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Diversity of clinical, radiographic and genealogical findings in 41 families with amelogenesis imperfecta

Diversity of clinical, radiographic and genealogical findings in 41 families with amelogenesis... 1,7* Amelogenesis imperfecta (AI) is a group of enamel development disorders Daniela ADORNO-FARIAS that alter the structure and chemical composition of the tissue. There is 1,7* Ana ORTEGA-PINTO great variability in the clinical presentation; according to Witkop, AI can be Paulina GAJARDO categorized into 14 subtypes, which makes its diagnosis extremely complex. Ana SALAZAR Objective: This study aimed to describe and determine the frequency of Irene MORALES-BOZO clinical and radiographic features and inheritance patterns found in 41 Fabiola WERLINGER Chilean families diagnosed with diverse types of AI. Material and Methods: Sandra ROJAS-FLORES We analyzed the clinical records, photographs, pedigrees and radiographs 4,7 of 121 individuals recruited between 2003 and 2016. All of the information Alfredo MOLINA-BERRÍOS was included in a database that was analyzed using the application Stata Sonia ECHEVERRÍA-LÓPEZ 14. Results: The 72 affected individuals had average age of 16 years, and 4,7 José JARA-SANDOVAL no sex association with the presence of AI was found. The most frequent 6,7 Lilian JARA clinical subtypes were as follows: 43% hypomature, 25% hypoplastic, 21% 4,7 Blanca URZÚA hypomature/hypoplastic, 7% hypocalcified and 4% hypocalcified/hypoplastic. The number of severely affected teeth was 22, which occurred in the patients with hypocalcified and hypocalcified/hypoplasic AI who presented the highest number of damaged teeth. Caries and periodontal disease were found in 47 and 32% of the patients, respectively. Malocclusions were observed in 43% of the individuals with AI, with open bite being the most frequent. Radiographically, the thickness of the enamel decreased in 51% of the patients, and 80% showed decreased radiopacity of the enamel compared to that of dentin. Autosomal dominant inheritance pattern was found in 37% of the families with hypoplastic AI, and autosomal recessive pattern was present in 56% of the other clinical subtypes, but more frequently in those affected with hypomature and hypocalcified AI. Conclusion: Of the five clinical subtypes, autosomal recessive hypomature, autosomal dominant hypoplastic and autosomal recessive hypomature/hypoplastic AI were the most prevalent subtypes in this group. Submitted: June 30, 2018 Keywords: Amelogenesis Imperfecta. Dental enamel. Malformations. Modification: September 9, 2018 Hypoplasia. Hypomineralization. Accepted: October 14, 2018 Corresponding address: Universidad de Chile, Facultad de Odontología, Departamento de Patología y Medicina Oral, Blanca Urzúa Orellana Santiago, Chile. Instituto de Investigación en Ciencias Odontológicas - Universidad de Chile, Facultad de Odontología, Santiago, Chile. Facultad de Odontología - Universidad de Chile. Universidad de Chile, Facultad de Odontología, Programa de Magister en Ciencias Odontológicas, Avenida Sergio Livingstone 943 - Comuna de Santiago, Chile. Independencia - Santiago - Chile. Universidad de Chile, Facultad de Odontología, Instituto de Investigación en Ciencias Odontológicas, Phone: +56 2 29781793 e-mail: brurzua@gmail.com; Santiago, Chile. brurzua@odontologia.uchile.cl Universidad de Chile, Facultad de Odontología, Departamento del Niño y Ortopedia Dentomaxilar, Santiago, Chile. Universidad de Chile, Facultad de Medicina, Instituto de Ciencias Biomédicas, Santiago, Chile. U-Odontología: Red de Investigación en Enfermedades Orales Complejas, Santiago, Chile. *These authors contributed equally to this manuscript. J Appl Oral Sci. 1/11 2019;27:e20180359 Diversity of clinical, radiographic and genealogical findings in 41 families with amelogenesis imperfecta Because AI is a rare and heterogeneous condition Introduction from a clinical and genetic point of view, dentists, in general, have difficulty in making a correct diagnosis Normal enamel is synthesized during tooth regarding the presence of AI and the determination development as an extracellular matrix in a process of its clinical subtype. In our experience, many called amelogenesis, which occurs in two stages. In the professionals who do not know about this condition secretory stage, the ameloblast produces a partially and its consequences in long-term treatment choose mineralized protein matrix, which will correspond to to refer these patients, which contributes to a greater the adult enamel. In the maturation stage, the protein psychosocial impact on them because they feel 1,2 matrix is degraded, and mineralization is completed. marginalized and are often left without a specific Amelogenesis imperfecta (AI) is a group of low- treatment solution and prognosis of their condition. prevalence hereditary conditions that cause alterations Given the above factors, the literature reports in the structure and chemical composition of the few AI case series that systematically describe 1-3 enamel matrix during development. Currently, the the characteristics associated with this phenotype. diagnosis of AI involves a clinical and radiographic Moreover, in our country, there have been no studies examination, and when possible, morphological that determine the prevalence, the different subtypes analysis, using ground sections and scanning electron of AI, or the patterns of inheritance associated with microscopy of the teeth, and molecular genetic each case. In the absence of previous data to refute 3-5 analysis of the DNA samples can be performed. this, our null hypothesis proposes that the clinical, AI is classified into three main types that are radiographic and genealogical findings observed in the related to the stages of the tissue formation process. group of Latin American patients studied are similar A fault in the secretory stage of amelogenesis produces to those reported in other populations. Therefore, this the hypoplastic type of AI, which is characterized by study aims to describe and determine the frequency enamel that is thinner than normal and that contrasts of clinical and radiographic features and inheritance 7,8 normally from dentine in the radiographic analysis. patterns found in 41 Chilean families diagnosed with AI In hypocalcified AI, there is an alteration in the initial and, thus, contribute to the identification of the clinical mineralization of the secretory stage; the enamel diagnostic tools used during routine dental practice. initially develops normal thickness, is orange-yellow at eruption and consists of poorly calcified matrix that is rapidly lost during normal function. In addition, the 6,7 enamel has a lower radiopacity than the dentin. In Material and methods hypomature AI, the defect occurs in the maturation stage of the enamel; is of normal thickness but has This research was conducted under the framework of a mottled appearance; is slightly softer than normal a funded research project, which has the authorization enamel; and chips from the crown. Radiographically, of the Ethics Committee and the Institutional it presents with approximately the same radiodensity Biosafety Committee of the Faculty of Dentistry 6,9 as that of dentin. and the University of Chile ( Certificate No. 2013/06 To adequately evaluate AI, a differential diagnosis and FDO No. 224 of June 2013, respectively), and with other defects and an investigation to determine in full accordance with the ethical principles of the if the enamel alterations are linked to environmental Declaration of Helsinki and local regulations. disturbances or have a discernible genetic transmission One hundred twenty-one individuals belonging 2,10,11 pattern are necessary. The signs frequently to 41 Chilean families with AI were recruited found in the enamel are a decrease in thickness, between 2003 and 2016 and included in this study. rough texture, mottled appearance, the presence of Each of the patients was evaluated by two oral cavitations (pits), horizontal or vertical bands and a pathologists. A record of personal and family history dull white, yellow or brown color. In addition, a delay was completed including possible alterations during in eruption, dental impaction, anterior or lateral open the intrauterine development stage. Affected and bite, ogival palate, gingival inflammation, teeth with unaffected individuals were evaluated clinically for the a decreased coronary sector and multiple diastemas presence of skin, hair, fingernail, kidney, cognitive, 12-14 can be observed. gingival, visual, auditory and osseous abnormalities J Appl Oral Sci. 2/11 2019;27:e20180359 ADORNO-FARIAS D, ORTEGA-PINTO A, GAJARDO P, SALAZAR A, WERLINGER F, ROJAS-FLORES S, ECHEVERRÍA-LÓPEZ S, MOLINA-BERRÍOS A, JARA-SANDOVAL J, JARA L, URZÚA B known to be a sign of systemic or syndromic conditions The significance was determined at a value of P<0.05. that could be associated with AI. In-depth interviews were conducted with at least two family members by a geneticist in order to construct their genealogies and Results analyze the inheritance pattern. Additionally, clinical photographs were taken, and complementary tests Sample description were requested such as periapical and panoramic A total of 121 individuals were evaluated from radiographs. 