Orthodontic Treatment of a Patient with Dentin Dysplasia Type I and Bilateral Maxillary Canine Impaction: Case Presentation and a Family-Based Genetic Analysis

Home , Dentin dysplasia, Maxillary canine

children

Case Report Orthodontic Treatment of a Patient with Dentin Dysplasia Type I and Bilateral Maxillary Canine Impaction: Case Presentation and a Family-Based Genetic Analysis

Alexandros Papagiannis 1,* , Galinos Fanourakis 2, Anastasia Mitsea 3 , Kety Karayianni 3, Heleni Vastardis 1 and Iosif Sifakakis 1

1 Department of Orthodontics, School of Dentistry, National and Kapodistrian University of Athens, 2 Thivon Str, 11527 Athens, Greece; [email protected] (H.V.); [email protected] (I.S.) 2 Department of Oral Biology, School of Dentistry, National and Kapodistrian University of Athens, 2 Thivon Str, 11527 Athens, Greece; [email protected] 3 Department of Oral Diagnosis and Radiology, School of Dentistry, National and Kapodistrian University of Athens, 2 Thivon Str, 11527 Athens, Greece; [email protected] (A.M.); [email protected] (K.K.) * Correspondence: [email protected]

Abstract: Dentin dysplasia is a rare hereditary disorder, transmitted by autosomal dominant mode, affecting both dentin and pulp. In Type I crown morphology is normal, but root dentin organization loss leads to shorter roots. Mutations in the SSUH2, VPS4B and SMOC2 genes have been reported as responsible for this condition. Orthodontic treatment was conducted on an 11-year-old female patient presenting the disorder along with bilaterally impacted permanent maxillary canines, in

close proximity to the roots of the lateral and central incisors. Treatment plan included lateral incisors extraction, surgical exposure and traction of the impacted canines. Light forces were applied

Citation: Papagiannis, A.; from a custom-made trans-palatal arch. Comprehensive orthodontic treatment was performed using Fanourakis, G.; Mitsea, A.; edgewise appliances. After 3 years and 2 months, group function occlusion was achieved. The canines Karayianni, K.; Vastardis, H.; underwent composite resin restorations. At one year post-retention, the dentition remained stable. Sifakakis, I. Orthodontic Treatment of Family-based genetic analysis did not reveal any mutations in the aforementioned genes pointing to a Patient with Dentin Dysplasia Type further genetic heterogeneity of this disorder. As dental medicine becomes more sophisticated and I and Bilateral Maxillary Canine personalized, the association between mutation type/function and orthodontic treatment response Impaction: Case Presentation and a may provide useful therapeutic insights. The positive treatment response of the presented case could Family-Based Genetic Analysis. be attributed to a more “benign” mutation awaiting to be identified. Children 2021, 8, 519. https:// doi.org/10.3390/children8060519 Keywords: dentin dysplasia type I; impacted canines; orthodontic treatment; genetic analysis; aesthetic restoration Received: 27 May 2021 Accepted: 16 June 2021 Published: 18 June 2021 1. Introduction Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in Dentin Dysplasia type I (DD-I) is a rare genetic developmental disorder that may exhibit published maps and institutional affil- an autosomal dominant pattern of inheritance and occurs in 1:100,000 individuals [1,2]. It iations. affects both the primary and permanent dentitions [3–5]. Clinically, the teeth present nearly normal crown morphology. However, malformed, short or absent roots [6], tooth mobility [7] or premature exfoliation may be observed. Delayed tooth eruption has also been reported in some cases [6,7]. Radiographic findings are key diagnostic tools in identifying the condition [8]. Roots Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. appear to be short, blunt, tapered or even absent [6,7]. Obliteration of pulp chambers is also This article is an open access article observed, with crescent-shaped pulp remnants parallel to the cementoenamel junctions [8]. distributed under the terms and Roots with obliterated pulp canals, as well as periapical radiolucent areas, associated with conditions of the Creative Commons absence of carious lesions, or any other kind of pathology, are common findings in patients Attribution (CC BY) license (https:// with DD-I [4,6–10]. creativecommons.org/licenses/by/ O’Carroll et al. [10] have introduced a subclassification of DD-I, based on radiographic 4.0/). characteristics: DD-Ia presents complete obliteration of the pulp, little or no root devel-

Children 2021, 8, 519. https://doi.org/10.3390/children8060519 https://www.mdpi.com/journal/children Children 2021, 8, 519 2 of 13

