RESUMO
BACKGROUND: Plexins are large transmembrane receptors for the semaphorin family of signalling proteins. Semaphorin-plexin signalling controls cellular interactions that are critical during development as well as in adult life stages. Nine plexin genes have been identified in humans, but despite the apparent importance of plexins in development, only biallelic PLXND1 and PLXNA1 variants have so far been associated with Mendelian genetic disease. METHODS: Eight individuals from six families presented with a recessively inherited variable clinical condition, with core features of amelogenesis imperfecta (AI) and sensorineural hearing loss (SNHL), with variable intellectual disability. Probands were investigated by exome or genome sequencing. Common variants and those unlikely to affect function were excluded. Variants consistent with autosomal recessive inheritance were prioritised. Variant segregation analysis was performed by Sanger sequencing. RNA expression analysis was conducted in C57Bl6 mice. RESULTS: Rare biallelic pathogenic variants in plexin B2 (PLXNB2), a large transmembrane semaphorin receptor protein, were found to segregate with disease in all six families. The variants identified include missense, nonsense, splicing changes and a multiexon deletion. Plxnb2 expression was detected in differentiating ameloblasts. CONCLUSION: We identify rare biallelic pathogenic variants in PLXNB2 as a cause of a new autosomal recessive, phenotypically diverse syndrome with AI and SNHL as core features. Intellectual disability, ocular disease, ear developmental abnormalities and lymphoedema were also present in multiple cases. The variable syndromic human phenotype overlaps with that seen in Plxnb2 knockout mice, and, together with the rarity of human PLXNB2 variants, may explain why pathogenic variants in PLXNB2 have not been reported previously.
Assuntos
Amelogênese Imperfeita , Deficiência Intelectual , Linhagem , Humanos , Animais , Masculino , Feminino , Camundongos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Amelogênese Imperfeita/genética , Amelogênese Imperfeita/patologia , Receptores de Superfície Celular/genética , Proteínas do Tecido Nervoso/genética , Alelos , Criança , Perda Auditiva/genética , Perda Auditiva/patologia , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Adulto , Mutação/genética , Adolescente , Pré-Escolar , FenótipoRESUMO
Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes (CREBBP, EP300) which encode for the proteins CBP and p300, which both have a function in transcription regulation and histone acetylation. As a group of international experts and national support groups dedicated to the syndrome, we realised that marked heterogeneity currently exists in clinical and molecular diagnostic approaches and care practices in various parts of the world. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria for types of RTS (RTS1: CREBBP; RTS2: EP300), molecular investigations, long-term management of various particular physical and behavioural issues and care planning. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimisation of diagnostics and care.
Assuntos
Proteína de Ligação a CREB , Proteína p300 Associada a E1A , Síndrome de Rubinstein-Taybi , Síndrome de Rubinstein-Taybi/genética , Síndrome de Rubinstein-Taybi/diagnóstico , Síndrome de Rubinstein-Taybi/terapia , Humanos , Proteína de Ligação a CREB/genética , Proteína p300 Associada a E1A/genética , Consenso , Gerenciamento Clínico , MutaçãoRESUMO
BACKGROUND: Pattern of dental anomalies encountered in cleft patients shows subtle signs of genetic involvement. This study aimed to evaluate the prevalence and pattern of tooth agenesis and supernumerary teeth in Thai cleft population according to the cleft type. METHODS: Data collected from patients with cleft lip and palate, who had been treated at Tawanchai Cleft Center, Khon Kaen University, Thailand, available during year 2012-2022, were investigated. Records from 194 patients with non-syndromic clefts met the inclusion criteria. Standard dental records, and at least either orthopantomogram (OPG) or cone beam computed tomography (CBCT), were examined. Statistical analysis was performed using chi-square and binominal test (p ≤ 0.05). RESULTS: Prevalence of tooth agenesis was higher (77.3%) than that of supernumerary teeth (5.7%) and was more common in bilateral cleft lip and palate (BCLP) (88.1%) than in unilateral cleft lip and palate (UCLP) (72.6%) (p = 0.017). The upper lateral incisor was more frequently affected (46.4%), followed by the upper second premolar. The number of missing teeth observed on the left side was significantly higher. Patients with left UCLP (ULCLP) had the highest prevalence of tooth agenesis. A total of 41 tooth agenesis code (TAC) patterns was found. The prevalence of supernumerary teeth was comparable with 6.6% of ULCLP, 5.1% of BCLP, and 4.5% of URCLP. Tooth-number anomalies were observed more often in the BCLP and were most likely to occur on the left side of the maxilla. Both types of anomalies could be featured in a small proportion of cleft patients. CONCLUSIONS: More than half of the patients with non-syndromic cleft lip and palate in this study, presented with tooth-number anomalies. Tooth agenesis was approximately 10-time more prevalent than supernumerary teeth. Tooth agenesis was likely to appear on the left-side of the maxilla regardless of the laterality of the cleft.
