Teeth are established as targets for vitamin D metabolites but have retained less attention than the well-defined bone cell metabolism. Here we report that VDRgem mice, which bear a point-mutated vitamin D receptor (VDR) unresponsive to the endogenous bioactive vitamin D, are more severely affected and have a greater severity of tooth and alveolar bone defects than VDR-null mice. Transcriptional profiling of postnatal day 5 VDRgem and VDR-null mutant incisors revealed vitamin D ligand signaling targets that promote mineralization, induce alveolar bone growth, and assure dentin integrity. RNA-sequencing analysis of VDRgem mutants uniquely showed defects in developmental targets- notably Hedgehog and Wnt signaling reductions. Micro computed tomography (μCT) and microscopy analysis of adult VDRgem mice unravels severely reduced alveolar bone density, with abnormal root and pulp morphology. VDRgem mutants have severely hypocalcified alveolar bone and dentin- comparatively worse than VDR-null mice- as confirmed by scanning electron microscopy and mineral analysis. This genetically confirmed that vitamin D, acting through its receptor, enables bone and tooth to accumulate enough calcium and phosphorous for structural integrity. In addition, enamel structure is defective in VDRgem mice, displaying hypomineralized areas. Collectively, the severe defects in VDRgem tooth and alveolar bone demonstrate the importance of vitamin D actions at early stages of tooth development.

Enamel–renal syndrome is a rare inherited disorder caused by mutations in FAM20A, characterized by severe dental defects and ectopic mineralization across multiple tissues. Although FAM20A is essential for mineralized tissue development, how its loss disrupts alveolar bone formation remains unclear. Here, we combined clinical, radiographic and patient-derived cell analyses to define the craniofacial and cellular consequences of FAM20A deficiency in a patient with a confirmed FAM20A mutation. Clinical and imaging evaluations revealed severe dental abnormalities and persistent impairment of craniofacial growth during adolescence. Patient-derived alveolar bone cells showed disrupted cellular organization, reduced proliferative capacity and defective osteogenic differentiation. These abnormalities were accompanied by reduced Wnt signaling activity, a central regulator of bone formation. Pharmacological activation of Wnt signaling partially restored osteogenic potential in patient-derived cells, supporting Wnt pathway dysfunction as a targetable mechanism. Together, our findings link FAM20A deficiency to impaired Wnt-dependent osteogenic signaling and provide mechanistic insight into alveolar bone pathology in enamel–renal syndrome.

Although the formation, structure, and biomechanical properties of dentin are well-studied, the impact of dentinogenesis imperfecta (DI) on dentin tissue structure and properties remains poorly understood. This perspective paper aims to summarize current knowledge on dentin and discuss the DI-related effects on dentin biological, structural and biomechanical properties. Macroscopically, DI is easily recognizable in clinics, characterized by a blue/gray appearance of the teeth and rapid pulp chamber obliteration after tooth eruption. Microscopically, the porous structure of healthy dentin is absent; tubules are scarce, and some areas are completely atubular. Clinically, the enamel of DI-affected teeth detaches quickly from the dentin, leading to rapid wear of the dentin under normal masticatory forces. The biomechanical properties of DI-affected dentin are poorly studied and challenging to compare with those of healthy dentin. Various factors, such as hydration, tissue heterogeneity, and the scale of analysis, significantly influence the measurement of these properties. An in-depth exploration of the micro- and nano-structure, as well as the biomechanical properties of dentin affected by DI, would provide a better understanding of the behavior of this diseased tissue in patients. This, in turn, would enable the adaptation of dental restoration treatments to meet the mechanical constraints specific to the oral environment. STATEMENT OF SIGNIFICANCE: This manuscript presents a comprehensive perspective on dentin as a biological material. We detail the dentinogenesis processes that govern healthy dentin formation and its microstructural development. We link dentin's functional biomechanics to its hierarchical organization. The work highlights how Dentinogenesis Imperfecta disrupts dentin structure at multiple scales, resulting in altered mechanical properties. Importantly, it draws direct connections between biological alterations and functional consequences, offering critical insights into structure-function relationships in mineralized tissues. This perspective bridges developmental biology, genetic diseases, and a biomaterials-based approach.

This study reports a skeletal disorder marked by facial dysmorphism and a distinct oro-dental phenotype including premaxillary and gingival overgrowth and hypercementosis. Whole-exome sequencing identified a homozygous missense variant in ENPP5 (c.173G>T; p.Gly58Val), affecting a conserved glycine residue predicted to be within a putative active binding site of the ENPP5 protein. In mice, RNA-seq and immunofluorescence confirmed Enpp5 expression in functional osteoblasts of the maxilla and mandible, periodontal ligament, odontoblasts, and ameloblasts. RT-qPCR confirmed region-specific expression, with higher Enpp5 expression in premaxillary-maxillary bones compared to the tibia, suggesting site-dependent functional roles. This report links, for the first time, a biallelic ENPP5 variant to a novel syndrome involving premaxillary development, bone and cementum growth, highlighting the need for further functional and clinical investigation.

