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European Journal of Medical Genetics 51 (2008) 383e408http://www.elsevier.com/locate/ejmg

Review

The genetic basis of inherited anomalies of the teeth.Part 2: Syndromes with significant dental involvement

Isabelle Bailleul-Forestier a,d,*, Ariane Berdal b, Frans Vinckier c,Thomy de Ravel d, Jean Pierre Fryns d, Alain Verloes e

a Paediatric Dentistry Department, Paris 7 University; AP-HP, Hotel-Dieu, Garanciere, Paris, Franceb INSERM, UMRS 872, Molecular Oral Physiopathology, University Denis-Diderot Paris 7,

Cordeliers Research Centre, University Pierre et Marie Curie, AP-HP, Hotel-Dieu, Paris, Francec Paediatric Dentistry and Special Care, Catholic University Leuven, Belgium

d Department of Human Genetics, Catholic University Leuven, Belgiume Clinical Genetics Unit, Department of Medical Genetics and INSERM U676,

AP-HP Hopital Robert Debre, Paris, France

Received 30 January 2008; accepted 2 May 2008

Available online 23 May 2008

Abstract

Teeth are specialized structural components of the craniofacial skeleton. Developmental defects occureither alone or in combination with other birth defects. In this paper, we review the dental anomalies inseveral multiple congenital anomaly (MCA) syndromes, in which the dental component is pivotal in therecognition of the phenotype and/or the molecular basis of the disorder is known. We will considersuccessively syndromic forms of amelogenesis imperfecta or enamel defects, dentinogenesis imperfecta(i.e. osteogenesis imperfecta) and other dentine anomalies. Focusing on dental aspects, we will reviewa selection of MCA syndromes associated with teeth number and/or shape anomalies. A better knowledgeof the dental phenotype may contribute to an earlier diagnosis of some MCA syndromes involving teethanomalies. They may serve as a diagnostic indicator or help confirm a syndrome diagnosis.� 2008 Elsevier Masson SAS. All rights reserved.

Keywords: Syndromic amelogenesis imperfecta; Syndromic enamel defects; Syndromic dentinogenesis imperfecta;

Osteogenesis imperfecta; Syndromic hypodontia; Ectodermal dysplasia; AxenfeldeRieger malformation

* Corresponding author. UFR d’Odontologie, 5 rue Garanciere, 75006 Paris, France. Tel.: þ33 1 57 27 87 20.

E-mail address: [email protected] (I. Bailleul-Forestier).

1769-7212/$ - see front matter � 2008 Elsevier Masson SAS. All rights reserved.

doi:10.1016/j.ejmg.2008.05.003

mailto:[email protected]

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384 I. Bailleul-Forestier et al. / European Journal of Medical Genetics 51 (2008) 383e408

1. Introduction

Dental anomalies, even when minor, have been reported as significant components of manysyndromes. Their presence may be a valuable diagnostic clue in the identification of specificpatterns of developmental disturbance. Teeth abnormalities may serve as a diagnostic indicatoror help confirm a syndromic diagnosis. The WintereBaraitser Database v 1.0.12 (previously:London Dysmorphology Database e LDDB) references 793 entities with abnormal teeth,among which 147 have abnormally shaped teeth, 219 oligodontia, 28 dentin and 128 enamelanomalies. A closer look at the relevant entries demonstrates that, in most situations, the exactdental anomalies are poorly or even inadequately described, or concern a minority of cases.

For didactic reasons, isolated abnormalities of the shape and/or structure of the teeth weredistinguished from the abnormalities of number associated with multiple congenital anomalies(MCAs). This oversimplification should not hide the fact that, in some instances, a mutation ina gene involved in MCA can also be reported as an isolated dental symptom.

In this paper, we will focus on the most important and most characteristic disorders. Thereader will find additional data on other syndromes in Tables IeX (Supplementary Material1). All the loci of the syndromes presented in these reviews are summarized in appendix 1(Supplementary Material 1).

2. Syndromes associated with amelogenesis imperfecta (AI) and enamel hypoplasia

Although usually isolated, AI is a component of several MCAs (Supplementary Material 1,Table I). Constitutional enamel anomalies must be considered cautiously as they can easily bemisdiagnosed, when they are secondary to metabolic or environmental factors (including exten-sive decay.), as shown in a review of oro-dental defects in the PradereWilli syndrome [5].

2.1. Tricho-dento-osseous syndrome

The tricho-dento-osseous syndrome (TDO, OMIM 190320) is characterized by kinky, coarseand/or curly, fair coloured hair, present at birth in 80% of cases. Half of the patients retain thisphenotype beyond infancy. More than 90% of individuals with TDO have an increased cranialthickness, obliterated diploe and absence of mastoid pneumatization [156]. Teeth show uni-formly thin or pitted hard enamel, enlarged pulp chambers, and taurodontism. The degree oftaurodontism and the distribution of affected teeth are highly variable. In some individuals thereis severe taurodontism of all the posterior teeth while the anterior teeth show only enlarged pulpchambers. Both primary and permanent teeth are typically affected [61]. Dental anomalies inTDO are similar to those observed in AI hypomaturationehypoplasia type with taurodontism(AIHHT, OMIM 104510), which is inherited as a highly penetrant autosomal dominant trait.AIHHT shows no alterations in hair or bone.

