Introduction

Ectodermal dysplasia (ED; ORPHA:79373) comprises a large, diverse group of over 200 disorders. ED was defined by the Ectodermal Dysplasias Classification Working Group as a group of genetic conditions that affect the development and/or homeostasis of two or more ectodermal derivatives, including hair, teeth, nails, and some glands; their genetic causes and clinical phenotypes are heterogeneous [1]. The group proposed a new classification, that aims to be more useful than the classical clinical one [2, 3], based on molecular pathways, and integrating clinical and molecular information (gene, molecular pathway, and/or protein function). The categories are the EDA/NFKappaB pathway, the WNT pathway, the TP63 pathway, the structure group and other/unknown [1].

The overall prevalence of ED syndromes varies [4], although it may be close to 6–9/10,000 [5]. Hypohidrotic ectodermal dysplasia (HED; ORPHA:238468; ICD-10: Q82.4; OMIM: 129490, 224900, 300291, 305100, 612132, 614940, 614941) is the most common form of ED and is estimated to affect at least 1 in 5,000–10,000 newborns, with a prevalence of 1–9/100,000 [6].

HED is caused by mutations in the genes of the EDA/NFKappaB pathway (EDA, EDAR, EDARADD, WNT10A), which are necessary for the correct development of various ectodermal structures, in 90% of cases [7]. It affects the skin, hair, nails, sweat glands and teeth. Patients with HED have a characteristic physical appearance: the scalp and body hair are sparse and light in color (hypotrichosis), and patients have soft, hypopigmented skin, sunken cheeks, saddle nose, a frontal protrusion, prominent supraorbital crests, periorbital hyperpigmentation, low set ears, dysplastic nails, everted lips, prominent chin and reduced lower facial height with the lower third of the face reduced, giving these patients an aged appearance. Hyperkeratosis may affect the palms of the hands and soles of the feet, and women often have aplastic or hypoplastic mammary glands [8].

The most common form of HED, previously referred to as Christ-Siemens-Touraine syndrome, have mutations or deletions in the ectodysplasin gene and it is inherited as an X-linked condition (XHED; ORPHA:181; ICD-10: Q82.4; OMIM: 305100). XHED, with a prevalence of 1–9/1 000 000 [5], presents a clinical picture of hypotrichosis, hypohidrosis, oligodontia, and a predisposition to respiratory disorders [9].

Other types of ED include anhidrotic ectodermal dysplasia, in which the sweat and sebaceous glands are absent, and hidrotic ectodermal dysplasia or Clouston syndrome (ORPHA:189; ICD-10: Q82.8; OMIM: 129500), which is autosomal dominant, where these glands develop normally [8]. ED patients present a wide spectrum of orofacial dysfunctions: alterations in the teeth (almost 100%), chewing and swallowing (82.6%), dryness of the mouth (45.7%), speech (43.5%), hoarse voice, etc. [10, 11].

The teeth are one of the four ectodermal structures included in the clinical classification proposed by Pinheiro and Freire-Maia (hair, teeth, nails, and sweat glands [3]. In fact, many children with ED are diagnosed after a first dental examination when there is a significant delay in the eruption of the primary teeth or when the first tooth appears in an atypical shape [12].

Agenesis is very common in all forms of ED, and different patterns of dental agenesis are observed (without considering the third molar): hypodontia (if < 6 teeth are missing), oligodontia (if ≥ 6 teeth are missing) and anodontia (total absence of permanent teeth) [13]. The most frequent missing teeth are the maxillary lateral incisors and first premolars and the mandibular incisors and first premolars. The permanent teeth most often present are the maxillary central incisors, first maxillary molars, first mandibular molars, and canines in both jaws. The anterior teeth are usually conical or tapered and the primary molars are sometimes ankylosed due to the absence of permanent premolars. Other dental alterations presented by patients with ED are taurodontism, enamel hypoplasia, delayed eruption of permanent teeth, and fused roots [10].

Dental agenesis affects the growth of the jaws and leads to deficient growth of the alveolar bone. Patients present bimaxillary retrusion with respect to the anterior cranial base, negative overjet, a decreased vertical dimension that favors antero-rotation of the jaw and a tendency to skeletal class III, increasing the projection of the chin [12].

