J CRITICAL
Dent Res 87(12) 2008
REVIEWS IN ORALDento-Craniofacial
BIOLOGY &Phenotypes
MEDICINE
Dento-Craniofacial Phenotypes and Underlying Molecular
Mechanisms in Hypohidrotic Ectodermal Dysplasia (HED):
a Review
F. Clauss1,4*, M.-C. Manière1, F. Obry1,
E. Waltmann1, S. Hadj-Rabia2, C. Bodemer2,
Y. Alembik3, H. Lesot4, and M. Schmittbuhl1,4
1Department of Pediatric Dentistry, Dental Faculty, Louis Pasteur
University, National French Reference Center for Dental Manifestations
of Rare Diseases, University Hospital, 1, place de l’Hôpital, F-67000
Strasbourg, France; 2Department of Dermatology, National French
Reference Center for Genodermatosis, Necker-Enfants Malades Hospital,
AP-HP, University Descartes-Paris V, France; 3Department of Medical
Genetics, University Hospital, Strasbourg, France; and 4INSERM UMR
595, Dental Faculty, Louis Pasteur University, Strasbourg, France;
*corresponding author, francois.clauss@chru-strasbourg.fr
J Dent Res 87(12):1089-1099, 2008
ABSTRACT
The hypohidrotic ectodermal dysplasias (HED) belong to a
large and heterogenous nosological group of polymalfomative
syndromes characterized by dystrophy or agenesis of
ectodermal derivatives. Molecular etiologies of HED consist
of mutations of the genes involved in the Ectodysplasin
(EDA)-NF-kB pathway. Besides the classic ectodermal
signs, craniofacial and bone manifestations are associated
with the phenotypic spectrum of HED. The dental phenotype
of HED consists of various degrees of oligodontia with
other dental abnormalities, and these are important in the
early diagnosis and identification of persons with HED.
Phenotypic dental markers of heterozygous females for EDA
gene mutation—moderate oligodontia, conical incisors,
and delayed dental eruption—are important for individuals
giving reliable genetic counseling. Some dental ageneses
observed in HED are also encountered in non-syndromic
oligodontia. These clinical similarities may reflect possible
interactions between homeobox genes implicated in early
steps of odontogenesis and the Ectodysplasin (EDA)-NF-
kB pathway. Craniofacial dysmorphologies and bone
structural anomalies are also associated with the phenotypic
spectrum of persons with HED patients. The corresponding
molecular mechanisms involve altered interactions between
the EDA-NF-kB pathway and signaling molecules essential
in skeletogenic neural crest cell differentiation, migration,
and osteoclastic differentiation. Regarding oral treatment
of persons with HED, implant-supported prostheses are
used with a relatively high implant survival rate. Recently,
groundbreaking experimental approaches with recombinant
EDA or transgenesis of EDA-A1 were developed from the
perspective of systemic treatment and appear very promising.
All these clinical observations and molecular data allow for
the specification of the craniofacial phenotypic spectrum in
HED and provide a better understanding of the mechanisms
involved in the pathogenesis of this syndrome.
Key words: Hypohidrotic ectodermal dysplasia, cranio­
facial dysmorphologies, bone density, NF-kB pathway.
Received February 8, 2008; Last revision May 9, 2008; Accepted
July 8, 2008
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in HED
1089
Background, purpose, and perspectives
T he hypohidrotic ectodermal dysplasias (HED) form a large and
complex nosological group of congenital disorders, involving
all the Mendelian modes of inheritance, and are characterized by
the pathological development and morphogenesis of ectodermal
structures (Pinheiro and Freire-Maia, 1994; Priolo and Lagana,
2001; Lamartine, 2003; Itin and Fistarol, 2004). The main
syndromes of HED and their associated clinical signs and genetic
defects are summarized in Table 1. The most prevalent form of
HED is X-linked hypohidrotic ectodermal dysplasia (XLHED),
and autosomal forms of the disorder are also found with a lower
frequency (Vincent et al., 2001; Lind et al., 2006; Van der Hout et
al., 2008).
Molecular etiologies of HED consist of mutations of the genes
involved in the Ectodysplasin (EDA)-NF-kB pathway. XLHED
corresponds to mutations of the EDA gene (Kere et al., 1996;
Schneider et al., 2001; Vincent et al., 2001; RamaDevi et al., 2008).
Autosomal-dominant and -recessive forms of HED involve both
EDA Receptor and EDA Receptor-associated Death-Domain genes
(EDAR and EDARADD) (Chassaing et al., 2006; Bal et al., 2007;
Van der Hout et al., 2008). Syndromic HED with immunodeficiency
and osteopetrosis is associated with mutations in NF-kB Essential
Modulator gene (NEMO) encoding Inhibitor Kappa Kinase g
sub-unit (IKKg) (Dupuis-Girod et al., 2002; Vinolo et al., 2006)
(Table 1). EDA is a member of the Tumor Necrosis Factor (TNF)
family, activating the NF-kB and Jun N-terminal Kinase (JNK)/
c-jun/c-fos pathways (Kere et al., 1996; Mikkola et al., 1999;
Cui et al., 2002) (Fig. 1). This collagenous protein is implicated
in ectodermal structure and morphogenesis (Kere et al., 1996;
Montonen et al., 1998), but is also implicated in osteogenesis
(Montonen et al., 1998). Functional interactions between EDA and
factors involved in migratory neural crest cell differentiation as Wnt
or BMP-Msx have been described and underline the role of the EDA
signaling pathway in craniofacial patterning and growth (Laurikkala
et al., 2001; Pummila et al., 2007). The NF-kB transcriptional
factor is essential in a wide range of cellular processes, especially
osteoclastic differentiation, through Receptor Activator NF-kB
(RANK) signaling (Franzoso et al., 1997; Galibert et al., 1998;
Asagiri and Takayanagi, 2007), and thus alterations of this complex
lead to bone phenotypic modifications (Fig. 1).
