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Growth promoting variants in PIK3CA cause a spectrum of developmental disorders, depending on the developmental timing of the mutation and tissues involved. These phenotypically heterogeneous entities have been grouped as PIK3CA-Related Overgrowth Spectrum disorders (PROS). Deep sequencing technologies have facilitated detection of low-level mosaic, often necessitating testing of tissues other than blood. Since clinical management practices vary considerably among healthcare professionals and services across different countries, a consensus on management guidelines is needed. Clinical heterogeneity within this spectrum leads to challenges in establishing management recommendations, which must be based on patient-specific considerations. Moreover, as most of these conditions are rare, affected families may lack access to the medical expertise that is needed to help address the multi-system and often complex medical issues seen with PROS. In March 2019, macrocephaly-capillary malformation (M-CM) patient organizations hosted an expert meeting in Manchester, United Kingdom, to help address these challenges with regards to M-CM syndrome. We have expanded the scope of this project to cover PROS and developed this consensus statement on the preferred approach for managing affected individuals based on our current knowledge.
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Classe I de Fosfatidilinositol 3-Quinases/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Padrão de Cuidado , Conferências de Consenso como Assunto , Diagnóstico Diferencial , Gerenciamento Clínico , Estudos de Associação Genética/métodos , Testes Genéticos , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/genética , Transtornos do Crescimento/terapia , Humanos , Fenótipo , Diagnóstico Pré-NatalRESUMO
Medical comics are a suitable educational tool for paediatric populations. The emotions conveyed by the characters should not evoke negative feelings, which could then be associated with care or caregivers. The eyes and mouth are the first areas of the face to be analysed. One study attempted to assess the ability of children to perceive the emotions of one of the protagonists through the representation of their mouth.
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Emoções , Boca , Criança , Emoções/fisiologia , Humanos , PercepçãoRESUMO
Periodontal Ehlers-Danlos syndrome (pEDS) is a rare condition caused by pathogenic variants in the C1R and C1S genes, encoding subunits C1r and C1s of the first component of the classical complement pathway. It is characterized by early-onset periodontitis with premature tooth loss, pretibial hyperpigmentation and skin fragility. Rare arterial complications have been reported, but venous insufficiency is rarely described. Here we report 13 novel patients carrying heterozygous pathogenic variants in C1R and C1S including three novel C1S variants (c.962G > C, c.961 T > G and c.961 T > A). In addition to the pEDS phenotype, three patients and one relative displayed widespread venous insufficiency leading to persistent varicose leg ulcers. One patient suffered an intracranial aneurysm with familial vascular complications including thoracic and abdominal aortic aneurysm and dissection and intracranial aneurysm rupture. This work confirms that vascular complications can occur, although they are not frequent, which leads us to propose to carry out a first complete non-invasive vascular evaluation at the time of the diagnosis in pEDS patients. However, larger case series are needed to improve our understanding of the link between complement pathway activation and connective tissue alterations observed in these patients, and to better assess the frequency, type and consequences of the vascular complications.
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Síndrome de Ehlers-Danlos/etiologia , Mutação , Adolescente , Adulto , Idoso , Aneurisma da Aorta Abdominal/genética , Pré-Escolar , Complemento C1r/genética , Complemento C1s/genética , Síndrome de Ehlers-Danlos/genética , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Úlcera Varicosa/etiologia , Úlcera Varicosa/genética , Adulto JovemRESUMO
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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Terminologia como Assunto , Anormalidades Dentárias/classificação , Anormalidades Dentárias/genética , Dente/patologia , Pontos de Referência Anatômicos , Predisposição Genética para Doença , Humanos , Cooperação Internacional , Mucosa Bucal/patologia , Radiografia Panorâmica , Dente/diagnóstico por imagem , Anormalidades Dentárias/diagnóstico por imagem , Dente Supranumerário/diagnóstico por imagemRESUMO
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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Amelogênese Imperfeita/terapia , Dente Decíduo/anormalidades , Adolescente , Criança , Pré-Escolar , Coroas , Colagem Dentária , Restauração Dentária Permanente , Dentição Permanente , Feminino , Humanos , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Ortodontia CorretivaRESUMO
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.
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Amelogênese Imperfeita/genética , Proteínas de Ligação a TGF-beta Latente/genética , Osteocondrodisplasias/genética , Adolescente , Amelogênese Imperfeita/diagnóstico por imagem , Animais , Sequência de Bases , Criança , Consanguinidade , Análise Mutacional de DNA , Feminino , Mutação da Fase de Leitura , Estudos de Associação Genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação de Sentido Incorreto , Osteocondrodisplasias/diagnóstico por imagem , Linhagem , Radiografia , Deleção de SequênciaRESUMO
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.
