Genetic Dental Anomalies - Approach

Tooth agenesis, inherited defects of enamel and dentine, primary failure of eruption and radiculomegaly: classification, genes, differential diagnosis with the syndromic forms, lifelong dental management and genetic counselling.

Literature and regulatory information updated: 29 October 2026.

0. Initial Reference Table

Genetic dental anomalies are organised by the phase of tooth development that is disturbed: initiation determines the number of teeth (agenesis or supernumerary teeth), morphodifferentiation determines size and shape (microdontia, taurodontism, radiculomegaly, conical teeth), and histodifferentiation, apposition and mineralisation determine the structure of enamel and dentine; eruption depends on a mechanism of its own, regulated by the dental follicle and the alveolar bone [1, 2]. The following table summarises the entities covered in this article.

Table sources: GeneReviews [3], French national protocol for oligodontia and anodontia [4], prevalence meta-analysis [5], AI [6–8], DGI and DD [1, 9], PFE [2, 10–13], OFCD [14, 15], cytogenetic locations and OMIM phenotypes of the genes [16–24], Orphanet [25–35].

Related entities: AXIN2-related oligodontia and colorectal cancer, ectodermal dysplasias, TP63-related disorders, OFCD, incontinentia pigmenti, PITX2-related Axenfeld-Rieger syndrome, osteogenesis imperfecta and amelogenesis imperfecta; other disorders with dental manifestations are cleidocranial dysplasia, hypophosphatasia and X-linked hypophosphataemic rickets.

1. Introduction

1.1. Teeth as a record of development

Hair, teeth, nails and epidermis are of ectodermal origin, and teeth, like hair follicles and sweat glands, result from a reciprocal interaction between the oral epithelium and the neural crest-derived ectomesenchyme; for this reason, an anomaly in one ectodermal appendage requires examination of the others [36, 37]. Enamel is an acellular tissue that does not remodel after eruption, so that both genetic diseases and transient metabolic disturbances are recorded in the appearance of the teeth; this property is the basis of diagnostic reasoning, because a defect that affects all teeth in a similar way suggests a genetic cause, whereas a defect with a chronological distribution suggests an insult limited in time [6]. The complete primary dentition has 20 teeth and the permanent dentition 32, and examination of a patient with suspected ectodermal dysplasia or dental anomaly includes counting the teeth, assessing their shape (conical or not) and, in the newborn, observing the gum ridges, whose flattening may indicate absence of tooth germs [36].

1.2. Historical milestones and classifications

Amelogenesis imperfecta (AI) was separated from dentinogenesis imperfecta (DGI) as an entity of its own in 1938 [7]. A succession of classifications followed: Weinmann and colleagues divided it in 1945 into hypoplastic and hypocalcified forms, on phenotype alone; Darling described five phenotypes in 1956; Witkop and Rao introduced in 1971 the tripartite division into hypoplastic, hypocalcified and hypomaturation; Winter and Brook (1975) and Sundell and Koch (1985) proposed other variants [6]. Witkop's 1988 classification, the most widely accepted, defines four categories by phenotype — hypoplastic, hypomaturation, hypocalcified and hypomaturation-hypoplastic with taurodontism — subdivided into 15 subtypes by phenotype and, secondarily, by inheritance [1, 6, 38]. Aldred and colleagues proposed in 2003 that inheritance be the primary discriminator and phenotype the secondary one, and the identification of genes has since enabled a classification that tends to be molecular, although recognition of characteristic phenotypes remains clinically useful [6, 7].

In disorders of dentine, Shields and colleagues proposed in 1973 the classification into three types of DGI and two of dentine dysplasia (DD), which coexists with Witkop's nomenclature: Shields DGI type I is the form that accompanies osteogenesis imperfecta; type II corresponds to «hereditary opalescent dentine» and type III to the Brandywine isolate [1]. The demonstration that DGI type II, DGI type III and DD type II result from variants in the same gene, DSPP, led to the 2015 proposal to regard them as degrees of severity of a single disease and to revise the classification of the isolated forms [39]. De La Dure-Molla, Fournier and Berdal analysed all published patients with DSPP variants according to the Witkop and Shields criteria and proposed that all forms caused by DSPP be called exclusively «dentinogenesis imperfecta», graded as mild, moderate and severe, and that DD type I become the only dysplasia, termed «radicular dentine dysplasia», of then unknown cause; syndromic Shields DGI type I falls outside this classification because it belongs to osteogenesis imperfecta [39]. The correspondence between the two classifications is as follows [39].

Shields DGI type I is not in the table because it is syndromic (osteogenesis imperfecta); OMIM 125400 now corresponds to the recessive SMOC2-related form, and the genetic heterogeneity of DD type I postdates the proposal [39, 40].

Primary failure of eruption (PFE) was described by Proffit and Vig in 1981 as a cause of posterior open bite in non-ankylosed teeth [41]. In 2008, Decker and colleagues identified heterozygous truncating variants in PTH1R (then called PTHR1) in 15 affected individuals from four families, which established haploinsufficiency of the parathyroid hormone receptor as the cause of the familial non-syndromic form [10]. Canine radiculomegaly associated with congenital cataract was recognised as a syndrome by Marashi and Gorlin in 1992, now called oculofaciocardiodental syndrome (OFCD) and caused by loss-of-function variants in BCOR [14]. The first gene for non-syndromic agenesis was MSX1, in a family with agenesis of second premolars and third molars (Vastardis 1996), and a family with orofacial cleft and agenesis caused by the same MSX1 variant was described by van den Boogaard in 2000 [42].

Before the 1981 definition, Shokeir had described in 1974 a family with autosomal dominant inheritance of failure of eruption of the permanent teeth, and Bosker and colleagues had published in 1978 «familial reinclusion of permanent molars» (OMIM 157950), whose radiographs Proffit and Vig recognised as identical to those of their patients [24]. In 2006, Ahmad and colleagues reviewed 40 cases and allowed that PFE might encompass a form of complete failure and another of secondary retention after initial eruption, or a single disease of variable severity; in 2007, Frazier-Bowers and colleagues proposed the division into types I, II and III, still in use [24]. The identification of PTH1R in 2008 turned PFE into an entity with possible molecular confirmation, and confirmation in German, North American, Danish, Italian and French families established genetic testing as a step prior to orthodontics [10, 11, 43, 44].

1.3. Definitions used

Tooth agenesis is the absence of one or more permanent teeth, excluding third molars, due to failure in the early stages of odontogenesis; non-syndromic tooth agenesis (NSTA) is that in which agenesis is the only clinical finding [3]. Hypodontia denotes the absence of up to five teeth, oligodontia that of six or more and anodontia the absence of all, the latter almost exclusive to syndromic forms; the expression «congenitally missing teeth» is inappropriate because the permanent germs continue to form after birth and the diagnosis is only possible at around six years of age [3]. The French National Diagnosis and Care Protocol (PNDS) of the Haute Autorité de Santé (HAS) for oligodontia and anodontia, of November 2021, uses the same three categories and adds that agenesis is «multiple» above two teeth, that the number and type of missing teeth should be recorded with the Fédération Dentaire Internationale (FDI) numbering and that a tooth clinically absent because of an eruption disturbance is termed a «tooth absent from the arch» and not agenesis [4]. The PNDS text is not consistent on the threshold: the introduction defines oligodontia as six or more missing teeth, whereas the summary and the definitions section write «more than six»; the French reimbursement criterion and GeneReviews use six or more, which is the threshold adopted in this article [3, 4]. According to the PNDS, oligodontia is more often associated with a syndrome than isolated, even when the extradental expression is subtle, and anodontia is always syndromic; the form associated with a systemic syndrome is termed syndromic oligodontia [4]. AI is a group of conditions of genomic origin that alter the structure and appearance of the enamel of all or nearly all teeth in a similar way, and may be associated with morphological or biochemical changes in other organs; the European group of the ERN CRANIO network estimates that it includes more than 100 distinct entities [6, 8]. DGI is an inherited disorder of dentine originating in histodifferentiation, isolated or part of osteogenesis imperfecta, and DD is a group of inherited dentine disorders with characteristic changes of the root and pulp chamber [1]. Radiculomegaly is increased root length, typical of the canines in OFCD [14]. Molar-incisor hypomineralisation (MIH), which affects first permanent molars and incisors and is of unknown aetiology, is not classified as AI [6].

2. Molecular Genetics and Pathophysiology

2.1. Phases of tooth development and type of anomaly

The type of anomaly reflects the developmental phase in which the disturbance occurs: alterations of initiation produce hypodontia or supernumerary teeth; alterations of morphodifferentiation produce anomalies of size and shape, such as macrodontia, microdontia, taurodontism and dens invaginatus; alterations of histodifferentiation, apposition and mineralisation produce enamel hypoplasia or hypomineralisation and the disorders of dentine [1]. At the bud stage, the thickened oral epithelium invaginates into the mesenchyme and the primary enamel knot, a signalling centre, forms; the WNT/β-catenin, BMP (bone morphogenetic proteins), FGF (fibroblast growth factors) and EDA/NF-κB pathways coordinate these stages, which explains why the same gene can cause isolated agenesis and ectodermal dysplasia [37, 45]. The USAG-1 protein, an antagonist of BMP and of the WNT co-receptor LRP5/6, limits the number of tooth germs; its inactivation in the mouse produces supernumerary teeth and reverses the agenesis of several genetic models, which underpins the therapeutic research described in section 7 [46].

2.2. Non-syndromic tooth agenesis

About 80% of non-syndromic agenesis is attributed to variants in genes of craniofacial and dental development, and the remaining 20% to exogenous factors acting during formation of the permanent germs — chemotherapy, radiotherapy, maternal rubella and drugs such as thalidomide and antineoplastic agents [3]. The French PNDS adds craniofacial trauma occurring during formation of the permanent germs, refers to more than 50 genes responsible for isolated or syndromic forms of hypodontia, oligodontia or anodontia and more than 60 OMIM syndromes with oligodontia in the phenotypic spectrum, and considers WNT10A the most frequently implicated gene, with the same genes (EDA, EDAR, EDARADD, MSX1, PAX9, IRF6, GREM2, AXIN2, LRP6, SMOC2, LTBP3, PITX2, WNT10A, WNT10B) involved in isolated and syndromic forms [4]. Agenesis was considered monogenic, but there is evidence of multilocus or oligogenic inheritance, with WNT10A variants co-segregating with variants of GREM2, LAMA3 or BCOR in the same family [3]. Reduced penetrance and intra- and interfamilial variability are frequent, and many agenesis genes have syndromic allelic disorders, so a continuous spectrum between the apparently isolated and the syndromic form is accepted; after a variant is identified, active search for syndromic features is recommended [3].

Source: GeneReviews, Table 1, which includes only genes with at least two families with non-syndromic agenesis after careful phenotyping [3]. HED, hypohidrotic ectodermal dysplasia.

WNT10A is the most frequent single genetic cause. In a Chinese case-control study with 505 patients and 451 controls, WNT10A variants were present in 15.8% of patients missing one to three teeth, in 51.6% of patients missing four or more and in 3.1% of individuals with a complete dentition; estimates from different cohorts attribute 35–50% of selective agenesis to WNT10A [47]. The most frequent variant in agenesis is NM_025216.3:c.682T>A, p.(Phe228Ile), present in about 3.43% of the general population and with reduced penetrance in the heterozygous state; the recurrent null allele c.321C>A, p.(Cys107Ter), occurs mainly in the homozygous state in severe forms, including odonto-onycho-dermal dysplasia [3, 47, 48]. Biallelic carriers have severe agenesis, whereas heterozygotes are unaffected or mildly affected: a single allele acts as a low-penetrance predisposing factor [47]. At the severe end of the spectrum, odonto-onycho-dermal dysplasia combines severe hypodontia, a smooth tongue with reduced fungiform and filiform papillae, nail dysplasia and palmoplantar keratoderma with hyperhidrosis, and Schöpf-Schulz-Passarge syndrome adds apocrine hidrocystomas of the eyelid margins, appearing in adulthood, and adnexal tumours such as eccrine syringofibroadenoma [47].

PAX9 produces a recognisable pattern. In a systematic review of 178 patients with 61 variants, agenesis affected mainly the molars, most often the second molar, and the mandibular first premolar was the least affected tooth; more teeth were missing in the maxilla than in the mandible; null variants caused more agenesis, and among in-frame variants those of the paired domain, especially of the binding peptide, were associated with absence of the second molar in all cases, whereas those at the C-terminal end caused fewer agenesis, rarely of second molars or anterior teeth [49]. PAX9 is located at 14q13.3, contiguous with NKX2-1; a deletion that includes both genes combines agenesis with the brain-lung-thyroid phenotype, so chorea, congenital hypothyroidism or neonatal respiratory distress in a patient with oligodontia justify study of the deletion size [49]. In a case-control study of 306 unrelated Portuguese individuals, single nucleotide polymorphisms of PAX9 were associated with a greater risk of agenesis of the maxillary lateral incisors, according to the review by Al-Ani and colleagues [37].

