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Dentin dysplasia (DD) Type I is a developmental condition affecting dentin, inherited in an autosomal-dominant pattern or occurring due to a new mutation. Whilst the crowns of DD Type I affected teeth appear clinically normal, the roots are blunt and shortened. Pulp necrosis and periapical pathoses may be seen in the absence of obvious causes. Pulp stones and calcifications are frequently encountered. Endodontic management of DD may be challenging. A case of DD Type I, sub-classification d, in which spontaneous irreversible pulpitis developed on three mandibular incisors is documented. The case was managed by conventional endodontic treatment. Knowledge of this uncommon dental condition may assist dentists to adequately diagnose and manage these cases. Extraction should not be considered the first-line treatment option when sufficient root length is available to attempt endodontic treatment. Referral for medical evaluation is recommended to rule out systemic diseases which may mimic this condition.

Objective Hereditary dentin defects can be categorised into two classes according to their clinical manifestations: dentinogenesis imperfecta (DGI), which includes three types (DGI-I, DGI-II and DGI-III), and dentin dysplasia (DD), which includes two types (DD-I and DD-II). This study investigated the phenotypic characteristics and genetic causes of hereditary dentin defects in seven Chinese families. Materials and methods Seven families affected with DGI-II, DGI-III or DD-II were enrolled. Clinical examinations were performed to determine the phenotypic characteristics, and DNA samples were collected for Sanger sequencing. Results Clinical diagnoses revealed DGI-II in five families, DGI-III in one family and DD-II in one family. Variants of the dentin sialophosphoprotein (DSPP) gene were found in six of the seven families. Of these, c.52G>T was identified in two families. Each of the remaining four families had a different variant: c.2684delG, c.52-2A>G, c.1874-1877delACAG and c.3509-3521del13bp; the last three variants were novel. Conclusions This is the first study to analyse all three important types of hereditary dentin defect and include comprehensive genetic analyses of both dentin sialoprotein and dentin phosphoprotein in Chinese families. This study expands the spectrum of DSPP variants, highlighting their associated phenotypic continuum.

Nonsyndromic dentin defects classified as type II dentin dysplasia and types II and III dentinogenesis imperfecta are caused by mutations in DSPP (dentin sialophosphoprotein). Most reported disease‐causing DSPP mutations occur within the repetitive DPP (dentin phosphoprotein) coding sequence. We characterized the DPP sequences of five probands with inherited dentin defects using single molecule real‐time (SMRT) DNA sequencing. Eight of the 10 sequences matched previously reported DPP length haplotypes and two were novel. Alignment with known DPP sequences showed 32 indels arranged in 36 different patterns. Sixteen of the 32 indels were not represented in more than one haplotype. The 25 haplotypes with confirmed indels were aligned to generate a tree that describes how the length variations might have evolved. Some indels were independently generated in multiple lines. A previously reported disease‐causing DSPP mutation in Family 1 was confirmed and its position clarified (c.3135delC; p.Ser1045Argfs*269). A novel frameshift mutation (c.3504_3508dup; p.Asp1170Alafs*146) caused the dentin defects in Family 2. A COL1A2 (c.2027G>A or p.Gly676Asp) missense mutation, discovered by whole‐exome sequencing, caused the dentin defects in Family 3. We conclude that SMRT sequencing characterizes the DPP repeat region without cloning and can improve our understanding of normal and pathological length variations in DSPP alleles.

Dentinogenesis imperfecta and dentin dysplasia are two common types of genetic oral diseases resulted from the aberrant differentiation of odontoblast. Understanding the mechanisms of odontoblast differentiation is crucial for finding the diagnosis candidate genes and treatment targets for such kinds of diseases. Previous work has identified a battery of transcription factors and growth factors regulating odontoblast differentiation; however, the post-transcriptional regulating mechanisms of them are poorly studied. MicroRNAs (miRNA) are a group of non-coding RNAs widely studied in organ development, inflammation, and tumorigenesis because of its inhibitory effects on the target mRNAs. Also, miRNAs along with their binding targets form a complex competing endogenous RNA (ceRNA) network where miRNAs serve as the fine tuning balancers between their targets. Recent reports demonstrated the essential role of the miRNA pathway in dentinogenesis and the regulatory role of several specific miRNAs in the in vitro model of odontoblast differentiation. Herein, we will discuss the general roles of miRNA in diseases, the function of miRNAs during odontoblast differentiation, and finally the potential pathological mechanisms through which miRNAs cause the odontoblast-related diseases.