41 Chilean families with an AI diagnosis; 58% of the The presence of alterations in the enamel was cases were female (Table 1). Most of the evaluated recorded in relation to the glossiness, texture, color, patients presented clinically with AI (60%), and the thickness and surface defects. The gloss of the enamel remaining individuals were direct relatives who did not was considered abnormal when it had an opaque manifest the disease. Although the number of women appearance. The texture was evaluated by gently was higher in the group of affected individuals, no passing the dental probe over the enamel, and the sex association was found in relation to the presence thickness of the enamel was considered diminished of AI (P=0.320). The group of individuals affected when there was presence of generalized diastemas, with AI had a significantly lower median age than the pits or bands; the evaluation was complemented by unaffected group (P=0.0004) (Table 1). the radiographic image. A radiographic analysis was conducted to evaluate the radiopacity and thickness Genealogical analysis of the enamel as well as the presence of dental and A significantly higher number of families affected bone alterations. with AI (56%) presented an autosomal recessive The diagnosis of AI and its respective subtypes inheritance pattern (P=0.006) (Table 2), followed was based on the criteria described in the classification by 15 families that showed an autosomal dominant of Witkop (1989); however, we considered only inheritance pattern, which represented 37% of the the following three main types of AI and their sample. possible combinations: “type I-Hypoplastic, type II-Hypomaturation and type III-Hypocalcified”. Intraoral clinical characteristics Taurodontism was recorded as one more characteristic, A total of 93% of the individuals had normal- among several others, that are associated with AI appearing mucosa (Table 3), and 7% had alterations and not as “type IV-Hypomaturation-hypoplastic with of the mucosa that corresponded to traumatic and/or taurodontism” from the Witkop’s classification. reactional injuries, canker sore and hyperpigmentation All of the information collected was included of the gum. Regarding the type of dentition, 71% of in a single database, and the statistical analysis the individuals had permanent dentition with a median was conducted using the Stata computer program, of 27 permanent teeth (range 0-32) present in the version 4 (StataCorp, College Station, TX, USA). The mouth at the time of the examination. Caries were continuous variables were assessed for normality observed in 47% of the patients, and restorations using the Shapiro-Wilk test. The data are presented were observed in 67% of the patients. A total of 39% as either the mean and standard deviation or as the of the patients had undergone exodontias, and the median and range. The data were compared using median number of teeth clinically observed that were the Fisher’s exact, Wilcoxon or Kruskal-Wallis test. severely affected with AI in the sample of patients was Table 1- Distribution of individuals affected and not affected with Amelogenesis Imperfecta from 41 Chilean families, according to sex and age FEMALE MALE TOTAL CONDITION No. (%) Med Age (Rank) No. (%) Med Age (Rank) No. (%) Med Age (Rank) v a Non affected 31 (44) 37 (2-64) 18 (35) 19 (1-63) 49 (40) 37 (1-64) & a Affected by AI 39 (56) 13 (2-44) 33 (65) 17 (6-84) 72 (60) 16 (2-84) TOTAL 70 (100) 28 (2-64) 51 (100) 17 (1-84) 121 (100) 21 (1-84) v & Data are presented as No. (%) and Median (yr) (Rank). 1 non-affected woman without age data, 2 affected woman without data od age. Wilcoxon test, P=0.0004 J Appl Oral Sci. 3/11 2019;27:e20180359 Diversity of clinical, radiographic and genealogical findings in 41 families with amelogenesis imperfecta 22 (range 4-31) (Table 3). hypoplastic AI (21%). Clinical subtypes of hypocalcified Malocclusions were observed in 43% of the AI and hypocalcified/hypoplastic AI were found in 7% individuals with AI, with open bite being the most and 4% of the patients, respectively. frequent form (17%). On the other hand, 26% Hypoplastic Amelogenesis Imperfecta (HPAI) of the patients presented some type of dental The 18 cases of HPAI presented enamel thickness symptomatology, and sensitivity to thermal changes alterations such as a generalized decrease in thickness, was the most frequently reported symptom (11%). which occurred in 82% of the cases (Table 4, Figures It is interesting to note that periodontal disease, the 2A and 2B), cavitations or pits in 41% of the cases, presence of diastemas, high or low lip frenum insertion and the presence of horizontal bands in 29% of the and ogival palate occurred with frequencies equal or patients (Table 4). Changes in enamel thickness were greater than 22% (Table 3). not similar within the same family. Different degrees of affection were also observed in the same individual as General and specific clinical characteristics of shown in Figure 2B. Diastemas were observed in 56% enamel of cases, and dentin sensitivity was observed in 33% With regard to glossiness and texture, 41% of the of the patients (Table 3). Dental wear and exodontias patients showed an opaque enamel, and 46% of them were very frequent in this group, which were observed showed that the texture of the tissue was rough (Table in 94% and 56% of the cases, respectively (Tables 3 4). The most commonly observed enamel coloration and 4, Figures 2A and 2B). Other clinical alterations (65% of the patients) was white/opaque with absence were opaque white spots in 53% of the patients, rough of translucency, which was more frequent than other texture in 47% of the patients, and opaque enamel in colorations (P<0.0001). Opaque white spots were 41% of cases (Table 4). observed in a high percentage of the patients with Alterations in occlusion were observed in 50% of AI (77%). Regarding surface defects of the enamel, the patients, with open bite being the most frequent 29% of the individuals had pitting and 65% showed finding (28% of the cases) (Table 3). Of the 18 cases wear (Table 4). of HPAI, radiographic images were available in 11 cases with evident enamel thickness reduction in Radiographic characteristics of the enamel 91%, and radiopacity in 82% of the cases (Table 5 and Radiographic analysis (Table 5) showed that normal Figure 2C). Of the 11 cases analyzed, none presented and decreased enamel thickness occurred equally in taurodontism (Table 5). Of the 6 families with HPAI, individuals with AI. A decrease in the radiopacity of 83% presented an autosomal dominant pattern of the enamel compared to that of dentine was observed inheritance (Table 2). in 80% of the patients. In this sample, only 16% of the patients presented taurodontism. Hypomature Amelogenesis Imperfecta (HMAI) Thirty-one cases were classified in this group, Clinical analysis of phenotypes from which the most frequently observed enamel Five clinical subtypes of AI were identified (Figure characteristics were opaque white spots in 100% of the 1). The most frequently observed clinical subtypes in cases, normal enamel thickness in 90% of the cases the 72 affected patients were hypomature AI (43%), (P<0.0001), white/opaque enamel color in 76% of the followed by hypoplastic AI (25%) and hypomature/ cases, enamel with normal glossiness in 69% of the Table 2- Inheritance patterns for the 41 Chilean families with Amelogenesis Imperfecta according to the subtype of AI diagnosed INHERITANCE PATTERN HPAI HMAI HCAI HM/HPAI HC/HPAI TOTAL No. % No. % No. % No. % No. % No. % Autosomal Dominant 5 83 5 26 1 20 2 25 2 67 15 37 Autosomal Recessive 0 0 14 74 4 80 4 50 1 33 23 56 X-linked 0 0 0 0 0 0 0 0 0 0 0 0 Two possible patterns* 0 0 0 0 0 0 2 25 0 0 2 5 Undetermined 1 17 0 0 0 0 0 0 0 0 1 2 TOTAL families 6 100 19 100 5 100 8 100 3 100 41 100 *Autosomal Recesive or Esporadic/Autosomal Dominant or X-linked; aFisher exact test P=0.006 J Appl Oral Sci. 4/11 2019;27:e20180359 ADORNO-FARIAS D, ORTEGA-PINTO A, GAJARDO P, SALAZAR A, WERLINGER F, ROJAS-FLORES S, ECHEVERRÍA-LÓPEZ S, MOLINA-BERRÍOS A, JARA-SANDOVAL J, JARA L, URZÚA B cases and normal texture in 66% of the cases (Table 4 normal enamel thickness was observed in 79% of the and Figures 2D and 2E). It is important to highlight that cases, and a decrease in radiopacity was observed in periodontal disease and malocclusions affected 29% 18 cases (75%) (Table 5, Figure 2F). In this subtype of of the patients (Table 3). In the radiographic study, a AI, the most observed pattern of inheritance was the Table 3- Distribution of the intraoral clinical characteristics observed in the individuals affected with Amelogenesis Imperfecta according to clinical subtype INTRAORAL CLINICAL HPAI HMAI HCAI HM/HPAI HC/HPAI TOTAL CHARACTERISTICS n=18 n=31 n=5 n=15 n=3 n=72 No. (%) No. (%) No. (%) No. (%) No. (%) No. (%) MOUTH Normal mucosa 16 (89) 30 (97) 5 (100) 13 (87) 3 (100) 67 (93) Altered Mucosa 2 (11) 1 (3) 0 (0) 2 (12) 0 (0) 5 (7) Low/high lip frenum insertion 5 (28) 6 (19) 2 (40) 5 (33) 1 (33) 19 (26) Short lip frenum 0 (0) 3 (10) 0 (0) 1 (7) 0 (0) 4 (6) DENTITION Permanent Dentition 16 (89) 23 (74) 4 (80) 5 (33) 3 (100) 51 (71) Mixed Dentition 2 (11) 8 (26) 1 (20) 8 (53) 0 (0) 19 (26) Primary Dentition 0 (0) 0 (0) 0 (0) 2 (13) 0 (0) 2 (3) Diastemas 10 (56) 4 (13) 1 (20) 5 (33) 3 (100) 23 (32) TREATMENTS Restorations 14 (78) 21 (68) 2 (40) 9 (60) 3 (100) 48 (67) Veneers or fixed prostheses 5 (28) 4 (13) 2 (40) 1 (7) 1 (33) 13 (18) Exodontias 10 (56) 13 (42) 2 (40) 2 (13) 1 (33) 28 (39) CONDITIONS / PATHOLOGIES Caries 7 (39) 15 (48) 3 (60) 7 (47) 2 (67) 34 (47) Agenesis 0 (0) 3 (10) 1 (20) 2 (13) 1 (33) 7 (10) Eruption delay 0 (0) 1 (3) 1 (20) 1 (7) 0 (0) 3 (4) Periodontal disease 5 (28) 9 (29) 3 (60) 6 (40) 0 (0) 23 (32) Gingival hyperplasia 1 (6) 2 (6) 0 (0) 0 (0) 0 (0) 3 (4) Ogival Palate 3 (17) 7 (23) 2 (40) 3 (20) 1 (33) 16 (22) OCCLUSSION Malocclusions (total): 9 (50) 9 (29) 4 (80) 8 (53) 1 (33) 31 (43) Anterior Openbite 5 (28) 2 (6) 2 (40) 2 (13) 1 (33) 12 (17) Lateral bite 1 (6) 2 (6) 1 (20) 1 (7) 0 (0) 5 (7) Crossbite 2 (11) 2 (6) 0 (0) 3 (20) 0 (0) 7 (10) Inverted bite 1 (6) 1 (3) 1( 20) 1 (7) 0 (0) 4 (6) Bis to bis bite 0 (0) 2 (6) 0 (0) 1 (7) 0 (0) 3 (4) SENSITIVITY Sensitivity associated to (total): 6 (33) 6 (19) 2(40) 2 (13) 3 (100) 19 (26) Thermal changes 2 (11) 2 (6) 0 (0) 1 (7) 3 (100) 8 (11) Chemical changes 1 (6) 3 (10) 0 (0) 0 (0) 0 (0) 4 (6) Both (thermal and Chemical) 3 (17) 0 (0) 2 (40) 1 (7) 0 (0) 6 (8) OTHERS Other alterations * 6 (33 ) 16 (52) 1 (20) 8 (53) 1 (33) 32 (44) AIHP=AI hypoplastic; AIHM=AI hypomature; AIHC=AI hypocalcified; AI HM/HP=AI hypomature/hypoplastic; AIHC/HP=AI hypocalcified/ hypoplastic; GS=Salivary Glands. * Fibromatosis, anterior covering bite, increased overjet, dental invaginations, irritative fibroma, Fordyce condition, angular cheilitis, bruxism, erythematous plaques on tongue, semi-bifid tongue, fissured tongue, microdontia, teeth with shape alteration, macrodontia, teeth included, extrinsic dental staining, change in coloration by tetracycline (each with 1%), in addition to crowding, prognathism, overbite, palatine torus, carabelli tubercle and pits and fissures in teeth, each with 3% and geographical tongue with 4% J Appl Oral Sci. 5/11 2019;27:e20180359 Diversity of clinical, radiographic and genealogical findings in 41 families with amelogenesis imperfecta autosomal recessive type (14 families, 74%) (Table 2). erupted teeth (Table 5). An interesting finding was that 40% of the patients presented taurodontism (Table Hypocalcified Amelogenesis Imperfecta (HCAI) 5). In this group, 80% of the families presented