Isolated dentinogenesis imperfecta: Novel DSPP variants and insights on genetic counselling.

OBJECTIVE: Dentinogenesis imperfecta (DI) is an inherited dentin defect and may be isolated or associated with disorders such as osteogenesis imperfecta, odontochondrodysplasia Ehler-Danlos and others. Isolated DI is caused mainly by pathogenic variants in DSPP gene and around 50 different variants have been described in this gene. Herein, we report on 19 patients from two unrelated Egyptian families with isolated DI. Additionally, we focused on genetic counselling of the two families. MATERIALS AND METHODS: The patients were examined clinically and dentally. Panoramic X-rays were done to some patients. Whole exome sequencing (WES) and Sanger sequencing were used. RESULTS: WES revealed two new nonsense variants in DSPP gene, c.288T > A (p.Tyr96Ter) and c.255G > A (p.Trp85Ter). Segregation analysis by Sanger sequencing confirmed the presence of the first variant in all affected members of Family 1 while the second variant was confirmed to be de novo in the patient of Family 2. CONCLUSIONS AND CLINICAL RELEVANCE: Our study extends the number of DSPP pathogenic variants and strengthens the fact that DSPP is the most common DI causative gene irrespective of patients' ethnicity. In addition, we provide insights on genetic counseling issues in patients with inherited DSPP variants taking into consideration the variable religion, culture and laws in our society.

Dentinogenesis imperfecta: case report with nanoceramic resin crowns restorative treatment.

Children with dentinogenesis imperfecta require restorative or prosthodontic treatment to minimize the aesthetic and functional impact of the condition. This clinical case report describes the oral rehabilitation procedure in a 12-year-old patient with dentinogenesis imperfecta type II using nanoceramic resin crowns fabricated with Computer-Aided Design/Computer-Aided Manufacturing (CAD/CAM) technology and the patient's progression over eight years. This minimal intervention approach enabled functional and aesthetic reestablishment along with tooth wear prevention. The result simplified an extensive prosthetic procedure and facilitated an affordable rehabilitation for the young patient while providing excellent long-term outcomes.

The Role of DSPP in Dentine Formation and Hereditary Dentine Defects.

The dentine sialophosphoprotein (DSPP) gene is the only identified causative gene for dentinogenesis imperfecta type 2 (DGI-II), dentinogenesis imperfecta type 3 (DGI-III) and dentine dysplasia type 2 (DD-II). These three disorders may have similar molecular mechanisms involved in bridging the DSPP mutations and the resulting abnormal dentine mineralisation. The DSPP encoding proteins DSP (dentine sialoprotein) and DPP (dentine phosphoprotein) are positive regulators of dentine formation and perform a function during dentinogenesis. The present review focused on the recent findings and viewpoints regarding the relationship between DSPP and dentinogenesis as well as mineralisation from multiple perspectives, involving studies relating to spatial structure and tissue localisation of DSPP, DSP and DPP, the biochemical characteristics and biological function of these molecules, and the causative role of the proteins in phenotypes of the knockout mouse model and in hereditary dentine defects.

Establishment of a clinical network for children with amelogenesis imperfecta and dentinogenesis imperfecta in the UK: 4-year experience.

BACKGROUND: Amelogenesis imperfecta (AI) and dentinogenesis imperfecta (DI) are two groups of genetically inherited conditions resulting in abnormal enamel and dentin formation, respectively. Children and young people may be adversely affected by these conditions, with significant reduction in oral health related quality of life. Dental management of children with AI and DI is often complex, which is exacerbated by the absence of clear referral pathways and scarce evidence-based guidelines. METHOD: The need for increased knowledge and peer support led to the development of a group of UK paediatric dentists with a special clinical interest in the management of children with AI and DI. PURPOSE: The aims of this paper are to describe the establishment of an AI/DI Clinical Excellence Network (AI/DI CEN) in paediatric dentistry including outputs and future plans, and to share our collective learning to help support others anywhere in the world advance the care of people with AI or DI.

