Amelogenesis Imperfecta: deciphering the enamel prisms

During the early stages of embryogenesis, craniofacial development is mediated by stem cells, called cranial neural crest cells (CNCs), responsible for all head structures except muscles of mesodermal origin. These CNCs are specializing and organizing elements such as bone and teeth and interacting with the epithelium that covers the face and oral cavity. The molecular relationship between CNCs and epithelium is regulated by proteins (encoded by specific genes) that induce cell differentiation: osteoblasts, odontoblasts, chondrocytes… Therefore, mutations in these genes will be responsible for different orofacial and dental alterations [26 ]. 

Although odontogenesis differs from osteogenesis in multiple aspects, dental (enamel, dentin, and cement) and bone mineralization are susceptible to alterations in parallel when there are pathologies that unbalance mineral metabolism, whether hypo or hypermineralization, such as hypophosphatemia, hypophosphatasia, or generalized arterial calcification in childhood [27]. 

Dental anomalies or dental dysplasias are alterations that occur from the embryonic process to the final constitution of the tooth, and may affect the number, shape, size, structure, position and color of the tooth (deciduous or definitive). More than 300 genes regulate these characteristics [26]. 

These genes, or the protein function derived from them, can be altered by mutations (inherited or de novo) or by systemic (metabolic, endocrine, toxic…) and local environmental factors, such as trauma. 

Dental anomalies are usually described as isolated alterations or associated with syndromes; however, on occasions they accompany silent alterations in childhood, but with late expression, which can give them diagnostic suspicion. 

Broadly speaking, there are 2 types of genes whose mutations generate dental dysplasias: some specific for the development of enamel and dentin and others called homeobox that, in addition to regulating dental morphodifferentiation, also regulate other organs of the body, which is called pleiotropy [28]. 

Within the homeobox genes, this group is recognized as the most relevant: PAX, MSX, DLX, LHX, BARX and RUNX2. 

The most important proteins or molecular signals in the regulation of dental embryogenesis are: BMP (bone morphogenetic protein), TGFb (transforming growth factor b), EGF (epidermal groth factor), SHH (sonic hedgehog) and WNT (wingless) [26 ]. 

The term Amelogenesis Imperfecta (AI) refers to a group of dental anomalies or dysplasias that alter enamel formation quantitatively or qualitatively. 

Clinically it is classified into 4 groups based on clinical, radiographic and thickness appearance, but within these 4 groups there are 17 subgroups, within the genetic spectrum, based on the mode of inheritance (dominant, recessive or associated with X chromosome). 

Let’s see the 4 clinical identification groups: 

Type 1. Hypoplasia (defect in the formation of the enamel matrix): little enamel formation that can be associated with small teeth (it can generate gaps) or normal teeth, but with little enamel thickness, with a variable surface between smooth or with grooves, wells or lines; and a whitish to yellow-brown color. Normal radiopacity in terms of contrast, but of reduced or absent thickness. 

Clinical summary: small or normal teeth with scant or fine but hard (white-yellow-brown) enamel, sometimes grooves, pits. 

Types 2 and 3 are hypomineralizations with different etiology: 

Type 2. Hypomaturation (defect in the processing of proteins and in the maturation of the hydroxyapatite crystals of the enamel): in this case, the size of the tooth is normal and the thickness of the enamel also when it erupts. The tooth is hard, but more easily erodible than normal. White, calcareous, cream or yellow-brown color. Normal radiopacity (since there is normal calcification). 

Clinical summary: tooth of normal size with hard (white-yellow-brown) enamel, but easily erodible. 

Type 3. Hypocalcified (defect in the calcification of the enamel matrix): the size of the tooth is normal, the thickness of the enamel also when the tooth erupts. As the enamel does not calcify correctly, it is soft and brittle (the occlusion itself fractures it) which facilitates dentin exposure (sensitivity). Orange yellow colour. Radiolucent (due to the absence of calcification). 

Clinical Summary: Tooth of normal size, but with soft (yellow-orange), porous, brittle, and radiolucent enamel. 

Type 4. Hypomaturation, hypoplasia and taurodontism. A combination of the previous three with associated taurodontism. 

Clinical summary: in my opinion we could call taurodontism the great forgotten, one of those signs that, as soon as you take it into account when studying a panoramic X-ray, it surprises you how we have underestimated it over time. In recently erupted sixes with soft and scant enamel, the excess size of the pulp chamber and a deficient dentin thickness generate great sensitivity and pain (a challenge for conservative dentistry). 

AI are enamel defects that are sometimes associated with other dental anomalies such as pulpal calcifications, delayed eruption, gingival hyperplasia and, as we have seen, taurodontism. 

Although being able to clinically differentiate the types of AI is somewhat challenging, things get complicated when we want to order the genetic contribution to these alterations: on the one hand, there is the mode of inheritance (autosomal or X-linked; dominant or recessive) and on the other the causative genes (it is not yet confirmed that all the genes that cause AI are known). As a summary of the OMIM (Online Mendelian Inheritance in Man) database, it would be: 

As I previously mentioned, there are two types of genes: some specific for the formation of enamel (they only affect teeth) and others called homeobox, which can affect teeth and other parts of the body, which is why they are more relevant. For example, in type 4: the sum of the AI symptoms (hypoplasia, hypomineralization) with the objectivity of the radiographic image (taurodontism) could have a predictive value for the named mutations. There are certain syndromes in which taurodontism has been identified and this is more evident: tricho-dento-osseous syndrome (a type of ectodermal dysplasia due to DLX3 gene mutation), osteogenesis imperfecta, Torg-Winchester syndrome, cleft lip and palatal…. But, sometimes, the dental characteristics of AI can be a first sign of other homeobox genetic mutations that later affect other parts of the organism and that can give an etiopathogenic explanation of clinical manifestations that are difficult to classify. The future will figure it out… 

The differential diagnosis with other structure and color alterations such as fluorosis, MIH or trauma can often be facilitated by the clinical history, but when the suspicion falls on a genetic origin that is related to other alterations, a genetic study may provide more data of relevance.