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SummaryOsteogenesis imperfecta (OI) is a disease causing bone fragility; however, it potentially affects all organs with a high content of collagen, including ears, teeth, and eyes. The study is cross-sectional and compares non-skeletal characteristics in adults with OI that clinicians should be aware of when caring for patients with OI.IntroductionOsteogenesis imperfecta (OI) is a hereditary connective tissue disorder. The skeletal fragility is pronounced; however, OI leads to a number of extra-skeletal symptoms related to the ubiquity of collagen type 1 throughout the human body. The vast majority of knowledge is derived from studies performed in the pediatric population. Thus, we aimed to investigate the nature and prevalence of ophthalmologic, odontologic, and otologic phenotypes in an adult population with OI.MethodsThe study population comprises 85 Danish OI patients (age 44.9 ± 15.9 years). Fifty-eight patients had OI type I, 12 OI type III, and 15 OI type IV according to the classification by Sillence. Audiometric evaluations and dental examinations were performed in 62 and 73 patients, respectively. Ophthalmologic investigations were performed in 64 patients, including measurements of the central corneal thickness.ResultsAll patients, except two, had corneal thickness below the normal reference value. Patients with OI type I and patients with a quantitative collagen defect had thinner corneas compared to patients with OI type III and other patients with a qualitative collagen defect. One patient in this cohort was diagnosed with and treated for acute glaucoma. Dentinogenesis imperfecta was diagnosed in one fourth of the patients, based on clinical and radiographic findings. This condition was predominately seen in patients with moderate to severe OI. Hearing loss requiring treatment was found in 15 of 62 patients, of whom three were untreated. The most prevalent type of hearing loss (HL) was sensorineural hearing loss, whereas conductive HL was solely seen in patients with OI type III. The patients with the most severe degrees of HL were patients with mild forms of OI. Age was associated with increased HL.ConclusionAlthough significant health problems outside the skeleton are frequent in adult patients with OI, the patients are not consistently monitored and treated for their symptoms. Clinicians treating adult patients with OI should be aware of non-skeletal health issues and consider including regular interdisciplinary check-ups in the management plan for adult OI patients.

Non-syndromic inherited defects of tooth dentin are caused by two classes of dominant negative/gain-of-function mutations in dentin sialophosphoprotein ( DSPP ): 5′ mutations affecting an N-terminal targeting sequence and 3′ mutations that shift translation into the − 1 reading frame. DSPP defects cause an overlapping spectrum of phenotypes classified as dentin dysplasia type II and dentinogenesis imperfecta types II and III. Using CRISPR/Cas9, we generated a Dspp −1fs mouse model by introducing a FLAG-tag followed by a single nucleotide deletion that translated 493 extraneous amino acids before termination. Developing incisors and/or molars from this mouse and a Dspp P19L mouse were characterized by morphological assessment, bSEM, nanohardness testing, histological analysis, in situ hybridization and immunohistochemistry. Dspp P19L dentin contained dentinal tubules but grew slowly and was softer and less mineralized than the wild-type. Dspp P19L incisor enamel was softer than normal, while molar enamel showed reduced rod/interrod definition. Dspp −1fs dentin formation was analogous to reparative dentin: it lacked dentinal tubules, contained cellular debris, and was significantly softer and thinner than Dspp +/+ and Dspp P19L dentin. The Dspp −1fs incisor enamel appeared normal and was comparable to the wild-type in hardness. We conclude that 5′ and 3′ Dspp mutations cause dental malformations through different pathological mechanisms and can be regarded as distinct disorders.

Dentinogenesis imperfecta is an autosomal dominant disease characterized by severe hypomineralization of dentin and altered dentin structure. Dentin extra cellular matrix is composed of 90% of collagen type I and 10% of non-collagenous proteins among which dentin sialoprotein (DSP), dentin glycoprotein (DGP) and dentin phosphoprotein (DPP) are crucial in dentinogenesis. These proteins are encoded by a single gene: dentin sialophosphoprotein (DSPP) and undergo several post-translational modifications such as glycosylation and phosphorylation to contribute and to control mineralization. Human mutations of this DSPP gene are responsible for three isolated dentinal diseases classified by Shield in 1973: type II and III dentinogenesis imperfecta and type II dentin dysplasia. Shield classification was based on clinical phenotypes observed in patient. Genetics results show now that these three diseases are a severity variation of the same pathology. So this review aims to revise and to propose a new classification of the isolated forms of DI to simplify diagnosis for practitioners.