The purposes of this review are to state precisely the dento-
craniofacial and bone phenotypes associated with HED, from both
an analysis of the literature and from persons with HED, and also
to point out the molecular mechanisms underlying these anomalies
from recent progress in the understanding of the EDA-NF-kB
pathway.
PERSONs & methods
Information for this review was gathered from the presentation of
different individuals examined in the National French Reference
Center for Dental Manifestations of Rare Diseases at the Strasbourg
University Hospital (France). Of the 11 persons presenting,
all but the heterozygous female exhibited the classic features
1089
1090 Clauss et al. J Dent Res 87(12) 2008

Table 1. Summary of the Main HED Syndromes

Disease Clinical Manifestations Genetic Etiologies

X-linked HED (XLHED) Alopecia, reduced number and dysfunction of sweat glands and Ectodysplasin (EDA) gene
mucous glands, oligodontia, dystrophic nails, hypoplastic skin,
craniofacial dysmorphic features.
Autosomal dominant and Same clinical signs as XLHED EDA Receptor (EDAR) and EDA Receptor
recessive forms of HED Less severe signs in autosomal-dominant forms of HED. Associated Death-Domain (EDARADD) genes
XLHED with immunodeficiency Ectodermal signs associated with immunodeficiency. NF-kB Essential Modulator (NEMO) gene
Osteopetrosis-lymphoedema-HED Ectodermal signs associated with osteopetrosis, lymphedema NEMO gene
and immunodeficiency.
Incontinentia pigmenti Ectodermal signs with skin lesions, neurological and retinal defects NEMO gene

Data derived from Pinheiro and Freire-Maia (1994), Priolo and Lagana (2001), Lamartine (2003), Itin and Fistarol (2004), Jonhson et al. (2002), Bal
et al. (2007), Dupuis-Girod et al. (2002).

of the XLHED phenotype. A rigorous clinical examination Epidemiological data and dental
was performed for each person, completed by photographs, phenotype analyses in PERSONS WITH HED
radiographs (panoramic, lateral projection, and, when possible, The differential dental phenotypic expressions of the genetic
CT examination), plaster casts, and molecular diagnosis (EDA defects associated with HED will be presented below.
gene sequencing). An overview of the main characteristics of
the persons with XLHED (sex, age, and genotype) is given in Tooth Number Anomalies
Table 2. Anomalies in Males Affected with X-linked HED
Primary Dentition
An average of 3.50 missing
teeth in the maxilla and 5.33
mandibular missing teeth has
been described (Barberia et al.,
2006) (Fig. 2a). This maxillary
and mandibular hypodontia in the
primary dentition of persons with
HED differs from non-syndromic
hypodontia, which exhibits an
opposite maxillary-mandibular
distribution of dental agenesis,
i.e., an average of 1.62 ageneses of
maxillary teeth vs. 0.25 mandibular
missing teeth (Barberia et al.,
2006). This maxillary-mandibular
discrepancy between HED and
non-syndromic hypodontia reveals
a more important disorder of the
molecular mechanisms responsible
for mandibular odontogenesis in
HED. Homeobox genes involved
in the patterning of the mandibular
odontogenic ectomesenchyme,
such as Msx-1, Msx-2, or Distal-
less Homeobox-2 (Dlx-2) and
Figure 1. Original overview of the main molecular interactions between the EDA pathway and the BMP-
belonging to the odontogenic
Msx, RANK-TRAF6-NF-kB, FGF, Wnt, and Activin-b pathways implicated in dental, craniofacial, and homeobox gene code (Jowett et al.,
bone phenotypes associated with HED. EDA activates NF-kB factor via its Receptor EDAR interacting 1993; Thomas and Sharpe, 1998),
with TRAF6, TAK1 Binding protein 2 (TAB2), TGF-b Activating Kinase 1 (TAK1) adapter molecules, and seem to be more influenced by
NEMO-IKKa/IKKb. Phosphorylation of the inhibitor factor IkB by IKKa/IKKb leads to its proteasomic
degradation and to the nuclear translocation of the dimeric NF-kB factor. NF-kB factor is involved in
EDA mutation. The most frequent
regulation of osteoclastic differentiation and ectodermal morphogenesis via Sonic Hedgehog (Shh) factor, tooth ageneses, with decreasing
Cyclin-D1, and Nuclear Factor of Activated T-cells (NFAT-1/2). Interactions between EDA-NF-kB and prevalence, are the mandibular
BMP-Msx are mediated by Ccn2-Connective Tissue Growth Factor (CTGF)/Follistatin BMP inhibitors. FGF incisors, lateral maxillary
activates Msx1-Pax9 expression via NF-kB factor. Functional interactions between EDA and RANKL-
RANK pathways are established through TRAF6 and NF-kB factors. EDA and EDAR transcriptions are
incisors, central maxillary
up-regulated by Wnt-b-catenin-Lef1 and Activin-b-smad pathways, respectively. incisors, mandibular molars, and
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J Dent Res 87(12) 2008 Dento-Craniofacial Phenotypes in HED 1091

maxillary first molars (Vierucci et Table 2. Characteristics of Persons with XLHED Treated in the National French Reference Center for
al., 1994; Ruhin et al., 2001; Tarjan Dental Manifestations of Rare Diseases at the Strasbourg University Hospital (France)
et al., 2005). Anodontia—congenital
absence of primary and permanent Sex Age Genotype Figure
teeth—was also encountered in HED
(Beliakov et al., 1998; Acikgoz et al., Patient 1 male 4 yrs old c.756T>G exon 7 mutation of EDA gene Fig. 2a
2007), and corresponds to the most (alteration of EDA TNF homology sub-domain)
severe phenotype. Dental hypodontia Patient 2 male 35 yrs old Exon 3 deletion of EDA gene (alteration of Figs. 2b, 2c
or anodontia in the primary dentition EDA proteolytic cleavage site)
