Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV doi: 10.2340/00015555-3428 biochemical Recent (2). material organic collagenous non- of traces with tissue mineralized 96%) imately Enamel is an epithelially derived and highly (approx malities mightoccurinvarious typesofEDS(Fig.1). modifying enzymes(1). collagen-encoding genesorinencodingcollagen- are causedbydisease-causingvariants(mutations)in EDS of types Most confirmation. diagnostic allow that genes known with monogenic, are which of 12 (1), sification recognizes 13 distinct types of EDS (Table I) blood vessels,andinternalorgans. The currentclas nective tissuefragility, mainlyaffecting skin, ligaments, nective tissuedisorderscharacterizedbyvariablecon E [email protected] of Innsbruck, Peter-Mayr-Straße 1, AT-6020 Innsbruck, Austria. E-mail: Corr: Acta DermVenereol 2020;100:adv00092. Accepted Feb 12,2020;EpubaheadofprintMar9,2020 nifestation; dentalanomaly. Key words: Ehlers-Danlos syndromes; hypermobility; oral ma EDS areboth rareandgenerally inconclusive. drome. Data on dental manifestations in other types of syn overlap imperfecta/EDS osteogenesis in consistent finding a is imperfecta Dentinogenesis (47.8%). fusion root molar and (34.8%), length root exceeding (52.2%), modifications shape were EDS vascular poplasia. Common dentalabnormalities observedin sical EDS were pulp calcification and localized root hy The maindentalfeatures listeddata analysis. inclas inthe withwere included aclinicaldiagnosisof EDS, control studies, reporting on atotal of 84individuals four individual and case reports/series 3 longer case- dental anomalies invarious types of EDS.Twenty- systematicallythe spectrum of published assessed data on the dental manifestations of EDS.This review fragility.tissue However,therearelimited published hypermobility, skin hyperextensibility, and variable byjoint disorderscharacterized ted connectivetissue 3 1 Ines KAPFERER-SEEBACHER Review Dental ManifestationsofEhlers-DanlosSyndromes: ASystematic Centenary theme section:GENODERMATOSES Ehlers-Danlos syndromes (EDS) areagroupinheri ofEhlers-Danlos(EDS) syndromes Acta DermVenereol 2020;100: adv00092 Service, Northwick Park Hospital,Harrow, UK Department ofDermatology,Chelsea&WestminsterHospitalNHSFoundationTrust,London,and Department of Operative and Restorative and The biology of dental tissues implies that tooth abnor genetically heterogeneousgroupofhereditarycon hlers-Danlos syndromes(EDS)areaclinicallyand Johannes Zschocke, Division of Human Genetics, Medical University 1 , Dagmar SCHNABL This isan open access article under the CC BY-NC license. www.medicaljournals.se/acta SYSTEMATIC REVIEW 1 , 2 Johannes ZSCHOCKE Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria, ------

types of collagens were isolated by differential salt differential by isolated were collagens of types (11). location anatomical specific its by terized Various regulate theprocessofmineral deposition(8). constituents matrix These (10). proteoglycans and (9) proteins non-collagenous of concentrations high with tooth development, odontoblasts secrete collagen fibrils tion, akey step in the formation ofdentine (7,8).During assembly of the collagenous matrixprior to mineraliza fluid. Electron microscopic studies have investigated the tubules harbourodontoblastcellprocessesandtissue from thedentino-enameljunctiontopulp(6). These and extending through the entire thickness of the dentine, work of dentinal tubules crossing the mineralized tissue proteoglycans. Histologicalstudieshaverevealedanet V collagen, associated with non-collagenous proteins and is enriched in type I collagen with traces of type III and 3-dimensional collagenous network. The organic matrix imately 70% hydroxyapatite crystals embedded in a synthesis andconsequentlyenamelformation. mation andmineralization,butalsorestrainamelogenin stages oftoothformation(5). They promotedentinefor studies haverevealedthatproteoglycanscontrolearly (4). Animal dentine to enamel bonding in VII collagen near thedentino-enameljunction,suggestingaroleof have localizedtype VII collagentotheorganic matrix studies Immunofluorescence 4). (3, VII and I collagen studies have found that enamel contains low amounts of reports was carried out. a systematic search of the medical literature for relevant practitioners, and dental medical for information specific Ehlers-Danlos syndromes, and create precise disease- In order toclarify the range of dental manifestations in problems can severely impactonpatients’ quality of life. (e.g. vascular and organ ruptures).Nevertheless, dental generalized joint hypermobility or life-threatening events serious systemic manifestations, suchascomplicationsof in Ehlers-Danlos syndromes are minor compared with the connective tissue diseases. Ingeneral, dentalproblems Ehlers-Danlos syndromes are a group of rare inherited SIGNIFICANCE The Dentine isamineralizedtissuecomposedofapprox dental pulpisalooseconnectivetissue charac Journal Compilation ©2020ActaDermato-Venereologica. 