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Anodontia , Fenda Labial , Fissura Palatina , Tomografia Computadorizada de Feixe Cônico , Dente Supranumerário , Humanos , Fenda Labial/epidemiologia , Fissura Palatina/epidemiologia , Dente Supranumerário/epidemiologia , Dente Supranumerário/diagnóstico por imagem , Tailândia/epidemiologia , Prevalência , Masculino , Feminino , Anodontia/epidemiologia , Anodontia/diagnóstico por imagem , Adolescente , Criança , Radiografia Panorâmica , Adulto Jovem , População do Sudeste AsiáticoRESUMO
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.
Assuntos
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
Biallelic loss-of-function variants in the thrombospondin-type laminin G domain and epilepsy-associated repeats (TSPEAR) gene have recently been associated with ectodermal dysplasia and hearing loss. The first reports describing a TSPEAR disease association identified this gene is a cause of nonsyndromic hearing loss, but subsequent reports involving additional affected families have questioned this evidence and suggested a stronger association with ectodermal dysplasia. To clarify genotype-phenotype associations for TSPEAR variants, we characterized 13 individuals with biallelic TSPEAR variants. Individuals underwent either exome sequencing or panel-based genetic testing. Nearly all of these newly reported individuals (11/13) have phenotypes that include tooth agenesis or ectodermal dysplasia, while three newly reported individuals have hearing loss. Of the individuals displaying hearing loss, all have additional variants in other hearing-loss-associated genes, specifically TMPRSS3, GJB2, and GJB6, that present competing candidates for their hearing loss phenotype. When presented alongside previous reports, the overall evidence supports the association of TSPEAR variants with ectodermal dysplasia and tooth agenesis features but creates significant doubt as to whether TSPEAR variants are a monogenic cause of hearing loss. Further functional evidence is needed to evaluate this phenotypic association.
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Anodontia/diagnóstico , Anodontia/genética , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/genética , Variação Genética , Fenótipo , Proteínas/genética , Alelos , Substituição de Aminoácidos , Estudos de Coortes , Feminino , Estudos de Associação Genética , Loci Gênicos , Humanos , Masculino , Mutação , Linhagem , RadiografiaRESUMO
Fraser syndrome (FS) is a rare autosomal recessive multiple congenital malformation syndrome characterized by cryptophthalmos, cutaneous syndactyly, renal agenesis, ambiguous genitalia, and laryngotracheal anomalies. It is caused by biallelic mutations of FRAS1, FREM2, and GRIP1 genes, encoding components of a protein complex that mediates embryonic epithelial-mesenchymal interactions. Anecdotal reports have described abnormal orodental findings in FS, but no study has as yet addressed the orodental findings of FS systematically. We reviewed dental radiographs of 10 unrelated patients with FS of different genetic etiologies. Dental anomalies were present in all patients with FS and included hypodontia, dental crowding, medial diastema, and retained teeth. A very consistent pattern of shortened dental roots of most permanent teeth as well as altered length/width ratio with shortened dental crowns of upper incisors was also identified. These findings suggest that the FRAS1-FREM complex mediates critical mesenchymal-epithelial interactions during dental crown and root development. The orodental findings of FS reported herein represent a previously underestimated manifestation of the disorder with significant impact on orodental health for affected individuals. Integration of dentists and orthodontists into the multidisciplinary team for management of FS is therefore recommended.
