast/odontoclast activity, altered periodontal structures, drug-induced root resorption and rebound effects after cessation of anti-resorptive treatment, chemotherapy, exposure to pets or viral infections, and other factors such as inflammatory conditions or trauma. To determine the causative factors for MICRR, as well as other oral-dental conditions, at minimum, a comprehensive health history should be collected for all patients by dental care providers, discussed with other health care providers and appropriate collaborations established. The examples highlighted in this perspective emphasize the need for transdisciplinary research collaborations coupled with integrated management strategies between medicine and dentistry in order to identify cause(s) early and improve clinical outcomes.

Radiographic Diagnosis in the Pediatric Dental Patient.

This article emphasizes the selection criteria for radiographic acquisition in children due to the greater sensitivity of children for radiation compared with adults. Diagnosis of common pediatric dental conditions, including dental caries, periodontitis, dental anomalies, cysts, tumors, and traumatic dental conditions, are discussed with relevant clinical scenarios.

Spatial mapping of polymicrobial communities reveals a precise biogeography associated with human dental caries.

Tooth decay (dental caries) is a widespread human disease caused by microbial biofilms. Streptococcus mutans, a biofilm-former, has been consistently associated with severe childhood caries; however, how this bacterium is spatially organized with other microorganisms in the oral cavity to promote disease remains unknown. Using intact biofilms formed on teeth of toddlers affected by caries, we discovered a unique 3D rotund-shaped architecture composed of multiple species precisely arranged in a corona-like structure with an inner core of S. mutans encompassed by outer layers of other bacteria. This architecture creates localized regions of acidic pH and acute enamel demineralization (caries) in a mixed-species biofilm model on human teeth, suggesting this highly ordered community as the causative agent. Notably, the construction of this architecture was found to be an active process initiated by production of an extracellular scaffold by S. mutans that assembles the corona cell arrangement, encapsulating the pathogen core. In addition, this spatial patterning creates a protective barrier against antimicrobials while increasing bacterial acid fitness associated with the disease-causing state. Our data reveal a precise biogeography in a polymicrobial community associated with human caries that can modulate the pathogen positioning and virulence potential in situ, indicating that micron-scale spatial structure of the microbiome may mediate the function and outcome of host-pathogen interactions.

Macrodontia Associated with Mandibular Distraction Osteogenesis.

Infants diagnosed with Pierre Robin sequence frequently have airway obstruction. In severe cases of obstruction, mandibular distraction osteogenesis (MDO) can alleviate the airway blockage through elongation of the mandible and subsequent anterior placement of the tongue. However, there are several complications associated with MDO in the very young child. Among those are injuries to teeth that develop in the area of the MDO osteotomies. Such injuries include distalization and/or morphologic anomalies of primary and permanent molars. We describe a case of an unusual macrodontia of the primary mandibular left second molar in a six-year-old male who underwent MDO as an infant. We believe that the mesial-distal elongation of the crown of the primary second molar occurred through distraction histogenesis of the tooth structures during the distraction of the mandible. We discuss the importance of preoperative planning to minimize such damages to the developing dentition.

Multiple External Root Resorption in a Pediatric Patient with Familial Expansile Osteolysis.

External root resorption (ERR) of permanent teeth is a pathological process that can lead to their loss. There are several systemic and/or genetic abnormalities that have been associated with ERR. Among them, familial expansile osteolysis (FEO) is an autosomal dominant disease characterized by skeletal defects, middle ear deafness, and abnormal root resorption. The purpose of this paper was to describe the case of a 10-year-old female with familial expansile osteolysis born with missing ossicles and, therefore, deafness. The patient was not diagnosed with FEO until the age of 10 years, when she presented to the dental clinic with advanced ERR in several permanent teeth. The series of tests she underwent for diagnosis and the treatments rendered are presented and discussed. It is recommended that when ERR cannot be explained by local etiologic factors, systemic abnormalities and genetic testing should be considered.

