Structural Variant Disrupting the Expression of the Remote FOXC1 Gene in a Patient with Syndromic Complex Microphthalmia.

Ocular malformations (OMs) arise from early defects during embryonic eye development. Despite the identification of over 100 genes linked to this heterogeneous group of disorders, the genetic cause remains unknown for half of the individuals following Whole-Exome Sequencing. Diagnosis procedures are further hampered by the difficulty of studying samples from clinically relevant tissue, which is one of the main obstacles in OMs. Whole-Genome Sequencing (WGS) to screen for non-coding regions and structural variants may unveil new diagnoses for OM individuals. In this study, we report a patient exhibiting a syndromic OM with a de novo 3.15 Mb inversion in the 6p25 region identified by WGS. This balanced structural variant was located 100 kb away from the FOXC1 gene, previously associated with ocular defects in the literature. We hypothesized that the inversion disrupts the topologically associating domain of FOXC1 and impairs the expression of the gene. Using a new type of samples to study transcripts, we were able to show that the patient presented monoallelic expression of FOXC1 in conjunctival cells, consistent with the abolition of the expression of the inverted allele. This report underscores the importance of investigating structural variants, even in non-coding regions, in individuals affected by ocular malformations.

Association between malocclusions and amelogenesis imperfecta genotype and phenotype: A systematic review.

INTRODUCTION: The aim of this systematic review (Prospero CRD42022323188) is to investigate whether an association exists in patients with amelogenesis imperfecta (AI) between occlusal characteristics and genotype on the one hand and enamel structural phenotype on the other. MATERIAL AND METHODS: Reports up to May 2023 assessing occlusion of individuals with AI were browsed in a systematic search using Medline, Embase, ISI Web of Science, and the grey literature. Randomised control trials, case control studies, and case series specifying both occlusion, assessed by cephalometric or clinical analysis, and genotype or dental phenotype in patients with AI were included without any age limitation. Two authors independently selected the publications and extracted the data in accordance with the PRISMA statement. The risk of bias was assessed with the Critical Appraisal Checklists from the Johanna Briggs Institute. RESULTS: Twenty-five articles were chosen from the 261 results. Most of the included publications were case series (n=22) and case control studies (n=3). Thirteen studies reported both a genotype (ENAM, FAM83H, FAM20A, DLX3, CNMM4, WDR72) and occlusal diagnostic. The methodological quality of the studies was moderate. All AI phenotypes showed an open bite (OB) rate around 35%, except mixed form. The other malocclusions were not often mentioned. No correlation between occlusal phenotype and genotype or AI phenotype could be identified in patients with AI, as most studies had short occlusal descriptions and small sample sizes. CONCLUSION: OB malocclusions were more frequently reported in AI. This review highlighted the need for a more accurate description of orofacial features associated with AI, to better clarify the role of amelogenesis genes in the regulation of craniofacial morphogenesis and identify patients requiring orthognathic surgery at an early stage.

Oral health status in patients with inherited epidermolysis bullosa: a comparative multicenter study.

OBJECTIVE: Epidermolysis bullosa (EB) is a rare genetic mucocutaneous disorder characterized by epithelial fragility leading to blister formation on skin and mucous membranes with even minor mechanical trauma. Most EB oral health publications give fragmented information, focusing on only one oral health aspect or one EB type. The aim of this study was to expand the knowledge of the overall oral health status of individuals with dystrophic, junctional, and simplex EB. METHOD AND MATERIALS: A comparative multicenter study, including a control group, and based on questionnaires and clinical examinations, was undertaken in three EB expert centers. RESULTS: Most EB (90.2%) participants brushed their teeth at least once a day despite the pain. The prevalence of enamel defects and caries experience did not differ between the 42 EB participants and the 42 age-/sex-matched healthy controls. Gingival inflammation unrelated to dental plaque accumulation was found in EB participants. Blisters, erythema, and erosion/ulceration mainly involved gingiva, buccal mucosa, lips, and palate, with different topographic patterns according to EB type. EB patients whatever the age showed a similar lesion distribution. Simplex and dystrophic EB patients under 12 years old displayed higher lesion severity than junctional EB ones. Only dystrophic type exhibited microstomia and ankyloglossia. CONCLUSION: Oral health status seemed to benefit from a close collaboration between dental practitioner and dermatologist, and from regular dental examination, starting at a young age and with a focus on prevention. The new appreciation of oral health involvement highlighted by this study is essential for EB patients care, regarding comorbidities and quality of life.