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.

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.

ObjectiveFanconi anemia (FA), a rare genetic disorder, has not been comprehensively studied regarding its dental and craniofacial phenotypes. This study aimed to systematically review the available evidence on dental, occlusion, and craniofacial anomalies in individuals with FA and to describe the occurrence of these anomalies in a cohort from two Brazilian referral centers.Materials and MethodsElectronic searches were conducted across six databases, supplemented by manual searches and gray literature. The Brazilian cohort included 46 patients diagnosed with FA.ResultsA total of 19 articles describing 158 cases of FA were analyzed. The estimated prevalence of dental/craniofacial anomalies ranged from 13.3% to 71.4%. In our cohort, 93.5% of patients exhibited anomalies, primarily root abnormalities (69.6%), tooth rotation (54.3%), and tooth agenesis (26%). Males (p = 0.031) and individuals with endocrine disorders (p = 0.047) were more likely to experience alterations in eruption and/or exfoliation. Anomalies in size and shape were significantly more prevalent among individuals who had undergone hematopoietic stem-cell transplantation at age 14 or older (p = 0.002).ConclusionThe high occurrence of dental/craniofacial anomalies in individuals with FA suggests that these anomalies are part of the disease's phenotypic spectrum, emphasizing the need to expand and standardize the diagnostic criteria of the disease.

Raine syndrome (RNS) is a rare autosomal recessive osteosclerotic dysplasia. RNS is caused by loss-of-function disease-causative variants of the FAM20C gene that encodes a kinase that phosphorylates most of the secreted proteins found in the body fluids and extracellular matrix. The most common RNS clinical features are generalized osteosclerosis, facial dysmorphism, intracerebral calcifications and respiratory defects. In non-lethal RNS forms, oral traits include a well-studied hypoplastic amelogenesis imperfecta (AI) and a much less characterized gingival phenotype. We used immunomorphological, biochemical, and siRNA approaches to analyze gingival tissues and primary cultures of gingival fibroblasts of two unrelated, previously reported RNS patients. We showed that fibrosis, pathological gingival calcifications and increased expression of various profibrotic and pro-osteogenic proteins such as POSTN, SPARC and VIM were common findings. Proteomic analysis of differentially expressed proteins demonstrated that proteins involved in extracellular matrix (ECM) regulation and related to the TGFβ/SMAD signaling pathway were increased. Functional analyses confirmed the upregulation of TGFβ/SMAD signaling and subsequently uncovered the involvement of two closely related transcription cofactors important in fibrogenesis, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Knocking down of FAM20C confirmed the TGFβ-YAP/TAZ interplay indicating that a profibrotic loop enabled gingival fibrosis in RNS patients. In summary, our in vivo and in vitro data provide a detailed description of the RNS gingival phenotype. They show that gingival fibrosis and calcifications are associated with, and most likely caused by excessed ECM production and disorganization. They furthermore uncover the contribution of increased TGFβ–YAP/TAZ signaling in the pathogenesis of the gingival fibrosis.

BACKGROUND:Oral health is an inherent part of overall health as an important physiological crossroad of functions such as mastication, swallowing or phonation; and plays a central role in the life of relationships facilitating social and emotional expression.Our hypothesis was that in patients with rare diseases, access to dental care could be difficult because of the lack of professionals who know the diseases and accept to treat the patients, but also because some patients with cognitive and intellectual disabilities could not find adequate infrastructure to assist in managing their oral health.METHODS:This study employed a qualitative descriptive design including semi-structured interviews using guiding themes. The transcripts were reviewed to identify key themes and interviews were performed until the data were saturated and no further themes emerged.RESULTS:Twenty-nine patients from 7 to 24 years old were included in the study of which 15 patients had an intellectual delay. The results show that access to care is complicated more by aspects concerning intellectual disability than by the fact that the disease is rare. Oral disorders are also an obstacle to the maintenance of their oral health.CONCLUSION:The oral health of patients with rare diseases, can be greatly enhanced by a pooling of knowledge between health professionals in the various sectors around the patient's care. It is essential that this becomes a focus of national public health action that promotes transdisciplinary care for the benefit of these patients.