opment, periapical lesions and tooth exfoliation. In DD-Ib, roots are extremely short and conical, presenting a horizontal crescent-shaped line along the cementoenamel junction. In DD-Ic, roots are half their normal length with two crescent-shaped horizontal lines concave towards each other. DD-Id roots have normal length and a pulp chamber is evident at the cementoenamel junction. Pulp stones are common findings. The characteristic pattern of DD-I indicates that a genetic background is responsible for the condition. SPARC-related modular calcium binding protein 2 (SMOC2) is a protein encoded by the SMOC2 gene, which encompasses 14 exons, lies in chromosome 6q27 and has been shown to be mutated in similar dental developmental defects [11]. Vacuolar protein sorting 4 homolog B (VPS4B) gene is located in chromosome 18 and has been identified as a disease-causing gene for DD-I [12]. Furthermore, a study using a large Chinese family with 14 DD-I patients revealed a missense mutation in the Ssu-2 homolog (SSUH2) gene, that disrupts normal dental formation and causes autosomal dominant DD-I [13]. These articles suggest that different mutations can result in the same phenotype and that DD-I exhibits genetic heterogeneity [14]. Identification of specific genetic variants on DD-I relevant genes associated with successful treatment results could allow clinicians to conduct treatment that would otherwise be considered venturesome. Although there are several dental case reports in the literature on patients with DD-I [5,6,15–17], there is little evidence of patients being treated with comprehensive orthodontic treatment [18]. The purpose of this article was to describe the orthodontic treatment of a female adolescent patient with DD-I, also presenting with two maxillary impacted canines. Clinical considerations about the treatment plan were discussed, as well as the limitations set by this disorder. Furthermore, the presence of the most common DD-I gene mutations was investigated.

2. Case Presentation An 11-year-old girl with a chief complaint of non-erupted maxillary permanent canines was referred for treatment to the Orthodontic Clinic of the Dental School. Her father was diagnosed with Dentin Dysplasia Type I. Permission was obtained from father and daughter to use the diagnostic records (initial, progress, ﬁnal), including photographs and X-rays, for scientiﬁc reasons.

2.1. Clinical Findings and Diagnosis Extra-oral examination of the child revealed a convex profile, slightly reduced lower facial height and increased labionasal angle. Intra-oral clinical examination showed a mixed dentition in Class II molar relationship, reduced overjet (2 mm) and overbite (10%) (Figure1). Patient’s oral hygiene was good. The pre-treatment panoramic radiograph revealed short root length of most of the teeth, delayed tooth eruption, obliteration of pulp chambers and periapical radio-lucencies, not associated with periodontal disease or pulp inflammation. Horizontal crescent-shaped lines along the cementoenamel junction were evident in several teeth. Based on radiographic characteristics, this patient was subclassified as DD-Ic [10]. The permanent maxillary canines were impacted (Figure1). Pre-treatment cone-beam-computed-tomography scans showed that the upper right maxillary canine (#13) was labially impacted; the con- tralateral canine (#23) displayed a more palatal position. Both teeth were above the roots of the adjacent lateral incisors, in close proximity to them and to the roots of the central incisors (Figure2). Sclerosis of the maxilla and the mandible was absent in this case, as well as in the skeleton (Figure3). ChildrenChildren2021 2021, 8,, 8 519, x FOR PEER REVIEW 3 3of of 13 13 Children 2021, 8, x FOR PEER REVIEW 3 of 13

FigureFigure 1. 1.Pre-treatment Pre-treatment extra-extra- andand intra-oralintra-oral photographs. Figure 1. Pre-treatment extra- and intra-oral photographs.

Figure 2. Pre-treatment panoramic radiograph and Cone Beam Computed Tomography 3D reconstruction of the maxilla, showing the impacted upper canines (R: right, L: left, upper canines dis- Figure 2. Pre-treatmentFigure 2. Pre-treatment panoramicplayed radiographin panoramic red). and radiograph Cone Beam and Computed Cone Beam Tomography Computed 3DTomography reconstruction 3D recon- of the maxilla, showing the impactedstruction upperof the caninesmaxilla, (R:showing right, L:the left, impacted upper canines upper canines displayed (R: in right, red). L: left, upper canines displayed in red).

Children 2021, 8, x FOR PEER REVIEW 4 of 13

Children 2021, 8, 519 4 of 13 Children 2021, 8, x FOR PEER REVIEW 4 of 13

Figure 3. Hand-wrist and long bone radiographic presentation of the daughter exhibiting no osse- ous defects. FigureFigure 3.3. Hand-wrist and and long long bone bone radi radiographicographic presentation presentation of the of thedaughter daughter exhibiting exhibiting no osse- no osseousous defects. defects. Pre-treatment cephalometric analysis showed no considerable deviations from the Pre-treatmentPre-treatment cephalometriccephalometric analysisanalysis showedshowed nonoconsiderable considerable deviationsdeviations fromfrom the the norms, except fornorms,norms, the anterior exceptexcept forfor facial the anteriorheight facial (UFH/TFH height height (UFH/TFH (UFH/TFH = 47%; LFH/TFH = =47%; 47%; LFH/TFH LFH/TFH = 53%), = 53%), facial = 53%), facial con- facial convexity (Z-angle =convexity 67°),vexity inclination (Z-angle (Z-angle = 67°), of = 67inclinationthe◦), lower inclination of central the oflower the incisors central lower (IMPA centralincisors incisors (IMPA= 98°) =and (IMPA 98°) labionasal and = labionasal 98◦) and angle (119°) (Figurelabionasalangle 4). (119°) angle (Figure (119 ◦4).) (Figure 4).

Figure 4. Pre-treatment lateral cephalometric radiograph and cephalometric analysis. *: ±1 Standard Deviation from the norm (light blue), **: ±2 Standard Deviations from the norm (orange), ***: ±3 Standard Deviations from the norm (red).

