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OBJECTIVES: Root resorption in permanent teeth is a common pathological process that often follows dental trauma or orthodontic treatment. More rarely, root resorption is a feature of genetic disorders and can help with diagnosis. Thus, the present review aims to determine which genetic disorders could induce pathological root resorptions and thus which mutated genes could be associated with them. METHODS: We conducted a systematic review following the PRISMA guidelines. Articles describing root resorptions in patients with genetic disorders were included from PubMed, Embase, Web of Science, and Google Scholar. We synthesized the genetic disorder, the type, severity, and extent of the resorptions, as well as the other systemic and oral symptoms and histological features. RESULTS: The synthetic analysis included 25 studies among 937 identified records. We analyzed 21 case reports, three case series, and one cohort study. Overall, we highlighted 14 different pathologies with described root resorptions. Depending on the pathology, the sites of resorption, their extent, and their severity showed differences. CONCLUSION: With 14 genetic pathologies suspected to induce root resorptions, our findings are significant and enrich a previous classification. Among them, three metabolic disorders, three calcium-phosphorus metabolism disorders, and osteolysis disorders were identified.
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OBJECTIVES: The COHQoL is a set of questionnaires used to evaluate the impact of oral health on children's quality of life. Although the CPQ8-10 and the P-CPQ have been translated and validated in French, the CPQ11-14 14 has not yet been validated. The aim was to develop a French version of the CPQ11-14 16-items. MATERIALS AND METHODS: The French version of CPQ11-14 was obtained by a forward-backward translation process and pretested. The final version was tested on children aged 11-14 and divided into three groups: children with orofacial clefts, children with rare dental diseases other than clefts, and children without anomalies. We conducted a cross-sectional study and evaluated the reliability with test-retest and internal consistency, and the questionnaire validity with construct validity and discriminant validity. We performed an Exploratory Factory Analysis (EFA). RESULTS: 187 children tested the questionnaire. The ICC of the test-retest was 0.76 and the Cronbach's alpha was 0.77. The correlation between the CPQ11-14 and self-assessment of oral health and general well-being was > 0.2. Patients with orofacial clefts and rare diseases had significantly higher scores for overall short-form CPQ11-14. The EFA revealed six factors. CONCLUSION: The French CPQ11-14 is valid to assess the impact of oral health on children's quality of life. CLINICAL RELEVANCE: The translation of this questionnaire into French will enable us to assess the impact of oral health on the quality of life of adolescents. This questionnaire complements the 8-10 years version of the CPQ, as well as the parental version that can be used in conjunction with the questionnaire.
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Salud Bucal , Calidad de Vida , Humanos , Niño , Encuestas y Cuestionarios , Femenino , Adolescente , Masculino , Estudios Transversales , Reproducibilidad de los Resultados , Francia , Traducciones , Fisura del Paladar/psicología , Labio Leporino/psicologíaRESUMEN
AIM: Oligodontia (OD) is a rare developmental condition characterized by the absence of six or more teeth. Dental implant placement may be challenging due to anatomical factors. This study aims to evaluate the alveolar bone dimensions in OD patients compared with controls. MATERIALS AND METHODS: On maxillary and mandibular cone-beam computed tomography (CBCT), bone height and width were measured at every tooth and edentulous site. The distance to the inferior alveolar nerve was also measured. Fifty-three OD patients (40 maxillary and 32 mandibular CBCT) and 82 controls (51 maxillary and 31 mandibular CBCT) were compared using mixed models. RESULTS: Compared with those in OD patients, maxillary permanent teeth and edentulous sites showed significantly higher mean height in control patients (incisive-canine site height: +2.12 mm; edentulous incisive-canine site height: +4.46 mm [p > .001]). For the mandibular permanent teeth, mean height was higher in controls than in OD patients at the incisive-canine (+3.82 mm [p > .001]) and premolar areas (+2.06 mm [p > .001]). Only edentulous incisive-canine sites were significantly different between controls and OD patients (mean: +0.52 mm [p > .001]). Changes in alveolar nerve position were observed in case of molar agenesis. CONCLUSION: Maxillary and mandibular bone dimensions are reduced in OD patients compared with controls both in sites with permanent teeth and in edentulous areas.
