Oral Diseases (2003) 9, 19–23 Ó 2003 Blackwell Munksgaard

All rights reserved 1354-523X/03


Oral and Maxillofacial Pathology

Amelogenesis imperfecta: a classification and catalogue for the 21st century
MJ Aldred1,2,3, R Savarirayan2,3,4, PJM Crawford5
Department of Dentistry, Royal Children’s Hospital, Melbourne, Australia; 2Murdoch Children’s Research Institute, Melbourne, Australia; 3Department of Paediatrics, The University of Melbourne, Melbourne, Australia; 4Genetic Health Services Victoria and Southern Cross Bone Dysplasia Centre, Royal Children’s Hospital, Melbourne, Australia; 5University of Bristol Dental School, Bristol, UK

Amelogenesis imperfecta (AI) is a collective term for a number of conditions with abnormal enamel formation. Many cases are inherited, either as an X-linked, autosomal dominant or autosomal recessive trait. Several classifications have evolved since 1945, based primarily on phenotype with the mode of inheritance being used in some systems as a secondary factor in allocating a case into a particular category. The benefits and shortcomings of these systems are reviewed. As we move into an era of establishing the molecular basis of AI we propose a robust mechanism for classification and cataloguing of the disorder which parallels systems used in medical genetics. This system is applicable to individuals and families irrespective of current or future knowledge of the molecular defect involved. We argue that this system is of more benefit to these individuals and families than previous classifications. Oral Diseases (2003) 9, 19–23 1 Keywords: amelogenesis imperfecta; classification; inherited; enamel; dental; genetic

Class A number of individuals, persons or things possessing common attributes and grouped together under a general or Ôclass’ name; a kind, sort, division. (Shorter Oxford English Dictionary, Third Edition, 1965) Classify To arrange or distribute in classes according to a method or system. (ibid) classify verb [T] To divide (things) into groups according to type. (Cambridge International Dictionary of English; http://dictionary.cambridge.org/)

Correspondence: Michael J Aldred, Department of Dentistry, Royal Children’s Hospital, Flemington Road, Parkville, Victoria 3052, Australia. Tel: +613 9439 7415, Fax: +613 9431 6897, E-mail: michael_aldred@bigpond.com Received 21 February 2002; revised 18 October 2002; accepted 30 October 2002

These definitions carry with them the understanding that classification is the process of methodically distributing items according to type or common feature. Where items share several common features, the method of classification may be based on any one of those features best suited to the purpose of the classifier. Thus, a gardener might wish to classify plants by season of flowering, by flower colour or even by scent. A botanist wishing to consider the relationships between plants would be more interested in a classification that recognized biological relationships. A toxicologist might consider a classification based on the biochemical nature of the toxins produced by plants. Classification in medicine has for long been cliniciancentred and often based on appearance (phenotype); thus many clinicians will have learned classifications for ÔSwellings of the neck’ or ÔWhite patches of the oral mucosa’ and so on. These classifications are designed to aid diagnosis; however, they do little to further study of the particular condition, or to inform the patient. A second form of classification is increasingly seen in developmental conditions. For example, in OMIM

