Local and systemic permanent second molar eruption pathology : diagnostic and therapeutic decision trees

Permanent second molar eruption anomalies, although rare, seem to have become increasingly frequent over the past decades. The present article first inventories and, when necessary, defines the many local and systemic etiologies. Then two decision trees are described, to help clinicians in case of non-eruption of second molars at the normal age; the first seeks to specify diagnosis, and the second to guide treatment planning.


INTRODUCTION
Eruption delay may concern a single tooth, with local etiology; this is the most frequent case 25 .However, a group of teeth or all the teeth may be involved, in which case etiology is more often systemic or genetic 16 .
The present article will list the various etiologies, with precise definitions as needed.
The most useful diagnostic data come from meticulous history-taking and radiology, with possible follicular biopsy.This information, included in a decision tree that will be presented below, guides treatment strategy.
Guiral-Desnoës H. Local and systemic permanent second molar eruption pathology: diagnostic and therapeutic decision trees 2

H. GUIRAL-DESNOËS
A reminder of some definitions will help understanding.
• Impaction: a tooth is said to be impacted when eruption is arrested by a clinically or radiologically detectable obstacle (mechanical failure of eruption: MFE) or by an eruption pathway abnormality (ectopia) 21 .Mesial angulation is often found (fig.1).• MFE due to an obstacle in the eruption path, visible on radiography or not 24 , is the main cause of impaction.
Pericoronary hamartoma: certain authors 5 described a tumor-like tissue deformity composed of an abnormal combination of elements normally Germ abnormalities impair the communications triggering eruption.They may be hereditary (impaired amelogenesis and dentinogenesis, enamel nodule, etc.) or acquired (trauma).
Loss of space due to unduly early avulsion, absence of guidance by the distal root of the first molar if the lat-ter has been extracted ("guidance" theory 10 ), dentomaxillary dysharmony due to relative macrodontia, short arcade and skeletal growth pattern 9 , as well as supernumerary teeth and/or odontomas may hinder harmonious second molar positioning.Retarded second molar progression may also be due to third molar agenesis (fig.2).
According to Andreasen, lack of space leads to follicular collision between germs 17 .Interference of cheeks, fingers, parafunctions.

Dental obstacles
The eruption pathway may be abnormal, usually with medial angulation, causing impaction.
Prevalence ranges from 45% to 85% 1 .PFE (in French, "arrêt idiopathique de l'éruption" 6 ) represents a dissociation between resorption forming the eruption pathway and the various motors of eruption (Proffit and Vig 1981 20 ).PFE associates most of these characteristics 20 , but with many phenotypic variants.found in the organ: osteodentine, cementum, pulp-analog components, multinuclear mesenchymal giant cells, dysplastic dental matrix.The deformity is of embryonic origin, and is also known as dysembryoplasia.
Radiologically, it is characterized by radiolucency surrounding a non-evolved tooth.The constituent elements induce active tissue remodeling, causing gingival fibrosis.Location is most often posterior mandibular, and there is systematically association with a non-erupted tooth.There may or may not be associated syndromes.
This lesion requires particular attention, as the radiologic aspect greatly resembles that of primary failure of eruption (PFE).Differential diagnosis looks for small radioopaque structures within an enlarged image of the follicle.Follicle biopsy analysis confirms diagnosis.In hamartoma, eruption follows its normal course after resection of the fibrous tissue.