2 * andF. Michael POPE 4 EDS SyndromeNationalDiagnostic 3,4 - - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV of Ehlers-Danlossyndrome. tissues implies that tooth abnormalities might occur in various subtypes 1. Thetooth tissues. Fig. itssupporting and AD: autosomal dominant; AR: autosomal recessive. hard connectivetissuethatanchorstheperiodontalliga III and XII (2). Acellular in groundsubstance–predominantlycollagentypesI, embedded bundles fibre collagen well-defined contains bone. Itisahighlyspecializedconnectivetissueand porting tissuesandanchorsthetoothroottoalveolar respectively (12). collagen, total the of 2% and 41% 56%, represented precipitation andextraction. Types I,IIIand V collagen Table I.PresentandpastclinicalclassificationsofEhlers-Danlossyndromes(EDS),inheritancepatterngeneticbasis Hypermobile EDS (hEDS) Hypermobile EDS (hEDS) Unresolved forms of EDS Cardiac-valvular EDS (cvEDS) Brittle cornea syndrome (BCS) Brittle cornea syndrome(BCS) Spondylodysplastic EDS (spEDS) Myopathic EDS (mEDS) Musculocontractural (mcEDS) Kyphoscoliotic EDS (kEDS) Classical-like EDS (clEDS) Dermatosparactic EDS (dEDS) Arthrochalastic EDS (aEDS) Arthrochalastic EDS (aEDS) Periodontal EDS (pEDS) Genetically defined raretypes Vascular EDS (vEDS) Classical EDS (cEDS) Genetically defined frequenttypes New nomenclature,2017 The periodontal ligament belongs to the tooth-sup

root cementumisamineralized Hypermobility type EDS progeroid type Kyphoscoliosis type – Dermatosparactic type Arthrochalastic type Arthrochalastic type EDS periodontitis Vascular type Classical type Classical type nomenclature, 1998 Villefranche The biology of dental Hypermobile, EDS III Hypermobile, EDS III Cardiac-valvular EDS Brittle cornea syndrome Brittle cornea syndrome EDS, spondylocheiro-dysplastic EDS EDS progeroid,β3GalT6-deficient EDS EDS EDS Kosho type; D4ST1-deficient Adducted thumbclubfoot syndrome EDS VI; EDS VIA EDS VI;EDS VIA – Human dermatosparaxis, EDS VIIC EDS VIIA, EDS VIIB EDS VIIA,EDS VIIB Arthrochalasis multiplexcongenita, EDS VIII Arterial-ecchymotic, EDS IV Mitis, EDS II Mitis, EDS II Gravis, EDS I names Former nomenclature/other - - cementum, andpulp)invarious typesofEDS. This assess manifestationsofdental tissues(dentine,enamel, periodontal manifestations of EDS(15). reviewed we 2017 In EDS. of types individual among handle ingeneraldentalpracticeandvaryconsiderably to difficult are complications EDS of complexities The lacking. currently are information disease-specific cise specific oral symptoms, and treatment guidelines and pre may not be familiar with special requirements or disease- individuals affected by rarediseases; the generaldentist sionals are often overwhelmed with the medical care of and impaired hygiene procedures,time-consumingdentaltreatments, oral during pain include issues Major life. of quality systemic manifestations, they can strongly impact on life-threatening, sometimes severe, with comparison in EDS-related dentalproblemsmayappearlessrelevant of teeth and complicated tooth extractions (14). Although spontaneousfractures tory muscles,periodontaldisease, valence oforalproblems,includingpaininthemastica unspecified types of EDS (n large groupofadultswithEDS,mostlyhypermobile or (13). handicap and fort, Aa among study questionnaire quality oflifeduetophysicalpain,psychologicaldiscom form theorganic matrix. collagenous proteins,includingseveralproteoglycans, non- and XII) and III type of traces with I type (mainly approximately 50%inorganic hydroxyapatite.Collagen and adapts to mechanical loading. Cementum consists of attachment. The cellular cementum covers the apical root tooth is function main Its root. tooth the to fibres ment The aim of the present study was to systematically to was study present the of aim The Patients with EDS often have a low oral health-related ? COL1A2 ZNF469; PRDM5 ZNF469; PRDM5 SLC39A13 B4GALT7; B3GALT6; COL12A1 COL12A1 DSE DSE CHST14 PLOD1; FKBP14 TNXB TNXB ADAMTS2 COL1A1; COL1A2 C1R; C1S C1R; C1S COL3A1 (COL1A1) (COL1A1) COL5A1; COL5A2 Gene(s)