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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.
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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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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.
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Displasia Ectodérmica/genética , Ectodisplasinas/genética , Receptor Edar/genética , Proteína de Domínio de Morte Associada a Edar/genética , Mutação , Proteínas Wnt/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Fenótipo , Adulto JovemRESUMO
BACKGROUND: People with special needs have high unmet oral healthcare needs, partly because dentists find it difficult to access their oral cavity. The Oral Accessibility Spatula aims to improve oral accessibility. This prospective multicenter interventional open-label non-randomized patient-self-controlled trial assessed the ability of the spatula to improve the oral accessibility of special-needs patients during dental examinations. METHODS: The cohort was a convenience sample of minor and adult patients with special needs due to physical, intellectual, and/or behavioral disorders who underwent dental check-up/treatment in five French tertiary hospitals/private clinics in 2016-2018 and evinced some (Venham-Score = 2-4) but not complete (Venham-Score = 5) resistance to oral examination. After inclusion, patients underwent oral examination without the spatula and then immediately thereafter oral examination with the spatula. Primary outcome was Oral Accessibility Score (0-12 points; higher scores indicate visualization and probing of the tooth sectors). Secondary outcomes were patient toleration (change in Venham-Score relative to first examination), safety, and Examiner Satisfaction Score (0-10; low scores indicate unsatisfactory examination). RESULTS: The 201 patients were mostly non-elderly adults (18-64 years, 65%) but also included children (21%), adolescents (11%), and aged patients (3%). One-quarter, half, and one-quarter had Venham-Score = 2, 3, and 4 at inclusion, respectively. The spatula significantly improved Oral Accessibility Score (4.8 to 10.8), Venham-Score (3.1 to 2.6), and Examiner Satisfaction Score (3.4 to 7.2) (all p<0.001). There were no severe spatula-related adverse events. CONCLUSION: The spatula significantly improved oral access, was safe and well-tolerated by the patients, and markedly improved oral examination quality.
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Assistência Odontológica para a Pessoa com Deficiência/instrumentação , Instrumentos Odontológicos/efeitos adversos , Diagnóstico Bucal/instrumentação , Pessoas com Deficiência , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Ansiedade ao Tratamento Odontológico , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Boca , Satisfação do Paciente , Estudos Prospectivos , Adulto JovemRESUMO
INTRODUCTION: Primary failure of eruption (PFE) can be defined as the partial or complete failure of eruption of at least one posterior tooth, without any mechanical obstacle; isolated and syndromic forms exist. PFE results from an abnormal dental eruption process that can affect temporary teeth and / or permanent teeth. Molars are the main affected teeth, inducing posterior infraclusions. Orthodontists are the specialists most often concerned by this rare pathology. Unsuccessful orthodontic-surgical traction therapies are commonly reported. MATERIALS AND METHODS: The aim of our study using a prospective survey was to evaluate the level of knowledge reported by the orthodontists and the therapeutic difficulties they reported. An anonymous questionnaire was submitted to practitioners practicing in north-eastern France (Grand Est and Bourgogne-Franche-Comté regions). RESULTS: The participation rate was 33.5%. In France, until 2015, specialization in orthodontics was obtained thanks to a local qualification, the Certificat d'Etudes Cliniques Spéciales - Mention Orthodontie (CECSMO), which has now been replaced by specialization following a national ranking competition. Most respondents obtained their qualification between 1980 and 2009 (80%), via the CECSMO (87%). Eighty-six per cent were aware of PFE but only 20% of them knew that PTHR1 (Parathyroid Hormone Receptor 1) gene could be involved in this pathology. The wide range of proposed therapies and the variable satisfaction rates highlight the difficulties encountered by practitioners. DISCUSSION: Phenotypic variability complicates the diagnosis and makes any therapeutic systematization uncertain. CONCLUSION: New clinical research projects, particularly in the field of molecular diagnosis, may improve understanding of genotype-phenotype correlations, and may potentially pilot therapeutic management.
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Ortodontistas , Erupção Dentária , França , Humanos , Estudos Prospectivos , Inquéritos e QuestionáriosRESUMO
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.
