Congenital Anomalies 2015; 55, 42–48
Dentomaxillofacial characteristics of ectodermal dysplasia Yumiko Nakayama1, Yoshiyuki Baba1,2, Michiko Tsuji1, Hiroki Fukuoka1, Takuya Ogawa1, Mizue Ohkuma1, and Keiji Moriyama1 Maxillofacial Orthognathics, Department of Maxillofacial Reconstruction and Function, Division of Maxillofacial/Neck Reconstruction, Graduate School, Tokyo Medical and Dental University, and 2Division of Dentistry, Department of Surgical Specialties, National Center for Child Health and Development, Tokyo, Japan
The aim of this retrospective hospital-based study was to elucidate the dentomaxillofacial characteristics of ectodermal dysplasia. Six Japanese individuals (one male and five female; age range, 12.7–27.2 years) underwent comprehensive examinations, including history recording, cephalometric analysis, panoramic radiography, and analysis of dental models. All the subjects had two or more major manifestations for clinical diagnosis of ectodermal dysplasia (e.g., defects of hair, teeth, nails, and sweat glands). They presented hypodontia (mean number of missing teeth, 9.5; range, 5–14), especially in the premolar region, and enamel dysplasia. Five subjects had bilateral molar occlusion, whereas one subject had unilateral molar occlusion. The common skeletal features were small facial height, maxillary hypoplasia, counterclockwise rotation of the mandible, and mandibular protrusion. Interestingly, the maxillary first molars were located in higher positions and the upper anterior facial height was smaller than the Japanese norm. The results suggest that vertical and anteroposterior maxillary growth retardation, rather than lack of occlusal support due to hypodontia, leads to reduced anterior facial height in individuals with ectodermal dysplasia. Key Words: hypoplasia
INTRODUCTION Ectodermal dysplasia is a group of congenital anomalies characterized by defects of two or more ectoderm-derived structures, such as hair, teeth, nails, and sweat glands (Hennekam et al. 2010). The reported incidence is in 7 in 10,000 births (Lamartine 2003; Itin and Fistarol 2004). The most frequent manifestations are dyshidrosis, hypotrichosis, hypodontia, fervescene, depressed nasal bridge, jaw deformity, microdontia, conical teeth, and lacrimal gland dysfunction (Schalk-Van Der Weide and Bosman 1996; Lexner et al. 2007b; Hennekam et al. 2010). Pinheiro and Freire-Maia (1994) introduced a comprehensive classification based on phenotypic characteristics. Now, more than 170 distinct clinical conditions affecting ectoderm-derived tissues are considered to be ectodermal dysplasia (Priolo and Laganà 2001; Correspondence: Michiko Tsuji, Assistant Professor, Maxillofacial Orthognathics, Department of Maxillofacial Reconstruction and Function, Division of Maxillofacial/Neck Reconstruction, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8549, Japan. Email: [email protected]
Received December 27, 2013; revised and accepted June 23, 2014. Declaration of interest: None.
© 2014 Japanese Teratology Society
Hennekam et al. 2010), but molecular causes have been detected in only 50 types (Priolo and Laganà 2001). The most common type is X-linked hypohidrotic ectodermal dysplasia (HED; OMIM #305100). Many studies have shown midfacial hypoplasia, reduced facial height, and hypodontia in individuals with ectodermal dysplasia (Johnson et al. 2002; Lexner et al. 2007a; Hennekam et al. 2010). We examined dentomaxillofacial anomalies for the purpose of clarifying the potential factors contributing to characteristic features of ectodermal dysplasia.
MATERIALS AND METHODS The subjects were six (one male and five female) Japanese individuals (age range, 12.7–27.2 years) with two or more major manifestations for clinical diagnosis of ectodermal dysplasia (e.g., defects of hair, teeth, nails, and sweat glands) in Division of Maxillofacial Orthodontics Hospital, Tokyo Medical and Dental University, Japan. None had received orthodontic treatment or genetic testing. Those with cleft lip and palate or limb anomalies were excluded. The subjects gave their informed consent for participation and the study adhered to the tenets of the amended Declaration of Helsinki. At the first visit, the subjects and their parents were interviewed to obtain information on systemic conditions and complications, birth height and weight, gestational age at birth, present height and weight, and manifestations of ectodermal dysplasia. Lateral cephalograms were taken for skeletal and dental evaluations. The dentition status was recorded by panoramic radiography, analysis of dental models and clinical records, and intraoral examinations. The following Japanese norms were used for comparison: birth height and weight at the corresponding gestational age in normal or preterm infants according to the Japanese Ministry of Health, Labor and Welfare (2010); height and weight at school age according to the Japanese Ministry of Education, Culture, Sports, Science, and Technology (2002); head circumference reported by Ishikawa et al. (1987); N-Me, N-ANS, ANS-Me, N-S, S-Ba, ANS-PNS, Ar-Go, Go-Pog, and N-S-Ba values reported by Masaki (1980); SNA, U-1 to FH, facial angle, SNB, MPA, gonial angle, L-1 to MP, ANB, and A-B plane angle values reported by Iizuka and Ishikawa (1957) and Iizuka (1958); and profilogram of craniofacial morphology reported by Sakamoto (1959). Cephalometric reference points and lines are shown in Figure 1. Cephalometric analysis was performed by an experienced orthodontist. To minimize measurement error, each measurement was repeated at least twice at an interval of over 2 weeks. Errors in landmark localization during tracing were evaluated by retracing all the cephalograms.