1982). ÔIf he (sic) is able to tell his patients about their past and present symptoms…also…what is going to happen. in cases of X-linked inheritance (Crawford and Aldred. However. Autosomal dominant rough hypoplastic 4. one condition’ then the case for the exclusivity of AI is clear. By Witkop and Rao’s (1971) strict definition the term AI ought to be applied only to inherited defects unassociated with generalized findings. The basis for classification of that group of enamel defects referred to as amelogenesis imperfecta (AI) has not yet been definitively established. 1993) the occurrence of the Lyonization (X-inactivation) phenomenon gives rise to different appearances in males and females. Witkop and Rao (1971) defined AI as Ôa group of disfiguring hereditary conditions’ which Ôaffect the clinical appearance of enamel of all or nearly all the teeth. 1992. and which may be associated with morphologic or biochemical changes elsewhere in the body. Autosomal dominant pitted hypoplastic 5. First. patients want information about their condition that relates not only to themselves but also to their families. It is important for us to reconsider what we mean by any condition being exclusive of association with any other. Pindborg. White hypomature spots? In a view which argues Ôone gene.gov/omim/). its implications and management. Subsequently. We do. however. which affect the structure and clinical appearance of enamel of all or nearly all the teeth.ncbi. Additionally. Secondly. Once this has been done. then attention can be paid to the phenotype. c. Later work describing variable expressivity in families with AI (Aldred and Crawford. believe that this approach is of benefit to individuals and families with AI and to the eventual clarification and elaboration of the molecular basis of their disorder. Backman et al. X-linked dominant rough hypoplastic (b) Hypocalcified 1. namely defects of dentine – hereditary brown opalescent dentine – and enamel – brown hypoplasia of enamel. 1993) suggests that the inclusion of the statement Ôall the individuals in the kindred show essentially the same defect’ is perhaps inappropriate. namely hypoplastic and hypocalcified. unrelated to any specific time or period of amelogenesis. X-linked recessive hypomaturation 2. The first definition of AI – as a disease caused by a primary defect in enamel – has been attributed to Weinmann et al (1945) who classified AI into two types. Nevertheless. Such refined classification which allows qualification and a degree of ambiguity recognizes our increasing understanding of the molecular biology of both health and disease and forms a foundation both for study and for the clearer informing of patients. as the complex interactions of both genomic position and biochemical activity are further revealed. we are left with three factors. OIC Ôthe phenotype of OI type II can be caused by mutation in either the COL1A1 gene (120150) or the COL1A2 gene (120160)’ (Online Mendelian Inheritance in Man: http://www. This definition was subsequently adopted by both Darling (1956) and Witkop (1957). (Hippocrates of Cos. or to any intermittent dietary abnormality or disease. a view reinforced by Crawford et al (1988) who described a family affected by autosomal dominant AI associated with taurodontism (ADAIT) in which both hypoplastic and hypomineralized forms of AI were reported. classification MJ Aldred et al 20 entry #166210 OSTEOGENESIS IMPERFECTA CONGENITA. This does not contradict the need for the phenotype to contribute to the establishment of the mode of inheritance.nlm. some authors have included enamel defects Ôassociated’ with inherited syndromes and metabolic diseases as examples of AI (Schulze.Amelogenesis imperfecta. The first contribution on the subject was a paper by Finn in 1938. Autosomal dominant hypoplastic–hypomaturation with taurodontism (a) Winter type (b) Crawford type 2. 1970. It follows that determining the probable mode of inheritance is integral and essential to the diagnosis of AI. In our attempts to systematize our understanding of AI. there is sufficient variability in the phenotypic expression of AI within individual pedigrees to make appearance invalid as a criterion for sorting.nih. 1988. with the advances in our knowledge of the human genome it would be logical to use genotypic information to distinguish between forms of AI. Snow-capped teeth. Autosomal recessive pigmented hypomaturation 3. Darling (1956) stated that AI implied a generalized fault of enamel structure affecting all the teeth of one or both dentitions. … people will have no qualms in putting themselves under his care’. hitherto unimaginable relationships may appear. as is the seeking of appropriate genetic advice and counselling. Table 1 Classification of amelogenesis imperfecta proposed by 3 Witkop and Rao (1971) (a) Hypoplastic 1. Backman et al. 1993. Aldred and Crawford. He also remarked on the inherited pattern of the disease and added that there was a possibility that the condition could occur spontaneously in one or more members of the same family. Thirdly. we suggest a refining of the definition of Witkop and Rao (1971) to define AI as: A group of conditions. autosomal dominant 4. as well as…the details they have omitted. who differentiated two groups of tooth anomalies based on clinical characteristics. Autosomal dominant local hypoplastic 6. In order to diagnose AI. Autosomal dominant smooth hypoplastic with eruption defect and resorption of teeth 3. 450 BC) Oral Diseases . which occur in kindreds such that all the individuals in the kindred show essentially the same defect and which are unassociated with known morphologic or biochemical changes elsewhere in the body’. Autosomal dominant hypocalcified (c) Hypomaturation 1. genomic in origin.

