Orodental Manifestations in Ectodermal Dysplasia—A Review Birgitta Bergendal* National Oral Disability Centre for Rare Disorders, The Institute for Postgraduate Dental Education, Jo¨nko¨ping, Sweden Manuscript Received: 8 October 2013; Manuscript Accepted: 12 March 2014

Oral signs and symptoms are present in most ectodermal dysplasias (EDs). The aim of this article is to summarize some of the literature on current knowledge of oral manifestations and orofacial function in EDs. The review will focus on the most common forms where dental manifestations can be crucial for a differential diagnosis of ED among individuals with hypodontia and oligodontia, and preferably where the investigations included persons who had a genetically verified diagnosis. Disturbances in tooth development are common and can appear as tooth agenesis, variations in size and shape of teeth, defects in the mineralized tissues, and problems in tooth eruption. Abnormalities in number, size, and shape of teeth, and reduced salivary secretion, present in isolated oligodontia as well as in hypohidrotic ED and incontinentia pigmenti. In some more rare EDs these symptoms appear in combination with clefts of lip and/or palate in some affected individuals. Leukokeratosis in the oral mucosa presents in 70% of genetically confirmed cases of pachyonychia congenita. Also, orofacial function is often affected in ED, due to malformations, an incomplete dentition, and low salivary secretion which can compromise chewing, swallowing, and speech. In conclusion, there is a clinical overlap in oral signs and symptoms between isolated oligodontia and the most common EDs. Studies with genetically confirmed diagnoses and larger cohorts, as well as multicenter collaboration and the establishing of international registries, would create a basis for refined diagnostics, where oral examinations should be an integrated part of clinical assessment. Ó 2014 Wiley Periodicals, Inc.

Key words: ectodermal dysplasia; oligodontia; dental; saliva; orofacial function

INTRODUCTION Oral signs and symptoms are often seen in rare disorders and can be significant clues in establishing a diagnosis. A search in the WinterBaraitser Dysmorphology Database (WBDD) gives 1591 matches for the search term face, and 1,074 matches for mouth, however, the dental search terms are often nonspecific [WBDD 2.2, 2000; Bergendal et al., 2009a]. Disturbances in tooth development can appear as numerical variations, variations in size and shape of teeth, defects in the mineralized tissues, and problems in eruption [Koch et al., 2009]. All of these aberrations are seen in ectodermal dysplasias (EDs). Also orofacial function can be affected in EDs,

Ó 2014 Wiley Periodicals, Inc.

How to Cite this Article: Bergendal B. 2014. Orodental manifestations in ectodermal dysplasia—A review. Am J Med Genet Part A 9999:1–7.

due to an incomplete dentition and low salivary secretion which compromise chewing, swallowing, and speech. Member families of the National Foundation for Ectodermal Dysplasias (NFED) with different ED diagnoses, have reported to the NFED database to have abnormalities of the teeth in around 80%, and problems related to the mouth were reported as chewing problems in 57%, speech problems in 40%, and salivary problems in 37% ( Aberrations in tooth development are frequent in ED and teeth represent one of four ectodermal structures in the clinical classification suggested by Freire-Maia and co-workers [Freire-Maia, 1971; Freire-Maia and Pinheiro, 1988]. Herein, current knowledge from the literature on oral and dental signs and symptoms and orofacial function in some of the most common EDs as well as isolated oligodontia are reviewed, when possible in genetically confirmed samples.

TERMINOLOGY AND PREVALENCE OF TOOTH AGENESIS The absence of teeth is a clinical sign with a clear definition, and hypodontia can be registered with high validity. Absence of teeth has been described to occur around the extremes of the continuous variable tooth size, where a certain physiological threshold exists where decreasing tooth size changes into absence of teeth [Schalk van der Weide, 1992]. A similar model was proposed by Brook, Conflict of interest: none.  Correspondence to: Birgitta Bergendal, National Oral Disability Centre for Rare Disorders, The Institute for Postgraduate Dental Education, P.O. Box 1030, SE-551 11 Jo¨nko¨ping, Sweden. E-mail: [email protected] Article first published online in Wiley Online Library ( 00 Month 2014 DOI 10.1002/ajmg.a.36571