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Boca Edéntula , Tomografía Computarizada de Haz Cónico Espiral , Humanos , Estudios Retrospectivos , Mandíbula/diagnóstico por imagen , Tomografía Computarizada de Haz Cónico/métodos , Maxilar/diagnóstico por imagenRESUMEN
STATEMENT OF PROBLEM: Cleft lip and palate are the most frequent congenital anomalies of the face and are often linked with lateral incisor agenesis. The therapeutic decision on whether and how to replace the lateral incisors is not straightforward, and a decision-making tree is needed. PURPOSE: The purpose of this systematic review was to evaluate the available literature reporting on treatments for the replacement of missing lateral incisors in cleft areas. By analyzing the success and survival rates of these treatments, a decision-making tree was developed. MATERIAL AND METHODS: The literature search was performed on the PubMed (MEDLINE), Web of Science, Cochrane, EMBASE, Dentistry of Oral and Science Source, and Google Scholar databases and was based on the question: Which treatment for patients with lateral incisor agenesis and cleft lip and palate has a good success rate? RESULTS: Twenty-six articles were included in this systematic review. A meta-analysis was performed on 14 articles (20 case series, 6 case controls). The estimated overall 5-year survival rates were 96.4% for implant-supported prostheses. CONCLUSIONS: Different treatment options are available, depending on the clinical situation. If the patient meets the conditions for implant placement, this treatment remains a preferred solution. If the prosthetic space is reduced, orthodontic space closure and composite resin restorations are possible. When these options are not possible, a resin-bonded fixed partial denture is the preferred option. If the teeth adjacent to the edentulous area require extensive restorations, a fixed partial denture may be a suitable alternative.
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Dental anomalies occur frequently in a number of genetic disorders and act as major signs in diagnosing these disorders. We present definitions of the most common dental signs and propose a classification usable as a diagnostic tool by dentists, clinical geneticists, and other health care providers. The definitions are part of the series Elements of Morphology and have been established after careful discussions within an international group of experienced dentists and geneticists. The classification system was elaborated in the French collaborative network "TÊTECOU" and the affiliated O-Rares reference/competence centers. The classification includes isolated and syndromic disorders with oral and dental anomalies, to which causative genes and main extraoral signs and symptoms are added. A systematic literature analysis yielded 408 entities of which a causal gene has been identified in 79%. We classified dental disorders in eight groups: dental agenesis, supernumerary teeth, dental size and/or shape, enamel, dentin, dental eruption, periodontal and gingival, and tumor-like anomalies. We aim the classification to act as a shared reference for clinical and epidemiological studies. We welcome critical evaluations of the definitions and classification and will regularly update the classification for newly recognized conditions.
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Terminología como Asunto , Anomalías Dentarias/clasificación , Anomalías Dentarias/genética , Diente/patología , Puntos Anatómicos de Referencia , Predisposición Genética a la Enfermedad , Humanos , Cooperación Internacional , Mucosa Bucal/patología , Radiografía Panorámica , Diente/diagnóstico por imagen , Anomalías Dentarias/diagnóstico por imagen , Diente Supernumerario/diagnóstico por imagenRESUMEN
BACKGROUND: The Child Perceptions Questionnaire (CPQ) belongs to a set of questionnaires measuring Child Oral Health Quality of Life (COHQOL). The CPQ is used to collect the perceptions of children on the impact of oral diseases on their quality of life. This cross-sectional study was aimed to translate the CPQ8-10 into French language and evaluate its psychometric properties. METHODS: The translation process complied with international recommendations. The final French version was tested on children aged 8-10 years old attending consultations in a Parisian public hospital and divided into three groups: children with oral-facial clefts, children with dental anomalies linked to a rare disease other than clefts and children presumed to be healthy and without anomalies. The internal consistency relating to the reliability of CPQ8-10 was evaluated by Cronbach's alpha. The intra-class correlation was used to measure reproducibility at the test-retest level. Construct validity was evaluated by Spearman's correlation and tested using factor analysis. The discriminant validity was assessed using Kruskall Wallis test. Criterion validity was calculated using Spearman's correlation. RESULTS: One hundred seventy-six children participated in this study. During the translation process, minor changes were made. The French version showed good reliability with a Cronbach's alpha of 0.81 for the total scale. The ICC of the test-retest was excellent (=0.90) demonstrating good reproducibility. The construct validity was acceptable with a statistically significant correlation between the scores of the French-CPQ8-10 and the evaluation of oral health (r = 0. 381 and p < 0.001) and its impact on oral health quality of life (r = 0.363 and p < 0.001). The loading weights obtained in the Exploratory Factor Analysis showed that this model revealed seven factors with eigenvalue greater than 1, explaining the 63,89% of the cumulative variance. The differences observed between the scores of the study groups revealed good discriminant validity. Criterion validity was supported by significant association between CPQ scores and pain. CONCLUSION: The French-CPQ8-10 is reliable and valid for use with the children of this age group.