Families with nonsyndromic dentinogenesis imperfecta (DGI) and the milder, dentin dysplasia (DD), have mutations in one allele of the dentin sialophosphoprotein (DSPP) gene. Because loss of a single Dspp allele in mice (and likely, humans) causes no dental phenotype, the mechanism(s) underling the dominant negative effects were investigated. DSPP mutations occur in three classes. (The first class, the mid-leader missense mutation, Y6D, was not investigated in this report.) All other 5′ mutations of DSPP result in changes/loss in the first three amino acids (isoleucine-proline-valine [IPV]) of mature DSPP or, for the A15V missense mutation, some retention of the hydrophobic leader sequence. All of this second class of mutations caused mutant DSPP to be retained in the rough endoplasmic reticulum (rER) of transfected HEK293 cells. Trafficking out of the rER by coexpressed normal DSPP was reduced in a dose-responsive manner, probably due to formation of Ca2+-dependent complexes with the retained mutant DSPP. IPV-like sequences begin many secreted Ca2+-binding proteins, and changing the third amino acid to the charged aspartate (D) in three other acidic proteins also caused increased rER accumulation. Both the leader-retaining A15V and the long string of hydrophobic amino acids resulting from all known frameshift mutations within the 3′-encoded Ca2+-binding repeat domain (third class of mutations) caused retention by association of the mutant proteins with rER membranes. More 5′ frameshift mutations result in longer mutant hydrophobic domains, but the milder phenotype, DD, probably due to lower effectiveness of the remaining, shorter Ca2+-binding domain in capturing normal DSPP protein within the rER. This study presents evidence of a shared underlying mechanism of capturing of normal DSPP by two different classes of DSPP mutations and offers an explanation for the mild (DD-II) versus severe (DGI-II and III) nonsyndromic dentin phenotypes. Evidence is also presented that many acidic, Ca2+-binding proteins may use the same IPV-like receptor/pathway for exiting the rER. © 2012 American Society for Bone and Mineral Research.

Dentin sialophosphoprotein (DSPP) mutations cause dentin dysplasia type II (DD-II) and dentinogenesis imperfecta types II and III (DGI-II and DGI-III, respectively). We identified two kindreds with DGI-II who exhibited vertical bands of hypoplastic enamel. Both families had a previously reported DSPP mutation that segregated with the disease phenotype. Oral photographs and dental radiographs of four affected and one unaffected participant in one family and of the proband in the second family were used to document the dental phenotypes. We aligned the 33 unique allelic DSPP sequences showing variable patterns of insertions and deletions (indels), generated a merged dentin phosphoprotein (DPP) sequence that includes sequences from all DSPP length haplotypes, and mapped the known DSPP mutations in this context. Analyses of the DSPP sequence changes and their probable effects on protein expression, as well as published findings of the dental phenotype in Dspp null mice, support the hypothesis that all DSPP mutations cause pathology through dominant-negative effects. Noting that Dspp is transiently expressed by mouse pre-ameloblasts during formation of the dentino-enamel junction, we hypothesize that DSPP dominant-negative effects potentially cause cellular pathology in pre-ameloblasts that, in turn, causes enamel defects. We conclude that enamel defects can be part of the dental phenotype caused by DSPP mutations, although DSPP is not critical for dental enamel formation.

Oral Diseases (2011) 17, 690–695 Objective: Dentin sialophosphoprotein (DSPP) gene mutations have been identified in isolated hereditary dentin defects; however, the genotype–phenotype correlations are poorly understood. We performed in vitro splicing assays to test the hypothesis that DSPP mutations in splice junctions as well as proposed missense/nonsense mutations experimentally result in aberrant pre-mRNA splicing. Materials and methods: The genomic fragment of the human DSPP gene was cloned into the pSPL3 splicing vector, and previously reported as well as informative de novo mutations were then introduced by PCR mutagenesis. The COS-7 cells were transfected with each plasmid vector, and total RNA was isolated. RT-PCR result was analyzed, and the band intensity of the product was calibrated using ImageJ. Results: The predictions by others of exon 3 skipping in specific DSPP mutations have been validated and a cryptic splicing donor site has been identified. However, the degree of mutational effect on pre-mRNA splicing varied considerably depending on the changed nucleotide. Conclusions: The predictions of exon 3 skipping in specific DSPP mutations have been validated, and a cryptic splicing donor site has been identified. Our data may provide insight into the contribution of DSPP mutations in the pathogenesis and genotype–phenotype correlations of hereditary dentin defects.

