Oligodontia in the Clinical Spectrum of Syndromes: A Systematic Review

The aim of this systematic review was to describe the clinical and genetic features of syndromes showing oligodontia as a sign. The review was performed according to the PRISMA 2020 checklist guidelines, and the search was conducted using PubMed, Scopus, Lilacs, Web of science, Livivo, and EMBASE and supplemented by a gray literature search on Google Scholar and ProQuest, applying key terms relevant to the research questions. The systematic review identified 47 types of syndromes in 83 studies, and the most common was hypohidrotic ectodermal dysplasia, which was reported in 24 patients in 22 studies. Other common syndromes that reported oligodontia included Axenfeld–Rieger syndrome, Witkop’s syndrome, Ellis–van Creveld syndrome, blepharocheilodontic syndrome, and oculofaciocardiodental syndrome. The X-linked mode of inheritance was the most reported (n = 13 studies), followed by the autosomal dominant (n = 13 studies). The review describes the main syndromes that may have oligodontia as a clinical sign and reinforces the need for orodental–facial examining for adequate diagnosis and treatment of the affected patients. Molecular analysis in order to better understand the occurrence of oligodontia is imperative.


Introduction
Tooth agenesis is defined as the absence of teeth from the normal series due to a failure to develop and encompasses hypodontia, oligodontia, and anodontia [1].The absence of up to five teeth is classified as hypodontia, the congenital absence of six or more teeth is defined as oligodontia, and anodontia refers to the complete absence of all teeth from the normal series [1].Tooth development is regulated by a series of signaling pathways, and genetic mutations in specific genes have been described as the causes of such defects [2,3].Moreover, environmental factors such as trauma, infections, toxins, and dietary deficiencies have been implicated and could interact with the genetic factors as a complex and multifactorial disease [4,5].
The occurrence of oligodontia can be observed as an isolated trait (non-syndromic oligodontia) or accompanying other features as part of a syndrome [6][7][8][9].In cases of non-syndromic oligodontia, the congenital absence of teeth stands as the sole discernible clinical characteristic [10].These instances are relatively uncommon, with a prevalence that varies from 0.08% to 0.36%, contingent upon the specific population under study [11][12][13].Nevertheless, the intricate interplay between oligodontia and syndromes has increasingly captured attention.The association of oligodontia with over 60 different syndromes, including but not limited to hypohidrotic ectodermal dysplasia (HED), Rieger's syndrome, Down's syndrome, and Van der Woude's syndrome [14], underscores its significance as a phenotypic marker and a consequence of intricate genetic interactions.Notably, while oligodontia assumes a central role as a diagnostic hallmark for numerous syndromes, additional dental anomalies may co-occur.These anomalies encompass microdontia, shortened roots, dental impactions, delayed tooth formation, delayed eruption, canine and premolar transpositions, taurodontism, and enamel hypoplasia [2,15,16].Tooth development is orchestrated by conserved signaling pathways that facilitate communication between ectodermal and mesenchymal tissues.In humans, mutations in WNT10A are the most commonly reported in the genetic etiology for syndromic oligodontia, and PAX9 mutations are the most commonly reported genetic etiology for isolated oligodontia [17].
Patients with oligodontia present serious deficiencies in their quality of life due to decreased masticatory function, phonetic ability, and maxillofacial aesthetics [18,19].As oligodontia can be a clinical manifestation of a large and heterogenous group of syndromes with multiple signs and symptoms, this systematic review aims to summarize the available literature concerning the presence of oligodontia in syndromes, emphasizing the phenotype and the molecular etiology in order to assist in the diagnosis and management of patients.

Protocol and Registration
This systematic review was performed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) checklist [20], and its protocol was recorded in the International Prospective Register of Systematic Reviews (PROSPERO) database under registration number CRD42020190814.

Eligibility Criteria
The PICOS approach was used to formulate the question for this study: P-participants (syndromic patients with oligodontia); I-intervention (none), C-comparison (none); Ooutcomes (frequency and types of syndromes associated with oligodontia, pattern of missing teeth, and frequency of pathogenic variants); S-study (case reports and case series).