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BACKGROUND: Rare diseases affecting the teeth, the oral cavity and the face are numerous, each of them present specific characteristics, and is a life-long condition. The aim of the study was to assess the association between Oral health-related quality of life (OHRQoL), and demographic characteristics, clinical and dental factors, and psycho-social characteristics to investigate that oral symptoms are not the main factors underlying a decrease in OHRQoL. MATERIAL AND METHODS: We conducted a national cohort study in French centres for rare diseases (RD) specialized in orofacial diseases. The inclusion criteria were: to have received care in RD centres over the last 5 years (2012-2017) and to have been between 6 and 17 years of age on September 1, 2017. Patients were invited to answer a questionnaire composed of socio-demographic, clinical and dental questions, psychosocial questions and then fill in the Child-OIDP Index. At the end of the questionnaire, a free space was left for the patient to add a verbatim comment to provide qualitative data. Thematic analysis was used to analyze the verbatim answers. RESULTS: Complete data were available for 110 patients. The sample included 44.5% boys and 55.5% girls. Ages ranged from 6 to 17 years old and 68.2% were between 6 to 12 years old and 31.8% were between 13 and 17 years old. Factor associated with a lower OHRQoL were: being a girl (p = 0.03), renouncement to dental care for financial reasons (p = 0.01), having syndromic disease (p = 0.01), having a problem with tooth shape and color (p = 0.03), feeling isolated, alone and different from other children (p = 0.003 and p = 0.02). Qualitative analysis highlighted very little recourse to psychological care and patients reported great anxiety and fear about the future. CONCLUSION: OHRQoL of children suffering from these diseases is impaired, especially from the psychosocial point of view but also from that of the course of treatment and access to care. There is a need to improve the legibility of care pathways and the financial coverage of treatments.
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Saúde Bucal , Doenças Raras , Adolescente , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Qualidade de Vida , Inquéritos e QuestionáriosRESUMO
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.
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Anormalidades Craniofaciais/genética , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Doenças Raras/genética , Anormalidades Dentárias/genética , Amelogênese Imperfeita/diagnóstico , Amelogênese Imperfeita/genética , Anormalidades Craniofaciais/diagnóstico , DNA/genética , Desenho de Equipamento , Sequenciamento de Nucleotídeos em Larga Escala/instrumentação , Humanos , Doenças Raras/diagnóstico , Anormalidades Dentárias/diagnósticoRESUMO
BACKGROUND: Conscious sedation is used in dentistry to improve access and quality of care in patients who have difficulty coping with treatment. The aim of this prospective study was to describe a postgraduate training course in conscious sedation for dentists, with specific evaluation of the safe and effective administration of a 50% nitrous oxide in oxygen premix. METHODS: 45 practitioners were trained between 2002 and 2004. They carried out 826 sessions of inhalation sedation in 662 patients. The clinical competency of this group was compared with an expert group. RESULTS: There was no difference between trainees and experts in ability to complete the planned dental treatment under sedation (89.6% vs 93.2%). Trainees were less successful than experts for patients with intellectual disability (87.4% vs 94.2%, p < 0.01). For both groups, the degree of cooperation improved between initial induction and each perioperative step (Wilcoxon test, p < 0.01). However, for trainees, Venham behaviour scores varied with the type of patient (Kruskal Wallis test, p < 0.001). No major adverse effects were recorded. Trainees reported more minor adverse effects than experts (13% vs. 5.3% respectively, Fisher exact test, p < 0.001) CONCLUSION: The trainee practitioners provided effective and safe inhalation sedation. This challenges the current French restriction of the 50% nitrous oxide in oxygen premix to the hospital setting. Further emphasis is required on the teaching of behaviour management skills for patients with intellectual disability.
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Educação Continuada em Odontologia/métodos , Óxido Nitroso/administração & dosagem , Óxido Nitroso/efeitos adversos , Anestesia Dentária/efeitos adversos , Anestesia Dentária/métodos , Anestesia Dentária/normas , Sedação Consciente/efeitos adversos , Sedação Consciente/métodos , Sedação Consciente/normas , Odontólogos/normas , Educação Continuada em Odontologia/normas , Humanos , Estudos Longitudinais , Satisfação do Paciente , Estudos ProspectivosRESUMO
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.
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Hemostasia Cirúrgica/métodos , Extração Dentária/métodos , Dente Impactado/cirurgia , Dente Supranumerário/cirurgia , Doença de von Willebrand Tipo 1/terapia , Celulose Oxidada/uso terapêutico , Criança , Desamino Arginina Vasopressina/administração & dosagem , Desamino Arginina Vasopressina/uso terapêutico , Feminino , Seguimentos , Técnicas Hemostáticas , Hemostáticos/administração & dosagem , Hemostáticos/uso terapêutico , Humanos , Infusões Intravenosas , Cuidados Intraoperatórios , Hemorragia Pós-Operatória/prevenção & controle , Pré-MedicaçãoRESUMO
[This corrects the article on p. 70 in vol. 7, PMID: 26973538.].