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Salud Bucal , Calidad de Vida , Encuestas y Cuestionarios/normas , Niño , Fisura del Paladar , Comparación Transcultural , Estudios Transversales , Femenino , Francia , Humanos , Lenguaje , Masculino , Percepción , Psicometría , Reproducibilidad de los Resultados , Anomalías Dentarias , TraduccionesRESUMEN
BACKGROUND: Amelogenesis imperfecta (AI) is a group of genetic diseases characterised by tooth enamel defects. AI was recently described in patients with familial hypercalciuria and hypomagnesaemia with nephrocalcinosis (FHHNC) caused by CLDN16 mutations. In the kidney, claudin-16 interacts with claudin-19 to control the paracellular passage of calcium and magnesium. FHHNC can be linked to mutations in both genes. Claudin-16 was shown to be expressed during amelogenesis; however, no data are available on claudin-19. Moreover, the enamel phenotype of patients with CLDN19 mutations has never been described. In this study, we describe the clinical and genetic features of nine patients with FHHNC carrying CLDN19 mutations and the claudin-19 expression profile in rat ameloblasts. METHODS: Six FHHNC Brazilian patients were subjected to mutational analysis. Three additional French patients were recruited for orodental characterisation. The expression profile of claudin-19 was evaluated by RT-qPCR and immunofluorescence using enamel epithelium from rat incisors. RESULTS: All patients presented AI at different degrees of severity. Two new likely pathogenic variations in CLDN19 were found: p.Arg200Gln and p.Leu90Arg. RT-qPCR revealed low Cldn19 expression in ameloblasts. Confocal analysis indicated that claudin-19 was immunolocalised at the distal poles of secretory and maturing ameloblasts. CONCLUSIONS: For the first time, it was demonstrated that AI is associated with FHHNC in patients carrying CLDN19 mutations. The data suggest claudin-19 as an additional determinant in enamel formation. Indeed, the coexistence of hypoplastic and hypomineralised AI in the patients was consistent with claudin-19 expression in both secretory and maturation stages. Additional indirect systemic effects cannot be excluded.
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BACKGROUND: Hereditary enamel defect diseases are regrouped under the name "Amelogenesis Imperfecta" (AIH). Both dentitions are affected. Clinical expression is heterogeneous and varies between patients. Mutations responsible for this multigene disease may alter various genes and the inheritance can be either autosomal dominant or recessive, or X-linked. Until now, no therapeutic consensus has emerged for this rare disease. CASE PRESENTATION: The purpose of this article was to report treatments of AIH patients from childhood to early adulthood. Treatment of three patients of 3, 8 16 years old are described. Each therapeutic option was discussed according to patients' age and type of enamel alteration. Paediatric crowns and resin based bonding must be preferred in primary teeth. In permanent teeth, non-invasive or minimally invasive dentistry should be the first choice in order to follow a therapeutic gradient from the less invasive options to prosthodontic treatments. CONCLUSION: Functional and aesthetic issues require patients to be treated; this clinical care should be provided as early as possible to enable a harmonious growth of the maxillofacial complex and to prevent pain.