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Síndrome de Fraser/etiologia , Coroa do Dente/anormalidades , Raiz Dentária/anormalidades , Adolescente , Adulto , Anodontia , Proteínas de Transporte/genética , Criança , Proteínas da Matriz Extracelular/genética , Feminino , Síndrome de Fraser/genética , Humanos , Incisivo/anormalidades , Masculino , Má Oclusão , Proteínas do Tecido Nervoso/genética , Radiografia Panorâmica , Coroa do Dente/crescimento & desenvolvimentoRESUMO
Cathepsin C (CatC) is a cysteine protease involved in a variety of immune and inflammatory pathways such as activation of cytotoxicity of various immune cells. Homozygous or compound heterozygous variants in the CatC coding gene CTSC cause different conditions that have in common severe periodontitis. Periodontitis may occur as part of Papillon-Lefèvre syndrome (PLS; OMIM#245000) or Haim-Munk syndrome (HMS; OMIM#245010), or may present as an isolated finding named aggressive periodontitis (AP1; OMIM#170650). AP1 generally affects young children and results in destruction of the periodontal support of the primary dentition. In the present study we report exome sequencing of a three generation consanguineous Turkish family with a recessive form of early-onset AP1. We identified a novel homozygous missense variant in exon 2 of CTSC (NM_148170, c.G302C, p.Trp101Ser) predicted to disrupt protein structure and to be disease causing. This is the first described CTSC variant specific to the nonsyndromic AP1 form. Given the broad phenotypic spectrum associated with CTSC variants, reporting this novel variant gives new insights on genotype/phenotype correlations and might improve diagnosis of patients with early-onset AP1.
Assuntos
Periodontite Agressiva/genética , Catepsina C/genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Periodontite Agressiva/diagnóstico por imagem , Catepsina C/química , Criança , Feminino , Estudos de Associação Genética , Homozigoto , Humanos , Masculino , Turquia , Sequenciamento do ExomaRESUMO
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.
Assuntos
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: Kohlschütter-Tönz syndrome (KTZS) is a rare autosomal-recessive disease characterised by epileptic encephalopathy, intellectual disability and amelogenesis imperfecta (AI). It is frequently caused by biallelic mutations in ROGDI. Here, we report on individuals with ROGDI-negative KTZS carrying biallelic SLC13A5 mutations. METHODS: In the present cohort study, nine individuals from four families with the clinical diagnosis of KTZS and absence of ROGDI mutations as well as one patient with unexplained epileptic encephalopathy were investigated by clinical and dental evaluation, parametric linkage analysis (one family), and exome and/or Sanger sequencing. Dental histological investigations were performed on teeth from individuals with SLC13A5-associated and ROGDI-associated KTZS. RESULTS: Biallelic mutations in SLC13A5 were identified in 10 affected individuals. Epileptic encephalopathy usually presents in the neonatal and (less frequently) early infantile period. Yellowish to orange discolouration of both deciduous and permanent teeth, as well as wide interdental spaces and abnormal crown forms are major clinical signs of individuals with biallelic SLC13A5 mutations. Histological dental investigations confirmed the clinical diagnosis of hypoplastic AI. In comparison, the histological evaluation of a molar assessed from an individual with ROGDI-associated KTZS revealed hypocalcified AI. CONCLUSIONS: We conclude that SLC13A5 is the second major gene associated with the clinical diagnosis of KTZS, characterised by neonatal epileptic encephalopathy and hypoplastic AI. Careful clinical and dental delineation provides clues whether ROGDI or SLC13A5 is the causative gene. Hypersensitivity of teeth as well as high caries risk requires individual dental prophylaxis and attentive dental management.
Assuntos
Amelogênese Imperfeita/genética , Demência/genética , Epilepsia/genética , Predisposição Genética para Doença/genética , Simportadores/genética , Alelos , Encefalopatias/genética , Estudos de Coortes , Exoma/genética , Feminino , Ligação Genética/genética , Humanos , Masculino , Proteínas de Membrana/genética , Mutação/genética , Proteínas Nucleares/genética , Linhagem , DenteRESUMO
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.