A common four base pair deletion in exon 3 of the human DLX3 gene located on humanchromosome 17q21.3eq22 [132] has been identified in TDO families [121]. Although the den-tal findings of the AIHHT are similar to those of TDO, AIHHT is a distinct condition, usuallynot linked to DLX3 [122]. Nevertheless, Dong et al. [35] identified a deletion of two nucleotidesin the homeodomain of the DLX3 gene in a large AIHHT pedigree, suggesting that some formsof AIHHT are allelic to TDO. The clinical pattern of expression of DLX3 mutations depends onthe altered functional domain of the DLX3 protein: AI and taurodontism are a constant featurebut hair and bone anomalies are observed with mutations outside the homeodomain [121].

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385I. Bailleul-Forestier et al. / European Journal of Medical Genetics 51 (2008) 383e408

Interestingly, the expression of DLX3 transcription factor was shown to be related to matrixsynthesis and biomineralisation in all skeletal tissues [44].

2.2. Coneerod dystrophy and amelogenesis imperfecta

The association of coneerod dystrophy with AI (OMIM 217080) has only been reportedtwice, in a large consanguineous Arabic family [62] and in a two-generation family from Kosovo[99]. Individuals present in the first few years of life with photophobia, horizontal nystagmus,and reduced central vision. Inability to see clearly in bright light (hemeralopia) is reported bythe end of the first decade. The progressive coneerod dystrophy is associated with hypoplastic/hypomineralized AI. Teeth are dysplastic, yellow/brown, with almost no visible enamel [99]. Bylinkage analysis in the first family Downey et al. [36] identified a locus on chromosome 2q11.

2.3. KohlschuttereTonz syndrome

KohlschuttereTonz syndrome (OMIM 226750) is a neuro-degenerative condition consistingof hypomineralized AI (with yellow teeth), seizures, progressive spasticity, ataxia and oftenpsychomotor regression. Onset is between 1 and 2 years and death occurs in childhood or adult-hood. Additional manifestations variably include myopia, cardiac ventricular enlargement, cer-ebellar vermis hypoplasia, dry skin, and broad thumbs/toes [27,163,158,49]. Data are consistentwith AR inheritance. It has been hypothesized that heterozygotes may express AI without neu-rological impairment [48].

2.4. AI with nephrocalcinosis (McGibbon syndrome)

AI with nephrocalcinosis (OMIM 204690) is rare and possibly underdiagnosed[89,83,50,31,109,117,57]. The common characteristics are the presence of thin or absent enamel(AI, hypoplastic type), intrapulpal calcifications, calculus, delayed tooth eruption, gingivalhypertrophy, bilateral nephrocalcinosis and normal plasma calcium (Fig. 1). Impaired renalfunction is variable, or delayed to adulthood, despite the presence of typical renal hyperechoge-nicity in childhood. McGibbon syndrome has been previously reported in consanguineous andnon-consanguineous families. Actually, the relationship between the enamel defect and nephro-calcinosis is still unknown. Kidney ultrasound scan should be performed in all AI patients inorder to exclude nephrocalcinosis and to determine if this alteration is exclusive to this raresyndrome or can be found in other forms of AI [117,57].

Suda et al. [145] reported a patient exhibiting AI, hypomaturation type, and bilateral cleft lipand palate, nephrocalcinosis and hematuria at the age of 15 years. These symptoms appeared tobe secondary to polycystic kidney disease. Based on a phenotypic homology with a mousemodel, the authors screened MSX2 and found a missense mutation (T447C) in this patient.MSX2 (HOX8) gain-of-function mutations are associated with dominant craniosynostosis,Boston type. The same point mutation has been identified in 10% of patients with non-syndromic sagittal craniosynostosis.

2.5. Vitamin D-dependent rickets

Vitamin D-dependent rickets, type I (VDDRI, OMIM 264700) is an AR defect in vitamin Dmetabolism. Patients with VDDRI have mutations of the 1-alpha-hydroxylase gene (located at

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Fig. 1. Amelogenesis imperfecta with nephrocalcinosis. (A) Oral view teeth with hypoplasic enamel and calculus, (B)

renal ultrasonography: medullary calcinosis with hyperechoic foci in the pyramids (arrow).


12q13.1eq13.3) resulting in decreased levels of 1,25(OH)2 vitamin D3 [74]. Clinical featuresinclude growth failure, hypotonia, rachitic bones and enamel hypoplasia. Zambrano et al.[159] described a patient with hypoplastic, yellow-to-brownish enamel on all permanent teeth,and periodontal disease. Dental radiographs showed large quadrangular pulp chambers andshort roots. Ultrastructural examination showed anomalies affecting both enamel and dentin.

2.6. Vitamin D-resistant rickets

Mutations in the vitamin D receptor gene (12q12eq14) cause vitamin D-resistant rickets,type II (VDDR II, OMIM 277440). The circulating levels of 1,25-(OH)2 D3 are increased.Most patients have total alopecia. Bailleul-Forestier et al. [4] showed that 1,25-dihydroxyvitaminD3 controls different stages of tooth crown development in humans. Several genes involvedin amelogenesis imperfecta are controlled by vitamin D [116].

2.7. Autoimmune polyendocrinopathy

Autoimmune polyglandular syndromes (APS) are characterized by multiple endocrine insuf-ficiencies. APS type 1 (APS 1), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, OMIM 240300) or Whitaker syndrome, is an AR disordercharacterized by chronic mucocutaneous candidiasis, multiple autoimmune endocrinopathies

omim:277440

omim:240300

Fig. 2. APECED syndrome: typical enamel hypoplasia; labial view.


