Amelogenesis imperfecta

X-linked forms of amelogenesis imperfecta

X-linked amelogenesis imperfecta (XAI) (OMIM #301200, Amelogenesis imperfecta 1, hypoplastic type, AIH1) shows the typical pattern of X-linked inheritance. Heterozygous females can pass on the mutant gene to children of either sex with the risk of this being 50%. The condition affects males and females in strikingly different ways. Males show the trait fully. They may have teeth which have only a thin layer of enamel of normal colour and translucency, or the enamel may be of normal thickness but poorly mineralised with loss of translucency and/or a yellow-brown discolouration. In some families, the phenotype appears to be both hypoplasia and abnormal mineralisation occurring together. When hypoplasia is the exclusive or predominant phenotype, there may be marked sensitivity of the teeth to thermal and osmotic stimuli. By contrast, females who inherit the mutant gene have vertical markings of the enamel as a result of X chromosome inactivation or Lyonisation. Thus, these heterozygous females may have teeth with vertical ridges and grooves as a result of hypoplasia of the enamel or have vertical bands of alternating normal and discoloured enamel [26].

The molecular basis of XAI has been established in some families. Positional cloning has demonstrated linkage of the disorder to the Xp22 region of the short arm of the X chromosome in some families and it has subsequently been shown that in these and other families the disorder is a result of mutations in the amelogenin gene AMELX [27–30]. Another locus on the long arm of the X chromosome has also been implicated in one family with XAI (AIH3) but this gene has not yet been cloned [16, 31].

The amelogenin gene (OMIM *300391)

The amelogenin gene AMELX maps to Xp22.3-p22.1 and codes for the amelogenin protein. It consists of seven exons spanning over 9 kilobases. Mutations reported include deletions of parts of the gene, single base mutations and premature stop codons. Certain parts of the gene may be critical in the control of enamel thickness, while other parts may play an important role in enamel mineralisation [32]. Alternative splicing of the amelogenin protein has been demonstrated but the clinical significance of this finding is yet to be determined. No evidence of pre-mutations has yet been found. Molecular analysis of the amelogenin gene may be helpful in confirming the diagnosis of XAI in particular cases, thereby allowing appropriate genetic counselling. There is no evidence of any mutations of the amelogenin gene AMELY (Yp11) on the Y chromosome (and the enamel forming role of genes on the Y chromosome and any mutations of these genes are as yet unknown, although it has been suggested that the Y site may contribute to tooth size [33]).

Autosomal forms of amelogenesis imperfecta

Positional cloning has shown that the disorder in some families with autosomal dominant AI maps to 4q11–q21. The albumin ALB, ameloblastin AMBN and enamelin ENAM genes all map to the same region and are therefore candidate genes for autosomal AI. Tuftelin is another enamel protein, which maps differently to 1q21, and may be involved in other cases of autosomal AI. Mutations in genes coding for enamel proteases, which are involved in the degradation of enamel proteins, might also cause AI.

Autosomal dominant amelogenesis imperfecta

Autosomal dominant AI (ADAI) typically affects one or more individuals in each generation of a family. There may be consistency in the clinical manifestations in every affected individual or there may be variable expression, resulting in substantial or subtle differences between different affected individuals in the same family.

The phenotype in ADAI may be predominantly or exclusively hypoplastic, manifested by thin enamel and spacing between the teeth, or in some pedigrees by rough, irregular or randomly pitted enamel. If the prime defect is in the amount of enamel matrix produced, the enamel will be hard, normally translucent and not subject to significant attrition. By contrast, in some individuals and families the phenotype may be predominantly or exclusively hypomineralised.

Some earlier classifications have subdivided these latter defects into hypocalcification defects, implying a more severe mineralisation abnormality, and hypomaturation defects, implying a lesser degree of hypomineralisation. At extremes, this subdivision is probably valid but in most cases it is difficult to be certain which would be the better descriptor, hence the use of the term dysmineralisation in recognition of the probable spectrum of defects of mineralisation of enamel in AI. Given the complexity of enamel formation, this is probably a realistic view until such time as the molecular and protein pathways of enamel formation have been elucidated. The most severe forms of dysmineralisation result in enamel that has a "cheesy" consistency and is easily lost, resulting in teeth of reduced size and considerable sensitivity.

