Oligodontia in the Clinical Spectrum of Syndromes: A Systematic Review

1. Introduction

Tooth agenesis is defined as the absence of teeth from the normal series by 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 cause of such defects [2,3]. Besides, 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 patients with non-syndromic oligodontia, the congenitally missing teeth are the only apparent clinical finding [10], and studies show that these cases are rare, with a prevalence ranging from 0.16% to 0.36%, depending on the population studied [11]. However, some patients can display mild phenotypes or the clinical expression of phenotypes other than oligodontia can only appear late in life, and the misdiagnosis of non-syndromic oligodontia can occur [12]. Oligodontia is a significant and integral diagnostic feature for many syndromes, but other concurrent dental anomalies may occur, including microdontia, short roots, dental impactions, delayed formation of teeth, delayed eruption, transposition of canines and premolars, taurodontism, and enamel hypoplasia [2,13,14]. Patients with oligodontia present serious deficiencies in their quality of life due to decreased masticatory function, phonetic ability and maxillofacial aesthetics [15,16]. As oligodontia can be a clinical manifestation of a large and heterogenous group of syndromes with multiple signs and symptoms, this systematic review aims summarize the available literature concerning the presence of oligodontia in syndromes, emphasizing the phenotype and the molecular etiology, in order to assist in diagnosis and management of the patients.

2. Materials and Methods

2.1. Protocol and Registration

This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist [17], and its protocol was recorded in the International Prospective Register of Systematic Reviews (PROSPERO) database, under registration number CRD42020190814.

2.2. 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), O—outcomes (frequency and types of syndromes associated with oligodontia, pattern of missing teeth and frequency of pathogenic variants), S—study (case reports and case series).

The criteria for the exclusion of articles were: (1) Non-syndromic cases; (2) Studies that did not report or report unclear dental X-rays; (3) Studies that did not report representative cases of oligodontia; (4) Studies that report cases of hypodontia or anodontia; (5) Studies that do not include pattern of tooth agenesis; (6) Reviews, letters, conference abstract, personal opinions, and in vitro or in vivo animal studies; (7) Full-text copy not available; (8) Duplicated data from other study; (9) Articles that were not in Roman alphabet; (10) Studies with absence of clinical information.

2.3. 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 August 8^th, 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). All references were transferred and worked on the Rayyan (Rayyan, Qatar Computing Research Institute, Qatar Foundation), developed specifically to expedite the initial screening of abstracts and titles [18].

The course of the research was established in two distinct phases. In the first phase, two authors (NLC and KKMR) independently read all titles and abstracts, taking into account the eligibility criteria initially defined. In cases of no consensus, a third author (ACA) was involved, who determined which articles would be included in the second phase. The second phase was carried out by the same authors, who performed a full-text reading of the screened articles. Disagreements were solved by discussion involving the third author (ACA).

2.4. Data Collection Process and Data Items

The data collection process was carried out by the two authors (NLC and KKMR) who selected the articles initially in the two phases, in which the necessary and relevant information of each study was collected. The information was checked by a third author (ACA).

2.5. Risk of Bias within Studies

The risk-of-bias was assessed by two authors (NLC and KKMR) using the Joanna Briggs Institute Critical Appraisal Tools for Studies Reporting Prevalence Data for Use in Systematic Reviews—referred to Case Reports [19]. The authors scored each item as “yes,” “no,” “unclear,” or “not applicable” when assessing the quality of each included study. Decisions about scoring were discussed by all reviewers, a study was characterized as having a high risk of bias when it reached a “yes” score of up to 49%, moderate when 50% to 69%, and low when >70%.

2.6. Interaction Analysis

The functional relevance of identified genes was further investigated with STRING, 11.0 version (search tool for the retrieval of interacting genes, http://string-db.org), which provides a P value after applying false discovery rate for correction of multiple testing.

3. Results

The searches conducted in the 6 databases resulted in 2,569 scientific articles. After removal of duplicates, 1,772 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), 91 articles were included for the qualitative synthesis. The studies excluded in the second phase are listed in the Supplementary Table S2. The review process is schematized in a flowchart depicted on Figure 1.