(hypoparathyroidism, adrenocortical failure, type 1 diabetes.) and ectodermal anomalies (vit-iligo, alopecia, dysplastic enamel.) [118]. Onset is in childhood. APECED is due to mutationsof the AIRE (autoimmune regulator) gene, located on chromosome 21q22.3. There is partialdefect of the cell-mediated immunity (resulting in chronic skin candidiasis), and ectodermaldysplasia. The most frequent abnormality is enamel hypoplasia of permanent teeth, whichaffects 75% of the patients [86,119]. Enamel hypoplasia can be the first sign of APECED,and oral examination could help establish a diagnosis (Fig. 2).

3. Syndromic forms of dentinogenesis imperfecta

Dentinogenesis imperfecta (DGI) and dentin dysplasia are reported in many syndromes(Tables IIeV summarize other syndromes involving dentin anomalies, see SupplementaryMaterial 1). We have limited our review to the most significant disorders, selected because theirmolecular basis is known, or because the dental anomaly is the usual key feature.

3.1. Syndromes associated with DGI with a collagen mutation

3.1.1. DGI in osteogenesis imperfectaNinety percent of the dentin matrix is made of collagen, mostly type I, but also to a smaller

extent types III and VII (www.bite-it.helsinki.fi). Dominantly inherited osteogenesis imperfecta(OI) results from mutations in COL1A1 (17q21) and COL1A2 (7q21.1), which encode the twochains of type I collagen. The association of DGI with OI is well known (cf. DGI type I inShield classification, [140]). OI is commonly subdivided into several types based on clinicalfeatures, radiological criteria and the presence of DGI [77,142] (Supplementary Material 1,Table II). The prevalence of DGI in the primary dentition varies from 28% to 80% [87,111].It is highest in OI types IIIB, and IVB [85,87,111], whereas it is rarer in OI type I. In OItype II e perinatal lethal, dental abnormalities may or may not be present [138,78,155]. Exceptwhen a parent is a mosaic, there is a very high concordance for the presence of DGI betweenaffected parents and children, and between affected siblings [93]. Dental abnormalities, whenpresent in a family, may be very helpful for early diagnosis of patients with mild bone fragility

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[47]. Patients with no signs of DGI at visual inspection can present with radiographic and/orhistological evidence of this disorder [88]. This can explain why DGI is underdiagnosed inOI patients [153].

The dental phenotype of OI consists of greyish or brownish discoloration of the teeth andfracture of the enamel cap with secondary attrition [82] (Fig. 3A). The phenotype may varybetween the primary and permanent dentition, and between teeth within a single dentition.O’Connell and Marini did not find a correlation with the nature of the mutation [111]. Toothdiscoloration and attrition are less severe in the permanent dentition than in the primary one. Ina study of 40 children, O’Connell and Marini were unable to distinguish OI type III from OItype IV by dental evaluation [111]. Radiographic anomalies of teeth include increased con-striction at the corono-radicular junction, progressive obliteration of the pulp by secondarydentin, and roots thinner and shorter than normal (Fig. 3B). In OI type I, an oval pulp chamberwith apical extensions into the coronal portions of the root has been reported [80]. These den-tal abnormalities are similar to those found in dentin dysplasia type II. In addition a well-circumscribed radiolucency involving the apices of all permanent mandibular incisors isobserved in some patients [79,80,85]. The frequency of teeth with denticles is higher in OIpatients type III and IV [87]. Malmgren and Lindskog [94] suggested that dysplastic changesin dentin are most likely an expression of genetic disturbances associated with OI and shouldnot be diagnosed as DGI. Other tooth anomalies include transverse bands of discoloration ofcrowns, crown translucency, ectopic eruption or impaction of permanent molars, and dentalagenesis [93]. In all types of OI, class III malocclusion, anterior and posterior cross-bitesand open bites are commonly seen [111].

Fig. 3. Dentinogenesis imperfecta in osteogenesis imperfecta. (A) Oral view grey brown primary teeth and (B)

orthopantomogram.


More than 150 different mutations have been reported in COL1A1 (www.le.ac.uk/genetics/collagen/colla1.html), 21 of them (in OI type I, III and IV) with the DGI-1 phenotype (Supple-mentary Material 2, Table I). In OI type 1, the presence of DGI is correlated with mutationsleading to the synthesis of abnormal procollagen fibres, as opposed to decreased synthesis ofnormal collagen [19]. In the COL1A2 gene, 17 mutations, were reported mostly associatedwith DGI (Supplementary Material 2, Table II). Mundlos et al. [103] described two largeexon deletions in the triple helical domain of the COL1A2 gene which present with differentphenotypes: DGI or DD.

Some linkage studies [41] failed to distinguish between the OI type I and OI type IV, with orwithout DGI, suggesting that these two clinical phenotypes may result from different mutationsof the pro alpha 2(I) chains. The finding that a mutation in the gene for the alpha 2(I) collagenchain with serious consequences for bone development has only minor effects in teeth suggeststhat odontoblasts, unlike osteoblasts, can largely compensate for this particular genetic defect,possibly by excluding the abnormal alpha 2(I) chains and forming alpha 1(I) homotrimericcollagen I which is expressed normally during initial dentinogenesis. The discrepant conse-quences in deciduous as opposed to permanent teeth and the specific localization of the dentinabnormalities in permanent teeth led Luder et al. to speculate that the exclusion of defectivealpha 2(I) chains could depend on the developmental stage and/or the rate of extracellularmatrix formation [84]. COL1A1, COL1A2 and DSPP gene mutations can have a similar dentalphenotype. Scriver et al. [135] proposed that mutations affecting the interaction of DSPP withcollagen I or II could result in the phenotype. Lund et al. [87] suggested a time- and tissue-dependent regulation of the genes coding for collagen I, or epigenetic factors influencing theinteraction of collagen I with other extracellular matrix proteins. Further clinical and molecularstudies are still required to clarify these observations.