FOSL2 truncating variants in the last exon cause a neurodevelopmental disorder with scalp and enamel defects.

PURPOSE: We aimed to investigate the molecular basis of a novel recognizable neurodevelopmental syndrome with scalp and enamel anomalies caused by truncating variants in the last exon of the gene FOSL2, encoding a subunit of the AP-1 complex. METHODS: Exome sequencing was used to identify genetic variants in all cases, recruited through Matchmaker exchange. Gene expression in blood was analyzed using reverse transcription polymerase chain reaction. In vitro coimmunoprecipitation and proteasome inhibition assays in transfected HEK293 cells were performed to explore protein and AP-1 complex stability. RESULTS: We identified 11 individuals from 10 families with mostly de novo truncating FOSL2 variants sharing a strikingly similar phenotype characterized by prenatal growth retardation, localized cutis scalp aplasia with or without skull defects, neurodevelopmental delay with autism spectrum disorder, enamel hypoplasia, and congenital cataracts. Mutant FOSL2 messenger RNAs escaped nonsense-mediated messenger RNA decay. Truncated FOSL2 interacts with c-JUN, thus mutated AP-1 complexes could be formed. CONCLUSION: Truncating variants in the last exon of FOSL2 associate a distinct clinical phenotype by altering the regulatory degradation of the AP-1 complex. These findings reveal a new role for FOSL2 in human pathology.

From Child to Adulthood, a Multidisciplinary Approach of Multiple Microdontia Associated with Hypodontia: Case Report Relating a 15 Year-Long Management and Follow-Up.

Oral rehabilitation of patients presenting multiple microdontia is a real therapeutic challenge. These alterations in size, often associated with other dental anomalies, have aesthetic and functional repercussions for patients and can lead to significant psycho-social consequences. We report here the case of an 11-year-old patient with bilateral sectorial microdontia and agenesis of teeth numbers 13 and 23. She also presented staturo-ponderal delay and a history of acute coronary syndrome with a lower coronary occlusion of unknown aetiology. At first, additive coronoplasties and an orthodontically retained interim prosthesis answered the aesthetic and functional need during childhood and adolescence. Once she reached adulthood, a multidisciplinary meeting was conducted and a treatment plan was established. The decision was made to rehabilitate the upper arch with a permanent bridge and the lower arch with indirect adhesive restorations. This solution solved the problem of the bilateral lateral infraocclusions and tooth agenesis, restoring both aesthetics and function. This paper presents 15 years of management and treatment of a patient presenting multiple microdontia associated with hypodontia. Both the multidisciplinary approach and coordination between the different medical team members was essential to maintain the existing dentition while preparing, planning, and carrying out a personalized treatment plan once maxillofacial growth was complete.

Dentine disorders and adhesive treatments: A systematic review.

OBJECTIVES: A better understanding of the microstructure and mechanical properties of enamel and dentine may enable practitioners to apply the current adhesive dentistry protocols to clinical cases involving dentine disorders (dentinogenesis imperfecta or dentine dysplasia). DATA/SOURCES: Publications (up to June 2020) investigating the microstructure of dentine disorders were browsed in a systematic search using the PubMed/Medline, Embase and Cochrane Library electronic databases. Two authors independently selected the studies, extracted the data in accordance with the PRISMA statement, and assessed the risk of bias with the Critical Appraisal Checklist. A Mann-Whitney U test was computed to compare tissues damage related to the two dentine disorders of interest. STUDY SELECTION: From an initial total of 642 studies, only 37 (n = 164 teeth) were included in the present analysis, among which 18 investigating enamel (n = 70 teeth), 15 the dentine-enamel junction (n = 62 teeth), and 35 dentine (n = 156 teeth). Dentine is damaged in cases of dentinogenesis imperfecta and osteogenesis imperfecta (p = 2.55E-21 and p = 3.99E-21, respectively). These studies highlight a reduction in mineral density, hardness, modulus of elasticity and abnormal microstructure in dentine disorders. The majority of studies report an altered dentine-enamel junction in dentinogenesis imperfecta and in osteogenesis imperfecta (p = 6.26E-09 and p = 0.001, respectively). Interestingly, enamel is also affected in cases of dentinogenesis imperfecta (p = 0.0013), unlike to osteogenesis imperfecta (p = 0.056). CONCLUSIONS: Taking into account all these observations, only a few clinical principles may be favoured in the case of adhesive cementation: (i) to preserve the residual enamel to enhance bonding, (ii) to sandblast the tooth surfaces to increase roughness, (iii) to choose a universal adhesive and reinforce enamel and dentine by means of infiltrant resins. As these recommendations are mostly based on in vitro studies, future in vivo studies should be conducted to confirm these hypotheses.