Assuntos
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
Latent-transforming growth factor beta-binding protein 3 (LTBP-3) is important for craniofacial morphogenesis and hard tissue mineralization, as it is essential for activation of transforming growth factor-ß (TGF-ß). To investigate the role of LTBP-3 in tooth formation we performed micro-computed tomography (micro-CT), histology, and scanning electron microscopy analyses of adult Ltbp3-/- mice. The Ltbp3-/- mutants presented with unique craniofacial malformations and reductions in enamel formation that began at the matrix formation stage. Organization of maturation-stage ameloblasts was severely disrupted. The lateral side of the incisor was affected most. Reduced enamel mineralization, modification of the enamel prism pattern, and enamel nodules were observed throughout the incisors, as revealed by scanning electron microscopy. Molar roots had internal irregular bulbous-like formations. The cementum thickness was reduced, and microscopic dentinal tubules showed minor nanostructural changes. Thus, LTBP-3 is required for ameloblast differentiation and for the formation of decussating enamel prisms, to prevent enamel nodule formation, and for proper root morphogenesis. Also, and consistent with the role of TGF-ß signaling during mineralization, almost all craniofacial bone components were affected in Ltbp3-/- mice, especially those involving the upper jaw and snout. This mouse model demonstrates phenotypic overlap with Verloes Bourguignon syndrome, also caused by mutation of LTBP3, which is hallmarked by craniofacial anomalies and amelogenesis imperfecta phenotypes.
Assuntos
Amelogênese/genética , Esmalte Dentário/anormalidades , Proteínas de Ligação a TGF-beta Latente/genética , Ameloblastos/metabolismo , Amelogênese Imperfeita/genética , Animais , Esmalte Dentário/ultraestrutura , Genótipo , Masculino , Camundongos , Camundongos Mutantes , Microscopia Eletrônica de Varredura , Mutação , Osteocondrodisplasias/genética , Fenótipo , Calcificação de Dente/genética , Fator de Crescimento Transformador beta/genética , Microtomografia por Raio-XRESUMO
BACKGROUND: Hypophosphatasia (HPP) is a rare inherited metabolic disease in which mutations in the ALPL gene (encoding tissue-nonspecific alkaline phosphatase) result in varying degrees of enzyme deficiency. HPP manifests in a spectrum of symptoms, including early primary tooth loss (root intact) and alveolar bone mineralisation defects. OBJECTIVE: To provide an overview of HPP for dental professionals to help recognise and differentially diagnose patients for appropriate referral to a specialist team. METHODS: A non-systematic review of publications on HPP was performed. RESULTS: Different forms of HPP are described, along with characteristic symptoms and laboratory findings. Diagnosis is challenging due to the rareness and variable presentation of symptoms. Low alkaline phosphatase levels are a signature of HPP, but reference ranges vary according to gender and age. Key features are defined and management strategies discussed, focusing on enzyme replacement therapy. Finally, a patient registry aimed at better defining the prevalence of HPP and raising awareness is described. CONCLUSIONS: HPP is a rare disease with a wide spectrum of manifestations, with orodental symptoms featuring prominently in the natural history. Dental professionals may be positioned at the beginning of the diagnostic pathway; thus, recognition of HPP features for timely referral and optimal disease management is important.
Assuntos
Assistência Odontológica para Crianças , Hipofosfatasia/diagnóstico , Criança , Diagnóstico Diferencial , Humanos , Encaminhamento e ConsultaRESUMO
Inherited dental malformations constitute a clinically and genetically heterogeneous group of disorders. Here, we report on a severe developmental dental defect that results in a dentin dysplasia phenotype with major microdontia, oligodontia, and shape abnormalities in a highly consanguineous family. Homozygosity mapping revealed a unique zone on 6q27-ter. The two affected children were found to carry a homozygous mutation in SMOC2. Knockdown of smoc2 in zebrafish showed pharyngeal teeth that had abnormalities reminiscent of the human phenotype. Moreover, smoc2 depletion in zebrafish affected the expression of three major odontogenesis genes: dlx2, bmp2, and pitx2.