FigureFigure 4. Pre-treatment 4. Pre-treatment lateral cephalometric lateral cephalometric radiograph and radiograph cephalometric and analysis. cephalometric *: ±1 Standard analys Deviationis. *: ±1from Standard the normDeviation (light blue), **:from±2 Standardthe norm Deviations (light blue), from the **: norm ±2 St (orange),andard ***: Deviations±3 Standard from Deviations the norm from the(orange), norm (red). ***: ±3 Standard Deviations from the norm (red).

Children 2021, 8, x FOR PEER REVIEW 5 of 13

Children 2021, 8, 519 5 of 13

2.2. Treatment Objectives 2.2.The Treatment diagnosis Objectives was set from clinical and pre-treatment radiographic findings. Treat- ment planThe diagnosisincluded wasextraction set from of clinical the upper and pre-treatmentlateral incisors, radiographic surgical exposure findings. of Treatment the im- pactedplan included canines extractionand canine of thesubstitution upper lateral of the incisors, extracted surgical lateral exposure incisors. of the The impacted upper lateral canines incisorsand canine were substitution extracted, of since the extracted they presented lateral incisors. poor long-term The upper prognosis, lateral incisors due wereto the extracted, short, malformedsince they presentedroots and poorthe reduced long-term crown prognosis, to root due ratio, to not the short,only because malformed of the roots disorder, and the butreduced possibly crown also to because root ratio, of notthe only interference because ofof the the disorder, upper canines but possibly with also the becauseroots of of the the lateralinterference incisors. of the upper canines with the roots of the lateral incisors.

2.3.2.3. Treatment Treatment Planning Planning TheThe orthodontic orthodontic treatment treatment was was initiated initiated with with the canine the canine exposure exposure (Figure (Figure 5) and5) trac- and tiontraction with light with forces light forces using usinga custom-made a custom-made trans-palatal trans-palatal arch for arch anchorage for anchorage purposes purposes (Fig- ures(Figures 6 and6 7).and An7). open An opensurgical surgical technique technique (apically (apically positioned positioned flap) was ﬂap) used was to used expose to theexpose labially the positioned labially positioned right canine right and canine a closed and technique a closed for technique the left, for which the left,was whichposi- tionedwas positioned palatally. Sectional palatally. mechanics Sectional were mechanics applied were during applied treatment during until treatment the eruption until theof alleruption permanent of all teeth permanent (Figure teeth8). The (Figure upper8 ).late Theral upperincisors lateral were incisors extracted were after extracted the success- after fulthe eruption successful of the eruption impacted of thecanines impacted and fo caninesr aesthetic and reasons. for aesthetic Subsequently, reasons. Subsequently,comprehen- sivecomprehensive orthodontic orthodontictreatment was treatment performed was performed using fixed using 0.018-inch-slot ﬁxed 0.018-inch-slot edgewise edgewise appliances.appliances. A lower A lingual lower lingual arch was arch placed was placedto preserve to preserve the leeway the leeway space thus space helping thus helping with thewith lower the crowing. lower crowing. The progression The progression of the ar ofchwire the archwire sequence sequence was from was 0.014-inch from 0.014-inch nickel- titaniumnickel-titanium to 0.016-inch to 0.016-inch Australian Australian archwires. archwires. Class III Class light IIIelastic light forces elastic were forces used were bilat- used erallybilaterally to help to with help space with spaceclosure closure on the on upper the upper arch. arch.

FigureFigure 5. 5.SurgicalSurgical exposure exposure of of the the upper upper right right (a ()a and) and left left impacted impacted canines canines (b (b).).

Children 2021, 8, 519 6 of 13 Children 2021, 8, x FOR PEER REVIEW 6 of 13 Children 2021, 8, x FOR PEER REVIEW 6 of 13

FigureFigure 6.6. TheThe custom-madecustom-made trans-palataltrans-palatal archarch usedused forfor thethe tractiontraction ofof thethe impactedimpacted canines.canines. Figure 6. The custom-made trans-palatal arch used for the traction of the impacted canines.

Figure 7. Progress photographs of the custom-made trans-palatal arch used for the traction of the impacted canines. Figure 7. ProgressProgress photographs of the custom-made trans-palatal arch used for the traction of the impacted canines.

Children 2021, 8, x FOR PEER REVIEW 7 of 13

Children 2021, 8, 519 7 of 13 Children 2021, 8, x FOR PEER REVIEW 7 of 13

Figure 8. Sectional mechanics used for the traction of the impacted canines.