The functional and aesthetic rehabilitation of these patients is a challenge for dentists, so a multidisciplinary team is necessary. Early treatment during childhood is essential to solve the problem of multiple missing teeth and enhance the growth of the jaws to achieve better oral function and facial aesthetics. Initial dental treatment should focus on preventing cavities, restoring teeth with alterations in shape, replacing absent pieces, controlling the position of existing teeth and preventing or correcting malocclusions [14]. The first rehabilitations are usually made with removable complete or partial prostheses supported on the existing teeth previously restored aesthetically. Often these prostheses carry expansion screws to accompany maxillomandibular growth. As the patient grows, there is a need for orthopedic and/or orthodontic treatments for the management of the available space, leveling and aligning the teeth, and for orthopedic correction of the dentoskeletal malocclusion or jaw deformities.

In addition to a multidisciplinary group of dentists, the simultaneous participation of psychologists and speech therapists, who increase the patient’s self-esteem, is necessary to achieve self-acceptance and social integration [14,15,16].

Since patients with ED require orthodontic and/or dentofacial orthopedic treatment for functional and aesthetic rehabilitation, we formulated the following question: Which orthodontic and dentofacial orthopedic treatments have been carried out in patients with ectodermal dysplasia to facilitate functional and aesthetic rehabilitation?

The question was organized using the PICO strategy [17]:

Q: patients with ectodermal dysplasia.

I: orthodontic and dentofacial orthopedic treatments carried out in patients with ectodermal dysplasia.

C: not applicable.

O: orthopedic correction of the dentoskeletal malocclusion and/or management of the available space to facilitate functional and aesthetic rehabilitation in patients with ectodermal dysplasia.

Methods

The systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement [18]. The review was registered as CRD42021288030 in the Centre for Reviews and Dissemination, University of York, York, United Kingdom.

Eligibility criteria

According to the selection criteria, the review included articles that described patients with any type of ED who received orthodontic or dentofacial orthopedic treatment to facilitate functional and aesthetic oral rehabilitation. Studies in animals, articles describing treatments for healthy patients or with other syndromes, studies describing aesthetic and/or functional treatments in patients with ED, but not requiring orthodontic or orthopedic correction, were excluded. Articles which stated that patient had been treated with orthodontics or dentofacial orthopedics, but without describing the procedure performed, were excluded.

Information sources, search strategy and selection process

An exhaustive search of original articles was carried out in PubMed, Web of Science, Scopus, Scielo, LILACS, EBSCOhost and Embase. The search was conducted until 6 January 2022 and was not restricted by language or year of publication.

The keywords used in the search corresponded to the MeSH terms: "ectodermal dysplasia", "orthodontic", "orthopedic", and "treatment". The Boolean operators "OR" and "AND" were used to join keywords and establish a single search equation. This was used in the same way in the various databases to obtain the largest number of references. The equation was: ((ectodermal dysplasia) AND (orthodontic OR orthopedic) AND (treatment)). In addition, we manually reviewed the references of all selected articles to check whether there were any relevant references not found during the initial search that could be included.

Data collection and quality assessment

We used a three-stage selection process. Firstly, we reviewed the title. Second, we read the abstract, but if this did not provide enough information to decide on inclusion, the entire article was reviewed. Third, the full text of the article was read. Two authors (MC and AJO) independently carried out the three stages and resolved any disagreement through discussion, until a consensus was reached. If disagreements persisted the authors consulted a third author (CS) who helped establish consensus. Data from the articles included were extracted by the same two authors and included authors, year of publication, country where the study was conducted, language, sample size, type of disease, sex, age of participants at the beginning of treatment, duration of treatment, type of treatment, dentition in which the treatment was performed, orthodontic/orthopedic treatment success, final rehabilitation, pattern of tooth agenesis, missing teeth, disturbances of the teeth, jaws affected, radiologic studies and cephalometric data.

The quality of the studies was assessed using the Joanna Briggs Institute Quality Assessment Scale, University of Adelaide, for case series and case reports [19] Quality was assessed by completing 8 items for each case report and 10 items for each case series. Items were answered "yes", "no", "unclear", or "not applicable" (Additional file 1: Tables 1 and 2). For each item of each article, the percentage of the answers "yes", "no", "not clear", or "not applicable" was calculated as was the maximum and minimum percentages of "yes" and "no" and their corresponding medians of all articles (Table 1). We set the median value of the percentage of 'Yes' as a limit to determine whether a study was of quality.