an The 5 cases of HCAI had opaque and rough enamel autosomal recessive inheritance pattern (Table 2). and decreased thickness (Table 4). In 60% of the cases, the enamel was brown, and in the remaining Hypomature/Hypoplastic Amelogenesis Imperfecta (HM/ HPAI) two cases, it was yellow (Table 4, Figures 2G and 2H). In this group, both HMAI and HPAI characteristics Regarding other clinical characteristics, 80% of the were observed in the same patient (Figures 2J and cases presented malocclusions, which were mainly 2K). The characteristics of HMAI were as follows: open bite, whereas 60% of the cases presented opaque enamel in 27% of cases, rough enamel in periodontal disease, and 40% presented sensitivity 40% of the patients, white/opaque enamel in 73% to both thermal and chemical stimuli (Table 3). This of cases and opaque white spots in 93% of cases clinical subtype presented more affected teeth than (Table 4). The following characteristics of HPAI were the other clinical subtypes. The imaging showed that observed: uniformly reduced thickness in 40% of all of the cases had less radiopacity of the enamel cases, vertical lines in 20% and pits in 27% of cases compared to dentin (Figure 2I), and 80% of the cases (Table 4). Among the intraoral alterations, periodontal presented a decrease in the enamel thickness of the Table 4- Distribution of the general and specific clinical characteristics of the enamel observed in the individuals affected with Amelogenesis Imperfecta (AI) according to clinical subtype CLINICAL CHARACTERISTICS OF HPAI HMAI HCAI HM/HPAI HC/HPAI TOTAL ENAMEL n=18 n=31 n=5 n=15 n=3 n=72 No. (%) No. (%) No. (%) No. (%) No. (%) No. (%) GLOSSINESS Normal 10 (59) 20 (69) 0 (0) 11 (73) 0 (0) 41 (59) Opaque 7 (41) 9 (31) 5 (100) 4 (27) 3 (100) 28 (41) TEXTURE Normal 9 (53) 19 (66) 0 (0) 9 (60) 0 (0) 37 (54) Rough 8 (47) 10 (34) 5 (100) 6 (40) 3 (100) 32 (46) COLOR White/opaque 12 (71) 22 (76) 0 (0) 11 (73) 0 (0) 45 (65) Yellow 5 (29) 5 (17) 2 (40) 4 (27) 1 (33) 17 (25) Brown 0 (0) 0 (0) 3 (60) 0 (0) 1 (33) 4 (6) White-yellow 0 (0) 1 (3.5) 0 (0) 0 (0) 1 (33) 2 (3) Yellow-brown 0 (0) 1 (3.5) 0 (0) 0 (0) 0 (0) 1 (1) THICKNESS Normal 3 (18) 26 (90) 0 (0) 9 (60) 0 (0) 38 (55) Decreased 14 (82) 3 (10) 5 (100) 6 (40) 3 (100) 31 (45) LINE BANDING Horizontal 5 (29) 3 (10) 0 (0) 0 (0) 0 (0) 8 (12) Vertical 2 (12) 3 (10) 0 (0) 3 (20) 0 (0) 8 (12) SPOTTING White/opaque spots 9 (53) 29 (100) 1 (20) 14 (93) 0 (0) 53 (77) Yellow-brown spots 4 (24) 8 (28) 1 (20) 5 (33) 1 (33) 19 (28) SURFACE DEFECTS Pits or cavitation 7 (41) 6 (21) 2 (40) 4 (27) 1 (33) 20 (29) Wear 16 (94) 13 (45) 4 (80) 10 (67) 2 (67) 45 (65) WITHOUT DATA No. Patients 1 (6)* 2 (7) 0 (0) 0 (0) 0 (0) 3 (4) & a, b Patients without data in these characteristics, * all teeth restored at the time of the examination. Fisher's exact test P<0.0001 J Appl Oral Sci. 6/11 2019;27:e20180359 ADORNO-FARIAS D, ORTEGA-PINTO A, GAJARDO P, SALAZAR A, WERLINGER F, ROJAS-FLORES S, ECHEVERRÍA-LÓPEZ S, MOLINA-BERRÍOS A, JARA-SANDOVAL J, JARA L, URZÚA B Table 5- Distribution of the radiographic characteristics observed in the individuals affected with Amelogenesis Imperfecta according to clinical subtype RADIOGRAPHIC HPAI HMAI HCAI HM/HPAI HC/HPAI TOTAL CHARACTERISTICS OF ENAMEL n=18 n=31 n=5 n=15 n=3 n=72 No. (%) No. (%) No. (%) No. (%) No. (%) No. (%) THICKNESS Normal 1 (9) 19 (79) 1 (20) 6 (50) 0 (0) 27 (49) Decreased 10 (91) 5 (21) 4 (80) 6 (50) 3 (100) 28 (51) RADIOPACITY* Normal 2 (18) 6 (25) 0 (0) 3 (25) 0 (0) 11 (20) Decreased 9 (82) 18 (75) 5 (100) 9 (75) 3 (100) 44 (80) PRESENCE OF Taurodontism 0 (0) 1 (4) 2 (40) 5 (42) 1 (33) 9 (16) WITHOUT DATA No. Patients 7 (64) 7 (29) 0 (0) 3 (25) 0 (0) 17 (31) * Radiopacity of the enamel in relation to the dentin Figure 1- Pie chart showing the distribution of clinical subtypes in the 72 patients affected with Amelogenesis Imperfecta disease was observed in 40% of cases, malocclusions The color of the enamel varied from brown to yellow in 53% and the presence of diastemas in 33% of cases and white-yellow, and 1 patient presented with pits (Table 3). The radiographic study showed a decrease or cavitations (Table 4). The radiographic study in radiopacity in 75% of cases (Table 5 and Figure 2L), showed a generalized decrease in enamel thickness a generalized decrease in enamel thickness in 50% of and decreased radiopacity compared to dentin (Table cases, and taurodontism in 42% of cases (Table 5). 5, Figure 2O). Of the 3 families analyzed, only 2 had In this subtype of AI, 50% of the families showed an autosomal dominant inheritance (Table 2). autosomal recessive inheritance pattern (Table 2). Hypocalcified/Hypoplastic Amelogenesis Imperfecta (HC/ HPAI) Discussion This group was formed by 3 individuals with presence of restorations, sensitivity to thermal AI is a term that encompasses several hereditary changes and diastemas (Table 3). These 3 patients conditions that affect the structure and appearance presented rough opaque enamel and a generalized 2,6,8 of tooth enamel. The lack of local information and decrease in thickness (Table 4, Figures 2M and 2N). the information in the literature about the clinical and J Appl Oral Sci. 7/11 2019;27:e20180359 Diversity of clinical, radiographic and genealogical findings in 41 families with amelogenesis imperfecta Figure 2- Clinical subtypes of Amelogenesis Imperfecta found in this study; A, B, C: Clinical subtype of Hypoplastic Amelogenesis Imperfecta; D, E, F: Subtype of Hypomature AI; G, H, I: Subtype of Hypocalcified AI; J, K, L: Subtype of Hypomature-hypoplastic AI; M, N, O: Subtype of Hypocalcified-hypoplastic AI radiographic signs associated with different subtypes were systemically healthy and were not receiving of AI was the motivation for the development of this pharmacological treatment at the time of the study, in which 121 individuals belonging to 41 Chilean examination, which supports the diagnosis of AI and families were evaluated from a clinical, radiographic excludes a possible environmental cause due to the and genealogical point of view. ingestion of medications. The majority of individuals with AI had exclusively Sample and clinical analysis permanent dentition and a higher frequency of tooth The patients were mainly young, with a median age loss due to exodontias (39%), which highlights the of 16 years (range 2-84 years). There were similar need for early diagnosis and intervention in these frequencies of men and women, which coincide with patients. Because 47% of the patients with AI present results reported in the literature for the profile of caries, exodontias can be justified. The high frequency 2,6,11 patients with AI. Although hypoplastic AI has been of caries is consistent with previous reports in which described as the most prevalent subtype occurring in more caries were observed in patients with AI than in 15,16 14,22,23 43.7% of the cases, the most frequent type found healthy individuals. However, the number of teeth in this work was hypomature AI followed by hypoplastic with caries in patients with AI in this study was similar AI. In addition, the third most frequent subtype to that found in healthy 12-year-old Chilean children . observed in patients consisted of mixed characteristics This suggests that caries in individuals with AI could be of hypomature and hypoplastic AI. explained by the time required to find a specialist that Even though an association between AI and can diagnose them and provide adequate treatment, in several extraoral alterations has been described in addition to the intrinsic susceptibility of their defective 18-21 the literature , most of the individuals in this study J Appl Oral Sci. 8/11 2019;27:e20180359 ADORNO-FARIAS D, ORTEGA-PINTO A, GAJARDO P, SALAZAR A, WERLINGER F, ROJAS-FLORES S, ECHEVERRÍA-LÓPEZ S, MOLINA-BERRÍOS A, JARA-SANDOVAL J, JARA L, URZÚA B enamel. Radiographic analysis The median number of restorations was 3 (range In the radiographic evaluation, a similar frequency of 0-26), which is higher than that reported in of patients with normal and diminished enamel healthy 12-year-old Chilean patients who presented a thickness was observed. However, a decrease in frequency of 1.03 teeth restored. However, a study the radiopacity of the enamel when compared with in healthy elderly Chilean adults observed an average dentin was an important feature for the majority of 8.9 restorations per individual, which indicated of the patients with AI. Patients with hypoplastic AI that our patients with AI, although much younger, showed more frequent decreased enamel thickness often had a concerning number of restorations that and radiopacity. Most of the patients with hypomature was closer to the number seen in elderly adults than AI presented with enamel with normal thickness to that in young people in the same age range. On and diminished radiopacity compared to dentin, and the other hand, 32% of the patients with AI presented individuals with hypocalcified AI showed a tendency periodontal pathology without differences among to have decreased enamel thickness and radiopacity. the different clinical subtypes, which is supported Although a 40% prevalence of taurodontism has been 3,14 6,13,30 by the literature. This is probably because enamel described in patients with AI, in the present study, alterations favor the retention of bacterial plaque. a low percentage of individuals with this characteristic In addition, dental hypersensitivity per se makes was found. adequate oral hygiene difficult. Several studies have indicated the association Genealogical analysis of AI with malocclusions such as anterior open bite In this study, 23 families (56%) presented 26-28 (AOB). Other reports of cases with different significantly more autosomal recessive inheritance types of AI describe the presence of prognathism, patterns, which corroborates with Wright’s study 11,27,29 posterior cross-bite and others anomalies. In (2011), in which 50% of their families showed this the present study, malocclusions were observed in type of inheritance. However, Chan (2011) reported 43% of the individuals with AI without a significant 15% autosomal recessive inheritance, and Backman difference among the different types. Eruption delay (1988) reported 12% of the cases as showing this and agenesis were rare in this study, but low/high lip type of inheritance. These differences may be due to frenum insertion and ogival palate, which are not often the genetic background, the degree of consanguinity reported