of persons with HED is a clinical Patient 3 female 41 yrs old Heterozygous for a 9-bp exon 8 deletion of Fig. 2d
predictor that should lead to further EDA gene (alteration of EDA TNF sub-domain) Fig. 3b
investigation (radiographic examination Patient 4 male 4 yrs old EDA gene exon 8 mutation Fig. 2e
and molecular analyses). Patient 5 male 7 yrs old EDA gene exon 3 mutation Fig. 2f
Patient 6 male 7 yrs old EDA gene exon 1 mutation (alteration of Fig. 2g
Permanent Dentition
EDA intracellular-transmembrane domain) Fig. 3d
Dental ageneses range between 11.2 Patient 7 male 6 yrs old R156C EDA gene exon 3 mutation Fig. 3a
and 16.4 absent teeth (Barberia et al., Patient 8 male 51 yrs old c.754C>A exon 7 mutation of EDA gene Fig. 3c
2006; Prager et al., 2006) (Figs. 2b, Fig. 3e
2c). In a sample of 30 persons with Patient 9 male 27 yrs old Undetermined genotype Fig. 3g
HED, oligodontia (absence of at least
6 teeth) and hypodontia occurred,
respectively, in 83% and 17% of
individuals (Prager et al., 2006). A
more severe dental phenotype was anodontia, present in 12% of
persons with HED, and oligodontia in all such persons has also
been reported (Yavuz et al., 2006). Frequency of tooth agenesis
seems to be higher for mandibular teeth than for maxillary
teeth (respectively, 7.9 and 6.8 missing teeth) (Prager et al.,
2006) (Fig. 2b). This more severe phenotype in the mandible
could be linked to specific effects of the EDA mutation that
may affect mandibular tooth organogenesis preferentially. The
most frequent missing teeth, in order of frequency, are: (in the
maxilla) lateral incisors (86%), second premolars (66%), and
second molars (53%); and (in the mandible) central incisors
(83%), lateral incisors (73%), second premolars (70%), and
second molars (53%) (Prager et al., 2006) (Fig. 2b). From these
clinical observations, the most posterior teeth of the incisor,
premolar, and molar series seem to be preferentially affected
by the EDA mutation, except for the mandibular central incisor
(Prager et al., 2006). The permanent teeth most likely to be
present are the maxillary central incisors (42%), maxillary first
molars (41%), mandibular first molars (39%), and maxillary
canines (22%) (Guckes et al., 1998). Some dental ageneses
observed in HED are also encountered in non-syndromic
oligodontia related to mutations of homeobox genes such as
Muscle Segment Homeobox-1 (Msx-1) and Paired Homeobox-9
genes (Pax-9) (Vastardis et al., 1996; Arte et al., 2001). The
similarities observed in dental agenesis may thus underline the
Figure 2. Dental phenotypes associated with XLHED (patients treated in
possible interactions between these genes and the Ectodysplasin the National French Reference Center for Rare Diseases, Strasbourg,
(EDA)-NF-kB pathway (Tucker et al., 1998; Ogawa et al., France). (a-c) Oligodontia in primary and permanent dentitions.
2006; Pummila et al., 2007). (a) The phenotype in the primary dentition consists of agenesis of
mandibular incisors and first primary molars, with absence of maxillary
Anomalies in Female Carriers of X-linked HED lateral primary and permanent incisors and the first left primary
Dental phenotype variability has been described in HED molar. (b-c) Permanent dentition lacking maxillary lateral incisors,
premolars, and molars (except for the right first molar), associated
heterozygous females, with moderate oligodontia (Fig. 2d)
with severe mandibular oligodontia (with only canines present). (d)
and delayed dental eruption observed in our department and Heterozygous female exhibiting lateral incisor agenesis, and slightly
reported in the literature (Cambiaghi et al., 2000; Nishibu et conical mandibular canines. (e-g) Different dental phenotypes
al., 2003; Lexner et al., 2007a). A higher frequency of dental observed in various mutations of the EDA gene. (e) Severe phenotype
agenesis was found in heterozygous HED females, particularly with mandibular anodontia and maxillary oligodontia, dysmorphic
developing permanent tooth germs of central maxillary incisors, and
involving the maxillary lateral incisors, mandibular incisors, dysmorphic primary canines (EDA gene exon 8 mutation). (f-g) Mild
and first molars; for these patients, the frequency of agenesis phenotypes with different degrees of oligodontia and taurodontism
ranged between 1 and 7 missing teeth (Cambiaghi et al., 2000; (respectively, EDA gene exon 3 and exon 1 mutations).

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1092 Clauss et al. J Dent Res 87(12) 2008
Nishibu et al., 2003; Lin et al., 2004; Lexner et al., 2007a). HED
heterozygous females thus exhibited moderate dental agenesis
(Fig. 2d) compared with that observed in homozygous females,
because of the X-chromosome inactivation—a frequency of 11.8
tooth ageneses being observed in the most severe phenotypes
associated with homozygous female patients (Visinoni et al.,
2003; Prager et al., 2006). However, no correlations were
established between the pattern of X-chromosome inactivation
and the frequency of agenesis (Vincent et al., 2001). Oligodontia
in the primary dentition encountered in females might predict an
EDA gene mutation at a probability of 1/50. In the permanent
dentition, this clinical feature could suggest an EDA mutation in
1/500 cases (Spfaer, 1981). Oligodontia in the primary dentition
appears to be an important clinical predictor sign of the EDA
mutation in females (Na et al., 2004). These dental phenotypic
manifestations thus play a crucial role in the detection and
diagnosis of EDA mutation female carriers and should lead to
further clinical, radiographic, and molecular investigation.
