Introduction

Did you know that the term ‘dentin’ is related to teeth? Dentin is the mineralised tissue of an entire tooth, protecting the vascular pulp, the life of the teeth and supporting the outermost enamel and cementum.

Dentin dysplasia (DD) occurs when a mutation happens in the gene responsible for dentin formation, and abnormal atypical dentin is formed with normal enamel and abnormal pulp features externally. This can be seen in both primary (milk tooth) and permanent(adult tooth), and it looks like a normal, healthy tooth outside. The tooth is rootless and mobile, easily shed from the jaw.¹

There are two types of dentin dysplasia based on which part of the teeth is affected and the radiographic features.

1. Type 1: Radicular dentin dysplasia
2. Type 2: Coronal dentin dysplasia

Dentin dysplasia type 1 is an autosomal dominant inherited disturbance in dentin formation. The affected teeth are rootless, and it seem normal clinically or light amber coloured, but the root portion is conical or blunted, and because of abnormal formation of dentin, the pulp chamber is narrow or sometimes obliterated, the tooth is mobile and easily gets shed from the jaw.²

The diagnosis of dentin dysplasia is very challenging, since initially it won't show any clinical symptoms, and the suspected person is not showing any significant medical history or any associated malocclusion of the jaw. There can or cannot be a family history of dentin dysplasia.³

The clinical presentation of DD can be very different in each person, and sometimes the patient comes with a tooth abscess or loosened teeth. It makes a delayed diagnosis because we can get solid features of dentin dysplasia through the radiographs only, and treatment could be challenging; a multidisciplinary approach is considered. 

The genetic disorder dentin dysplasia shows similarities with other dental disorders, like dentinogenesis imperfecta have the same clinical and radiographic features, mainly affecting the dentin part of the teeth.

Finding the genetic basis of the disease will play a pivotal role in the management of the disease, as it will give a clear idea about which gene at what stage of tooth formation undergoes mutation, hence the dentist can easily tailor the treatment.⁴

Clinical and histological features of DD-I clinical features

Clinically, the crowns of affected teeth are normal in appearance, and loosening of teeth and pain and abscess related to non-carious teeth are the main features. Sometimes a patient comes with a missing tooth. Both primary and permanent teeth are affected.⁵

Radiographic features

Teeth have short, blunted and malformed roots, a large obliterated pulp chamber, the presence of multiple radiolucencies, and dark areas around the tip of the teeth.

There are 4 subtypes based on the radiographic features

1. DD-1a: the most severe form with complete absence of root canal and root formation of non-carious teeth
2. DD-1b: presence of short roots with crescent-shaped pulp chamber, may present with radiolucency around the teeth
3. DD-1c: root showing a length half of normal, pulp chamber is new moon shaped
4. DD-1d: normal-root length and pulp chamber, presence of pulpal stone

Histopathological findings

Dentinal tubules are irregular and are disorganised in shapes and arrangements. Variation in the structure of dentinal matrix, with unmineralized or hypomineralized dentin. Tubular dentin in the central part of the root gives a ‘’stream flowing around the boulders” appearance. Partially or completely obliterated pulp chamber.⁶

Current understanding of the genetic basis

Dentin dysplasia type 1 is an autosomal dominant disease, which implies that about 50% of mutated genes from either of the inherited parents is sufficient to pass the disease to offspring, regardless of the gender of the child; every generation of the family has the disease. It can be seen in males and females. The incidence rate is 1in every 100,000 people.

Since the disease is caused by the mutation of different genes, it is a genetically inherited heterogeneous disease.

The known genes are:

• SMOC2 - secreted molecular calcium-binding protein 2
• SSUH2
• VPS4B- vacuolar protein sorting 4B

SMOC2

It comes under the SPARC(secreted protein acidic rich in cysteine) gene family, which helps in cell adhesion, cell growth and ECM extracellular matrix formation. These genes also promote and suppress the tumour cell growth.

SMOC2 affects tooth development, and any mutation of this gene causes microdontia, oligodontia, dental shape anomalies, and short root size.⁷

SMOC2 is expressed during the developing stage of the tooth germ, and it activates the differentiation of odontoblasts.This gene encodes the human stem cell from the apical papilla(hSCAP), the active stem cells responsible for dentin formation and root development.⁸

SSUH2

This gene is considered the transcriptional factor for DNA transcription and protein-to-protein interaction in tooth formation. DSPP, DMP1, Runx2, and Dlx2 are the key odontogenic factors responsible for tooth development. Mutation of SSUH2 can impair the signalling pathway of those encoded genes and result in dentin dysplasia type 1 with short roots and altered dentin structure.⁷

SSUH2 acts as a chaperone.