In MSX1, the same variant can cause isolated agenesis, isolated orofacial cleft or both in the same family, which is reflected in the OMIM name «selective tooth agenesis 1, with or without orofacial cleft»; agenesis typically involves premolars and second molars [42]. MSX1 variants are present in about 2% of non-syndromic cleft lip and palate and should be sought when the cleft is transmitted dominantly or co-segregates with dental anomalies [50]. MSX1 lies at 4p16.2, in the region lost in larger 4p deletions, and deletions that include it contribute hypodontia to the picture of Wolf-Hirschhorn syndrome [3, 42]. Witkop syndrome (tooth-nail syndrome, ectodermal dysplasia 3) is an autosomal dominant hidrotic ectodermal dysplasia of teeth and nails, with sweating and hair spared; its attribution to MSX1 is disputed by ClinGen [36, 42].

WNT10B causes selective tooth agenesis 8 (OMIM 617073), with a variant p.(Arg211Gln) (published protein designation, NP_003385.2, MANE transcript NM_003394.4) in a Chinese family and three further variants found in 145 individuals with oligodontia, with preferential involvement of the lateral incisors; in the homozygous state, another variant causes split-hand/foot malformation 6 [51]. LRP6 causes selective tooth agenesis 7 (OMIM 616724) through loss-of-function variants: Massink and colleagues identified three truncating variants and one signal-peptide missense variant in probands with a family history, and in a series of 14 patients from eight families there was agenesis in 5, oral exostoses in 7, root defects in 6, as well as microdontia, tooth fusion, odontomas and mesiodens [52]. Conversely, activating LRP6 variants in the first β-propeller domain cause autosomal dominant osteosclerosis with teeth encased in bone, and the association with coronary artery disease rests on a single family and should be treated as susceptibility and not as a monogenic diagnosis [52]. GREM2 (selective tooth agenesis 9, OMIM 617275) has been described in seven patients with agenesis, microdontia, short roots and taurodontism; in a Polish series, the variant p.(Gln76Glu) (published protein designation, NP_071914.3, MANE transcript NM_022469.4) was found in 2 of 95 patients and in no controls; ClinGen classifies the gene-disease relationship as limited (January 2025) [53].

In hypohidrotic ectodermal dysplasia, EDA (X-linked) accounts for 50–60% of cases, EDAR 10–15%, WNT10A 15–20%, EDARADD 2–3%, and about 10% remain without an identified cause; EDA also causes X-linked selective tooth agenesis (OMIM 313500) without the full picture [54, 55]. In the classic form the dentition ranges from hypodontia to anodontia, with a mean of nine permanent teeth, conical anterior teeth and delayed eruption; 60–80% of EDA carrier females can be identified by dental examination (conical teeth) [45]. A common coding EDAR variant in East Asia corresponds to a normal trait of hair thickness and should not be reported as disease [54]. The term «ectodermal dysplasias» covers more than 170 entities with altered development of at least two ectodermal derivatives (scalp hair, body hair, eyelashes, eyebrows, nails, teeth, sweat, salivary and mammary glands), with a combined frequency of about 7 per 10,000 births cited by the PNDS; hidrotic and hypohidrotic forms are distinguished mainly by involvement of the sweat glands, more severe in the anhidrotic form [4].

2.3. Amelogenesis imperfecta: genes, proteins and pathways

More than 95% of the volume of mature enamel is occupied by large, rigorously organised hydroxyapatite crystals, whose formation is controlled by ameloblasts through matrix proteins (amelogenin, enamelin, ameloblastin), proteases that degrade them (MMP20 and kallikrein 4) and adhesion and transport proteins [6, 7]. The proteins implicated in AI fall into matrix proteins (AMELX, ENAM, AMBN), matrix proteases (MMP20, KLK4), cell-cell and cell-matrix adhesion proteins (ITGB6, LAMB3, LAMA3, COL17A1, AMTN, FAM83H), transporters (WDR72, SLC24A4), controllers of amelogenesis (FAM20A, DLX3) and a group with diverse functions (C4orf26/ODAPH in crystal nucleation, GPR68 as a proton sensor, ACP4 of unknown function) [7]. Some Amelx and Enam variants activate the unfolded protein response and ameloblast apoptosis in the animal model, which shows that absence of the protein is not always the mechanism and opens the hypothesis, still preclinical, of chemical chaperones such as 4-phenylbutyrate [7].

In May 2017, the AI LOVD variant database gathered 192 published variants in 270 families with non-syndromic AI; four genes accounted for 60.4% of families — FAM83H (19.3%), FAM20A (15.2%), ENAM (14.4%) and AMELX (11.5%) — and inheritance was autosomal dominant in 48.9%, autosomal recessive in 40.4% and X-linked in 11.5% [7]. These figures describe published families with an identified variant, not the population frequency of the subtypes.

Source: AI LOVD, May 2017 [7]; supplementary clinical notes [56–59].

In AMELX (Xp22.2), whose AI OMIM classifies as X-linked dominant (AI type 1E, OMIM 301200) — the Oxford Desk Reference describes it as X-linked recessive, with carrier females showing vertical grooves, which reflects the same reality of more mildly affected women [19, 36] —, loss-of-function variants — large deletions and 5' truncations — produce hypoplastic and hypomaturation enamel with a «snow-capped» appearance, whereas signal-peptide defects and 3' truncations produce severe hypoplasia or almost absent enamel, attributed to a toxic effect of non-secreted protein [60]. In heterozygous women, random X inactivation produces vertical bands of normal and abnormal enamel, and the proportion follows the skewing of inactivation [6, 60]. In a North American cohort, AMELX accounted for 6 of 26 solved AI families (23%); whole-gene deletions have been described, so copy number variant testing is needed when sequencing is negative [60]. The gametologue AMELY, on the Y chromosome, is used in forensic sex determination and is not an enamel disease gene [60].

In ENAM, allele dosage determines the phenotype: the dominant form (AI1B, OMIM 104500) produces localised hypoplasia, with horizontal rows of pits or a band of thin enamel on the buccal surfaces, or smooth generalised hypoplasia with small, spaced teeth; the recessive form (AI1C, OMIM 204650) produces generalised thin or absent enamel with anterior open bite. In consanguineous Turkish families, homozygotes for a two-base insertion had generalised AI with open bite and heterozygotes only localised pits [6, 61]. In AMBN, biallelic loss produces yellow hypoplastic AI and monoallelic variants produce hypomaturation AI with pits or white hypoplastic AI; one autosomal dominant family also had dentine involvement [58]. LAMB3 has two distinct relationships: biallelic loss causes junctional epidermolysis bullosa (LAMB3 accounts for about 70% of junctional forms), with enamel dysplasia, and heterozygous truncating variants of the last exon, which escape NMD, cause AI type IA (OMIM 104530) without skin fragility [59].

The hypomaturation genes (KLK4, MMP20, WDR72, SLC24A4, GPR68, ODAPH) produce enamel of almost normal thickness but soft, dull or «agar jelly» in appearance, with brown pigment in the middle layers, which chips and wears after eruption and has reduced radiographic contrast relative to dentine [57, 62–65]. WDR72 deserves attention because a subset of patients have hereditary distal renal tubular acidosis, with hyperchloraemic normal anion gap metabolic acidosis, hypokalaemia, inappropriately alkaline urine (pH above 5.3), hypercalciuria, hypocitraturia and almost constant nephrocalcinosis [57]. RELT causes hypomineralised AI (AI3C, OMIM 618386), with a founder variant in the Pakistani population of the United Kingdom; the short stature and severe infections described in two probands of the original report were not confirmed in later series [66]. ITGB6 (AI1H, OMIM 616221) produces a mixed phenotype, so the diagnosis should not be excluded because the enamel does not fit a single Witkop type; six families had been published by 2023 [67].

2.4. Syndromic forms of enamel defect

Enamel-renal syndrome (OMIM 204690), due to biallelic FAM20A variants, combines generalised hypoplastic AI with thin or absent enamel in both dentitions, delayed or failed eruption with multiple impacted teeth, intrapulpal calcifications, hyperplastic dental follicles visible as pericoronal radiolucencies, hypodontia in some patients and gingival hyperplasia that may contain calcified nodules; the renal component is bilateral nephrocalcinosis or nephrolithiasis, asymptomatic in childhood and detected only when sought, with usually normal plasma calcium [56]. The entity formerly called AI with gingival fibromatosis corresponds to the same disease in patients without renal assessment. A 2021 systematic review gathered 69 patients aged 1 to 64 years, with no sex predominance, consanguinity in about a quarter and a FAM20A variant in all those tested; a series of four homozygous children published in 2026 described hypophosphataemia, raised FGF-23, hypocalciuria and low tubular phosphate reabsorption with preserved filtration rate [56].

Tricho-dento-osseous syndrome (TDO, OMIM 190320), autosomal dominant and caused by DLX3 (17q21), combines curly hair from birth, taurodontism (enlarged pulp chambers and short roots), enamel hypoplasia and increased thickness and density of the skull bones, without mastoid pneumatisation, with an obtuse mandibular angle, short ramus and brittle nails in about half of patients [68, 69]. It was defined by Lichtenstein and colleagues in 1972 in 107 individuals from a single family [68]. The 4 bp deletion NM_005220.3:c.571_574del, p.(Gly191ArgfsTer66), is the classic variant; the 2 bp deletion c.561_562del, p.(Tyr188GlnfsTer13), produces an attenuated phenotype corresponding to hypomaturation-hypoplastic AI with taurodontism (OMIM 104510), so that the two designations form a variant-dependent severity spectrum [48, 70]. The protein notation p.(Y166Qfs*13) in the AI LOVD database for the latter variant does not match validation on the MANE transcript and should not be used [7, 48]. In a 2025 systematic review of 297 individuals, the most frequent findings were taurodontism (70.5%), increased bone density or thickness (43.8%), enamel hypoplasia (34.5%), dental infections (28.7%) and sparse hair (27.2%) [70].

Jalili syndrome (OMIM 217080), due to CNNM4, autosomal recessive, combines progressive cone-rod dystrophy with AI of both dentitions; in a series of seven patients from six families, the mean age at presentation was 6.7 years (3–16), all had nystagmus and six photophobia, and structural and functional progression was documented in all [71]. Dental anomalies and short stature syndrome (OMIM 601216), due to biallelic LTBP3 variants, combines hypoplastic AI with very reduced enamel, oligodontia, taurodontism and mandibular failure of eruption with short stature with platyspondyly; heterozygous LTBP3 variants cause geleophysic dysplasia, without agenesis [3, 72]. Kohlschütter-Tönz syndrome (OMIM 226750), which Orphanet records as amelocerebrohypohidrotic syndrome and also as epilepsy-dementia-AI syndrome, integrates AI into a neurological picture [6, 73]. In junctional epidermolysis bullosa due to LAMB3 or COL17A1, pitted enamel dysplasia persists even in forms compatible with adult life [3, 59].

2.5. Dentine: DSPP, dentine dysplasia and osteogenesis imperfecta

The extracellular matrix of dentine consists of 90% type I collagen and 10% non-collagenous proteins, among them dentine sialoprotein, glycoprotein and phosphoprotein, encoded by a single gene, DSPP, and processed by cleavage, glycosylation and phosphorylation [39]. The gene, at 4q22.1, has five exons, the first non-coding; exons 2 to 4 encode most of the sialoprotein and exon 5 encodes its C-terminus and the whole phosphoprotein [16]. DSPP variants cause DGI types II (OMIM 125490) and III (OMIM 125500) and DD type II (OMIM 125420), which genetics has shown to be degrees of severity of the same disease [9, 39]. In the 2015 review, the 38 pathogenic variants then described lay in the signal peptide, the sialoprotein region and the phosphoprotein region, none in the glycoprotein region; 28 were associated with DGI type II, eight with DD type II and two with DGI type III, and the same variant could give a moderate or severe phenotype in the same family [39]. The phosphoprotein binds collagen fibrils at hydroxyapatite nucleation sites and, in vitro, initiates crystal formation at low concentration and inhibits its growth at high concentration; the sialoprotein:phosphoprotein molar ratio of about 1:10 and the existence of three proteins from one gene complicate genotype-phenotype correlation [39]. The mechanism is not haploinsufficiency (ClinGen assigns a haploinsufficiency score of 0): most variants lie in exon 5 and cause a −1 frameshift that produces a hydrophobic C-terminal extension, a toxic gain-of-property mechanism; a gene deletion is therefore not equivalent to a pathogenic frameshift [9]. Exon 5 contains more than 200 tandem 9 bp repeats (DSS domain), which hampers sequencing; in a 2026 study of 112 individuals (42 index cases and 70 relatives) with signs of DGI or DD, pathogenic or likely pathogenic variants were identified in 41 families, 22 variants in total (14 novel), and long-range polymerase chain reaction (PCR) with long-read sequencing solved cases in which short-read methods had failed [9]. Variable expressivity within families means that the clinically assigned Shields label does not strictly correspond to the genotype [9]. Progressive high-frequency sensorineural hearing loss (DFNA39, OMIM 605594) rests on a single 2001 report of three Chinese families with DGI, two with hearing loss and missense variants in the signal peptide/transmembrane segment region; the evidence is weak and ClinGen validates only the relationship with DGI [9].