Anomalies in Autosomal Forms of HED
Dental phenotypic manifestations in the primary and permanent
dentitions of HED autosomal-dominant and -recessive forms
are associated with the EDAR-EDA Receptor Associated Death-
Domain (EDARADD) gene mutations (Aswegan et al., 1997;
Kobielak et al., 2001a; Chassaing et al., 2006; Bal et al., 2007,
RamaDevi et al., 2008; Van der Hout et al., 2008) and are also
characterized by multiple missing teeth (Aswegan et al., 1997).
In the permanent dentition, ageneses of mandibular incisors seem
to be encountered with a high prevalence. Agenesis of maxillary
incisors and agenesis of canines and premolars also occur with
decreasing prevalence (Aswegan et al., 1997). However, the
oligodontia is more severe in the autosomal-recessive than in
-dominant forms of HED (Chassaing et al., 2006; Van der Hout
et al., 2008). If both maxillary incisor and canine ageneses in the
HED autosomal forms are confirmed by epidemiologic survey,
this clinical sign would provide an interesting phenotypic marker
of the EDAR mutation.
Dental Dysmorphic Features Associated with HED
Anomalies in Males Affected with X-linked HED
Tooth dysmorphologies are associated with HED, and are
induced by alterations of the EDA-EDAR-NF-kB pathway
morphogenetic functions during odontogenesis (Pispa et
al., 2004; Tucker et al., 2004; Tariq et al., 2007a,b) (Figs.
2c-2e). Microdontia and cone-shaped teeth were frequent
morphological features observed in affected individuals (Fig.
2c) (Ruhin et al., 2001). Crown form abnormalities have been
found in both primary and permanent dentitions (Prager et al.,
2006), and most frequently involve the anterior maxillary teeth
(Yavuz et al., 2006). The conical crown results from the largest
mesio-distal diameter being displaced apically (Crawford
et al., 1991). Moderate to severe taurodontism is known to
affect preferentially the second primary mandibular molars in
some individuals with HED (Jorgenson, 1982; Crawford et
al., 1991; Glavina et al., 2001) (Figs. 2f, 2g). Nevertheless,
this feature is also found in permanent molars and provides
a dental marker of developmental abnormality (Figs. 2f,
2g). Taurodontism may result from abnormal mesodermal-
ectodermal interactions linked to EDA mutations (Ruhin et
al., 2001). Other dental dysmorphologies are also observed in
HED. Root shape abnormalities are depicted in 30% of HED
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cases; external root resorption is present in 15% of children
with HED (Yavuz et al., 2006). Persistence of primary teeth,
especially second primary molars and canines, corresponds to
another abnormality (Yavuz et al., 2006). Enamel dysplasias
linked to alterations in ameloblast cytodifferentiation (Ruhin
et al., 2001) are also observed in EDA mutation. These clinical
manifestations are also encountered in the Tabby mouse model
(XLHED experimental model) (Risnes et al., 2005).
Anomalies in Female Carriers of X-linked HED
Cone-shaped incisors and microdontia are associated with EDA
mutation heterozygous females (Lexner et al., 2007a) (Fig. 2d).
A reduction in molar mesio-distal dimensions is observed in
EDA mutation heterozygous females, which might be another
interesting dental phenotypic marker of an EDA mutation gene
carrier (Cambiaghi et al., 2000; Nishibu et al., 2003; Lexner
et al., 2007a). These tooth morphological anomalies provide
clinical criteria for the detection of female carriers of the EDA
mutation (Glavina et al., 2001) and should be considered in
genetic counseling.
The genotypic heterogeneity in XLHED:
a pathway toward dental phenotype
variablity
A variablity affecting various exons of the EDA locus has been
described in XLHED (Kobielak et al., 2001b; Schneider et al.,
2001; Hashiguchi et al., 2003; Lin et al., 2004; Huang et al.,
2006; RamaDevi et al., 2008). The most prevalent mutations
were located between exons 3 and 9 of the EDA locus (94.4%)
(Monreal et al., 1998); they clustered preferentially in three
functionally important molecular domains of EDA-A1 isoform:
(1) the extracellular TNF homology sub-domain necessary for
receptor binding, which corresponds to exons 7-9 (Tariq et al.,
2007a; RamaDevi et al., 2008); (2) the collagen sub-domain
(exons 5-6); and (3) the proteolytic cleavage site for a furin
protease (exon 3) (Pääkkönen et al., 2001; Schneider et al.,
2001). Rare mutations involve exon 1 and affect intracellular,
transmembrane, and extracellular domains of EDA-A1 (Kere
et al., 1996; Ferguson et al., 1998; Hashiguchi et al., 2003).
Different phenotypic expressions seem to be found in persons
affected by these various mutations (Figs. 2e, 2f, 2g). A milder
phenotype, including moderate oligodontia and absence of both
dermatological manifestations and infectious susceptibility,
was observed in a mutation of exon 9 (Hashiguchi et al., 2003).
A similar expression characterized by moderate oligodontia,
hypotrichosis, and hypohydrosis was found in EDA gene exon
1 mutation. However, hypodontia can be the only phenotypic
manifestation associated with a substitution mutation of
exon 1 (Schneider et al., 2001). The more classic phenotype
of XLHED, with dental abnormalities, hypohydrosis, and
craniofacial dysmorphologies, was also linked to mutated
exons 5 and 6 (Vincent et al., 2001). As indicated by these
observations, the genetic variability seems to lead to various
dental phenotypes in XLHED (Figs. 2e, 2f, 2g). More precise
dental phenotypic analyses could, therefore, allow for a better
understanding of the genetic influence on the etiopathogenesis
of tooth anomalies in XLHED.
Molecular mechanisms underlying dental
abnormalities in HED
Specific interactions between EDA and BMP signaling
J Dent Res 87(12) 2008 Dento-Craniofacial Phenotypes in HED 1093

have been demonstrated

(Pummila et al., 2007). EDA
induces the expression of two
BMP inhibitors, Ccn2/Ctgf
(Cyr61 CTGF Nov family
protein 2/connective tissue
growth factor) and follistatin
(Pummila et al., 2007) (Fig.