Table 1 Classification of case reports and case series according to the Joanna Briggs Institute critical appraisal checklist
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In addition, for each item, the percentage of answers "yes", "no", "not clear" and "not applicable" of the total of the articles of "case reports" (Table 2) and "case series" (Table 3) was calculated. Items for which the answer was "no" and "not clear" in > 50% of articles could introduce a bias in the interpretation of the results [20].

Table 2 Classification of case reports according to the Joanna Briggs Institute critical appraisal checklist sub-items
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Table 3 Classification of case series according to the Joanna Briggs Institute critical appraisal checklist sub-items
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Results

Selection of studies

The initial search yielded 403 references. After deleting duplicate articles, 232 references remained. It was essential to read the abstracts of the 232 articles because the titles did not show, in most cases, the type of treatment. We discarded 183 references. Of the remaining 49, four [21,22,23,24] were eliminated due to the impossibility of obtaining the full text, even when requested from the authors. Six studies [25,26,27,28,29,30] were excluded because, although the summary indicated it, no orthodontic or dentofacial orthopedic treatment was performed; three [31,32,33] because it was another syndrome, the type of syndrome was not specified or it was in healthy patients; seven [34,35,36,37,38,39,40] because, although orthodontics or orthopedics were carried out in patients with ED, the type of treatment was not described. Twenty-nine articles met the inclusion criteria. (Fig. 1).

Fig. 1
figure 1

Flow diagram for search strategy

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Of the 29 studies, the oldest was published in 1974 [41] and the most recent in 2021 [42]. Twenty-five of the references found were in English [14,15,16, 42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63], and one each in German [39], Turkish [64], French [65] and Slovenian [66].

Twenty-six articles were case reports [14,15,16, 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57, 59, 61,62,63,64, 66] and three were case series [58, 60, 65].

Quality of studies

The median percentage of "Yes" answers for case reports was 87.5%, and 22 studies were considered of quality [14,15,16, 41,42,43, 45, 46, 48,49,50,51, 54, 56, 57, 59, 61,62,63,64, 66], while five did not meet the quality criterion [44, 47, 52, 53, 55]. The median value for case series was 80%: two articles were considered of quality [58, 60], and one was not [65] (Table 1).

Item 7 "Adverse events or unforeseen treatment events " had a percentage of "no" or "unclear" responses of > 50% for case reports (Table 2) and item 4 "selection of participants" and 10 "appropriate statistical analysis" in case series (Table 3).

Syntheses of studies

Twenty-five patients (6 female and 19 male) were included in the 23 articles: 21 articles only included one patient [14,15,16, 41,42,43, 45, 46, 48,49,50,51, 54, 56, 57, 59, 61,62,63,64, 66] and 2 [58, 60] included 2 patients. The age of patients included ranged from 34 months [45] to 24 years [56] (Table 4).

Table 4 Characteristics of case reports and case series included
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Most patients had hypohidrotic and/or anhidrotic ED [14, 15, 43, 45, 46, 48, 49, 53, 56, 57, 59, 60, 62], specifically X-linked in two studies [43, 60]. In one study [50], the patient had Wiktop syndrome (ORPHA:2228; ICD-10: Q82.4; OMIM:189500). In the rest [16, 41, 42, 57, 58, 61, 63, 64, 66], the type of ED was not specified.

Type of treatments

Diverse treatments were carried out.

  1. a.

    Fixed orthodontic appliances or simple acrylic plates designed for tooth movement including leveling and aligning, closing of diastema, retraction of impacted teeth in the dental arch.

    Four studies [45, 60(P1), 61, 64] used only fixed orthodontics to close the diastema between the anterosuperior teeth. In one [45], there was a recurrence, and the patient was treated again with fixed orthodontics. In others [46, 60(P2)], a removable acrylic resin plate with a spring was used to close the existing diastema. In one [46], after a recurrence due to the loss of the removable device, a fixed cemented device was chosen in the first molars, with an open coil spring to close the diastema again. In eight studies [14, 43, 48, 54, 56, 57, 63, 66], orthodontics was used to achieve a correct dental position through alignment with brackets. In two [43, 48], in addition to aligning the teeth, fixed appliances were used to traction a tooth retained in the jaw. In two studies [14, 66], in addition to alignment, spaces were maintained for future fixed prosthetic rehabilitation. One study [63] described two-phase orthodontic treatment, the first with removable orthodontics to obtain space to perform an autologous transplant and the second with brackets to align the teeth, maintain the spaces and adjust the occlusion.

  2. b.

    Clear aligners.

    One article [42] included the use of aligners designed with Digital Smile Design software to position the teeth.