3.1.2. DGI and DD with other hereditary defects of collagenSyndromes associated with collagen mutations and DGI type II and DD are summarized in

Table II (see Supplementary Material 1).

3.1.3. EhlerseDanlos syndrome (EDS)In most instances, patients with EDS have no evidence of dentin dysplasia. A partial duplica-

tion of COL1A2 gene has been demonstrated in a single patient with EDS type VII and opalescentteeth [124]. Moreover EDS type VIIC patients with a nonsense mutation in ADAMTS2 eenzymes which excise the N-propeptide of procollagens e were recently described with multipletooth agenesis, dentin structural anomalies, and dysplastic roots [30].

3.1.4. Goldblatt syndromeThis rare syndrome (OMIM 184260) combines spondylometaphyseal dysplasia, joint laxity and

DGI or dentin dysplasia type II. Deciduous teeth are opalescent whilst the permanent teeth are al-most normal [11]. The latter authors found a decrease in synthesis of collagen type I (A1 and A2),and a single-base substitution in the COL2A1 gene. They proposed that this mutation has sequentialeffects on tissue-specific regulatory sequences that control the expression of type I collagen genes.

3.2. Syndromes associated with DGI without a collagen mutation

Several syndromes are associated with dental findings, which are clinically and radiograph-ically similar to those observed in DGI (Supplementary Material 1, Table III) [65].

http://www.le.ac.uk/genetics/collagen/colla1.html

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omim:184260

Fig. 4. Schimke syndrome orthopantomogram indicating obliterated pulp chamber.


3.2.1. Schimke immunoosseous dysplasia (SIOD)SIOD is an autosomal recessive disorder characterized by spondyloepiphyseal dysplasia,

renal dysfunction, and T-cell immunodeficiency. It is due to mutations in SMARCAL1 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin 1) [10]. da Fonseca[28] reported dental findings resembling DGI. The teeth have a yellowish grey discoloration,bulbous crowns and marked cervical constriction of the primary and permanent molars. Thepulp chambers are small or obliterated. Both enamel and dentin are softer than normal (Fig. 4).

4. Syndromes involving dentin anomalies

Besides DGI, abnormal dentin can be seen in disorders involving phosphocalcic metabolismand often growth retardation. Syndromes associated with dentin dysplasia type I are listed inTable IV (Supplementary Material 1).

4.1. Hyperphosphatemic familial tumoral calcinosis (HFTC)

HFTC (OMIM 211900) is a rare autosomal recessive disorder characterized by progressivedeposition of calcified masses in cutaneous and subcutaneous tissues, associated with elevatedcirculating levels of phosphate. The disease was initially found to result from mutations in theGALNT3 gene mapped to 2q24eq31 (OMIM 601756) [7,150] and encoding a glycosyltransfer-ase (ppGalNacT3). Mutations in GALNT3 are also responsible for HyperostosiseHyperphosphatemia Syndrome (HHS) [42]. More recently, recessive loss-of-function muta-tions in FGF23, located on 12p13.3, encoding a phosphaturic protein were also identified inHFTC [6,76]. Interestingly, dominant gain-of-function mutations in FGF23 gene result in au-tosomal dominant hypophosphatemic rickets (ADHR, OMIM 605380). Patients with HFTCcaused by GALNT3 mutations have dentin dysplasia with short bulbous roots, pulp stonesand partial obliteration of the pulp cavity [144,59]. In a patient with a FGF23 mutation, Che-fetz et al. [24] observed delayed eruption of permanent teeth and diminished root length. In thisgroup of conditions the dental phenotype may thus orient molecular diagnosis. Physiologicalinteractions between FGF23 and GALNT3 await further studies.

4.2. Familial hypophosphatemic vitamin D-resistant rickets

Familial hypophosphatemic vitamin D-resistant rickets or X-linked dominant hypophospha-temia (XLH) presents with growth retardation, rachitic and osteomalacic bone disease, hypo-phosphatemia, renal defects in phosphate reabsorption and vitamin D metabolism, and dental

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findings [129]. The patients often have multiple periodontal abscesses, but no evidence of den-tal caries, trauma, or periodontal disease on the corresponding teeth. Radiographic examinationof teeth shows root dysplasia and enlarged pulp chamber. The histological examination showsmarked globular dentin and increased predentin width [105,13]. The abscesses are thought to becaused by pulp infection, which arise from bacterial invasion through enamel cracks and dentinmicrocleavage of the teeth [54]. XLH is caused by mutations in the phosphate-regulatingendopeptidase gene (PHEX ) located in Xp22.2ep22.1.

Various syndromes with dentin anomalies are associated with primordial dwarfism. Primor-dial ‘‘dwarfism’’ is used to describe patients with severe intrauterine and postnatal growth re-tardation, and they can be subclassified into three main types: Seckel syndrome, microcephalicosteodysplastic primordial dwarfism (MOPD) type I/III and MOPD type II [98,92]. Variants ofMOPD or Seckel-like syndrome have been described [139,16].