2.4. Treatment Results After a total treatment of 3 years and 2 months, a group function occlusion was achieved, with positive overjet and overbite. No interferences in the non-working side were present with lateral movements. The canines underwent composite resin restorations to resemble the lateral incisors (Figure 9). The post-treatment lateral cephalometric analysis did not reveal considerable FigureFigure 8.8. SectionalSectional mechanicsmechanics usedused forfor thethe tractiontraction ofof thethe impactedimpacted canines.canines. changes (Figure 10). Upper and lower anterior facial heights remained approximately the 2.4.2.4.same TreatmentTreatment (UFH/TFH ResultsResults = 46%; LFH/TFH = 54%), and so did the inclination of the lower incisors (IMPA = 97°). Labionasal (100°) and Z-angles (75°) improved and a more pleasant soft AfterAfter aa totaltotal treatmenttreatment ofof 33 yearsyears andand 22 months,months, aa groupgroup functionfunction occlusionocclusion waswas tissue profile was established. achieved,achieved, withwith positivepositive overjetoverjet andand overbite.overbite. NoNo interferencesinterferences inin thethe non-workingnon-working sideside The post-treatment radiographic evaluation showed no further root resorption (Fig- werewere presentpresent with with lateral lateral movements. movements. The The canines canines underwent underwent composite composite resin resin restorations restora- ure 11). totions resemble to resemble the lateral the lateral incisors incisors (Figure (Figure9). 9). The post-treatment lateral cephalometric analysis did not reveal considerable changes (Figure 10). Upper and lower anterior facial heights remained approximately the same (UFH/TFH = 46%; LFH/TFH = 54%), and so did the inclination of the lower incisors (IMPA = 97°). Labionasal (100°) and Z-angles (75°) improved and a more pleasant soft tissue profile was established. The post-treatment radiographic evaluation showed no further root resorption (Fig- ure 11).

FigureFigure 9. 9.Post-treatment Post-treatment extra- extra- and and intra-oral intra-oral photographs. photographs.

The post-treatment lateral cephalometric analysis did not reveal considerable changes (Figure 10). Upper and lower anterior facial heights remained approximately the same (UFH/TFH = 46%; LFH/TFH = 54%), and so did the inclination of the lower incisors (IMPA = 97◦). Labionasal (100◦) and Z-angles (75◦) improved and a more pleasant soft tissue proﬁle was established. Figure 9. Post-treatment extra- and intra-oral photographs.

Children 2021, 8, x FOR PEERChildren REVIEW2021 , 8, 519 8 of 138 of 13

Children 2021, 8, x FOR PEER REVIEW 8 of 13

FigureFigure 10. Post-treatment 10. Post-treatment lateral cephalometric lateral cephalometric radiograph and radiogra cephalometricph and analysis. cephalometric *: ±1 Standard analysis. Deviation *: ±1 from Stand- the normard (light Deviation blue),Figure **: from± 10.2 StandardPost-treatment the norm Deviations (light lateral blue), from cephalometric the **: norm ±2 Standard (orange), radiogra ***:ph Deviations and±3 Standardcephalometric from Deviations the analysis. norm (red). *: (orange), ±1 Stand- ***: ±3 Standard ardDeviations Deviation (red).from the norm (light blue), **: ±2 Standard Deviations from the norm (orange), ***: ±3 Standard DeviationsThe (red). post-treatment radiographic evaluation showed no further root resorption (Figure 11).

FigureFigure 11. Post-treatment11. Post-treatment panoramic panoramic radiograph. radiograph. No rootNo root resorption resorption was was observed observed (R: right,(R: right, L: left). L: left). 2.5. Retention Figure 11.2.5. Post-treatment Retention The panoramic retention radi protocolograph. included No root bonded resorption retainers was between observed #13–23 (R: and right, #33–43 L: (0.0215- left). The retentioninch twistﬂex), protocol as included well as Hawleybonded andretainers Essix appliancesbetween #13–23 on the and upper #33–43 and lower arch, (0.0215-inchrespectively. twistflex), as Treatment well as Hawley results remainedand Essix stableappliances at one-year on the post-retention upper and lower (Figure 12). 2.5. Retentionarch, respectively. Treatment results remained stable at one-year post-retention (Figure 12). The retention protocol included bonded retainers between #13–23 and #33–43 (0.0215-inch twistflex), as well as Hawley and Essix appliances on the upper and lower arch, respectively. Treatment results remained stable at one-year post-retention (Figure 12).

Children 2021, 8, x FOR PEER REVIEW 9 of 13 Children 2021, 8, 519 9 of 13

FigureFigure 12.12. Extra- and intra-oral photographs photographs at at one- one-yearyear post-debonding. post-debonding. Treatment Treatment results results re- remainedmained stable. stable.