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Amelogénesis Imperfecta/terapia , Diente Primario/anomalías , Adolescente , Niño , Preescolar , Coronas , Recubrimiento Dental Adhesivo , Restauración Dental Permanente , Dentición Permanente , Femenino , Humanos , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Ortodoncia CorrectivaRESUMEN
BACKGROUND: The Parental-Caregivers Perceptions Questionnaire (P-CPQ) is a measure of parental/caregivers' perceptions of the impact of children's oral health on quality of life. The aim of the study was evaluate the psychometric properties of the French version of the P-CPQ. METHOD: The original P-CPQ was developed in English language and has 31 items divided into four sub-scales. This cross-sectional study used the translation-back translation method. The translated questionnaire was pretested on 14 parents-caregivers to obtain the final French version. The psychometric properties were tested on 142 parents/caregivers of three clinical groups of children from 8 to 10 years old without dental/facial anomalies (presumed healthy), with oral-facial clefts and with oral-dental anomalies linked to a rare disease other than cleft, approached in the waiting room of the Centre of the Hospital Rothschild in Paris, France, where the children attended treatment. Internal consistency was assessed by Cronbach's alpha and test-retest reliability by Intra-class Correlation Coefficient (ICC). Construct validity was measured by correlations between the total scores and the global ratings of oral health and overall wellbeing, and tested using exploratory factor analysis (EFA) and the factorial structure was evaluated by the partial confirmatory factor analysis (PCFA). Discriminant validity was determined using Kruskall-Wallis test. RESULTS: The mean (standard deviation) P-CPQ score was 18.73(18.79). Internal consistency was confirmed by a Cronbach alpha of 0.85. The test-retest reliability revealed that the responses to items were satisfactorily stable (ICC = 0.88). Construct validity was demonstrated by significant correlation coefficients between the total scale and the global ratings (r = 0.54 and 0.46; p < 0.001). Factor analysis with Principal Component Analysis extracted seven factors explaining 65.23% cumulative variance. Goodness-of-fit indices for partial confirmatory factor analysis were satisfactory for the 7-factors model of the French-PCPQ version. There were statistically significant differences between clinical groups regarding the total scale, thus demonstrating discriminant validity (p < 0.001). CONCLUSION: This French P-CPQ version showed reliability and validity comparable to the previous versions. However, the cross-cultural structure of the subscales should be further evaluated.
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Salud Bucal/estadística & datos numéricos , Padres , Calidad de Vida/psicología , Niño , Femenino , Francia/epidemiología , Humanos , Masculino , Anomalías de la Boca/epidemiología , Anomalías de la Boca/psicología , Padres/psicología , Psicometría , Reproducibilidad de los Resultados , Encuestas y Cuestionarios , TraducciónRESUMEN
BACKGROUND: Orodental diseases include several clinically and genetically heterogeneous disorders that can present in isolation or as part of a genetic syndrome. Due to the vast number of genes implicated in these disorders, establishing a molecular diagnosis can be challenging. We aimed to develop a targeted next-generation sequencing (NGS) assay to diagnose mutations and potentially identify novel genes mutated in this group of disorders. METHODS: We designed an NGS gene panel that targets 585 known and candidate genes in orodental disease. We screened a cohort of 101 unrelated patients without a molecular diagnosis referred to the Reference Centre for Oro-Dental Manifestations of Rare Diseases, Strasbourg, France, for a variety of orodental disorders including isolated and syndromic amelogenesis imperfecta (AI), isolated and syndromic selective tooth agenesis (STHAG), isolated and syndromic dentinogenesis imperfecta, isolated dentin dysplasia, otodental dysplasia and primary failure of tooth eruption. RESULTS: We discovered 21 novel pathogenic variants and identified the causative mutation in 39 unrelated patients in known genes (overall diagnostic rate: 39%). Among the largest subcohorts of patients with isolated AI (50 unrelated patients) and isolated STHAG (21 unrelated patients), we had a definitive diagnosis in 14 (27%) and 15 cases (71%), respectively. Surprisingly, COL17A1 mutations accounted for the majority of autosomal-dominant AI cases. CONCLUSIONS: We have developed a novel targeted NGS assay for the efficient molecular diagnosis of a wide variety of orodental diseases. Furthermore, our panel will contribute to better understanding the contribution of these genes to orodental disease. TRIAL REGISTRATION NUMBERS: NCT01746121 and NCT02397824.