Assuntos
Proteínas de Ligação ao Cálcio/genética , Mapeamento Cromossômico , Displasia da Dentina/genética , Exoma , Homozigoto , Análise de Sequência de DNA , Dente/crescimento & desenvolvimento , Proteínas Adaptadoras de Transdução de Sinal , Animais , Proteínas de Transporte/genética , Criança , Pré-Escolar , Cromossomos Humanos Par 6 , Consanguinidade , Displasia da Dentina/diagnóstico , Feminino , Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Estudos de Associação Genética , Humanos , Camundongos , Dados de Sequência Molecular , Proteínas de Neoplasias/genética , Linhagem , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimentoRESUMO
Importance: Kindler epidermolysis bullosa is a genetic skin-blistering disease associated with recessive inherited pathogenic variants in FERMT1, which encodes kindlin-1. Severe orofacial manifestations of Kindler epidermolysis bullosa, including early oral squamous cell carcinoma, have been reported. Objective: To determine whether hypoplastic pitted amelogenesis imperfecta is a feature of Kindler epidermolysis bullosa. Design, Settings, and Participants: This longitudinal, 2-center cohort study was performed from 2003 to 2023 at the Epidermolysis Bullosa Centre, University of Freiburg, Germany, and the Special Care Dentistry Clinic, University of Chile in association with DEBRA Chile. Participants included a convenience sampling of all patients with a diagnosis of Kindler epidermolysis bullosa. Main Outcomes and Measures: The primary outcomes were the presence of hypoplastic pitted amelogenesis imperfecta, intraoral wounds, gingivitis and periodontal disease, gingival hyperplasia, vestibular obliteration, cheilitis, angular cheilitis, chronic lip wounds, microstomia, and oral squamous cell carcinoma. Results: The cohort consisted of 36 patients (15 female [42%] and 21 male [58%]; mean age at first examination, 23 years [range, 2 weeks to 70 years]) with Kindler epidermolysis bullosa. The follow-up ranged from 1 to 24 years. The enamel structure was assessed in 11 patients, all of whom presented with enamel structure abnormalities. The severity of hypoplastic pitted amelogenesis imperfecta varied from generalized to localized pitting. Additional orofacial features observed include gingivitis and periodontal disease, which was present in 90% (27 of 30 patients) of those assessed, followed by intraoral lesions (16 of 22 patients [73%]), angular cheilitis (24 of 33 patients [73%]), cheilitis (22 of 34 patients [65%]), gingival overgrowth (17 of 26 patients [65%]), microstomia (14 of 25 patients [56%]), and vestibular obliteration (8 of 16 patients [50%]). Other features included chronic lip ulcers (2 patients) and oral squamous cell carcinoma with lethal outcome (2 patients). Conclusions and Relevance: These findings suggest that hypoplastic pitted amelogenesis imperfecta is a feature of Kindler epidermolysis bullosa and underscore the extent and severity of oral manifestations in Kindler epidermolysis bullosa and the need for early and sustained dental care.
Assuntos
Epidermólise Bolhosa , Humanos , Masculino , Feminino , Adulto , Adulto Jovem , Pré-Escolar , Adolescente , Criança , Epidermólise Bolhosa/complicações , Pessoa de Meia-Idade , Estudos Longitudinais , Doenças Periodontais/complicações , Doenças Periodontais/epidemiologia , Carcinoma de Células Escamosas/patologia , Amelogênese Imperfeita/complicações , Amelogênese Imperfeita/genética , Amelogênese Imperfeita/patologia , Estudos de Coortes , Neoplasias Bucais/patologia , Neoplasias Bucais/complicações , Gengivite/patologia , Gengivite/etiologia , Queilite , ChileRESUMO
Rare genetic diseases are difficult to diagnose and this translates in patient's diagnostic odyssey! This is particularly true for more than 900 rare diseases including orodental developmental anomalies such as missing teeth. However, if left untreated, their symptoms can become significant and disabling for the patient. Early detection and rapid management are therefore essential in this context. The i-Dent project aims to supply a pre-diagnostic tool to detect rare diseases with tooth agenesis of varying severity and pattern. To identify missing teeth, image segmentation models (Mask R-CNN, U-Net) have been trained for the automatic detection of teeth on patients' panoramic dental X-rays. Teeth segmentation enables the identification of teeth which are present or missing within the mouth. Furthermore, a dental age assessment is conducted to verify whether the absence of teeth is an anomaly or a characteristic of the patient's age. Due to the small size of our dataset, we developed a new dental age assessment technique based on the tooth eruption rate. Information about missing teeth is then used by a final algorithm based on the agenesis probabilities to propose a pre-diagnosis of a rare disease. The results obtained in detecting three types of genes (PAX9, WNT10A and EDA) by our system are very promising, providing a pre-diagnosis with an average accuracy of 72 %.