cosmetic appearance. Dental health profes Dental manifestationsofEDS ? loss of A2 chain) loss of A2 chain) Type I collagen (complete ZNF469; PRDM5 ZNF469; PRDM5 ZIP13 Galactosyltransferase I/II Collagen XII Collagen XII epimerase-1 Dermatan sulphate sulphotransferase-1 Dermatan-4 FKBP22 Lysyl hydroxylase 1; Tenascin XB ADAMTS-2 ADAMTS-2 exon 6 Type I collagen loss of C1r; C1s C1r; C1s Type III collagen p.Arg312Cys) I collagenmutation Type V collagen(Type Protein = 144), revealed a high pre Theme issue:Genodermatoses AD AR AR AR AD/AR AR AR AR AR AD AD AD AD pattern Inheritance 153 - - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Genodermatoses (iii ) clinical characteristics of dental manifestations; (iv) lable: avai as individual each for extracted were outcomes secondary manifestation(s). following dental The of type EDS subtype;(ii) (i) extracted: individually were outcome(s) main following The Data extraction and highriskofbiasifoneormorekeydomainswere“absent”. moderate risk of bias if one or more “present”, key domains as were judged “unclear”, were criteria quality all if bias of risk low groups: following the into classified was study Each (18). tralia) performed according to the Joanna Briggs Institute (Adelaide, Aus (Bethesda, MD, USA) (17). Quality assessment of case reports was were available from the National Heart, Blood, and Lung Institute Quality assessmenttoolsforcaseseriesandcase-controlstudies Quality assessment following factors: (i The heterogeneity of the included studies was evaluated based on Assessment ofheterogeneity discussed regularly. articles. Discrepancies detected during the selection process were in full-textassessmenttoavoidexclusionofpotentiallyrelevant listed thecriteria. Abstracts to with unclear regard methodology were included with checked were abstracts and Titles reviews. and studies, animal studies, laboratory culture cell were: criteria Exclusion included. were journals scientific peer-reviewed in studies, cohortcaseseries,andreportspublished 1969 to 2019). Clinical trials, case-control studies, cross-sectional There were no restrictions on publication date (available data from (iii) English, German, or Italian language; (iv) fulltextavailable. come: dental anomalies (enamel, dentine, cementum or the pulp); (ii) out EDS; of type any with affected individuals population: The inclusion criteria applied during the literature search were: ( Screening andselection on the reference lists of the selected articles and identified reviews. opengrey.eu) was browsed and a “manual search” was performed OR dentine OR dentinogenesis). In addition, grey literature (www. crodontia OR transposition OR “supernumerary teeth” OR enamel mi OR deformities” “root OR color” “tooth OR colour” “tooth OR “hypercementosis” OR stones” “pulp OR anomaly” “dental OR anomalies” “dental abnormality” “dental OR abnormalities” me” OR “joint hypermobility” OR JHS OR BJHS) AND (“dental syndro (“Ehlers-Danlos keywords: following the with searched (PubMed), LIVIVO, and Google Scholar.Medline Medline databases: (PubMed) electronic was following the in 2019 April 1 to up literature the searched systematically DS) (IK, authors Two Literature search strategy (PRISMA) guidelines(16)andwasregisteredatPROSPERO. Meta-Analysis and Review Systematic for Items Reporting red A systematic literature search was performed according to Prefer Protocol andregistration MATERIALS ANDMETHODS practicing clinicians. for implications clinical with EDS, of types specific in anomalies dental of delineation the allows approach 154 I. Kapferer-Seebacheretal. ) study design, and(ii) subjects’ characteristics. i ) ------editor (28) and 2 case reports (29, 30) were excluded were 30) (29, reports case 2 and (28) editor the to letter One 27). (26, disorders craniomandibular other thantoothanomalies,suchasaberrantfrenulaor manifestations oral on or (22–25), etc. therapy, caries on unspecific dental treatments, such asbut tooth extraction, (21), manifestations dental EDS on report not