Systemic Conditions associated with Delayed Tooth Eruption

Bone defects

Osteoclasts have an elementary role in clearing the eruption pathway for the developing tooth by resorbing the cortical shell of alveolar bone occlusally.⁸ Defects in osteoclastic function subsequently have the propensity to delay or even preclude normal eruption. Cherubism (Figure 1), an autosomal dominant fibro-osseous disorder resulting in bilateral symmetrical enlargement of the maxilla and mandible demonstrates the clinical sequalae of defective osteoclastic function.¹¹ The SH3BP2 gene, which is mutated in cherubism has a cardinal role in signalling transduction pathways, which ultimately increase osteoclastic function during tooth eruption,¹¹ with bone being replaced by fibrous hypervascular tissue.

The effects of osteopetrosis (marble bone disease) on DTE are clearly discernible and attributed to inactivity or absence of fully functioning osteoclasts. Genetically, mutations in one of the several genes that support acidification, and consequential dissociation of calcium hydroxyapatite at the resorption pit, cause the defective bone resorption seen in osteopetrosis. By a comparable mechanism, DTE is consistently observed in patients with pycnodyostosis, a lysosomal storage disorder characterized by sclerosing bony dysplasia. It is a rare autosomal recessive disorder with an estimated prevalence of 1 in 1 million.¹² Mutations in cathepsin K (CTSK) lead to defective osteoclastic resorption. CTSK is a lysosomal cysteine protease that has a central role in bony remodelling and is highly expressed by osteoclasts.

Multiple tumours or cysts

Cherubism provides an example of a syndromic condition that results in DTE by more than one mechanism. Bony expansion and distortion of the alveolar ridges by soft fibrous tissue histologically comparable to giant cell granulomas obscures the eruption pathway manifesting as failed eruption or DTE (Figure 1). Gorlin–Goltz syndrome, is an autosomal dominant condition characterized by basal cell carcinomas, odontogenic ketatocysts, palmoplantar pits, bifid ribs, calcification of the falx cerebri and coarse facial features among other characteristics.¹³ The presence of multiple odontogenic keratocysts may displace unerupted teeth, thus contributing to delayed eruption. Finally, the presence of osteomas in up to 82% of patients with familial adenomatous polyposis explains a mechanism by which DTE may also be attributed to tumours in addition to supernumerary teeth.¹⁴

Gingival hyperplasia

Hereditary gingival fibromatosis has the propensity to impede normal eruption by providing a mucosal barrier. The array of syndromes reported in the literature describing gingival fibromatosis is diverse (Table 2). Cowden syndrome, an autosomal dominant disorder, is characterized by multiple hamartomas histologically presenting as papillomatous lesions or fibromas.¹⁵ Comparatively, patients with enamel renal syndrome (ERS), a genetic disorder caused by mutations in the FAM20A gene, is characterized by hypoplastic amelogenesis imperfecta and nephrocalcinosis.^16,17 Patients with ERS can present with focal ectopic calcification of gingival connective tissue, tissue in proximity to odontogenic epithelium, vasculature, and in the pericoronal follicles of impacted teeth.¹⁶ Infantile systemic hyalinosis on the other hand, presents with excessive hyaline deposition in multiple tissues including the gingiva. Despite variations in the exact histology of the overgrowth, the clinical manifestations of hereditary gingival fibromatosis are comparable. Commonly, the overgrowth is slowly progressive involving either the marginal and/or attached gingiva. Dentists have a fundamental role in understanding the various causes of drug-induced, idiopathic and syndromic causes of gingival fibromatosis and should liaise with appropriate medical colleagues as necessary.

Defective resorption of the primary tooth

Hyperimmunoglobulin E (HIES) (Job syndrome) is a primary immunodeficiency syndrome characterized by high serum levels of immunoglobulin E (IgE).² Genetically, mutations in the signal transducer and activator of transcription 3 (STAT3) gene manifest as defective antibody maturation and B-cell development resulting in recurrent Staphylococcus aureus, Haemophilus influenzae and Streptococcus pneumoniae infections.¹⁸ An example of this is seen in Figure 2, depicting a patient with STAT3 dominant negative loss of function mutation (autosomal dominant hyper IgE syndrome) and Crouzon-like craniosynostosis. Impaired and delayed resorption of primary roots is a commonly cited occurrence in STAT3-hyperimmunoglobulin-E syndrome, with the suspected aetiology being persistence of cells of the Hertwig's epithelial root sheath (HERS).¹⁸ Another proposed mechanism of delayed root resorption is defective odontoclastic function. Osteopontin (OPN), a protein involved in bony remodelling by promoting osteoclastic activity, has been found to be deficient in HIES patients, providing another possible theory for retained primary teeth. Without appropriately prescribed extractions of retained primary teeth in HIES, delayed tooth eruption of the permanent dentition is the norm. The dental radiographs at 8, 10 and 12 years of age illustrate these points.

Hormonal changes

Thyroid hormones have receptors in numerous body systems, with dysfunction in endocrine systems having multi-system effects. Congenital hypothyroidism is the most common paediatric endocrinopathy;¹⁹ however, delayed tooth eruption is also commonly reported in hypopituitarism, hypoparathyroidism and pseudohyoparathyroidism.³ The RANKL/OPG axis, an important mechanism for maintaining the relationship between osteoclastic resorption and osteoblastic production of new bone is regulated by various hormones including thyroid hormones.¹⁰ Hypothyroidism results in localized decreased synthesis and degradation of proteins, causing both delayed tooth development and eruption.¹⁰