Some cases will show both enamel hypoplasia and dysmineralisation. Thus, in a number of individuals, the teeth will be reduced in size ab initio with thinner enamel, small crowns and spacing as well as showing a yellowish-brown hue as evidence of a coincidental mineralisation defect.

ENAM 4q21

The enamelin gene (ENAM) has been mapped to chromosome 4q, to the same region as AIH2 (Amelogenesis imperfecta 2, hypoplastic local, AIH2, OMIM #104500). Rajhpar et al. have described an extensive family in which the causative gene mapped to 4q11–q21 [18].

Kida et al. reported an extensive Japanese family with an apparently similar phenotype, whose condition was linked to "a single-G deletion within a series of 7 G residues at the exon 9-intron 9 boundary of the enamelin gene" in this region [19]. A local, hypoplastic form of the autosomal dominant inherited condition was traced by Mardh et al. [20] to a nonsense mutation in the enamelin gene. This gave rise to a truncated protein which was expressed as the mentioned local hypoplasia, rather than a generalised form seen with a "splice-site" mutation. The work of Kim et al. further relates phenotype to genotype and identifies a mid-crown, horizontal form of genetically determined hypoplasia [34].

Chromosome 8q24.3

An additional locus for autosomal dominant amelogenesis imperfecta has been found recently on chromosome 8q24.3 [35].

Autosomal recessive amelogenesis imperfecta

Autosomal recessive AI (ARAI) should be considered if there is known consanguinity in a family with an affected individual. This may be more often encountered in certain ethnic and cultural groups where intermarriage within the family may be more common (for example, AI in association with cone rod dystrophy, a syndromic condition [24, 36]). ARAI will also be more prevalent where there is a high frequency of the mutant gene in a population, such as in some Polynesian communities [37, 38].

ENAM 4q21

Amelogenesis imperfecta, hypoplastic, and openbite malocclusion, OMIM #608563; Hypoplastic enamel pitting, localized, included #608563.

Most interestingly, Hart et al. (2003) described three probands with ostensibly autosomal recessive AI [17]. They found that where the individuals were homozygous for the g.13185_13186insAG ENAM mutation on chromosome 4, they showed enamel pitting with an anterior open bite, whereas heterozygosity presented only with the enamel pitting. They described this as "dose dependency". Enamel phenotypes of ENAM mutations may be dose-dependent, with generalised hypoplastic AI segregating as a recessive trait and localised enamel pitting segregating as a dominant trait [39].

Other authors associated with the same centre presented an extensive survey at the clinical, familial, radiographic, microscopic and protein analysis level of nine Jordanian families with ARAI. They found a wide diversity of phenotypes. Whilst supporting the principle of classification first by inheritance pattern, they suggested the existence of four clear sub-types of ARAI [40].

KALLIKREIN 4

The first mutation in the kallikrein gene family, the KLK4 gene (that maps to chromosome 19q13.4), has recently been identified as being associated with autosomal recessive hypomaturation amelogenesis imperfecta [41].

MMP-20

A mutation in the matrix metalloproteinase 20 gene (MMP-20) in the region 11q22.3–q23 has been described as being associated with autosomal recessive pigmented hypomaturation amelogenesis imperfecta [42, 43].

Sporadic cases of amelogenesis imperfecta

Apparently sporadic cases of AI may have one of several causes. They may represent examples of ARAI, or they may be due to new mutations, or they may be illustrative of variable expression with or without incomplete penetrance of a dominant gene. Careful examination of other family members is vital in such instances, and it is important to avoid inappropriate classification of individuals as AI if, in fact, their tooth abnormality is due to non-genetic causes (such as fluorosis or tetracycline staining). We do not yet know whether new mutations will be passed on as an autosomal dominant trait, though evidence from other genetic disorders would suggest this to be a likely scenario.

Of recent years, a condition referred to as Molar-Incisor Hypomineralisation (MIH) has become prominent [44, 45]. The aetiology of this condition, which affects one or more of the first permanent molars in a chronologically-reminiscent but unrelated pattern, together with a seemingly random number of permanent anterior teeth, is unknown. There are reports of affected sibs [46]. MIH is not presently classified as amelogenesis imperfecta.

