Orodental phenotype and genotype findings in all subtypes of hypophosphatasia

<p>Abstract</p> <p>Background</p> <p>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 (<it>ALPL</it>). 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.</p> <p>Aim</p> <p>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.</p> <p>Methods</p> <p>Clinical and radiographic examinations were carried out. We collected medical and dental history in the kindred and biochemical data. Finally, mutations in the <it>ALPL </it>gene were tested by DNA sequencing in SESEP laboratory.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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.</p

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&gt;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

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

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 Novel Mutation Involving the Initiation Codon of FGF3 in a Family Described with Complete Inner Ear Agenesis, Microtia and Major Microdontia (LAMM Syndrome)

LAMM syndrome (OMIM #610706) is a rare autosomal recessive syndrome characterized by the association of Michel aplasia, microdontia and malformation of the external ear. Different mutations in FGF3 gene were reported in several families presenting with this syndrome. Clinical features and genetic results observed in a family with LAMM syndrome are reported. The diagnosis of isolated Michel aplasia was initially made in this family composed of two affected children. Microtia and microdontia was recently evidenced in both patients suggesting the diagnosis of LAMM syndrome. New auditory and orodental iconography was performed permitting to describe the patients’ phenotype in depth and to report rare findings of LAMM syndrome. The sequencing of FGF3 gene identified a novel missense mutation (c.2T>G), substituting the first initiator methionine in arginine, in the fibroblast growth factor 3 (FGF3) at the homozygous state in both patients. LAMM syndrome was confirmed and appropriate genetic counseling performed

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.journal articleresearch support, non-u.s. gov't2016 Feb2015 10 26importe

Défauts primaires d’éruption : état des lieux auprès des spécialistes en orthopédie dento-faciale des régions Grand Est et Bourgogne-Franche-Comté

Introduction : Les défauts primaires d’éruption (DPE) correspondent à l’échec partiel ou total d’éruption d’une ou de plusieurs dents, sans obstacle mécanique; des formes isolées et syndromiques de cette pathologie existent. Ils résultent d’une anomalie des processus d’éruption qui peut toucher les dents temporaires et/ou les dents permanentes. Les molaires sont les principales dents atteintes, provoquant des infraclusions postérieures. Pathologie rare, les DPE sont essentiellement pris en charge par les spécialistes en orthopédie dento-faciale (ODF). Les tentatives de traction chirurgico-orthodontiques se soldent généralement par un échec. Matériels et méthodes : Le but de ce travail était d’évaluer, par une enquête prospective basée sur un questionnaire anonyme, les connaissances des orthodontistes et la complexité de la prise en charge de cette anomalie de l’éruption. Les praticiens des régions Grand Est et Bourgogne-Franche-Comté ont été sollicités. Résultats : Le taux de participation était de 33,5 %. Les participants ont principalement obtenu leur qualification entre 1980 et 2009 (80 %), via le Certificat d’Études Cliniques Spécialisées Mention Orthodontie (CECSMO) (87 %). Quatre-vingt-six pour cent d’entre eux connaissaient les DPE mais 20 % seulement l’implication possible du gène PTHR1 (Parathyroid Hormone Receptor 1). Le vaste panel de thérapeutiques envisagées et les faibles taux de satisfaction soulignent les difficultés rencontrées par les praticiens. Discussion : La variabilité phénotypique complique le diagnostic et rend difficile toute systématisation de la prise en charge. Conclusion : De nouveaux projets de recherche clinique, notamment en matière de diagnostic moléculaire, amélioreront les connaissances sur les corrélations génotype-phénotype, et conditionneront éventuellement la prise en charge thérapeutique

Influence of Child’s Temperament on Behaviour Management Problems in the Dental Office: A Literature Review

Background: A child’s temperament could have an influence on his/her behaviour in the dental environment. This review aims to present the main temperament surveys and their clinical use and to discuss the relationship between certain temperament dimensions and Dental Behaviour Management Problems (DBMP). Methods: A literature search was conducted in Medline/PubMed, ScienceDirect, Wiley Online Library and Cochrane library electronic databases for publications, up to June 2022, investigating the link between child’s temperament and DBMP. Results: From 733 potentially eligible studies, 12 were included in qualitative synthesis. Conclusion: According to studies using the Child Behaviour Questionnaire (CBQ) scale, the most impactful dimensions are activity, extraversion and surgency, high-intensity pleasure and attention control. For those using the Emotionality–Activity–Sociability (EAS) scale, emotionality and shyness have a statistically significant positive linear correlation with dental anxiety and DBMP. It has yet to be determined whether the use and interpretation of these questionnaires can be carried out in a daily clinical situation as an aid to sharpen the indications for the several levels of sedation

Prise en charge multidisciplinaire des agénésies dentaires multiples associées aux dysplasies ectodermiques hypohidrotiques

Les dysplasies ectodermiques hypohidrotiques (DEH) constituent un groupe hétérogène et complexe de syndromes caractérisés par un phénotype dento-cranio-facial associant une oligodontie sévère, une brachygnathie-endognathie maxillaire et une concavité faciale notamment. Les paramètres céphalométriques sont révélateurs d’une insuffisance de croissance squelettique maxillaire sagittale, d’une position mandibulaire prognathique, d’une réduction des hauteurs ramiques et faciales, ainsi que de modifications basi-crâniennes. Un diagnostic et une prise en charge au sein d’une équipe multi-disciplinaire précoce sont nécessaires. En denture temporaire, un traitement prothétique initial est préconisé, pouvant être associé éventuellement à un traitement interceptif orthopédique. En denture mixte, le traitement de l’insuffisance maxillaire transversale consiste en la mise en place d’un disjoncteur sur gouttière ou d’un quadhélix, dans le cas de phénotypes modérés avec présence de moyens d’ancrage suffisants. Le repositionnement orthopédique antérieur du maxillaire repose sur l’utilisation d’un masque facial. En denture permanente, les étapes essentielles correspondent aux aménagements orthodontiques pré-implantaires et pré-prothétiques, ainsi qu’à la préparation orthodontique pré-chirurgicale avant une éventuelle chirurgie orthognathique mono- ou bi-maxillaire. Les ancrages squelettiques temporaires de type mini-vis ou plaque peuvent être indiqués dans les cas avec déficit d’ancrage