4.3. Seckel syndrome

Seckel syndrome (SCKL1, OMIM 210600) is a rare AR disorder characterized by postnatalproportional short stature, microcephaly with mental retardation, and a characteristic ‘‘bird-headed’’ facial appearance. This condition can be caused by mutations in the ATR gene(3q22.1eq24) that encodes the ataxia-telangiectasia and RAD3-related protein [46]. Other locifor Seckel syndromes have been mapped to chromosome 18p11-q11 (SCKL2; OMIM: 606744)[12] and 14q23 (SCKL3; OMIM: 608664) [68]. Dental anomalies have been reported before themolecular subdivision of the syndrome and correlations between dental phenotype and gene mu-tations have not been reported. Teeth anomalies include atrophic or absent teeth and hypoplasiaof the enamel [43]. Kjaer et al. [69] described four siblings with Seckel syndrome. Agenesis oftwo or more teeth occurred in all four children, and all children lacked the upper lateral incisors.Short roots and taurodontic molars were also observed. Complete and semitaurodontic rootshapes were noted in the girls. Contrasting with bone age delay, dental maturation was normal.Seymen et al. [136] reported a seven-year-old boy with microdontia, missing lateral maxillaryand central mandibular incisors (permanent dentition) and dentin dysplasia. In two youngpatients (24 and 34 months) with Seckel syndrome, Buebel et al. [16] reported cleft of the softpalate, hypodontia of maxillary (and in one case mandibular) lateral incisors, and enamel hypo-plasia in one patient, but no radiographic examination was performed. Another dental phenotypewith proportionate primordial short stature has been reported with hypoplastic alveolarprocesses, severe microdontia, opalescent teeth, and rootless molars (OMIM 607561) [66,67].

Patients affected with the two types of MOPD can easily be distinguished from those withSeckel syndrome by being disproportionately short and having distinct radiological features[90e92]. The dental phenotype has not been emphasized even though microdontia, hypodontia,and dentin dysplasia occur in this group of patients. Lin et al. [81] described microdontia inboth dentitions, bulbous crowns and short roots in patients with MOPD type II. Dentin anom-alies vary from dentin dysplasia type I to opalescent rootless teeth [110].

Other rare syndromes with an abnormal dentin phenotype report are listed in Table V(Supplementary Material 1).

5. Syndromes with supernumerary teeth (hyperdontia)

Usually hyperdontia is an isolated feature, but when many supernumerary teeth are observedthey could be part of a syndrome.

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Fig. 5. Cleidocranial dysplasia. (A) Oral view after treatment, with open bite and (B) orthopantomogram before treat-

ment showing unerupted supernumerary teeth (arrows).


5.1. Cleidocranial dysplasia

Cleidocranial dysplasia is an AD disorder affecting bone and teeth development and iscaused by mutations in RUNX2, a gene encoding an osteoblast-specific transcription factorwhich maps to 6p21 (OMIM 119600) [104]. The symptoms include hypoplastic calvarial bonesand clavicles. Dental abnormalities include supernumerary teeth (sometimes leading to a ‘‘thirddentition’’), delayed eruption, failure of exfoliation of the primary dentition, and malocclusion(Fig. 5).

5.2. Familial adenomatous polyposis (FAP), Gardner syndrome

Gardner syndrome, a clinical variant of FAP, is an autosomal dominant disease characterizedby gastrointestinal polyps, multiple osteomas, and skin and soft tissue tumours (OMIM 175100,APC Adenomatous Polyposis of the Colon, 5q21eq22) [53]. Cutaneous findings includeepidermoid cysts, desmoid, and other benign tumours. Polyps have a 100% risk of undergoingmalignant transformation; consequently, early identification of the disease is critical.

Fader et al. [40] first reported impacted teeth, supernumerary teeth, congenitally missingteeth, and abnormally long and pointed roots of the posterior teeth in Gardner syndrome[21]. Jarvinen et al. [63] found dental anomalies in only 18% of patients but jaw osteomaswere very frequent. Occult radio-opaque osteomas of the jaw are an important early sign ofthe condition, preceding clinical and radiological evidence of colonic polyposis. The mandibleis the most common location; however, osteomas may occur in the skull and the long bones.Thakker et al. [148] presented a diagnostic scoring system, the Dental Panoramic RadiographsScore (DPRS). This takes into account the nature, extent, and sight of osseous and dental

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changes, as well as the incidence of the anomaly in the general population. The DPRS isa reproducible and valid index for assessing individuals at 50% risk of FAP [1].

The APC gene product indirectly regulates transcription of a number of critical cell prolifera-tion genes, loss of APC function increases transcription of b catenin targets. These targets includecyclin D, C-myc, ephrins and caspases. APC also interacts with numerous actin and microtubuleassociated proteins. APC itself stabilizes microtubules (http://atlasgeneticsoncology.org/Genes/APC118.html). The relationship between APC mutations and dental abnormalities remainscontroversial [29,114].

5.3. NanceeHoran syndrome

NanceeHoran syndrome is an X-linked disorder characterized by congenital cataracts, dys-morphic features, anomalous form of teeth and in some cases mental retardation (OMIM302350). The syndrome is caused by mutations in the NHS gene, whose function is not known.Screwdriver shaped and supernumerary incisors are reported [151].

6. Syndromes with congenital absence of teeth

Missing teeth, either hypodontia, oligodontia, or anodontia are a very common and relativelynon-specific finding in MCA syndromes (see part 1). It is a key feature of the ectodermal dys-plasias group (Supplementary Material 1, Table VI), where it is associated with abnormal shapeof the remaining teeth, whereas the present teeth are often normal in the other syndromes(Supplementary Material 1, Tables VII, VIII, IX). We review some of these disorders below.Other entities are summarized in Table X (Supplementary Material 1).