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Kohlschütter-Tönz syndrome (KTS) is a rare autosomal recessive disorder characterized by severe intellectual disability, early-onset epileptic seizures, and amelogenesis imperfecta. Here, we present a novel Rogdi mutant mouse deleting exons 6-11- a mutation found in KTS patients disabling ROGDI function. This Rogdi-/- mutant model recapitulates most KTS symptoms. Mutants displayed pentylenetetrazol-induced seizures, confirming epilepsy susceptibility. Spontaneous locomotion and circadian activity tests demonstrate Rogdi mutant hyperactivity mirroring patient spasticity. Object recognition impairment indicates memory deficits. Rogdi-/- mutant enamel was markedly less mature. Scanning electron microscopy confirmed its hypomineralized/hypomature crystallization, as well as its low mineral content. Transcriptomic RNA sequencing of postnatal day 5 lower incisors showed downregulated enamel matrix proteins Enam, Amelx, and Ambn. Enamel crystallization appears highly pH-dependent, cycling between an acidic and neutral pH during enamel maturation. Rogdi-/- teeth exhibit no signs of cyclic dental acidification. Additionally, expression changes in Wdr72, Slc9a3r2, and Atp6v0c were identified as potential contributors to these tooth acidification abnormalities. These proteins interact through the acidifying V-ATPase complex. Here, we present the Rogdi-/- mutant as a novel model to partially decipher KTS pathophysiology. Rogdi-/- mutant defects in acidification might explain the unusual combination of enamel and rare neurological disease symptoms.
Assuntos
Amelogênese Imperfeita , Demência , Epilepsia , Anormalidades Dentárias , Humanos , Animais , Camundongos , Amelogênese Imperfeita/genética , Convulsões , Mutação , Proteínas de Membrana/genética , Proteínas Nucleares/genéticaRESUMO
Tooth formation results from specific epithelial-mesenchymal interactions, which summarize a number of developmental processes. Tooth anomalies may thus reflect subclinical diseases of the kidney, bone and more broadly of the mineral metabolism, skin or nervous system. Odontogenesis starts from the 3rd week of intrauterine life by the odontogenic orientation of epithelial cells by a first PITX2 signal. The second phase is the acquisition of the number, shape, and position of teeth. It depends on multiple transcription and growth factors (BMP, FGF, SHH, WNT). These ecto-mesenchymal interactions guide cell migration, proliferation, apoptosis and differentiation ending in the formation of the specific dental mineralized tissues. Thus, any alteration will have consequences on the tooth structure or shape. Resulting manifestations will have to be considered in the patient phenotype and the multidisciplinary care, but also may contribute to identify the altered genetic circuity.
Title: La dent : un marqueur d'anomalies génétiques du développement. Abstract: L'odontogenèse résulte d'évènements reflétant de multiples processus impliqués dans le développement : crêtes neurales, interactions épithélio-mésenchymateuses, minéralisation. Les anomalies dentaires sont donc d'excellents marqueurs de l'impact de mutations de gènes qui affectent différents systèmes biologiques, tels que le métabolisme minéral, l'os, le rein, la peau ou le système nerveux. Dans cette revue, nous présentons de façon synthétique les gènes impliqués dans plusieurs maladies rares au travers de défauts des dents caractéristiques, de nombre, de forme et de structure.
Assuntos
Transdução de Sinais , Dente , Humanos , Epitélio , Dente/metabolismo , Odontogênese/genética , Diferenciação Celular/genética , Regulação da Expressão Gênica no DesenvolvimentoRESUMO
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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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.
Assuntos
Amelogênese Imperfeita , Má Oclusão , Mordida Aberta , Humanos , Amelogênese Imperfeita/genética , Amelogênese Imperfeita/complicações , Amelogênese Imperfeita/diagnóstico , Genótipo , Fenótipo , Esmalte Dentário , Má Oclusão/complicações , Proteínas/genéticaRESUMO
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.