Amelogenesis imperfecta (AI) is a group of rare genetic conditions characterized by quantitative and/or qualitative tooth enamel alterations. AI can manifest as an isolated trait or as part of a syndrome. Recently, five biallelic disease-causing variants in the RELT gene were identified in 7 families with autosomal recessive amelogenesis imperfecta (ARAI). RELT encodes an orphan receptor in the tumor necrosis factor (TNFR) superfamily expressed during tooth development, with unknown function. Here, we report one Brazilian and two French families with ARAI and a distinctive hypomineralized phenotype with hypoplastic enamel, post-eruptive enamel loss, and occlusal attrition. Using Next Generation Sequencing (NGS), four novel RELT variants were identified (c.120+1G>A, p.(?); c.120+1G>T, p.(?); c.193T>C, p.(Cys65Arg) and c.1260_1263dup, p.(Arg422Glyfs*5)). Our findings extend the knowledge of ARAI dental phenotypes and expand the disease-causing variants spectrum of the RELT gene.

Dentinogenesis imperfecta (DI) is the main orodental manifestation of osteogenesis imperfecta (OI) caused by COL1A1 or COL1A2 heterozygous pathogenic variants. Its prevalence varies according to the studied population. Here, we report the molecular analysis of 81 patients with OI followed at reference centers in Brazil and France presenting COL1A1 or COL1A2 variants. Patients were submitted to clinical and radiographic dental examinations to diagnose the presence of DI. In addition, a systematic literature search and a descriptive statistical analysis were performed to investigate OI/DI phenotype–genotype correlation in a worldwide sample. In our cohort, 50 patients had COL1A1 pathogenic variants, and 31 patients had COL1A2 variants. A total of 25 novel variants were identified. Overall, data from a total of 906 individuals with OI were assessed. Results show that DI was more frequent in severe and moderate OI cases. DI prevalence was also more often associated with COL1A2 (67.6%) than with COL1A1 variants (45.4%) because COL1A2 variants mainly lead to qualitative defects that predispose to DI more than quantitative defects. For the first time, 4 DI hotspots were identified. In addition, we showed that 1) glycine substitution by branched and charged amino acids in the α2(I) chain and 2) substitutions occurring in major ligand binding regions—MLRB2 in α1(I) and MLBR 3 in α2(I)—could significantly predict DI ( P < 0.05). The accumulated variant data analysis in this study provides a further basis for increasing our comprehension to better predict the occurrence and severity of DI and appropriate OI patient management.

Developmental Defects of Enamel (DDE) such as Dental Fluorosis (DF) and Molar Incisor Hypomineralization (MIH) are a major public health problem. Their clinical aspects are extremely variable, challenging their early and specific diagnosis and hindering progresses in restorative treatments. Here, a combination of macro-, micro-and nano-scale structural and chemical methods, including, among others, Atom Probe Tomography recently applied on tooth enamel, were used to study and compare MIH, DF and healthy teeth from 89 patients. Globally, we show that DF is characterized by an homogenous loss of mineral content and crystallinity mainly disrupting outside layer of enamel, whereas MIH is associated with localized defects in the depth of enamel where crystalline mineral particles are embedded in an organic phase. Only minor differences in elemental composition of the mineral phase could be detected at the nanoscale such as increased F and Fe content in both severe DDE. We demonstrate that an improved digital color measurement of clinical relevance can discriminate between DF and MIH lesions, both in mild and severe forms. Such discriminating ability was discussed in the light of enamel composition and structure, especially its microstructure, organics presence and metal content (Fe, Zn). Our results offer additional insights on DDE characterization and pathogenesis, highlight the potentiality of colorimetric measurements in their clinical diagnosis and provide leads to improve the performance of minimally in-vasive restorative strategies.Statement of significance Developmental Defects of Enamel (DDE) are associated to caries and tooth loose affecting billions of people worldwide. Their precise characterization for adapted minimally invasive care with optimized materials is highly expected. Here In this study, first we propose the use of color parameters measured by a spectrophotometer as a means of differential clinical diagnosis. Second, we have used state-of-the-art techniques to systematically characterize the structure, chemical composition and mechanical optical properties of dental enamel teeth affected by two major DDE, Dental Fluorosis (DF) or Molar Incisor Hypomineralization (MIH). We evidence specific enamel structural and optical features for DF and MIH while chemical modifications of the mineral nanocrystals were mostly correlated with lesion severity. Our results pave the way of the concept of personalized dentistry. In the light of our results, we propose a new means of clinical diagnosis for an adapted and improved restoration protocol for these patients.(c) 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Purpose: To review the oral prosthetic rehabilitation of patients with epidermolysis bullosa hereditaria (EBH) and study the level of evidence and quality of the presented available articles and establish clinical recommendations for the prosthetic management of these patients. Materials and Methods: An electronic search was done in July 2022 in five databases following PICOTS elements. The quality of the reports was established using the modified Pierson, Bradford Hills, and Ottawa Newcastle scale. Results: Data extracted from 19 case reports for protocolized analysis corresponded to 64 patients and 80 dental prostheses, with almost 9 out of 10 patients being completely edentulous. The distribution of EBH types was 84% dystrophic, 10.5% junctional, and 5.5% simplex. The difficulties encountered by the authors synthesized in this review characteristically reflected those most likely encountered in dental practice. Most rehabilitations were implant-supported prostheses (85%), followed by removable dentures (10%) and dental-supported rehabilitations (5%). Fixed full-arch implant-supported prostheses represented 76.4% of implant-supported prostheses, and this prosthetic solution reflected the highest scientific quality. Conclusions: For an individualized approach to treatment, we recommend that in cases of total edentulism, fixed full-arch implant-supported prostheses are the most appropriate because they allow the best computer-aided planning, design, manufacture, and fitting of the prosthesis in such a complex clinical context. Int J Prosthodont 2024;37:699-710. doi: 10.11607fijp.8791

