Primary failure of eruption: From molecular diagnosis to therapeutic management.

Introduction: Primary Failure of Eruption (PFE) is a rare condition affecting posterior teeth eruption resulting in a posterior open bite malocclusion. Differential diagnosis like ankylosis or mechanical eruption failure should be considered. For non-syndromic forms, mutations in PTH1R, and recently in KMT2C genes are the known etiologies. The aim of this work was to describe the variability of clinical presentations of PFE associated with pathogenic variants of PTHR1. Material and methods: Diagnosis of non-syndromic PFE has been suggested for three members of a single family. Clinical and radiological features were collected, and genetic analyses were performed. Results: The clinical phenotype (type and number of involved teeth, depth of bone inclusions, functional consequences) is variable within the family. Severe tooth resorptions were detected. A heterozygous substitution in PTH1R (NM_000316.3): c.899T > C was identified as a class 4 likely pathogenic variant. The multidisciplinary management is described involving oral biology, pediatric dentistry, orthodontics, oral surgery, and prosthodontics. Conclusion: In this study, we report a new PTH1R variant involved in a familial form of PFE with variable expressivity. Therapeutic care is complex and difficult to systematize, hence the lack of evidence-based recommendations and clinical guidelines.

Elements of morphology: Standard terminology for the teeth and classifying genetic dental disorders.

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.

A New SLC10A7 Homozygous Missense Mutation Responsible for a Milder Phenotype of Skeletal Dysplasia With Amelogenesis Imperfecta.

Amelogenesis imperfecta (AI) is a heterogeneous group of rare inherited diseases presenting with enamel defects. More than 30 genes have been reported to be involved in syndromic or non-syndromic AI and new genes are continuously discovered (Smith et al., 2017). Whole-exome sequencing was performed in a consanguineous family. The affected daughter presented with intra-uterine and postnatal growth retardation, skeletal dysplasia, macrocephaly, blue sclerae, and hypoplastic AI. We identified a homozygous missense mutation in exon 11 of SLC10A7 (NM_001300842.2: c.908C>T; p.Pro303Leu) segregating with the disease phenotype. We found that Slc10a7 transcripts were expressed in the epithelium of the developing mouse tooth, bones undergoing ossification, and in vertebrae. Our results revealed that SLC10A7 is overexpressed in patient fibroblasts. Patient cells display altered intracellular calcium localization suggesting that SLC10A7 regulates calcium trafficking. Mutations in this gene were previously reported to cause a similar syndromic phenotype, but with more severe skeletal defects (Ashikov et al., 2018;Dubail et al., 2018). Therefore, phenotypes resulting from a mutation in SLC10A7 can vary in severity. However, AI is the key feature indicative of SLC10A7 mutations in patients with skeletal dysplasia. Identifying this important phenotype will improve clinical diagnosis and patient management.

Protocol GenoDENT: Implementation of a New NGS Panel for Molecular Diagnosis of Genetic Disorders with Orodental Involvement.

Rare genetic disorders are often challenging to diagnose. Anomalies of tooth number, shape, size, mineralized tissue structure, eruption, and resorption may exist as isolated symptoms or diseases but are often part of the clinical synopsis of numerous syndromes (Bloch-Zupan A, Sedano H, Scully C. Dento/oro/craniofacial anomalies and genetics, 1st edn. Elsevier, Boston, MA, 2012). Concerning amelogenesis imperfecta (AI), for example, mutations in a number of genes have been reported to cause isolated AI, including AMELX, ENAM, KLK4, MMP20, FAM83H, WDR72, C4orf26, SLC24A4, and LAMB3. In addition, many other genes such as DLX3, CNNM4, ROGDI, FAM20A, STIM1, ORAI1, and LTBP3 have been shown to be involved in developmental syndromes with enamel defects. The clinical presentation of the enamel phenotype (hypoplastic, hypomineralized, hypomature, or a combination of severities) alone does not allow a reliable prediction of possible causative genetic mutations. Understanding the potential genetic cause(s) of rare diseases is critical for overall health management of affected patient. One effective strategy to reach a genetic diagnosis is to sequence a selected gene panel chosen for a determined range of phenotypes. Here we describe a laboratory protocol to set up a specific gene panel for orodental diseases.