VPS4B

This gene controls root formation. Knocking down of vps4b results in reduced tooth number, and shortening the root length results in dentin dysplasia type 1 features.⁸

Both dentinogenesis imperfecta and dentin dysplasia are genetic disorders caused by a mutation in dentin protein DSPP (dentin sialophosphoprotein)located on chromosome 4q21. They overlap in the same clinical and histological features.⁹

Molecular mechanisms underlying DD-I

Many theories explain the molecular mechanism of dentin dysplasia type 1

• Logan et al stated that the causative tissue responsible for abnormalities in root development is the dentinal papilla
• Through a Scanning electron microscope(SEM), it is found that the abnormal dentin formation is due to the invagination of the epithelial root sheath
• Wesley's hypothesis states that the wrong interaction of the ameloblast with the odontoblast leads to the abnormal differentiation and function of the odontoblast
• Carroll et al stated that the timing of dentinal disorganisation is responsible for the abnormal root and pulp formation. Early dentinal disorganisation can cause short roots or rootless teeth with no pulp. Later dentinal disorganisation caused a tooth with short roots and a crescent-shaped pulp chamber can cause a tooth with a normal length root with pulp stones¹³

Experiments are conducted on animals to examine characteristics of molecular mechanisms that regulate dentinogenesis in a healthy, normal tooth and also in genetic disorders like DD and DGI.

The knock-out and knock-in mice model is used to study the genes(SMOC2, SSUH2, DSPP) involved in dentin dysplasia. Knock-out mice models of SSUH2 showed characteristic features of DD-1, like pulp obliteration. 

Animal model: Dspp knock-out mice are used. The resultant Dspp null mice showed decreased mineralisation of dentin, and increased pulp volume and predentin width, as well as a defect in enamel maturation. These are the characteristics of dentinogenesis imperfecta.¹⁴

Diagnostic approaches and genetic testing

History, clinical examination, and radiographs are used for diagnosing dentin dysplasia type 1

The following approaches are used to diagnose dentin dysplasia type 1:

• History
• Clinical Examinations
• Radiographs

Patients come up with multiple missing teeth or tooth abscesses with pain related to the teeth, which are free of decay. They are also very conscious about their aesthetics.

Clinical diagnosis

The morphology and colour of the teeth are normal; primary teeth can show a slightly amber or blackish-brown colour. There can be shorter or smaller crowns than normal. The affected teeth are slightly mobile due to the short roots hence can easily be shed out from the jaw.

Tooth abscesses are seen, and there may be missing teeth.

Diagnosis using radiographs

When using radiographs to diagnose DD Type 1, the following features are used:

• Constriction of the tip of the root/rootless teeth/short root
• Absent root canal
• The presence of a dark area around each tooth indicates an infection of the tooth
  pulp obliteration or crescent-shaped pulp chamber

Genetic testing

Genetic testing has a crucial role in confirming the diagnosis and inheritance pattern of dentin dysplasia type 1. Here patient’s DNA is examined, analysed by the physician and the specific gene that underwent mutation. It's helpful for genetic counselling and family planning.

It is used when the clinical and radiographic features are inconclusive. It is very useful in the early stage of the disease when no visible symptoms
appear. It is very helpful for the patient who is well-informed about their condition so that they can monitor the disease and take proactive care, which will make the complication less severe.¹⁰

Availability of genetic panels for hereditary dentin defects

Genetic panels mainly focus on hereditary dentin diseases like dentinogenesis imperfecta and dentin dysplasia to detect enamel and dentin anomalies.

The panels mainly screen the genes like DSPP in the case of dentinogenesis imperfecta and dentin dysplasia. COLIA1A1 and COLIA2A2 are seen as the responsive genes in the case of osteogenesis imperfecta.

The commonly used genetic panels are amelogenesis imperfecta and dentinogenesis imperfecta panels. They are using specific protein strands of DNA that underwent mutation, as in the case of next-generation sequencing(NGS).

Whole exome sequencing(WES) is used in cases of unresolved undiagnosed genetic hereditary disorder, where the entire sequence of protein strands of the gene is examined and analysed for any strands that show causative variation.¹¹

Genotype-phenotype correlation

It is seen that the same mutation can happen in different strands of DNA genes or different mutations in the same strands of DNA, or different mutations in different strands of genes. This genotypic variation could result in the same or different phenotypes or external expression of the dentin disorders.