Morbidity and Mortality Review in a University Dental Hospital: A Necessary Tool to Improve Quality of Care.

OBJECTIVE: The study aimed to describe and to analyze the first morbidity and mortality review (MMRs) set up within a Dental University Hospital using detailed case reports to highlight the benefits of MMRs for patients, practitioners, teachers and to implement appropriate protocols to prevent recurrence. MATERIALS AND METHODS: The MMRs were performed within the dentistry departments of the hospital over the 1-year study period. Each case was reviewed according to a protocol based on a tool defined by the Clinical Risk Unit and the Association of Litigation and Risk Management (ALARM). RESULTS: Four cases were selected based on an oral report by a doctor from the dental service, a downstream service, or by the attending physician. The first case report related to a patient who suffered a breathing shock. The second concerned a tooth inhalation by a young disabled boy. The third was a therapeutic failure instigated by a student during a tooth preparation, and the fourth case involved an unexpected face-to-face meeting between a prisoner accompanied by police guards and an ancient victim at the dental hospital. DISCUSSION: Clinical incidents were investigated with the ALARM protocol. This process is also less focused on the individual who makes the error and more on contributing systemic factors. The systematic analysis of cases associated with bibliographic reviews improves learning and performance outcomes. Clear answers were given in response to the problems raised during these MMRs. CONCLUSION: In dental hospitals, the culture of MMRs needs to be integrated into resident training like in medical hospitals.

Gingival Biopsy to Detect Mosaicism in Overgrowth Syndromes: Report of Two Cases of Megalencephaly-Capillary Malformation Syndrome with Periodontal Anomalies.

BACKGROUND: Megalencephaly-capillary malformation (MCAP) is a rare overgrowth syndrome caused by postzygotic activating mutations in the PIK3CA gene. AIM: To illustrate the benefits of gingival biopsy in the genetic diagnosis of overgrowth syndromes. DESIGN: Gingival biopsy was performed on a 13-year-old patient and a 16-year-old patient with MCAP and who suffered from periodontal disease. PIK3CA sequencing was performed on DNA extracted from gingival biopsies, blood, and saliva. RESULTS: Pathogenic p.Glu365Lys and p.Glu545Asp PIK3CA mutations were found in the gingival biopsies with an allelic frequency of 22% and 35%, respectively, while they were undetectable in blood or saliva. The genetic diagnosis of MCAP through detection of PIK3CA somatic mosaicism in a periodontal biopsy is unprecedented. CONCLUSIONS: Considering the tissue distribution and level of somatic mosaicism for PIK3CA mutation, the composite embryologic origin of periodontium and its high fibroblast cell content make it an ideal target for molecular analysis in overgrowth syndromes, and multidisciplinary approach including paediatric dentists should be encouraged. In addition, our clinical findings suggest that periodontal disease is part of the MCAP phenotypic spectrum and should be systematically investigated.

Orofacial manifestations of SAPHO syndrome: a systematic review of case reports.

SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome is a poorly known disease with cutaneous and osteo-articular manifestations requiring a multidisciplinary care. The aim of this study was to review the case reports that have described oral manifestations in patients suffering for this syndrome. A systematic review of case reports was performed on PubMed and Science Direct on January 2020 among all the articles dealing with the disease. In vitro, preclinical, and clinical studies have not been included to select only the case reports. Eighteen articles, published between 1999 and 2019, were included. All the patients presented mandibular osteomyelitis or sclerosis, associated with various other symptoms such as trismus, temporomandibular joint arthritis, or dysphagia. The data highlight the high variability in the disease's manifestations between people and also in the treatments applied. Knowing the orofacial signs of the SAPHO syndrome, the dental surgeon has a crucial role in the diagnosis procedure and must take place in the multidisciplinary medical team involved in the patient following. Some care adaptations are needed for oral interventions in these patients, depending on their treatments and their handicap. Key Points • Orofacial manifestations of SAPHO syndrome mainly occur on the mandible. • In cases of mandible sclerosis, decorticalization surgeries may be performed. • Oral care are encouraged, especially the preventive treatments to limit the necessity of surgeries. • The complexity in the management of patients suffering for a SAPHO syndrome concerns the oral manifestations, the patient general health and the treatments he has to take every day.

LEF1 haploinsufficiency causes ectodermal dysplasia.