1). Nevertheless, an important
decrease in BMP expression is
required for placodal ectoderm
formation and neural crest
cell differentiation; these two
cellular groups are involved in
the initial steps of odontogenesis
(Tucker et al., 1998; Zhang
et al., 2003). The homeobox
genes Msx-1 and Msx-2 are
downstream components of
the BMP signaling pathway,
and are, respectively, involved
in the early differentiation of
maxillary incisor and molar
mesenchyme from neural-crest
cells (Bei and Maas, 1998;
Bei et al., 2000; Lidral and
Reising, 2002; Han et al., 2003;
Ramos and Robert, 2005). EDA
mutations are therefore likely to
alter EDA-BMP-Msx molecular
interactions, and could be
responsible for the disturbance
of odontogenesis.
The possibility for
convergence between EDA and
Fibroblast Growth Factor (FGF)
signaling pathways may be
evoked in normal odontogenesis
(Pispa et al., 1999) (Fig. 1). The
NF-kB heterotrimeric factor was
recently observed to mediate
FGF signaling and, particularly,
the FGF regulation of Msx-1
mesenchymal expression (Bei
and Maas, 1998; Bushdid et
al., 2001). In the Tabby mouse,
the FGF (Fgf-3 and Fgf-10)
level of expression appeared
to be decreased in the dental
mesenchyme, and Fgf-4 was
reduced in the enamel knot
of the molar cap (Pispa et al.,
1999). Fgf-10 has been shown to
stimulate cell division in dental
epithelium, and Fgf-4 stimulates Figure 3. Craniofacial and bone phenotypes associated with XLHED (persons treated in the National French
Reference Center for Rare Diseases, Strasbourg, France). (a-c) Craniofacial differences between persons with
cell proliferation in both dental XLHED and healthy individuals, highlighted by cephalometric radiographic analyses: (a) XLHED child, (b)
epithelial and mesenchymal heterozygous female, (c) XLHED adult. For each measurement, values are given for both persons with HED and
tissues (Jernvall et al., 1994; control individuals. Data from the control sample are derived from Johnson et al. (2002). Linear measurements
Kettunen and Thesleff, 1998). are expressed in mm and angles in degrees. (d-g) Bone structural changes in XLHED. Orthoradial CT slices of
the mandible showing (d) enlargement of the bone thickness and (e) hypermineralization of the medullary bone.
Alterations of FGF signaling (f-g) Bone densitometric profile. (f) Control individual: low density (D3-D4) in medullary bone (Lekholm, 1986)
induce defective development and higher density for mandibular cortex (D2-D1); (g) person with XLHED: characteristic hypermineralization of
of Tabby tooth germs, leading medullary bone (D2-D1) in the mandibular symphyseal area.
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1094 Clauss et al. J Dent Res 87(12) 2008
to an absence of anteroconid and hypoconulid cusps as well as
third molars (Pispa et al., 1999). Interestingly, a partial recovery
of morphogenesis associated with a stimulation of additional
cusp development was obtained in cultured Tabby molars by the
addition of exogenous Fgf-10 (Pispa et al., 1999).
The Ectodysplasin/NF-kB signaling pathway thus appears
to be involved in tooth growth and morphogenesis at different
stages during development (Laurikkala et al., 2001; Courtney
et al., 2005). Furthermore, the disturbance of this pathway
could lead to the dental phenotypic abnormalities associated
with HED.
Craniofacial-specific traits in PERSONS
WITH XLHED
Craniofacial dysmorphologies associated with HED have been
documented by several studies, but their precise descriptions
remain rare, since these studies were limited to case reports and
a few cephalometric studies (Johnson et al., 2002; Bondarets
et al., 2002; Ferrario et al., 2004; Yavuz et al., 2006; Arslan
et al., 2007, Lexner et al., 2007b). The classic craniofacial
dysmorphic features described in HED include maxillary
hypoplasia, mandibular prognathism, facial concavity, a
depressed nasal bridge, and growth alteration of the cranial
base (Figs. 3a-3c) (Ruhin et al., 2001; Bondarets et al., 2002;
Johnson et al., 2002, Arslan et al., 2007; Lexner et al., 2007b).
Frontal prominence, reduced facial height (Figs. 3a-3c), cranial
vertex hypoplasia, retroclined nasal bone, and antimongoloid
slant of the eyes are other reported craniofacial phenotypic
manifestations (Ruhin et al., 2001; Alcan et al., 2006; Lexner
et al., 2007b). Maxillary hypoplasia consists of reduced length
and height of this bone. Maxillary hypodevelopment seems to
be accentuated during growth, as indicated by the increasing
age-dependent differences in the maxillary dimensions for
persons with HED compared with healthy individuals (Johnson
et al., 2002). Angular measurements describing the sagittal
position of the maxilla (Sella turcica-Nasion-A point: SNA,
Anterior Nasal Spine-Nasion-Sella turcica: ANS-Na-S)
confirm this morphological tendency (Bondarets et al., 2002)
(Figs. 3a-3c). The retrognathism of the maxilla appears to be
the most striking craniofacial feature, whatever the degree
of hypodontia in XLHED males or heterozygous females
(Figs. 3a-3c). The transverse dimension of the maxilla is also
reduced (Saksena and Bixler, 1990). Interestingly, the palatal
width is not affected (Dellavia et al., 2006). In some persons,
the mandible exhibited a decreased length of the body (Fig.
3a); despite this, it presents an increased relative prognathic
position compared with the midface, as indicated by the angle
Pogonion-Nasion-Sella turcica (Pog-Na-S) (Fig. 3c) and the
distance S-Pog (Bondarets et al., 2002; Johnson et al., 2002).