For recent review on the molecular genetics of AI see [47, 48].

Syndromes including amelogenesis imperfecta

Earlier strict definitions of AI have specified an enamel defect without the involvement of other structures. However, there is an intellectual problem in adopting too narrow a definition and such a restriction is probably counterproductive as far as families are concerned.

AI is a genetic disease that may exist either in isolation or associated to or with other features in syndromes. It is either related to a single gene defect or arises from a microdeletion or chromosomal defect. AI, showing linkage to 2q11 and associated with cone-rod dystrophy, is such an example [24, 25].

Amelogenesis imperfecta a syndrome in itself

Clinically, a skeletal anterior open bite is seen in approximately 50% of patients with AI of either X-linked or autosomal inheritance. Such an association might be regarded as a syndrome but this does not appear as such in any classification. The significance of this common association has yet to be elucidated.

Predominantly phenotypic classifications of AI have included a variant with taurodontism as an intrinsic feature – AI with taurodontism (AIT) (OMIM #104510). This also goes beyond the strict definition of AI yet it is reasonable to include the condition in any classification of AI given that taurodontism is regarded as an ectodermal trait. The sheath of Hertwig, that maps the shape of the roots of teeth, is a derivative of the enamel organ and is also responsible for differentiation of the inner dental epithelial cells to ameloblasts producing enamel proteins. The subtle dentine changes reported by Winter et al. (1969) add further to our difficulties in understanding the complexities involved in some cases [49].

Amelogenesis imperfecta in syndromes

Less clearly, there are strong similarities between AIT and the tricho-dento-osseous (TDO) syndrome (OMIM #190320), which has the additional features of "curly hair" and skeletal changes including bone sclerosis. While the hair changes might represent a common ectodermal defect in TDO, the bony changes are more difficult to explain via a common pathway, as this assumes a mesodermal defect. TDO is caused by a mutation in the DLX3 gene [50]. One molecular study has reported that AIT and TDO are genetically distinct [51], whereas a later paper suggests that TDO and Amelogenesis imperfecta hypoplastic-hypomaturation with taurodontism (AIHHT) are allelic for DLX3 [52].

The literature records further examples of seemingly AI-like changes associated with other whole body findings, hitherto excluded from a diagnosis of AI. If we accept that AI may occur as an isolated trait, but also in association with a range of other abnormalities, then many different syndromes need to be considered in the differential diagnosis of patients with enamel defects. For further information regarding the full range of symptoms associated with AI, the reader is referred to Online Mendelian Inheritance in Man (For example see Kohlschutter syndrome, OMIM %226750; Platyspondyly with amelogenesis imperfecta, OMIM 601216; Amelogenesis imperfecta and nephrocalcinosis, OMIM 204690; cone rod dystrophy and amelogenesis imperfecta, OMIM %217080).

The published association of hypoplastic amelogenesis imperfecta with nephrocalcinosis may raise the question of the need for renal examination when a diagnosis of AI is given [53].

Enamel defects but not Amelogenesis imperfecta in syndromes

Differential diagnosis of the causes of enamel defects is important for both therapeutic, professional and patient-personal reasons. There are many alternative causes of enamel defects but, for example, a localised defect of a central incisor, coupled with the non-eruption of an adjacent tooth, may point to an injury in childhood and possible damage to the unerupted tooth. Rarely, the recognition of regional odontodysplasia, a rare developmental abnormality of all three dental tissues, enamel, dentine and pulp affecting a segment of the dentition, will assist in its management, which has all too often previously condemned the teeth to extraction [54].

Many persons affected by these conditions are concerned for the teeth of their children. A careful diagnosis, particularly in relation to inheritance, will be important to many such affected families.

Clinical

The family history, pedigree plotting, clinical observation and meticulous recording form the backbone of diagnosis in this, as in any potentially inherited condition. Extra-oral radiographs may reveal the presence of unerupted and sometimes spontaneously resorbing teeth. Intra-oral radiographs will reveal the relative contrast between enamel and dentine in cases where mineralisation may have been affected. The same films in conjunction with clinical observation will provide information on the degree of any enamel hypoplasia.

Genetic diagnosis

Laboratory genetic diagnosis is presently only a research tool.