REVIEW ARTICLE Dental agenesis: genetic and clinical perspectives P. J. De Coster 1 , L. A. Marks 1 , L. C. Martens 1 , A. Huysseune 2 1 Department of Paediatric Dentistry and Special Care, Paecamed Research, Ghent University; 2 Department of Biology, Ghent University, Ghent, Belgium Dental agenesis is the most common developmental anomaly in humans and is frequently associated with several other oral abnormalities. Whereas the incidence of missing teeth may vary considerably depending on dentition, gender, and demographic or geographic pro- files, distinct patterns of agenesis have been detected in the permanent dentition. These frequently involve the last teeth of a class to develop (I2, P2, M3) suggesting a possible link with evolutionary trends. Hypodontia can either occur as an isolated condition (non-syndromic hypodontia) involving one (80% of cases), a few (less than 10%) or many teeth (less than 1%), or can be associated with a systemic condition or syndrome (syndromic hypodontia), essentially reflecting the genetically and phenotypically heterogeneity of the condition. Based on our present knowledge of genes and transcription factors that are involved in tooth devel- opment, it is assumed that different phenotypic forms are caused by different genes involving different inter- acting molecular pathways, providing an explanation not only for the wide variety in agenesis patterns but also for associations of dental agenesis with other oral anomalies. At present, the list of genes involved in human non-syndromic hypodontia includes not only those encoding a signaling molecule (TGFA) and tran- scription factors (MSX1 and PAX9) that play critical roles during early craniofacial development, but also genes coding for a protein involved in canonical Wnt signaling (AXIN2), and a transmembrane receptor of fibroblast growth factors (FGFR1). Our objective was to review the current literature on the molecular mechanisms that are responsible for selective dental agenesis in humans and to present a detailed overview of syndromes with hypodontia and their causative genes. These new per- spectives and future challenges in the field of identifi- cation of possible candidate genes involved in dental agenesis are discussed. J Oral Pathol Med (2009) 38: 1–17 Keywords: Dental agenesis; growth factors; hypodontia; patterning defects; signaling molecules Introduction: patterns of dental agenesis in humans Hypodontia (congenital lack of teeth or dental agenesis) is the most common developmental anomaly in man, often representing a significant clinical problem (1–3). It is frequently associated with other oral anomalies, such as cleft lip and / or palate (4–9), microdontia, reduction in tooth size and / or malformation of other teeth (10–16), short root anomaly (17, 18), impaction, delayed formation and / or delayed eruption of other teeth (19–24), crowding (25–27) and / or malposition of other teeth (28–30), maxillary canine / first premolar transposi- tion (31, 32), taurodontism (20, 24, 33, 34), enamel hypoplasia (12), and altered craniofacial growth (35, 36). Clinicians often claim that dental agenesis has increased during recent decades (37, 38). There is, however, no evidence as to whether this is an evolu- tionary trend or an observation as a result of more advanced screening and diagnosis of oral anomalies. The incidence of missing permanent teeth has been reported to vary from 2.6% to 11.3% depending on demographic and geographic profiles, excluding third molars, which are absent in 9–30% of the population (39–51). In the permanent dentition, the mandibular second premolars are most often missing, and maxillary lateral incisors are involved almost equally (39, 52, 53). The incidence of missing teeth in the primary dentition is considerably lower, i.e. 0.4–0.9% in the European (54– 57) and Brazilian population (58), and about 2.4% in the Japanese population (59, 60). Agenesis of one primary tooth, most commonly a lateral incisor (43, 59, 61), has been found in 60% of the cases. Absence of more than two primary teeth was found in 8% of children with hypodontia in the primary dentition (61, 62). Distinct patterns of agenesis have been detected in the permanent dentition (i.e. unilateral agenesis more common than bilateral; third molars and second pre- molars commonly missing in all quadrants and / or combinations of these two tooth types and the incisors) doi: 10.1111/j.1600-0714.2008.00699.x J Oral Pathol Med (2009) 38: 1–17 ª 2008 The Authors. Journal compilation ª 2008 Blackwell Munksgaard Æ All rights reserved www.blackwellmunksgaard.com/jopm Correspondence: Prof. Dr. Peter J. De Coster, Dental School – Poli 8, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Tel: +32 9 3329461, Fax: +32 9 3323851, E-mail: peter.decoster@ugent.be Accepted for publication May 18, 2008