Severe Gingivitis Associated with Ascorbic Acid-Deficiency in a Pediatric Patient.

Plaque-induced gingivitis, a common condition in children, responds well to proper oral hygiene practices. Persistent severe gingivitis, on the other hand, should prompt investigation of etiological factors. Nutritional elements are implicated in periodontal health. This case report describes a pediatric patient with severe persistent gingivitis caused by vitamin C deficiency. The events that led to a diagnosis of scurvy and a resolution of the systemic and localized manifestations of the disease, after vitamin C administration, are presented. It is recommended that vitamin C deficiency be considered in cases of refractory gingivitis, especially in pediatric patients with special health care needs who have aversion to foods rich in ascorbic acid.

Complement-Dependent Mechanisms and Interventions in Periodontal Disease.

Periodontitis is a prevalent inflammatory disease that leads to the destruction of the tooth-supporting tissues. Current therapies are not effective for all patients and this oral disease continues to be a significant public health and economic burden. Central to periodontal disease pathogenesis is a reciprocally reinforced interplay between microbial dysbiosis and destructive inflammation, suggesting the potential relevance of host-modulation therapies. This review summarizes and discusses clinical observations and pre-clinical intervention studies that collectively suggest that complement is hyperactivated in periodontitis and that its inhibition provides a therapeutic benefit. Specifically, interception of the complement cascade at its central component, C3, using a locally administered small peptidic compound (Cp40/AMY-101) protected non-human primates from induced or naturally occurring periodontitis. These studies indicate that C3-targeted intervention merits investigation as an adjunctive treatment of periodontal disease in humans.

Retrospective Analysis of Candida-related Conditions in Infancy and Early Childhood Caries.

PURPOSE: The purpose of this study was to assess whether there is an association between oral thrush or other Candida-related conditions in infancy and early childhood caries (ECC) diagnosed by pediatricians. METHODS: We conducted a retrospective cohort study using electronic health records from six national children's hospitals that participate in the PEDSnet research network. There were 1,012,668 children with a visit at ages one to 12 months and another visit at ages 13 to 71 months. The independent variables were diagnosis of thrush or Candida-related conditions in the first year of life, while the dependent variable was diagnosis of ECC between 13 to 71 months old. RESULTS: Oral thrush detection was strongly associated with ECC, particularly between 13 and 36 months (rate ratio between 2.7 [95 percent confidence interval (95% CI) equals 2.5 to 2.9; P<.001] and 3.0 [95% CI, equals 2.8 to 3.4; P<.001]). A similar trend was observed with other Candida-related conditions. CONCLUSIONS: Oral thrush may be a risk factor for early childhood caries.

Candida albicans and Early Childhood Caries: A Systematic Review and Meta-Analysis.

Oral Candida albicans has been detected in children with early childhood caries (ECC) and has demonstrated cariogenic traits in animal models of the disease. Conversely, other studies found no positive correlation between C. albicans and caries experience in children, while suggesting it may have protective effects as a commensal organism. Thus, this study aimed to examine whether oral C. albicans is associated with ECC. Seven electronic databases were searched. The data from eligible studies were extracted, and the risk of bias was evaluated. A fixed effects model (Mantel-Haenszel estimate) was used for meta-analysis, and the summary effect measure was calculated by odds ratio (OR) and 95% confidence interval (CI). Fifteen cross-sectional studies were included for the qualitative assessment and 9 studies for meta-analysis. Twelve studies revealed higher oral C. albicans prevalence in ECC children than in caries-free children, while 2 studies indicated an equivalent prevalence. A pooled estimate, with OR = 6.51 and 95% CI = 4.94-8.57, indicated a significantly higher ECC experience in children with oral C. albicans than those without C. albicans (p < 0.01). The odds of experiencing ECC in children with C. albicans versus children without C. albicans were 5.26 for salivary, 6.69 for plaque, and 6.3 for oral swab samples. This systematic review indicates that children with oral C. albicans have >5 times higher odds of having ECC compared to those without C. albicans. Further prospective cohort studies are needed to determine whether C. albicans could be a risk factor for ECC, and whether it is dependent on different sample sources (saliva/plaque).