Ectopic eruption pathway
Non-hereditary PFE Posterior teeth are more involved than anterior teeth.PFE generally begins with the first permanent molar, by ankylosis of the deciduous second molar (fig.3a).More rarely, premolars and canines may be involved, but never the incisors.Teeth distal to the first affected tooth are all involved to a greater or lesser degree (types I and II).
Affected teeth may have begun eruption but ceased at a certain point: primary and secondary retention.PFE covers a wide phenotypic spectrum, with severity ranging from simple retarded eruption to complete inclusion.Different mutations may be implicated.
Deciduous and permanent teeth may be involved.
The phenomenon may be uni-or bilateral, but is most often asymmetric and unilateral.
The alveolar bone above the crown is resorbed, creating a radiologically visible eruption pathway.. Affected permanent teeth generally show no ankylosis.However, applying orthodontic force to reposition the teeth in the arcade is generally unsuccessful and leads to ankylosis.The affected teeth do not show normal orthodontic response; they may sometimes slowly be pulled for 1 or 2 mm, but then egression stops.Isolated cases (idiopathic, sporadic mutation) have been reported.
The phenomenon induces a posterior gap, the size of which depends on the severity of the pathology (fig.3b).
When involvement begins only with the second molar, diagnosis cannot be made before 14 years of age; this is known as moderate PFE.Certain wisdom teeth in retention may be concerned by PFE: it is not lack of space that prevents eruption.
Proffit and Vig hypothesized an anteroposterior eruption gradient along the dental lamina, which might explain the greater frequency found in the more posterior teeth (M3++).
There may be a genetic link between local molar ankylosis and PFE, as the two may be found in different quadrants in the same subject.
According to Frazier-Bowers 12 , etiology may be distinct between ankylosis, primary retention, secondary retention and PFE.
Idiopathic eruption failure is probably genetic, but etiology may also be multifactorial.Secondary retention, the causes of which remain unelucidated, may associate physiological, mechanical and/or genetic factors 12 .Most cases are related either to ankylosis or, more often, to PFE.
The morphologic characteristics are the same as in hereditary PFE.

SYSTEMIC SECOND MOLAR ERUPTION PATHOLOGIES
Retention in these cases is usually due to generalized gingival fibrosis, supernumerary teeth or growth defect, rather than PFE as such.Well-conducted medical history taking regarding patient and forebears guides diagnosis.
LOCAL AND SYSTEMIC PERMANENT SECOND MOLAR ERUPTION PATHOLOGY: DIAGNOSTIC AND THERAPEUTIC DECISION TREES Moreover, developmental and hormonal genes interact: gene promoter sequences show hormonal response.
Local paracrine regulation and circulating hormones control bone tissue development and remodeling throughout life.
Endocrine disorders may affect both craniofacial development and alveolo-dental growth; eruption may be affected to a greater or lesser degree according to the hormone in question and age at onset.Genetic and acquired endocrine disorders may be distinguished.Bone base and alveolar process growth may be involved, greatly delaying eruption by slowing alveolar bone formation or causing MFE by dentomaxillary dysharmony.
Hypothalamic and pituitary functions, and especially the GHRH-GH-IGF-1 axis, are determining in regulating growth 4 .Acting via IGF-1, growth hormone (GH) or somatotropin is the main growth determinant (hypopituitarism), and is synthesized and released by the anterior pituitary.Thyroid hormones also play an essential role in statural growth, and especially in the skeletal maturation of the growth plate (hypothyroidism, hypoparathyroidism).Thyroxin stimulates the growth cartilage, and thyrocalcitonin inhibits bone catabolism and promotes osteogenesis.The effects are both direct and indirect, via activation of GH gene transcription.PTH (parathyroid hormone) has hypercalcemic and hypophosphatemic action, stimulating both bone formation and resorption, thus renewing the bone while maintaining skeletal integrity.PTHrP (parathyroid-related protein) is required for dental eruption (Philbrick, cited by Frazier-Bowers, Puranik, Mahaney 12 )., and may also delay eruption.• Likewise, retarded eruption is found in severe prematurity 16 .

Deficiencies
Many medical treatments may slow eruption: long-course chemotherapy (fig.4), or prostaglandin pathway blockers that reduce periodontal osteoclastic activity: aspirin, acetaminophen, ibuprofen, indomethacin, clodronate 26 , dihydantoin (used to treat epilepsy), or phenytoin (causing gingival hyperplasia) 24 .Chemically modified tetracyclines inhibit matrix metalloproteinase.Bisphosphonates (pamidronate and alendronate), prescribed to children for primary and secondary osteoporosis, including impaired osteogenesis, delay or inhibit dental eruption by impairing activity 14 .The exact etiology of PFE remains undetermined, but reports of hereditary cases 8,13,21,28 tend to show a link with a genetic mutation of incomplete penetrance and variable expression.Dominant transmission linked to the X chromosome cannot be ruled out.Frazier-Bowers' team situates the main origin of PFE in the alveolar bone 12 .Candidate genes are thus those involved in bone remodeling.It may be wondered whether PFE and ankylosis belong to the same spectrum of mutations …
Recently, PTH1R mutations were identified in cases of non-syndromic familial PFE with autosomal dominant high-penetrance transmission and variable expression 8,13 .Haploinsufficiency in the common PTH1R receptor of PTH and PTHrP is probably implicated in PFE.

