Introduction

A few days ago, a concerned friend called me seeking advice for her younger sibling, who is soon getting married. He wanted some cosmetic dental work to cover up the visible space. Following my suggestion, they visited a dentist, only to be shocked by the revelation that he never actually had the tooth erupt in the first place. Imagine sitting in the dentist’s chair only to discover that one of your teeth never really showed up-, like simply deciding not to make an appearance. As strange as it sounds, such cases happen more often than we realise. This condition, where one or more of your teeth are missing due to a lack of development, is called ‘tooth agenesis’. (Agenesis = A (without) + Genesis (development)).

Tooth agenesis, a developmental abnormality, is influenced primarily by our genes. Before we dig deep into the causes of tooth agenesis, let us first understand some basics about the development of teeth.

Overview of tooth development

Our teeth start developing around 6 weeks in our mother’s womb. Each one of us is blessed with two sets of teeth in our lifetime.

The first one is called ‘primary or deciduous dentition’, which begins to appear around 6 months and starts falling out by the time we are 6 years of age. The total number of primary teeth is 20.

Once the primary teeth start falling out, they are replaced by a new set of teeth called the ‘permanent teeth or ‘permanent dentition’. The total number of permanent teeth, including the 4 wisdom teeth (third molars), is 32. These are for the rest of our lives if we take care of them.

There are empty spaces if we lose these permanent teeth to dental caries (infection of the teeth) or any other conditions (periodontal diseases, injury, extraction, etc.). This is artificially rehabilitated, such as with implants, dentures, or bridges.

Tooth agenesis

Tooth agenesis, commonly referred to as ‘hypodontia’, is a congenital and developmental condition or abnormality in which one or more teeth are missing. It impacts the primary teeth and/or the permanent teeth.

Tooth agenesis not only affects the appearance, and function but can also be seen with other craniofacial deformities. It also leads to a lot of psycho-social challenges for individuals with severe cases of tooth agenesis.^2,5

Causes

Tooth agenesis is primarily attributed to genetic and environmental influences, the former affects around 80% of total cases.

Characteristics

• Absence of one or more teeth
• Unusual spacing between teeth
• Small or peg-shaped teeth
• Malaligned teeth
• Difficulty in speech
• Difficulty in eating 
• Difficulty in maintaining oral hygiene
• Low self- esteem
• Social anxiety in severe cases

Prevalence

Research suggests that the distribution of tooth agenesis or hypodontia varies worldwide, with the highest prevalence in Asians and the lowest in North Americans.³ It is almost gender-neutral for primary teeth; however, with permanent teeth, gender assigned female at birth (AFAB) is more susceptible.

Role of genetics in tooth development

Each individual inherits one set of genes from each parent. These genes provide the blueprint for all bodily functions, including the formation of teeth. Similarly, they are also responsible for the development and positioning of each tooth in our mouth.

Different genes are expressed at specific stages that regulate tooth development (positioning, size, shape) and its eruption. A mutation is a permanent change in the DNA structure, which can either be harmful or beneficial for the body.

However, when one or more of these genes mutate, they develop malformed or missing teeth.

Some of the commonly associated genes with tooth agenesis are as follows:¹

1. Syndrome-associated genes: 

• MSX1 (Muscle Segment Homeobox 1): related to Witkop syndrome, Wolf-Hirschhorn syndrome, and Pierre Robin syndrome-known to cause hypodontia or oligodontia (6 or more missing permanent teeth)
• AXIN2 (Axis Inhibition protein 2): related to the oligodontia-colorectal cancer syndrome- known to cause hypodontia

2. Non-syndrome-associated genes: 

• PAX9 (Paired Box gene 9): known to cause hypodontia or oligodontia, as well as microdontia (one or more teeth are smaller in size than normal)

Role of the MSX1 gene in tooth agenesis

MSX1 provides critical information during the early stages of organ and tissue development. Concerning tooth formation, MSX1 plays the following role:

• Formation of the tooth bud: Before actual teeth are developed, while still in the mother’s womb, we all have tooth buds which later mature into actual teeth
• Position and pattern: The MSX1 gene determines which teeth will form the incisors, canines, premolars and molars and their position in the mouth
• Size and shape: The MSX1 gene also plays an important role in regulating the size and shape of each tooth in the mouth

MSX1 gene mutation and tooth agenesis

MSX1 gene mutation can disturb the normal tooth development process and lead to tooth agenesis. This can happen when they are inherited in an autosomal dominant pattern (only one copy of the mutated gene from either parent can cause tooth agenesis in the child).