Ectodermal dysplasias are a family of genodermatoses commonly associated with variants in the ectodysplasin/NF-κB or the Wnt/ß-catenin pathways. Both pathways are involved in signal transduction from ectoderm to mesenchyme during the development of ectoderm-derived structures. Wnt/ß-catenin pathway requires the lymphoid enhancer-binding factor 1 (LEF1), a nuclear mediator, to activate target gene expression. In mice, targeted inactivation of the LEF1 gene results in a complete block of development of multiple ectodermal appendages. We report two unrelated patients with 4q25 de novo deletion encompassing LEF1, associated with severe oligodontia of primary and permanent dentition, hypotrichosis and hypohidrosis compatible with hypohidrotic ectodermal dysplasia. Taurodontism and a particular alveolar bone defect were also observed in both patients. So far, no pathogenic variants or variations involving the LEF1 gene have been reported in human. We provide further evidence for LEF1 haploinsufficiency role in ectodermal dysplasia and delineate its clinical phenotype.

Evolutionary Analysis Predicts Sensitive Positions of MMP20 and Validates Newly- and Previously-Identified MMP20 Mutations Causing Amelogenesis Imperfecta.

Amelogenesis imperfecta (AI) designates a group of genetic diseases characterized by a large range of enamel disorders causing important social and health problems. These defects can result from mutations in enamel matrix proteins or protease encoding genes. A range of mutations in the enamel cleavage enzyme matrix metalloproteinase-20 gene (MMP20) produce enamel defects of varying severity. To address how various alterations produce a range of AI phenotypes, we performed a targeted analysis to find MMP20 mutations in French patients diagnosed with non-syndromic AI. Genomic DNA was isolated from saliva and MMP20 exons and exon-intron boundaries sequenced. We identified several homozygous or heterozygous mutations, putatively involved in the AI phenotypes. To validate missense mutations and predict sensitive positions in the MMP20 sequence, we evolutionarily compared 75 sequences extracted from the public databases using the Datamonkey webserver. These sequences were representative of mammalian lineages, covering more than 150 million years of evolution. This analysis allowed us to find 324 sensitive positions (out of the 483 MMP20 residues), pinpoint functionally important domains, and build an evolutionary chart of important conserved MMP20 regions. This is an efficient tool to identify new- and previously-identified mutations. We thus identified six functional MMP20 mutations in unrelated families, finding two novel mutated sites. The genotypes and phenotypes of these six mutations are described and compared. To date, 13 MMP20 mutations causing AI have been reported, making these genotypes and associated hypomature enamel phenotypes the most frequent in AI.

Necrotizing Periodontal Diseases in Children: A Literature Review and Adjustment of Treatment.

Necrotizing ulcerative gingivitis, sometimes observed in young children, may lead to necrotizing stomatitis and noma. Therefore, its interception is a necessity and a challenge for the paediatric practitioners. First, this article aims to propose a systematic review of recent literature on the use of local antiseptic and antibiotic prescription in this particular periodontal condition. Then, a protocol is proposed to have a simple, costless and reproducible treatment on children.

A targeted next-generation sequencing assay for the molecular diagnosis of genetic disorders with orodental involvement.

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.

Prise en charge de l'ostéopériostite chronique dentaire chez l'enfant: à propos d'un cas

L'ostéopériostite est un état inflammatoire aigu ou chronique du périoste et de l'os sous-jacent. Le but du traitement de l'adolescent est la dent causale d'avulser pour empêcher des complications septiques dentaires point de départ dentaire pour Staphylococcus aureus sensible à la méthicilline. Nous rapportons le cas d'une jeune fille de 10 ans anxieuse sans antécédents médicaux significatifs avec une ostéite de Garré évoluant depuis plusieurs mois. Le patient a été mis sous antibiotiques et examiné une semaine après la disparition des signes cliniques. Une technique, le type d'anesthésie Akinosi a été réalisée sous sédation consciente car l'anesthésie générale nécessite une préparation plus intense avant le traitement et une période de récupération plus longue après le traitement. Il a permis de pratiquer sans douleur à l'ouverture de pression de la chambre pulpaire de la première molaire mandibulaire gauche et de faciliter le drainage. L'avulsion de la dent causale se pratique alors en racine de séparation pour préserver le capital osseux

The osteoperiostitis is an acute or chronic inflammatory condition of the periosteum and the underlying bone. the goal of treatment of the teenager is avulsed causal tooth to prevent septic complications dental starting point for methicillin-sensitive staphylococcus aureus. we report the case of a young 10 year old girl anxious without significant medical history with osteitis of garré evolving for several months. The patient was put on antibiotics and review one week after resolution of clinical signs. one technique the type of anesthesia akinosi was performed under conscious sedition because general anesthesia requires a more intense preparation before treatment and a longer recovery period after treatment. it allowed to practice without pain to the pressure opening of the pulp chamber of the mandibular first molar left and facilitate drainage. the avulsion of the causal tooth is then practiced separation roots to preserve the bone capital.