A novel approach to full-mouth rehabilitation of dentinogenesis imperfecta type II: Case series with review of literature.

RATIONALE: Dentinogenesis imperfecta (DI) is an autosomal-dominant disorder. The most common clinical manifestations, including obliterated tooth tissues and severe tooth wear, usually lead to tooth extractions. It remains a great challenge for dentists to preserve the residual tooth tissue and establish the esthetics and occlusion of dentitions. PATIENTS CONCERNS: 25-year-old twin sisters, who had suffered from dentinogenesis imperfecta type II for more than 10 years, presented with continuous tooth wear and discomfort from wearing a removable partial denture for more than 3 years. DIAGNOSIS: Intraoral examination showed extensive tooth wear with enamel exfoliation and typical amber-brown color with an opalescent discoloration. Their panoramic radiographs revealed completely obliterated tooth tissues and severe tooth wear. INTERVENTIONS AND OUTCOMES: The dentitions were restored with post-and-core crowns and pin lays after preparing root post paths and pin holes guided by computer-aided design/computer-aided manufacturing (CAD/CAM) procedures, resulting in a successful repair. LESSONS: Severe tooth wear and tooth tissue obliteration are typical clinical manifestations in DI-affected dentitions, increasing the complexity and difficulty in dental restorations. Early diagnosis and appropriate treatments are essential to achieve a favorable prognosis. CAD/CAM procedures, permitting accurate and effective treatment, possess promising potential in the treatment of DI-affected dentitions.

[Recognition on dentin dysplasia type â ¡].

Dentin dysplasia type Ⅱ (DD-Ⅱ) is a subtype of hereditary dentin disorders. The dentin sialophosphoprotein (DSPP) gene has been revealed to be the causative gene, whose mutations could affect the normal tooth development process. The lesions involve both deciduous and permanent dentition, mainly manifested as tooth discoloration, attrition and even the subsequent malocclusion. If not treated in time, it will significantly affect the physical and psychological health of patients. The disease is difficult to be diagnosed in clinic accurately as its low incidence and hidden manifestations. The present article aims to discuss the clinical and radiographic characteristics, diagnosis, treatment of DD-Ⅱ, in order to improve the overall understanding on DD-Ⅱ for clinicians.

AAV6-Mediated Gene Therapy Prevents Developmental Dentin Defects in a Dentinogenesis Imperfecta Type â ¢ Mouse Model.

Dentin is a major type of hard tissue of teeth and plays essential roles for normal tooth function. Odontoblasts are responsible for dentin formation. Mutations or deficiency in various genes affect the differentiation of odontoblasts, leading to irreversible dentin developmental defects in animals and humans. Whether such dentin defects can be reversed by gene therapy for odontoblasts remains unknown. In this study, we compare the infection efficiencies of six commonly used adeno-associated virus (AAV) serotypes (AAV1, AAV5, AAV6, AAV8, AAV9, and AAVDJ) in cultured mouse odontoblast-like cells (OLCs). We show that AAV6 serotype infects OLCs with the highest efficiency among the six AAVs. Two cellular receptors, which are able to recognize AAV6, AAV receptor (AAVR), and epidermal growth factor receptor (EGFR), are strongly expressed in the odontoblast layer of mouse teeth. After local administration to mouse molars, AAV6 infects the odontoblast layer with high efficiency. Furthermore, AAV6-Mdm2 was successfully delivered to teeth and prevents the defects in odontoblast differentiation and dentin formation in Mdm2 conditional knockout mice (a mouse model of dentinogenesis imperfecta type Ⅲ). These results suggest that AAV6 can serve as a reliable and efficient vehicle for gene delivery to odontoblasts through local injection. In addition, human OLCs were also successfully infected by AAV6 with high efficiency, and both AAVR and EGFR are strongly expressed in the odontoblast layer of extracted human developing teeth. These findings suggest that AAV6-mediated gene therapy through local injection may be a promising treatment approach for hereditary dentin disorders in humans.