3.3. GeneticGenetic AnalysisAnalysis ofof thethe FamilyFamily 3.1.3.1. SalivaSaliva Sampling,Sampling, DNADNA Isolation,Isolation, PCRPCR andand SangerSanger SequencingSequencing TheThe mostmost commoncommon geneticgenetic mutationsmutations responsibleresponsible forfor thethe DD-IDD-I areare thethe c.84c.84 + + 1G1G >> TT mutationmutation inin thethe SMOC2SMOC2 genegene [[11],11], thethe IVS7IVS7 ++ 46C46C >> GG mutationmutation inin thethe VPS4BVPS4B genegene [[12],12], andand thethe c.353Cc.353C > A A mutation mutation in in the the SSUH2SSUH2 genegene [13]. [13 ].Thus, Thus, we we aimed aimed to investigate to investigate the thepresence presence of these of these mutations. mutations. Family Family dental dental history history revealed revealed that thatthe present the present patient patient (pro- (proband)band) shared shared the thesame same phenotypic phenotypic characteristics characteristics of the of thecondition condition with with the thefather, father, but but not notwith with the themother. mother. The The protocol protocol was was approved approved by the by Ethics the Ethics Committee, Committee, Dental Dental School School (No. (No.357/29 357/29 March March 2018). 2018). Written Written informed informed consen consentt was was obtained obtained from from all allthree three members members of of this family. this family. Saliva samples were collected from all three family members and DNA extraction Saliva samples were collected from all three family members and DNA extraction was performed (QIAamp DNA Blood Mini Kit, Qiagen, Hilden, Germany), according to was performed (QIAamp DNA Blood Mini Kit, Qiagen, Hilden, Germany), according to the manufacturer’s instructions. DNA concentration was determined using a NanoDrop the manufacturer’s instructions. DNA concentration was determined using a NanoDrop One spectrophotometer (ThermoFisher Scientiﬁc, Waltham, MA, USA). Primers and PCR One spectrophotometer (ThermoFisher Scientific, Waltham, MA, USA). Primers and PCR conditions used for amplifying intron 1 of the SMOC2 gene, the region between exon 7 and conditions used for amplifying intron 1 of the SMOC2 gene, the region between exon 7 exon 8 of the VPS4B gene and the exon 2 of the SSUH2 gene were described elsewhere, and exon 8 of the VPS4B gene and the exon 2 of the SSUH2 gene were described elsewhere, respectively [11–13]. Both forward and reverse PCR products for all three genes were respectively [11–13]. Both forward and reverse PCR products for all three genes were di- directly sequenced, using a 3730xl DNA analyzer (Applied Biosystems, ThermoFisher rectly sequenced, using a 3730xl DNA analyzer (Applied Biosystems, ThermoFisher Sci- Scientiﬁc). All chromatograms produced from sequencing were examined. entific). All chromatograms produced from sequencing were examined. 3.2. Results of the Genetic Analysis 3.2. Results of the Genetic Analysis No mutations were found in any of the samples examined (Figure 13). No mutations were found in any of the samples examined (Figure 13).

Children 2021, 8, x FOR PEERChildren REVIEW2021, 8, 519 10 of 13 10 of 13

FigureFigure 13. (a )13. Pedigree (a) Pedigree of the family. of the Affectedfamily. Affected subjects are subjects denoted ar ine denoted black. DDI-3 in black. is the DDI-3 proband. is the (b–d proband.) DNA sequence chromatograms(b–d) DNA obtained sequence from chromatograms Sanger sequencing obtained revealing from normal Sanger status sequencing of (b) the c.84 revealing + 1G > Tnormal mutation status in the of SMOC2 gene,(b (c)) the IVS7c.84 ++ 46C1G > > T G mutation in in the the VPS4B SMOC2 gene gene, and (d(c)) the the c.353C IVS7 >+ A46C mutation > G mutation in the SSUH2 in the gene, VPS4B in all three familygene members and (d (DDI-1,) the c.353C DDI-2 > and A DDI-3).mutation Mutation in the SSUH2 sites previously gene, in reported all three are family indicated members by blue (DDI-1, arrows. DDI- 2 and DDI-3). Mutation sites previously reported are indicated by blue arrows. 4. Discussion 4. Discussion 4.1. Orthodontic Treatment 4.1. Orthodontic TreatmentThe orthodontic treatment in this patient was necessary due to the extremely unfavorable position of the upper canines. Many case reports of impacted upper canines in the orthodontic The orthodonticliterature treatment demonstrated in this patient root resorption was necessary of the central due and to lateralthe extremely incisors [19 unfa-–23]. Resorption vorable position ofof the the upper central ca incisorsnines. wouldMany becase devastating reports of in impacted this case, due upper to the canines poor long-term in the prognosis orthodontic literatureof the demonstrated entire dentition. root resorption of the central and lateral incisors [19– 23]. Resorption of the centralThe dental incisors age and would the adversebe devastating tooth prognosis in this incase, this due patient to the necessitated poor the use long-term prognosisof aof custom the entire made dentition. trans-palatal arch for the traction of the canines. This arch was bonded The dental ageon and the the permanent adverse ﬁrst tooth molars, prognosi as wells in as this the patient palatal andnecessitated buccal surfaces the use of of the right and left deciduous second molars, respectively. The appliance was further stabilized on the a custom made trans-palatal arch for the traction of the canines. This arch was bonded on hard palate mucosa with an acrylic button. This design allowed the even distribution of the permanent firstthe molars, reciprocal as well forces as during the palatal the canine and tractionbuccal surfaces on the aforementioned of the right and structures. left deciduous second molars,Orthodontic respectively. treatment The isappliance challenging was in further patients stabilized with DD-I, on mainly the hard because of the palate mucosa withpotential an acrylic adverse button. effects This of thedesign forces allowed on the the short, even malformed distribution roots. of Comprehensive the reciprocal forces duringorthodontic the canine treatment traction and heavy on the forces aforementioned may induce root structures. resorption [24,25]. The heavier the Orthodontic treatmentforces applied, is challenging the larger the in total patients root resorption with DD-I, volume, mainly as shownbecause by of microCT the imaging potential adverse effectstechniques of the [26 forces]. The treatmenton the short, plan andmalformed the biomechanics roots. Comprehensive selected for this or- patient aimed thodontic treatmentto and avoid heavy root resorption:forces may entityinduce of root tooth resorption forces was [24,25]. kept to The low heavier levels, a the custom made trans-palatal arch was used for the traction of the canines and only round archwires/light forces applied, the larger the total root resorption volume, as shown by microCT imaging forces were applied. The present patient exhibited no caries or tooth mobility, maintained techniques [26]. Thevital treatment pulp response plan and and athe healthy biomechanics periodontium. selected The upperfor this right patient canine aimed showed a minor to avoid root resorption:recession entity after of alignment,tooth forces although was kept the to height low levels, of the a attached custom made gingiva trans- during surgical palatal arch was used for the traction of the canines and only round archwires/light forces were applied. The present patient exhibited no caries or tooth mobility, maintained vital pulp response and a healthy periodontium. The upper right canine showed a minor recession after alignment, although the height of the attached gingiva during surgical exposure was preserved with an apically positioned flap. Further extrusion of this tooth was