6.1. Down syndrome

Congenital absence of teeth has been reported in 69.8% of females and 90.7% of the maleswith Down syndrome, in a Danish population [128]. Lateral maxillary incisors, lower centralincisors and second premolars are the most commonly missing teeth. One or both primary up-per lateral incisors were missing in more than 10% of the patients, and peg-shaped maxillarylateral incisors are seen in 10% [47]. Shapira et al. [137] studied dental anomalies in 34 indi-viduals with Down syndrome in Israel. Excluding third molars, 59% had missing teeth and 25%of the individuals had small or peg-shaped upper lateral incisors.

6.2. WolfeHirschhorn syndrome

The WolfeHirschhorn syndrome (WHS) is caused by deletions of a subterminal region(WHCR) of chromosome 4p. Reported dental abnormalities are delayed eruption, fusion of in-cisors and oligodontia. A single case with congenital tooth agenesis has been described [17].Oligodontia is probably due to the loss of one copy of MSX1, which is located at 4p16.1 [108].

6.3. Holoprosencephaly

Holoprosencephaly (HPE) is a developmental field defect in which midline cleavage of theforebrain and craniofacial structures is impaired. HPE is etiologically heterogeneous, caused byteratogens or genetic factors. It occurs in 1/16,000 newborns, half of whom have chromosomal

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Fig. 6. Holoprosencephaly: paucisymptomatic expression with solitary median maxillary central incisor. (A) Face and

(B) Oral view of solitary maxillary central incisor.


anomalies [126]. Based on the analysis of HPE patients with chromosome rearrangements, atleast 16 loci for the disorder, have been assigned; seven genes are identified (SupplementaryMaterial 1, Table VII). Mutations and deletions in these genes are observed in roughly 20%of non-chromosomal cases. The sonic hedgehog gene (SHH ) at 7q36 (HPE3 locus) is themost frequently involved. An extreme intrafamilial phenotypic variability is observed, rangingfrom the classical phenotype with alobar HPE and typical severe craniofacial abnormalities tovery mild clinical signs of choanal stenosis or solitary median maxillary central incisor(SMMCI) (Fig. 6).

6.4. Kallmann syndrome

Kallmann syndrome is a developmental disease that combines hypogonadotropic hypogo-nadism and anosmia/hyposmia. The prevalence is estimated at 1/10,000 in males and at


1/50,000 in females, with sporadic more frequent than familial cases [160]. Kallmann syn-drome is genetically heterogeneous. An X-linked form is due to mutations in the KAL1 gene(Xp22.3) [51]. An autosomal dominant form is due to mutations in fibroblast growth factor re-ceptor 1 (FGFR1) (KAL2 locus at 8p12) [33]. A rare autosomal recessive form is reported forwhich no causal mutation has been identified. KAL1 and KAL2 mutations account for only 20%of Kallmann syndrome [33,130,131,2,120].

To date, dental agenesis is described only in KAL2, and may or may not be associated withcleft palate or lip. The type of dental anomalies varies from a single central maxillary incisor tolateral maxillary incisor agenesis, and premolar agenesis. In some cases the first four permanentmolars and mandibular canine are missing [131] (Supplementary Material 1, Table VIII).

6.5. Ectodermal dysplasias

Ectodermal dysplasias form a large and complex group of disorders characterized by variouscombinations of defects in hair, nails, teeth and sweat glands, either isolated or associated withmalformations. Of the approximatively 170 clinical types of ectodermal dysplasias described sofar, a gene is identified in less than 30. The clinical classification is more complex than thegenetic one, and some genes have been associated with many clinical entities. Lamartine[75] proposed a new classification of ectodermal dysplasias based on the function of the proteinencoded by the mutated gene. He divided ectodermal dysplasias into four groups: cellecellcommunication and signalling; adhesion; regulation of transcription; and development (Supple-mentary Material 1, Table VI).

6.5.1. Hypohidrotic ectodermal dysplasia (HED)The X-linked form of the disease (XLHED, OMIM 305100) is caused by EDA (ectodysplasin

A) gene mutations and represents 75e95% of familial and 50% of sporadic cases[102,133,115,152]. By alternative splicing EDA encodes various isoforms of a signalling mole-cule of the TNF-related ligands family. The EDA signalling pathway involves at least two iso-forms of 391 and 389 amino acids: ectodysplasin EDA-A1 and EDA-A2. The autosomaldominant and recessive forms of HED have been associated with mutations in the EDAR(EDA Receptor) gene [102] or the EDARADD (EDAR-associated death domain) gene [52].Mutations in EDAR account for one-quarter of non-EDA-related HED [23]. Headon et al. [52]found that EDAR is activated by EDA and uses EDARADD as an adaptor to build an intracel-lular signal-transducing complex.

Common clinical findings are fine, dry, brittle and sparse hair. The skin is thin, glossy,smooth and dry with hypohidrosis. In the X-linked form of HED, females have sparse, thinscalp hair and mosaic patchy distribution of skin anomalies. Many of them have abnormalteeth. Patients with full-blown HED have sparse hair, diminished sweating and decreasedsalivary and lacrimal secretions [106]. Oligodontia is almost constant and the remaining teethare misshapen (Figs. 7 and 8). Complete anodontia is occasionally seen. When present, upperincisors, upper and lower first molars, and lower second molars are significantly smaller andmisshapen. Seventy-three percent of obligate heterozygous females of the X-linked formhave one or more missing teeth, and most have smaller teeth. These findings suggest that theX-linked form of HED is a highly penetrant X-linked trait with intermediate expression inthe heterozygous female. Carrier detection of the X-linked form is often possible by dental ex-amination: small, peg-shaped incisors and canines, and missing teeth are usually found, and the

omim:305100

Fig. 7. Ectodermal dysplasia with abnormal-shaped, conical incisor and missing teeth.