Oral Diseases (2011) 17, 314–319 Objective: Hereditary dentin defects can be grouped into three types of dentinogenesis imperfecta (DGI) and two types of dentin dysplasia. Tooth enamel is considered normal in patients with hereditary dentin defects, but is easily worn down and fractured due to DSPP mutation-induced altered dentin properties. The purposes of this study were to identify genetic cause of a family with type II DGI and enamel defects. Materials and methods: We identified a family with type II DGI and a unique form of hypoplastic enamel defect affecting occlusal third of the crown. Family members were recruited for the genetic analysis and DNA was obtained from peripheral whole blood. Results: Mutational analysis revealed a T to A transversion in exon 3 of the DSPP (c.53T>A, p.V18D). Haplotype analysis showed that the same mutation arose separately in two different families having DGI with similar enamel defects, indicating that this phenotype is associated with this specific DSPP mutation. Clinical features suggest that enamel formation was affected in the affected individuals during early amelogenesis, in addition to the dentin defect. Conclusions: We observed that a DSPP gene mutation not only influences dentinogenesis but also affects early stage amelogenesis.

Dentin sialophosphoprotein (Dspp) is critical for proper dentin biomineralization because genetic defects in DSPP cause dentin dysplasia type II and dentinogenesis imperfecta types II and III. Dspp is processed by proteases into smaller subunits; the initial cleavage releases dentin phosphoprotein (Dpp). We incubated fluorescence resonance energy transfer (FRET) peptides containing the amino acid context of the Dpp cleavage site (YEFDGKSMQGDDPN, designated Dspp-FRET) or a mutant version of that context (YEFDGKSIEGDDPN, designated mutDspp-FRET) with BMP-1, MEP1A, MEP1B, MMP-2, MMP-8, MMP-9, MT1-MMP, MT3-MMP, Klk4, MMP-20, plasmin, or porcine Dpp and characterized the peptide cleavage products. Only BMP-1, MEP1A, and MEP1B cleaved Dspp-FRET at the G–D peptide bond that releases Dpp from Dspp in vivo. We isolated Dspp proteoglycan from dentin power and incubated it with the three enzymes that cleaved Dspp-FRET at the G–D bond. In each case, the released Dpp domain was isolated, and its N-terminus was characterized by Edman degradation. BMP-1 and MEP1A both cleaved native Dspp at the correct site to generate Dpp, making both these enzymes prime candidates for the protease that cleaves Dspp in vivo. MEP1B was able to degrade Dpp when the Dpp was at sufficiently high concentration to deplete free calcium ion concentration. Immunohistochemistry of developing porcine molars demonstrated that astacins are expressed by odontoblasts, a result that is consistent with RT-PCR analyses. We conclude that during odontogenesis, astacins in the predentin matrix cleave Dspp before the DDPN sequence at the N-terminus of Dpp to release Dpp from the parent Dspp protein. © 2011 American Society for Bone and Mineral Research.

Dentin defects represent a cluster of relatively rare heritable disorders affecting the formation and mineralization of dentin. Major clinical features include loss of enamel with extreme wear of exposed dentin, opalescent tooth discoloration, short roots with pulpal calcification and increased tooth mobility, and frequent periapical radiolucencies. Historically, these inherited conditions have been classified by Shields et al. (1) as either dentinogenesis imperfecta (DGI) types I, II and III, or dentin dysplasia (DD) types I and II. DGI type I is now universally designated as osteogenesis imperfecta with dentinogenesis imperfecta (OI/DGI) and is caused by type I collagen mutations. Among the genes expressing the non-collagenous proteins in dentin, only the DSPP gene has been implicated in the etiology of DD type II and all DGI types, suggesting that heritable dentin defects can be viewed as a continuum rather than as distinct disease entities. Dental treatment strategies should aim to preserve the affected dentitions by protecting teeth from wear, restoring them to compliance with the specific structural characteristics of the defective dentin, and anticipating early tooth loss. Endodontic treatment of the affected teeth is very challenging because of the peculiar pulp morphology and most often has poor prognosis. If conventional therapy is not an option, periapical curettage and retrograde filling is a possible alternative, except in the case of teeth with short roots.