Children 2021, 8, 519 11 of 13

exposure was preserved with an apically positioned ﬂap. Further extrusion of this tooth was excluded due to the root morphology. Alternative treatment plans including upper distalization or extractions in the lower arch were not considered due to the poor long-term prognosis of the entire dentition. Under these conditions and for functional reasons, full orthodontic treatment could be justiﬁed in patients with DD-I, providing all risks are meticulously evaluated and thoroughly explained to the patient and the family before the onset of treatment, and carefully monitored during the course of treatment.

4.2. Differential Diagnosis In the present case, the diagnosis was based on the clinical and radiographic findings, as well as on the patient’s and family dental history. Dentin defects are classified into Dentinogenesis Imperfectas (DIs, types I–III) and Dentin Dysplasias (DDs, types I, II) [27,28]. Radiographically, it resembles the phenotype of DD-I; narrow roots and small or obliterated pulp chambers and root canals are common findings. Teeth appear blue-gray or amber brown and opalescent, characteristics that were not evident in our case. DI type I is also accompanied by osteogenesis imperfecta, a disorder of bone fragility, and DI type II by hearing loss [27,28]. The present patient exhibited neither bone/hearing defects according to her medical history nor any of the clinical dental characteristics of DI. Therefore, this entity was excluded from the differential diagnosis. The genetic analysis of the family members did not reveal any of the most common mutations for DD-I. All family members showed identical sequence pattern. Absence of known mutations indicates that novel mutations in the same genes or other encoding products for dentin formation may be responsible for the phenotypic variability of DD-I. An extended pedigree was not acquired for this patient because of the few family members and lack of dental history for the previous generations. Other genes have also been reported to be involved in dentin formation. Dentin sialophosphoprotein gene (DSPP) encodes three major non-collagenous dentin matrix proteins: the dentin sialoprotein (DSP), the dentin glycoprotein (DGP) and the dentin phos- phoprotein (DPP) [27]. DSPP is expressed a hundred-fold more in dentin than in other tissues [27]. Mutations in DSPP have been found to be the major cause for DI types II and III and DD type II [27,29–31]. Normal teeth crown morphology excluded this gene from being a proper candidate to examine. Type I collagen forms the organic phase of the dentin [27]. Most cases of osteogenesis imperfecta are associated with mutations in the procollagen type I genes COL1A1 and COL1A2, leading to abnormal collagen I fibrils formation [32]. However, the clinical characteristics of osteogenesis imperfecta do not resemble these of the present case. Enamel malformations include a wide clinical spectrum of enamel phenotypes; hypoplastic, hypocalcified, hypo-maturation, and hypo-maturation-hypoplastic with tau- rodontism, caused by known gene defects [33]. During tooth formation two proteinases are secreted by ameloblasts: enamelysin (MMP-20) and kallikrein-4 (KLK4)[33]. Mutations of MMP-20 and KLK4 cause autosomal-recessive amelogenesis imperfecta (ARAI) [33]. Also, mutation in FAM20A gene resulted in hypoplastic amelogenesis imperfecta. Fam- ily with sequence similarity 20 (FAM20) includes three members (FAM20A, FAM20B and FAM20C). FAM20A encodes a secreted glycoprotein [34]. The most severe type, the hypocalcified amelogenesis imperfecta, is mostly caused by nonsense mutations in the FAM83H gene [35]. Nonetheless, the clinically normal crown morphology in this patient set enamel malformations very low to the differential diagnosis list.

4.3. Genetic Analysis Genetic analyses in this family did not reveal any mutations in the SSUH2, VPS4B or SMOC2 genes. Most reported DD-I cases are neither genetically studied nor treated orthodontically and, therefore, the mutation type cannot be associated with the orthodontic Children 2021, 8, 519 12 of 13

result. Reporting cases with genotype-phenotype associations could provide evidence on where good response to orthodontics is expected.

5. Conclusions Orthodontic treatment can be cautiously conducted in patients with DD-I, when functional and other reasons pertaining to tooth survival demand it. In these cases, the clinical and radiographic examination should be carefully co-evaluated with the familial dental history. The patient’s chief complaint and the biomechanical limitations must be carefully considered. In the present case, the primary goal to maintain the anterior dentition was accomplished. Additionally, a familial genetic analysis was performed in order to enrich our understanding of the defective dental genes and eventually contribute to a more personalized treatment. This combination concept of a case report/genetic analysis is becoming more feasible and more essential in managing atypical orthodontic patients.