Some family members can present with malocclusion along with dentin dysplasia.

The clinical and genetic data from the patient help to reach out for better diagnostic tools, personalised treatment patterns, and better treatment outcomes.¹²

Unknowns and research gaps

Incomplete identification of causative genes

DSPP is the gene responsible for dentin formation and maturation. The mutation of this gene causes either dentinogenesis imperfecta or dentin dysplasia.  It shows variant phenotypic features of the same pathogenic genes.

It is also reported that dentin dysplasia type 1 is caused by a recessive mutation in SMOC2 and dominant mutations of SSUH2 and VPS4B. Hence, the molecular genetic basis of DD-1 is still unknown, and a more continuous research study is needed to study the exact role of these genes in dentin formation.¹⁵

Cases with no identifiable mutations in known genes

Many cases are presented with diagnostic symptoms of dentin dysplasia type 1, and are not caused by the mutation of known genes like SMOC2, SSUH2, and VPS4B. So studies have to extend to genes that have not been discovered yet. This implies the genetic heterogeneity of dentin dysplasia.

DD-type 1 showed ambiguity at cellular, molecular, clinical, radiographic, and biomechanical levels. Treatment can also be varied because of varying phenotypic features.¹⁶

Epigenetic and environmental influences

Epigenetic and environmental factors are also responsible for the severity and morphological changes in dentin dysplasia type-1, provided that the genetic factor is primarily influencing the cause of the disease.

Diet, pollutants, stress, and inflammation alter gene expression. This affects the various stages of tooth development by DNA methylation and histone modification. They alter gene regulation, the quality, shape and structure of dental anomalies.¹⁷

Future directions

Advances in genetic and molecular technologies

CRISPR/Cas9: a powerful gene editing tool used in genetic dental disorders. Here, the specific genes responsible for the mutation are introduced into mice. An animal model is created to study the pathological effects and therapeutic interventions. It also helps clinicians to find how the genetic defect causes stress at the cellular and molecular levels for dentin formation and disease development. So in the future, it can contribute to the evolution of advanced therapy that can improve dentin formation.¹⁸

Transcriptomics: used in RNA sequencing, it analyses the complete set of RNA strands in cells and tissues like odontoblasts, dental pulp cells of affected individuals and the healthy controls. In dentin dysplasia, it identifies the dysregulated genes like RUNX2. Thus, it gives a clear idea about the causes of molecular pathogenesis, like pulp obliteration, root defects, abnormal dentin formation and the target therapeutic agents. Also, the reparative dentin induction is used for the repair of the disease. Transcriptomics deeply analyse the genetic basis of any dental genetic pathologies and gives a precise and accurate early diagnosis.¹⁹

Single-cell analysis is used to find specific mutations occurring in mesenchymal cells of a particular disorder. It gives clarity for the genetic mechanism of dentin dysplasia regarding dentin defects. It paves a pathway for new diagnostic approaches and targeted therapies for underlying genetic abnormalities.

Comprehensive genotype-phenotype mapping: Here, the gene that expresses a particular phenotype, like tooth colour, root length, allows a precise diagnosis. It also helps to find how the different mutations in the same gene produce variable phenotypes. It predicts the course of the disease, the severity and progression of the disease.

It can provide minute information about the inheritance pattern, thereby helping the suspected individuals with family planning through genetic counselling.²⁰

Summary

Dentin dysplasia type 1 is a complex hereditary disorder, mainly affecting the root development of teeth. The tooth is rootless and has a crown morphology of normal teeth.

SSUH2, SMOC2, and VPS4B are the pathogenic genes that are assumed to cause genetic mutations associated with dentin dysplasia type 1, but the exact cause of the disorder is not confirmed universally. Hence, expanded genetic studies like whole genome or whole exome sequencing of affected individuals' genes have to be analysed to find out the pattern of mutation and the root dentin development.

Dentin dysplasia is genetically heterogeneous; different mutation of the same set of genes or the same mutation in different sets of genes makes the exact genetic causes confusing. No specific gene mutation has been confirmed. Also, it causes the same phenotypic features in different families or different morphologic features in members of the same family.

A multidisciplinary approach is required for managing dentin dysplasia type-1. The main aim is to preserve the tooth for as long as possible, with routine follow-up and conservative management. 

It is important to monitor the periodontal health of the mobile tooth. Depending on patient age, condition of health and the nature of the presenting complaint, prosthetic rehabilitation using dentures, overdentures, or dental implants is advised. The molecular mechanism and genetic causes of DD-1 are still inconclusive. However, more continuous and collaborative studies are needed.