Dentin dysplasia type I (DDI) is a rare hereditary disturbance of dentin formation. It is characterized by clinically normal-appearing crowns; obliteration of pulp chambers; and short, blunted and malformed roots that are commonly associated with periodontal attachment loss (PAL). In this context, we report three cases within a family with similar clinical and radiographic features of DDI but with differing microbiologic and periodontal conditions.A 42-year-old white female and her two daughters (25 and 10 years of age) presented with a diagnosis of DDI. Probing depth (PD), clinical attachment level (CAL), visible plaque, and bleeding on probing (BOP) were recorded. Subgingival biofilm samples were randomly collected and analyzed by checkerboard DNA-DNA hybridization.The mother presented 34.9% of sites with PDor =4 mm, 41.3% of sites with CALor =4 mm, and 57% of sites with BOP; both daughters presented no sites with PD or CAL3 mm and10% of sites with BOP. Microbiologic analysis detected Gemella morbillorum, Neisseria mucosa, and Staphylococcus aureus inor =50% of the mother's samples. The daughters showed high levels (10(4) bacterial cells) of some periodontopathic bacteria, including members of the red (Porphyromonas gingivalis) and orange (Fusobacterium periodonticum and F. nucleatum polymorphum) complexes and beneficial species of the yellow (Streptococcus gordonii) and purple (Veillonella parvula) complexes. The mother presented high mean levels only for four tested species (N. mucosa, Prevotella melaninogenica, Treponema denticola, and V. parvula).A combination of radiographs, microbiologic analysis, and preventive professional monitoring care is important to avoid PAL and to provide oral health in patients with DDI.

Transforming growth factor-beta1 (TGF-beta1) is a key regulator of many cellular processes, including cell adhesion, the immune response and synthesis of extracellular matrix proteins. In the present study, we report the characterization of enamel defects in a transgenic mouse model overexpressing TGF-beta1 in odontoblasts and ameloblasts, its expression being driven by the promoter sequences of the dentin sialophosphoprotein gene. As reported earlier, these mice develop distinct dentin defects similar to those seen in human dentin dysplasia and dentinogenesis imperfecta. A further detailed examination of enamel in these mice revealed that from the early secretory stage, ameloblasts began to detach from dentin to form cyst-like structures. A soft X-ray analysis revealed that this cyst-like structure had a disorganized and partially mineralized matrix with an abnormal mineralization pattern and a globular appearance. In the molars, the enamel was not only pitted and hypoplastic, but enamel rods were completely lost. Thus, altered TGF-beta1 expression in the tooth seems to trigger detachment of ameloblasts and abnormal secretion and deposition of minerals in the cyst-like structures adjoining the dentin. We speculate that the altered expression of TGF-beta1 in teeth impacts the adhesion process of ameloblasts to dentin.

A rare compound mutation involving a 36 bp deletion and 18 bp insertion within exon 5 of the dentin sialophosphoprotein (DSPP) gene has been identified in a family with dentinogenesis imperfecta type III (DGI-III). The DSPP gene encodes two major tooth matrix proteins dentin sialoprotein (DSP) and dentin phosphoprotein (DPP). DSPP mutations associated with DGI-III results in an in frame truncation of the serine aspartic acid triplet repeat found in DPP near the highly conserved carboxyl terminal region shortening the protein by six amino acids. Clinically this family presents with discolored amber opalescent teeth and severe attrition of the tooth structure. This study is the first report of a mutation within DPP associated with a genetic dentin disease. Our study indicates that DGI-III is allelic with some forms of DGI-II with and without progressive hearing loss and dentin dysplasia type II that have been shown to be caused by mutations within the DSP coding or signal peptide regions.

Dentinal dysplasia (DD) Type I, is a hereditary disturbance in dentine formation. In this anomaly, teeth in both primary and secondary dentitions are affected, and radiographically show short and blunted roots with obliterated root canals and periapical pathosis. Management of patients with DD has presented dentists with problems. Extraction has been suggested as a treatment alternative for teeth with pulp necrosis and periapical abscess. Follow-up and routine conservative treatment is another choice of treatment plan in DD. Another approach for the treatment of teeth with DD has included periapical surgery and retrograde filling, which is recommended in the teeth with long roots. The purpose of this report is to present an unusual case of dentinal dysplasia Type I in a 22-year-old woman showing upper and lower teeth with obliterated root canals and periapical radiolucencies. In this case, conventional endodontic treatment was performed. Postoperative radiographs and clinical evaluation demonstrated periapical healing and successful results. Based on the results of this case report, conventional endodontic treatment for cases with pulp necrosis and periapical radiolucencies in dentinal dysplasia is highly recommended.