1. it is of merit to consider those that have been used before. The resulting. This classification was insufficient on its own to distinguish between all the cases seen. localized opacities 7 Hypomaturation. the clinical appearance alone would not seem to justify allocation to diagnostic groups where there is known to be considerable variation in appearance.1. All three of these classifications used both clinical features and inheritance patterns to allocate individual diagnoses. classification MJ Aldred et al Table 2 Classification of amelogenesis imperfecta proposed by Winter and Brook (1975) Hypoplasia I Autosomal dominant.1 Basic form 1. characterized by their varying modes of inheritance and different appearances.3 Pitted basic form 1. rough Hypocalcification I Autosomal dominant Hypomaturation I X-linked recessive II Autosomal recessive pigmented III Snow-capped teeth Hypomaturation–hypoplasia with taurodontism I Autosomal dominant with occasional hypoplastic pits II Autosomal dominant with thin hypoplasia Table 4 Classification of amelogenesis imperfecta proposed by Sundell and Koch (1985) 1.1.Amelogenesis imperfecta.2 Thin enamel 1. randomly pitted IV Autosomal dominant. in the present case. the classification presented by Witkop and Rao in 1971 divided the conditions first into three groups according to the predominant phenotype within a pedigree and then by the particular expression (Table 1).1. Sundell and Valentin (1986) presented a modified classification of AI (Table 5) formed by the addition of family (genetic) pedigrees into the Ôclinical appearance’ classification of Sundell and Koch (1985). The classification of AI Of the classification systems for AI often cited. 1988).3. there are a number of subtypes. Before exploring further the nature of any new classification.1 Thin enamel 2. they seem to have confused Ôincidence’ with Ôexistence’ of a condition. localized or general Dominant (autosomal or X-linked) Autosomal recessive Autosomal dominant with incomplete penetrance Dominant (X-linked or autosomal) Dominant (Autosomal or X-linked) Autosomal dominant Autosomal dominant (X-linked dominant or recessive) Autosomal recessive The incidence of AI has been reported to vary from approximately 1 : 14 000 (Witkop.1.2 Pitted with horizontal grooves 1. Hypomineralized 2.3 Pitted with vertical grooves 1.1 Rough 1.2 Smooth 1.1.1. However. This in turn was rearranged by Winter and Brook in 1975 according to the presumed underlying developmental defect (Table 2).1. unspecified 5 Smooth thin Hypomineralized 6 Hypomaturation. horizontal grooves 4 Rough. of what is an inherited condition. Hypoplastic 1. although parallels might be drawn with ornithology where identification is sometimes aided by reference to a Ômigrants’ or Ôaccidentals’ list.3. In their paper. 1957) to <1 : 800 (Backman and Holmgren.1. Note the confusing and inconsistent use of Arabic and Roman numerals (or lack thereof). generalized opacities 8 Hypocalcification.1 Localized opacities 2.1.1 Localized or generalized 21 Table 3 Classification of amelogenesis imperfecta proposed by Witkop and Sauk (1976) Hypoplasia Autosomal dominant pitted hypoplastic Autosomal dominant local hypoplastic Autosomal dominant smooth hypoplastic Autosomal dominant rough hypoplastic Autosomal recessive rough (enamel agenesis) X-linked dominant smooth Hypomaturation Autosomal dominant hypomaturation–hypoplasia with taurodontism X-linked recessive hypomaturation Autosomal recessive pigmented Snow-capped teeth Hypocalcified Autosomal dominant hypocalcified Autosomal recessive hypocalcified Table 5 Classification of amelogenesis imperfecta proposed by Sundell and Valentin (1986) Hypoplastic 1 Rough thin enamel 2 Rough pitted 3 Rough. Sundell and Koch (1985) used a classification based solely on clinical findings in a large study of Swedish children (Table 4).3.4 Horizontal grooves 1. localised V X-linked dominant.2. list is very difficult to compare with those previously cited and Oral Diseases .5 Unspecified appearance 1. The incidence of a condition is not particularly relevant to its position in a classification.1 Hypomaturated 2.2 Hypocalcified 2. Witkop and Sauk (1976) proposed an elision of these two classifications (Table 3). The condition is not a single entity. and rather confusing.1 Pitted thin 1. They argued that previous classifications were of questionable value as they did not take into account the relative frequencies of the different types of AI. thin and rough III Autosomal dominant. especially within families.2 Generalized opacities 2.2. thin and smooth with eruption defect and resorption II Autosomal dominant.