did studies Six 20). (19, EDS with patients including not imperfecta dentinogenesis on study cohort a was other the syndrome; Keratitis-ichthyosis-deafness with child a in treatment dental described one EDS: on report not evaluation. subsequent Twoafter excluded were 20 did Dutch) werealsoexcluded. or French (Japanese, languages other in studies 6 and or orthodontic treatment. Six reviews, 2 animal studies, specific oral treatments, such as wisdom tooth extraction disease, mucosalalterationsandaberrantfrenula,ornon- implants, temporomandibular joint disorders, periodontal other dental aspects in patients with EDS, such as dental not reportoneitherEDSortoothanomalies,covered did 45 these, Of abstract. and title on based excluded Out of a total of 106 studies identified originally, 59 were The articleselectionprocessisdocumentedinFig.2. RESULTS dental manifestationsinthepresentcohort. descriptive measures,suchasabsoluteandrelativefrequenciesof teristics available on the subjects level were analysed by standard selection process. and search literature study the illustrating diagram flow Meta-Analyses) PRISMA (Preferred Reporting Items for Systematic2. ReviewsFig. and Types andprevalenceofdentalmanifestations clinicalcharac clinical and/orgeneticdiagnosisof EDS; (v Reviews andMeta-Analyses; The PRISMA Statement.PLoSMed6(7):e10000097.doi:10.1371/journal.pmed1000097 From: MoherD,Liberati A, Tetzlaff J, Allman DG. The PRISMA group(2009).PreferredReportingItemsforS

Included Eligibility Screening Identification review, full-text for selected publications 47 of Out assessed foreligibility qualitative synthesis Records identifiedthrough Studies includedin Records afterduplicatesremoved Full-text articles Titles/abstracts database searching screened (n=106) (n=27) (n=47) (n=80) (n=106) Animal study(n=2) Language(n=6) Otheroralmanifestations(n=27) Nooralmanifestations(n=8) NotdealingwithEDS(n=10) Reviews(n=6) Records excluded(n=59): Nooriginalresearch(n=1) Nofulltext(n=2) Highriskofbias(n=8) Questionnairestudy(n=1) Nodentalmanifestations(n=6) NotdealingwithEDS(n=2) Full-text articlesexcluded(n=20): Additional recordsidentified through othersources ) EDS-specific features. (n=39) ystematic - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Table II.ClinicalstudiesondentalmanifestationsofclassicalEhlers-Danlos (cEDS)syndrome genetic on reported Twostudies scarring. atrophic and joint hypermobility, skinhyper-elasticity, easybruising, cEDS was based on the clinical characteristic features of Clinical manifestations( included studieswereof2different designs: (cEDS), reportedvariousdentalmanifestations. The ted individuals with classical Ehlers-Danlos syndromes Study characteristics. Seven studies, including 17 affec Classical Ehlers-Danlossyndromes kyphoscoliotic EDS. with one and (aEDS), EDS arthrochalastic with one EDS overlap syndrome, 2 with periodontal EDS (pEDS), dermatosparactic EDS, 3 with / 17 with cEDS, 10 with spondylodysplastic EDS, 3 with (vEDS), EDS vascular with 23 hEDS, with 24 review: systematic this in included were EDS with individuals 84 total, In 40). Twotwice. (39, reported were subjects of classicalEDS(cEDS)andhypermobile(hEDS) Two studies addressed only histological dental anomalies Population MP based on clinical descriptions provided in the paper. by reclassification necessitating EDS of classification and 5asmoderatequalityduetolackofdataorincorrect quality high as judged were 22 which of studies), trol reports/series with 1–3 individuals each and 3 case-con analysis (31–38). or EDS-specific manifestations were excluded from data dental on data insufficient to due bias of risk high with duction (14). Finally, after content classification, 8 papers intro the in mentioned is but quality, data insufficient of because analysis data clinical from excluded was study on EDS oral symptoms including 144 individuals questionnaire One available. was text full no because n/a: not available. was validated by inspectionof theorthopantomographs provided. 