Genetic etiologies associated with syndromes
Many syndromes are associated with retarded eruption of the permanent teeth (fig.5).
In 2002, Wise listed 25, half of which involved genetic mutation 27 .Such syndromes are not systematically familial, and may implicate sporadic mutation.Except for Levy-Hollister syndrome and progeria, which affect only permanent teeth, all other syndromes affect both dentitions, usually inducing severe delay rather than primary failure of eruption.eruption may be impacted at different stages, with correspondingly different severity.
The only syndromes presently known to be associated with true PFE are: -Albers-Schönberg osteopetrosis; -GAPO syndrome (Anderson and Pindborg: OMIM #230740); -and Fairbanks syndrome (osteoglophonic dysplasia).Early diagnosis of dental abnormalities 19 is useful, and indispensable to broader genetic diagnosis and ap-  syndrome and Murk-Jansen metaphyseal chondrodysplasia.In general, however, PFE patients do not have associated skeletal abnormalities.However, Frazier-Bowers' team recently reported 2 families with associated osteoarthritis 11 .It thus seems unlikely that PTH1R haplo-insufficiency prevents systemic osteoclast formation and functioning.Non-syndromic PFE is probably caused by defective interaction in epithelial-mesenchymal cells immediately adjacent to the eruption path, altering the delicate balance between bone resorption and formation 8 .In PFE, osteoclasts seem not to express functional PTH1R receptors on their surface.Instead, the dental follicle may contain a paracrine or juxtacrine signaling pathway comprising PTH1R positive cells on the surface.Moreover, the fact that only posterior regions are involved remains unexplained.PTH1R gene products may have specific temporal and spatial action 13 .Although PTH1R gene mutations seem clearly implicated in PFE, other genes may also well be involved.PTH1R mutation affects a whole local paracrine regulation system in PFE, although this remains to be identified.

Genetic etiologies
In 2011, Yamagushi's team 28 identified 3 other PTH1R gene mutations that may underlie PFE (6 mutations in all so far?), as well as mutations of the TGFBR2 and PROKR2 genes involved in bone metabolism.

Ionizing radiation
Accidental uranium irradiation or head and neck tumor radiotherapy may cause ankylosis, periodontal ligament lesions and maxillary growth defect.Based on the Orphanet questionnaire (fig.7), a certain number of points were raised to guide history-taking toward the various above Depending on the answers to the history-taking questionnaire, clinical observation and radiographic examinations, various authors 7,22,24

Figure 2
Figure 2 Patient aged 13 years 7 months.Retarded second molar progression with wisdom tooth agenesis.

Figure 4
Figure 4 Second molar abnormality and retarded eruption secondary to chemotherapy during infancy.

Figure 6 a
Figure 6 a) Agenesis and retarded eruption; 2 other siblings, father and grandfather affected; syndrome nonidentified.b) Panoramic view, 13 years.
have etiologies.The questionnaire should remain open-ended, with new observations being added from new cases.published therapeutic decisiontrees.These have been recast in the light of recent discoveries (figs 8 and 9).QUESTIONNAIRE DIAGNOSTIC AND THERAPEUTIC DECISION-TREES J Dentofacial Anom Orthod 2015;18:404 13 LOCAL AND SYSTEMIC PERMANENT SECOND MOLAR ERUPTION PATHOLOGY: DIAGNOSTIC AND THERAPEUTIC DECISION TREES
18ble of syndromes associated with retarded and/or arrested eruption, according to Wise27, completed by Molla15, Suri24and Orphanet18.
Guiral-Desnoës H. Local and systemic permanent second molar eruption pathology: diagnostic and therapeutic decision trees 8 Guiral-Desnoës H. Local and systemic permanent second molar eruption pathology: diagnostic and therapeutic decision trees 10