Study Selection
The selection process of the studies was performed using an individual search in each bibliographic database: PubMed, Scopus, Lilacs, Web of science, Livivo, and EMBASE.A gray literature search was conducted using Google Scholar and ProQuest.The research was performed in December 2022.However, a second literature search was performed using the same terms on 8th August 2021, retrieving articles published between January and August 2023.The search strategy can be assessed in Supplementary Table S1.The duplicate references were removed by reference manager software (EndNote X7, Thomson Reuters, Toronto, ON, Canada).All references were transferred and worked on the Rayyan (Rayyan, Qatar Computing Research Institute, Qatar Foundation, Doha, Qatar), developed specifically to expedite the initial screening of abstracts and titles [21].

Results
The searches conducted in the six databases resulted in 2569 scientific articles.After removal of duplicates, 1772 articles were totalled.The gray literature search resulted in 81 articles.After reading the titles and abstracts in the first phase, 288 articles were selected for the next phase.At the end of reading the full articles (second phase), 83 articles were included for the qualitative synthesis .The review process is schematized in a flowchart depicted on Figure 1.
The main data of each selected article are summarized in Table 1.Together, the studies reported 97 patients, ages ranging from 3 to 75 years old, with oligodontia as a clinical feature of different types of syndromes.The risk-of-bias assessment in each study is reported in Supplementary Table S2.All included articles were classified as having a low risk of bias, except for eight articles.These articles had unclear information regarding the demographics of the patients, the timeline of diagnosis, and, most importantly, the diagnostic tests used for the final diagnosis.
Out of 97 patients, 10 patients were affected by oligodontia in both primary and permanent dentitions; in 2 cases, oligodontia was observed in the primary dentition; and in the other cases, oligodontia was observed in the permanent dentition (Table 1).The number of missing teeth ranged from 6 to 13 in the primary dentition and from 6 to 27 in the permanent dentition.In the deciduous dentition, the absence of the first molars and lateral and central incisors was observed in 76.9% of patients, and the second molars and canines were absent in 61.5% of patients (Table 1).In the permanent dentition, lateral incisors (76.2% of patients), first molars (75.5% of patients), central incisors (69.7% of patients), premolars (66% of patients), and second molars (40% of patients) were the more-affected teeth (Table 1).The main data of each selected article are summarized in Table 1.Together, the studies reported 97 patients, ages ranging from 3 to 75 years old, with oligodontia as a clinical feature of different types of syndromes.The risk-of-bias assessment in each study is reported in Supplementary Table S2.All included articles were classified as having a low risk of bias, except for eight articles.These articles had unclear information regarding the demographics of the patients, the timeline of diagnosis, and, most importantly, the diagnostic tests used for the final diagnosis.
Out of 97 patients, 10 patients were affected by oligodontia in both primary and permanent dentitions; in 2 cases, oligodontia was observed in the primary dentition; and in the other cases, oligodontia was observed in the permanent dentition (Table 1).The num-  The lower face was short, the oral fissure was narrow, the middle face sank, and the lips protruded, resembling the so-called prematurely aged face in the profile, scalp hair thin and soft, and oligodontia Hyperkeratosis on the pal mar aspect of both hands, dystrophy of the toe nails, and ichthyosis of posterior aspect of legs The genetic profile of the different studies is summarized in Table 1.HED was the most-found syndrome, and the X-linked mode of inheritance was the most common for this syndrome.The most reported mode of inheritance for oculofaciocardiodental syndrome, incontinentia pigmenti and Christ-Siemens-Touraine syndrome was X-linked.The mode of inheritance for Carvajal syndrome, Noonan syndrome, ARS, Witkop's syndrome, Apert syndrome, BCDS, and Kabuki syndrome was the autosomal dominant, whereas microcephalic osteodyplastic primordial dwarfism type II, tricho-odonto-onychodermal dysplasia, and EVCS were reported under autosomal recessive (Table 1).
The genetic profile of the different studies is summarized in Table 1.HED was the most-found syndrome, and the X-linked mode of inheritance was the most common for this syndrome.The most reported mode of inheritance for oculofaciocardiodental syndrome, incontinentia pigmenti and Christ-Siemens-Touraine syndrome was X-linked.The mode of inheritance for Carvajal syndrome, Noonan syndrome, ARS, Witkop's syndrome, Apert syndrome, BCDS, and Kabuki syndrome was the autosomal dominant, whereas microcephalic osteodyplastic primordial dwarfism type II, tricho-odonto-onychodermal dysplasia, and EVCS were reported under autosomal recessive (Table 1).