local autosomal dominant IC – hypoplastic. from a large number of case studies. 1995) we had anticipated that the advances in medical molecular genetics would rapidly have been mirrored in dental genetics. As already cited.Amelogenesis imperfecta. descriptions of phenotypic variation within single pedigrees and. a reliance on phenotypic characteristics has proven to be unreliable in the light of molecular genetic investigations. In an attempt to use these findings to bring order to a confused field. It would seem that the only definitive and reproducible diagnosis would arise from a study of the genetic composition of affected individuals and families. Moreover. 1970. These systems have proved to be more Ôuser-friendly’ as well as lending themselves to being a better tool for understanding how the genotype leads to the specific phenotype (i. rough autosomal dominant IG – enamel agenesis. classification MJ Aldred et al 22 Table 6 Classification of amelogenesis imperfecta proposed by Witkop (1988) Type I Hypoplastic IA – hypoplastic. first. Congleton and Burkes. IIC – snow-capped teeth. 1988). It is therefore logical and prudent to consider both the modes of inheritance and molecular genetic data in conjunction with the specific phenotype in any classification where there exists an overlap of clinical features. Crawford et al. autosomal dominant Table 7 Classification of amelogenesis imperfecta proposed by Aldred and Crawford (1995) Genetic location Mutation Biochemical outcome Mode of inheritance Phenotype leaves out at least one well-documented condition. X-linked lID – autosomal dominant? Type III Hypocalcified IIA – autosomal dominant IIB – autosomal recessive Type IV -Hypomaturation–hypoplastic with taurodontism IVA – Hypomaturation–hypoplastic with taurodontism.e. There are over 100 of these syndromes that were classified primarily on the basis of their clinical phenotypes (Cohen. A workable classification for AI In our previous proposal for classification of AI (Aldred and Crawford. pigmented autosomal recessive IIB – hypomaturation. There is clear evidence. smooth X-linked dominant IF – hypoplastic. 1986). In saying this we seek to distinguish between a method of classification and the formation of a catalogue. hypocalcified and hypomaturation–hypoplastic) and then subdivided into 15 subtypes based primarily on phenotype and. by mode of inheritance. further diagnostic confusion arises from phenotypic variability. In view of this. The recent explosion of knowledge regarding the genetic basis of these conditions has rendered this classification less useful as many disorders have been discovered to be allelic conditions. many individuals within a particular family who were diagnosed to have different clinical conditions (based solely on phenotype) have been shown to have identical gene mutations (Jabs. hypomaturation. in general terms. An example of this is in the classification of the various craniosynostosis (premature fusion of one or more of the calvarial sutures) syndromes. secondly. However. Aldred and Crawford (1995) proposed a new classification based on the molecular defect (when known). Regrettably. pitted autosomal dominant lB – hypoplastic. 1969. biochemical result (when known). we propose a format for the classification of AI (which might also be applied to other inherited dental anomalies) until such time as the molecular basis of these disorders is clarified. As a result. we present an argument for a modified version of this suggestion which is presently workable. Again. our increasing knowledge of genomic genetics. although some papers in other areas have suggested that this might be useful in other dental genetic disorders (Dean et al. the use of a classification based on incidence and generated from one geographical area is likely to restrict the conditions studied to a single genetic pool. of what is an inherited condition. autosomal dominant IVB – Hypoplastic–hypomaturation with taurodontism. classification relies upon a method or system. Witkop (1988) further developed the predominantly phenotypic classification of Witkop (1957). Crawford. . local autosomal recessive ID – hypoplastic. autosomal recessive Type II Hypomaturation IIA – hypomaturation. smooth autosomal dominant IE – hypoplastic. This proposal might also become the basis of a future catalogue of inherited dental conditions as has been developed in other inherited disorders. neither does the clinical appearance alone seem to justify allocation to diagnostic groups even within families. At one level. The lack of present uptake may reflect the as yet limited data available for classification based on the molecular defect in an individual or family. this is not surprising as ADAIT has been described in only a few families to date. the incidence of a condition hardly seems relevant to its position in a classification. mode of inheritance and then phenotype (Table 7). of the genetic aetiology of at least 10 forms of AI. This proposal has not yet been adopted. 1998). Previous efforts to base classes of AI on Oral Diseases appearance have been overtaken by two major events. namely ADAIT (Winter et al. Witkop and Rao (1971) and Witkop and Sauk (1976) into a further classification (Table 6). 1997). in the best interests of individuals and families with AI and capable of later extension. our understanding of the molecular genetic basis of dental abnormalities has not progressed as quickly as might have been expected. secondarily. In other aspects of genetics. socalled Ôfunctional genomics’). Four major types were recognized based on phenotype (hypoplastic. 1979. although it may be that the former eventually contributes to the latter.