Dental phenotype of ectodermal dysplasia
Fig. 1 Reference points and lines. A, A point; ANS, anterior nasal spine; Ar, articulare; B, B point; Ba, basion; FH, Frankfort horizontal plane; Go, gonion; L-1, long axis of the mandibular central incisor; Me, menton; MP, mandibular plane; N, nasion; PNS, posterior nasal spine; Pog, pogonion; S, sella turcica; U-1, long axis of the maxillary central incisor; U6, upper first molar.
The mesiodistal dimensions of the permanent teeth excluding the second and third molars on the dental models were measured with an analog caliper (accuracy, 100 μm; Mitsutoyo, Tokyo, Japan). The greatest distance between the proximal contact areas of each tooth was considered as the mesiodistal crown diameter. Microdontia was defined as a mesiodistal dimension below −2SD (Otsubo 1957). Teeth with cone-shaped crowns and no morphological structures (e.g., ridges and knots) were defined as conical teeth. The number of cusps was compared with the general number. A specialist in maxillofacial anatomy evaluated enamel dysplasia. Occlusion was checked at the first and second molars.
Fig. 2 Cephalometric findings of the subjects with ectodermal dysplasia. A-B plane, angle between N-Pog and A-B; ANB, angle between SNA and SNB; ANS-Me, distance between ANS and Me; ANSPNS, distance between ANS and PNS;N-ANS, distance between N and ANS; Ar-Go, distance between Ar and Go; facial angle, angle between FH and N-Pog; gonial angle, angle between MP and gonial plane; Go-Pog, distance between Go and Pog; L-1 to MP, angle between L-1 and MP; MPA, angle between MP and FH; N-Me, distance between N and Me; N-S, distance between N and S; N-S-Ba, angle between N, S, and Ba; ramus inclination, complementary angle of the angle between Ar-Go and FH; S-Ba, distance between S and Ba; SNA, angle between SN plane and N-A; SNB, angle between SN plane and N-B; U-1 to FH, angle between U-1 and FH. Each symbol represents Z-scores (measurement − norm)/ SD. Each Z-score was compared with the gender- and age-matched Japanese norms.
RESULTS Ectodermal dysplasia is a group of congenital anomalies characterized by defects of two or more ectoderm-derived structures (Hennekam et al. 2010). Subjects’ demographic details are shown in Table 1. All the subjects had dental anomalies, and five had skin anomalies, such as softening, thinning, dryness, eczema, and depigmentation (Table 2). In addition, one subject had hypohidrosis. Three, three, and four subjects showed light hair, scanty hair, and scanty eyebrows, respectively. Nail dystrophy was seen in two subjects. Dry oral mucosa was observed in three subjects. One subject had both lacrimal gland dysfunction and diminished salivary secretion. The cephalometric measurements are summarized in Table 3 and depicted in Figure 2. All the subjects except subject 5 had low N-Me, N-ANS, and ANS-Me values. High N-S and low S-Ba values were commonly noted, and the N-S-Ba values varied. The SNA
values were comparable to the Japanese norm, but the SNB values were high. Further, all the subjects had maxillary first molars in higher positions than the Japanese norm (Fig. 3). Ramus inclination values were also uniformly higher than the Japanese norm. Counterclockwise rotation of the mandible was common (Fig. 3). The MPA values were low. Although the Ar-Go values were comparable to the Japanese norm, the Go-Pog values were high. All the subjects showed hypodontia; the average number of missing teeth was 9.5 (range, 5–14). Premolars were the most commonly missing teeth (Table 4). All the subjects also had enamel dysplasia (Table 5). In addition, three subjects had microdontia; subjects 1 and 4 had conical tooth. Cuspal defects were observed in four subjects. Bilateral molar occlusion was seen in five subjects, whereas subject 4 had unilateral molar occlusion. © 2014 Japanese Teratology Society