Shields DGI type I is part of osteogenesis imperfecta and is caused by COL1A1 or COL1A2, not by DSPP; a patient with fragile teeth and fractures needs study of the collagen genes [1, 9]. DD type I is genetically heterogeneous: SMOC2 causes an autosomal recessive form (OMIM 125400) in consanguineous families, with marked microdontia, oligodontia and abnormal tooth shape; VPS4B has been proposed as the cause of a dominant form (OMIM 621440) on the basis of a single Chinese family of ten affected individuals with an intronic variant creating a new splice donor site, and the heterozygous mouse does not reproduce the phenotype; SSUH2 (OMIM 621559) completes the list, and at least one family with DD type I was negative for all three genes [40, 74]. Odontochondrodysplasia (OMIM 184260), autosomal recessive and caused mainly by TRIP11, combines DGI more marked in the primary dentition with short-limbed dwarfism, mesomelia, joint laxity and platyspondyly with coronal clefts [75].

2.6. Eruption: PTH1R

The parathyroid hormone type 1 receptor (PTH1R) is a G protein-coupled receptor that responds to parathyroid hormone (PTH) and PTH-related protein (PTHrP), activating the cAMP/protein kinase A and phospholipase C/protein kinase C pathways; PTHrP–PTH1R signalling in dental follicle cells, osteoblasts and osteoclasts (via RANKL) creates the microenvironment that allows eruption [2, 76]. The direction of the effect determines the phenotype: activating variants cause Jansen metaphyseal chondrodysplasia, with delayed eruption and impaction; biallelic loss causes Blomstrand chondrodysplasia, which is lethal; biallelic hypomorphic variants cause Eiken syndrome; and heterozygous loss of function causes PFE, with high penetrance and variable expressivity [10, 77]. A PTH1R report must therefore specify whether the variant activates or inactivates the receptor, and the zygosity [77].

A 2026 review gathered 77 PTH1R variants associated with PFE between 2010 and 2025 (transcript NM_000316.3): 45 missense, 13 nonsense, 7 frameshift, 9 splicing and 3 in-frame or synonymous, most heterozygous, de novo or familial, distributed across all domains without a clear genotype-phenotype correlation; truncating variants tend to involve more quadrants, and many missense variants lack functional study [2]. Transmission is usually autosomal dominant and, less often, autosomal recessive; the review also describes the mechanism of missense variants as dominant negative, but the founding article and most data support haploinsufficiency [2, 10]. Other candidate genes in non-syndromic PFE (TMEM119, KMT2C, POSTN) lack consolidated evidence [2].

The variants of the original description, in four German families with 15 affected individuals, were two splicing variants and one nonsense variant, which on the MANE transcript are written NM_000316.3:c.543+1G>A, NM_000316.3:c.1050-3C>G (in two families) and NM_000316.3:c.463G>T, p.(Glu155Ter); they were absent in unaffected relatives and in 178 German controls, and the prediction of premature degradation of the precursor or a non-functional receptor supported the haploinsufficiency model [10, 24, 43, 48]. The c.463G>T variant was later found in Danish and Italian patients, without a haplotype study that would distinguish a common origin from recurrent events [2, 11]. In a North American family of 12 people, a splicing variant published as c.1353-1G>A, with skipping of exon 15, segregated with PFE in the five affected individuals; the original notation is not valid on the MANE transcript, because the position indicated falls in exonic sequence, and the variant corresponds to NM_000316.3:c.1354-1G>A, the notation adopted in later reviews [44, 48, 78].

In a study of 10 families (54 people) and 7 isolated cases with clinical PFE, only two families had truncating variants, NM_000316.3:c.996dup, p.(Ala333ArgfsTer66) (published as c.996_997insC), and NM_000316.3:c.572del, p.(Tyr191SerfsTer14) (published as c.572delA); eight families had no non-synonymous coding variant, one family showed incomplete penetrance, and five carriers from two families had osteoarthritis, which led the authors to propose a dose-dependent model for isolated PFE and osteoarthritis [48, 79]. The 2023 review from the Strasbourg reference centre considers that non-syndromic forms have no associated skeletal manifestations, apart from these rare cases of osteoarthritis [78]. Incomplete penetrance was also documented in an Italian family: the nonsense variant NM_000316.3:c.505G>T, p.(Glu169Ter), in exon 7, absent from gnomAD, was identified in a 26-year-old man with bilateral open bite and in his clinically unaffected mother [12, 48]. This finding contrasts with the description of high penetrance in the gene curation and changes counselling (section 8) [12, 77].

Recessive forms are exceptional. The variant NM_000316.3:c.611T>A, p.(Val204Glu) was described in the homozygous state in a family with PFE and hypodontia in four women aged 12 to 21 years, and the variant NM_000316.3:c.103G>A, p.(Glu35Lys), also homozygous, in a patient with Eiken dysplasia, pseudoepiphyses of the hands and PFE, which documents the continuity between the dental form and the recessive skeletal form [11, 48, 78]. Mouse models support the role of the dental follicle: biallelic conditional deletion of Pth1r in Osx+ follicular progenitors causes failure of eruption, incomplete roots, ankylosis and absent periodontal ligament insertion, heterozygous deletion produces a thinner, disorganised periodontal ligament, and, in another model (Pthrp-CreER), follicular progenitors differentiate prematurely into cementoblasts and immature osteoblasts, with molar failure of eruption similar to human PFE [2]. KMT2C has been proposed as a second cause of familial non-syndromic PFE, with evidence limited to a few families [2, 78].

2.7. Radiculomegaly: BCOR

In OFCD, loss-of-function variants of BCOR (BCL6 corepressor, Xp11.4) — deletions, truncations and frameshifts — cause an X-linked dominant disease with presumed lethality in male fetuses, so almost all patients are women and transmission is from mother to daughter [14, 15]. Canine radiculomegaly is considered almost pathognomonic; BCOR missense variants in men cause an allelic form of Lenz microphthalmia syndrome, X-linked recessive [14, 15]. A BCOR variant has also been described co-segregating with WNT10A variants in apparently isolated agenesis [3].

2.8. OMIM catalogue of the entities of the class

The table brings together the phenotypic entries of Online Mendelian Inheritance in Man (OMIM) corresponding to the entities covered, with the locus, gene and inheritance recorded by OMIM and the feature each entry highlights; entities marked «?» have a provisional gene-phenotype relationship in OMIM.

OMIM also records, for DSPP, that the gene belongs to the SIBLING family of secreted phosphoproteins involved in mineralisation, and that the nascent protein is cleaved into sialoprotein and phosphoprotein, present in mature dentine at a molar ratio of about 1:10 [16]. For ENAM, OMIM describes enamel with 85% of its volume occupied by hydroxyapatite crystals, a value different from the more than 95% cited by Crawford and colleagues, which reflects differences in metric between sources [6, 23].

3. Clinical Spectrum and Manifestations by System

3.1. Tooth agenesis

Non-syndromic agenesis tends to be unilateral and affects maxilla and mandible with similar frequency; the teeth most frequently missing, excluding third molars, are the mandibular second premolar, followed by the maxillary lateral incisor and the maxillary second premolar, and bilateral agenesis of the maxillary lateral incisors is more common than unilateral [3, 5]. Polder's meta-analysis grouped teeth into common absences (mandibular second premolar, maxillary lateral incisor, maxillary second premolar), less common (mandibular central incisor, mandibular lateral incisor, maxillary first premolar, maxillary canine and mandibular second molar) and rare (maxillary second and first molars, mandibular canine, mandibular first molar and maxillary central incisor), and showed that 83% of affected individuals have only one or two missing teeth [5]. Agenesis of the mandibular incisors is more frequent in Asian populations [3].

In the primary dentition agenesis is rare, with a prevalence below 1% in Caucasian populations and higher in Japanese populations; primary maxillary lateral and mandibular central incisors account for 50–90% of missing primary teeth, and a missing primary tooth usually predicts agenesis of the permanent successor [3, 37]. Associated findings include microdontia (peg-shaped lateral incisors), prolonged retention of primary teeth — which may last until 40–50 years —, short roots in other permanent teeth (about 46%), taurodontism (29% of mandibular first molars in Dutch patients with oligodontia, compared with 10% of controls), ectopic positioning and transposition, infraocclusion of primary molars, palatal or impacted maxillary canines, deep overbite and a tendency to a low mandibular angle, reduced lower facial height and skeletal class III [3, 37]. The consequences are aesthetic, functional (mastication, speech, occlusion and alveolar bone development), psychosocial and financial [37, 42]. Agenesis is frequent in non-syndromic cleft lip and palate, especially of the maxillary lateral incisor and the more severe the cleft [3, 37].

Gene-specific patterns guide the hypothesis: PAX9 and MSX1 mainly affect posterior teeth (second molars and premolars); AXIN2, IRF6 and WNT10A affect anterior and posterior teeth; WNT10A and EDA are associated with microdontia and abnormally shaped teeth; WNT10B affects lateral incisors; GREM2 and WNT10A are associated with taurodontism; LRP6 is associated with oral exostoses and root defects [3, 49, 52, 53].

The French PNDS describes, based on the gene-specific agenesis pattern analysis of Fournier and colleagues (2018), complementary topographical signatures. In the primary dentition, the decreasing order of frequency is mandibular incisors, maxillary lateral incisors, maxillary central incisors, mandibular molars and maxillary first molar. In X-linked ectodermal dysplasia, the mean is 8 primary agenesis, more in the mandible (5.3) than in the maxilla (3.5), and 13.5 permanent agenesis, a phenotype of severe oligodontia; in the permanent dentition, EDA-related agenesis follows the order mandibular incisors, maxillary lateral incisors, mandibular second premolar, maxillary second premolar and second molar. WNT10A, the most prevalent cause, produces agenesis of incisors and premolars with minor ectodermal signs, and PAX9 agenesis of the posterior sectors [4]. For MSX1, the PNDS also describes an incisor-premolar pattern, whereas GeneReviews and the MSX1 curation describe a posterior pattern (premolars and second molars) [3, 4, 42]. The work of Fournier and colleagues, cited by the PNDS, is a systematic review with meta-analysis of the dental phenotypes of 522 patients described in 101 articles (MEDLINE, 1986 to June 2016), including third molars; it is not a cohort and its values are not equivalent to population frequencies [126]. In the 80 patients with MSX1 variants (21 articles, 24 variants), the mean was 11.54 missing teeth (1 to 28), with oligodontia in 88.75%; the most frequently missing were the maxillary (86.71% of the teeth described) and mandibular second premolars (83.75%), the maxillary (83.85%) and mandibular third molars (86.03%) and the maxillary first premolars (57.59%), whereas the maxillary lateral incisors were missing in only 30.38% (36.71% of patients) and the second molars in 18.35% (maxillary) and 27.50% (mandibular) [126]. The authors conclude that MSX1, like PITX2, is associated with agenesis of third molars and premolars, and PAX9 with that of all molars and the mandibular central incisors; the primary data thus support the posterior premolar and third-molar pattern and not the incisor-premolar pattern of the PNDS (section 7.1) [126].

The craniofacial repercussions of oligodontia are described in small clinical series with selection bias. The most frequently reported skeletal changes are reduced anterior facial height and a more retrusive position of the maxilla (reduced SNA and ANB angles), with a tendency to class III due to maxillary hypoplasia, in which pseudoprognathism results from loss of vertical dimension or anteroposterior discrepancy; these findings are not constant and vary with the age and origin of the patients [4]. The soft tissues show reduction of the lower third of the face, opening of the nasolabial angle, a straight or bi-retrusive profile, a marked labiomental fold and eversion of the lower lip, more marked the more severe the oligodontia [4]. In a CBCT study of nine patients with ectodermal dysplasia, upper aerodigestive tract volume was slightly reduced, without a significant difference from controls, and the authors allow a greater propensity to obstructive sleep apnoea due to deficient maxillomandibular development [4]. In a study of 60 patients from Macedonia, the incisors were retroclined with an opened interincisal angle, and in a series of 900 patients with agenesis (De Stefani, 2021) the most prevalent malocclusion was class II division 2, especially with premolar agenesis, class III being frequent with agenesis of maxillary lateral incisors; deep overbite is common, the palate tends to be flat and most published cases have an alveolar bone deficit in height and width requiring pre-implant surgery [4]. Eruption of the teeth present is delayed by about two years on average; ankylosis of primary molars without a successor causes infraocclusion that is more severe the earlier it occurs, and impaction and transposition of maxillary canines and distal tipping of the mandibular second premolar are common [4]. The PNDS classifies infraocclusion as mild (occlusal surface 1 mm below the occlusal plane), moderate (at the level of the contact point of the adjacent tooth) and severe (below the contact point, at gingival level), and lists as complications tipping of adjacent teeth, extrusion of antagonists, reduced arch length, disturbance of posterior occlusion and lateral tongue interposition [4]. Premolar agenesis is frequently associated with microdontia of the maxillary lateral incisors, palatal impaction of the canines and infraocclusion of primary molars, a «dental anomaly pattern» that Peck attributed to a common genetic origin [4]. Patients with ectodermal dysplasia have more numerous or more severe dental developmental anomalies than patients with isolated oligodontia, and tongue interposition at rest and on swallowing and speech and chewing defects are frequent reasons for consultation [4]. The later the diagnosis, the more severe the malocclusions due to secondary migration of the teeth bounding the edentulous spaces, such as mesial tipping of the mandibular second molar [4].