Novel dentin sialophosphoprotein gene frameshift mutations affect dentin mineralization.

OBJECTIVE: This study aimed to identify candidate genes for inheritable dentin defects in three Chinese pedigrees and characterize the property of affected teeth. DESIGN: Clinical and radiological features were recorded for the affected individuals. Genomic DNA obtained from peripheral venous blood or saliva were analyzed by whole-exome sequencing. The density and microhardness of affected dentin was measured. Scanning electron microscopy (SEM) was also performed to obtain the microstructure phenotype. RESULTS: 1) General appearance: the affected dentitions shared yellowish-brown or milky color. Radiographs showed that the pulp cavity and root canals were obliterated in varying degrees or exhibited a pulp aspect in the 'thistle tube'. Some patients exhibited periapical infections without pulpal exposure, and some affected individuals showed shortened, abnormally thin roots accompanied by severe alveolar bone loss. 2) Genomic analysis: three new frameshift mutations (NM_014208.3: c.2833delA, c.2852delGand c.3239delA) were identified in exon 5 of dentin sialophosphoprotein (DSPP) gene, altering dentin phosphoprotein (DPP) as result. In vitro studies showed that the density and microhardness of affected dentin were decreased, the dentinal tubules were sparse and arranged disorderly, and the dentinal-enamel-junction (DEJ) was abnormal. CONCLUSIONS: In this study, we identified three novel frameshift mutations of dentin sialophosphoprotein gene related to inherited dentin defects. These mutations are speculated to cause abnormal coding of dentin phosphoprotein C-terminus, which affect dentin mineralization. These results expand the spectrum of dentin sialophosphoprotein gene mutations causing inheritable dentin defects and broaden our understanding of the biological mechanisms by which dentin forms.

Hereditary dentin defects with systemic diseases.

OBJECTIVE: This review aimed to summarize recent progress on syndromic dentin defects, promoting a better understanding of systemic diseases with dentin malformations, the molecules involved, and related mechanisms. SUBJECTS AND METHODS: References on genetic diseases with dentin malformations were obtained from various sources, including PubMed, OMIM, NCBI, and other websites. The clinical phenotypes and genetic backgrounds of these diseases were then summarized, analyzed, and compared. RESULTS: Over 10 systemic diseases, including osteogenesis imperfecta, hypophosphatemic rickets, vitamin D-dependent rickets, familial tumoral calcinosis, Ehlers-Danlos syndrome, Schimke immuno-osseous dysplasia, hypophosphatasia, Elsahy-Waters syndrome, Singleton-Merten syndrome, odontochondrodysplasia, and microcephalic osteodysplastic primordial dwarfism type II were examined. Most of these are bone disorders, and their pathogenic genes may regulate both dentin and bone development, involving extracellular matrix, cell differentiation, and metabolism of calcium, phosphorus, and vitamin D. The phenotypes of these syndromic dentin defects various with the involved genes, part of them are similar to dentinogenesis imperfecta or dentin dysplasia, while others only present one or two types of dentin abnormalities such as discoloration, irregular enlarged or obliterated pulp and canal, or root malformation. CONCLUSION: Some specific dentin defects associated with systemic diseases may serve as important phenotypes for dentists to diagnose. Furthermore, mechanistic studies on syndromic dentin defects may provide valuable insights into isolated dentin defects and general dentin development or mineralization.

Identification of DSPP novel variants and phenotype analysis in dentinogenesis dysplasia Shields type II patients.

