Failure of eruption of primary and/or permanent teeth is a rare condition caused by four possible causes. The first is ankylosis of the tooth roots, which, in the absence, even partial, of the alveolar ligament, join the surrounding bone. The second possible cause is failure of eruption due to mechanical impediment, in the presence of a cyst or lack of resorption of the bone overlying the developing tooth, or due to severe lack of space or an abnormal inclination of the tooth's eruption path. The third cause, called Primary Failure of Eruption (PFE), is genetic in nature due to insufficient production of the factors that determine tooth eruption. In this case, molars are the most affected teeth, and pathogenic variants of the PTH1R gene are often observed. The fourth possibility is delayed tooth eruption. In cases of ankylosis and PFE, orthodontic treatments to help recover the teeth in the arch may fail.

This interventional study, comprising a retrospective cohort, aims to evaluate the clinical signs of dental eruption disorders to identify criteria to facilitate clinical diagnosis. Furthermore, in cases where PFE is suspected, diagnostic testing for the PTH1R gene will be performed.

The study will be conducted at the Fondazione Policlinico Universitario "A. Gemelli" IRCCS in Rome and will enroll 50 consecutive patients with dental eruption disorders of deciduous and/or permanent molars. The primary outcome will be to strengthen the differential diagnostic hypothesis. The study will also examine the phenotype/genotype correlation in patients tested for PTH1R gene variants. The characteristics of the sample will be compared with those of the sample enrolled in the previous study (C.E. UCSC ID 565-11/2015), which will be examined retrospectively. Extending the analysis to the patient cohort enrolled since 2015 is particularly valuable given the rarity of the diseases under study and the resulting small number of cases available for research.

The study results will provide new data on pathogenic variants of PTH1R and on the phenotype/genotype correlation of the various diseases characterized by tooth eruption disorder. They will also help identify more sustainable and effective clinical strategies.

Tooth eruption is characterized by the movement of the developing tooth from its origin in the bone to its functional position in the oral cavity [1]. In the mouse model, the eruption process is orchestrated by stem cells surrounding the tooth and the periodontal ligament (PDL). The development of the PDL is determined by the expression of Pth1r, a protein-coding gene encoding the parathyroid hormone receptor [2;3]. During this process, eruption failure may occur, which could be diagnosed as primary failure of eruption (PFE; OMIM # 125350) or ankylosis. In the case of PFE, loss of Pth1r function within Pthrp-expressing cells affects the PDL and root phenotype, resulting in eruption failure [4]. This condition is most evident in the first permanent molars, and the eruption phenotype is partially penetrant. The eruption path is unobstructed because parathyroid hormone-related protein (PTHLH; OMIM168470) is normally expressed in coronal dental epithelial cells, whereas it is deficient in mesenchymal cells surrounding the roots. In humans with pathogenic variants of parathyroid hormone receptor 1 (PTH1R, OMIM168468), the eruption path is unobstructed, but eruption ceases and the affected tooth partially erupts. Orthodontic forces may be futile to move the affected teeth. PTH1R is a receptor for both parathyroid hormone (PTH; OMIM 168450) and parathyroid hormone-related protein (PTHLH). Previous studies described the involvement of the PTH1R gene in 2010 [5;6]; Previously published studies generally refer to "unexplained cessation of eruption" or a "poorly understood condition" [7-9], observing clinical signs more representative of PFE. In cases with a high probability of PFE, it is useful to search for variants of the PTH1R gene. Since genetic testing is not accessible to some, determining whether there is a family history represents a valid alternative.

In the case of ankylosis, the distinctive differential diagnosis is fusion of the tooth root surface with the surrounding bone. The pathogenesis of ankylosis is less well understood but has been associated with a history of trauma [10;11]; the presence of residual Malassez epithelial cells has been found to be essential for preventing fusion between the alveolar bone and the tooth. Overexpression of WNT is responsible for cementum overgrowth and ankylosis [12]. Regardless of this distinctive histological feature, definitive diagnosis of ankylosis is difficult and often nearly impossible. In practice, the diagnosis of ankyloses relies more on the exclusion of other causes of eruption failure and the clinical context (i.e., usually isolated). Non-eruption of permanent molars is the rarest impaction of permanent teeth [13]. This finding is always challenging for the dentist, even more so when it affects a child. From a clinical point of view, it is very difficult to distinguish between PFE and ankyloses during an early diagnosis process. In both cases, the affected teeth either fail to erupt or occupy an infra-occluded position. Ankylosed teeth should elicit a high-pitched metallic sound upon percussion [14] and have little or no mobility [15]. However, relying on differences in percussive sounds elicited by percussion with an instrument can vary greatly from operator to operator and may not be reproducible. In contrast, the use of an Osstell Mentor (Osstell, Gothenburg, Sweden) that detects resonance frequency analysis, as used in implantology, offers some promise [16]. In PFE, the affected teeth are normally mobile but become ankylotic in response to orthodontic force. If ankylosis is suspected, panoramic radiography does not clearly and definitively demonstrate the absence of the periodontal ligament, especially in multirooted teeth. As demonstrated by Raghoebar et al. [17;18], the areas of ankylosis are small and often located between the roots.

Early diagnosis is based on the clinical observation of delayed first molar eruption and on signs detected on panoramic radiography of the dental arches. Unfortunately, differential diagnosis is very difficult. During childhood, the causes of Mechanical Failure of Eruption (MFE) are easier to identify, mainly due to lack of space in the arch or the presence of cysts or supernumerary teeth that prevent eruption. Another possible cause of the absence of the first permanent molars in the arch is delayed eruption, which alters the timing of occlusion development, but not the eruption mechanism [19].

Failure to erupt in permanent first molars is a rare event [Roulias et al., 2022], but it presents clinicians with two significant challenges. First, the correct diagnostic classification can be difficult to confirm, and second, the resulting treatment options are often limited and yield suboptimal outcomes. Among the professionals who may first discover an eruption disorder in a child (e.g., general practitioners and pediatric dentists), neither may choose to provide therapeutic management for this malocclusion, as it often falls within the scope of work most often performed by an orthodontist. However, when this problem is observed in a child, if the practitioner fails to make a timely and correct diagnosis and treatment, the prognosis is poor. This means that the affected tooth or teeth fail to erupt, their position within the jaws worsens, and more or less severe alterations in occlusal relationships are observed. Tongue function is also affected, and the patient's face may develop asymmetry.

With this study, we aim to refine the identification of the distinctive clinical features of ankylosis, MFE, PFE, and delayed tooth eruption. We also aim to broaden and deepen our understanding of the pathogenic variants of PTH1R related to PFE.

HYPOTHESIS The clinical signs associated with dental eruption failure may have a different prevalence and severity in relation to ankylosis, MFE, PFE, and delayed tooth eruption. Furthermore, the identification of new pathogenic variants of PTH1R related to PFE could help clarify the genetic mechanisms underlying primary eruption failure.

Inclusion Criteria:

• Partial or complete failure of one or more deciduous and/or permanent molar teeth to erupt
• Diagnostic records (medical history, orthopantomography, clinical photographs)
• Age between 5 and 80 years
• Ability to understand and sign consent forms from patients, if adults, or their parents/guardians

Exclusion Criteria:

• Malformative syndromes and/or systemic diseases
• Lack of diagnostic records
• Failure of eruption due to traumatic causes