On the whole, these cephalometric analyses of persons with
HED indicated a class III tendency (Lexner et al., 2007b)
(Figs. 3a-3c). In a transverse plane, the lower facial width
(bigonial diameter Gonion-Gonion: Go-Go) demonstrated
a reduced value compared with that in control individuals
(Saksena and Bixler, 1990). Facial vertical dimensions were
affected in HED, and the total anterior face height (Nasion-
Menton: Na-Me), lower anterior face height (ANS-Me), and
upper anterior face height (Na-ANS) were reduced in children
and adolescent groups (Johnson et al., 2002) (Fig. 3a). These
differences seem to decrease in adults, since they were all
within normal limits (Johnson et al., 2002). The cranial base
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International and American Associations for Dental Research
is also severely affected in HED, as indicated by the abnormal
anterior and posterior cranial base lengths (respectively, S-Na
and Basion-S: Ba-S). While the anterior cranial base exhibits
a tendency to hypoplasia, the posterior cranial base undergoes
an anteroposterior hyperplasia (Figs. 3a-3c), an increased
deviation from the norm for the corresponding length being
registered (51.9 mm vs. 43.8 mm at ages 13-17 yrs) (Johnson
et al., 2002). Nevertheless, the total cranial base length seems
to be within normal limits in some adults with HED, revealing
a form of reciprocal compensation between the two areas of the
cranial base (Johnson et al., 2002). The flexure of the cranial
base is abnormally emphasized in HED, as demonstrated by the
progressive reduction of the angle Ba-S-Na (123.5° vs. 128.1°,
respectively, in adults with HED and healthy individuals)
(Johnson et al., 2002) (Fig. 3c). Moreover, a narrow cranial
base seems to be another craniofacial change observed in
HED (Skrinjarić et al., 2003). Paranasal sinuses sometimes
exhibit abnormal size variations in HED. Cases of reduced
frontal sinuses as well as cases of hypertrophic maxillary
sinuses have been reported (Ruhin et al., 2001). Nevertheless,
all the previous craniofacial abnormalities were probably
underestimated when the cephalometric measurements were
referred to Riolo’s cephalometric standards (1974) instead of
Johnson’s. For example, the mean length of the maxilla (ANS-
PNS) in children with HED children (5-12 yrs) was 42.1 mm,
compared with 44.8 mm by Johnson’s standards and 53.4 mm
by Riolo’s.
Heterozygous females, carriers of XLHED, also exhibit
craniofacial phenotypic features that can be severe, despite a
moderate dental phenotype (Saksena and Bixler, 1990) (Fig.
3b). Maxillary hypoplasia, mandibular hypoplasia, midface
hypoplasia, everted lips, saddle nose, and abnormal anterior
and total cranial base lengths can also be found (Cambiaghi
et al., 2000) (Fig. 3b). A prognathic mandible can also be
associated with the phenotype of heterozygous females for
EDA mutation, characterized by an increase in the Pog-Na-S
angular measurement (Fig. 3b). These craniofacial traits could
be considered as important clinical predictor signs contributing
to reliable genetic counseling leading to the diagnosis and
identification of heterozygous female carriers of the EDA gene
mutation.
The improvement in masticatory function through early
implant treatment and prosthesis allows for a partial recovery
of facial growth and provides a limited rescue of the associated
dysmorphology, as demonstrated by the slightly more
normative cephalometric features in treated persons (Boj et al.,
1993; Franchi et al., 1998; Johnson et al., 2002; Alcan et al.,
2006).
These observations emphasize the major role of genetic
factors in craniofacial development associated with XLHED.
Craniofacial features in PERSONS
WITH autosomal HED
In autosomal forms of HED, a craniofacial phenotypic
variability seems to be linked to different mutation sites
(Chassaing et al., 2006; Bal et al., 2007). Indeed, genetic
defects in autosomal-dominant and -recessive HED can
involve both EDAR and EDARADD genes (Bal et al., 2007;
RamaDevi et al., 2008; Van der Hout et al., 2008). Severe
craniofacial abnormalities with prominent forehead, depressed
nasal bridge, and small nose have been reported in autosomal-
J Dent Res 87(12) 2008 Dento-Craniofacial Phenotypes in HED 1095
recessive EDAR mutations (Chassaing et al., 2006). A moderate
craniofacial phenotype, including mild frontal bossing and
zygomatic flattening, has generally been associated with
autosomal-dominant forms (Aswegan et al., 1997; Chassaing
et al., 2006). More precise craniofacial phenotypic analyses
are necessary to improve genotype-phenotype correlations in
autosomal forms of HED. In this context, experimental mouse
models of HED, i.e., Tabby (XLHED experimental model),
Downless, or Crinkled (autosomal HED mouse models),
would be helpful for a better understanding of the X-linked
and autosomal HED phenotypic spectrum and craniofacial
variability.
All the present results allow for a better detection of
persons with HED, and underscore the use of anthropometric
approaches for screening HED carriers and selecting those
individuals for molecular genetic testing.
Molecular mechanisms suggested in THE
HED craniofacial phenotype
The EDA gene mutations and alterations in the developmental
molecular function of EDA could be responsible for
disturbances in craniofacial derivatives through alterations
of neural crest cell differentiation and migration. A
strong expression of EDA transcripts has been localized
in neuroectodermal cells involved in craniofacial skeletal
patterning (Montonen et al., 1998; Kanzler et al., 2000).
Moreover, molecular dysfunction in interactions between EDA
and Wnt-b-catenin- Lymphocyte Enhancer Factor-1 (Lef1)
pathways (Fig. 1) is likely to contribute to other abnormalities
of neuroectodermal derivatives (Laurikkala et al., 2001), since
Wnt factor is known to be a neural-crest inducer (Basch and
Bronner-Fraser, 2006).