Discussion
Within the realm of syndromes characterized by oligodontia, questions arise regarding the consistency of this phenotype across cases, its varying expressiveness, its diagnostic utility, and the specific teeth most affected.This review sought to comprehensively address these queries by collating pertinent information from a diverse array of syndromes exhibiting oligodontia within their clinical spectrum.The exploration commenced by surveying the literature and transcending temporal constraints, leading to the identification of 47 distinct syndromes cataloged within the Online Mendelian Inheritance in Man.Among these, HED emerged as the most frequent.The hallmark trifecta of HED, involving hair, teeth, and sweat gland anomalies [106], was evident in the affected patients.The spectrum of dental agenesis in HED spans mainly oligodontia, but reports of hypodontia and even anodontia are found in the literature, with a predilection for the mandible.This remarkable variability necessitates close attention for correct diagnosis [107,108].Notably, the distinctive conical shape of the anterior teeth, when present, offers a diagnostic clue.Furthermore, the potential confluence of maxillary retrusion, sagittal jaw underdevelopment, jaw displacement, and craniofacial alterations underlines the complex interplay of factors characterizing this syndrome [107][108][109].
Within our systematic review, several syndromes stood out for their prevalence and diverse oral manifestations.One of the noteworthy conditions identified was Ellis-van Creveld syndrome (EVCS), an autosomal recessive skeletal dysplasia.EVCS presents a range of oral phenotypes alongside limb abnormalities, including occlusion irregularities, labiogingival adhesions, hypertrophied labiogingival frenulum, accessory frenula, serrated incisal margins, dental transposition, diastemas, conical teeth, enamel hypoplasia, and congenital absence of multiple teeth [110,111].The propensity for premature eruption or exfoliation further complicates the dental anomalies associated with EVCS.In our study, we observed an average of 6 deciduous teeth (one case) and 8.5 permanent teeth (two cases) missing in individuals with reported EVC2 mutations.Another syndrome we examined was oculofaciocardiodental syndrome, a rare multi-systemic anomaly, with a higher prevalence in females.This syndrome showcases the intricate interplay between congenital cataracts, facial dysmorphisms, and dental anomalies, including radiculomegaly and oligodontia, in addition to congenital heart defects [77,112].In our study, we noted an average of nine permanent teeth (three cases) missing in individuals with reported WNT10A mutations.Witkop syndrome, an uncommon autosomal dominant genetic disorder attributed to mutations in MSX1, held our attention due to its distinct dental and nail dysplasia characteristics.This syndrome is primarily marked by dental agenesis, primarily oligodontia, although the absence of up to five teeth (hypodontia) is also reported.Dental features often include conical-shaped teeth and teeth with narrow crowns [113].In our study, we observed an average of 16.75 permanent teeth (four cases) missing in individuals with reported MSX1 mutations.Axenfeld-Rieger syndrome (ARS), a condition characterized by ocular dysgenesis and systemic anomalies affecting the teeth, heart, craniofacial structure, and abdominal wall, was another significant focus.ARS is frequently associated with a 6p25 distal microdeletion but may also manifest in connection with other genetic loci such as 4q25 or 13q14.Several genes, including FOXC1, FOXC2, and FKHL7, have been implicated in the context of ARS [29,114].In our study, we found an average of 9 primary teeth (one case) and 14.3 permanent teeth (nine cases) missing in individuals with reported PITX2 mutations.Lastly, we explored branchio-oculofacial syndrome (BCDS), an autosomal dominant disorder known for congenital facial clefting, oligodontia, euryblepharon, lagophthalmos, and ectropion.While the extent of its expression can vary, the common features often encompass cleft lip and/or palate, ectropion, and lagophthalmos [76,115].In our study, we observed an average of 8.5 primary teeth (four cases) and 15.4 permanent teeth (seven cases) missing in individuals with reported CDH1 mutations.
Interrogating the consistency of oligodontia across syndromic cases is of paramount importance.The range of dental presentations, spanning from hypodontia to anodontia, underscores the variable expressiveness within these syndromes.Consequently, the man-ifestation of oligodontia should be viewed as a continuum instead of an absolute trait.This variable expressivity poses challenges in diagnosis and underscores the importance of considering broader phenotypic traits in conjunction with dental anomalies.Regarding the most-affected teeth, patterns emerged from the collated data.In deciduous dentition, absence of first molars and lateral and central incisors was observed in the majority of patients, with second molars and canines affected in a significant proportion.In permanent dentition, lateral incisors, first molars, central incisors, premolars, and second molars exhibited the highest susceptibility to oligodontia.HED is the most frequently mentioned syndrome with oligodontia, while EDA and WNT10A mutations constitute the most frequently determined genetic cause: 30.4% of the syndromic oligodontia.These findings are consistent with previous reports which established WNT10A variants accounting for up to 50% of various HED syndromes with missing teeth [17,116].These patterns may offer clues for diagnosis and genetic assessment.However, as previously reported, there are several mechanisms that are involved in tooth development and other tissues of the body, establishing very heterogeneous phenotypes in affected individuals.Thus, radiographic and molecular diagnoses may be necessary.The analysis of dental radiographs is an important part of the diagnostic process in daily clinical practice, and interpretation by an expert includes teeth detection and numbering [117][118][119].In the reading of the articles included, panoramic radiographs with poor quality were evidenced, which can affect the diagnosis and consequent interpretation of the case report.The detailed radiographic report of the observed alterations was also absent in most studies.