Objectives This study investigated the nanomechanical properties, microstructure, and composition of dentinogenesis imperfecta type II (DGI-II) peritubular dentin (PTD) and intertubular dentin (ITD) and examined the correlations between them. Materials and methods Six samples from each of the normal and DGI-II groups were prepared by cutting the midcoronal dentin perpendicular to the dentin tubules. The number and morphology of the dentin tubules were then observed by scanning electron microscopy (SEM). Hydroxyapatite (HAP) was detected using high-resolution atomic force microscopy (HR-AFM). The chemical composition was determined using atomic force microscopy-infrared spectroscopy (AFM-IR). The nanomechanical properties were evaluated using amplitude modulation-frequency modulation (AM-FM) techniques. Finally, a multiple linear regression (MLR) model was used to verify the correlations between PTD and ITD. Results SEM of the DGI-II dentin revealed a considerable reduction in the number and area of the tubules. HR-AFM revealed dramatic increases in the HAP particle size and DGI-II dentin nanoscale roughness, especially PTDs. AFM-IR revealed that in the DGI-II groups, the phosphate content decreased in both the PTDs and ITDs, whereas the amide I (A-I) and amide II (A-II) content was elevated in the ITDs. AM-FM testing revealed a considerable reduction in the Young’s modulus and increases in the PTD and ITD indentations in the DGI-II dentin. MLR demonstrated that the changes in microstructure and composition were related to a decrease in the nanomechanical properties of the DGI-II dentin. Conclusions The DGI-II dentin nanomechanical properties deteriorated considerably, especially those of the PTDs, presumably because of alterations in the HAP and chemical composition. Clinical relevance Understanding the nanomechanical properties, microstructure, and composition of DGI-II dentin could help dentists develop novel individualized restorative techniques.

By the Shields classification, articulated over 30 years ago, inherited dentin defects are divided into 5 types: 3 types of dentinogenesis imperfecta (DGI), and 2 types of dentin dysplasia (DD). DGI type I is osteogenesis imperfecta (OI) with DGI. OI with DGI is caused, in most cases, by mutations in the 2 genes encoding type I collagen. Many genes are required to generate the enzymes that catalyze collagen’s diverse post-translational modifications and its assembly into fibers, fibrils, bundles, and networks. Rare inherited diseases of bone are caused by defects in these genes, and some are occasionally found to include DGI as a feature. Appreciation of the complicated genetic etiology of DGI associated with bony defects splintered the DGI type I description into a multitude of more precisely defined entities, all with their own designations. In contrast, DD-II, DGI-II, and DGI-III, each with its own pattern of inherited defects limited to the dentition, have been found to be caused by various defects in DSPP (dentin sialophosphoprotein), a gene encoding the major non-collagenous proteins of dentin. Only DD-I, an exceedingly rare condition featuring short, blunt roots with obliterated pulp chambers, remains untouched by the revolution in genetics, and its etiology is still a mystery. A major surprise in the characterization of genes underlying inherited dentin defects is the apparent lack of roles played by the genes encoding the less-abundant non-collagenous proteins in dentin, such as dentin matrix protein 1 (DMP1), integrin-binding sialoprotein (IBSP), matrix extracellular phosphoglycoprotein (MEPE), and secreted phosphoprotein-1, or osteopontin (SPP1, OPN). This review discusses the development of the dentin extracellular matrix in the context of its evolution, and discusses the phenotypes and clinical classifications of isolated hereditary defects of tooth dentin in the context of recent genetic data respecting their genetic etiologies.