J Oral Pathol Med (2010) 39: 424–430 Background: The present study was designed to study the effect of β-aminopropionitrile (β-APN), present in Lathyrus sativus grass pea consumed in drought prone areas, on dentin of the continuously erupting rat incisors. Methods: Eighteen adult male rats were used. In the experimental group (18 rats), lathyrism was induced by a once daily subcutaneous administration of β-APN for 40 days. The maxillary and mandibular incisors were examined ultrastructurally and morphometrically. Results: The mean number of patent tubules, the mean area, perimeter and the area percent of the tubules were analyzed. Ultrastructurally, the dentinal tubules of both coronal and radicular dentin in the lathyritic group were narrower or even obliterated compared with those in the control. The coronal and radicular dentin of the lathyritic group exhibited an irregular lattice of non-mineralized small branching collagen fibrils obliterating the dentinal tubules. The mean number of patent tubules in the control and lathyritic groups revealed an insignificant difference. The mean area of the tubules showed a statistically significant difference in lathyritic radicular dentin (P = 0.0353). The percentage of the total surface area of the dentinal tubules significantly decreased in the radicular dentin of the lathyritic group (P = 0.024). Conclusions: These findings indicated a deleterious effect of lathyrism on dentin, with a possible negative impact on developing teeth integrity.

The clinical, radiographic and histologic findings are described in two cases of Ehlers Danlos Syndrome Type I with novel dental features. Defective dentinogenesis principally affecting the mandibular incisors result in aplasia or hypoplasia of root development predisposing to localized periodontal disease. A striking radiographic appearance with a bulbous enlargement of the roots together with pulp stones is seen in other teeth. 'Giant channels' and vascular inclusions resembling 'intermediate cementum' are prominent within this area. No evidence of Type III procollagen or collagen was detected with indirect immunofluorescence. It is suggested that an inherited collagen abnormality in a component common to dentin, skin, ligament and tendon probably explains both EDS I and the dentin dysplasia.

A three-generation family with dentin dysplasia (DD) Type II is presented. Affected family members share common radiologic features with clinically varied expression of tooth discoloration and occlusal wear. Both the primary and the permanent dentition appear to be affected. No generalized connective tissue involvement is found. The mode of inheritance is autosomal dominant. Histologically, the findings are consistent with DD Type II. In indirect immunofluorescence, the irregular radicular dentin of an affected permanent tooth failed to stain with specific antibodies against Type III collagen and the N-terminal propeptide of Type III procollagen.

The classification and prevalence of amelogenesis imperfecta is updated based upon new information in the literature. Problems with the currently used classification of inherited dentin defects are discussed.

SUMMARY Patients with unusual congenital dental anomalies are often referred to the hospital dentistry team for evaluation and treatment recommendations. Communication between oral surgeon, orthodontist, pedodontist, periodontist, and prosthodontist after a combined single examination may simplify the treatment alternatives and save the patient the frustration and confusion of seeking treatment from a number of specialists. When necessary, com- bined treatment can be efficiently coordinated at the original consultation appointment. The recommendations of each specialist are then recorded together in the hospital record. This' simplifies follow-up treatment and allows for easy transfer of information should the patient move to another location. In complex treat- ment cases, the pooling of dental specialist re- sources may permit conservatism and answer the patient's needs with lifetime perspectives.

Rats were injected with 5 mg NaF/100 g or 125 mg SrCl2/100 g. Animals injected once were killed at intervals of 4, 6, 12 and 24 days after injection. Other animals received pairs of injections, separated by intervals of four or nine days. One maxillary incisor from each animal was embedded in methacrylate, sectioned transversely, and microradiographs prepared. The other incisor was demineralized, sectioned, and the sections stained with histochemical methods for polysac-charide-protein complexes. In the microradiographs, the abnormally mineralized layers of dentin produced by the injections became less distinct as they aged. This recovery was detectable in all animals within two weeks after injection. The histochemical changes were less marked, but the weakly stained (hypomineralized) layers of matrix became more nearly normal as recovery occurred. Apparently, fluoride accelerates the maturation (secondary mineralization) of a thin layer of dentin, while both fluoride and strontium inhibit primary mineralization of predentin. In time, mineralization in the hypomineralized layers overtakes the normally mineralized dentin, and the normally mineralized dentin overtakes the hypermineralized layers.

— Cyclophosphamide in doses of 25, 50, 75. 100, 125, and 150 mg/kg was administered to 60 rats in 6 groups. Histomorphologic investigations of maxillary and mandibular incisors two weeks later revealed the following dose-dependent reactions: (1) interruped odontogenesis, (2) circular and mesio-distal dental constrictions, (3) niche-like dentinal defects, (4) differentiation of a postexperimental tooth, and (5) cyst formation and circulatory disturbances. Differences were observed in the frequencies of lesions in maxillary and mandibular incisors, and between labial and lingual aspects of the teeth. The results were related to roentgen irradiation effects, with which they largely concur