3.2. Amelogenesis imperfecta

AI affects all or nearly all teeth of both dentitions in a similar way, without a chronological distribution; the enamel may be hypoplastic (reduced quantity, with thin enamel, diastemas or pits, but hard and translucent), hypomineralised (normal thickness, but soft, rough and discoloured, easily lost after eruption) or both, and the teeth are often sensitive to thermal and osmotic stimuli [6]. In the hypocalcified form the enamel has normal thickness, a smooth surface and reduced hardness; in the pitted hypoplastic form it has normal thickness and hardness; in the generalised hypoplastic form it has reduced thickness; in hypomaturation it has normal thickness, a chipped surface, reduced hardness and opaque white colouring, which may be mistaken for fluorosis [1, 6]. Men with X-linked AI show the full phenotype and heterozygous women have vertical grooves or bands [6].

Skeletal anterior open bite occurs in about half of patients with AI, X-linked or autosomal; according to the American Academy of Pediatric Dentistry (AAPD), its frequency is 50% in hypoplastic AI, 31% in hypomaturation AI and 60% in hypocalcified AI [1, 6]. Other findings include accelerated or delayed eruption, low caries susceptibility, rapid attrition, excessive calculus deposition, gingival hyperplasia, enlarged follicles, impacted teeth, ectopic eruption, agenesis (including of second molars), coronal or root resorption, pulp calcifications and, rarely, enamel resorption and ankylosis [1]. The psychosocial impact is great: patients who cover their teeth with paper or chewing gum, adolescents who isolate themselves and ask for their teeth to be extracted, and, in a study cited by the AAPD, adults with AI with fewer long-term relationships and fewer children than unaffected individuals [1, 6]. The burden on quality of life is greater than had been recognised [61].

3.3. Disorders of dentine

In all types of DGI the teeth have a colour ranging from blue-grey to yellow-brown, opalescent, because the abnormal dentine shows through the enamel; the unsupported enamel fractures and the dentine wears rapidly, and the dentition may be worn down to the gingiva if untreated; severity varies even within the family [1]. In DGI type I (osteogenesis imperfecta) the primary dentition is the most affected, followed by the permanent incisors and first molars, the second and third molars being the least altered; radiographically there are bulbous crowns, cervical constriction, thin roots, early obliteration of chambers and canals, periapical radiolucencies and root fractures [1]. In type II both dentitions are equally affected and pulp obliteration may begin before eruption; the pulp chambers are initially larger than normal and close progressively [1, 9]. Type III, rare, has bell-shaped crowns and «shell teeth» with enamel of normal thickness, very thin dentine, greatly enlarged pulps and multiple pulp exposures [1]. Despite the wear, teeth with DGI do not appear to be more susceptible to caries [36]. In the 2015 classification, the clinical and radiographic criteria form a continuum of severity, summarised in the following table [39].

In all cases reviewed, primary teeth were more affected than permanent teeth: primary teeth mainly had moderate to severe changes and mild forms were described only in permanent teeth [39]. In the five cases of DGI type III with enlarged pulps in primary teeth, the children were 2 to 4 years old; as obliteration may progress, the authors recommend waiting for the permanent dentition for a definitive diagnosis of the severe form [39].

In DD type I («rootless teeth») the crowns have almost normal colour and shape, but the roots are short, conical or absent; the variability depends on the timing of disorganisation of the radicular dentine, from absent roots without detectable pulp to shortened roots with a crescent-shaped chamber or roots of normal length with pulp stones; primary teeth have pulps obliterated before eruption, and multiple periapical radiolucencies in caries-free teeth are the most discriminating sign; the teeth are mobile and exfoliate early [1, 40]. In DD type II the roots are of normal length, the primary teeth are amber as in DGI and the permanent teeth are of normal colour, with «thistle-tube»-shaped pulp chambers and multiple pulp stones, without periapical radiolucencies [1]. In the SMOC2 form, microdontia, abnormal shape and agenesis accompany the root defect [40]. In the 2015 review, DD type I is transmitted as an autosomal dominant trait with complete penetrance, crown colour is not always normal (there are reports of brownish-blue or greyish-yellow discoloration or brown incisal opacity), and the shorter the root, the more complete the pulp obliteration and the more frequent periodontal disease [39].

3.4. Primary failure of eruption

PFE mainly affects posterior teeth, in one to four quadrants, causing posterior open bite with deficient vertical growth of the alveolar process; the distribution is typically unilateral and asymmetric, and involvement tends to extend to all molars distal to the most mesial affected tooth; it may involve primary teeth [2, 76]. The teeth are not initially ankylosed, but do not respond to orthodontic forces, which promote ankylosis [2]. Mechanical failure of eruption, by contrast, results from an identifiable obstacle (retained primary tooth, odontoma, cyst, supernumerary tooth), is sporadic, usually involves a single molar and, when there is ankylosis, produces a metallic sound on percussion [2, 76]. Failure of eruption is also part of syndromic pictures: enamel-renal syndrome (FAM20A), GAPO syndrome (ANTXR1), oculodental syndrome (FGFR3), Nance-Horan syndrome (NHS) and osteoglophonic dysplasia (FGFR1) [2].

The classification of Frazier-Bowers and colleagues (2007) started from 97 cases of posterior failure of eruption, of which 38 were classified as PFE and 19 as mechanical failure due to ankylosis, with 32 left without a definitive diagnosis for lack of longitudinal data: in type I (17 of the 38), all affected teeth have a similar lack of eruptive potential, with a progressive open bite from anterior to posterior; in type II (11), a tooth distal to the most mesial affected tooth has greater, but insufficient, eruptive potential; in type III (10), both patterns coexist in different quadrants; the distribution of types did not differ between cases with and without a family history [24]. Type II is the one most easily confused with ankylosis, because the second molar erupts more than the first [127].

The systematic review by Hanisch and colleagues (2018) gathered 17 publications from 2006 to 2017, with 314 patients with non-syndromic PFE; sex and age were poorly described (8 to 58 years in the 27 patients with data) and age at diagnosis was generally uncertain [11]. Molars were affected in all cases, molars and premolars in 81 of the 118 with data (68.6%), primary teeth in 38 of 156 (24.3%); involvement was bilateral in 95 of 148 (64.1%), there was a family history in 143 of 170 (84.1%), and types I, II and III accounted for 41.7%, 31.5% and 26.8% of the 127 classified; of the 34 patients with a recorded skeletal class, 27 had class III, 5 class II and 2 class I [11]. Additional dental anomalies were described in 39 patients, mainly altered root morphology (11), impacted teeth (10), delayed eruption of other teeth (6) and hypodontia (5); in the earlier review by Ahmad and colleagues (2006), with 40 cases, hypodontia affected 13% and a family history of eruption problems 40% [11, 24]. These numbers come from reports and series with incomplete data, selected by criteria requiring distal involvement, and do not describe the natural history of an unselected cohort.

Involvement of anterior teeth is an open question. The 2007 description and the 2018 review consider that PFE affects only posterior teeth, but in the 2014 German series all carriers of a PTH1R variant met a criterion that includes disturbed eruption of an anterior tooth associated with posterior involvement, and the case in section 10 had affected incisors and a canine [11, 24, 76, 128]. In the primary dentition, primary retention mainly affects second molars, which become deeply impacted and move away from the occlusal plane with age, sometimes with an open «chimney» to the alveolar crest; there was also a case of generalised retention of the entire permanent dentition in a six-year-old girl, described in 1999 without molecular study [24]. In a French family with the variant NM_000316.3:c.899T>C, p.(Leu300Pro), the 39-year-old father, without previous orthodontic treatment, had severe bilateral posterior open bite with class III, caries and infectious foci in partially erupted teeth, internal or external resorption in nine teeth and areas of secondary ankylosis on tomography, whereas his daughters, aged 12 and 7 years, had involvement of primary teeth and of a single quadrant in the elder, which illustrates intrafamilial variability and the accumulation of complications in adults [48, 78].

3.5. Radiculomegaly and OFCD

In OFCD, described in more than 60 cases up to the edition consulted, there is mild intellectual disability in 15–20%, a long, narrow face, high nasal bridge, bifid nasal tip with septate cartilages, cleft palate, congenital cataract, microphthalmia, microcornea and secondary glaucoma, cardiac septal defects (mainly atrial septal defect) and skeletal anomalies (hammer toes, radioulnar synostosis, 2–3 toe syndactyly, scoliosis) [14]. The dental findings are delayed and persistent primary dentition with multiple impacted teeth, radiculomegaly of the permanent dentition, missing, duplicated or fused teeth, hypodontia of the maxillary incisors and, occasionally, a single central incisor; the permanent dentition is affected in all cases and requires orthodontics, and there is conductive or sensorineural hearing loss in about 15% [14].

3.6. Dental anomalies in common syndromes

In X-linked hypohidrotic ectodermal dysplasia there is hypodontia to anodontia (mean of nine permanent teeth), conical anterior teeth, a deficient alveolar ridge and delayed eruption [45]. In incontinentia pigmenti, 80% of patients have dental anomalies (missing, small, conical teeth, with accessory cusps, delayed eruption) [36]. In TP63-related disorders there is hypodontia, microdontia, extensive caries, enamel hypoplasia and barrel-shaped central incisors [3, 36]. In Van der Woude syndrome some carriers have missing teeth [50]. In TDO the teeth wear, discolour, develop periapical abscesses and are lost between the second and third decades [68]. In Witkop syndrome, hypodontia affects the permanent dentition to a variable degree, with conical, spaced teeth, and the nail and hair signs become milder in adulthood [36].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

Unusual spacing in a child's dentition should lead the paediatrician and the dentist to suspect agenesis, confirmed by orthopantomogram after six years of age, when all permanent germs (excluding third molars) should be visible [3]. Absence of a primary tooth is an early sign of agenesis of the corresponding permanent tooth [3]. In adults, review of previous dental records and assessment of the edentulous spaces allow agenesis to be distinguished from extractions or losses due to periodontal disease [3]. AI can be recognised at eruption of the first primary tooth, at around six months, and assessment should begin at that point [8]. PFE is often recognised only during attempted orthodontic treatment, when the teeth do not respond to the applied force [2]. The French PNDS describes four circumstances in which multiple agenesis is discovered: absence of teeth noticed by the parents during primary or permanent eruption; an incidental finding on an orthopantomogram taken for orthodontic study; identification of agenesis within a syndromic picture already known or under investigation; and early consultation by families with a history of agenesis [4]. The most frequent presenting sign is delayed eruption of the permanent teeth between 6 and 12 years, and diagnosis of agenesis of permanent teeth is possible with relative certainty from 6–8 years [4].

The history should include the age at eruption of both dentitions, the number, shape, size and spacing of the teeth, and a three-generation pedigree with questions targeted at hair, teeth, nails, skin, sweating, clefts and deaths in childhood; in women, mosaic asymmetry of the skin, hair or sweating is sought [36]. Four questions guide the diagnosis of enamel defects: whether other relatives have a similar change; whether all teeth are affected in a similar way; whether there is a chronological distribution; and whether there is a medical history capable of disturbing enamel formation [6].

Infraocclusion of a primary molar or of a permanent first molar that has stopped erupting after reaching a supracrestal position, especially when there are relatives with posterior open bite or failed orthodontic treatment, should lead to consideration of PFE before any orthodontic traction, because early diagnosis avoids years of ineffective treatment [11, 43, 129].

4.2. Warning signs of systemic disease

Table sources: [3, 4, 9, 15, 45, 49, 50, 56, 57, 70, 71, 77].

A child with photophobia, nystagmus and low vision whose teeth are abnormal has Jalili syndrome until proven otherwise, and an almost normal fundus does not exclude the diagnosis [71]. Hypohidrotic ectodermal dysplasia is often recognised only when the teeth fail to erupt at 6–9 months or erupt with a conical shape, but the newborn may present with scaling skin and periorbital hyperpigmentation, and hyperthermia is the life-threatening risk [45, 55]. A child with unexplained fractures should be assessed for DGI as an indicator of undiagnosed osteogenesis imperfecta, which helps to distinguish this disease from abuse [1]. Congenital cataract in a woman, including unilateral cataract, should prompt consideration of BCOR [15]. There is no newborn screening for these anomalies.