The main data of each selected article are summarized in Supplementary Table S3. Together, the studies reported 106 patients, ages ranging from 3 to 75 years old, with oligodontia as a clinical feature of different types of syndromes. Risk-of-bias assessment in each study is reported in Supplementary Table S4.

The syndromes more frequently identified, in decreasing order, were hypohidrotic ectodermal dysplasia (HED) (24 patients in 22 studies), Axenfeld-Rieger syndrome (ARS) (8 patients in 5 studies), Witkop’s syndrome (6 patients in 5 studies), Ellis-van Creveld syndrome (EVCS) (5 patients in 4 studies), blepharocheilodontic syndrome (BCDS) (5 patients in 2 studies), oculo-facio-cardio-dental syndrome (4 patients in 4 studies), incontinentia pigmenti (3 patients in 3 studies), Hallermann-Streiff syndrome (3 patients in 3 studies), polycistic ovarian syndrome (3 patients in 2 studies), Down syndrome (2 patients in 2 studies), Carvajal syndrome (2 patients in 2 studies), Carpenter syndrome (2 patients in 2 studies) and Kabuki syndrome (2 patients in 2 studies). Other uncommon syndromes listed in Supplementary Table S3 were reported in 1 patient each.

Out of 106 patients, 10 patients were affected by oligodontia in both primary and permanent dentitions, 3 had oligodontia only in the primary dentition, and in the other cases, oligodontia was exclusively 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 30 in the permanent dentition. In the deciduous dentition, the absence of the first molars, 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), third molars (60% of patients) and second molars (40% of patients) were the more affected teeth (Table 1).

The genetic profile of the different studies is summarized in Supplementary Table S3. 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 oculo-facio-cardio-dental 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-onycho-dermal dysplasia, Rothmund-Thomson syndrome and EVCS were reported under autosomal recessive (Supplementary Table S3).

Eight studies reported mutations in EDA or WNT10A in HED, Christ-Siemens-Touraine syndrome, tricho-odonto-onycho-dermal dysplasia and odonto-onycho-dermal dysplasia. MSX1 was related twice in cases of Witkop’s syndrome. Others studies have reported mutations in DSP (Carvajal/Naxos syndrome), PITX2 (ARS), PCNT (microcephalic osteofysplastic dwarfism type 2), TBCE (Sanjad-Sakati syndrome), EDARADD (HED), LEF1 (HED), AXIN2 (HED), PTCH1 (basal cell nevus syndrome), FZD7 (del(2q32) syndrome), EVC2 (EVCS), NPHP1 (juvenile nephronophtisis), SRCAP (Floating-Harbor syndrome), BCOR (oculo-facio-cardio-dental syndrome), IKBKG (incontinentia pigmenti), and FGFR2 (Beare-Stevenson syndrome). Together, these genes participate of 227 biological processes and 20 pathways. The most significant biological processes were odontogenesis (GO:0042476, P = 9.55e-11), animal organ morphogenesis (GO:0009887, P = 6.51e-07) and epithelium development (GO:0060429, P = 2.90e-06), and the pathways were of basal cell carcinoma (hsa05217, P = 2.34e-07), pathways in cancer (hsa05200, P = 6.77e-06) and pathways of the gastric cancer (hsa05226, P = 6.77e-06) (Supplementary Table S5 and S6). The networks included 18 predicted interactions (Figure 2).

4. Discussion

Within the realm of syndromes characterized by oligodontia, questions arise regarding the consistency of this phenotype across cases, its varying expressiveness, 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 an extensive expanse of literature, transcending temporal constraints, leading to the identification of 49 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 [22], was evident in the affected patients. The spectrum of dental agenesis in HED spans mainly oligodontia, but reports of hypodontia and even anodontia is found in the literature, with a predilection for the mandible. This remarkable variability necessitates close attention for correct diagnosis [23,24]. Notably, the distinctive conical shape of 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 [23,25].