OBJECTIVES: To investigate the genetic causes and teeth characteristics of dentin dysplasia Shields type II(DD-II) in three Chinese families. MATERIALS AND METHODS: Data from three Chinese families affected with DD-II were collected. Whole-exome sequencing (WES) and whole-genome sequencing (WGS) were conducted to screen for variations, and Sanger sequencing was used to verify mutation sites. The physical and chemical characteristics of the affected teeth including tooth structure, hardness, mineral content, and ultrastructure were investigated. RESULTS: A novel frameshift deletion mutation c.1871_1874del(p.Ser624fs) in DSPP was found in families A and B, while no pathogenic mutation was found in family C. The affected teeth's pulp cavities were obliterated, and the root canals were smaller than normal teeth and irregularly distributed comprising a network. The patients' teeth also had reduced dentin hardness and highly irregular dentinal tubules. The Mg content of the teeth was significantly lower than that of the controls, but the Na content was obviously higher than that of the controls. CONCLUSIONS: A novel frameshift deletion mutation, c.1871_1874del (p.Ser624fs), in the DPP region of the DSPP gene causes DD-II. The DD-II teeth demonstrated compromised mechanical properties and changed ultrastructure, suggesting an impaired function of DPP. Our findings expand the mutational spectrum of the DSPP gene and strengthen the understanding of clinical phenotypes related to the frameshift deletion in the DPP region of the DSPP gene. CLINICAL RELEVANCE: A DSPP mutation can alter the characteristics of the affected teeth, including tooth structure, hardness, mineral content, and ultrastructure.

Unequal Impact of COL1A1 and COL1A2 Variants on Dentinogenesis Imperfecta.

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.

Dentinogénesis Imperfecta y Displasia Dentinaria. A propósito de un caso / Dentinogenesis Imperfecta and Dentin Dysplasia. Case Report

La flexibilidad de la dentina permite resistir las fuerzas masticatorias. Esta propiedad hace que el esmalte subyacenteno se fracture. En los casos de dentinogénesis imperfecta y displasia dentinaria los pacientes tienen mas riesgo de fracturas y atriciones dentarias en edades muy tempranas. Se presenta un caso clínico de un paciente varón de 3,7 años que acude por primera vez a la consulta por dolor. A la exploración presenta múltiples caries, absceso de origen dentario, atriciones, dimensión vertical disminuida y dentinogénesis imperfecta. En los casos leves de osteogénesis imperfecta es posible que la dentinogénesis imperfecta sea la primera manifestaciónen ser detectada, por lo tanto, el odontólogo debe estar capacitado para saber diagnosticar y derivar al paciente al especialista para permitir un diagnóstico precoz de la enfermedad. La primera visita odontológica del niño/aal cumplir el año de vida es necesaria para detectar cualquier anomalía en el crecimiento de los dientes, huesos y establecer una relación entre el niño/a, el especialista y su entorno. (AU)

The flexibility of dentin allows it to resist masticatory forces. This property prevents the underlying enamel from fracturing. In cases of dentinogenesis imperfecta and dentin dysplasia, patients have a higher risk of fractures and dental attrition at a very early age. A clinical case of a 3.7-year-old male patient who comes to the clinic for the first time due to pain is presented. On examination he presented multiple caries, abscess of dental origin, attrition, decreased vertical dimension and dentinogenesis imperfecta. In mild cases of osteogenesis imperfecta, it is possible that dentinogenesis imperfecta is the first manifestation to be detected, therefore, the dentist must be trained to know how to diagnose and refer the patient to the specialist to allow an early diagnosis of the disease.The first dental visit of the child at the ageof one year is necessary to detect any anomaly in the growth of the teeth, bones and establish a relationship between the child, the specialist and their environment (AU)

A novel DSPP frameshift mutation causing dentin dysplasia type 2 and disease management strategies.

The present study aims to investigate the mutation in a Chinese family with dentin dysplasia type II (DD-II) and to summarize mutation hotspots, clinical manifestations, and disease management strategies. Phenotype analysis, clinical intervention, mutation screening, and cosegregation analysis within the enrolled family were performed. A summary of the reported mutations in the dentin phosphoprotein (DPP) region of dentin sialophosphoprotein (DSPP) was analyzed. Pathogenicity prediction analysis of the physical properties and function of DSPP variants was performed by bioinformatic processing. Clinical management strategies are discussed. A novel pathogenic mutation (c.2035delA) in the DPP region of DSPP was identified, which was cosegregated in the family. The immature permanent teeth of patients with DD-II presented with X-shaped root canal phenotypes. Most of the identified mutations for DD-II were clustered in the DPP region between nucleotides 1686-2134. Points of differential diagnosis, clinical interventions, and management strategies are proposed. This study revealed a novel DSPP frameshift mutation and presented new clinical features of DD-II. The locus involving nucleotides 1686-2134 of DSPP may represent a mutational hotspot for the disease. Appropriate management of DD-II at different stages is important to avoid the development of secondary dental lesions.