2 combining polygenic and environmental factors [Brook, 1984]. A polygenic mode of inheritance was recently confirmed in a study of 167 individuals with hypodontia [Vieira et al., 2013]. Variation in the number of teeth missing from agenesis can be described by different terms, which has caused confusion in the literature. According to the present version of the Glossary of Prosthodontics Terms [GPT-8, 2005], the following definitions apply: Hypodontia congenital absence of one or more, but not all, of the normal complement of teeth, Anodontia a rare dental condition characterized by congenital absence of all teeth (both deciduous and permanent). Oligodontia, also called severe hypodontia, and defined as the congenital absence of six or more permanent teeth, was suggested by Hobkirk and Brook [1980] to describe individuals with a strong need for oral habilitation. Schalk van der Weide [1992], made a stricter criterion adding that third molars should be excluded. Thus oligodontia represents a stronger clinical expression of hypodontia, and has been used in over 3,000 publications in the PubMed/Medline database (U.S. National Library of Medicine, National Institutes of Health). As an example of the lack of consistent use of definitions, the search term oligodontia in the WBDD gives 219 matches to different rare disorders. However, the search term means the congenital missing of one or more teeth [Bergendal, 2010]. In a widely used dictionary, oligodontia was defined as the “absence of many teeth, usually associated with small tooth size and other anomalies” [Dorland, 2007]. A majority of individuals with tooth agenesis miss only few teeth; in a large Danish study in more than 3,000 school children with tooth agenesis 85% were missing one or two permanent teeth [Rolling, 1980]. There is a correlation between tooth agenesis and conically shaped maxillary lateral incisors, as well as a smaller tooth size in teeth that are present [Hobkirk and Brook, 1980; Koch et al., 2009]. The prevalence of oligodontia has been found to vary between 0.084% and 0.16% in Scandinavian population based samples [Rolling and Poulsen, 2001; Nordgarden et al., 2002; Bergendal et al., 2006], or around 1–2 in 1,000 individuals, whereas hypodontia in a meta-analysis was shown to be reported in 6–10% [Polder et al., 2004], or up to 1 in 10 individuals.

OLIGODONTIA AND ECTODERMAL DYSPLASIA From the 1990s clinical studies in individuals with oligodontia have reported a high proportion of individuals with EDs. A clinical study in 167 patients with oligodontia, recruited from specialist clinics in the Netherlands, reported 53% to have isolated oligodontia, and 47% to have oligodontia as part of a syndrome or with a suspicion of a syndrome [Schalk-van der Weide et al., 1994]. Out of 48 patients (28.7%) with a defined syndrome 85.4% had ED. A Norwegian study of 68 individuals, with oligodontia referred to a resource center for rare disorders, found disturbances in hair, nails, and/or sweat production in 57% and classified them clinically as an ED-group [Nordgarden et al., 2001]. Genetic testing was not performed in these studies, and both studies comprised clinic-referred samples. In a population based Swedish sample of 8- to 21-year-olds with oligodontia, recruited from a population of near one million inhabitants, no individual with ED was identified. Genetic analyses in three genes known to cause isolated oligodontia; AXIN2, MSX1, and PAX9, and three genes known to cause hypohidrotic ED; EDA, EDAR, and EDARADD, in 93 probands

AMERICAN JOURNAL OF MEDICAL GENETICS PART A from this cohort found mutations in 10 individuals (10.8%) [Bergendal et al., 2011]. There were no differences in oral parameters when comparing individuals with and without mutations, but a family history of oligodontia was three times more frequent for probands with mutations. A Dutch study recently reported mutations in the WNT10A-gene in 56% in clinic referred patients with isolated oligodontia [van den Boogaard et al., 2012]; however, a recent analysis in the Swedish population based material found 26 probands (27.7%) with mutations in the WNT10A-gene [Arzoo et al., 2014]. Thus, genetic studies have so far disclosed the genetic cause of isolated oligodontia in 38.5% of individuals from a population based cohort. Mutations in EDA, EDAR, and EDARADD, known to cause hypohidrotic ED, have all been reported to cause also nonsyndromic hypodontia and oligodontia [Mikkola, 2009; Bergendal et al., 2011]. On group level, some differences in the dental phenotype between individuals with and without mutations associated with isolated oligodontia have been described; however, in the individual case it does not seem possible to infer what gene is mutated from the distribution or type of missing teeth. Still about 60% of cases with isolated oligodontia remain unexplained, and the vast majority of individuals with oligodontia do not have an ED or another syndrome.

ORAL AND DENTAL SIGNS IN HYPOHIDROTIC ECTODERMAL DYSPLASIA In hypohidrotic ED (HED) the four genes EDA, EDAR, EDARADD, and WNT10A were shown to account for 90% of cases [Cluzeau et al., 2011]. Still many small boys with X-linked hypohidrotic ED (XLHED) the most common form of ED, receive their diagnosis after a dental examination when no teeth erupt before 12–18 months of age, or when the first tooth appears late with an atypical form in an atypical place. Tooth agenesis is common in many different EDs, which if many teeth are missing also can affect the growth of the jaws, especially the development of the alveolar processes. In a clinically characterized material of 61 patients with HED, a tendency to develop a negative overjet with time was demonstrated [Bondarets et al., 2002]. The typical facial and oral signs and symptoms in boys affected by XLHED have been described in numerous studies, many of them case reports, but only few have used study persons with genetically confirmed diagnoses. In a Danish dissertation the material comprised individuals with confirmed mutations in the EDA-gene [Lexner, 2007]. In a study on tooth formation the study groups comprised 23 males with XLHED and 36 heterozygous females [Lexner et al., 2007b]. The mean number of missing permanent teeth in males was 22 (range 14–28) and in females 4 (range 0–22). The mean number of present teeth was five (range 0–14). Maxillary lateral incisors and first premolars, as well as all mandibular incisors and first premolars were missing in 100% of affected males. The most stable permanent teeth were the maxillary central incisors, followed in order of presence by the maxillary first molars, mandibular first molars, and canines of both jaws. Abnormal crown morphology was seen in 100% of the males and 84% of the females. All maxillary incisors in affected males were malformed, with both tapered and conical morphology. In heterozygous females, the crown morphology of the maxillary incisors was more tapered and the mandibular incisors were more conical.