Cohen MM (1986). Winter GB. Some observations on amelogenesis imperfecta and calcification of the dental enamel. Darling AI (1956).Amelogenesis imperfecta. Sundell S. Holmgren G (1988). 1997) to avoid overdue emphasis on phenotypic characteristics. Hereditary disturbances of enamel formation and calcification. Oral Surg Oral Med Oral Pathol 73: 449–455. Oral Dis 1: 2–5. A rare autosomal dominant type. until such time as the molecular basis of all forms of AI is established. Evans RD. Inherited defects in tooth structure. Hartsfield JK. the primary structure for the classification of AI be based on the mode of inheritance. Such a concept is not particularly novel. Developmental abnormalities of the teeth and jaws. Aldred MJ. Aldred MJ. Aldred MJ (1988). this system forms the basis of Online Mendelian Inheritance in Man. Svoboda JF. A revision of inherited dentine defects along these lines has been suggested (Dean et al. X-linked amelogenesis imperfecta. apart from in the dental literature. As information on the molecular basis of the disorder in particular individuals or families becomes known. Sauk JJ (1976). Hereditary amelogenesis imperfecta. St Louis: Mosby. Amelogenesis imperfecta. Acta Genet Stat Med 7: 236–239. Goldman HM. J Oral Pathol 2 Med 17: 327–323. Dent Clin North Am 19: 3–24. Congleton J. Engstrom EU et al (1993). Community Dent Oral Epidemiol 14: 211–216. Crawford JL (1970). Hereditary amelogenesis imperfecta. Koch G (1985). Witkop CJ (1957). Clin Genet 53: 79–86. References Aldred MJ. Pindborg JJ (1982). Heritable defects of enamel. Winter GB. Mosby: St Louis. Crawford PJM (1988). dentinogenesis imperfecta and dentin dysplasia revisited: problems in classification. 6th edn. we propose that. Hereditary defects in enamel and dentin. Aetiology of developmental enamel defects not related to fluorosis. Craniosynostosis: diagnosis. Acta Odontol Scand 51: 79–89. J Am Dent Assoc Dental Cosmos 25: 1240–1249. Aldred MJ (1992). Crawford PJM (1993). Burkes EJ (1979). Hereditary opalescent dentin. Amelogenesis imperfecta: autosomal dominant hypomaturation-hypoplasia type with taurodontism. J Craniofac Genet Dev Biol 17: 172–177. Jabs EW (1998). Thoma’s oral pathology. evaluation and management. Rao SR (1971). 96–178. Concomitant taurodontism and amelogenesis imperfecta in the American Caucasian. classification MJ Aldred et al Table 8 New scheme proposed for the classification and cataloguing of amelogenesis imperfecta Mode of inheritance (autosomal dominant ⁄ autosomal recessive ⁄ X-linked ⁄ isolated case) Molecular basis [chromosomal localization ⁄ locus ⁄ mutation (when known)] Biochemical outcome (putative result of mutation when known) Phenotype (description of clinical and ⁄ or radiographic features and ⁄ or other relevant findings) Whereas all previous authors have used a general division by phenotype as a primary discriminator. Finn SB (1938). Johnson NW (1969). Backman B. Oral facial genetics. Furthermore. Br Dent J 164: 71–73. this can be added to the description of the cases. Dean JA. Crawford PJM. Enamel hypoplasia and anomalies of the enamel. J Dent Child 37: 83–87. Hart TC (1997). J Am Dent Assoc 32: 397–418. An analysis of the literature on hereditary anomalies of tooth colour. Amelogenesis imperfecta – towards a new classification. Presentation of two kindreds and a review of the literature. eds. Crawford PJM (1995). In: Gorlin RJ. Wright JT. Amelogenesis imperfecta: a genetic study. Birth Defects Orig Artic Ser 7: 153–184. Crawford PJM. Amelogenesis imperfecta with taurodontism. Lee KW. The absence of correlations between a clinical classification and ultrastructural findings in amelogenesis imperfecta. Raven Press: New York. Sundell S. In: Stewart RE. Swed Dent J 9: 157–169. Dentin dysplasia type II linkage to chromosome 4q. pp. Clinical features of a family with X-linked amelogenesis imperfecta mapping to a new locus (AIH3) on the long arm of the X chromosome. 23 Oral Diseases . Witkop CJ (1988). Oral Surg Oral Med Oral Pathol 76: 187–191. Witkop CJ. Backman B. Epidemiology and clinical classification in a Swedish child population. 1. I. Weinmann JP. Proc R Soc Med 49: 759–765. Int Dent J 32: 123–134. Schulze C (1970). Toward understanding the pathogenesis of craniosynostosis through clinical and molecular correlates. Valentin J (1986). J Oral Pathol 17: 547–553. with the clinical and radiographic appearances (and any other features) being the secondary discriminators (Table 8). Brook AH (1975). Hum Hered 38: 189–206. Prescott GH. Chapter 7. eds. Br Dent J 127: 157–164. Lundgren T. Woods RW (1945). Variable expression in amelogenesis imperfecta with taurodontism. Oral Surg Oral Med Oral Path 48: 540–544. Witkop CJ. Hereditary aspects and classification of hereditary amelogenesis imperfecta.