Safety and Efficacy of the Complement Inhibitor AMY-101 in a Natural Model of Periodontitis in Non-human Primates.

Periodontitis is a chronic inflammatory disease associated with overactivation of the complement system. Recent preclinical studies suggest that host-modulation therapies may contribute to effective treatment of human periodontitis, which may lead to loss of teeth and function if untreated. We previously showed that locally administered AMY-101 (Cp40), a peptidic inhibitor of the central complement component C3, can inhibit naturally occurring periodontitis in non-human primates (NHPs) when given once a week. This study was undertaken to determine the local safety of increasing doses of the drug as well as its efficacy when given at a reduced frequency or after systemic administration. Our findings have determined a local dose of AMY-101 (0.1 mg/site) that is free of local irritation and effective when given once every 3 weeks. Moreover, a daily subcutaneous dose of AMY-101 (4 mg/kg bodyweight) was protective against NHP periodontitis, suggesting that patients treated for systemic disorders (e.g., paroxysmal nocturnal hemoglobinuria) can additionally benefit in terms of improved periodontal condition. In summary, AMY-101 appears to be a promising candidate drug for the adjunctive treatment of human periodontitis, a notion that merits investigation in human clinical trials.

Milk fat globule epidermal growth factor 8 inhibits periodontitis in non-human primates and its gingival crevicular fluid levels can differentiate periodontal health from disease in humans.

AIM: We have previously shown that the secreted glycoprotein milk fat globule epidermal growth factor 8 (MFG-E8) has anti-inflammatory and anti-osteoclastogenic properties. Our objective was to investigate the potential of MFG-E8 as a diagnostic or therapeutic agent in periodontitis. MATERIALS AND METHODS: Periodontitis was induced in non-human primates (NHPs) by placing ligatures around posterior teeth on both halves of the mandible for a split-mouth design: one side was treated with MFG-E8-Fc and the other with Fc control. Disease was assessed by clinical periodontal examinations, radiographic analysis of bone loss, and analysis of cytokine mRNA expression in gingival biopsy samples. Gingival crevicular fluid (GCF) was collected from human healthy volunteers or subjects with gingivitis, chronic moderate periodontitis, or chronic severe periodontitis. Additionally, GCF was collected from a subset of severe periodontitis patients following scaling and root planing (SRP) and after pocket reduction surgery. GCF was analysed to quantify MFG-E8 and periodontitis-relevant cytokines using multiplex assays. RESULTS: In NHPs, sites treated with MFG-E8-Fc exhibited significantly less ligature-induced periodontal inflammation and bone loss than Fc control-treated sites. In humans, the GCF levels of MFG-E8 were significantly higher in health than in periodontitis, whereas the reverse was true for the proinflammatory cytokines tested. Consistently, MFG-E8 was elevated in GCF after both non-surgical (SRP) and surgical periodontal treatment of periodontitis patients. CONCLUSION: MFG-E8 is, in principle, a novel therapeutic agent and biomarker of periodontitis.

Oral literacy demand in the pediatric dental clinic: a pilot study.

BACKGROUND: The parent's ability to obtain, process, and understand important oral health information (i.e., their oral health literacy) is directly related to their child's oral health status. AIM: To assess the relationship between oral literacy demands placed on parents by dentists and parents' understanding of dental information given to them. DESIGN: Thirty-one consenting primary caregivers of children attending their first dental visit completed a demographic survey, a REALD-30 test, and a survey to test understanding of dental information. Dental appointments, performed by eight pediatric dental residents, were audio-recorded and transcribed for qualitative analysis and descriptive statistics. RESULTS: Factors associated with language complexity were significantly higher in dental residents (R) than participants (P), that is, total number of words spoken (R: 1615.09 + 859.91 vs P: 480.68 + 232.034) and words per sentence (R: 8.82 + 1.74 vs P: 4.91 + 1.71). Speaking turns did not differ between resident and parent (R: 94.64 vs P: 83.27). CONCLUSIONS: Although the dialogue between the participating dentists and parents was highly unequal, parents understood about 86% of the information provided by the resident. Future studies are needed to identify factors associated with gaps in the educational process of parents in the dental setting.