Fig. 8. Ectodermal dysplasia. (A) Face and (B) labial view.



deciduous second molar teeth usually show taurodontism [106,143,45]. Studies in two familiesshowed that X-linked non-syndromic hypodontia resulted from EDA mutations [146,147].

6.5.2. Incontinentia pigmenti, hypohidrotic ectodermal dysplasia and immune deficiency(HED-ID)

Incontinentia Pigmenti (IP) is an X-linked dominant condition, lethal in males. IP affectsskin, teeth, eyes and the nervous system. The most common mutation is a genetic rearrange-ment, resulting in deletion of part of the NEMO (NFkB essential modulator) gene [149]. Thedisease shares some characteristics with X-linked ectodermal dysplasia [8]. Dental anomaliesare present in 70% of the patients [101,157,3]. Both dentitions are affected: hypodontia, peggedor conical teeth and delayed eruption are reported in 30% of cases (Fig. 9).

A form of ectodermal dysplasia with immunodeficiency segregates as an X-linked recessivetrait [164,34]. Hypohidrosis and abnormal dentition are similar to those in other forms of

Fig. 9. Incontinenta pigmenti. (A) Face and (B) orthopantomogram.


ectodermal dysplasias. Affected males manifest with dysgammaglobulinemia and infectionscan be lethal. Female carriers show no clinical signs of immunodeficiency but may have hypo-dontia and conical teeth. Mutations in NEMO have been found in HED-ID patients. IKK-gamma is required for activation of NFkB, a transcription factor transducing TNF signalling.NFkB transduces signalling via ectodysplasin/EDAR, which presumably explains the pheno-typic similarities between HED and HED-ID [73,71]. Dental examination of four familieswith HED-ID studied by Zonana et al. [164] showed hypodontia/oligodontia in the primaryand permanent dentition, as well as cone-shaped teeth. Ku et al. [72] suggested screeningNEMO in boys with conical incisors and unusual infectious diseases.

The osteopetrosiselymphedemaeanhidrotic ectodermal dysplasia-immunodeficiency (OL-EDA-ID) syndrome and IP are allelic. Loss of function of NEMO is responsible for IP andhypomorphic mutations for OL-EDA-ID. The dental phenotype is poorly described in theliterature but delayed eruption and incomplete dentition are mentioned [95,37].

6.5.3. p63 mutation related syndromesSeveral autosomal dominant syndromes are caused by mutations in the p63 gene on 3q27. p63

is involved in growth and differentiation of ectoderm-derived oral tissues. The p63 syndromefamily includes the ectodermal dysplasiaeectrodactylyecleft lip and palate syndrome type 3(EEC3), ankyloblepharoneectodermal dysplasiaeclefting syndrome (AEC), acro-dermato-ungual-lacrimal-tooth syndrome (ADULT), limbemammary syndrome, and non-syndromicsplit-hand/foot malformation (Supplementary Material 1, Table VI-b). All types are AD withvariable expression. A clear genotypeephenotype correlation can be recognized for EEC andAEC syndromes [15]. EEC syndrome is genetically heterogeneous: besides the common EEC(EEC3), EEC type 1 syndrome maps to 7q11.2eq21.3 [123] and EEC type 2 to the pericentro-meric region of chromosome 19 in a Dutch kindred [112].

The ectodermal dysplasia features seen in the patients with EEC syndrome are sparse hair,dystrophic nails, hypopigmentation or pigmented nevi of the skin, and abnormal dentition[18,125]. Anomalies of the lacrimal ducts, urogenital defects, and conductive hearing losshave been reported [125]. Congenitally missing permanent teeth and conical teeth are common.Buss et al. [18] reported dental features in 24 patients with EEC syndrome: the permanent den-tition of all patients is affected by oligodontia and microdontia. The teeth are not as strikinglyconical as in X-linked EDA, being more often straight-edged with gaps; taurodontism is alsoreported. The number of teeth is normal in the primary dentition, but with abnormal morphol-ogy of the tooth crowns. Chranowska et al. [26] described a family with anodontia of permanentteeth as the sole clinical sign of EEC. There are no available data on possible differences indental anomalies between EEC type 3 and the much rarer types 1 and 2. Hypodontia hasbeen reported in the AEC syndrome with p63 mutations [97]. However, neither dental anom-alies nor p63 mutations have been reported in the split-hand/foot malformation (SHFM,OMIM 183600) [58].

6.6. Lacrimo-auriculo-dento-digital syndrome

Lacrimo-auriculo-dento-digital syndrome (LADD, OMIM 149730) is an autosomal dominantMCA disorder characterized by aplasia, atresia or hypoplasia of the lacrimal and salivary sys-tems, cup-shaped ears, hearing loss, dental and digital anomalies. The dental features includesmall and peg-shaped or absent lateral maxillary incisors and mild enamel dysplasia [56,20].LADD is genetically heterogeneous. Rohmann et al. [127] identified heterozygous missense

omim:183600

omim:149730


mutations in FGFR2, FGFR3 and FGF10. Additional LADD loci are on chromosomes 10q26,4p16.3 and 5p13ep12.