In the child with oligodontia and suspected ectodermal dysplasia, the French PNDS directs the search for extra-ectodermal involvement by groups, each with its own referral pathway: immune and neurological (immunodeficiency with osteopetrosis, incontinentia pigmenti, ectodermal dysplasia with intellectual disability); major skeletal (TP63-related disorders such as EEC, ADULT and limb-mammary syndrome, cranioectodermal dysplasia, tricho-dento-osseous syndrome, ectodermal dysplasia with cleft); cornea and deafness; endocrinopathies and retinal degeneration; and atopic background [4]. Immunodeficiency has the greatest practical consequence: hypomorphic NEMO variants and hypermorphic variants of the IκBα inhibitor cause ectodermal dysplasia with immunodeficiency through alteration of the NF-κB pathway, which may be associated with osteopetrosis and lymphoedema and manifest as hypogammaglobulinaemia, hyper-IgM syndrome, defective NK cell cytotoxicity or autoimmunity, sometimes revealed by severe pneumonia; a history of recurrent, opportunistic or mycobacterial infections should be sought, because immunodeficiency may contraindicate implants or pre-implant grafts and requires antibiotic prophylaxis to be planned [4]. Suspected visual impairment (cornea, retina) requires a complete ophthalmological examination, deafness or endocrinopathy otorhinolaryngological and laboratory investigation, and AXIN2-related oligodontia an active search for familial colorectal cancer [4].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical and radiographic assessment

There are no formal published diagnostic criteria for these anomalies; diagnosis is clinical and radiographic, and genetic testing identifies the cause and subtype [3, 9]. In agenesis, assessment includes a medical and dental history, a complete physical examination looking for syndromic features, a detailed oral examination with review of current and previous radiographs to identify how many and which permanent teeth are missing and what other anomalies exist, and a three-generation family history that includes enamel and tooth shape defects; it may be necessary for an experienced professional to examine relatives directly, given the difficulty of distinguishing agenesis from tooth loss in adults [3]. Clinical and radiographic examination also serves to exclude impacted teeth and absences due to caries or trauma [3]. The orthopantomogram is the baseline examination; bitewings, individual periapicals, lateral cephalometric radiograph and cone-beam computed tomography (CBCT) complete the assessment according to age and problem [3].

The French PNDS stresses that a diagnosis of agenesis can only be made when it is confirmed that the tooth never existed: history and imaging exclude avulsions, early losses due to caries or trauma and exposure to toxins, drugs or teratogens during odontogenesis, and the family history establishes transmission [4]. The examination looks for extraoral signs (skin appendages, sweating, especially palmar and plantar, dry skin, absence of the lateral eyebrows, nail dystrophy) and, in frontal and profile views, midface hypoplasia, reduced lower facial third, class II or III dysmorphosis and frontal bossing; in the mouth, the odontogram is compared with that expected for chronological age and infraocclusions, teeth of abnormal shape or size (with an impact on prosthesis retention and bonding of orthodontic appliances), persistent primary teeth, diastemas, vertical and sagittal atrophy of the alveolar ridge, oral dryness, short or hypertrophic frena, loss of vertical dimension and occlusal changes are recorded [4]. The initial documentation is completed with models (by conventional or optical impression) mounted on a physical or digital articulator, with a reproducible occlusal record and an orthodontic-prosthetic-surgical set-up, and extraoral (smile and rest, frontal and profiles) and intraoral photographs (maximum intercuspation, centric relation and mouth half-open in severe overbite) [4]. Re-education of orofacial dysfunctions should precede any rehabilitation [4].

In prescribing radiographs, the PNDS applies the reinforced justification and optimisation required in paediatric age and the ALADAIP principle (as low as diagnostically acceptable), which replaced ALARA to avoid exposures so low that the images become useless, and follows the 2020 document of the European Academy of Paediatric Dentistry (EAPD) on radiographs in children [4]. The specific recommendations are: isolated periapicals as first choice for localised absences; orthopantomogram as first choice for generalised anomalies of number, with programmes that restrict the field to the arches; avoid the 21-film intraoral status; first orthopantomogram indicated from 4–6 years when absence of permanent germs is suspected; follow-up with isolated periapicals; CBCT never as first choice, reserved for the pre-implant phase and performed close to the time of surgery, with low-dose paediatric protocols (adapted kV, mA and time), small or medium field of view and without high-resolution protocols for morphological assessments [4].

In enamel defects, the diagnosis of AI requires exclusion of extrinsic causes, establishment of the inheritance pattern, recognition of the phenotype and its correlation with the chronology of tooth formation to exclude a time-limited disturbance; extraoral radiographs reveal impacted and possibly resorbing teeth, and intraoral radiographs show the contrast between enamel and dentine (reduced when mineralisation is affected) and the degree of hypoplasia [6]. Scanning electron microscopy of exfoliated or extracted teeth is a described adjunct [60]. In DGI, bulbous crowns, short thin roots and progressive pulp obliteration in opalescent teeth are almost pathognomonic of the phenotype, but do not identify the gene or the subtype [9].

When PFE is suspected, the algorithm published in 2026 starts from delayed or incomplete eruption of posterior teeth, assesses posterior open bite, involvement of several quadrants and the pattern of involvement of the distal molars, and uses the orthopantomogram and high-resolution CBCT to exclude mechanical obstruction and primary ankylosis; when the clinical picture and imaging are compatible, molecular study of PTH1R supports the diagnosis, which should precede any attempt at orthodontic traction [2]. The six clinical elements described for PFE are posterior involvement (especially of the first molar), obligatory involvement of the teeth distal to an affected molar, a clear eruption path, the vertical alveolar process of the affected tooth lying below that of its neighbours, open bite and possible involvement of primary teeth in the mixed dentition [76].

The relationship between clinical criteria and the molecular result has been studied in European and North American cohorts, whose results measure the proportion of carriers in a population selected by clinical suspicion, and not the clinical sensitivity of the test.

Sources: [43, 79, 127, 128].

The six criteria of the 2014 German series were predominant involvement of posterior teeth, disturbed eruption of an anterior tooth associated with posterior involvement, resorption of the alveolar bone coronal to the affected tooth, involvement of primary and permanent teeth, deficient vertical alveolar growth and severe posterior open bite; all carriers could be included in one of the three extension patterns, whereas 4 of the 13 non-carriers did not correspond to any [128]. Sanger sequencing of the coding exons and exon-intron junctions, used in most of these series, does not detect whole-exon deletions or duplications or deep intronic variants; next-generation panels targeted to orodental disorders, such as GenoDENT, allow the genetic differential diagnoses to be studied simultaneously [78]. A negative result does not exclude PFE, and most published missense variants remain of uncertain significance for lack of functional studies, so family segregation carries weight in classification [2, 127].

5.2. Genetic strategy

In agenesis, sequential single-gene testing may be considered when the pattern points to a gene: posterior agenesis → MSX1 and/or PAX9; anterior and posterior hypodontia or oligodontia → AXIN2, IRF6 and/or WNT10A; microdontia (peg-shaped laterals) or abnormally shaped teeth → WNT10A and/or EDA [3]. A multigene panel with the agenesis and ectodermal dysplasia genes is the approach most likely to identify the cause while limiting variants of uncertain significance (VUS); the genes included, sensitivity and methods (sequencing, deletions and duplications) vary between laboratories, and some panels do not include the rare genes [3]. The exome, and possibly the genome, are alternatives that do not require a prior hypothesis [3]. When agenesis is associated with dysmorphism, intellectual disability or malformations, chromosomal array or exome/genome is indicated; the karyotype is rarely useful if development is normal, but may be justified in an isolated woman with severe hypohidrotic ectodermal dysplasia [36, 49].

In France, the PNDS stipulates that genetic testing for oligodontia be prescribed in a hospital setting by a clinical geneticist or by a specialist from a rare disease reference or competence centre, able to explain the consequences to the patient and family, on a blood or saliva sample [4]. The first choice is a next-generation sequencing panel, such as GenoDENT (a panel with 63 entries of genes for disorders with orodental expression, which includes, besides the agenesis genes, ANTXR1, BCOR, EVC/EVC2, FGF10, FGFR2, GRHL2, IKBKG, KREMEN1, OFD1, PITX2, POLR3A/POLR3B, TP63, TSPEAR, UBR1 and TBX3) or the Cochin Hospital panel (31 genes, with CDH3, GJB6, IFT122, IFT43, WDR19, WDR35, NECTIN4, PKP1 and KCTD1); exome or genome is used as second choice when the panel is negative, or from the outset when the clinical picture is broad and does not suggest a precise diagnosis, by decision shared with the family and the reference network [4]. Access to the genome under the France Genomic Medicine Plan 2025 is through the pre-indication «syndromic forms of rare diseases with orodental expression» or through the pre-indications for the associated syndromes (genodermatoses, constitutional bone diseases) [4]. Analysis is, as a rule, performed as a trio (proband and parents) to study segregation; testing of symptomatic relatives and of at-risk adult relatives follows, and variants of uncertain significance are reported as such and may be reinterpreted as knowledge evolves [4]. When the history or examination suggests a syndromic form, the patient is directed to the O-Rares centres, which organise the regional clinical and molecular diagnostic pathway with the geneticist and refer, if necessary, to the centres for the associated syndrome [4].

In AI, diagnostic yield is limited: a focused clinical exome identified the cause in 18 of 65 syndromic and non-syndromic cases (27.7%), and Sanger sequencing of candidate genes in 36.6–48.7% of families, which indicates genes yet to be discovered and undetected variants, such as intronic and regulatory variants and copy number variants larger than one exon [7]. Complete AMELX deletions require CNV analysis when sequencing is negative, and the genome detects variants that the exome does not [7, 60]. The European group recommends confirming the diagnosis with a rare disease specialist and/or geneticist from two years of age and considering genetic testing especially when a syndromic form is suspected; genetic diagnosis can confirm or exclude enamel-renal or Jalili syndrome [8]. In the United Kingdom, knowledge of the genetics of AI led to the creation of a targeted genetic test in the National Health Service [7].

In DGI and DD, the main technical limitation is exon 5 of DSPP: short-read panels and exomes may miss variants in the 9 bp repeats, so a negative result in a patient with a convincing dentine phenotype does not exclude DSPP, and long-read sequencing should be considered before abandoning the diagnosis [9]. Exclusion of osteogenesis imperfecta (history of fractures, blue sclerae, bone mineral density) and, if relevant, study of COL1A1/COL1A2 are part of the assessment [9]. Audiometry is a reasonable precaution in carriers of variants in the signal-peptide region of DSPP, without constituting established surveillance [9]. There is no clinical assay of dentine proteins [9].

5.3. Limits of the tests and content of the report

A negative test does not exclude a genetic cause: panels vary in content and coverage, copy number variants and deep intronic variants may not be detected, somatic mosaicism may escape analysis of leucocytes, and reduced penetrance (especially of WNT10A, GREM2 and PTH1R) means that a carrier parent may appear unaffected [2, 3, 7]. A common low-penetrance variant, such as WNT10A p.(Phe228Ile), present in about 3.4% of the population, should not be interpreted on its own as a complete explanation of a severe phenotype [3]. The report should state the gene, the reference transcript with version (for example, NM_025216.3 for WNT10A, NM_000316.3 for PTH1R, NM_005220.3 for DLX3), the Human Genome Variation Society (HGVS) nomenclature at c. and p. level, zygosity and classification according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) [2, 48]. For genes with opposite effects, such as PTH1R and LRP6, the report should say whether the variant is activating or inactivating, because the phenotype and recurrence risk depend on it [52, 77]. VUS require family segregation study; in PFE, segregation contributes to the ACMG classification of missense variants [2].

5.4. Prenatal and preimplantation diagnosis

Once the familial variant has been identified, prenatal diagnosis and preimplantation genetic testing are technically possible; the perspectives of professionals and families on their use in these conditions may differ, and the discussion should take place before pregnancy [3]. In hypohidrotic ectodermal dysplasia, identification of carrier females has additional value in allowing care for the male newborn to be prepared [36].

6. Differential Diagnosis

6.1. Apparently isolated agenesis versus syndromic forms

The table reproduces, with adaptations, the GeneReviews differential diagnosis table, which is limited to disorders without characteristic dysmorphism and/or cognitive impairment [3].

Sources: [3, 14, 36, 37]. XL, X-linked.

In a child with a cleft lip involving the alveolus, missing teeth are frequent and do not by themselves imply a syndrome [50]. The French PNDS adds to the list of syndromes with oligodontia trisomy 21, blepharo-cheilo-dontic syndrome, Zlotogora-Ogur syndrome (cleft lip and palate with ectodermal dysplasia, the same entity as the NECTIN1 row), Williams-Beuren syndrome, craniosynostoses, oral-facial-digital syndromes and chromosomal anomalies in general, and considers ectodermal dysplasia, incontinentia pigmenti, Axenfeld-Rieger syndrome and colorectal cancer predisposition the most frequent syndromic associations of oligodontia [4]. Phenotypic overlap between isolated and syndromic forms, for example in WNT10A variants, makes the differential difficult and justifies a systematic medical history (chronic infections, neurological, cardiac, ophthalmological or skeletal involvement) [4]. Thalidomide was associated with hypodontia in 7.7% of children with embryopathy, compared with 0.4% of the others [37].

6.2. Enamel defects

Sources: [1, 6].

Hypomaturation-hypoplastic AI with taurodontism has dental findings similar to those of TDO, but normal hair and bone; in TDO, the bone differential includes the osteopetroses (more marked sclerosis, without dental or hair changes), pycnodysostosis (persistent anterior fontanelle and osteolysis of the distal phalanges) and trichothiodystrophy (brittle hair, ichthyosis, photosensitivity, cognitive and growth impairment) [69].

6.3. Disorders of dentine

DD type II and DGI form a continuum: both have amber teeth and obliterated chambers, but in DD type II the chambers do not close before eruption, permanent teeth are of normal colour, a «thistle-tube» chamber in a single-rooted tooth favours DD, crowns are of normal size and shape (in DGI they are bell-shaped with cervical constriction) and roots are normal (in DGI they are short and narrow) [1]. DD type I is distinguished by short or absent roots and by periapical radiolucencies in non-carious teeth [1]. In the face of early tooth loss, changes in root length point to DD type I and away from hypophosphatasia [39]. In patients classified as DD type II, examination of relatives often reveals DGI type II in other members or discoloration of the permanent teeth in the patient, an argument for their inclusion in mild DGI [39]. Pulpal dysplasia, unrelated, produces «thistle-tube» chambers and pulp stones in clinically normal teeth of both dentitions [1]. Osteogenesis imperfecta, other collagen disorders, odontochondrodysplasia and several syndromes have phenotypes similar to DGI [1, 75].