EDA also influences BMP signaling, which is essential
for the development of skeletogenic cranial neural crest cells
(Kanzler et al., 2000; Ashique et al., 2002; Haworth et al.,
2004; Knight and Schilling, 2006; Raible, 2006). Perturbation
of EDA alters BMP regulation via Ccn2/Ctgf and follistatin
(Pummila et al., 2007). A gradient of BMP activity specifies
the expression of Msx genes encoding homeobox proteins,
essential for early cranial neural crest development (Ishimura et
al., 2000; Tribulo et al., 2003; Levi et al., 2006).
Interaction between EDA and FGF has been demonstrated
(Pispa et al., 1999), and mutations of the EDA gene may
influence the role of FGF signaling in later neural crest cell
proliferation and craniofacial skeletal patterning. FGF activity
in the ectoderm and mesoderm plays a crucial role during
craniofacial skeletogenesis, and FGF-dependent regulation of
Msx1 expression is regulated by the NF-kB factor, suggesting
a molecular confluence between EDA and FGF signaling
pathways (Bushdid et al., 2001; Nie et al., 2006). FGF, acting
downstream of Tumor Growth Factor-b (TGF-b) signaling,
is involved in the expression of the developmental potential
of neural crest cells and their osteogenic or chondrogenic
differentiation through induction of mesenchymal homeobox
gene expression as Bar subclass Homolog-1 (Barx-1), Dlx-1,
and Msx-1 in the craniofacial primordia (Bei and Maas, 1998;
Meyers et al., 1998; Barlow et al., 1999; Shigetani et al., 2000;
Crump et al., 2004; Sasaki et al., 2006).
Regulation of growth hormone (GH) secretion appears
to be altered in HED. Indeed, EDA has been detected in the
developing adenohypophysis (Mikkola et al., 1999; Nordgarden
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International and American Associations for Dental Research
et al., 2001a). The craniofacial dysmorphologies and alterations
of bone growth observed in HED (Motil et al., 2005) may be
emphasized by adenohypophysis dysfunction and reduced GH
secretion (Isgaard et al., 1986; Van Erum et al., 1997; Ramirez-
Yanez et al., 2005).
The NF-kB factor inactivation in developing ectoderm
leads to craniofacial phenotypic manifestations with alteration
of palatal development, as observed in the keratin 5 (K5)-GR
transgenic mouse, which exhibits a phenotype of ectodermal
dysplasia induced by ectoderm-targeted overexpression of the
glucocorticoid receptor (GR) (Cascallana et al., 2005).
Mandibular and maxillary bone
phenotypic modifications
associated with HED
Bone structural modifications seem to be associated with
XLHED, as suggested by our craniofacial CT-scan
examinations (Figs. 3d-3g). Areas of medullary bone
hyperdensity–D1-D2 densities (Lekholm, 1986)—were
observed, particularly in the mandibular symphysis (Figs. 3d,
3e). The high densitomeric profiles found with CT-examination
seem to confirm the medullary bone hypermineralization
(Fig. 3g). Variability in medullary bone hypermineralization
appears to exist among persons with XLHED, as demonstrated
by the different degrees of bone densities observed in the
persons examined (Figs. 3d, 3e). A topographic variation of
bone hypermineralization was also found in the mandible and
corresponded to high bone density in the inter-foraminal area
and to subnormal bone densitometric profiles in posterior
areas. The variations of bone densities may be linked to
genotypic heterogeneity in XLHED, as suggested by some
genotype-bone phenotype correlations. For example, a D1
bone density was associated with EDA exon 7 mutation,
whereas a D2 density was observed in an EDA exon 1 mutation
(Figs. 3d, 3e). Other bone structural abnormalities consist of
hypermineralization of mandibular cortical bone associated
with an increased cortical thickness, as demonstrated by CT
examinations and cortex measurements (Figs. 3d-3g).
Similar bone structural modifications have also been
observed in the Tabby mouse experimental model of XLHED
(Hill et al., 2002). Micro-computed tomography analyses
of the Tabby tibial trabecular structure showed a significant
increase in trabecular bone volume, trabecular connections,
and trabecular numbers associated with a decrease in inter-
trabecular spaces (Hill et al., 2002). This osteopetrotic
phenotype could be linked to disturbance of the NF-kB pathway
and osteoclastic differentiation (Montonen et al., 1998; Lomaga
et al., 1999).
Molecular mechanisms suggested in
HED bone structural and metabolic
modifications
EDA has been expressed not only in ectodermal structures
(Kere et al., 1996; Mikkola et al., 1999; Laurikkala et al., 2001;
Schmidt-Ullrich et al., 2006), but also in osteoblasts (Montonen
et al., 1998). EDA transcripts were intensively expressed during
human embryonic development from 12 wks of gestation in
rib osteoblasts; intense expression of EDAmRNA was also
observed in calvarial bone osteoblasts at 16 wks of in utero
development (Montonen et al., 1998). These observations
highlight the role of EDA in osteogenesis and emphasize the
1096 Clauss et al. J Dent Res 87(12) 2008
potential bone alterations linked to EDA mutations.
Endocrine disturbance, expressed as a reduction in
parathyroid hormone (PTH), is another feature of EDA mutation
(Söderholm and Kaitila, 1985). Since PTH is a major regulator
of calcium homeostasis and osteoclastic differentiation,
especially via Receptor Activator NF-kB Ligand (RANKL)
activation (Fu et al., 2002), the EDA mutation could be
responsible for disorders of bone remodeling, characteristic of
osteopetrosis.
