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.

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.

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.

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.

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.

The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data.

The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online.

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.

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.

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.

Mutations in WNT10A are frequently involved in oligodontia associated with minor signs of ectodermal dysplasia.

Ectodermal dysplasias (ED) are a clinically and genetically heterogeneous group of hereditary disorders that have in common abnormal development of ectodermal derivatives. Hypohidrotic ectodermal dysplasia (HED) is characterized by abnormal development of eccrine sweat glands, hair, and teeth. The X-linked form of the disease, caused by mutations in the EDA gene, represents the majority of patients with the hypohidrotic form. Autosomal dominant and autosomal recessive forms are occasionally seen, and result from mutations in at least three genes (WNT10A, EDAR, or more rarely EDARADD). We have screened for mutations in EDAR (commonly involved in the hypohidrotic form) and WNT10A (involved in a wide spectrum of ED and in isolated hypodontia) in a cohort of 36 patients referred for EDA molecular screening, which failed to identify any mutation. We identified eight EDAR mutations in five patients (two with homozygous mutations, one with compound heterozygous mutations, and two with heterozygous mutation), four of which were novel variants. We identified 28 WNT10A mutations in 16 patients (5 with homozygous mutations, 7 with compound heterozygous mutations, and 4 with heterozygous mutations), seven of which were novel variants. Our study allows a more precise definition of the phenotypic spectrum associated with EDAR and WNT10A mutations and underlines the importance of the implication of WNT10A among patients with ED.

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.

Nephrocalcinosis (enamel renal syndrome) caused by autosomal recessive FAM20A mutations.

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.

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.

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.

Ectodermal dysplasia-like syndrome with mental retardation due to contiguous gene deletion: further clinical and molecular delineation of del(2q32) syndrome.

We report on a patient with an interstitial deletion of the long arm of chromosome 2 at 2q31.2q33.2. She had prenatal and postnatal growth retardation, microcephaly, facial dysmorphism, cleft palate, camptodactyly, bilateral talipes equinovarus, severe intellectual disability, and ectodermal anomalies. She showed thin, atrophic skin, sparse, brittle, slowly growing hair, oligodontia with abnormally shaped teeth, normal sweating, and normal fingernails, consistent with a diagnosis of ectodermal dysplasia. Array CGH analysis (Agilent 44K) showed the deletion to span 26 Mb, between cytogenetic bands 2q31.2 and 2q33. The deletion leads to hemizygosity for the HOXD cluster and its regulatory elements, COL3A1/COL5A2, GTF3C3, CASP8, CASP10, and SABT2 could perhaps interfere with long range control of DLX1 and DLX2 expression. This girl confirms the existence of a clinically recognizable 2q32 microdeletion syndrome, as recently delineated by Van Buggenhout et al. and confirms a novel putative locus for ectodermal dysplasia on chromosome 2q31q33. We recommend considering cytogenetic and/or molecular screening for del(2q32) in patients with developmental disability and ectodermal dysplasia-like phenotype, including thin skin, oligodontia, dysplastic teeth, and sparse hair.

Dental agenesis in Kallmann syndrome individuals with FGFR1 mutations.

BACKGROUND: Kallmann syndrome (KS) is a rare genetic disorder characterised by central hypogonadism with a lack of sense of smell and in some cases renal aplasia, deafness, syndactyly, cleft lip/palate, and dental agenesis. To date, five genes for KS have been identified: KAL1, located on the X chromosome, and FGFR1, PROKR2, PROK2 and FGF8, which are involved in autosomally transmitted forms of KS. AIM: The study characterised the dental ageneses of individuals with KS associated with mutations in the FGFR1 gene. DESIGN: Six individuals displaying dental agenesis were included. Clinical and radiological dental evaluations as well as medical anamneses were carried out. RESULTS: Microdontia, screwdriver-shaped mandibular incisors, thin molar roots, and patterns of dental agenesis in both dentitions were observed. One to nine teeth were missing, most frequently, in descending order, lateral mandibular incisors, second premolars of upper and lower jaws, and lateral maxillary incisors. The pattern of dental agenesis is associated with four new mutations in the FGFR1 gene. CONCLUSION: Dental agenesis may be a clinical feature of Kallmann syndrome caused by a mutation in the FGFR1 gene. These findings highlight the role that odontologists can play in the early diagnosis and treatment of gonadotropic deficiency.