6.4. Failures of eruption

PFE is distinguished from mechanical failure of eruption by the absence of an obstacle, familial aggregation, involvement of the distal teeth and frequent association with skeletal class III, and from primary ankylosis by the absence of a metallic sound on percussion and of signs of ankylosis on CBCT; in doubtful cases, PTH1R testing clarifies [2, 76]. Multiple failures of eruption in a syndromic context point to enamel-renal syndrome, GAPO, oculodental syndrome, Nance-Horan, osteoglophonic dysplasia or Jansen chondrodysplasia [2, 56, 77].

Sources: [2, 11, 24, 56, 78, 80, 82, 127, 134–138].

The list of rare disorders with failure of eruption compiled in the 2018 review also includes cherubism (OMIM 118400), hypodontia with nail dysgenesis syndrome (189500), McCune-Albright syndrome (174800), Nance-Horan syndrome (302350), Rutherfurd oculodental syndrome (180900), regional odontodysplasia and osteoglophonic dwarfism (166250), all identifiable by their extradental or radiographic signs [11]. In cleidocranial dysplasia, extraction of primary teeth does not accelerate eruption of the permanent teeth, and malformed roots make extraction difficult, so confusion with PFE also has therapeutic consequences [136].

7. Treatments and Risk Management Strategies

7.1. General principles and available guidelines

There is no pharmacological treatment targeted at isolated genetic dental anomalies; management is preventive, restorative, orthodontic, prosthetic and surgical, multidisciplinary and prolonged from early childhood into adulthood [1, 3, 8]. The available guidelines are of three types: the GeneReviews chapter on non-syndromic agenesis (2021), which states that there is no standard of care or clinical practice guideline and proposes assessments, treatments and surveillance by author consensus; the AAPD guideline on heritable dental anomalies (AI, DGI and DD), revised in 2013 and based on 39 articles reviewed and on expert opinion where evidence was insufficient, which the AAPD Council on Clinical Affairs considered in 2018 no longer necessary and proposed to retire; and the AI care pathway drawn up by the ERN CRANIO orodental group in 2025 [1, 3, 8, 139]. The AAPD refers oral care in ectodermal dysplasia to the parameters of the National Foundation for Ectodermal Dysplasias (NFED) [1]. None of these documents rests on randomised trials; the recommendations are consensus-based. The French PNDS expressly states that few studies have a high level of evidence and that the surveillance schedule results from the consensus of the O-Rares centres [4].

The PNDS and the other sources diverge on several points, which the following table sets out; in practical decisions, the PNDS is the most recent document and the only one specific to oligodontia and anodontia, whereas GeneReviews covers all non-syndromic agenesis, including hypodontia, whose treatment is simpler.

Sources: [3–5, 8, 36, 42, 140].

7.2. Tooth agenesis

The initial assessments recommended by GeneReviews are examination by a paediatric dentist in children, with clinical examination including hard tissues and radiographs (bitewings, individual periapicals, orthopantomogram), referral to orthodontics and prosthodontics, assessment of feeding and chewing in children with oligodontia (with referral to a feeding specialist when necessary), assessment by orthodontics or general dentistry in adolescents and adults (orthopantomogram, lateral cephalometric radiograph, CBCT), genetic counselling and assessment of family and social support needs [3].

Source: GeneReviews, Table 4 [3].

The decision between closing and opening the space of a missing mandibular second premolar depends on age, crowding, the state of the primary tooth, the malocclusion and the patient's circumstances; extraction of primary molars in the early mixed dentition may allow favourable movements, but space closure is often incomplete (in one study, a 2 mm space remained in the mandible), and extraction close to the pubertal growth peak was associated, in a study of only 11 patients, with spontaneous closure; the preferred time for orthodontics in agenesis of mandibular second premolars is early adolescence [37]. In adults, caries, periodontal disease and the absence of growth complicate treatment [37]. In ectodermal dysplasia, prostheses may begin at two years, with successive replacements during growth and implants later, under the guidance of an experienced orthodontist, alongside prevention of hyperthermia [36]. In a cleft with alveolar involvement, orthodontics does not usually begin before the early mixed dentition, at 7–8 years [50].

The French PNDS organises the rehabilitation of oligodontia and anodontia by age group, with the aims of preserving the teeth and bone present, restoring mastication, speech and aesthetics, promoting harmonious growth of the bony bases and psychological well-being, and preparing the definitive adult rehabilitation [4]. Coordination lies with one of the dentists of the reference or competence centre together with a geneticist, and involves paediatric dentistry, orthodontics (with a central role from the earliest phases, through interceptive and orthopaedic treatment whenever a transverse or sagittal skeletal discrepancy compromises the prosthesis), oral and maxillofacial surgery, prosthodontics, implantology, periodontology, restorative dentistry, radiology, paediatrics and the specialties of the organs affected, as well as a genetic counsellor, speech therapist, physiotherapist, psychologist and social worker [4]. The initial assessment also evaluates the reason for consultation, the motivation and neuropsychological maturity of the child and parents and any oral feeding disorders, because treatment extends over many years [4].

Source: PNDS HAS, Table 3 and section 5.3 [4].

In adult anodontia, the preferred solution is fixed, with 6–8 maxillary and 4–6 mandibular implants after bone augmentation in both arches and fixed prostheses after 18 years; alternatives include removable «bar-to-bar» rehabilitation on 8 maxillary and 6 mandibular implants (which requires the absence of a neuromuscular deficit preventing handling of the prosthesis), two zygomatic implants with four maxillary and four mandibular implants under a fixed prosthesis, or an upper complete denture with a lower overdenture on two implants [4]. About 20% of patients described in the literature received implants before 18 years [4]. The out-of-pocket costs of these rehabilitations are high and forgoing care for financial reasons is a frequent obstacle (→ section 9.4) [4].

Symphyseal implants before the end of growth. HAS assessed favourably in 2004 the placement of pre-prosthetic implants in multiple agenesis linked to ectodermal dysplasias or other rare diseases and, in 2006, treatment of the child with oligodontia with 2 implants (at most 4) only in the anterior region of the mandible, from 6 years until the end of growth, after failure of or intolerance to the conventional prosthesis [4]. Published cases do not describe major local, systemic or craniofacial complications, so the PNDS considers the benefit-risk ratio favourable when the criteria are respected; the evidence comes from series and case reports, without comparative trials [4].

Source: PNDS HAS, section 5.3.3 [4].

Orthodontics. In the primary and mixed dentition, early prostheses and coronal rehabilitations prevent secondary migrations, maintain vertical dimension and stimulate mastication; closure of anterior diastemas at the request of the child or parents requires very prolonged retention, and functional re-education and surgery of pathological frena may be necessary [4]. Follow-up of a Japanese patient with anodontia and hypohidrotic ectodermal dysplasia from 6 to 18 years suggests that early rehabilitation with regularly renewed complete dentures reduces the deficit in skeletal and alveolar development [4]. The transverse and sagittal dimensions of the maxilla are monitored because of the tendency to maxillary hypoplasia and pseudoprognathism, and early orthopaedic intervention should be as simple as possible, because treatment consumes cooperation over many years; in severe dysmorphoses, bone-anchored devices may be used (bone-borne maxillary expansion and anchorage plates for class III orthopaedics at the pubertal peak) [4]. In adolescence, the team decides jointly to close, open or redistribute the spaces; the maxillary canine may be allowed to migrate mesially in agenesis of the lateral incisor, by extracting the primary lateral and canine, to form alveolar bone useful for a future implant; anchorage reinforcement (extraoral forces, functional appliances, mini-screws) compensates for missing teeth and short roots; autotransplantation of third molars or premolars has been described without medium- and long-term success data; a primary tooth without severe infraocclusion, without caries and with good morphology, often the mandibular second molar, may be kept for many years; and the space for a maxillary lateral incisor should be 6 mm mesiodistally, at both occlusal and root level [4]. Retention maintains the spaces for implants until the appropriate age, with onlays on infraoccluded primary teeth, space maintainers with prosthetic teeth or provisional implants, the latter with little follow-up [4]. In adults, orthodontic-surgical treatment comprises orthodontic decompensation, surgery for the skeletal discrepancy and joint definition, with the prosthodontist, of the mesiodistal and vertical spaces, overjet and occlusal vertical dimension [4]. Orthodontic treatment started after 16 years is not reimbursed in France (→ section 9.4) [4].

7.3. Amelogenesis imperfecta

The aim is to treat each problem as it arises, within an overall plan that anticipates future needs, with timely intervention to avoid psychosocial consequences [1]. The ERN CRANIO group recommends the first examination at eruption of the first primary tooth (at around six months), caries risk assessment, hygiene and dietary education and application of high-concentration fluoride varnish even without restorative need, for caries prevention, remineralisation and desensitisation [8]. The AAPD adds meticulous hygiene, calculus removal, mouthwashes and desensitising agents [1]. Brushing may be difficult because of hypersensitivity, and desensitisation is a long-term goal [8].

Between two years and the mixed dentition, in the presence of severe caries, absent enamel or risk of loss of occlusal vertical dimension (OVD), preformed paediatric crowns are indicated: metal (nickel-chromium) on primary molars when there is no aesthetic demand and zirconia on all primary teeth when the defects are severe and there is an aesthetic complaint; a space maintainer or paediatric prosthesis compensates for missing primary teeth; these treatments are often carried out under general anaesthesia or conscious sedation [6, 8]. Glass ionomer serves as a provisional restoration in very young or poorly cooperative children, and composite resin is preferred when definitive treatment is possible [8]. The AAPD indicates anterior composite or veneered crowns and posterior steel or veneered crowns in the primary dentition, for function and arch maintenance [1].

In the mixed (6–8 years), adolescent and young permanent dentitions, surveillance is multidisciplinary and focuses on prevention, preservation of OVD, reduction of sensitivity and aesthetics; crown preparations carry an increased risk of pulp exposure because of the pulp volume [8]. The restorative choice depends on the type of AI: intact but discoloured enamel may benefit from bleaching and/or microabrasion; hypocalcified enamel may retain composite or porcelain veneers if bonding is possible; if bonding is not possible, full-coverage restorations are needed; periodontal therapy precedes veneers or crowns when there is gingivitis or gingival hyperplasia [1]. Direct composites last less long in hypomaturation or hypomineralised AI than in hypoplastic AI and are regarded as provisional until the end of growth [8]. Ceramic crowns in adolescents and young adults with severe AI have high survival and success rates, few adverse events and reduce costs, which justifies earlier intervention; definitive veneers or crowns are recommended from early adolescence [8, 60]. Many adults with AI report that they would have preferred definitive aesthetic restorations earlier in adolescence, when appearance carries greater social weight [6].

Orthodontics in AI aims to facilitate hygiene, align the teeth, maintain masticatory function and prevent open or crossbites; it faces bracket bonding failures, longer treatments, more complications and more pain; an examination between 6 and 8 years allows anomalies to be identified early; treatment proceeds in phases (impactions, eruption problems, space management, serial extractions, functional appliances or face mask, maxillary expansion), followed by retention with bonded wires and night-time splints; aligners are an alternative well tolerated by patients with hypersensitivity, but retention is limited by the short crowns; skeletal discrepancies are reassessed in adulthood for possible surgery [8]. Anterior open bite may require surgical as well as restorative treatment [6]. In the permanent dentition the plan may include periodontics, endodontics, orthodontics, orthognathic surgery, veneers, crowns, implants and fixed or removable prostheses, and an occlusal splint to restore vertical dimension before complete rehabilitation [1]. Psychological support, especially at puberty, is part of treatment [1, 8].

In enamel-renal syndrome, in addition to specialised dental treatment of the hypoplastic teeth, the impacted teeth and the gingival hyperplasia, renal imaging and prolonged nephrological follow-up are needed; in the only published renal series (four children), management consisted of hyperhydration and cautious vitamin D supplementation, without a dose described in the sources consulted [7, 56].

7.4. Dentinogenesis imperfecta and dentine dysplasia

In DGI the aims are to prevent the attrition associated with loss of enamel and wear of the poorly mineralised dentine, to rehabilitate worn dentitions, to optimise aesthetics and to prevent caries and periodontal disease [1]. In mild to moderate forms, the usual restorative techniques are effective, especially in permanent teeth, which are less affected than primary teeth; in severe forms, with enamel fracture and rapid wear, the treatment of choice is full-coverage crowns in both dentitions, with better results when crown and root have a shape and size close to normal, which reduces the risk of cervical fracture [1]. Stabilisation should take place before excessive wear and loss of vertical dimension; in cases with severe loss, overdentures over teeth covered with fluoride-releasing glass ionomer have been used successfully [1]. Bleaching has a limited effect because the colour comes from the dentine; veneers mask the opalescence [1]. Multiple periapical abscesses, due to pulp strangulation secondary to obliteration or exposure due to wear, justify periodic radiographs; instrumentation of obliterated canals risks lateral perforation, and apical surgery may be necessary [1]. In osteogenesis imperfecta, procedures that transmit force to the jaws require caution because of the risk of fracture, and some forms of protective stabilisation are contraindicated [1].