  3. c.

    Fixed and/or removable appliances for the correction of skeletal and/or dentoalevolar relationships.

    Some patients underwent removable prosthetic-orthopedic apparatus with expansion screws [15, 16, 58] or telescopic devices [15] to replace missing teeth while stimulating or accompanying the growth of the jaws. Another patient [51] presented a concave profile (ANB: − 6.7º), with a retrognathic maxilla (SNA: 72.7º) and a decreased lower facial height, who initially needed an upper prosthesis with an expansion screw and, later, fixed orthodontics with brackets to align the teeth. After orthopedic and orthodontic treatment, a face with normal vertical dimensions was observed and the anteroposterior skeletal discrepancy had improved (ANS: 73.8º; ANB: − 0.4º).

    One study [50] described a patient with Witkop syndrome who presented skeletal class II (ss-n-sm: 7.7º) with an increased overjet (12. 5 mm). A functional device was used to stimulate the growth of the jaw, achieving an ss-n-sm angle of 6.06º and an overjet of 3.51mm. Finally, brackets were used for dental alignment. Another study [41] used fixed orthodontics with bands in the canines to increase the intercanine width, after carrying out a first phase of orthopedics with a type I U-activator to stimulate the growth of the jaws. In another study [62], a hybrid maxillary expansion appliance was used, with dental anchorage in the first two upper molars and skeletal anchorage by means of two microscrews in the anterior area of the palate.

  4. d.

    Palatal expanders in combination with face masks for orthopedic traction of the maxilla.

    In one study [49], palatine disjunction was carried out and a facial mask was placed to improve the growth of the maxilla in the transverse and sagittal planes.

  5. e.

    Orthognathic surgery.

    In one study [59], the treatment began at 9 years of age, with two implants placed in the jaw in order to place an implant-supported prosthesis that would improve function and replace the missing teeth. At the age of 11, a fixed orthodontic treatment in the maxilla was carried out to align, close and consolidate spaces. Retention after orthodontic treatment consisted of a Hawley plate that incorporated the missing teeth. Once the patient's growth was complete (18–19 y.) they underwent orthognathic surgery (Lefort type I) and subsequent fixed orthodontics with braces.

Treatment duration

The treatment duration varied from 7 weeks [45] to 10 years [15], depending on the purpose and type of treatment. Seven weeks were necessary to close an inter-incisor gap with fixed appliances [45].

In seven studies, treatment lasted for 4 to 12 months. Of these, 5 used fixed orthodontics: one [57] to align; two [46, 61] to close the inter-incisor gap and two [43, 48] to traction a tooth included in the maxilla and align. One study [42] used aligners and another [62] orthopedics to achieve rapid palatal disjunction.

Several studies had treatment periods of > 12 months: two carried out a first phase with orthopedics and a second with fixed orthodontics, lasting 2 years [41] and 3 years and 3 months [50]. In a study [63] in which treatment lasted 4 years and 10 months, orthodontics prior to an autotransplant and subsequent orthodontics were carried out. In another study treatment lasted five years [49] using first a disjunction and then a face mask. In two studies, treatment lasted seven years: in one there was an initial phase with an upper removable prosthesis with an expansion screw and then dental alignment with brackets [51] and, in a second there was fixed orthodontic treatment before and after a LeFort type I surgery [59]. The maximum treatment period was 10 years [15]: firstly, there was rehabilitation with a removable prosthesis with upper and lower expansion screws and in a second phase these were replaced by another upper prosthesis with an expansion screw and a lower one with a telescopic device. The remaining studies did not specify [14, 16, 54, 56, 58, 60, 64, 66] the treatment duration.

Discussion

To our knowledge, this is the first systematic review of the different orthodontic and dentofacial orthopedic treatments carried out in patients with ED.

Discussion of the methodology

As we reviewed orthodontic and dentofacial orthopedic treatments in patients with ED to facilitate aesthetic and functional rehabilitation, the type of studies found in the search were case series and case reports. These are observational studies and, therefore, the scientific evidence is not high. This is the main limitation of our study. Another limitation was the difference between the studies analyzed in the type of treatment performed, the age of participants, the follow-up time, and the provision of cephalometric data before and after treatment. The lack of effect measures in the studies did not allow a meta-analysis. Although randomized controlled trials have the highest level of evidence, they are very difficult to carry out in this type of patient, since they need individualized treatment to provide the function and aesthetics necessary for a normal quality of life.