[Mutation of dentin sialophosphoprotein and hereditary malformations of dentin].

The classification as well as the clinical manifestations of hereditary malformations of dentin are of great concern and have been deeply elucidated. The understanding of its genetic basis also increases progressively. Dentin sialophosphoprotein (DSPP) is the pathogenic gene of dentinogenesis imperfecta type Ⅱ, dentinogenesis imperfecta type Ⅲ and dentin dysplasia type Ⅱ. In this article, the classification of DSPP mutations as well as the resultant dysfunction of the mutant DSPP are summarized respectively and the corresponding clinical manifestations are analyzed. This work will provide a reference for the diagnosis and treatment of hereditary malformations of dentin.

Mutation of dentin sialophosphoprotein and hereditary malformations of dentin / 中华口腔医学杂志

The classification as well as the clinical manifestations of hereditary malformations of dentin are of great concern and have been deeply elucidated. The understanding of its genetic basis also increases progressively. Dentin sialophosphoprotein (DSPP) is the pathogenic gene of dentinogenesis imperfecta type Ⅱ, dentinogenesis imperfecta type Ⅲ and dentin dysplasia type Ⅱ. In this article, the classification of DSPP mutations as well as the resultant dysfunction of the mutant DSPP are summarized respectively and the corresponding clinical manifestations are analyzed. This work will provide a reference for the diagnosis and treatment of hereditary malformations of dentin.

Tratamiento integral de una adolescente con dentinogénesis imperfecta tipo I / Comprehensive treatment of an adolescent with type I dentinogenesis imperfecta

La dentinogénesis imperfecta (DI) es un desorden hereditario de carácter autosómico dominante, que se origina durante la etapa de histodiferenciación en el desarrollo dental y altera la formación de la denti-na. Se considera una displasia dentinaria que puede afectar ambas denticiones con una incidencia de 1 en 6000 a 8000 nacimientos. El tratamiento del pa-ciente con DI es complejo y multidisciplinario, supone un desafío para el odontólogo, ya que por lo general están involucradas todas las piezas dentarias y afec-ta no solo la salud buco dental sino el aspecto emo-cional y psicológico de los pacientes. Objetivo: des-cribir el tratamiento integral y rehabilitador realiza-do en una paciente adolescente con diagnóstico de DI tipo I. Relato del caso: Paciente de sexo femenino de 14 años, que concurrió en demanda de atención a la Cátedra de Odontología Integral Niños de la FOU-BA derivada del Hospital "Prof. Dr. Juan P. Garrahan" con diagnóstico de osteogénesis imperfecta tipo III (OI). Nunca recibió atención odontológica y el motivo de consulta fue la apariencia estética de sus piezas dentarias. Se realizó el examen clínico y radiográfico arrojando el diagnóstico de DI tipo I asociada a OI. Conclusión: El tratamiento rehabilitador de la DI tipo I en los pacientes en crecimiento y desarrollo debe estar dirigido a intervenir de manera integral y tem-prana para resolver la apariencia estética y funcio-nal, evitar las repercusiones sociales y emocionales y acompañar a los pacientes y sus familias (AU)