In some situations, in the differential diagnosis process, sequencing analysis is useful, and further exploration of the identified mutations can assist in the interpretation of the phenotypes (genotype-phenotype correlation).The important role of genetics has been increasingly recognized in recent years with regard to the understanding of dental anomalies such as tooth agenesis [120].However, many of the included studies in this systematic review did not perform molecular analysis.Only 23 studies [41,43,52,53,56,63,[66][67][68]70,73,74,76,78,79,[87][88][89][90]92,94,98,105] performed genetic analysis and reported the genetic variants associated with the syndromes.These genes can be grouped into two major groups: one with crucial roles at multiple stages of tooth development, also involving skin and sweat glands (AXIN2, CDH1, DSP, EDA, EDARADD, EVC2, FGFR2, LEF1, MSX1, PITX2, and WNT10A), which are involved in the signal pathway essential for ectodermal structure development [121,122]; the other with genes that intermediate cellular function and development (NPHP1, PCNT, PTCH1, IKBKG, SRCAP, and TBCE).Interestingly, some of the identified genes are also associated with non-syndromic oligodontia, but in these cases, the mutations cause reduced expression, decreased receptor-binding affinity, or altered signaling-intensity of the mutated protein, whereas the mutations associated with syndromic oligodontia are characterized by a more intense impact on protein function [123].
The teeth affected by oligodontia often exhibit various dental anomalies, such as reduced size, a conical shape, and delayed eruption [12,[121][122][123][124][125][126].These shared features suggest the influence of similar genetic mechanisms [124].Our findings align with previous research [120], indicating that permanent dentition is more frequently affected by oligodontia compared to primary dentition.In our study of 97 patients, we observed bilateral agenesis of maxillary lateral incisors in 64 patients, while 13 patients displayed unilateral absence of the second mandibular premolar.It is worth noting that clinical studies have reported that bilateral agenesis of the maxillary lateral incisors is more common than unilateral agenesis, and unilateral agenesis of the second mandibular premolar is more prevalent than bilateral cases [127].
However, it is important to acknowledge the limitations of this study.One significant limitation arises from the varied terminology used to define oligodontia, including terms such as severe hypodontia or partial anodontia.This inconsistency in nomenclature can lead to challenges in accurately classifying cases.Additionally, the absence of radiographic data for correct oligodontia diagnosis was a noteworthy limitation that impacted our sample size.Many studies included in this review did not perform genetic tests, which precluded a more comprehensive phenotype-genotype correlation analysis.Furthermore, some very rare disorders may not have been reported in the literature, potentially limiting the scope of our review with regard to syndromes associated with oligodontia.
In addition to its academic significance, the findings from this review hold substantial implications for clinical practice.Identifying specific dental anomalies and their association with syndromes can play a pivotal role in the diagnostic process.When assessing patients with oligodontia, it is essential for clinicians to consider the potential presence of an underlying syndrome.The number and type of missing or affected teeth can serve as valuable diagnostic clues, but a holistic evaluation of the patient's overall clinical presentation, including physical and developmental features, is indispensable.Furthermore, the genetic insights garnered from this review offer the potential for more precise and personalized patient care.Understanding the genetic underpinnings of syndromic oligodontia can facilitate early diagnosis, inform genetic counseling, and guide treatment planning.Genetic testing, where applicable, can provide confirmation and assist in tailoring therapeutic strategies.This knowledge can also pave the way for the development of targeted therapies or interventions with which to address the dental and craniofacial challenges associated with syndromic oligodontia.
Looking ahead, there is a compelling need for further research in this field.Delving deeper into the genetic underpinnings of syndromic oligodontia and exploring the phenotypic heterogeneity in greater detail are paramount.Studies that employ consistent terminology and diagnostic methods will contribute to a more comprehensive understanding of this complex condition.Additionally, further investigations into genotype-phenotype correlations and the development of standardized diagnostic criteria for syndromic oligodontia are warranted.Comprehensive radiographic assessment and molecular analysis will be instrumental in elucidating the underlying mechanisms and genetic factors associated with these syndromes.