Dentinogenesis imperfecta type 1 (OIDI) is considered a relatively rare genetic disorder (1:5000 to 1:45,000) associated with osteogenesis imperfecta. OIDI impacts the formation of collagen fibrils in dentin, leading to morphological and structural changes that affect the strength and appearance of teeth. However, there is still a lack of understanding regarding the nanoscale characterization of the disease, in terms of collagen ultrastructure and mechanical properties. Therefore, this research presents a qualitative and quantitative report into the phenotype and characterization of OIDI in dentin, by using a combination of imaging, nanomechanical approaches. For this study, 8 primary molars from OIDI patients and 8 primary control molars were collected, embedded in acrylic resin and cut into longitudinal sections. Sections were then demineralized in 37% phosphoric acid using a protocol developed in-house. Initial experiments demonstrated the effectiveness of the demineralization protocol, as the ATR-FTIR spectral fingerprints showed an increase in the amide bands together with a decrease in phosphate content. Structural and mechanical analyses were performed directly on both the mineralized and demineralized samples using a combination of scanning electron microscopy, atomic force microscopy, and Wallace indentation. Mesoscale imaging showed alterations in dentinal tubule morphology in OIDI patients, with a reduced number of tubules and a decreased tubule diameter compared to healthy controls. Nanoscale collagen ultrastructure presented a similar D-banding periodicity between OIDI and controls. Reduced collagen fibrils diameter was also recorded for the OIDI group. The hardness of the (mineralized) control dentin was found to be significantly higher (p<0.05) than that of the OIDI (mineralized) dentine. Both the exposed peri- and intratubular dentinal collagen presented bimodal elastic behaviors (Young's moduli). The control samples presented a stiffening of the intratubular collagen when compared to the peritubular collagen. In case of the OIDI, this stiffening in the collagen between peri- and intratubular dentinal collagen was not observed and the exposed collagen presented overall a lower elasticity than the control samples. This study presents a systematic approach to the characterization of collagen structure and properties in OIDI as diagnosed in dentin. Structural markers for OIDI at the mesoscale and nanoscale were found and correlated with an observed lack of increased elastic moduli of the collagen fibrils in the intratubular OIDI dentin. These findings offer an explanation of how structural changes in the dentin could be responsible for the failure of some adhesive restorative materials as observed in patients affected by OIDI.

Objective This study aims to analyze the clinical features and genetic mutation characteristics of a family with Dentinogenesis Imperfecta Shields type II (DGI-II) and to observe the behavior of the stem cells from human exfoliated deciduous teeth (SHED) to explore the relationship between the locus of dentin sialophosphoprotein ( DSPP ) mutations and family clinical manifestations. Materials and methods After collecting clinical data from the family, Whole Genome Sequencing (WGS) followed by Sanger sequencing was used to identify pathogenic genes sites. The physical characteristics of the patient’s teeth were examined using Micro-CT, scanning electron microscopy (SEM), and microhardness analysis. The behavior of SHEDs was studied through flow cytometry, adipogenic and osteogenic differentiation, quantitative real-time PCR (qRT-PCR), Western blotting, CCK-8 proliferation assays, colony formation, and cell migration experiments. Results A novel frameshift mutation, DSPP c.2695delA.N899fs, was identified in the family. Micro-CT showed significant wear in the patient’s teeth. SEM results revealed reduced and irregular dentinal tubules. Microhardness analysis showed significantly lower hardness in the patient’s teeth. CCK-8, colony formation, and migration assays demonstrated reduced proliferation and migration capacities in the patient’s SHEDs. qRT-PCR and Western blot results showed lower expression of DSPP , RUNX2 , OCN , and ALP compared to controls, but higher DSPP protein level in the patient’s SHEDs. Osteogenic differentiation tests indicated reduced mineralization capacity of the patient’s SHEDs. Conclusion This study identified a novel frameshift mutation, DSPP c.2695delA.N899fs, in a DGI-II family and demonstrated its impact on SHED proliferation, migration, and mineralization. The findings demonstrated that this novel variant disturbs dentinal characteristics and cell behavior of SHED. Significance This study provides insights into the genetic and cellular basis of DGI-II, elucidating the role of a novel DSPP mutation in tooth structure development and stem cell behavior. However, in vivo validation of this DSPP mutation is important to further confirm this conclusion.

Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by fragile bones and skeletal deformities. Individuals with OI may have dental abnormalities such as dentinogenesis imperfecta (DI) type I, malocclusions, and unerupted or missing teeth. This review comprehensively examines these dental abnormalities to assess their prevalence among the OI population and explore potential differences across different clinical types of OI and pathogenic variants. In accordance with the PRISMA guidelines, a systematic literature search in PubMed, Embase, and Web of Science was conducted that included articles up to June 2024. Out of 672 articles screened, 34 were included. The included studies confirmed that dental abnormalities are prevalent in OI, with DI prevalence ranging from approximately 20 to 48%. Those with a more severe skeletal phenotype (OI type III/IV) exhibited more dental abnormalities than those with a milder skeletal phenotype (OI type I). Notably, OI type V individuals generally do not have DI, although a few isolated cases have been reported. The prevalence of occlusion types varied: Class I occlusion ranged from 14.8 to 50% and Class II malocclusion ranged from 0 to 37.5%, while Class III malocclusion from 4.1 to 84%. This differs from the general population, where Class III malocclusion is typically the least common. Open bites, cross-bites, and unerupted and missing teeth are also commonly reported, particularly in OI types III and IV. This review emphasizes the need for comprehensive dental examinations in OI due to the high prevalence of dental abnormalities. Additionally, the review draws attention to the lack of clear guidelines for diagnosing DI.

Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by bone fragility. Its association with dentinogenesis imperfecta (DI) is well documented, but the concurrent presentation with nephrocalcinosis is uncommon and poorly understood. We documented the case of an 18-year-old male presenting with a triad of OI, DI, and nephrocalcinosis. The patient exhibited characteristic features including blue sclera, multiple fractures, dental abnormalities, bowing of long bones, a short stature, and biochemical evidence of altered calcium metabolism. Genetic testing revealed mutations in COL1A1, confirming the diagnosis of OI Type I. This case highlights the importance of comprehensive evaluation in OI patients, emphasizing the need for dental and renal assessment. The presence of nephrocalcinosis in OI demands further investigation into the mechanisms of calcium dysregulation in disorders of these kinds.

Osteogenesis imperfecta (OI) is a heterogeneous group of disorders of connective tissue, caused mainly by mutations in the collagen I genes (COL1A1 and COL1A2). Dentinogenesis imperfecta (DGI) and other dental aberrations are common features of OI. We investigated the association between collagen I mutations and DGI, taurodontism, and retention of permanent second molars in a retrospective cohort of 152 unrelated children and adolescents with OI. The clinical examination included radiographic evaluations. Teeth from 81 individuals were available for histopathological evaluation. COL1A1/2 mutations were found in 104 individuals by nucleotide sequencing. DGI was diagnosed clinically and radiographically in 29% of the individuals (44/152) and through isolated histological findings in another 19% (29/152). In the individuals with a COL1A1 mutation, 70% (7/10) of those with a glycine substitution located C-terminal of p.Gly305 exhibited DGI in both dentitions while no individual (0/7) with a mutation N-terminal of this point exhibited DGI in either dentition (p = 0.01). In the individuals with a COL1A2 mutation, 80% (8/10) of those with a glycine substitution located C terminal of p.Gly211 exhibited DGI in both dentitions while no individual (0/5) with a mutation N-terminal of this point (p = 0.007) exhibited DGI in either dentition. DGI was restricted to the deciduous dentition in 20 individuals. Seventeen had missense mutations where glycine to serine was the most prevalent substitution (53%). Taurodontism occurred in 18% and retention of permanent second molars in 31% of the adolescents. Dental aberrations are strongly associated with qualitatively changed collagen I. The varying expressivity of DGI is related to the location of the collagen I mutation. Genotype information may be helpful in identifying individuals with OI who have an increased risk of dental aberrations.