in the literature, were observed in more than and differences in the allelic frequencies of the genes 20% of the individuals with AI. involved in the genetic etiology of the AI in the Patients in this sample had a large number of teeth distinct population groups analyzed. With regard to damaged by AI, with a median of 22 severely affected the different clinical subtypes of AI with recessive teeth (range of 4-31) at the time of the examination. inheritance patterns, it should be noted that, although It is interesting to note that all individuals with the majority had HMAI (14 cases), this type of hypocalcified AI, alone or associated with hypoplastic inheritance was also found in the clinical subtypes HC, AI, presented enamel with opaque gloss, rough texture HM/HP and HC/HP of AI. In addition, as previously and reduced thickness. The majority of patients with mentioned, autosomal recessive inheritance was found hypomature and hypoplastic AI phenotypes presented in families with hypocalcified AI. These results contrast whitish enamel. The decrease in thickness was with the study by Wright (2011), which reported a frequently observed in the hypoplastic type of AI, but high prevalence of hypomature AI with autosomal a normal enamel thickness was present in 90% of the recessive inheritance and hypocalcified AI mainly patients with hypomature AI and 60% in the combined associated with autosomal dominant inheritance. This type of hypomature/hypoplastic AI. could be due to the misinterpretation of incomplete Finally, regarding clinical analysis, it is important information on pedigrees, given the impossibility of 6,10,15,17 to point out that, as reported in the literature, conducting clinical examinations for several members we also found great variability in the phenotypic of the studied families. On the other hand, 37% of expression of AI. We observed differences in the the families showed autosomal dominant inheritance teeth of the same patient and between members of patterns as described in studies involving several 15,17 the same family. families. J Appl Oral Sci. 9/11 2019;27:e20180359 Diversity of clinical, radiographic and genealogical findings in 41 families with amelogenesis imperfecta In our study, the X-linked pattern of inheritance Conclusions was absent. However, a classic article on AI that involved a significant number of families established Considering the low worldwide prevalence of that approximately 5-10% of all the cases of AI this pathology, i.e., 1 in 14,000 cases of all types of are X-linked. In this context, Wright’s work with AI combined, this study involving a large group of 71 families reported that 6 (23%) cases presented affected families is the first to determine the frequency X-linked patterns of inheritance. The study by Chan of clinical, radiographic and genealogical characteristics (2011), carried out with 39 families, showed that 4 of five clinical subtypes of AI found in the Chilean of them (12%) presented this type of inheritance. population. Our study shows that autosomal recessive Considering this information, in two of our families hypomature AI, autosomal dominant hypoplastic AI with hypomature/hypoplastic AI, there were two and autosomal recessive hypomature/hypoplastic AI possible inheritance patterns involved, one of which are the most prevalent in this group and that the most was probably X-linked, but this was not possible to frequently found characteristics are the presence of determine. This is due to a lack of information in the opaque white spots, reduction of thickness and enamel pedigree and to the fact that in these cases, it was wear, malocclusions, and the presence of restorations, difficult to determine the status of the condition in among others. key individuals, given the number of restorations and This work represents a source of complementary missing teeth. information for other studies and is of relevance and For these last few years, the heterogeneous genetic clinical utility for general dentists and specialists etiology of AI has been elucidated to a great extent, because it gathers information collected through the but not completely to date. Mutations in the genes analysis of a significant number of patients with AI. ENAM, COL17A1, LAMB3, ACPT, AMBN and IGTB6 Additionally, it provides more tools for the adequate are responsible for the hypoplastic forms of AI, with diagnosis of this pathology, which will allow for autosomal dominant and/or recessive inheritance early intervention by the professional and adequate 5,8 patterns. On the other hand, hypomature forms preventive and restorative actions in a multidisciplinary of AI are caused by mutations in the genes AMTN, framework. KLK4, MMP20, WDR72, SLC24A4, C4orf26 and GPR8, all of which are associated with autosomal recessive Acknowledgments 5,8 inheritance. Finally, the only causative gene of We are grateful to the families with Amelogenesis hypocalcified autosomal dominant AI known thus far Imperfecta for their participation in this study. This 5,8 is FAM83H. For this reason, the genetic molecular work was supported by the National Fund for Scientific analysis of a significant number of families should and Technological Development FONDECYT Project consider these 16 genes (and those involved in number 1140905 and the Vice-Rectorate for Research syndromic forms of AI) in the design of a targeted gene and Development (VID), University of Chile, U-redes panel for massive sequencing for diagnostic purposes. Project number URED/2014-007. We also thank Mr. Although the main strength of this 13-years-long Juan Fernández from the Language and Translation study is the inclusion of a large number of patients services of the Faculty of Dentistry for kindly with AI in its sampling, it also has some limitations proofreading and checking the spelling and grammar related to our nonrandom convenience sample formed of this article. The authors declare no potential conflicts by patients who came for treatment or were referred of interest with respect to the authorship and/or by other dentists due to severe alterations. Moreover, publication of this article. in many cases it was not possible to obtain complete information for the genealogical analysis, and the molecular genetic analyses are only recently underway. J Appl Oral Sci. 10/11 2019;27:e20180359 ADORNO-FARIAS D, ORTEGA-PINTO A, GAJARDO P, SALAZAR A, WERLINGER F, ROJAS-FLORES S, ECHEVERRÍA-LÓPEZ S, MOLINA-BERRÍOS A, JARA-SANDOVAL J, JARA L, URZÚA B 17- Chan HC, Estrella NM, Milkovich RN, Kim JW, Simmer JP, Hu JC. References Target gene analyses of 39 amelogenesis imperfecta kindreds. Eur J Oral Sci. 2011;119(Suppl. 1):311-23. 1- Aldred MJ, Savarirayan R, Crawford PJ. Amelogensis imperfecta: a 18- Parry DA, Mighell AJ, El-Sayed W, Shore RC, Jalili IK, Dollfus H, et st classification and catalogue for the 21 century. Oral Dis. 2003;9(1):19- al. Mutations in CNNM4 cause Jalili syndrome, consisting of autosomal- recessive cone-rod dystrophy and amelogenesis imperfecta. Am J Hum 2- Crawford PJ, Aldred M, Bloch-Zupan A. Amelogenesis imperfecta. Genet. 2009;84(2):266-73. Orphanet J Rare Dis. 2007;2:17. 19- Chaitanya V, Sangeetha B, Sandeep P, Varalaxmi B, Sridhar 3- Urzúa B, Martínez C, Ortega-Pinto A, Adorno D, Morales-Bozo I, AV, Aparna G, et al. Amelogenesis imperfecta and nephrocalcinosis Riadi G, et al. Novel missense mutation of the FAM83H gene causes syndrome. Indian J Nephrol. 2014;24(4):260-1. retention of amelogenin and a mild clinical phenotype of hypocalcified 20- De la Dure-Molla M, Quentric M, Yamaguti PM, Acevedo AC, Mighell enamel. Arch Oral Biol. 2015;60(9):1356-67. AJ, Vikkula M, et al. Pathognomonic oral profile of Enamel Renal 4- Toupenay S, Fournier BP, Manière MC, Ifi-Naulin C, Berdal A, de La Syndrome (ERS) caused by recessive FAM20A mutations. Orphanet J Dure-Molla M. Amelogenesis imperfecta: therapeutic strategy from Rare Dis. 2014;14;9:84. primary to permanent dentition across case reports. BMC Oral Health. 21- Yuen WY, Pasmooij AM, Stellingsma C, Jonkman MF. Enamel defects 2018; 18(1):108. in carriers of a novel LAMA3 mutation underlying epidermolysis bullosa. 5- Prasad MK, Geoffroy V, Vicaire S, Jost B, Dumas M, Le Gras S, et Acta Derm Venereol. 2012;92(6):695-6. al. A targeted next-generation sequencing assay for the molecular 22- Pousette Lundgren G, Morling Vestlund GI, Trulsson M, Dahllöf G. A diagnosis of genetic disorders with orodental involvement. J Med Genet. randomized controlled trial of crown therapy in young individuals with 2016;53(2):98-110. amelogenesis imperfecta. J Dent Res. 2015;94(8):1041-7. 6- Witkop CJ Jr. Amelogenesis imperfecta, dentinogenesis imperfecta 23- Pousette Lundgren G, Wickström A, Hasselblad T, Dahllöf G. and dentin dysplasia revisited: problems in classification. J Oral Pathol. Amelogenesis imperfecta and early restorative crown therapy: an 1989;17(9-10):547-53. interview study with adolescents and young adults on their experiences. 7- Gadhia K, McDonald S, Arkutu N, Malik K. Amelogenesis imperfecta: PLoS One. 2016;11(6):e0156879. an introduction. Br Dent J. 2012; 212(8):377-9. 24- Universidad Mayor. Facultad de Odontología. Diagnóstico nacional 8- Smith CE, Poulter JA, Antanaviciute A, Kirkham J, Brookes SJ, de salud bucal del adolescente de 12 años y evaluación del grado de Inglehearn CF, et al. Amelogenesis imperfecta; genes, proteins, and cumplimiento de los objetivos sanitarios de salud bucal 2000-2010 pathways. Front Physiol. 2017;8:435. [online]. Santiago: Ediciones Universidad Mayor; 2007 [cited 2018 9- Nusier M, Yassin O, Hart TC, Samimi A, Wright JT. Phenotypic Sep 9]. 118 p. Available from: http://www.minsal.cl/portal/url/item/7 diversity and revision of the nomenclature for autosomal recessive f2e0f67ebbc1bc0e04001011e016f58.pdf. amelogenesis imperfecta. Oral Surg Oral Med Oral Pathol Oral Radiol 25- Moya P, Chappuzeau E, Caro JC, Monsalves MJ. Situación de salud Endod. 2004;97(2):220-30. oral y calidad de vida de los adultos mayores. Rev Estomatol Herediana 10- Wright JT, Torain M, Long K, Seow K, Crawford P, Aldred MJ, et al. [serial on Internet]. 2012 [cited 2018 Sep 9];22(4):197-202. Available Amelogenesis imperfecta: genotype-phenotype studies in 71 families. from: http://www.upch.edu.pe/vrinve/dugic/revistas/index.php/REH/ Cells Tissues Organs. 2011;194(2-4):279-83. article/viewFile/85/70. 