Mutations in FGFR2 cause several craniosynostosis syndromes (Pfeiffer, Crouzon, andApert syndromes). Mutations in FGFR2 causing LADD are situated in the tyrosine kinasedomain, which appears to be the critical domain for lacrimal, and salivary gland development,as well as morphogenesis of ears, teeth, and digits. Loss-of-function mutations in FGF10 aredescribed in aplasia of the lacrimal and salivary glands (ALSG, OMIM 180920) [38]. RecentlyMilunsky et al. [100] found a nonsense mutation (K137X) of FGF10 in a 19-year-old motherwith ALSG and in her 2-year-old daughter with LADD syndrome.

6.7. AxenfeldeRieger malformation and Rieger syndrome

The AxenfeldeRieger malformation (ARM) consists of various anomalies of the anteriorchamber of the eye [141,25]. Its incidence has been estimated as 1/200,000 [47]. Fifty percentof affected individuals have a propensity to develop glaucoma. Rieger syndrome is character-ized by the association of RiegereAxenfeld malformation with dental, craniofacial, andsomatic anomalies, such as redundancy of periumbilical skin [70]. Dental abnormalities arethe key features to differentiate Rieger syndrome from the AxenfeldeRieger malformation[32].

The predominant anomaly is congenitally missing teeth in both the deciduous and perma-nent dentitions. Incisors and canines are most often absent. The second premolars and molarsare occasionally missing. Other tooth abnormalities include enamel hypoplasia, conical-shapedteeth, short roots, taurodontism, and delayed eruption [25,14,60] (Fig. 10). Patients with PITX2mutations have been reported with normal number of teeth and short roots [64].

At least seven loci are associated with ARM, and three genes are identified: PITX2, FOXC1and GJA1 (Supplementary Material 1, Table IX). Dominant negative and dominant positive

Fig. 10. AxenfieldeRieger syndrome. (A) Oral view of abnormal-shaped maxillary incisor and agenesis of lateral in-

cisors in upper and lower arches and (B) orthopantomogram.

omim:180920


mutations of the homeodomain transcription factor PITX2 contribute to the variable ARM phe-notype [39]. Berry et al. [9] identified a functional link between the transcription factors,FOXC1 and PITX2, which underpins the similar ARM phenotype caused by mutations of thesegenes. Furthermore, PITX2A can function as a negative regulator of FOXC1 transactivity. Cellaet al. [22] observed a family with concomitant structural alterations in the FOXC1 and GJA1genes resulting in a less severe phenotype than that observed in patients with the FOXC1 mu-tation alone within the same family.

6.8. JohanssoneBlizzard syndrome

The JohanssoneBlizzard syndrome (JBS, OMIM 243800) is an AR disorder characterizedby congenital insufficiency of the exocrine pancreas with malabsorption, hypoplasia of the alaenasi, congenital deafness, hypothyroidism, postnatal growth retardation, mental retardation,midline scalp defects, and absent permanent teeth. Zenker et al. [161] mapped the gene to15q14eq21.1 and described two mutations in the UBR1 gene. The dental phenotype includesdelay of primary teeth eruption, microdontia, and severe oligodontia of the permanent teeth.The first mandibular permanent molars are the most conserved teeth followed by maxillaryfirst molars and central incisors. Additional or missing tubercles are noted on dental crowns[162].

6.9. Wilkie oculo-facio-cardio-dental syndrome

Wilkie [154] reported a syndrome characterized by heart defects (ASD and VSD), micro-phthalmia, cataracts, and hyperplastic primary vitreous. The nose is narrow with an enlargedtip and notching of the alae nasi. Cleft palate, genital, digestive and digital anomalies maybe present and laterality defects (asplenia and dextrocardia) have been reported [55,134]. Thereare missing teeth and delayed eruption of secondary teeth. The crowns and roots of several in-cisors and canines are unusually large with radiculomegaly, and peg-shaped incisors [96,113](Fig. 11). Wilkie syndrome is X-linked dominant, with lethality in males and skewed X-inactivation and results from mutations in the BCOR gene located in Xp11 [107]. The proteinis an interacting corepressor of BCL6, which is required for germinal centre formation and mayinfluence apoptosis.

Other syndromes with tooth agenesis are listed in Table X (Supplementary Material 1).

Fig. 11. Oculo-facio-cardio-dental syndrome: oral view with macrodontia of maxillary central incisors.

omim:243800


7. Conclusion

Dental anomalies are innumerable in MCA syndromes. Although their true clinical impor-tance may be secondary in many complex and disabilitating disorders, good characterization ofthe dental phenotype may be helpful in early recognition of some progressive or highly variableconditions. The dental phenotype could be similar for different genotypes, adverse environmentor systemic anomalies, and thus the search of etiologic factors must be very accurate. Theycould sometimes be pivotal in the strategy of molecular screening. Clinical anomalies in syn-dromes are also a mean to make sense of the developmental pathways required for proper toothdevelopment.

Dental dysmorphology is still largely an unknown field. In many cases, dental dysmorphismis poorly or even incorrectly reported, partially because clinical dysmorphologists are poorlytrained in recognizing and accurately describing dental defects (including their radiologicalaspects) and partially because dentists are often unaware of the extra-odontologic aspects ofthe oral anomalies, with which they are associated. This review illustrates the importance tonote all other organ findings in case of dental abnormalities. It illustrates the importance ofteamwork between odontologists and geneticists.

Acknowledgements

The authors thank Dr M. Gert for explanations on collagen mutations.

Appendix. Supplementary data

Supplementary data associated with this article can be found, in the online version, atdoi:10.1016/j.ejmg.2008.05.003.

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