MSX1 gene mutation contributes to tooth agenesis in one of the ways:

• Defective tooth bud formation, particularly the upper lateral incisors and second premolar
• Reduced number of teeth, resulting in missing permanent teeth, commonly affected are the incisors and molars

Case study

When the MSX1 gene is mutated in these families, affected individuals may be missing certain permanent teeth, like molars or incisors, which can be observed across generations. This can be confirmed through genetic testing, which looks for specific mutations in the MSX1 gene.

Role of the PAX9 gene in tooth agenesis

PAX9 plays the following role in tooth formation:

• Development of the tooth bud: The PAX9 gene initiates the growth of tooth buds and guides the development 
• Determines tooth patterns: It plays a major role in determining the location and number of teeth
• Formation of tissue layers: Influence of PAX9 gene on the formation of the enamel and dentin layers

PAX9 gene mutation and tooth agenesis

It contributes to tooth agenesis by:

• PAX9 mutations are most commonly associated with missing permanent teeth — the molars (back teeth) 
• Missing second molars are the most notable effects of the PAX9 gene mutation
• Some individuals with PAX9 mutations may be missing only one or two teeth, while others may be missing multiple teeth in the molar region

Case study

In families with oligodontia caused by PAX9 mutations, affected individuals often have missing second molars but can also have other missing teeth. Genetic testing can identify specific mutations in the PAX9 gene to confirm the diagnosis.

Role of AXIN2 gene in tooth agenesis

The AXIN2 gene is crucial for many aspects of embryonic development, including tooth development. 

Wnt signalling pathway: AXIN2 helps regulate the Wnt signalling pathway by controlling the accumulation of certain proteins that influence the development and growth of tooth tissues

This signalling pathway is critical for:

• Tooth bud initiation: The early stages of tooth formation, where the tooth begins to develop
• Tooth number and patterning: AXIN2 helps ensure that the right number of teeth develop in the correct locations

Tooth size and anatomy: The AXIN2 gene also contributes to the proper anatomy of teeth by regulating the processes that influence tooth size and shape during development.

AXIN2 gene mutation and tooth agenesis

Mutations in the AXIN2 gene have been associated with tooth agenesis, particularly affecting the permanent teeth. These mutations contribute as follows:

• AXIN2 mutations are typically associated with the absence of permanent teeth, especially the incisors and molars. These teeth may not form at all, leading to gaps in the smile or the dental arch
• Individuals with AXIN2 mutations may experience ‘delayed eruption of teeth’ (teeth taking longer to emerge) or ‘developmental defects’ in other parts of the body
• A mutation in AXIN2 can disrupt the Wnt signalling pathway, causing irregularities in tooth development

Genetic testing, diagnosis, and tooth agenesis management

Genetic testing helps identify the underlying genetic factors that result in tooth agenesis.

Role of genetic testing in diagnosis

• Identification of specific gene mutations
• Differentiating between types of tooth agenesis
• Establishing the inheritance pattern - autosomal dominant or autosomal recessive traits
• Early detection

Role of genetic testing in management

• Guides in treatment planning: The absence of specific teeth (such as molars or incisors) can be anticipated, and strategies for replacing these missing teeth (e.g., implants, bridges) can be prepared in advance
• Prosthetic alternatives: It helps in guiding the decision to use prosthetics (such as dentures, implants, or braces) for aesthetic and functional purposes
• Orthodontic management: Tooth agenesis can lead to misalignment of remaining teeth, and affect the bite and overall dental health. Genetic testing helps orthodontists understand the extent of agenesis and plan appropriate treatments to manage bite problems or misalignment
• Monitoring tooth eruption: Genetic testing can help monitor and predict how remaining teeth will develop, allowing orthodontists to intervene early if needed
• Monitoring for associated health issues: In some cases, tooth agenesis is part of a broader syndrome that affects other parts of the body (e.g., colorectal cancer, ectodermal dysplasia or cleidocranial dysostosis)

Summary

Tooth agenesis is a congenital condition that results in one or more missing teeth due to the lack or absence of their development. The primary cause is linked to genetic factors that influence the formation and development of the teeth in both primary and permanent teeth. 

Genes are the set of instructions or the information that is used to form different tissues and perform functions in the body. Genes also regulate the development of teeth. Commonly associated genes for tooth agenesis are MSX1, PAX9, and AXIN2.

The MSX1 and PAX9 genes are important for tooth bud formation, tooth positioning, and regulating their size and shape. The mutation of this gene results in tooth agenesis. AXIN2 is linked with colorectal cancer and tooth agenesis. It may be associated with other syndromes.

Genetic testing and counselling play a crucial role in detecting and managing tooth agenesis. Further research is being conducted for a detailed understanding of the subject.