2005 (41) excluded). No crown malformations or were reported. None of the individuals presented with or periodontal bone loss, which Six case reports/series and 1 case-control study on a total of 17 individuals with cEDS were published to April 2019. Age range was 11–40 years (with De Coster et al., De Coster etal., 2005 (41) (n Cho, 2011 (42)(n Authors Sadeghi et al., 1989 (47) (n Selliseth, 1965(46)(n Premalatha etal., 2010(45) (n Pope et al., 1992 (44) (n Hakki etal., 2017(43)(n • • • The review thus included a total of 27 articles (24 case analyses (44). histological provided also series case clinical 1 40); Histological studiesonextractedteeth(n 1–3 affected individuals)(42–47). Case reportsandseries(n Case-control studies(n = 1) = 1) = 3) = 1) = 1) = 9) = 1) Table II). The diagnosisof = 1) (41). = No stones/obliterations Pulp calcification:pulp Yes Yes N/a Yes (n Yes Yes Yes (n 6; with sample sizes of sizes sample with 6; = 3) = 9) = 2) (39, 2) Yes aplasia, bulbousroots Root deformities:hypo-, Yes Yes N/a Yes (n Yes Yes (n - - - = 3) = 2) Study characteristics. Two case-control studies investiga Vascular Ehlers-Danlossyndromes and postnatallylocatedincrementallines. a high frequency of postnatally hypomineralized enamel focused on enamel analysis of primary teeth, exhibiting of irregular size and diameter (40). Klingberg et al. (39) and irregularly branched; collagen fibres were short and ill-defined (enlarged), dysplastic were tubules dentinal tubules. dentinal the of Across-sections and of number (40) reported on consistently fewer uniform dimensions gated samples. Both Pope et al. (44) and De Coster et al. strated significant structural abnormalities in all investi demon tissues dental The 44). 40, (39, teeth extracted reported onhistologicalandultrastructuralfeaturesof teeth 26 including papers Three Histological analysis. by inspectionofthepublishedorthopantomographs. tooth discoloration or hypodontia, the latter was validated rary teeth (42, 45). None showed crown malformations, rather than more common dental pathologies, such as formation dentine affected vEDS with patients with Clinical manifestations.Dentalabnormalitiesobserved of toothnumber, shapeandstructures. radiographs and bitewings were Panoramic examined for anomalies. anomalies pulp or root as well as injury), abnormalities andsecondarylesions(decay, traumatic were clinically and radiologically assessed for structural connective tissue diseases (41, 48). In both studies, teeth cardiovascular, endocrine,haematological,infectious or and 95 age- and sex-matched controls with no history of and genetically diagnosed vEDS (age range 4–61 years) ted dental manifestations in 23 individuals with clinically (43,44). root aplasiamayleadtoprematuretoothlossmimicking Technically,(44). individuals 9 in roots bulbous severe of toothroots,alsodescribedasshortenedorsometimes cEDS changesincludedlocalizedaplasiaorhypoplasia stones to complete pulp obliteration. Other typical pulp dental single from ranging calcification, pulp variable distribution was36%maleto64%female. sex years; 11–40 was range age The 43). (41, testing Two of 17 patients with cEDS showed 2–5 supernume showed cEDS with individuals 17 of out Fifteen 23, 24 No No N/a No No No (code ofteeth) Tooth transposition Dental manifestationsofEDS Theme issue:Genodermatoses Supernumerary teeth number Abnormalities intooth No No Supernumerary teeth No No No 155 - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV or tooth discolorations. If notstatedotherwise,number(n Two case-controlstudieson23individualswithclinicallyandgenetically diagnosedvEDS werepublisheduptoApril2019.Noneof thecasesreportedcrownmalformations Table III.ClinicalstudiesondentalmanifestationsofvascularEhlers-Danlossyndrome(vEDS) Clinical manifestations ( Theme issue:Genodermatoses Table IV.Clinicalstudiesondentalmanifestationsofhypermobile Ehlers-Danlossyndrome(hEDS) of None reported. discoloration tooth or malformations crown were cases the of none In 53). (50, individuals 2 in reported were teeth single of transposition and/or Rotation 56). 51, (49, reported were teeth pernumerary su 1–8 individuals, 4 In 53). 