Amelogenesis imperfecta: therapeutic strategy from primary to permanent dentition across case reports.

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.

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.

Dento-maxillo-facial phenotype and implants-based oral rehabilitation in Ectodermal Dysplasia with WNT10A gene mutation: report of a case and literature review.

PURPOSE: To report the dento-craniofacial phenotype of a family affected by a WNT10A HED and to describe the implant-based oral rehabilitation of a patient presenting a severe oligodontia linked to this mutation. A molecular hypothesis concerning the involvement of Wnt-ß-catenin pathway in implant osteointegration will be proposed. MATERIAL AND METHODS: Patients affected by a WNT10A mutation were included from a large group of HED patients. WNT10A gene was sequenced in second intention for patients negative for EDA-EDAR-EDARADD mutations. Dento-craniofacial phenotype was described based on clinical and radiological data. RESULTS: Severe oligodontia was observed in the patient affected by a compound heterozygous mutation of WNT10A gene. CT exams showed marked maxillary bone hypoplasia in the posterior areas with a sub-normal mandible treatment consisted in the placement of 4 mandibular implants and in 2 implant-supported bridges. In the maxilla, an autogenous bone graft was indicated. The post-operative radiological follow-up showed partial bone resorption of the grafts, treated with ramus bone shaving and a membrane, followed by the placement of 4 maxillary implants. CONCLUSION: Patients affected by WNT10A HED require multi-disciplinary dental diagnosis and treatment. A close post-operative radiological follow-up appears necessary given the biological functions of Wnt-ß-catenin in bone repair.

Rehabilitation of children with ectodermal dysplasia. Part 1: an international Delphi study.

PURPOSE: An international Delphi study was undertaken to determine by consensus an agreed approach to the management of children with dental manifestations of ectodermal dysplasia, including the use of dental implants. This was done using a questionnaire developed by an interdisciplinary team. MATERIALS AND METHODS: The Delphi study questionnaire was built around 19 areas of clinical relevance and included 90 items. Topic areas included dental disability; initial diagnosis; global disability; oral health aspects of dental treatment (orthodontics, hypodontia, anodontia, implants); and case studies of selected treatment options. Eleven teams from six countries contributed to three iterations of the questionnaire. An algorithm was designed to standardize analysis of the questionnaire answers, all of which were blinded to ensure anonymity. The second and third rounds of the questionnaire excluded previously agreed-upon items but included the responses to the questions from the earlier rounds. The nonconsensus items inquired about the use of radiographs at initial diagnosis; sedation of an uncooperative child; use of a pretreatment questionnaire; the age range for specific treatments (eg, dentures, orthodontics, implants); specific uses of implants (eg, partial prostheses, overdentures, cantilevered prostheses); and case study 2. The residual nonconsensus questions were subsequently discussed at a 2-day meeting. RESULTS: Among the 90 questions and partial questions, there was progressive consensus, with agreements in rounds 1, 2, and 3 of 61%, 21%, and 8%, respectively. At the conclusion of round 3, there was 90% agreement and it was considered that the nonconsensus items required in-depth face-to-face discussion at a consensus meeting, which is described in part 2 of the study. CONCLUSION: The Delphi study provided an opportunity to engage specialist teams in recognized centers to integrate their clinical knowledge and draw on published data to develop a consensus of evidence-based responses.

Rehabilitation of children with ectodermal dysplasia. Part 2: an international consensus meeting.

A consensus meeting was arranged to provide an opportunity to discuss the residual nonconsensus questions following three rounds of a Delphi study. It was hoped that the nonagreements could be resolved to define a comprehensive protocol for the management of ectodermal dysplasia, particularly with respect to the use of dental implants in growing patients. An international panel of expert clinicians in pediatric dentistry, prosthodontics, and orthodontics was invited to be part of the Delphi study to develop agreement on clinical questions through a consensus of ideas. Each expert had been invited to form a study group or team within his or her home institution. As required by the Delphi protocol, a 90-part questionnaire was considered by the collaborating teams and progressed through three iterations with increasing agreement. This process is discussed in part 1 of the study. The residual nonconsensus questions, which represented 10% of the questionnaire, required collaborative interaction for resolution. The consensus meeting was held in London, England, over a 2-day period with support from Nobel Biocare and the British Dental Association.

