**Background:** Oligodontia, defined as the congenital absence of six or more teeth, can occur as an isolated trait or as part of a syndrome. Over 60 syndromes have been associated with oligodontia, including hypohidrotic ectodermal dysplasia (HED), Rieger syndrome, Down syndrome, and Van der Woude syndrome. Tooth development is regulated by conserved signaling pathways, and mutations in genes such as *WNT10A* and *PAX9* are commonly implicated. This systematic review aimed to summarize the literature on oligodontia in syndromes, focusing on phenotype and molecular etiology to assist diagnosis and management.
**Methods:** The review followed PRISMA guidelines and was registered in PROSPERO (CRD42020190814). Six databases (PubMed, Scopus, Lilacs, Web of Science, Livivo, EMBASE) and gray literature (Google Scholar, ProQuest) were searched in December 2022, with an update in August 2023. Eligible studies were case reports and case series of syndromic patients with oligodontia confirmed by dental radiographs. Exclusion criteria included non-syndromic cases, unclear radiographs, hypodontia or anodontia, reviews, animal studies, and unavailable full texts. Two authors independently screened titles/abstracts and full texts, with disagreements resolved by a third author. Data extraction included patient demographics, syndrome type, missing tooth pattern, and genetic findings. Risk of bias was assessed using the Joanna Briggs Institute tool for case reports. Protein–protein interaction networks were analyzed using STRING version 11.0.
**Key Results:** From 2569 initial records, 83 articles were included, reporting 97 patients (age range 3–75 years). The most frequent syndromes were HED (24 patients in 22 studies), Axenfeld-Rieger syndrome (9 patients in 5 studies), blepharocheilodontic syndrome (7 patients in 2 studies), Witkop syndrome (4 patients in 4 studies), oculofaciocardiodental syndrome (3 patients in 3 studies), incontinentia pigmenti (3 patients in 3 studies), Hallermann-Streiff syndrome (3 patients in 3 studies), polycystic ovarian syndrome (3 patients in 2 studies), Ellis-van Creveld syndrome (2 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). Ten patients had oligodontia in both primary and permanent dentitions; two had only primary dentition involvement. The number of missing teeth ranged from 6 to 13 in primary dentition and 6 to 27 in permanent dentition. In deciduous dentition, first molars and lateral/central incisors were absent in 76.9% of patients, and second molars and canines in 61.5%. In permanent dentition, lateral incisors (76.2% of patients), first molars (75.5%), central incisors (69.7%), premolars (66%), and second molars (40%) were most affected. Genetic analysis was performed in 23 studies, identifying mutations in *EDA*, *WNT10A*, *AXIN2*, *CDH1*, *DSP*, *EDARADD*, *EVC2*, *FGFR2*, *IKBKG*, *LEF1*, *MSX1*, *NPHP1*, *PCNT*, *PITX2*, *PTCH1*, *SRCAP*, and *TBCE*. The most common genetic cause was *EDA* or *WNT10A* mutations, accounting for 30.4% of syndromic oligodontia cases. Protein–protein interaction analysis revealed significant enrichment in odontogenesis (GO:0042476; p = 1.56 × 10⁻⁷), gland development (GO:0048732; p = 7.29 × 10⁻⁶), and epithelium development (GO:0060429; p = 1.65 × 10⁻⁵).
**Clinical Implications:** The pattern of missing teeth—particularly bilateral agenesis of maxillary lateral incisors and unilateral agenesis of mandibular second premolars—can serve as diagnostic clues for underlying syndromes. Clinicians evaluating patients with oligodontia should consider common syndromic associations such as HED, Axenfeld-Rieger syndrome, Witkop syndrome, Ellis-van Creveld syndrome, blepharocheilodontic syndrome, and oculofaciocardiodental syndrome. Comprehensive radiographic assessment and genetic testing (e.g., for *EDA*, *WNT10A*, *PITX2*, *MSX1*) can confirm diagnosis, inform genetic counseling, and guide multidisciplinary management including dental rehabilitation and monitoring for systemic manifestations. The variable expressivity of oligodontia (ranging from hypodontia to anodontia) underscores the need for a holistic evaluation of the patient's overall clinical presentation.