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Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mutación , Anomalías Dentarias/genética , Amelogénesis Imperfecta/genética , Autoantígenos/genética , Deleción Cromosómica , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 11/genética , Estudios de Cohortes , Coloboma/genética , Displasia de la Dentina/genética , Francia , Pérdida Auditiva Sensorineural/genética , Humanos , Colágenos no Fibrilares/genética , Reproducibilidad de los Resultados , Colágeno Tipo XVIIRESUMEN
Enamel is a unique tissue in vertebrates, acellular, formed on a labile scaffolding matrix and hypermineralized. The ameloblasts are epithelial cells in charge of amelogenesis. They secrete a number of matrix proteins degraded by enzymes during enamel mineralization. This ordered cellular and extracellular events imply that any genetic or environmental perturbation will produce indelible and recognizable defects. The specificity of defects will indicate the affected cellular process. Thus, depending on the specificity of alterations, the teratogenic event can be retrospectively established. Advances in the field allow to use enamel defects as diagnostic tools for molecular disorders. The multifunctionality of enamel peptides is presently identified from their chemical roles in mineralization to cell signaling, constituting a source of concrete innovations in regenerative medicine.
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Esmalte Dental/fisiología , Ameloblastos/citología , Ameloblastos/metabolismo , Amelogénesis/fisiología , Animales , Esmalte Dental/química , Esmalte Dental/efectos de los fármacos , Esmalte Dental/ultraestructura , Hipoplasia del Esmalte Dental/genética , Hipoplasia del Esmalte Dental/fisiopatología , Proteínas del Esmalte Dental/fisiología , Durapatita/química , Órgano del Esmalte/fisiología , Fluorosis Dental/etiología , Humanos , Técnicas de Diagnóstico Molecular , Nanosferas , Péptido Hidrolasas/fisiología , Teratógenos/farmacología , Calcificación de Dientes/fisiologíaRESUMEN
Endocrine-disrupting chemicals (EDCs), including bisphenol A (BPA), are environmental ubiquitous pollutants and associated with a growing health concern. Anecdotally, molar incisor hypomineralization (MIH) is increasing concurrently with EDC-related conditions, which has led us to investigate the effect of BPA on amelogenesis. Rats were exposed daily to BPA from conception until day 30 or 100. At day 30, BPA-affected enamel exhibited hypomineralization similar to human MIH. Scanning electron microscopy and elemental analysis revealed an abnormal accumulation of organic material in erupted enamel. BPA-affected enamel had an abnormal accumulation of exogenous albumin in the maturation stage. Quantitative real-time PCR, Western blotting, and luciferase reporter assays revealed increased expression of enamelin but decreased expression of kallikrein 4 (protease essential for removing enamel proteins) via transcriptional regulation. Data suggest that BPA exerts its effects on amelogenesis by disrupting normal protein removal from the enamel matrix. Interestingly, in 100-day-old rats, erupting incisor enamel was normal, suggesting amelogenesis is only sensitive to MIH-causing agents during a specific time window during development (as reported for human MIH). The present work documents the first experimental model that replicates MIH and presents BPA as a potential causative agent of MIH. Because human enamel defects are irreversible, MIH may provide an easily accessible marker for reporting early EDC exposure in humans.
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Compuestos de Bencidrilo/toxicidad , Hipoplasia del Esmalte Dental/inducido químicamente , Disruptores Endocrinos/toxicidad , Fenoles/toxicidad , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Amelogénesis/efectos de los fármacos , Animales , Biomarcadores/metabolismo , Western Blotting , Hipoplasia del Esmalte Dental/metabolismo , Proteínas del Esmalte Dental/metabolismo , Femenino , Humanos , Calicreínas/metabolismo , Masculino , Microscopía Electrónica de Rastreo , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Distribución Aleatoria , Ratas , Ratas Wistar , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Ameloblastin (AMBN), a member of the enamel matrix protein family, has been recently identified as integral part of the skeleton beyond the enamel. However, the specific role of endogenous AMBN in bone tissue is not fully elucidated. This study aims at investigating mRNA expression of AMBN in wild-type mice in different bone sites from early embryonic to adult stages. AMBN mRNA expression started at pre-dental stages in mouse embryos (E10.5) in both head and body parts. Using laser capture microdissection on 3-day-old mice, we showed an unambiguous mRNA expression of AMBN in extra-dental tissue (mandible bone). Screening of AMBN mRNA expression in adult mice (15-week-old) revealed that mRNA expression of AMBN varied according to the bone site; a higher mRNA levels in mandibular and frontal bone compartments were observed when compared to tibia and occipital bones. These results strongly suggest that AMBN expression may be regulated in a site-specific manner and identify AMBN as a putative in vivo marker of the site-specific fingerprint of bone organs.