Among the most commom syndromes idetifieded in the systematic review was EVCS, an autosomal recessive skeletal dysplasia that encompasses an intriguing spectrum of oral manifestations. Alongside limb abnormalities, the oral phenotype includes occlusion irregularities, labiogingival adhesions, hypertrophied labiogingival frenulum, accessory frenula, serrated incisal margins, dental transposition, diastemas, conical teeth, enamel hypoplasia, and congenital absence of serevral teeth [26,27]. The propensity for premature eruption or exfoliation accentuates the complexity of dental anomalies associated with EVCS. Oculo-facio-cardio-dental syndrome, a rare multi-systemic anomaly more prevalent in females, demonstrates an intricate interplay between congenital cataracts, facial dysmorphisms, dental anomalies like radiculomegaly and oligodontia, and congenital heart defects [28,29]. Witkop syndrome is an uncommon genetic disorder inherited in an autosomal dominant pattern, attributed to mutations occurring in MSX1. This gene holds significance in the formation of the teeth, nails, hair follicles and various other anatomical structures of ectoderma origin. Consequently, the syndrome is distinguished by two primary features: dental agenesis, mainly oligodontia, but the absence of up to 5 teeths (hypodontia) is also reported, and nail dysplasia. Conical-shaped teeth and teeth with narrow crowns are common dental features of Witkop syndrome [30]. ARS is a condition characterized by ocular dysgenesis affecting the anterior segment, along with concurrent systemic anomalies involving the teeth, heart, craniofacial structure and abdominal wall. It is frequently associated with a 6p25 distal microdeletion. However, diverse manifestations of this syndrome may also show connections with other genetic loci like 4q25 or 13q14. Various genes, including FOXC1, FOXC2, and FKHL7, are implicated in the context of ARS [31,32]. BCDS is an uncommon autosomal dominant disorder characterized by congenital facial clefting, oligodontia, euryblepharon, lagophthalmos, and ectropion. While the extent of its expression can differ, the prevalent features often include cleft lip and/or palate, ectropion and lagophthalmos [33].

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 manifestation 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, 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, third molars, and second molars exhibited the highest susceptibility to oligodontia. 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 diagnosis may be necessary. 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 [34,35,36]. 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 [37]. However, many of the included studies in this systematic review did not perform molecular analysis. Only 13 studies [38,51] performed genetic analysis and reported the genetic variants associated with the syndromes. These genes can be grouped in two groups. These genes can be grouped in two major groups. One with crucial roles at multiple stages of tooth development, skin and sweat glands (EDA, EDARADD, WNT10a, MSX1, DSP, LEF1, EVC2, PITX2, FGFR2, and AXIN2), which are involved in the signal pathway essential for ectodermal structure development [52,53], and the other with genes that intermedia the function and developmental cellular (PCNT, TBCE, PTCH1, TBCE, FZD7, SRCAP, NPHP1, IKBKG, and BCOR). 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 mutated protein, whereas the mutations associated with syndromic oligodontia are characterized by a more intense impact on protein function [54].

The teeth in patients with oligodontia frequently are affected by dental anomalies, including reduction in size, assuming a conoid shape, and delayed eruption [52,53,54,55,56,57,58], indicating a control by similar genetic mechanisms [55]. Corroborating with previous literature [37], our findings demonstrated that the permanent dentition is more frequently affected by oligodontia than primary dentition. Out of 106 patients, 68 patients showed bilateral agenesis of maxillary lateral incisors and 13 patients showed unilateral absence of the second mandibular premolar. Clinical studies have described that bilateral agenesis of the maxillary lateral incisors occurred more often than unilateral agenesis, and unilateral agenesis of the second mandibular premolar is more common than bilateral one [59].

The study has limitations, which are the result of use of different terminology to define oligodontia, including severe hypodontia or partial anodontia. The unavailability of radiographies to the correct diagnosis of oligodontia was alarming, reducing the sample size. This study was also limited by the fact that many studies did not perform genetic tests, precluding a more complete phenotype-genotype correlation. In addition, cases of very rare disorders may not be reported in the literature, limiting our map for syndrome with oligodontia.

5. Conclusion

Phenotype identification can reduce uncertainty in the diagnosis when the phenotype is highly predictive for a specific syndrome. Based on this review, during the diagnosis process of patients with oligodontia, clinians and geneticists should be aware of the most common syndromes with oligodontia as clinical sign, including HED, ARS, Witkop’s syndrome, EVCS, BCDS and oculo-facio-cardio-dental syndrome.