50, (41, individuals 24 of out 5 in reported were roots shortened and/or stones, Partial ortotalpulpobliterationsofseveralteeth, al. 2005(41)). females (noabsolutefrequenciesgivenbyDeCosteret from 10 to 15 years, sex distribution was 6 males and 2 permobility without major features of EDS. Ages hy ranged joint obvious on primarily based was hEDS of sis (hEDS). The included studies were of 2 different designs: manifestations inhypermobileEhlers-Danlossyndromes dental on reported individuals, affected 24 including studies, clinical 9 of total Study characteristics. A Hypermobile Ehlers-Danlossyndromes ted enamel opacities, possiblyduetocaries(Table III). morphology. De Coster et al. (41) reported on demarca crown or number tooth in observed were abnormalities in 34.8%, and molar root fusion in 47.8% of patients. No root length,especiallyinthesecondmandibularmolars cation occurred. Root malformations included exceeding in 52.2% of patients with vEDS; however, no pulp calcifi difications (e.g. reduction in pulp volume) were reported caries, pain or periodontal features (48). Pulp shape mo 156 the provided orthopantomographs. cases, crown malformations or tooth discolorations were reported. None of the individuals presented with periodontal bone loss, which was validated by inspection of Seven case reports/seriesand onecase-control study on23individualswithhEDS werepublisheduptoApril2019.Agerange was 10–15years of age.Innone of the Ferre et al., 2012 (48) (n De Coster etal., 2005 (41) (n Authors Awal etal., 2015(49)(n Authors Cohen-Levy & Cohen,2014(50)(n De Coster etal., 2005 (41) (n Ferreira et al., 2008(56) (n Norton, 1997=1984 (54) (n Melamed etal., 1994(51) (n Kaurani etal., 2014(55) (n Yassin & Rihani, 2006(53)(n • • There were no consistent dental features reported. features dental consistent no were There (Norton & Assael (52)andNorton(54)). described thesameindividualonseparateoccasions reports case Two 49–56). (41, individuals) affected Case reportsandseries(n Case-control studies(n I. Kapferer-Seebacheretal. = 1) = 17) = 1) = 1) = 1) = 2) = 1) = 6) = 16) Table IV). The clinical diagno = 1) = = 1) (41). 8; with sample sizes of 1–2 obliteration Pulp stones, Pulp calcification: No Yes Yes (n No N/a No No Yes 0 n (%) number Abnormalities intooth 0 = 3) ) and percentage (%) of affected individuals are given. Malocclusion Yes Yes Not available No Not available Not available Yes No ------12 (70.6) n (%) modifications Pulp shape 0 scoliotic EDS,pEDS,spondylodysplasticandos These includedaEDS,dermatosparacticEDS,kypho­ nifestations in 20 individuals with rare subtypes of EDS. published up to April 2019 described various dental ma reports/series case clinical Nine Study characteristics. Rare subtypes lines. The dentinewasalwaysnormal. mineralized enamelandpostnatallylocatedincremental hypo postnatally of areas exhibited teeth 9 of out Four primary teeth of individuals diagnosed with hEDS (39). paper,one by reported were teeth extracted 8 including Histological analysis.observationsof tion oftheorthopantomographsprovided. both thedentineandpulp. tooth demonstratedabnormalcollagenouspatternsin extracted an of examination Microscopic present. were teeth deciduous of abnormalities root or modifications, oration and (60). No pulp stones, pulp shape on availableX-rays. evident or reported were abnormalities other No (59). ded irregularocclusalmorphologyandmalocclusion localized toothpulpobliteration(n enamel of the deciduous dentition (n ous molars(n teeth (n permanent 4 of agenesis included individuals separate Dental features of dermatosparactic EDS described in 3 Clinical andhistologicalmanifestations( individual was separately included in 2 papers (57, 58). teogenesis imperfecta (OI)/EDS overlap syndrome. One the individualshadhypodontia,asvalidatedbyinspec In acaseofkyphoscolioticEDSdentalchangesinclu One female diagnosed with transposition Rotation, No Yes Not available No Not available Not available No Yes = 2), irregular occlusal morphology of decidu of morphology occlusal irregular 2), 8 (47.1) n (%) Root fusion 0 = 2), localized tooth discoloration (n discoloration tooth localized 2), number Abnormalities intooth Supernumerary teeth No No Supernumerary teeth Supernumerary teeth No No Hypodontia n (%) Exceeding rootlength 11 (64.7) 0 aEDS had enamel discol = 1) (58). findings Other dental Ectopic tooth None None None Odontokeratocyst None None None Table V). n (%) calcification Pulp 0 0 = 2), and 2), = 2), ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV (48). Root abnormalities, including root fusion (50%) or fected individuals, but in only 30% of healthy individuals malformed pulp chambers, were reported in 75% of af shape modifications, such as decreased pulp volume and of 23 affected individuals and 96 healthy controls. Pulp control studiesevaluatedoralmanifestationsinatotal case- TwovEDS. for available is abnormalities