Complement inhibition in pre-clinical models of periodontitis and prospects for clinical application.

Periodontitis is a dysbiotic inflammatory disease leading to the destruction of the tooth-supporting tissues. Current therapies are not always effective and this prevalent oral disease continues to be a significant health and economic burden. Early clinical studies have associated periodontitis with elevated complement activity. Consistently, subsequent genetic and pharmacological studies in rodents have implicated the central complement component C3 and downstream signaling pathways in periodontal host-microbe interactions that promote dysbiosis and inflammatory bone loss. This review discusses these mechanistic advances and moreover focuses on the compstatin family of C3 inhibitors as a novel approach to treat periodontitis. In this regard, local application of the current lead analog Cp40 was recently shown to block both inducible and naturally occurring periodontitis in non-human primates. These promising results from non-human primate studies and the parallel development of Cp40 for clinical use highlight the feasibility for developing an adjunctive, C3-targeted therapy for human periodontitis.

Immune and regulatory functions of neutrophils in inflammatory bone loss.

Although historically viewed as merely anti-microbial effectors in acute infection or injury, neutrophils are now appreciated to be functionally versatile with critical roles also in chronic inflammation. Periodontitis, a chronic inflammatory disease that destroys the tooth-supporting gums and bone, is particularly affected by alterations in neutrophil numbers or function, as revealed by observations in monogenic disorders and relevant mouse models. Besides being a significant debilitating disease and health burden in its own right, periodontitis is thus an attractive model to dissect uncharted neutrophil-associated (patho)physiological pathways. Here, we summarize recent evidence that neutrophils can contribute to inflammatory bone loss not only through the typical bystander injury dogma but intriguingly also through their absence from the affected tissue, where they normally perform important immunomodulatory functions. Moreover, we discuss recent advances in the interactions of neutrophils with the vascular endothelium and - upon extravasation - with bacteria, and how the dysregulation of these interactions leads to inflammatory tissue damage. Overall, neutrophils have both protective and destructive roles in periodontitis, as they are involved in both the maintenance of periodontal tissue homeostasis and the induction of inflammatory bone loss. This highlights the importance of developing approaches that promote or sustain a fine balance between homeostatic immunity and inflammatory pathology.

Inhibition of pre-existing natural periodontitis in non-human primates by a locally administered peptide inhibitor of complement C3.

AIM: Human periodontitis is associated with overactivation of complement, which is triggered by different mechanisms converging on C3, the central hub of the system. We assessed whether the C3 inhibitor Cp40 inhibits naturally occurring periodontitis in non-human primates (NHPs). MATERIALS AND METHODS: Non-human primates with chronic periodontitis were intra-gingivally injected with Cp40 either once (5 animals) or three times (10 animals) weekly for 6 weeks followed by a 6-week follow-up period. Clinical periodontal examinations and collection of gingival crevicular fluid and biopsies of gingiva and bone were performed at baseline and during the study. A one-way repeated-measures anova was used for data analysis. RESULTS: Whether administered once or three times weekly, Cp40 caused a significant reduction in clinical indices that measure periodontal inflammation (gingival index and bleeding on probing), tissue destruction (probing pocket depth and clinical attachment level) or tooth mobility. These clinical changes were associated with significantly reduced levels of pro-inflammatory mediators and decreased numbers of osteoclasts in bone biopsies. The protective effects of Cp40 persisted, albeit at reduced efficacy, for at least 6 weeks following drug discontinuation. CONCLUSION: Cp40 inhibits pre-existing chronic periodontal inflammation and osteoclastogenesis in NHPs, suggesting a novel adjunctive anti-inflammatory therapy for treating human periodontitis.