11- Sabandal MM, Schäfer E. Amelogenesis imperfecta: review 26- Pavlic A, Battelino T, Trebusak Podkrajsek K, Ovsenik M. Craniofacial of diagnostic findings and treatment concepts. Odontology. characteristics and genotypes of amelogenesis imperfecta patients. Eur 2017;104(3):245-56. J Orthod. 2011;33(3):325-31. 12- Cartwright AR, Kula K, Wright TJ. Craniofacial features 27- Millet C, Duprez JP. Multidisciplinary management of a child with associated with amelogenesis imperfecta. J Craniofac Genet Dev Biol. severe open bite and amelogenesis imperfecta. J Contemp Dent Pract. 1999;19(3):148-56. 2013;14(2):320-6. 13- Poulsen S, Gjørup H, Haubek D, Haukali G, Hintze H, Løvschall 28- Alachioti XS, Dimopoulou E, Vlasakidou A, Athanasiou AE. H, et al. Amelogenesis imperfecta - a systematic literature review of Amelogenesis imperfecta and anterior open bite: etiological, associated dental and oro-facial abnormalities and their impact on classification, clinical and management interrelationships. J Orthod patients. Acta Odontol Scand. 2008;66(4):193-9. Sci. 2014;3(1):1-6. 14- Pousette Lundgren G, Dahllöf G. Outcome of restorative treatment 29- Pulgar Encinas R, García-Espona I, Navajas Rodriguez de Mondelo in young patients with amelogenesis imperfecta. A cross-sectional, JM. Amelogenesis imperfecta: diagnosis and resolution of a case with retrospective study. J Dent. 2014;42(11):1382-9. hypoplasia and hypocalcification of enamel, dental agenesis, and 15- Backman B. Amelogenesis imperfecta – clinical manifestations skeletal open bite. Quintessence Int. 2001;32(3):183-9. in 51 families in a northern Swedish county. Scand J Dent Res. 30- Koruyucu M, Bayram M, Tuna EB, Gencay K, Seymen F. Clinical 1988;96(6):505-16. findings and long-term managements of patients with amelogenesis 16- Markovic D, Petrovic B, Peric T. Case series: clinical findings and imperfecta. Eur J Dent. 2014;8(4):546-52. oral rehabilitation of patients with amelogenesis imperfecta. Eur Arch Paediatr Dent. 2010;11(4):201-8. 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Diversity of clinical, radiographic and genealogical findings in 41 families with amelogenesis imperfecta

Diversity of clinical, radiographic and genealogical findings in 41 families with amelogenesis imperfecta

Abstract

1,7* Amelogenesis imperfecta (AI) is a group of enamel development disorders Daniela ADORNO-FARIAS that alter the structure and chemical composition of the tissue. There is 1,7* Ana ORTEGA-PINTO great variability in the clinical presentation; according to Witkop, AI can be Paulina GAJARDO categorized into 14 subtypes, which makes its diagnosis extremely complex. Ana SALAZAR Objective: This study aimed to describe and determine the frequency of Irene MORALES-BOZO clinical and radiographic features and inheritance patterns found in 41 Fabiola WERLINGER Chilean families diagnosed with diverse types of AI. Material and Methods: Sandra ROJAS-FLORES We analyzed the clinical records, photographs, pedigrees and radiographs 4,7 of 121 individuals recruited between 2003 and 2016. All of the information Alfredo MOLINA-BERRÍOS was included in a database that was analyzed using the application Stata Sonia ECHEVERRÍA-LÓPEZ 14. Results: The 72 affected individuals had average age of 16 years, and 4,7 José JARA-SANDOVAL no sex association with the presence of AI was found. The most frequent 6,7 Lilian JARA clinical subtypes were as follows: 43% hypomature, 25% hypoplastic, 21% 4,7 Blanca URZÚA hypomature/hypoplastic, 7% hypocalcified and 4% hypocalcified/hypoplastic. The number of severely affected teeth was 22, which occurred in the patients with hypocalcified and hypocalcified/hypoplasic AI

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1678-7757
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10.1590/1678-7757-2018-0359
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Abstract

1,7* Amelogenesis imperfecta (AI) is a group of enamel development disorders Daniela ADORNO-FARIAS that alter the structure and chemical composition of the tissue. There is 1,7* Ana ORTEGA-PINTO great variability in the clinical presentation; according to Witkop, AI can be Paulina GAJARDO categorized into 14 subtypes, which makes its diagnosis extremely complex. Ana SALAZAR Objective: This study aimed to describe and determine the frequency of Irene MORALES-BOZO clinical and radiographic features and inheritance patterns found in 41 Fabiola WERLINGER Chilean families diagnosed with diverse types of AI. Material and Methods: Sandra ROJAS-FLORES We analyzed the clinical records, photographs, pedigrees and radiographs 4,7 of 121 individuals recruited between 2003 and 2016. All of the information Alfredo MOLINA-BERRÍOS was included in a database that was analyzed using the application Stata Sonia ECHEVERRÍA-LÓPEZ 14. Results: The 72 affected individuals had average age of 16 years, and 4,7 José JARA-SANDOVAL no sex association with the presence of AI was found. The most frequent 6,7 Lilian JARA clinical subtypes were as follows: 43% hypomature, 25% hypoplastic, 21% 4,7 Blanca URZÚA hypomature/hypoplastic, 7% hypocalcified and 4% hypocalcified/hypoplastic. The number of severely affected teeth was 22, which occurred in the patients with hypocalcified and hypocalcified/hypoplasic AI who presented the highest number of damaged teeth. Caries and periodontal disease were found in 47 and 32% of the patients, respectively. Malocclusions were observed in 43% of the individuals with AI, with open bite being the most frequent. Radiographically, the thickness of the enamel decreased in 51% of the patients, and 80% showed decreased radiopacity of the enamel compared to that of dentin. Autosomal dominant inheritance pattern was found in 37% of the families with hypoplastic AI, and autosomal recessive pattern was present in 56% of the other clinical subtypes, but more frequently in those affected with hypomature and hypocalcified AI. Conclusion: Of the five clinical subtypes, autosomal recessive hypomature, autosomal dominant hypoplastic and autosomal recessive hypomature/hypoplastic AI were the most prevalent subtypes in this group. Submitted: June 30, 2018 Keywords: Amelogenesis Imperfecta. Dental enamel. Malformations. Modification: September 9, 2018 Hypoplasia. Hypomineralization. Accepted: October 14, 2018 Corresponding address: Universidad de Chile, Facultad de Odontología, Departamento de Patología y Medicina Oral, Blanca Urzúa Orellana Santiago, Chile. Instituto de Investigación en Ciencias Odontológicas - Universidad de Chile, Facultad de Odontología, Santiago, Chile. Facultad de Odontología - Universidad de Chile. Universidad de Chile, Facultad de Odontología, Programa de Magister en Ciencias Odontológicas, Avenida Sergio Livingstone 943 - Comuna de Santiago, Chile. Independencia - Santiago - Chile. Universidad de Chile, Facultad de Odontología, Instituto de Investigación en Ciencias Odontológicas, Phone: +56 2 29781793 e-mail: brurzua@gmail.com; Santiago, Chile. brurzua@odontologia.uchile.cl Universidad de Chile, Facultad de Odontología, Departamento del Niño y Ortopedia Dentomaxilar, Santiago, Chile. Universidad de Chile, Facultad de Medicina, Instituto de Ciencias Biomédicas, Santiago, Chile. U-Odontología: Red de Investigación en Enfermedades Orales Complejas, Santiago, Chile. *These authors contributed equally to this manuscript. J Appl Oral Sci. 1/11 2019;27:e20180359 Diversity of clinical, radiographic and genealogical findings in 41 families with amelogenesis imperfecta Because AI is a rare and heterogeneous condition Introduction from a clinical and genetic point of view, dentists, in general, have difficulty in making a correct diagnosis Normal enamel is synthesized during tooth regarding the presence of AI and the determination development as an extracellular matrix in a process of its clinical subtype. In our experience, many called amelogenesis, which occurs in two stages. In the professionals who do not know about this condition secretory stage, the ameloblast produces a partially and its consequences in long-term treatment choose mineralized protein matrix, which will correspond to to refer these patients, which contributes to a greater the adult enamel. In the maturation stage, the protein psychosocial impact on them because they feel 1,2 matrix is degraded, and mineralization is completed. marginalized and are often left without a specific Amelogenesis imperfecta (AI) is a group of low- treatment solution and prognosis of their condition. prevalence hereditary conditions that cause alterations Given the above factors, the literature reports in the structure and chemical composition of the few AI case series that systematically describe 1-3 enamel matrix during development. Currently, the the characteristics associated with this phenotype. diagnosis of AI involves a clinical and radiographic Moreover, in our country, there have been no studies examination, and when possible, morphological that determine the prevalence, the different subtypes analysis, using ground sections and scanning electron of AI, or the patterns of inheritance associated with microscopy of the teeth, and molecular genetic each case. In the absence of previous data to refute 3-5 analysis of the DNA samples can be performed. this, our null hypothesis proposes that the clinical, AI is classified into three main types that are radiographic and genealogical findings observed in the related to the stages of the tissue formation process. group of Latin American patients studied are similar A fault in the secretory stage of amelogenesis produces to those reported in other populations. Therefore, this the hypoplastic type of AI, which is characterized by study aims to describe and determine the frequency enamel that is thinner than normal and that contrasts of clinical and radiographic features and inheritance 7,8 normally from dentine in the radiographic analysis. patterns found in 41 Chilean families diagnosed with AI In hypocalcified AI, there is an alteration in the initial and, thus, contribute to the identification of the clinical mineralization of the secretory stage; the enamel diagnostic tools used during routine dental practice. initially develops normal thickness, is orange-yellow at eruption and consists of poorly calcified matrix that is rapidly lost during normal function. In addition, the 6,7 enamel has a lower radiopacity than the dentin. In Material and methods hypomature AI, the defect occurs in the maturation stage of the enamel; is of normal thickness but has This research was conducted under the framework of a mottled appearance; is slightly softer than normal a funded research