The NF-kB transcriptional factor is a major regulator of
skeletal development and osteoclastic differentiation, requiring
activation of the RANKL-RANK-TNF Receptor Associated
Factor-6 (TRAF6) complex (Franzoso et al., 1997; Aradhya
and Nelson, 2001; Courtois et al., 2001; Smahi et al., 2002;
Chaisson et al., 2004; Asagiri and Takayanagi, 2007; Kurihara
et al., 2007). EDA activates the NF-kB transduction pathway
via the EDA receptor (EDAR), TRAF, and NF-kB Essential
Modulator-Inhibitor Kappa Kinase a-Inhibitor Kappa Kinase
b (NEMO-IKK-a-IKK-b) complex (Courtney et al., 2005;
Morlon et al., 2005) (Fig. 1). An alteration of the NF-kB
transduction pathway linked to the EDA mutation might
interfere with EDA-TRAF6-RANK molecular interaction and
thus with osteoclastic differentiation, leading to osteopetrosis
(Galibert et al., 1998; Dupuis-Girod et al., 2002). Such
molecular interactions are emphasized by the TRAF6-deficient
mice exhibiting osteopetrosis, with an increase in long bone
and vertebral body radiopacities (Lomaga et al., 1999). A
defect in osteoclast function, rather than differentiation, seems
to be responsible for osteopetrosis. The NF-kB factor also plays
a critical role in the maturation of osteoclasts. Abnormalities
of the present complex, as in NF-kB p50 and p52 subunit
inactivation, lead to a lack of mature osteoclasts in the mouse
model, thus exhibiting osteopetrosis (Franzoso et al., 1997)
Therapeutic aspects and perspectives in HED
Endosteal Dental Implant Therapy
Oral treatment of persons with HED exhibiting severe
phenotypes of oligodontia or anodontia benefits increasingly
from implant-supported prostheses (Guckes et al., 2002;
Umberto et al., 2007). However, clinical difficulties
encountered in these therapies are partly linked to alveolar
bone hypotrophy (Kramer et al., 2007). Early implant therapy
in children has been described as not affecting the growth
and development of the craniofacial complex (Kearns et al.,
1999; Becktor et al., 2001; Alcan et al., 2006), and a relatively
high implant survival rate (85%) was observed (Guckes et al.,
2002). In adults, the 24-month implant survival rate was 95%,
with consistently higher survival for implants placed in the
mandible than for those placed in the maxilla. Nevertheless,
27% of the recipients had a failed implant whatever their age
or the anatomical location of the implant (Guckes et al., 2002).
These negative clinical outcomes may be linked to the lack of
development of the alveolar ridge in the maxilla and to bone
structural hypermineralization, as suggested by our observations
(Figs. 3d-3g). Indeed, the thickened mandibular cortex appears
to be difficult to drill, leading to potential surgical thermic
trauma with alterations in implant osteointegration.
Treatment Perspectives
Recombinant EDA-A1 administration provides the basis for
possible treatment in XLHED (Gaide and Schneider, 2003).
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Recombinant proteins containing the receptor-binding domain
of EDA fused to the C terminus of an IgG1 Fc domain
(Fc:EDA1) have been engineered to cross the placental barrier,
and were administered to pregnant Tabby mice. This treatment
permanently rescued the Tabby phenotype in the offspring. The
jaw and molars regained both their normal sizes and the classic
wild-type pattern of sharp cusps (Gaide and Schneider, 2003).
However, Fc:EDA1-treated mice did not correct hypodontia in
offspring (Gaide and Schneider, 2003).
Transgenic Tabby mice bearing the mouse EDA-A1
isoform show almost complete restoration of the wild-type
phenotype. The wild-type number of 3 molars was observed
in transgenic mice, but these teeth were still generally smaller
and exhibited fewer and flattened cusps. Incisors regained their
wild-type size (Srivastava et al., 2001).
Both reversion of oligodontia and dental dysmorphologies
were obtained by post-natal single or multiple EDA-A1
intravenous administrations in XLHED dogs (Casal et al.,
2007). All the teeth showed normal development, confirmed
by clinical and radiographic examinations. The present model,
developed to approach the conditions of future therapeutic use
of recombinant EDA-A1 in humans, could show the ability of
recombinant EDA-A1 to correct the pathological features of
XLHED (Casal et al., 2007).
CONCLUSION
In conclusion, this review, supplemented by our phenotypic
analyses of persons with HED, adds to our understanding of the
dental and craniofacial manifestations of this syndrome and its
phenotypic variability. Craniofacial bone hypermineralizations
are an integral part of the clinical picture of HED, and need
to be considered in all persons with HED, but especially
when dental implant therapy is planned. Changes in molecular
interaction between EDA-NF-kB and BMP-Msx, as well as
FGF pathways linked to an absence, reduced level, or non-
functional extracellular EDA (Fig. 1), seem to be involved in
the odontogenic abnormalities observed in HED. The EDA-
NF-kB pathway is also implicated in skeletogenic neural crest
cell differentiation, through BMP-Msx gradient regulation (Fig.
1), and its molecular dysfunction seems to lead to craniofacial
dysmorphologies and bone remodeling associated with HED.
Oral treatment of persons with HED benefits increasingly from
implant-supported prostheses, with a relatively high implant
survival rate. However, the lack of development of the alveolar
ridge in the maxilla and the bone structural hypermineralization
seem to lead to some implant failure. Recently, groundbreaking
experimental approaches with recombinant EDA or transgenesis
of EDA-A1 have been developed from the perspective of a
systemic treatment in HED and seem to provide promising
results.
ACKNOWLEDGMENTS
We thank Bruno Grollemund, DDS (orthodontist, Department
of Orthodontics, Dental Faculty, Strasbourg, France) for his
assistance in cephalometric analysis. We are grateful to Olivia
Niclas (President of the French Association of Ectodermal
Dysplasia). We thank Professor Roger K. Hall (OAM, MDSc,
FRACDS, FICD, FADI, Department of Pharmacology,
University of Melbourne, Royal Children’s Hospital,
Melbourne, Australia) for his kind and helpful review of the
manuscript.
J Dent Res 87(12) 2008 Dento-Craniofacial Phenotypes in HED 1097
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