Autoimmune Neutropenia as a Cause of Periodontal Disease in Preschool Children.

In autoimmune neutropenia, autoantibodies attack neutrophils resulting in their destruction or alteration of their function. Since neutrophils have important immunologic functions, aberrations in their homeostasis lead to increased susceptibility to diseases, such as periodontitis. Periodontitis as a manifestation of neutropenia can affect adults and children. In this paper, we describe the treatment of periodontal disease in a 2-year-old female with autoimmune neutropenia. The importance of an interdisciplinary approach, frequent recalls, and meticulous mechanical therapy in stabilizing her periodontal condition, despite ongoing systemic infections is emphasized.

DEL-1 restrains osteoclastogenesis and inhibits inflammatory bone loss in nonhuman primates.

DEL-1 (developmental endothelial locus-1) is an endothelial cell-secreted protein that regulates LFA-1 (lymphocyte function-associated antigen-1) integrin-dependent leukocyte recruitment and inflammation in various tissues. We identified a novel regulatory mechanism of DEL-1 in osteoclast biology. Specifically, we showed that DEL-1 is expressed by human and mouse osteoclasts and regulates their differentiation and resorptive function. Mechanistically, DEL-1 inhibited the expression of NFATc1, a master regulator of osteoclastogenesis, in a Mac-1 integrin-dependent manner. In vivo mechanistic analysis has dissociated the anti-inflammatory from the anti-bone-resorptive action of DEL-1 and identified structural components thereof mediating these distinct functions. Locally administered human DEL-1 blocked inflammatory periodontal bone loss in nonhuman primates-a relevant model of human periodontitis. The ability of DEL-1 to regulate both upstream (inflammatory cell recruitment) and downstream (osteoclastogenesis) events that lead to inflammatory bone loss paves the way to a new class of endogenous therapeutics for treating periodontitis and perhaps other inflammatory disorders.

Complement Involvement in Periodontitis: Molecular Mechanisms and Rational Therapeutic Approaches.

The complement system is a network of interacting fluid-phase and cell surface-associated molecules that trigger, amplify, and regulate immune and inflammatory signaling pathways. Dysregulation of this finely balanced network can destabilize host-microbe homeostasis and cause inflammatory tissue damage. Evidence from clinical and animal model-based studies suggests that complement is implicated in the pathogenesis of periodontitis, a polymicrobial community-induced chronic inflammatory disease that destroys the tooth-supporting tissues. This review discusses molecular mechanisms of complement involvement in the dysbiotic transformation of the periodontal microbiome and the resulting destructive inflammation, culminating in loss of periodontal bone support. These mechanistic studies have additionally identified potential therapeutic targets. In this regard, interventional studies in preclinical models have provided proof-of-concept for using complement inhibitors for the treatment of human periodontitis.

Neutrophil homeostasis and inflammation: novel paradigms from studying periodontitis.

Once viewed as simply antibacterial effector cells packed with antimicrobials, neutrophils are now increasingly appreciated for their regulatory roles in immunity and inflammation. The homeostatic regulation of neutrophils is thus crucial for optimal operation of the immune system. An attractive model to understand mechanistically the role of neutrophils is periodontitis, an oral inflammatory disease that is particularly sensitive to neutrophil alterations in numbers or function. The recruitment and proper activation of neutrophils are largely dependent on leukocyte integrins and complement. This review discusses how these processes are affected by host genetic or microbial factors leading to the development of periodontitis. For instance, both hypo- and hyper-recruitment of neutrophils as a result of deficiencies in the expression of ß2 integrins or their negative regulators, respectively, causes unwarranted IL-17-dependent inflammatory bone loss. Moreover, microbial hijacking of C5aR (CD88) signaling in neutrophils impairs their antimicrobial function while promoting destructive inflammatory responses. These studies not only support the concept that neutrophil homeostasis is key to periodontal health but also reveal promising, new therapeutic targets as discussed in the review.