Direct Microscopy: A Useful Tool to Diagnose Oral Candidiasis in Children and Adolescents.

INTRODUCTION: Oral candidiasis is one of the most common opportunistic fungal infections of the oral cavity in human. Among children, this condition represents one of the most frequent affecting the mucosa. Although most diagnoses are made based on clinical signs and features, a microbiological analysis is sometimes necessary. We performed a literature review on the diagnosis of oral candidiasis to identify the techniques most commonly employed in routine clinical practice. MATERIALS AND METHODS: A Medline-PubMed search covering the last 10 years was performed. RESULTS: Microbiological techniques were used in cases requiring confirmation of the clinical diagnosis. In such cases, direct microscopy was the method most commonly used for diagnosing candidiasis. CONCLUSION: Direct microscopy appears as the method of choice for confirming clinical diagnosis and could become a routine chair-side technique.

Genotypic and phenotypic variation in six patients with solitary median maxillary central incisor syndrome.

Solitary Median Maxillary Central Incisor occurs in 1 of 50,000 live births. It is the mildest manifestation of the holoprosencephaly spectrum and is genetically heterogeneous. Here we report six patients with solitary median maxillary central incisor, and a range of other phenotypic anomalies with different degrees of severity, varying from mild signs of holoprosencephaly to associated intellectual disability, and with different genetic background. Using array comparative genomic hybridization, pathogenic copy number variants were found in three of the six patients. Two patients had a deletion at the 18p11 chromosomal region that includes TGIF1 while the other patient had a deletion at 7q36, including the SHH gene. In one patient, a mutation in SIX3 was detected with exome sequencing, while in the two remaining patients all known holoprosencephaly genes were excluded using multiplex ligation-dependent probe amplification and sequencing, and remain unsolved. One of the two latter patients had isolated solitary median maxillary central incisor without other visible dentofacial anomalies, while the other had clinical features not part of the known holoprosencephaly spectrum.

Proteus syndrome: Report of a case with AKT1 mutation in a dental cyst.

Proteus syndrome (PS) is a sporadic and rare congenital disorder characterized by a patchy or mosaic postnatal overgrowth, sometimes involving the face. The onset of overgrowth typically occurs in infancy and can commonly involve skin, connective tissue, central nervous system, eyes and viscera. The progressive overgrowth causes severe complications, such as skeletal deformities, cystic lung disease, invasive lipomas, connective tissue hyperplasia, benign and malignant tumours and deep venous thrombosis with pulmonary embolism, which can cause premature death. This disorder is caused by somatic mosaicism for a specific activating AKT1 mutation that would be lethal in a non-mosaic state. In this report, current knowledge of the aetiology, the diagnosis and the craniofacial manifestations of the disorder are reviewed. The short-term management of a 7-year-old patient with unusual oral manifestations is described. For the first time mutation of AKT1 (c.49G > A) gene was detected both in cranial exostosis and in central odontogenic fibroma of the lower jaw.

Mutations in the latent TGF-beta binding protein 3 (LTBP3) gene cause brachyolmia with amelogenesis imperfecta.

Inherited dental malformations constitute a clinically and genetically heterogeneous group of disorders. Here, we report on four families, three of them consanguineous, with an identical phenotype, characterized by significant short stature with brachyolmia and hypoplastic amelogenesis imperfecta (AI) with almost absent enamel. This phenotype was first described in 1996 by Verloes et al. as an autosomal recessive form of brachyolmia associated with AI. Whole-exome sequencing resulted in the identification of recessive hypomorphic mutations including deletion, nonsense and splice mutations, in the LTBP3 gene, which is involved in the TGF-beta signaling pathway. We further investigated gene expression during mouse development and tooth formation. Differentiated ameloblasts synthesizing enamel matrix proteins and odontoblasts expressed the gene. Study of an available knockout mouse model showed that the mutant mice displayed very thin to absent enamel in both incisors and molars, hereby recapitulating the AI phenotype in the human disorder.