BERGENDAL Taurodontism was reported in 82% in males and 67% in females, and fused roots in 45% and 53%, respectively. In boys with XLHED the order of eruption is often different and the time of eruption of the first primary teeth is often late (Fig. 1). The first tooth usually appears in the incisor region of the maxilla with a pointed tip of the crown (Fig. 2a). The permanent canines can have a tilted horizontal position in the frontal part of the mandible which compromises eruption (Fig. 2b). In a material of 13 patients with ED where all permanent teeth had erupted, primary canines and second molars were the teeth that most often persisted when there was no permanent successor [Prager et al., 2006]. Maxillary primary canines can erupt late and be very stable, and perform in between a primary and a permanent tooth, sometimes called hybrid teeth. However, it is not possible to predict for how long they will persist. A study in 27 patients with HED from 24 unrelated families with mutations in the EDA- or EDAR-genes systematically found a more severe oligodontia in the mandible than in the maxilla in the primary as well as the permanent dentition [Clauss et al., 2010]. Examinations of salivary secretion in the Danish material were performed using the draining method, where normal values are >0.25 ml/min and very low values are T mutation in the EDAR-gene [Lind et al., 2006] and oral examinations in 15 individuals showed that all had hypodontia and were missing 3–16 permanent teeth. A common sign in all

FIG. 1. Newly erupted conical primary maxillary central incisors in 2-year-old boy with XLHED, and no erupted teeth in the mandible.


FIG. 2. a,b: Erupting permanent maxillary central incisors in 7year-old boy with XLHED with agenesis of 19 permanent teeth. Note horizontally placed mandibular canines.

affected individuals was agenesis of some of the permanent mandibular incisors. EDARADD-induced HED is much less frequent and the dental phenotype is incompletely known. WNT10A- mutations were reported in 12 patients with a phenotype ranging from isolated oligodontia to odonto-onycho-dermal dysplasia, OODD [Bohring et al., 2009]. Typical symptoms in OODD included hair and nail abnormalities and, less frequently, palmoplantar hyperkeratosis, and hyperhidrosis. The most specific diagnostic criterion was missing permanent teeth. Ten dentate individuals were reported with oligodontia and a mean of 18 missing permanent teeth, third molars excluded (range ¼ 10–28). An example of a girl with biallelic mutations in the WNT10A-gene and no permanent teeth is shown in Figure 3. In a study of 36 referred patients with mild signs of ED who tested negative for EDA, molecular screening identified WNT10A-mutations in 44%, and EDAR-mutations in 14% [Plaisancie et al., 2013]. Mutations in the WNT10A-gene were associated with a phenotype with oligodontia and in some cases minor signs of ED.

ORAL AND DENTAL SIGNS IN INCONTINENTIA PIGMENTI In a project aiming at establishing a comprehensive care program, 30 individuals, 29 female and one male from 17 families, with a clinical diagnosis of incontinentia pigmenti, IP, were recruited



FIG. 3. Panoramic radiograph of 9-year-old girl with WNT10Aassociated ED, with a primary dentition and agenesis of all permanent teeth.

from pediatric and habilitation clinics all over Sweden [Holmstrom et al., 2002]. The diagnosis was confirmed by examinations by a multidisciplinary team of specialists in medicine and dentistry. All had typical dermatological manifestations, and neurological symptoms were registered in 31%. Twenty-three (77%) had abnormalities of the eyes; 13 (43%) had serious or vision-threatening manifestations, out of which seven were blind on one eye [Holmstrom and Thoren, 2000]. Oral examinations comprised a panoramic radiograph and clinical oral examination including testing of salivary secretion (Unpublished data). The mean number of missing permanent teeth in 26 examined individuals was 5.9 (median ¼ 5, range ¼ 0–18). Eleven (42%) had oligodontia, while four (15%) had no agenesis of permanent teeth. Aberrations in tooth shape were seen in all individuals, such as conical and tapered maxillary incisors, which in a few cases also had incisal notching and talon cusps (Fig. 4a–e). Many of the permanent canines were tapered, often to a concave shape on one or both sides corresponding to the approximal lobes of the crown. In 23 individuals who could comply with testing of chewing-stimulated whole saliva, the mean salivary secretion rate was 0.9 ml/min (range 0.3–2.2). Ten individuals (43%) had lower salivary secretion than normal (

Orodental manifestations in ectodermal dysplasia-a review.

Oral signs and symptoms are present in most ectodermal dysplasias (EDs). The aim of this article is to summarize some of the literature on current kno...
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