Author Contributions: Conceptualization, A.P., H.V. and I.S.; methodology, A.P., G.F., H.V. and I.S.; investigation, A.P. and G.F.; writing—original draft, A.P.; supervision, I.S.; writing—review & editing, A.P., G.F., A.M., K.K., H.V.and I.S. All authors have read and agreed to the published version of the manuscript. Funding: Department of Orthodontics, Dental School, National and Kapodistrian University of Athens, Greece. Institutional Review Board Statement: The study was conducted according to the guidelines of the Declarations of Helsinki, and approved by the Ethics Committee, Dental School, National and Kapodistrian University of Athens, Greece (No. 357/29 March 2018). Informed Consent Statement: Informed consent has been obtained from all subjects involved in the study. Data Availability Statement: Not applicable. Conﬂicts of Interest: The authors declare no conﬂict of interest.

References 1. Kim, J.W.; Simmer, J.P. Hereditary dentin defects. J. Dent. Res. 2007, 86, 392–399. [CrossRef][PubMed] 2. Witkop, C.J., Jr. Hereditary defects of dentin. Dent. Clin. N. Am. 1975, 19, 25–45. [PubMed] 3. Van Dis, M.L.; Allen, C.M. Dentinal dysplasia type I: A report of four cases. Dentomaxillofac. Radiol. 1989, 18, 128–131. [CrossRef] [PubMed] 4. Neumann, F.; Würfel, F.; Mundt, T. Dentin dysplasia type I—A case report. Ann. Anat. 1999, 181, 138–140. [CrossRef] 5. Shanky, P.E.; Mackie, I.C.; Sloan, P. Dentinal dysplasia type I: Report of a case. Int. J. Paediatr. Dent. 1999, 9, 37–42. [CrossRef] 6. Kalk, W.W.; Batenburg, R.H.; Vissink, A. Dentin dysplasia type I: Five cases within one family. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endodontol. 1998, 86, 175–178. [CrossRef] 7. Özer, L.; Karasu, H.; Aras, K.; Tokman, B.; Ersoy, E. Dentin dysplasia type I: Report of atypical cases in the permanent and mixed dentitions. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endodontol. 2004, 98, 85–90. [CrossRef] 8. Ye, X.; Li, K.; Liu, L.; Yu, F.; Xiong, F.; Fan, Y.; Xu, X.; Zuo, C.; Chen, D. Dentin dysplasia type I—Novel findings in deciduous and permanent teeth. BMC Oral Health 2015, 15, 163. [CrossRef] 9. Shields, E.D.; Bixler, D.; el-Kafrawy, A.M. A proposed classification for heritable human dentin defects with a description of a new entity. Arch. Oral Biol. 1973, 18, 543–553. [CrossRef] 10. Carroll, M.K.O.; Duncan, W.K.; Perkins, T.M. Dentin dysplasia: Review of the literature and a proposed subclassification based on radiographic findings. Oral Surg. Oral Med. Oral Pathol. 1991, 72, 119–125. [CrossRef] 11. Bloch-Zupan, A.; Jamet, X.; Etard, C.; Laugel, V.; Muller, J.; Geoffroy, V.; Strauss, J.P.; Pelletier, V.; Marion, V.; Poch, O.; et al. Homozygosity mapping and candidate prioritization identify mutations, missed by whole-exome sequencing, in SMOC2, causing major dental developmental defects. Am. J. Hum. Genet. 2011, 89, 773–781. [CrossRef] 12. Yang, Q.; Chen, D.; Xiong, F.; Chen, D.; Liu, C.; Liu, Y.; Yu, Q.; Xiong, J.; Liu, J.; Li, K.; et al. A splicing mutation in VPS4B causes dentin dysplasia I. J. Med. Genet. 2016, 53, 624–633. [CrossRef] 13. Xiong, F.; Ji, Z.; Liu, Y.; Zhang, Y.; Hu, L.; Yang, Q.; Qiu, Q.; Zhao, L.; Chen, D.; Tian, Z.; et al. Mutation in SSUH2 causes autosomal-dominant dentin dysplasia type I. Hum. Mutat. 2017, 38, 95–104. [CrossRef][PubMed] 14. Chen, D.; Li, X.; Lu, F.; Wang, Y.; Xiong, F.; Li, Q. Dentin dysplasia type I—A dental disease with genetic heterogeneity. Oral Dis. 2019, 25, 439–446. [CrossRef] 15. Rocha, C.T.; Nelson-Filho, P.; Da Silva, L.A.B.; Assed, S.; De Queiroz, A.M. Variation of dentin dysplasia type I: Report of atypical findings in the permanent dentition. Braz. Dent. J. 2011, 22, 74–78. [CrossRef][PubMed] Children 2021, 8, 519 13 of 13