In DD the aim is to keep the teeth as long as possible, but in DD type I the prognosis for prolonged retention is poor, early loss due to periodontitis is frequent and the unfavourable crown-root ratio leaves prostheses (dentures, overdentures, partial prostheses and/or implants) as the only practical route to rehabilitation [1]. In DD type II, teeth of normal shape, size and support can receive full crowns, and discoloured anterior teeth can be treated with resin, veneers or aesthetic crowns; even superficial occlusal restorations may cause pulp necrosis, because vascular channels of the pulp extend close to the amelodentinal junction; in the presence of periapical lesions, the plan is guided by root length [1].

7.5. Primary failure of eruption

Teeth with PFE do not respond to orthodontic forces, which promote ankylosis; orthodontic extrusion is ineffective and potentially harmful and should be avoided, and diagnosis, supported by PTH1R testing when the clinical picture is doubtful, should precede orthodontics to avoid inappropriate interventions [2]. Diagnosis in childhood makes it possible to avoid therapeutic errors with consequences for occlusion and jaw development [2]. The sources consulted do not describe an evidence-based rehabilitation protocol; the 2026 algorithm stresses multidisciplinary planning and the risk of traction failure and secondary ankylosis [2].

No scientific society has published a guideline for PFE, and the Strasbourg reference centre describes treatment as complex and difficult to systematise, without evidence-based recommendations [78]. In the 2018 systematic review, treatment was described in only 22 of the 314 patients: extraction of the affected teeth (7), unsuccessful orthodontics (6), no treatment (5) and, in one patient each, alignment of the labial segments, orthodontic extrusion of the unaffected teeth, overdenture and segmental osteotomy [11]. The 2010 North American family led the authors to recommend that teeth with PFE and ankylosed teeth be treated with the same caution, without a continuous orthodontic archwire including them, because this intrudes the neighbouring teeth and tilts the occlusal plane [44, 127].

No drug has an indication or is in trials for PFE; the applicable pharmacological measure is topical fluoride for caries prevention in partially erupted teeth, which are difficult to clean, at the doses in section 7.6 [78, 140]. A search of ClinicalTrials.gov identified an observational study from Strasbourg University Hospital on clinical, radiological and genetic criteria for PFE and its therapeutic consequences (NCT03580785), started in October 2018, with 50 planned participants, estimated completion in October 2025 and status «recruiting» at the last update, of August 2025 [141]. Once growth has finished, several multidisciplinary strategies can partially resolve the posterior open bite, and treatment should be planned with teams experienced in PFE, such as the ERN CRANIO reference centres for rare oral diseases [78, 129, 142].

7.6. Topical fluoride: the only routine pharmacological measure

Topical fluoride is the only pharmacological measure consistently recommended in these conditions, for prevention of caries and sensitivity [1, 3, 8]. The dose comes from the AAPD paediatric guideline, which applies to caries prevention in general and is extrapolated to dental anomalies, with no specific dose published for these conditions.

Source: AAPD, Fluoride Therapy (2023 revision) [140]. Systemic fluoride supplementation is considered only with caution in children at risk who drink water with fluoride below the optimum (for example, 0.25 mg/day from 6 months to 3 years if the water has less than 0.3 ppm), because it may exceed the recommended intake and cause fluorosis [140].

Antibiotic prophylaxis in implant surgery. The French PNDS requires antibiotic prophylaxis for placement of symphyseal implants in children, without specifying drug or dose [4]. In the absence of a specific dose, the single-dose regimen of the AAPD (2026) and the American Heart Association (2021) for invasive dental procedures is used by extrapolation, whose original indication is prevention of endocarditis and distant infections in at-risk patients, including primary immunodeficiencies; the 2026 Cochrane review supports, in adults without bone grafting, preoperative amoxicillin, usually 2 g one hour before, which probably reduces early implant failure (relative risk 0.33; 95% CI 0.16–0.67; number needed to treat 25 with a baseline failure of 6%), with no optimal regimen defined and no paediatric data [143–145].

Sources: [143, 144, 146]. Clindamycin is no longer recommended because it causes more serious reactions, including Clostridioides difficile colitis [143, 144]. The paediatric dose should not exceed the adult dose [146]. In ectodermal dysplasia with immunodeficiency, the AAPD recommends deciding on prophylaxis with the treating physician and allows additional doses or a pre- and postoperative course when the host response is compromised [143].

7.7. Regulatory status

Sources: [140, 147, 148].

7.8. Trials and new developments in the last 12 months

Sources: [147, 148].

The preclinical rationale is the demonstration, in mice with agenesis of various genetic causes, that blocking USAG-1 by gene inactivation or by antibody restores tooth formation through increased BMP signalling [46]. The phase I trial did not assess efficacy, no tooth regeneration in humans has been demonstrated, and the phase IIa notification to the PMDA is not an authorisation; information on these trials comes from company press releases reported by the specialist press, without scientific publication of the results or direct consultation of the Japanese registry [148]. The target of availability in 2030 announced by the investigators is a projection dependent on the success of the subsequent phases [148]. Other approaches remain preclinical: antisense oligonucleotides that correct AMELX splicing defects in an experimental system (2026) and chemical chaperones for the forms of AI with endoplasmic reticulum stress [7, 60]. A search of ClinicalTrials.gov in October 2026 (conditions amelogenesis imperfecta, dentinogenesis imperfecta, tooth agenesis, hypodontia and primary failure of eruption) did not identify trials of targeted drugs; the registered studies concern restorative materials, implantology, quality of life and genetics, among them a study of renal and vascular characterisation of FAM20A-related enamel-renal syndrome (NCT07285421, not yet recruiting, planned start January 2026) and a study of the oral quality of life of children with AI treated with veneers (NCT07250906, recruiting since November 2025); the terminated or withdrawn studies found relate to sample collection and implant techniques, with no safety reason stated [149]. A negative search does not prove that other trials do not exist.

7.9. Special populations and situations

In young children, extensive treatment often requires sedation or general anaesthesia, a difficult decision for parents, but one that delay may make unavoidable in order to extract carious and painful teeth [1, 6]. Transition from paediatric to adult care takes place at around 14 years in agenesis, and the paediatric dentist should hand over to the adult restorative dentist a motivated patient, with good hygiene and without therapeutic options compromised by previous interventions [3, 6]. Implants are placed only after most skeletal growth has been completed [3]. The sources consulted do not describe specific recommendations for pregnancy or lactation in these conditions, apart from caution with forces on the jaws in osteogenesis imperfecta [1]. In implant surgery in children, the French PNDS indicates general anaesthesia as first choice, and prior identification of an immunodeficiency may contraindicate implants and pre-implant bone grafts or require adapted antibiotic prophylaxis (→ section 7.6) [4].

The PNDS places transition to adult care between 15 and 20 years, adapted to each patient, with detailed reports between specialists and transfer of images to avoid repetition; at the first adult visit, the history is reviewed, the examination repeated, the mode of transmission and the risk of recurrence in a pregnancy explained again, understanding of the disease checked, information on social support provided and the treatment plan adapted [4]. Oral quality of life is affected by aesthetics, functional limitation and social discomfort, so the PNDS recommends complementing normative dental indices with subjective measures and, according to the AAPD, a psychological assessment at each stage of treatment, with psychological and medico-social support offered to the whole family from the announcement of the diagnosis [4]. Therapeutic education, centred on the patient and open to the parents, covers knowledge of the disease, oral hygiene and diet, the care pathway, what to do in risk situations (gingival inflammation, fracture or debonding of a restoration or bracket) and psychological aspects; in France, the DentO-RarEduc programme of the Strasbourg reference centre is intended for rare diseases of the teeth and oral cavity [4]. There is no emergency card for isolated oligodontia, but there are cards for some syndromic forms, such as ectodermal dysplasia and incontinentia pigmenti; the health record should inform emergency services of the diagnosis, associated malformations and ongoing treatments [4].

8. Reproductive Options and Family Counselling

8.1. Risks by mode of inheritance

In non-syndromic agenesis, AXIN2, EDAR, FGFR1, GREM2, IRF6, LRP6, MSX1, PAX9 and WNT10B are transmitted in an autosomal dominant manner, EDA in an X-linked manner, and WNT10A in a dominant or recessive manner, with reduced penetrance and variable expressivity even within the family and with complex inheritance proposed; when agenesis is part of a known syndrome, counselling follows that of the syndrome [3].

Sources: [2, 3, 6, 9, 10, 12, 14, 78].

An apparently negative family history cannot be accepted without examining the parents, because the disease may not have been recognised, penetrance is reduced and expression variable; in agenesis, the proportion of de novo cases is unknown [3]. In sporadic cases of AI, the hypotheses are recessive inheritance, a new variant or variable expression of a dominant gene, which requires examination of relatives and not classifying as AI defects of non-genetic cause, such as fluorosis or tetracycline staining [6]. In oligodontia, the French PNDS recommends trio testing of the proband and parents, to confirm segregation, then offering testing to symptomatic relatives and at-risk adult relatives, and repeating to the young adult the information on transmission and recurrence risk initially given to the parents [4]. In the PFE of the case described in section 10, the variant was inherited from the father, affected with a different distribution of teeth, and the mother was not a carrier [76].

In PFE, incomplete penetrance requires the variant to be studied in both parents even when neither has signs, because an asymptomatic carrier parent raises the siblings' risk to 50%; in the series with data, about 16% of patients had no affected relatives, which may reflect de novo variants, incomplete penetrance or insufficient examination of relatives [11, 12]. Clinical and radiographic examination of first-degree relatives and testing for the familial variant in at-risk children have direct clinical utility, because confirmation in childhood avoids ineffective orthodontic treatment and allows the permanent dentition to be planned [43, 78, 129].

8.2. At-risk relatives and carrier females

It is appropriate to clarify the clinical status and, when the familial variant is known, the genetic status of at-risk relatives, younger and older, so as to start dental treatment early; the assessment includes complete intraoral and extraoral examination and radiographs [3]. In X-linked hypohidrotic ectodermal dysplasia, possible carrier females should be examined and tested even without an affected male in the family; the starch-iodine sweat test, which shows a mosaic pattern along the lines of Blaschko, detects more than 90% of carriers, and dental examination identifies 60–80% by the presence of conical teeth [36, 45]. Identification of carriers allows care for the male newborn to be prepared before the diagnosis is suspected [36].

8.3. Prenatal and preimplantation diagnosis

Once the familial variant has been identified, prenatal diagnosis and preimplantation genetic testing are possible; the ideal time to discuss the risk and options is before pregnancy, and counselling should be offered to affected young adults [3]. The use of these tests in conditions that mainly affect the dentition gives rise to different perspectives among professionals and families, and the decision is considered personal [3]. Many families with AI worry about their children's teeth, and a risk estimate based on inheritance is valued even when the gene has not been identified [6].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Tooth agenesis

The prevalence of agenesis ranges from 1.6% to 36.5% depending on the population and on whether third molars are included; excluding them, most studies describe 3–10% for hypodontia and 0.1–0.5% for oligodontia [3]. At least one in five people lacks a third molar [37]. Polder's meta-analysis, with data from Caucasian populations of North America, Australia and Europe, estimated prevalences of 4.6% in men and 6.3% in women in Europe, 5.5% and 7.6% in Australia and 3.2% and 4.6% in North American Caucasians, with a prevalence 1.37 times higher in women; for African Americans, Chinese and Arabs the data were only indicative [5]. GeneReviews describes a higher frequency in Asians, followed by northern European populations and African Americans, cites a prevalence of 8.5% in Japan and a female:male ratio of 3:2, and attributes to a meta-analysis of 33 studies values of 5.5% in Europe and 6.3% in Australia; these values correspond to those that Al-Ani and colleagues take from Polder's meta-analysis, and the North American prevalence of 1% that GeneReviews associates with it does not match the original abstract [3, 5, 37]. The prevalence in New Zealand is consistent with the European one, and prevalence may be increasing, without evidence that this is not simply better diagnosis [37]. The French PNDS cites for agenesis a prevalence of 1.6–9.6% depending on the study and an aggregate value of 4.34% for hypodontia, oligodontia and anodontia, with no difference between sexes; for hypodontia, about 5% in the permanent dentition (Polder) and 0.4–0.9% in the primary dentition; for third molars about 20%, for second premolars 2.91–3.22% and for maxillary lateral incisors 1.55–1.78%; and for oligodontia and anodontia 0.14% of the population, a value taken from a French review on reference centres (Boy-Lefèvre and colleagues, 2014) [4]. The absence of a difference between sexes contrasts with the female excess in Polder's meta-analysis [5]. These figures come from clinical and school samples and are not equivalent to national estimates.