Y. Nakayama et al.
Table 1 Systemic condition
Sex Gestational age at birth (weeks) Birth height (cm) Birth weight (g) Present age (years) Present height (cm) Present weight (kg) Present head circumference (cm)
M 39 50.5 (0.68) 3,104 (0.01) 19.1 167.8 (ND) 86.0 (ND) 57.0 (ND)
Subject 3 F Unknown 46.0 (ND) 2,662 (ND) 19.3 Unknown Unknown 56.0 (ND)
37 46.0 (−0.45) 2,250 (−1.14) 14.6 144.3 (−2.37) 49.1 (−0.22) 54.5 (−0.18)
F 40 Unknown 1,800 (−3.91) 27.2 135.8 (ND) 50.0 (ND) 50.6 (ND)
F 41 50.0 (0.31) 3,046 (−0.42) 15.8 Unknown Unknown 55.0 (ND)
28 30.0 (ND) 605 (ND) 12.7 141.1 (−1.85) 34.2 (−1.21) 55.0 (−0.45)
Each individual’s birth height/weight, present height/weight and head circumference. Values in parentheses are Z scores [(measurement – Japanese norm)/SD]. Each Z score was evaluated by the gender- and age-(weeks) matched Japanese norms. ND, not determined because of the lack of age-matched Japanese norm; SD, standard deviation.
Dental anomalies Hypohidrosis Skin anomalies Light hair color Scanty hair Scanty eyebrows Nail dystrophy Lacrimal gland dysfunction Dry oral mucosa Diminished salivary secretion Inflammation in the parotid glands
+ − + − + − − + + + +
+ − + − − − − − + − +
+ − − + − + − − − − −
+ − + + + + + − − − +
+ + + − − + + − + − −
+ − + + + + − − − − −
Asthma Inner epicanthic folds Hypacusis, hearing loss Short stature Mental retardation
+ − + − −
+ + + − −
− − − + −
+ + + + −
+ − − − ±
− + − − −
+, present; −, absent; ±, suspected.
Figure 4 shows representative maxillofacial and dental characteristics found in one case with the ectodermal dysplasia. The cephalogram and profilogram shows hypoplasia of the midface, mandibular protrusion, and short facial height compared with a healthy individual (Fig. 4A). A total of 21 teeth with tooth agenesis were identified in the mandibular central incisor, the maxillary and mandibular second premolars, and second molars (Fig. 4B). Enamel dysplasia (Fig. 4C), microdontia, conical tooth, cuspal defects, and crossbite were observed (Fig. 4D).
DISCUSSION Ectodermal dysplasia was initially classified on the basis of the clinical phenotypes (Pinheiro and Freire-Maia 1994). Since the first genetic mutation (EDA) was reported (Kere et al. 1996), rapid © 2014 Japanese Teratology Society
advances were made to identify other causal genes. Many of the conditions with almost indistinguishable phenotypes involve different genes affecting closely related components of a common molecular pathway (e.g., EDA1, EDAR, and EDARADD in the NF-κB pathway) (Epstein et al. 2004; Wright et al. 2009). Nevertheless, careful clinical analysis is also essential for efficient diagnosis. All the subjects of this study were diagnosed with ectodermal dysplasia by medical and dental specialists, and none had undergone genetic testing. Yavuz et al. (2006) reported that the most frequent abnormality in ectodermal dysplasia is skin disorders (93%), followed by hair and nail disorders (86%). In HED, hypohidrosis (100%) is the most common characteristic, followed by hair disorders (91%) and dental anomalies (89%) (Kajii et al. 1998). In the present study, all the subjects had hypodontia, five had skin defects (subjects 1, 2, and
ANB (°) A – B plane (°)