To assess the quality of case series and case reports, most systematic reviews use the Newcastle–Ottawa Quality Scale (NOS), which is specific for case–control and cohort studies, but not for case series and case reports. Therefore, we opted to use the quality assessment scale of the Joanna Briggs Institute of the University of Adelaide for case series and case reports [19]. A "no" or "unclear" answer to any of the items causes a negative impact on the overall quality of the study analyzed. Therefore, studies that did not exceed or equal the percentage of the median "yes" were eliminated [44, 47, 52, 53, 55]. In addition, items with a "no", or "unclear" response rate of > 50%, which could have introduced bias in the evaluation of the articles, were item 7 "adverse events or unforeseen events of the treatment" in case reports and item 4 “selection of participants" and item 10 "appropriate statistical analysis" in the case series. These items, in our case, did not introduce bias since, in the case reports, the fact that an adverse effect is not described does not necessarily indicate that it may exist and, in the case series, there is no prior selection of participants, and neither is a statistical analysis essential.

Discussion of results

Historically, the oral rehabilitation of patients with ED was carried out using partial or completely removable prostheses, whether mucous or dento-supported. Currently, when the number and position of the teeth is favorable, the treatment of choice is usually fixed prostheses on natural teeth with crowns or bridges [14, 43, 54, 56, 57, 61, 66] implant-supported prostheses [42, 43, 54, 61, 66] or implant-retained overdentures [57]. Orthodontic and dentofacial orthopedic treatment has been used, fundamentally, to facilitate subsequent prosthetic rehabilitation to restore the necessary function and aesthetics.

The most frequent orthodontic treatments were the closure of diastemas in the anterosuperior region [41,42,43,44,45,46, 60, 61, 64], the alignment or maintenance of spaces [14, 43, 48, 50, 54, 56, 57, 63, 66] and the traction of teeth included in the palate [43, 48], All are aimed at facilitating the placement of implants and/or subsequent prosthetic treatment. Although ED presents with a lack of maxillomandibular development, we found only four studies whose main objective was to improve maxillomandibular growth. Karwetzky et al. [41] placed a type I U-activator to stimulate maxillary development; Gruber et al. [49] used a palatine circuit breaker with a face mask to stimulate the growth of the maxilla horizontally and sagittally; Altug-Atac et al. [50] used a functional device to correct an open bite due to lingual habits plus an orthopedic device to stimulate mandibular growth, and Ierardo et al. [62] used a fixed breaker with bands in 6 + 6 and two microscrews on the anterior palate to achieve rapid disjunction. Other authors have used removable prostheses, necessary to replace the missing teeth, for orthopedic purposes, since these devices included expansion screws or telescopic screw, both in the maxilla and the jaw [15, 16, 51, 58].

The poor results obtained in terms of maxillomandibular growth could explain why only three studies [50, 51, 57] made cephalometric records of the follow-up of orthodontic and orthopedic treatments.

Almost all the treatments fulfilled the initial objective proposed, allowing aesthetic and functional rehabilitation. The duration of treatment varied widely and depended on the type of treatment. However, it was close to the duration of orthodontic or orthopedic treatment in a patient without ED, where the average treatment duration was 24.9 months [67]. This indicates that the tooth movement rate is probably not affected in the case of ED.

Patients with ED should be treated from a very early age with the aim of stimulating maxillomandibular bone growth, which is the main challenge in the aesthetic and functional rehabilitation of these patients. In addition, a multidisciplinary approach is necessary, where pediatric dentists, orthodontists, oral and maxillo-facial surgeons, prosthodontists, psychologists, speech therapists, etc. intervene with the aim of maintaining the existing dentition, improving aesthetics, speech, and masticatory efficiency, and acceptance by the patient and their environment, thus helping their psychological well-being and social integration.

Studies with a higher level of evidence, and more patients grouped by age, types of treatments and the use of cephalometric data before and after the procedures are needed to establish treatment protocols in these patients.

Conclusions

Due to the nature of the problem, most studies reviewed had a low level of evidence. Most dentofacial orthopedic and orthodontic treatments described focused on correcting dental malpositions and asymmetries in the jaws and not on stimulating growth from an early age. Studies with more scientific evidence are needed to determine the best treatment for these patients.

Greater efforts should be made to stimulate maxillomandibular growth from birth in patients with ectodermal dysplasia to facilitate subsequent aesthetic-functional rehabilitation. A multidisciplinary approach would aid psychological well-being and social integration in these patients.