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Huesos/metabolismo , Proliferación Celular/fisiología , Proteínas del Esmalte Dental/metabolismo , Osteogénesis/fisiología , Animales , Animales Recién Nacidos , Biomarcadores/análisis , Huesos/citología , Células Cultivadas , Regulación del Desarrollo de la Expresión Génica/fisiología , RatonesRESUMEN
Tooth formation results from specific epithelial-mesenchymal interactions, which summarize a number of developmental processes. Tooth anomalies may thus reflect subclinical diseases of the kidney, bone and more broadly of the mineral metabolism, skin or nervous system. Odontogenesis starts from the 3rd week of intrauterine life by the odontogenic orientation of epithelial cells by a first PITX2 signal. The second phase is the acquisition of the number, shape, and position of teeth. It depends on multiple transcription and growth factors (BMP, FGF, SHH, WNT). These ecto-mesenchymal interactions guide cell migration, proliferation, apoptosis and differentiation ending in the formation of the specific dental mineralized tissues. Thus, any alteration will have consequences on the tooth structure or shape. Resulting manifestations will have to be considered in the patient phenotype and the multidisciplinary care, but also may contribute to identify the altered genetic circuity.
Title: La dent : un marqueur d'anomalies génétiques du développement. Abstract: L'odontogenèse résulte d'évènements reflétant de multiples processus impliqués dans le développement : crêtes neurales, interactions épithélio-mésenchymateuses, minéralisation. Les anomalies dentaires sont donc d'excellents marqueurs de l'impact de mutations de gènes qui affectent différents systèmes biologiques, tels que le métabolisme minéral, l'os, le rein, la peau ou le système nerveux. Dans cette revue, nous présentons de façon synthétique les gènes impliqués dans plusieurs maladies rares au travers de défauts des dents caractéristiques, de nombre, de forme et de structure.
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Transducción de Señal , Diente , Humanos , Epitelio , Diente/metabolismo , Odontogénesis/genética , Diferenciación Celular/genética , Regulación del Desarrollo de la Expresión GénicaRESUMEN
OBJECTIVE: This study aims to (1) assess the efficacy of a face-to-face emergency protocol in children and adults and (2) measure the efficacies of prediagnosis at the triage level and clinical diagnosis at the emergency department level during the COVID-19 pandemic. METHODS: A triage protocol was applied for patients at the entry of the Rothschild Hospital (AP-HP) between March 18th and May 11th, 2020. First, patients underwent a triage based on self-reported symptoms. If their condition was deemed urgent, they were oriented toward dental professionals, who performed an intraoral examination leading to a clinical diagnosis. Triage and diagnoses were categorized into four emergency groups: infectious, prosthetic, traumatic, and others. The agreement between triage and clinical diagnosis was tested (χ2 test). Positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity for each diagnostic category were assessed to evaluate the performance and efficacy of the triage. RESULTS: Out of 1562 dental visits, 1064 were included in this analysis. The most frequently reported symptoms by children at triage were pain (31.5%) and trauma (22%). Adults mainly complained of abscesses (45.1%) and pulpitis (20.5%). The most frequent clinical diagnoses were abscesses (29.2%) and pulpitis (20.5%) among children and adults, respectively. Tooth extraction was the most frequent treatment modality. Systemic antibiotics were prescribed for 49.2% of patients. Regardless of the age class, the PPV was high for groups 1 to 3, ranging from 78.9% to 100%. The NPV was high in all groups, ranging from 68.8% to 99.1%. CONCLUSION: This study demonstrates that the triage implanted during the first COVID-19 lockdown was effective and is an appropriate tool for the referral of adults and children before clinical examination.