Conclusions
The identification of specific phenotypes associated with oligodontia can significantly reduce diagnostic uncertainty, particularly when these phenotypes are highly predictive of a specific syndrome.Based on the insights gained from this review, it is advisable that clinicians and geneticists, during the diagnosis process of patients with oligodontia, remain vigilant for the most common syndromes with oligodontia as a clinical sign.These syndromes include hypohidrotic ectodermal dysplasia (HED), Axenfeld-Rieger Syndrome (ARS), Witkop's syndrome, Ellis-van Creveld syndrome (EVCS), Branchio-oculofacial syndrome (BCDS), and oculofaciocardiodental syndrome.These findings contribute to a more informed and precise diagnostic approach, ultimately enhancing patient care and management.

29 Figure 1 .
Figure 1.Flow diagram of literature search and selection criteria adapted via the preferred reporting items for systematic reviews and meta-analyses (PRISMA) [20].

Figure 1 .
Figure 1.Flow diagram of literature search and selection criteria adapted via the preferred reporting items for systematic reviews and meta-analyses (PRISMA) [20].

Figure 2 .
Figure 2. Protein-protein interaction network with the genes associated with syndromes with oligodontia.Two nodes of interactions, involving AXIN2, CDH1, DSP, EDA, EDARADD, EVC2, FGFR2, LEF1, MSX1, PTCH1, PITX2, and WNT10A (p < 1.0 × 10 −16 ) and between PCNT and IKBKG (p = 0.04) were identified.Different colors represent different levels of evidence of connection between proteins; light blue represents curated databases, purple experimental evidence, green gene neighborhood, light green evidence from text mining, black co-expression, and violet protein homology.This analysis had an average confidence score of 0.657, suggesting a low rate for falsepositive interactions.

Table 1 .
Manifestations of oligodontia in primary and permanent dentition in the included articles (n = 83).

Table 1 . Cont. Author Year/Country Geographic Origin Type of Study (CR/SC) Syndrome Name (#OMIM) Sex (M/F) Age (Yrs) Mode of Inheritance (AD/AR/X-LINKED) Causative Gene Dentition Number of Teeth Affected Teeth Systemic Manifestations Craniofacial Manifestations
Capacity to sweat is reducedFine sparse hair, dry and thin skin, frontal bossing, cherub-like lips, no body hair on arms and legs