project, which has the authorization enamel; and chips from the crown. Radiographically, of the Ethics Committee and the Institutional it presents with approximately the same radiodensity Biosafety Committee of the Faculty of Dentistry 6,9 as that of dentin. and the University of Chile ( Certificate No. 2013/06 To adequately evaluate AI, a differential diagnosis and FDO No. 224 of June 2013, respectively), and with other defects and an investigation to determine in full accordance with the ethical principles of the if the enamel alterations are linked to environmental Declaration of Helsinki and local regulations. disturbances or have a discernible genetic transmission One hundred twenty-one individuals belonging 2,10,11 pattern are necessary. The signs frequently to 41 Chilean families with AI were recruited found in the enamel are a decrease in thickness, between 2003 and 2016 and included in this study. rough texture, mottled appearance, the presence of Each of the patients was evaluated by two oral cavitations (pits), horizontal or vertical bands and a pathologists. A record of personal and family history dull white, yellow or brown color. In addition, a delay was completed including possible alterations during in eruption, dental impaction, anterior or lateral open the intrauterine development stage. Affected and bite, ogival palate, gingival inflammation, teeth with unaffected individuals were evaluated clinically for the a decreased coronary sector and multiple diastemas presence of skin, hair, fingernail, kidney, cognitive, 12-14 can be observed. gingival, visual, auditory and osseous abnormalities J Appl Oral Sci. 2/11 2019;27:e20180359 ADORNO-FARIAS D, ORTEGA-PINTO A, GAJARDO P, SALAZAR A, WERLINGER F, ROJAS-FLORES S, ECHEVERRÍA-LÓPEZ S, MOLINA-BERRÍOS A, JARA-SANDOVAL J, JARA L, URZÚA B known to be a sign of systemic or syndromic conditions The significance was determined at a value of P<0.05. that could be associated with AI. In-depth interviews were conducted with at least two family members by a geneticist in order to construct their genealogies and Results analyze the inheritance pattern. Additionally, clinical photographs were taken, and complementary tests Sample description were requested such as periapical and panoramic A total of 121 individuals were evaluated from radiographs. 41 Chilean families with an AI diagnosis; 58% of the The presence of alterations in the enamel was cases were female (Table 1). Most of the evaluated recorded in relation to the glossiness, texture, color, patients presented clinically with AI (60%), and the thickness and surface defects. The gloss of the enamel remaining individuals were direct relatives who did not was considered abnormal when it had an opaque manifest the disease. Although the number of women appearance. The texture was evaluated by gently was higher in the group of affected individuals, no passing the dental probe over the enamel, and the sex association was found in relation to the presence thickness of the enamel was considered diminished of AI (P=0.320). The group of individuals affected when there was presence of generalized diastemas, with AI had a significantly lower median age than the pits or bands; the evaluation was complemented by unaffected group (P=0.0004) (Table 1). the radiographic image. A radiographic analysis was conducted to evaluate the radiopacity and thickness Genealogical analysis of the enamel as well as the presence of dental and A significantly higher number of families affected bone alterations. with AI (56%) presented an autosomal recessive The diagnosis of AI and its respective subtypes inheritance pattern (P=0.006) (Table 2), followed was based on the criteria described in the classification by 15 families that showed an autosomal dominant of Witkop (1989); however, we considered only inheritance pattern, which represented 37% of the the following three main types of AI and their sample. possible combinations: “type I-Hypoplastic, type II-Hypomaturation and type III-Hypocalcified”. Intraoral clinical characteristics Taurodontism was recorded as one more characteristic, A total of 93% of the individuals had normal- among several others, that are associated with AI appearing mucosa (Table 3), and 7% had alterations and not as “type IV-Hypomaturation-hypoplastic with of the mucosa that corresponded to traumatic and/or taurodontism” from the Witkop’s classification. reactional injuries, canker sore and hyperpigmentation All of the information collected was included of the gum. Regarding the type of dentition, 71% of in a single database, and the statistical analysis the individuals had permanent dentition with a median was conducted using the Stata computer program, of 27 permanent teeth (range 0-32) present in the version 4 (StataCorp, College Station, TX, USA). The mouth at the time of the examination. Caries were continuous variables were assessed for normality observed in 47% of the patients, and restorations using the Shapiro-Wilk test. The data are presented were observed in 67% of the patients. A total of 39% as either the mean and standard deviation or as the of the patients had undergone exodontias, and the median and range. The data were compared using median number of teeth clinically observed that were the Fisher’s exact, Wilcoxon or Kruskal-Wallis test. severely affected with AI in the sample of patients was Table 1- Distribution of individuals affected and not affected with Amelogenesis Imperfecta from 41 Chilean families, according to sex and age FEMALE MALE TOTAL CONDITION No. (%) Med Age (Rank) No. (%) Med Age (Rank) No. (%) Med Age (Rank) v a Non affected 31 (44) 37 (2-64) 18 (35) 19 (1-63) 49 (40) 37 (1-64) & a Affected by AI 39 (56) 13 (2-44) 33 (65) 17 (6-84) 72 (60) 16 (2-84) TOTAL 70 (100) 28 (2-64) 51 (100) 17 (1-84) 121 (100) 21 (1-84) v & Data are presented as No. (%) and Median (yr) (Rank). 1 non-affected woman without age data, 2 affected woman without data od age. Wilcoxon test, P=0.0004 J Appl Oral Sci. 3/11 2019;27:e20180359 Diversity of clinical, radiographic and genealogical findings in 41 families with amelogenesis imperfecta 22 (range 4-31) (Table 3). hypoplastic AI (21%). Clinical subtypes of hypocalcified Malocclusions were observed in 43% of the AI and hypocalcified/hypoplastic AI were found in 7% individuals with AI, with open bite being the most and 4% of the patients, respectively. frequent form (17%). On the other hand, 26% Hypoplastic Amelogenesis Imperfecta (HPAI) of the patients presented some type of dental The 18 cases of HPAI presented enamel thickness symptomatology, and sensitivity to thermal changes alterations such as a generalized decrease in thickness, was the most frequently reported symptom (11%). which occurred in 82% of the cases (Table 4, Figures It is interesting to note that periodontal disease, the 2A and 2B), cavitations or pits in 41% of the cases, presence of diastemas, high or low lip frenum insertion and the presence of horizontal bands in 29% of the and ogival palate occurred with frequencies equal or patients (Table 4). Changes in enamel thickness were greater than 22% (Table 3). not similar within the same family. Different degrees of affection were also observed in the same individual as General and specific clinical characteristics of shown in Figure 2B. Diastemas were observed in 56% enamel of cases, and dentin sensitivity was observed in 33% With regard to glossiness and texture, 41% of the of the patients (Table 3). Dental wear and exodontias patients showed an opaque enamel, and 46% of them were very frequent in this group, which were observed showed that the texture of the tissue was rough (Table in 94% and 56% of the cases, respectively (Tables 3 4). The most commonly observed enamel coloration and 4, Figures 2A and 2B). Other clinical alterations (65% of the patients) was white/opaque with absence were opaque white spots in 53% of the patients, rough of translucency, which was more frequent than other texture in 47% of the patients, and opaque enamel in colorations (P<0.0001). Opaque white spots were 41% of cases (Table 4). observed in a high percentage of the patients with Alterations in occlusion were observed in 50% of AI (77%). Regarding surface defects of the enamel, the patients, with open bite being the most frequent 29% of the individuals had pitting and 65% showed finding (28% of the cases) (Table 3). Of the 18 cases wear (Table 4). of HPAI, radiographic images were available in 11 cases with evident enamel thickness reduction in Radiographic characteristics of the enamel 91%, and radiopacity in 82% of the cases (Table 5 and Radiographic analysis (Table 5) showed that normal Figure 2C). Of the 11 cases analyzed, none presented and decreased enamel thickness occurred equally in taurodontism (Table 5). Of the 6 families with HPAI, individuals with AI. A decrease in the radiopacity of 83% presented an autosomal dominant pattern of the enamel compared to that of dentine was observed inheritance (Table 2). in 80% of the patients. In this sample, only 16% of the patients presented taurodontism. Hypomature Amelogenesis Imperfecta (HMAI) Thirty-one cases were classified in this group, Clinical analysis of phenotypes from which the most frequently observed enamel Five clinical subtypes of AI were identified (Figure characteristics were opaque white spots in 100% of the 1). The most frequently observed clinical subtypes in cases, normal enamel thickness in 90% of the cases the 72 affected patients were hypomature AI (43%), (P<0.0001), white/opaque enamel color in 76% of the followed by hypoplastic AI (25%) and hypomature/ cases, enamel with normal glossiness in 69% of the Table 2- Inheritance patterns for the 41 Chilean families with Amelogenesis Imperfecta according to the subtype of AI diagnosed INHERITANCE PATTERN HPAI HMAI HCAI HM/HPAI HC/HPAI TOTAL No. % No. % No. % No. % No. % No. % Autosomal Dominant 5 83 5 26 1 20 2 25 2 67 15 37 Autosomal Recessive 0 0 14 74 4 80 4 50 1 33 23 56 X-linked 0 0 0 0 0 0 0 0 0 0 0 0 Two possible patterns* 0 0 0 0 0 0 2 25 0 0 2 5 Undetermined 1 17 0 0 0 0 0 0 0 0 1 2 TOTAL families 6 100 19 100 5 100 8 100 3 100 41 100 *Autosomal Recesive or Esporadic/Autosomal Dominant or X-linked; aFisher exact test P=0.006 J Appl Oral Sci. 4/11 2019;27:e20180359 ADORNO-FARIAS D, ORTEGA-PINTO A, GAJARDO P, SALAZAR A, WERLINGER F, ROJAS-FLORES S, ECHEVERRÍA-LÓPEZ S, MOLINA-BERRÍOS A, JARA-SANDOVAL J, JARA L, URZÚA B cases and normal texture in 66% of the cases (Table 4 normal enamel thickness was observed in 79% of the and Figures 2D and 2E). It is important to highlight that cases, and a decrease in radiopacity was observed in periodontal disease and malocclusions affected 29% 18 cases (75%) (Table 5, Figure 2F). In this subtype of of the patients (Table 3). In the radiographic study, a AI, the most observed pattern of inheritance was the Table 3- Distribution of the intraoral clinical characteristics observed in the individuals affected with Amelogenesis Imperfecta according to clinical subtype INTRAORAL CLINICAL HPAI HMAI HCAI HM/HPAI HC/HPAI TOTAL CHARACTERISTICS n=18 n=31 n=5 n=15 n=3 n=72 No. (%) No. (%) No. (%) No. (%) No. (%) No. (%) MOUTH Normal mucosa 16 (89) 30 (97) 5 (100) 13 (87) 3 (100) 67 (93) Altered Mucosa 2 (11) 1 (3) 0 (0) 2 (12) 0 (0) 5 (7) Low/high lip frenum insertion 5 (28) 6 (19) 2 (40) 5 (33) 1 (33) 19 (26) Short lip frenum 0 (0) 3 (10) 0 (0) 1 (7) 0 (0) 4 (6) DENTITION Permanent Dentition 16 (89) 23 (74) 4 (80) 5 (33) 3 (100) 51 (71) Mixed Dentition 2 (11) 8 (26) 1 (20) 8 (53) 0 (0) 19 (26) Primary Dentition 0 (0) 0 (0) 0 (0) 2 (13) 0 (0) 2 (3) Diastemas 10 (56) 4 (13) 1 (20) 5 (33) 3 (100) 23 (32) TREATMENTS Restorations 14 (78) 21 (68) 2 (40) 9 (60) 3 (100) 48 (67) Veneers or fixed prostheses 5 (28) 4 (13) 2 (40) 1 (7) 1 (33) 13 (18) Exodontias 10 (56) 13 (42) 2 (40) 2 (13) 1 (33) 28 (39) CONDITIONS / PATHOLOGIES Caries 7 (39) 15 (48) 3 (60) 7 (47) 2 (67) 34 (47) Agenesis 0 (0) 3 (10) 1 (20) 2 (13) 1 (33) 7 (10) Eruption delay 0 (0) 1 (3) 1 (20) 1 (7) 0 (0) 3 (4) Periodontal disease 5 (28) 9 (29) 3 (60) 6 (40) 0 (0) 23 (32) Gingival hyperplasia 1 (6) 2 (6) 0 (0) 0 (0) 0 (0) 3 (4) Ogival Palate 3 (17) 7 (23) 2 (40) 3 (20) 1 (33) 16 (22) OCCLUSSION Malocclusions (total): 9 (50) 9 (29) 4 (80) 8 (53) 1 (33) 31 (43) Anterior Openbite 5 (28) 2 (6) 2 (40) 2 (13) 1 (33) 12 (17) Lateral bite 1 (6) 2 (6) 1 (20) 1 (7) 0 (0) 5 (7) Crossbite 2 (11) 2 (6) 0 (0) 3 (20) 0 (0) 7 (10) Inverted bite 1 (6) 1 (3) 1( 20) 1 (7) 0 (0) 4 (6) Bis to bis bite 0 (0) 2 (6) 0 (0) 1 (7) 0 (0) 3 (4) SENSITIVITY Sensitivity associated to (total): 6 (33) 6 (19) 2(40) 2 (13) 3 (100) 19 (26) Thermal changes 2 (11) 2 (6) 0 (0) 1 (7) 3 (100) 8 (11) Chemical changes 1 (6) 3 (10) 0 (0) 0 (0) 0 (0) 4 (6) Both (thermal and Chemical) 3 (17) 0 (0) 2 (40) 1 (7) 0 (0) 6 (8) OTHERS Other alterations * 6 (33 ) 16 (52) 1 (20) 8 (53) 1 (33) 32 (44) AIHP=AI hypoplastic; AIHM=AI hypomature; AIHC=AI hypocalcified; AI HM/HP=AI hypomature/hypoplastic; AIHC/HP=AI hypocalcified/ hypoplastic; GS=Salivary Glands. * Fibromatosis, anterior covering bite, increased overjet, dental invaginations, irritative fibroma, Fordyce condition, angular cheilitis, bruxism, erythematous plaques on tongue, semi-bifid tongue, fissured tongue, microdontia, teeth with shape alteration, macrodontia, teeth included, extrinsic dental staining, change in coloration by tetracycline (each with 1%), in addition to crowding, prognathism, overbite, palatine torus, carabelli tubercle and pits and fissures in teeth, each with 3% and geographical tongue with 4% J Appl Oral Sci. 5/11 2019;27:e20180359 Diversity of clinical, radiographic and genealogical findings in 41 families with amelogenesis imperfecta autosomal recessive type (14 families, 74%) (Table 2). erupted teeth (Table 5). An interesting finding was that 40% of the patients presented taurodontism (Table Hypocalcified Amelogenesis Imperfecta (HCAI) 5). In this group, 80% of the families presented an The 5 cases of HCAI had opaque and rough enamel autosomal recessive inheritance pattern (Table 2). and decreased thickness (Table 4). In 60% of the cases, the enamel was brown, and in the remaining Hypomature/Hypoplastic Amelogenesis Imperfecta (HM/ HPAI) two cases, it was yellow (Table 4, Figures 2G and 2H). In this group, both HMAI and HPAI characteristics Regarding other clinical characteristics, 80% of the were observed in the same patient (Figures 2J and cases presented malocclusions, which were mainly 2K). The characteristics of HMAI were as follows: open bite, whereas 60% of the cases presented opaque enamel in 27% of cases, rough enamel in periodontal disease, and 40% presented sensitivity 40% of the patients, white/opaque enamel in 73% to both thermal and chemical stimuli (Table 3). This of cases and opaque white spots in 93% of cases clinical subtype presented more affected teeth than (Table 4). The following characteristics of HPAI were the other clinical subtypes. The imaging showed that observed: uniformly reduced thickness in 40% of all of the cases had less radiopacity of the enamel cases, vertical lines in 20% and pits in 27% of cases compared to dentin (Figure 2I), and 80% of the cases (Table 4). Among the intraoral alterations, periodontal presented a decrease in the enamel thickness of the Table 4- Distribution of the general and specific clinical characteristics of the enamel observed in the individuals affected with Amelogenesis Imperfecta (AI) according to clinical subtype CLINICAL CHARACTERISTICS OF HPAI HMAI HCAI HM/HPAI HC/HPAI TOTAL ENAMEL n=18 n=31 n=5 n=15 n=3 n=72 No. (%) No. (%) No. (%) No. (%) No. (%) No. (%) GLOSSINESS Normal 10 (59) 20 (69) 0 (0) 11 (73) 0 (0) 41 (59) Opaque 7 (41) 9 (31) 5 (100) 4 (27) 3 (100) 28 (41) TEXTURE Normal 9 (53) 19 (66) 0 (0) 9 (60) 0 (0) 37 (54) Rough 8 (47) 10 (34) 5 (100) 6 (40) 3 (100) 32 (46) COLOR White/opaque 12 (71) 22 (76) 0 (0) 11 (73) 0 (0) 45 (65) Yellow 5 (29) 5 (17) 2 (40) 4 (27) 1 (33) 17 (25) Brown 0 (0) 0 (0) 3 (60) 0 (0) 1 (33) 4 (6) White-yellow 0 (0) 1 (3.5) 0 (0) 0 (0) 1 (33) 2 (3) Yellow-brown 0 (0) 1 (3.5) 0 (0) 0 (0) 0 (0) 1 (1) THICKNESS Normal 3 (18) 26 (90) 0 (0) 9 (60) 0 (0) 38 (55) Decreased 14 (82) 3 (10) 5 (100) 6 (40) 3 (100) 31 (45) LINE BANDING Horizontal 5 (29) 3 (10) 0 (0) 0 (0) 0 (0) 8 (12) Vertical 2 (12) 3 (10) 0 (0) 3 (20) 0 (0) 8 (12) SPOTTING White/opaque spots 9 (53) 29 (100) 1 (20) 14 (93) 0 (0) 53 (77) Yellow-brown spots 4 (24) 8 (28) 1 (20) 5 (33) 1 (33) 19 (28) SURFACE DEFECTS Pits or cavitation 7 (41) 6 (21) 2 (40) 4 (27) 1 (33) 20 (29) Wear 16 (94) 13 (45) 4 (80) 10 (67) 2 (67) 45 (65) WITHOUT DATA No. Patients 1 (6)* 2 (7) 0 (0) 0 (0) 0 (0) 3 (4) & a, b Patients without data in these characteristics, * all teeth restored at the time of the examination. Fisher's exact test P<0.0001 J Appl Oral Sci. 6/11 2019;27:e20180359 ADORNO-FARIAS D, ORTEGA-PINTO A, GAJARDO P, SALAZAR A, WERLINGER F, ROJAS-FLORES S, ECHEVERRÍA-LÓPEZ S, MOLINA-BERRÍOS A, JARA-SANDOVAL J, JARA L, URZÚA B Table 5- Distribution of the radiographic characteristics observed in the individuals affected with Amelogenesis Imperfecta according to clinical subtype RADIOGRAPHIC HPAI HMAI HCAI HM/HPAI HC/HPAI TOTAL CHARACTERISTICS OF ENAMEL n=18 n=31 n=5 n=15 n=3 n=72 No. (%) No. (%) No. (%) No. (%) No. (%) No. (%) THICKNESS Normal 1 (9) 19 (79) 1 (20) 6 (50) 0 (0) 27 (49) Decreased 10 (91) 5 (21) 4 (80) 6 (50) 3 (100) 28 (51) RADIOPACITY* Normal 2 (18) 6 (25) 0 (0) 3 (25) 0 (0) 11 (20) Decreased 9 (82) 18 (75) 5 (100) 9 (75) 3 (100) 44 (80) PRESENCE OF Taurodontism 0 (0) 1 (4) 2 (40) 5 (42) 1 (33) 9 (16) WITHOUT DATA No. Patients 7 (64) 7 (29) 0 (0) 3 (25) 0 (0) 17 (31) * Radiopacity of the enamel in relation to the dentin Figure 1- Pie chart showing the distribution of clinical subtypes in the 72 patients affected with Amelogenesis Imperfecta disease was observed in 40% of cases, malocclusions The color of the enamel varied from brown to yellow in 53% and the presence of diastemas in 33% of cases and white-yellow, and 1 patient presented with pits (Table 3). The radiographic study showed a decrease or cavitations (Table 4). The radiographic study in radiopacity in 75% of cases (Table 5 and Figure 2L), showed a generalized decrease in enamel thickness a generalized decrease in enamel thickness in 50% of and decreased radiopacity compared to dentin (Table cases, and taurodontism in 42% of cases (Table 5). 5, Figure 2O). Of the 3 families analyzed, only 2 had In this subtype of AI, 50% of the families showed an autosomal dominant inheritance (Table 2). autosomal recessive inheritance pattern (Table 2). Hypocalcified/Hypoplastic Amelogenesis Imperfecta (HC/ HPAI) Discussion This group was formed by 3 individuals with presence of restorations, sensitivity to thermal AI is a term that encompasses several hereditary changes and diastemas (Table 3). These 3 patients conditions that affect the structure and appearance presented rough opaque enamel and a generalized 2,6,8 of tooth enamel. The lack of local information and decrease in thickness (Table 4, Figures 2M and 2N). the information in the literature about the clinical and J Appl Oral Sci. 7/11 2019;27:e20180359 Diversity of clinical, radiographic and genealogical findings in 41 families with amelogenesis imperfecta Figure 2- Clinical subtypes of Amelogenesis Imperfecta found in this study; A, B, C: Clinical subtype of Hypoplastic Amelogenesis Imperfecta; D, E, F: Subtype of Hypomature AI; G, H, I: Subtype of Hypocalcified AI; J, K, L: Subtype of Hypomature-hypoplastic AI; M, N, O: Subtype of Hypocalcified-hypoplastic AI radiographic signs associated with different subtypes were systemically healthy and were not receiving of AI was the motivation for the development of this pharmacological treatment at the time of the study, in which 121 individuals belonging to 41 Chilean examination, which supports the diagnosis of AI and families were evaluated from a clinical, radiographic excludes a possible environmental cause due to the and genealogical point of view. ingestion of medications. The majority of individuals with AI had exclusively Sample and clinical analysis permanent dentition and a higher frequency of tooth The patients were mainly young, with a median age loss due to exodontias (39%), which highlights the of 16 years (range 2-84 years). There were similar need for early diagnosis and intervention in these frequencies of men and women, which coincide with patients. Because 47% of the patients with AI present results reported in the literature for the profile of caries, exodontias can be justified. The high frequency 2,6,11 patients with AI. Although hypoplastic AI has been of caries is consistent with previous reports in which described as the most prevalent subtype occurring in more caries were observed in patients with AI than in 15,16 14,22,23 43.7% of the cases, the most frequent type found healthy individuals. However, the number of teeth in this work was hypomature AI followed by hypoplastic