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COVID-19 , Pulpitis , Adulto , Niño , Humanos , COVID-19/epidemiología , Triaje/métodos , Pandemias , Absceso , Control de Enfermedades Transmisibles , Servicio de Urgencia en Hospital , HospitalesRESUMEN
Amelogenesis imperfecta (AI) is a group of rare genetic conditions characterized by quantitative and/or qualitative tooth enamel alterations. AI can manifest as an isolated trait or as part of a syndrome. Recently, five biallelic disease-causing variants in the RELT gene were identified in 7 families with autosomal recessive amelogenesis imperfecta (ARAI). RELT encodes an orphan receptor in the tumor necrosis factor (TNFR) superfamily expressed during tooth development, with unknown function. Here, we report one Brazilian and two French families with ARAI and a distinctive hypomineralized phenotype with hypoplastic enamel, post-eruptive enamel loss, and occlusal attrition. Using Next Generation Sequencing (NGS), four novel RELT variants were identified (c.120+1G>A, p.(?); c.120+1G>T, p.(?); c.193T>C, p.(Cys65Arg) and c.1260_1263dup, p.(Arg422Glyfs*5)). Our findings extend the knowledge of ARAI dental phenotypes and expand the disease-causing variants spectrum of the RELT gene.
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Amelogénesis Imperfecta , Humanos , Amelogénesis Imperfecta/genética , Amelogénesis Imperfecta/patología , Receptores del Factor de Necrosis Tumoral/genética , Fenotipo , Brasil , LinajeRESUMEN
Amelogenesis imperfecta (AI) is a heterogeneous group of genetic rare diseases disrupting enamel development (Smith et al., Front Physiol, 2017a, 8, 333). The clinical enamel phenotypes can be described as hypoplastic, hypomineralized or hypomature and serve as a basis, together with the mode of inheritance, to Witkop's classification (Witkop, J Oral Pathol, 1988, 17, 547-553). AI can be described in isolation or associated with others symptoms in syndromes. Its occurrence was estimated to range from 1/700 to 1/14,000. More than 70 genes have currently been identified as causative. Objectives: We analyzed using next-generation sequencing (NGS) a heterogeneous cohort of AI patients in order to determine the molecular etiology of AI and to improve diagnosis and disease management. Methods: Individuals presenting with so called "isolated" or syndromic AI were enrolled and examined at the Reference Centre for Rare Oral and Dental Diseases (O-Rares) using D4/phenodent protocol (www.phenodent.org). Families gave written informed consents for both phenotyping and molecular analysis and diagnosis using a dedicated NGS panel named GenoDENT. This panel explores currently simultaneously 567 genes. The study is registered under NCT01746121 and NCT02397824 (https://clinicaltrials.gov/). Results: GenoDENT obtained a 60% diagnostic rate. We reported genetics results for 221 persons divided between 115 AI index cases and their 106 associated relatives from a total of 111 families. From this index cohort, 73% were diagnosed with non-syndromic amelogenesis imperfecta and 27% with syndromic amelogenesis imperfecta. Each individual was classified according to the AI phenotype. Type I hypoplastic AI represented 61 individuals (53%), Type II hypomature AI affected 31 individuals (27%), Type III hypomineralized AI was diagnosed in 18 individuals (16%) and Type IV hypoplastic-hypomature AI with taurodontism concerned 5 individuals (4%). We validated the genetic diagnosis, with class 4 (likely pathogenic) or class 5 (pathogenic) variants, for 81% of the cohort, and identified candidate variants (variant of uncertain significance or VUS) for 19% of index cases. Among the 151 sequenced variants, 47 are newly reported and classified as class 4 or 5. The most frequently discovered genotypes were associated with MMP20 and FAM83H for isolated AI. FAM20A and LTBP3 genes were the most frequent genes identified for syndromic AI. Patients negative to the panel were resolved with exome sequencing elucidating for example the gene involved ie ACP4 or digenic inheritance. Conclusion: NGS GenoDENT panel is a validated and cost-efficient technique offering new perspectives to understand underlying molecular mechanisms of AI. Discovering variants in genes involved in syndromic AI (CNNM4, WDR72, FAM20A ) transformed patient overall care. Unravelling the genetic basis of AI sheds light on Witkop's AI classification.