Previously undescribed pulpal and periodontal ligament calcifications in systemic sclerosis: a case report.

Systemic sclerosis (SSc), a multisystem autoimmune disease characterized by widespread fibrosis, vascular alterations, autoimmunity, and inflammation, has effects on the hard and soft tissues of the orofacial region. The most common oral radiographic features correspond to widening of the periodontal ligament space and to mandibular resorption. In this report, cone-beam computerized tomography (CBCT) confirmed not only the well described periodontal features associated with SSc but also revealed previously undescribed calcifications within the periodontal ligament space of most maxillary teeth. Moreover, CBCT showed pulp calcifications in some incisors and premolars with these calcifications leading to root canal obliterations. Such manifestations (which could be linked to different major pathogenic features of SSc such as calcinosis, vasculopathy, and fibrosis) contribute to the phenotypic spectrum of the disease.

Only four genes (EDA1, EDAR, EDARADD, and WNT10A) account for 90% of hypohidrotic/anhidrotic ectodermal dysplasia cases.

Hypohidrotic and anhidrotic ectodermal dysplasia (HED/EDA) is a rare genodermatosis characterized by abnormal development of sweat glands, teeth, and hair. Three disease-causing genes have been hitherto identified, namely, (1) EDA1 accounting for X-linked forms, (2) EDAR, and (3) EDARADD, causing both autosomal dominant and recessive forms. Recently, WNT10A gene was identified as responsible for various autosomal recessive forms of ectodermal dysplasias, including onycho-odonto-dermal dysplasia (OODD) and Schöpf-Schulz-Passarge syndrome. We systematically studied EDA1, EDAR, EDARADD, and WNT10A genes in a large cohort of 65 unrelated patients, of which 61 presented with HED/EDA. A total of 50 mutations (including 32 novel mutations) accounted for 60/65 cases in our series. These four genes accounted for 92% (56/61 patients) of HED/EDA cases: (1) the EDA1 gene was the most common disease-causing gene (58% of cases), (2)WNT10A and EDAR were each responsible for 16% of cases. Moreover, a novel disease locus for dominant HED/EDA mapped to chromosome 14q12-q13.1. Although no clinical differences between patients carrying EDA1, EDAR, or EDARADD mutations could be identified, patients harboring WNT10A mutations displayed distinctive clinical features (marked dental phenotype, no facial dysmorphism), helping to decide which gene should be first investigated in HED/EDA.

Orodental phenotype and genotype findings in all subtypes of hypophosphatasia.

BACKGROUND: Hypophosphatasia (HP) is a rare inherited disorder characterized by a wide spectrum of defects in mineralized tissues and caused by deficiency in the tissue non-specific alkaline phosphatase gene (ALPL). The symptoms are highly variable in their clinical expression, and relate to numerous mutations in this gene. The first clinical sign of the disease is often a premature loss of deciduous teeth, mostly in the moderate forms. AIM: The purpose of this study was to document the oral features of HP patients and to relate theses features to the six recognized forms of HP in 5 patients with known genotype and to investigate the genotype-phenotype correlations. METHODS: Clinical and radiographic examinations were carried out. We collected medical and dental history in the kindred and biochemical data. Finally, mutations in the ALPL gene were tested by DNA sequencing in SESEP laboratory. RESULTS: We have for the first time related the known dental anomalies which occur as integral features of HP to the recognized clinical forms of HP. We also pointed out striking dental abnormalities which were never described in association with this rare disease. Accurate genotype-phenotype severity correlations were observed. CONCLUSION: This work allowed us to compare orodental manifestations in all the clinical forms of HP within the patient's sample. According to the severity of the disorder, some dental defects were infrequent, while other were always present. The long term prognosis of the permanent teeth varies from a patient to another. As premature loss of primary teeth is often the first, and sometimes the only visible symptom of the milder forms, the paediatric dentist plays a critical role in the detection and diagnosis of the disease.