Ar – Go (mm) Go – Pog (mm) Facial angle (°) SNB (°) MPA (°) Gonial angle (°) Ramus inclination (°) L – 1 to MP (°)
ANS – PNS (mm) SNA (°) U – 1 to FH (°)
N – S (mm) S – Ba (mm) N–S–Ba (°)
−2.4 (−2.14) 3.1 (2.5)
50.6 (0.24) 82.4 (1.18) 91.0 (1.03) 86.0 (2.35) 21.0 (−0.83) 124.4 (0.86) 13.5 (2.62) 86.4 (−1.15)
52.7 (−0.55) 83.6 (0.58) 105.4 (−0.63)
70.9 (2.31) 50.1 (−2.43) 129.0 (−0.60)
120.2 (−1.65) 54.2 (−2.78) 66.2 (−1.17)
−3.4 (ND) 4.2 (4.87)
44.7 (−0.54) 75.5 (0.27) 89.4 (2.26) 82.0 (3.48) 28.0 (−0.99) 131.7 (0.93) 13.7 (2.34) 86.8 (−1.18)
44.6 (−3.45) 78.6 (−0.56) 118.3 (4.78)
66.4 (1.38) 43.4 (−4.76) 130.0 (−0.72)
117.7 (−0.79) 52.2 (−0.96) 65.5 (−0.75)
4.8 (0.8) −7.2 (−0.78)
49.7 (0.45) 80.3 (1.45) 87.9 (1.01) 81.4 (0.72) 21.2 (−1.46) 119.3 (−0.64) 8.1 (1.18) 89.7 (−1.15)
55.0 (0.69) 86.1 (1.10) 103.9 (−1.31)
71.2 (2.74) 45.9 (−3.31) 132 (−0.27)
120.5 (−0.46) 54.5 (−0.38) 68.8 (−0.05)
−4.6 (−4.51) 7.4 (3.39)
48.0 (0.07) 75.7 (0.21) 95.6 (3.53) 94.3 (4.46) 29.0 (0.04) 134.2 (2.60) 15.2 (2.79) 83.5 (−2.22)
48.2 (−2.04) 89.7 (2.14) 103.4 (−1.40)
59.3 (−1.27) 43.6 (−4.26) 115.0 (−3.47)
116.3 (−1.31) 50.7 (−1.55) 66.3 (−0.56)
−1.9 (ND) 1.9 (3.86)
46.1 (0.32) 79.0 (2.85) 90.3 (2.58) 80.0 (2.28) 32.9 (0.10) 133.9 (1.53) 11.0 (1.55) 63.1 (−5.03)
43.6 (−3.47) 78.1 (−0.70) 111.0 (0.28)
63.3 (0.54) 46.8 (−2.70) 139.5 (0.93)
125.6 (1.65) 54.7 (0.50) 70.9 (0.81)
3.0 (−0.22) −6.4 (−0.55)
46.0 (−0.39) 78.1 (0.85) 88.3 (1.14) 80.2 (0.38) 21.0 (−1.49) 122.2 (−0.01) 11.1 (1.86) 84.1 (−2.12)
51.0 (−0.92) 83.2 (0.26) 108.4 (−0.49)
72.3 (3.11) 44.7 (−3.81) 127.0 (−1.21)
116.4 (−1.29) 54.4 (−0.41) 62.7 (−1.31)
A, point A; A-B plane, angle between N-Pog and A-B; ANB, angle between SNA and SNB; ANS, anterior nasal spine; ANS-Me, distance between and ANS and Me; ANS-PNS, distance between ANS and PNS; Ar, articulare; Ar-Go, distance between Ar and Go; B, point B; Ba, basion; facial angle, angle between FH plane and N-Pog; FH, Frankfort horizontal plane; Go, gonion; gonial angle, angle between MP and gonial plane; Go-Pog, distance between Go and Pog; L-1, long axis of mandibular central incisor; L-1 to MP, angle between L-1 and MP; Me, menton; MP, mandibular plane; MPA, angle between mandibular plane and FH; N, nasion; N-ANS, distance between N and ANS; N-Me, distance between N and Me; N-S, distance between N and S; N-S-Ba, angle between N, S, and Ba; PNS, posterior nasal spine; Pog, pogonion; S, sella turcica; S-Ba, distance between S and Ba; ramus inclination, complementary angle of the angle between Ar-Go and FH; SNA, angle between SN plane and N-A; SNB, angle between SN plane and N-B; U-1, long axis of maxillary central incisor; U-1 to FH, angle between U-1 and FH. Each parentheses represents Z-scores [(measurement – norm)/SD]. Each Z-score was evaluated by the gender- and age- matched Japanese norms. ND; not determined because of the lack of age-matched Japanese norm.
Maxilla – Mandible
N – Me (mm) N – ANS (mm) ANS – Me (mm)
Dental phenotype of ectodermal dysplasia 45
© 2014 Japanese Teratology Society
© 2014 Japanese Teratology Society
+ − + + + + + + + + + + 8
Mother*2 Maternal grandfather*2 Father*2
12 Mother*1 2
+, present; −, absent. *1, permanent tooth agenesis and light hair color; *2, permanent tooth agenesis.