Abstract Background Around 8000 rare diseases are currently defined. In the context of individual vulnerability and more specifically the one induced by rare diseases, ensuring oral health is a particularly important issue. The objective of the study is to evaluate the pattern of oral health care course for patients with any rare genetic disease. Description of oral phenotypic signs—which predict a theoretical dental health care course—and effective orientation into an oral healthcare were evaluated. Materials and methods We set up a retrospective cohort study to describe the consideration of patient oral health and potential orientation to an oral health care course who have at least been seen once between 1 January 2017 and 1 January 2020 in Necker Enfants Malades Hospital. We recruited patients from this study using the data warehouse, Dr Warehouse® (DrWH), from Necker-Enfants Malades Hospital. Results The study sample included 39 rare diseases, 2712 patients, with 54.7% girls and 45.3% boys. In the sample studied, 27.9% of patients had an acquisition delay or a pervasive developmental disorder. Among the patient files studied, oral and dental phenotypic signs were described for 18.40% of the patients, and an orientation in an oral healthcare was made in 15.60% of patients. The overall "network" effect was significantly associated with description of phenotypic signs (corrected p = 1.44e−77) and orientation to an oral healthcare (corrected p = 23.58e−44). Taking the Defiscience network (rare diseases of cerebral development and intellectual disability) as a reference for the odd ratio analysis, OSCAR, TETECOU, FILNEMUS, FIMARAD, MHEMO networks stand out from the other networks for their significantly higher consideration of oral phenotypic signs and orientation in an oral healthcare. Conclusion To our knowledge, no study has explored the management of oral health in so many rare diseases. The expected benefits of this study are, among others, a better understanding, and a better knowledge of the oral care, or at least of the consideration of oral care, in patients with rare diseases. Moreover, with the will to improve the knowledge on genetic diseases, oral heath must have a major place in the deep patient phenotyping. Therefore, interdisciplinary consultations with health professionals from different fields are crucial.

Craniofacial and jaw bones have unique physiological specificities when compared to axial and appendicular bones. However, the molecular profile of the jaw osteoblast (OB) remains incomplete. The present study aimed to decipher the bone site-specific profiles of transcription factors (TFs) expressed in OBs in vivo. Using RNA sequencing analysis, we mapped the transcriptome of confirmed OBs from 2 different skeletal sites: mandible (Md) and tibia (Tb). The OB transcriptome contains 709 TF genes: 608 are similarly expressed in Md-OB and Tb-OB, referred to as “OB-core”; 54 TF genes are upregulated in Md-OB, referred to as “Md-set”; and 18 TF genes are upregulated in Tb-OB, referred to as “Tb-set.” Notably, the expression of 29 additional TF genes depends on their RNA transcript variants. TF genes with no previously known role in OBs and bone were identified. Bioinformatics analysis combined with review of genetic disease databases and a comprehensive literature search showed a significant contribution of anatomical origin to the OB signatures. Md-set and Tb-set are enriched with site-specific TF genes associated with development and morphogenesis (neural crest vs. mesoderm), and this developmental imprint persists during growth and homeostasis. Jaw and tibia site-specific OB signatures are associated with craniofacial and appendicular skeletal disorders as well as neurocristopathies, dental disorders, and digit malformations. The present study demonstrates the feasibility of a new method to isolate pure OB populations and map their gene expression signature in the context of OB physiological environment, avoiding in vitro culture and its associated biases. Our results provide insights into the site-specific developmental pathways governing OBs and identify new major OB regulators of bone physiology. We also established the importance of the OB transcriptome as a prognostic tool for human rare bone diseases to explore the hidden pathophysiology of craniofacial malformations, among the most prevalent congenital defects in humans.