dental tissue abnormalitiesinspecifictypesofEDS. adequate informationontheprevalenceofdentalhard- (15). periodontitis and cEDS Weprovide to aimed now with individuals any reveal not did data published of aplasia (44). In contrast, our recent systematic evaluation root to due teeth of loss early describing individuals 3 (70). This assumption isbased onacase series including duals affected bycEDSareathigherriskofperiodontitis Peri-Implant Diseases and Conditions claims that indivi and Periodontal of Classification recent the example, For assumptions. incorrect various to led has evidence of Lack EDS. of phenotypes oral the of understanding features inEDSfromotherconditionshaveconfusedthe dental separating of problems and confirmation genetic of absence the Previously, unknown. is relevance and tal anomaliesinEDS(66–69),butthetrueprevalence Various narrative reviews and case reports describe den DISCUSSION further abnormalitieswerereported. No dente. in dens a with presented individual other the and supernumeraryteethoccurredinoneindividual, and 10 years, diagnosed with 7 aged children, 2 in destruction periodontal than other level ofcalcification. structure orqualityofcollagenandnottoadecreased abnormal the to attributed was which controls, the of those than lower significantly was dentine and enamel dentinal tubules. The hardness and elasticity of probands’ typical of loss and masses calcified unorganized tained Table V.ClinicalstudiesondentalmanifestationsofraretypesEhlers-Danlossyndromes(EDS) n/a: not available; OI: osteogenesis imperfecta. Nine case reports/series on 20 individuals diagnosedwithrare subtypes of EDS were published up to April 2019. subjected to histological analysis (61). The dentine con was incisor primary exfoliated malformed severely A were diagnosed with dentinogenesis imperfecta (61–63). Ooshima et al., 1990 (60) (n Authors Nicholls et al., 2000 (62) (n Shi etal., 2015 (63)(n Budsamongkol etal., 2019(61) (n Van Damme et al., 2018 (65) Majorana & Facchetti, 1992(64)(n Arun etal., 2006 (59) (n Malfait etal., 2004(58)=De Costeretal., 2003 (57)(n Three individuals with individuals Three To date, the strongest evidence of disease-specific of evidence strongest the date, To features dental described (64) Facchetti & Majorana = 1) 1) = 1) = 1) 1) = 1) ( n = 10) = 1) = 2) OI/EDS overlapsyndrome pEDS. Pulp calcifications 3) = 3) EDS type OI/EDS overlap syndrome OI/EDS overlap syndrome OI/EDS overlap syndrome Spondylodysplastic EDS Periodontal EDS Kyphoscoliotic EDS dDermatosparactic EDS Arthrochalastic EDS - - - -

dermatosparactic EDS(n has also been reported in individuals with hEDS (n carious and/or tooth restorations (70). Pulp calcification as such irritants, chronic to response a is calcification homeostasis. The general opinion is that pulp chamber implies a regulatory function of collagen V in pulp heterozygous mutations in COL5A1 or COL5A2, this by mainly caused is cEDS Since individuals. 15/17 in (Fig. 3), is a common finding in cEDS and was reported findings werereported. cification, abnormalities in tooth number or other dental showing pulpstones(blackcircle)in themandibularrightfirstmolar and genetically diagnosed with periodontal Ehlers-Danlos syndrome (pEDS), Fig. 3.Pulp stones. Dental radiograph of a 41-year-old woman, clinically controls (20% and 2%, respectively) (48). No pulp cal pulp No (48). respectively) 2%, and (20% controls in than vEDS with diagnosed genetically and clinically molars, were significantly more prevalent in individuals exceeding rootlength(69%),especiallyinmandibular Calcification of the pulp,i.e.stonesorobliteration Dental abnormalitiesreported Dentinogenesis imperfecta Dentinogenesis imperfecta Dentinogenesis imperfecta Hypodontia; hypoplastic teeth; dentinogenesis imperfecta One supernumerary tooth;densin dente; malocclusion Crown malformations; malocclusion discoloration; irregular occlusal morphology Agenesis of two teeth; pulp calcifications; shortenedroots;tooth Tooth discoloration; crown malformation Dental manifestationsofEDS = 1) and pEDS (n pEDS and 1) Theme issue:Genodermatoses = 1). Howe 1). = 5), . 