with caries in patients with AI in this study was similar AI. In addition, the third most frequent subtype to that found in healthy 12-year-old Chilean children . observed in patients consisted of mixed characteristics This suggests that caries in individuals with AI could be of hypomature and hypoplastic AI. explained by the time required to find a specialist that Even though an association between AI and can diagnose them and provide adequate treatment, in several extraoral alterations has been described in addition to the intrinsic susceptibility of their defective 18-21 the literature , most of the individuals in this study J Appl Oral Sci. 8/11 2019;27:e20180359 ADORNO-FARIAS D, ORTEGA-PINTO A, GAJARDO P, SALAZAR A, WERLINGER F, ROJAS-FLORES S, ECHEVERRÍA-LÓPEZ S, MOLINA-BERRÍOS A, JARA-SANDOVAL J, JARA L, URZÚA B enamel. Radiographic analysis The median number of restorations was 3 (range In the radiographic evaluation, a similar frequency of 0-26), which is higher than that reported in of patients with normal and diminished enamel healthy 12-year-old Chilean patients who presented a thickness was observed. However, a decrease in frequency of 1.03 teeth restored. However, a study the radiopacity of the enamel when compared with in healthy elderly Chilean adults observed an average dentin was an important feature for the majority of 8.9 restorations per individual, which indicated of the patients with AI. Patients with hypoplastic AI that our patients with AI, although much younger, showed more frequent decreased enamel thickness often had a concerning number of restorations that and radiopacity. Most of the patients with hypomature was closer to the number seen in elderly adults than AI presented with enamel with normal thickness to that in young people in the same age range. On and diminished radiopacity compared to dentin, and the other hand, 32% of the patients with AI presented individuals with hypocalcified AI showed a tendency periodontal pathology without differences among to have decreased enamel thickness and radiopacity. the different clinical subtypes, which is supported Although a 40% prevalence of taurodontism has been 3,14 6,13,30 by the literature. This is probably because enamel described in patients with AI, in the present study, alterations favor the retention of bacterial plaque. a low percentage of individuals with this characteristic In addition, dental hypersensitivity per se makes was found. adequate oral hygiene difficult. Several studies have indicated the association Genealogical analysis of AI with malocclusions such as anterior open bite In this study, 23 families (56%) presented 26-28 (AOB). Other reports of cases with different significantly more autosomal recessive inheritance types of AI describe the presence of prognathism, patterns, which corroborates with Wright’s study 11,27,29 posterior cross-bite and others anomalies. In (2011), in which 50% of their families showed this the present study, malocclusions were observed in type of inheritance. However, Chan (2011) reported 43% of the individuals with AI without a significant 15% autosomal recessive inheritance, and Backman difference among the different types. Eruption delay (1988) reported 12% of the cases as showing this and agenesis were rare in this study, but low/high lip type of inheritance. These differences may be due to frenum insertion and ogival palate, which are not often the genetic background, the degree of consanguinity reported in the literature, were observed in more than and differences in the allelic frequencies of the genes 20% of the individuals with AI. involved in the genetic etiology of the AI in the Patients in this sample had a large number of teeth distinct population groups analyzed. With regard to damaged by AI, with a median of 22 severely affected the different clinical subtypes of AI with recessive teeth (range of 4-31) at the time of the examination. inheritance patterns, it should be noted that, although It is interesting to note that all individuals with the majority had HMAI (14 cases), this type of hypocalcified AI, alone or associated with hypoplastic inheritance was also found in the clinical subtypes HC, AI, presented enamel with opaque gloss, rough texture HM/HP and HC/HP of AI. In addition, as previously and reduced thickness. The majority of patients with mentioned, autosomal recessive inheritance was found hypomature and hypoplastic AI phenotypes presented in families with hypocalcified AI. These results contrast whitish enamel. The decrease in thickness was with the study by Wright (2011), which reported a frequently observed in the hypoplastic type of AI, but high prevalence of hypomature AI with autosomal a normal enamel thickness was present in 90% of the recessive inheritance and hypocalcified AI mainly patients with hypomature AI and 60% in the combined associated with autosomal dominant inheritance. This type of hypomature/hypoplastic AI. could be due to the misinterpretation of incomplete Finally, regarding clinical analysis, it is important information on pedigrees, given the impossibility of 6,10,15,17 to point out that, as reported in the literature, conducting clinical examinations for several members we also found great variability in the phenotypic of the studied families. On the other hand, 37% of expression of AI. We observed differences in the the families showed autosomal dominant inheritance teeth of the same patient and between members of patterns as described in studies involving several 15,17 the same family. families. J Appl Oral Sci. 9/11 2019;27:e20180359 Diversity of clinical, radiographic and genealogical findings in 41 families with amelogenesis imperfecta In our study, the X-linked pattern of inheritance Conclusions was absent. However, a classic article on AI that involved a significant number of families established Considering the low worldwide prevalence of that approximately 5-10% of all the cases of AI this pathology, i.e., 1 in 14,000 cases of all types of are X-linked. In this context, Wright’s work with AI combined, this study involving a large group of 71 families reported that 6 (23%) cases presented affected families is the first to determine the frequency X-linked patterns of inheritance. The study by Chan of clinical, radiographic and genealogical characteristics (2011), carried out with 39 families, showed that 4 of five clinical subtypes of AI found in the Chilean of them (12%) presented this type of inheritance. population. Our study shows that autosomal recessive Considering this information, in two of our families hypomature AI, autosomal dominant hypoplastic AI with hypomature/hypoplastic AI, there were two and autosomal recessive hypomature/hypoplastic AI possible inheritance patterns involved, one of which are the most prevalent in this group and that the most was probably X-linked, but this was not possible to frequently found characteristics are the presence of determine. This is due to a lack of information in the opaque white spots, reduction of thickness and enamel pedigree and to the fact that in these cases, it was wear, malocclusions, and the presence of restorations, difficult to determine the status of the condition in among others. key individuals, given the number of restorations and This work represents a source of complementary missing teeth. information for other studies and is of relevance and For these last few years, the heterogeneous genetic clinical utility for general dentists and specialists etiology of AI has been elucidated to a great extent, because it gathers information collected through the but not completely to date. Mutations in the genes analysis of a significant number of patients with AI. ENAM, COL17A1, LAMB3, ACPT, AMBN and IGTB6 Additionally, it provides more tools for the adequate are responsible for the hypoplastic forms of AI, with diagnosis of this pathology, which will allow for autosomal dominant and/or recessive inheritance early intervention by the professional and adequate 5,8 patterns. On the other hand, hypomature forms preventive and restorative actions in a multidisciplinary of AI are caused by mutations in the genes AMTN, framework. KLK4, MMP20, WDR72, SLC24A4, C4orf26 and GPR8, all of which are associated with autosomal recessive Acknowledgments 5,8 inheritance. Finally, the only causative gene of We are grateful to the families with Amelogenesis hypocalcified autosomal dominant AI known thus far Imperfecta for their participation in this study. This 5,8 is FAM83H. For this reason, the genetic molecular work was supported by the National Fund for Scientific analysis of a significant number of families should and Technological Development FONDECYT Project consider these 16 genes (and those involved in number 1140905 and the Vice-Rectorate for Research syndromic forms of AI) in the design of a targeted gene and Development (VID), University of Chile, U-redes panel for massive sequencing for diagnostic purposes. Project number URED/2014-007. We also thank Mr. Although the main strength of this 13-years-long Juan Fernández from the Language and Translation study is the inclusion of a large number of patients services of the Faculty of Dentistry for kindly with AI in its sampling, it also has some limitations proofreading and checking the spelling and grammar related to our nonrandom convenience sample formed of this article. The authors declare no potential conflicts by patients who came for treatment or were referred of interest with respect to the authorship and/or by other dentists due to severe alterations. Moreover, publication of this article. in many cases it was not possible to obtain complete information for the genealogical analysis, and the molecular genetic analyses are only recently underway. J Appl Oral Sci. 10/11 2019;27:e20180359 ADORNO-FARIAS D, ORTEGA-PINTO A, GAJARDO P, SALAZAR A, WERLINGER F, ROJAS-FLORES S, ECHEVERRÍA-LÓPEZ S, MOLINA-BERRÍOS A, JARA-SANDOVAL J, JARA L, URZÚA B 17- Chan HC, Estrella NM, Milkovich RN, Kim JW, Simmer JP, Hu JC. References Target gene analyses of 39 amelogenesis imperfecta kindreds. Eur J Oral Sci. 2011;119(Suppl. 1):311-23. 1- Aldred MJ, Savarirayan R, Crawford PJ. Amelogensis imperfecta: a 18- Parry DA, Mighell AJ, El-Sayed W, Shore RC, Jalili IK, Dollfus H, et st classification and catalogue for the 21 century. Oral Dis. 2003;9(1):19- al. 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Published: Jan 1, 2019

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