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BACKGROUND/AIMS: Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood. METHODS: We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption). To identify the causative gene, we performed genome-wide linkage analysis, exome capture, next-generation sequencing, and Sanger sequencing. RESULTS: All patients had bi-allelic FAM20A mutations segregating with the disease; 20 different mutations were identified. CONCLUSIONS: This autosomal recessive disorder, also known as enamel renal syndrome, of FAM20A causes nephrocalcinosis and amelogenesis imperfecta. We speculate that all individuals with biallelic FAM20A mutations will eventually show nephrocalcinosis.
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Amelogénesis Imperfecta/genética , Proteínas del Esmalte Dental/genética , Predisposición Genética a la Enfermedad/genética , Mutación , Nefrocalcinosis/genética , Adolescente , Adulto , Amelogénesis Imperfecta/complicaciones , Amelogénesis Imperfecta/patología , Niño , Consanguinidad , Exoma/genética , Salud de la Familia , Femenino , Genes Recesivos/genética , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Nefrocalcinosis/complicaciones , Nefrocalcinosis/patología , Linaje , Análisis de Secuencia de ADN/métodos , Síndrome , Adulto JovenRESUMEN
Oral mucosal lesions are common in the pediatric population and, apart from traumatic and tumoral etiologies, they can be symptoms of viral, bacterial, fungal or parasitic diseases. Yet, pediatricians and pediatric dentists find it challenging to reach a diagnosis and provide appropriate care when facing lesions of the masticatory or lining mucosa, of the hard or soft palate, of the tongue or salivary glands. Here, we propose a decision tree for the diagnosis of the most frequent viral, bacterial, and fungal diseases starting from their oral lesions in children. By first focusing on describing the elementary lesion itself before its localization and characteristics, it aims to guide the practitioner toward the diagnosis and any necessary complementary exams. To generate this tool, we conducted a literature review of the childhood viral, bacterial, fungal and parasitic diseases with oral mucosal symptoms. For each of the 42 reported diagnoses-20 viral, 9 bacterial, 5 fungal, and 8 parasitic-we collected the infection mechanism and agent(s), the oral lesions and their description, the associated systemic signs and the incidence/prevalence. In fine, our decision tree indexes the 28 diseases for which epidemiological data was available, mainly in Europe and the United States.
RESUMEN
Background: Singleton-Merten syndrome type 1 (SGMRT1) is a rare autosomal dominant disorder caused by IFIH1 variations with blood vessel calcifications, teeth anomalies, and bone defects. Aim: We aimed to summarize the oral findings in SGMRT1 through a systematic review of the literature and to describe the phenotype of a 10-year-old patient with SGMRT1 diagnosis. Results: A total of 20 patients were described in the literature, in nine articles. Eight IFIH1 mutations were described in 11 families. Delayed eruption, short roots, and premature loss of permanent teeth were the most described features (100%). Impacted teeth (89%) and carious lesions (67%) were also described. Our patient, a 10-year-old male with Singleton-Merten syndrome, presented numerous carious lesions, severe teeth malposition, especially in the anterior arch, and an oral hygiene deficiency with a 100% plaque index. The panoramic X-ray did not show any dental agenesis but revealed very short roots and a decrease in the jaw alveolar bone height. The whole-genome sequencing analysis revealed a heterozygous de novo variant in IFIH1 (NM_022168.4) c.2465G > A (p.Arg822Gln). Conclusion: Confused descriptions of oral features occurred in the literature between congenital findings and "acquired" pathology, especially carious lesions. The dental phenotype of these patients encompasses eruption anomalies (delayed eruption and impacted teeth) and lack of root edification, leading to premature loss of permanent teeth, and it may contribute to the diagnosis. An early diagnosis is essential to prevent teeth loss and to improve the quality of life of these patients. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42022300025].