157 - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Genodermatoses OI, aswellaEDSandcardio-valvular EDS. faulty structuralproteinresponsible formanytypesof (which are normal in aEDS). Type I collagen is the major microscopy of dermal cutaneous collagen fibril patterns aEDS vs. mutations between exons 7 and 16) or electron DNAin mutations deletion or splicing 6 (exon analysis fractures. aEDS is distinguishable from OI/EDS both bone by variable with hypermobility joint increased and mutations typically cause dentinogenesis imperfecta tion, N-terminal helical collagen also known as OI/EDS overlap syndrome. In this condi 166200), OMIM (OI; I type imperfecta osteogenesis of forms milder certain with overlaps also disorder This bility andassemblyoftriplehelicalcollagentype I. sta altered consequence, in and, 617821) and 120160 collagen by procollagen N-propeptidase (OMIM 130060, alpha2(I) or alpha1(I) either of propeptide N-terminal COL1A2, leadingtofailureenzymaticallyremovethe aEDS iscausedbylossofexon6ineitherCOL1A1or tion the presenting finding in a high number of patients. joint hypermobility, with bilateral congenital hip disloca severe particularly by characterized is which aEDS, of test thishypothesis. to needed are cEDS validated with cohort a in studies prospective Further EDS. of type this of manifestation dental specific a is aplasia root that possible appears it ming that these individuals may also have had cEDS, Assu 35). (32, EDS of subtyping clinical appropriate case reports with identical dental phenotype, but without the lower front teeth (43, 44). There were also 2 further clinical phenotypeofsevererootaplasiarestrictedto identical an with presented cEDS with patients Four the course of periodontitis requires periodontal treatment. tooth mobilityfromreducedperiodontalattachmentin splinted tominimizesubsequentboneloss.Incontrast, securely be should roots hypoplastic with teeth mobile essential, as adequate treatment is completely different: (44). The diagnostic distinction of these 2 pathologies is of thetoothcanmimiclocalizedperiodontaldestruction loosening Subsequent cEDS. to specific and common or localizedroothypoplasia(shortenedroots)isboth endodontic therapy(72). stones shouldnotbeinterpretedasadisorderrequiring the absenceofanyadditionalsignsorsymptoms,pulp In (72). anatomy internal the alter and orifices canal to their large sizeinthepulpchambermayblockaccess and treatments, canal root complicates calcification However, (71). variation biological or pathology sents or subjective symptoms, it is not clear whether it repre disease pulp cause usually not does calcification Since be acoincidenceratherthandiseasemanifestation. may cases individual in calcification pulp and EDS of the general population (71), and the mutual in presentation calcification pulp of prevalence high a is there ver, 158 Dentinogenesis imperfectaisararepublishedfeature enlargement bulbous with dentinogenesis Defective I. Kapferer-Seebacheretal. COL1A1 andCOL1A2 - - - - - manifestations of various EDS subtypes (15) and identi themselves, mostly isolated cases were reported; there reported; were cases isolated mostly themselves, majority ofreports.Duetotheraritysyndromes data supportingaparticulardiagnosisaremissinginthe fail toadequatelyspecifyEDStyping,andmolecular descriptions dental with cases published Many papers. EDS type based on molecular data was missing in themany of Specification limitations. substantial has EDS of EDSaremissing. analyses ofperiodontalmanifestationsinmostsubtypes stringent manifestations, dental like Just EDS. of types not appeartobepartoftheclinical phenotype ofother severe periodontitisisthehallmarkofpEDS,butdoes tic EDS (58). Our systematic review concluded that early ment was described in 3 individuals with dermatosparac enlarge gingival Severe rare. were EDS of types other in manifestations periodontal on Reports (48). patients a papyraceous aspect) was observed in 94% of affected the gingiva and the mucosa, and decreased stippling with val phenotype(generalizedthinnessandtranslucencyof more likelyrepresentpEDS.InvEDS,aparticulargingi hEDS (74), although with from current one knowledge these in cases and (73) vEDS with diagnosed clinically severe periodontitis was also reported in one individual Early features. predominant the were gingiva, attached gingival recession (87.1%), as well as a striking lack of of EDS. In pEDS, early severe periodontitis (98.4%) and fied 30 articles on pEDS and 13 articles on other subtypes REFERENCES are inconclusive. 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