Dentinogenesis imperfecta (DI) is an autosomal dominant inherited disorder that originates during the histodifferentiation stage of tooth development and alters dentin formation. It is considered a den-tin dysplasia that can affect both dentitions with an incidence of 1 in 6000 to 8000 births. The treatment of patients with DI is complex and multidisciplinary, it is a challenge for the dentist, since in general all the teeth are involved and it affects not only oral health but also the emotional and psychological aspect of the patients. Objective: To describe the comprehen-sive and rehabilitative treatment carried out in an adolescent patient with a diagnosis of DI type I. Case report: A 14-year-old female patient, who required dental attention at the Department of Pediatric Den-tistry of FOUBA and was referred from the Hospital "Prof. Dr. Juan P. Garrahan" with a diagnosis of os-teogenesis imperfecta type III (OI). The patient never received dental care and the reason for consultation was esthetic appearance of her teeth. A clinical and radiographic examination was performed, resulting in a diagnosis of DI type I associated with OI. Conclu-sion: Rehabilitative treatment of DI in growing and developing patients will be aimed at early and com-prehensive intervention to resolve esthetic and func-tional appearance, avoid social and emotional reper-cussions and accompany patients and their families (AU)

[Clinical and genetic analysis of a pedigree affected with hereditary dentinogenesis imperfecta type II].

OBJECTIVE: To explore the clinical and genetic characteristics of a Chinese pedigree affected with hereditary dentinogenesis imperfecta (DGI) type II. METHODS: Clinical data of the pedigree members were collected. Genomic DNA was extracted from peripheral blood samples and subjected to whole exome sequencing. RESULTS: Clinical characteristics of the affected family members have included amber teeth along with significant attrition, constricted roots and dentine hypertrophy leading to pulpal obliteration, which were suggestive of DGI type II. All of the affected members were found to have harbored a novel heterozygous c.2837delA (p.Asp946Valfs*368) variant of the DSPP gene which was predicted to be likely pathogenic. CONCLUSION: The c.2837delA variant of the DSPP gene probably underlay the disease in this pedigree. Above finding has expanded the variant spectrum of DSPP gene and provided a basis for molecular diagnosis and genetic counseling for this pedigree.

A Review of Dentinogenesis Imperfecta and Primary Dentin Disorders in Dogs.

This review describes the clinical, radiographic and histologic characteristics of dentinogenesis imperfecta diagnosed in two unrelated young dogs without evidence of concurrent osteogenesis imperfecta. The dentition was noted to have generalized coronal discoloration ranging from grey-blue to golden brown. Clinical pulp exposure, coronal wear and fractures were observed as was radiographic evidence of endodontic disease, thin dentin walls or dystrophic obliteration of the pulp canal. The enamel was severely affected by attrition and abrasion despite histologically normal areas; loss was most likely due to poor adherence or support by the underlying abnormal dentin. Histologically, permanent and deciduous teeth examined showed thin, amorphous dentin without organized dentin tubules and odontoblasts had dysplastic cell morphology. Primary dentin disorders, including dentinogenesis imperfecta and dentin dysplasia, have been extensively studied and genetically characterized in humans but infrequently reported in dogs. Treatment in human patients is aimed at early recognition and multi-disciplinary intervention to restore and maintain normal occlusion, aesthetics, mastication and speech. Treatment in both humans and canine patients is discussed as is the documented genetic heritability of primary dentin disorders in humans.

Interdisciplinary Management of a Patient with Dentinogenesis Imperfecta Type II Using a Combination of CAD-CAM and Analog Techniques: A Clinical Report.

Type II dentinogenesis imperfecta is an autosomal dominant condition that affects dentin which increases the complexity of the predictability of restorative treatment. Computer-aided design and computer-aided manufacturing (CAD-CAM) technologies permit the creation of highly accurate devices and dental prostheses that simplify the planning and execution of advanced implant surgery and full-mouth rehabilitation. This clinical report presents the interdisciplinary management of a 20-year-old male with dentinogenesis imperfecta type II. In this article, a combination of analog and CAD-CAM technologies were used to fabricate devices that aided planning, assisted intermaxillary fixation and implant placement, served as interim prostheses, and permitted the accurate establishment of esthetics and occlusion of the definitive full-arch prostheses.