16. Depprich, R.A.; Ommerborn, M.A.; Handschel, J.G.; Naujoks, C.D.; Meyer, U.; Kübler, N.R. Dentin dysplasia type I: A challenge for treatment with dental implants. Head Face Med. 2007, 3, 31. [CrossRef][PubMed] 17. Khandelwal, S.; Gupta, D.; Likhyani, L. A case of dentin dysplasia with full mouth rehabilitation: A 3-year longitudinal study. Int. J. Clin. Pediatr. Dent. 2014, 7, 119–124. [PubMed] 18. Bespalez-Filho, R.; De Azambuja Berti Couto, S.; Souza, P.H.C.; Westphalen, F.H.; Jacobs, R.; Willems, G.; Tanaka, O.M. Orthodontic treatment of a patient with dentin dysplasia type I. Am. J. Orthod. Dentofac. Orthop. 2013, 143, 421–425. [CrossRef] [PubMed] 19. Ericson, S.; Kurol, J. Incisor root resorptions due to ectopic maxillary canines imaged by computerized tomography: A comparative study in extracted teeth. Angle Orthod. 2000, 70, 276–283. 20. Ericson, S.; Bjerklin, K.; Falahat, B. Does the canine dental follicle cause resorption of permanent incisor roots? A computed tomographic study of erupting maxillary canines. Angle Orthod. 2002, 72, 95–104. 21. Milberg, D.J. Labially impacted maxillary canines causing severe root resorption of maxillary central incisors. Angle Orthod. 2006, 76, 173–176. 22. Alqerban, A.; Jacobs, R.; Lambrechts, P.; Loozen, G.; Willems, G. Root resorption of the maxillary lateral incisor caused by impacted canine: A literature review. Clin. Oral Investig. 2009, 13, 247–255. [CrossRef] 23. Lai, C.S.; Bornstein, M.M.; Mock, L.; Heuberger, B.M.; Dietrich, T.; Katsaros, C. Impacted maxillary canines and root resorptions of neighboring teeth: A radiographic analysis using cone-beam computed tomography. Eur. J. Orthod. 2013, 35, 529–538. [CrossRef] 24. Walker, S. Root resorption during orthodontic treatment. Evid.-Based Dent. 2010, 11, 88. [CrossRef] 25. Weltman, B.; Vig, K.W.; Fields, H.W.; Shanker, S.; Kaizar, E.E. Root resorption associated with orthodontic tooth movement: A systematic review. Am. J. Orthod. Dentofac. Orthop. 2010, 137, 462–476. [CrossRef][PubMed] 26. Zhong, J.; Chen, J.; Weinkamer, R.; Darendeliler, M.A.; Swain, M.V.; Sue, A.; Zheng, K.; Li, Q. In vivo effects of different orthodontic loading on root resorption and correlation with mechanobiological stimulus in periodontal ligament. J. R. Soc. Interface 2019, 16, 20190108. [CrossRef][PubMed] 27. Hart, P.S.; Hart, T.C. Disorders of human dentin. Cells Tissues Organs 2007, 186, 70–77. [CrossRef] 28. de La Dure-Molla, M.; Philippe Fournier, B.; Berdal, A. Isolated dentinogenesis imperfecta and dentin dysplasia: A revision of the classiﬁcation. Eur. J. Hum. Genet. 2015, 23, 445–451. [CrossRef][PubMed] 29. Zhang, X.; Chen, L.; Liu, J.; Zhao, Z.; Qu, E.; Wang, X.; Chang, W.; Xu, C.; Wang, Q.K.; Liu, M. A novel DSPP mutation is associated with type II dentinogenesis Imperfecta in a chinese family. BMC Med. Genet. 2007, 8, 52. [CrossRef][PubMed] 30. Lee, S.-K.; Lee, K.-E.; Jeon, D.; Lee, G.; Lee, H.; Shin, C.-U.; Jung, Y.-J.; Lee, S.-H.; Hahn, S.-H.; Kim, J.-W. A novel mutation in the DSPP gene associated with dentinogenesis imperfecta Type II. J. Dent. Res. 2009, 88, 51–55. [CrossRef] 31. Zhang, J.; Wang, J.; Ma, Y.; Du, W.; Zhao, S.; Zhang, Z.; Zhang, X.; Liu, Y.; Xiao, H.; Wang, H.; et al. A novel splicing mutation alters DSPP transcription and leads to dentinogenesis imperfecta Type II. PLoS ONE 2011, 6, e27982. [CrossRef] 32. Augu´sciak-Duma,A.; Witecka, J.; Siero´n,A.L.; Janeczko, M.; Pietrzyk, J.J.; Ochman, K.; Galicka, A.; Borszewska-Kornacka, M.K.; Pilch, J.; Jakubowska-Pietkiewicz, E. Mutations in the COL1A1 and COL1A2 genes associated with osteogenesis imperfecta (OI) types I or III. Acta Biochim. Pol. 2018, 65, 79–86. [CrossRef][PubMed] 33. Lee, S.-K.; Seymen, F.; Kang, H.-Y.; Lee, K.-E.; Gencay, K.; Tuna, B.; Kim, J.-W. MMP20 hemopexin domain mutation in amelogenesis imperfecta. J. Dent. Res. 2010, 89, 46–50. [CrossRef][PubMed] 34. Nalbant, D.; Youn, H.; Nalbant, S.I.; Sharma, S.; Cobos, E.; Beale, E.G.; Du, Y.; Williams, S.C. FAM20: An evolutionarily conserved family of secreted proteins expressedin hematopoietic cells. BMC Genom. 2005, 6, 11. [CrossRef][PubMed] 35. Wang, X.; Wang, W.; Qin, M.; Zhao, Y. Novel FAM83H mutations in patients with amelogenesis imperfecta. Sci. Rep. 2017, 7, 6075. [CrossRef]