+ + + + + + + + + + + + + − − − − − − − − − + −
+ + − − − − + + − − − + + + − + − + + + + + − +
+ + − + − − + + + + − − + + + + + + + + + + + −
+ − + + + + + + + + + + + + − + − − + + + + − −
+ + − + − + + + + + − + + + − − − − + + − − − +
+ + + + + + + + + + + +
− − + + + + − − + + + + 7
Total number of missing teeth Subject
Positions of missing permanent teeth
Maxilla Mandible Maxilla Mandible Maxilla Mandible Maxilla Mandible Maxilla Mandible Maxilla Mandible
Right Premolar Molar
− − − − − − − + − − + −
Premolar Left Incisor Incisor Fig. 3 Profilograms of the subjects with ectodermal dysplasia. The profilogram of each subject and the age- and gender-matched Japanese norms are denoted by dotted and solid lines, respectively (Sakamoto 1959).
4–6), and four had scanty eyebrows (subjects 3–6). Therefore, all had two or more typical manifestations of ectodermal dysplasia. Individuals with ectodermal dysplasia display midfacial distortion and small facial height. Lexner et al. (2007a) reported that the maxilla of HED-affected male patients and HED-heterozygous female patients were significantly shorter and retrognathic, and the facial height is small. The present subjects also exhibited short maxilla. Counterclockwise rotation of the mandible, mandibular protrusion, and small facial height were other common findings. On the other hand, SNA values were comparable to the Japanese norm. Non-syndromic severe hypodontia results in the underdevelopment of the anterior lower face, counterclockwise rotation of the mandible, and the mandibular prognathism (Nodal et al. 1994; Øgaard and Krogstad 1995) because of a lack of occlusal support. Endo et al. (2004) suggested higher positions for the maxillary first molars in non-syndromic hypodontia. In this study, hypodontia was a notable finding in all the subjects, but five had bilateral molar occlusion. Moreover, higher positions of the maxillary first molars and smaller anterior upper facial height were indicated. Therefore, the typical facial features in ectodermal dysplasia are attributable to vertical and anteroposterior growth reduction of the maxilla. Regarding the distribution of the missing teeth, Tan et al. (2011) and Vahid-Dastjerdi et al. (2010) reported that the most common tooth agenesis in non-syndromic severe hypodontia involves agenesis of the maxillary lateral incisors followed by the maxillary premolars, mandibular premolars, and mandibular lateral incisors. On the other hand, Endo et al. (2004), Endo et al. (2006), and Muller et al. (1970) suggested that the incidence of maxillary lateral incisor agenesis decreases with increasing hypodontia severity. In the present study, average number of missing teeth was 9.5, and five individuals had severe hypodontia (i.e., absence of more than six teeth, excluding the third molars). The maxillary second premolars were the most commonly missing (91.7%), followed by the man-
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Dental phenotype of ectodermal dysplasia Table 5
Dental morphologic defects and occlusion Morphologic defects
Subject 1 Subject 2 Subject 3 Subject 4 Subject 5 Subject 6
+ − − + + −
+ − − + − −
+ + − − + +
+ + + + + +
+ + + + + +
+ + + − + +
+, found; −, not found.
Fig. 4 Representative maxillofacial and dental characteristics of ectodermal dysplasia. (A) Lateral cephalogram. (B) The panoramic radiograph shows agenesis of the mandibular central incisor, maxillary and mandibular second premolars, and second molars. (C) The dental radiograph shows enamel dysplasia with thin enamel (white arrow). (D) The intraoral photographs show total crossbite, conical teeth (black arrowheads), and microdontia (white arrowheads).
dibular second premolars, maxillary first premolars, mandibular first premolars, maxillary lateral incisors, and maxillary canines, as reported previously (Endo et al. 2004; Endo et al. 2006 and Muller et al. 1970). In contrast, in ectrodactyly-ectodermal dysplasiaclefting syndrome, which is also classified as a disease of ectodermal anomalies with distal limb anomaly, cleft lip and/or palate, lacrimal duct anomalies and severe hypodontia, maxillary lateral incisors, second premolars and mandibular incisors are commonly missing (Komurasaki et al. 1997; Okamura et al. 2013). These characteristics of the missing teeth distribution might help the differential diagnosis of diversified ectodermal anomalies.
ACKNOWLEDGMENTS The authors thank Dr. Tastuo Terasima for his helpful advice on the tooth evaluation. This work was supported in part by the Global Center of Excellence (COE) Program “International Research
Center for Molecular Science in Tooth and Bone Diseases” and the Japan Society for the Promotion of Science (JSPS).
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