9.2. Amelogenesis imperfecta, dentine disorders and PFE

The prevalence of AI is described as between 1:700 and 1:14,000, the lower value in the USA, depending on the population studied; the ERN CRANIO group considers that these figures do not reflect the diversity of AI or its genetic aetiology and that there are no data by European country, and therefore proposes a European registry [1, 6, 8]. Autosomal recessive AI is more frequent in populations with consanguinity and in some Polynesian communities [6]. The AI LOVD database shows recurrent variants by origin: ENAM NM_031889.3:c.157A>T in seven Swedish families and NM_031889.3:c.92T>G in five British ones, DLX3 c.571_574del in seven North American families, AMELX NM_182680.1:c.208C>A p.(Pro70Thr) (= NM_001142.2:c.166C>A p.(Pro56Thr) on the MANE transcript) in six North American ones, KLK4 NM_004917.5:c.632del in five Pakistani ones and ODAPH NM_178497.5:c.229C>T in four Omani ones; the FAM20A variant NM_017565.4:c.406C>T includes a Brazilian family [7]. RELT has a founder variant in the Pakistani population of the United Kingdom, families with KLK4 and with recessive ENAM-related AI are mostly consanguineous (Pakistani and Turkish), DGI type III was described in the Brandywine isolate and Jalili syndrome in siblings from Gaza [9, 61, 62, 66, 71].

The AAPD gives a frequency of DGI of about 1 in 8000 and of DD of 1 in 100,000 [1]. These values derive from Witkop's 1975 data (DGI between 1/6000 and 1/8000, DD 1/100,000), obtained only in the USA and, according to the 2015 review, the only epidemiological data published until then; in the triracial Brandywine isolate, in Maryland, DGI affects 1 in 15 people [39]. Orphanet gives for DGI type 2 a point prevalence of 14.6/100,000 in Europe, an expert estimate without a confidence interval; for DD type I 1.0/100,000 in Europe and for DD type II a class below 1/1,000,000, with 19 published families [9]. Enamel-renal syndrome has a prevalence below 1/1,000,000 in Orphanet, which records 11 cases; a 2021 review gathered 69 patients [56]. For PFE there is no validated population estimate: the 2018 and 2023 reviews cite a prevalence of 0.06% and a male:female ratio of 1:2.25 attributed to Baccetti (2000), whose Italian study assessed the association between failure of eruption of permanent first and second molars and other dental anomalies (1520 non-syndromic individuals with uncrowded arches, compared with 1000 controls), without the current PFE criteria or molecular study; the value measures molar failure of eruption in an orthodontic population and not confirmed PFE [11, 13, 77, 78]. The series with molecular study come mainly from Germany, Denmark, Italy, France, the USA and Japan, and the sources consulted do not describe founder variants of PTH1R [2, 11, 78]. For OFCD there are no estimates either [14].

9.3. Portugal and Brazil

In the sources consulted, Portuguese data are limited to a case-control study of 306 individuals, in which PAX9 polymorphisms were associated with agenesis of the maxillary lateral incisors [37]. From Brazil, there is one family with FAM20A-related AI NM_017565.4:c.406C>T in the AI LOVD database [7]. The sources consulted on PFE do not include Portuguese or Brazilian patients [2, 11]. No prevalence estimates for either country were found in the sources consulted, which does not mean that none exist.

9.4. European networks and patient associations

Centres specialising in rare oral diseases have been part since 2017 of the European Reference Network ERN CRANIO (rare craniofacial anomalies and ear, nose and throat disorders, https://www.ern-cranio.eu), which maintains an orodental group, a European registry and the CPMS 2.0 clinical consultation platform among members [8, 142]. In France, the O-Rares reference centres (https://www.o-rares.com), of the TETECOU network (https://www.tete-cou.fr), have existed since 2016; in the United Kingdom there is a clinical network for children with AI; in the Netherlands and Denmark treatment of these diseases is centralised; the patient association Amélogenèse France supports families [8]. For oligodontia and anodontia, the French PNDS describes a reference centre with a coordinating site at Strasbourg University Hospitals and a constituent site at the Rothschild Hospital (Assistance Publique–Hôpitaux de Paris) and 16 competence centres (Angoulême, Besançon, Bordeaux, Dijon, Lyon, Marseille, Montpellier, Nancy, Nantes, Créteil, Pitié-Salpêtrière, Reims, Rennes, Rouen, Toulouse and Tours), with regular multidisciplinary team meetings in the O-Rares network and the TETECOU network; syndromic forms are followed in coordination with the FIMARAD (rare dermatological diseases), AnDDI-Rares (developmental anomalies) and OSCAR (rare diseases of bone, calcium and cartilage) networks [4]. The associations cited are the Association Française des Dysplasies Ectodermiques (AFDE, https://afde.net), which took part in drafting the PNDS, and the Association pour la Reconnaissance de l'Agénésie Dentaire (ARAD) [4].

In France, oligodontia, isolated or syndromic, is recognised as an off-list long-term condition (ALD 31) [4]. The application may be made by a physician from a reference or competence centre (with the centre's stamp), or by a dentist or stomatologist with the signature of the treating physician; it includes the ALD form, a completion aid sheet (child over 6 years still growing or patient whose growth has finished) with the dental formula, the agenesis and other absences, imaging and treatment stages, a recent good-quality orthopantomogram and, to assess bone age, a hand and wrist radiograph in boys from 17 years and in girls from 14; the rare disease diagnosis must be confirmed by a geneticist or by a physician from a rare disease centre [4]. Since 28 June 2007, the Health Insurance reimburses, in children over 6 years and until the end of growth, 2 to 4 implants in the anterior region of the mandible after failure of or intolerance to a conventional prosthesis, mandibular oligodontia being defined as agenesis of at least 6 permanent teeth in the lower arch; since 9 January 2012, in adults whose growth has finished, it reimburses up to 10 implants when at least 6 permanent teeth are missing (excluding wisdom teeth) and at least one of them is one of the following: 17, 16, 14, 13, 11, 21, 23, 24, 26, 27, 47, 46, 44, 43, 42, 41, 31, 32, 33, 34, 36 or 37 [4]. Transport is reimbursed when the home is more than 150 km from the centre or treatment requires 4 journeys of at least 50 km in two months; orthodontics started after 16 years is not reimbursed, and the additional fees for successive prostheses and orthodontics hinder access, and the patient may apply to the supplementary benefits fund of their insurance office [4]. These rules are French; the sources consulted do not describe equivalent schemes in Portugal or Brazil. For agenesis, GeneReviews lists the National Organization for Rare Disorders (NORD); for ectodermal dysplasias, the Ectodermal Dysplasia Society (United Kingdom) and the National Foundation for Ectodermal Dysplasias (NFED, https://www.nfed.org) [3, 36].

10. Illustrative Clinical Case

10.1. Familial primary failure of eruption with a PTH1R variant

Zha and colleagues described in 2023 a Chinese family followed at the First Affiliated Hospital of Jinan University, in Guangzhou [76]. The proband was a 13-year-old adolescent, 180 cm tall, without craniofacial or skeletal dysmorphism and without tongue-thrusting or sucking habits, whose right maxillary anterior teeth (11, 12 and 13) were below the occlusal plane, with a 4 mm anterior open bite, and whose left maxillary first molar (26) had slightly insufficient eruption; the impacted teeth had no caries or enamel defects, and the molar relationship was mesial bilaterally (Figure 1 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC10362615/figure/Fig1/) [76]. The orthopantomogram showed well-developed roots, without tumours, cysts or other barriers, and CBCT showed no periapical radiolucencies or signs of ankylosis, with an intact periodontal space; percussion was normal [76].

As the patient was at the growth peak, he was observed for one year, during which the open bite increased; vertical traction with bonded lingual buttons and intermaxillary elastics followed for six months, without reduction of the open bite, and three-dimensional superimposition of the CBCT scans showed that only the third molars had grown and that the anterior teeth had barely moved; one year later, the anterior and posterior open bite had increased [76]. His 12-year-old brother had the right mandibular first molar (46) below the occlusal plane with a normal root, and the tooth became progressively submerged while its neighbours grew; the father had impacted first molars 16 and 36, with open bites of 3 mm on the right and 6 mm on the left, and chronic periodontitis [76].

Sanger sequencing of the PTH1R exons identified in the three affected individuals a 12-nucleotide deletion in exon 14, inherited from the father, absent in the mother and in the population databases consulted by the authors, deposited in ClinVar (SCV003915837) (pedigree and electropherogram in Figure 9: https://pmc.ncbi.nlm.nih.gov/articles/PMC10362615/figure/Fig9/) [76]. On the MANE transcript, the variant is described as NM_000316.3:c.1325_1336del, p.(His442_Met445del), an in-frame deletion of four amino acids in the seventh transmembrane segment, and not as a truncation, the term used in the article [48, 76]. The family illustrates three points: variable expressivity within the same family, with atypical anterior involvement in the proband and posterior involvement in the others; the difficulty of distinguishing PFE from mechanical failure when the pattern is atypical; and the ineffectiveness of orthodontic traction, which later reviews advise against because it may induce ankylosis — the management in the report should not be taken as routine [2, 76]. The images were identified from the captions in the full text; direct viewing of the figures on the PMC site was subject to an automated check.

10.2. OFCD: radiculomegaly

Smith's atlas illustrates a 26-year-old woman with OFCD, a long, narrow face, bifid nasal tip, deep-set eyes with cataracts and bulky gums («gummy smile») reflecting the radiculomegaly; the radiographs show missing teeth (left maxillary first molar, right maxillary canine, left maxillary lateral incisor, left maxillary first premolar, right maxillary first molar and mandibular first molars), radiculomegaly and root dilaceration [14].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

In isolated forms, the prognosis depends on preservation of the dentition, masticatory and phonetic function, aesthetics and psychosocial impact, and treatment needs extend into adult life [6, 37]. In agenesis, 83% of affected individuals have only one or two missing teeth, whereas oligodontia requires prosthetic rehabilitation and implants after growth [3, 5]. In AI, early and intensive intervention improves function and quality of life, and ceramic crowns in adolescence have high survival [6, 8]. In untreated DGI, the dentition may wear down to the gingiva, and in DD type I the prognosis for tooth preservation is poor [1]. In TDO, teeth are frequently lost between the second and third decades due to periapical abscesses, without an increase in fractures and with normal intellect [68, 69]. In enamel-renal syndrome, nephrocalcinosis is silent and the long-term renal prognosis has not been established; renal function was preserved in the 2026 paediatric series, and nephrocalcinosis may only appear later in life; a normal initial ultrasound therefore does not exclude future nephrocalcinosis [56, 101]. In PFE, attempted traction worsens the outcome through secondary ankylosis [2]; in untreated adults caries, infectious foci and resorption accumulate in partially erupted teeth, and the Strasbourg reference centre considers that diagnosis in childhood and regular follow-up improve the prognosis [78]. In Jalili syndrome, the retinal dystrophy is progressive [71].

11.2. Surveillance

The six-month interval for dental review and for fluoride is consistent across GeneReviews, the AAPD and the European AI pathway [3, 8, 140]. The intervals for renal surveillance in enamel-renal syndrome, radiographic surveillance in DGI and clinical and radiographic surveillance in PFE are not defined in the sources consulted. In oligodontia and anodontia, the French PNDS proposes reviews at least annually above 6 years in a stable phase, more widely spaced than the six-monthly review of GeneReviews, and does not set intervals for follow-up radiographs, which must be justified case by case [3, 4].

12. Summary and Final Considerations

Genetic dental anomalies form a heterogeneous group that is best understood by the developmental phase disturbed: initiation (agenesis), morphodifferentiation (shape and size, including radiculomegaly), formation of the hard tissues (enamel and dentine) and eruption. Agenesis, especially hypodontia of second premolars and lateral incisors, is the most frequent anomaly, with a prevalence of about 5–6% in Europe excluding third molars; WNT10A, PAX9, MSX1, AXIN2, EDA and LRP6 are the main genes, and reduced penetrance and oligogenic inheritance limit prediction. AI and the disorders of dentine, rare and of dominant, recessive or X-linked inheritance, require differential diagnosis with fluorosis, chronological hypoplasias and molar-incisor hypomineralisation, and a search for the syndromic forms with renal (FAM20A, WDR72), retinal (CNNM4), bone and hair (DLX3) or generalised bone (osteogenesis imperfecta) involvement. Genetic tests have moderate yield and their own technical limits, such as the repeats of DSPP exon 5 and AMELX deletions. PFE due to PTH1R haploinsufficiency should be recognised before orthodontics, because traction of the affected teeth fails and causes ankylosis; incomplete penetrance, variable expressivity and the absence of a variant in some clinical cases require study of the family and cautious interpretation of a negative test, and rehabilitation depends on age, the degree of infraocclusion and local complications. In oligodontia and anodontia, the French national protocol adds prosthetic rehabilitation from 2–3 years, the exception of 2 to 4 symphyseal implants from 6 years in severe mandibular oligodontia after prosthesis failure, radiation protection in the choice of imaging, the search for immunodeficiency before surgery and coordination by reference centres with specific reimbursement. Treatment is dental, multidisciplinary and continuous: prevention with fluoride and sealants from eruption, preformed crowns in childhood, planned orthodontics, definitive restorations in adolescence and implants after growth, with psychological support. The only biological therapy in clinical trials, the anti-USAG-1 antibody, is at an early phase with no demonstrated efficacy in humans. Genetic counselling clarifies the recurrence risk and identifies relatives and carrier females who benefit from early care.

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