Dentinogenesis imperfecta type II results from mutations in genes encoding dentin structural matrix proteins, i.e., phosphoproteins and collagens.

As an isolated trait, it is caused by mutations in the dentin sialophosphoprotein DSPP gene (4q21.3), which belongs to the SIBLINGs family and encodes three major non-collagenous dentin matrix proteins-dentin sialoprotein (DSP), dentin glycoprotein (DGP), and dentin phosphoprotein (DPP) [8–14]. When associated with osteogenesis imperfecta, DI is caused by mutations in type I collagen genes and other related genes.

The intraoral clinical features are characteristic and lead to the diagnosis. Both primary and permanent dentitions are affected. The primary dentition is usually more severely affected. Dentin is abnormal in color appearing dull and bluish brown, amber, or opalescent. Enamel shedding occurs rapidly due to a defective enamel/dentin junction exposing the colored dentin to bacterial contamination within the oral cavity. The dentin has reduced wear resistance and the teeth rapidly wear from occlusal or biting stresses. The crowns appear bulbous radiographically with a marked cervical constriction. Pulp chambers and root canals are narrow or totally obliterated, and roots are short. Multiple pulp exposures and multiple abscesses may occur. Osteogenesis imperfecta is not a feature.

Enamel defects in addition to dentinogenesis imperfecta and DSPP mutations are described in a few families [15, 16].

At the ultrastructural level, enamel presents with an irregular surface and cracks [17]. Irregular dentin tubules, smooth dentinoenamel junction, abnormal enamel structure, and abnormal amounts of fibril bundles around dentin tubules were described in a family with a nonsense mutation in DSPP [17].

Dentinogenesis imperfecta type III has been described in a US population called the Brandywine isolate from Maryland and Washington, DC (an inbred triracial population of Caucasians, African Americans, and Native Americans) [18]. This disease is a phenotypic variation of dentinogenesis imperfecta DGI-II. The two diseases are allelic conditions sharing all the already described genetic DSPP mutations and clinical features [19]. However, in DGI-III, primary teeth often look like “shell” teeth on radiographs. Pulps of developing teeth are larger than normal during early development but rapidly become obliterated. Associated anterior open bite has been described.

The disease affects both dentitions and is associated with the premature loss of teeth. Tooth crown morphology and color are normal but teeth might be hypermobile. Upon radiography, the roots are short with pointed ends, and conical apical constrictions. Aberrant dentine growth leads to total pulpal obliteration in the primary dentition and reduced pulp space in permanent teeth. Teeth are lost generally due to trauma, inducing easily exfoliation. Delayed eruption is reported. Periapical radiolucencies are often seen in non-carious teeth.

This condition is allelic to DGI-II and is caused by mutations in the DSPP gene [20–22].

Primary teeth are opalescent and amber, resembling the phenotype of DGI-II.

On radiographs, pulp chambers are obliterated by abnormal dentin. However, the permanent teeth have a normal appearance with normal crown shape and color. They may show mild radiographic abnormalities with “thistle tube”-shaped pulp chambers and multiple intra-pulpal calcifications.

The nature of the dentin defects, i.e., dentin dysplasia versus dentinogenesis imperfecta, might be related to the type of DSPP mutations [23].

In this rare autosomal recessive disease caused by mutations in the SMOC2 gene (6q72) that encodes the SPARC-related modular calcium-binding protein-2 [24, 25], the radicular dentin dysplasia is associated with extreme microdontia in the primary dentition and oligodontia in the permanent dentition.

Osteogenesis imperfecta (OI), also called brittle bone disease, is a group of generalized heritable autosomal dominant or recessive disorders characterized by bone fragility and deformity, accompanied by osteoporosis, susceptibility to fracture, short stature, laxity of skin and ligaments, blue sclera and hearing loss, and eventually dentinogenesis imperfecta. Over 90 % of OI type I–IV disorders (OMIM #166200, #166240, #166210, #610854, #259420, #166220) are primarily caused by mutations in COL1A1 (17q21.31-q22.05) and COL1A2 (7q22.1), genes that encode the two alpha chains of type I collagen, which is the major component of the bone matrix.

COL1A mutations have, however, been described in individuals with DGI-II without skeletal abnormalities [28].

Mutations in genes coding for collagen modifying enzymes and chaperones have been discovered (SERPINF1 (type VI), CRTAP, LEPRE1, PPIB, SERPINH1, FKBP10, SP7, BMP1, TMEM38B, WNT1 (type XV)) in rare autosomal recessive forms of type VI–XV osteogenesis imperfecta (OMIM #613982, #610682, #610915, #259440, #613848, #610968, #613849, #614856, #615220, respectively) [29–36].

In types IB, IC, II, III, IVB, X, and XI, teeth demonstrate features of dentinogenesis imperfecta or eventually a phenotype similar to coronal dentin dysplasia type II (type IC).

Severe ultrastructural changes in dentin from patients affected with OI with clinically obvious dentinogenesis imperfecta show occluded tubules, multiple parallel channels, and occluded pulp chambers [37].

Even in the absence of a clear dental phenotype during clinical and radiographic examinations, histopathologic examination, at the ultrastructural level, disclosed characteristic dentin defects such as unevenly calcified matrixes, irregular tubular patterns, obliterated dentinal tubules, and cellular inclusions in the circumpulpal dentin of primary teeth leading to a diagnosis of OI type IV in a patient [38].

Osteogenesis imperfecta type V is a specific OI (#610967) phenotype with interosseous membrane calcification of the forearm and hyperplastic callus formation as typical features. The causative mutations for OI type V have been recently discovered in the gene encoding interferon-induced transmembrane protein 5 (IFITM5).

Blue sclera and dentinogenesis imperfecta were not evident in any patient. However, hypodontia in the permanent teeth, ectopic eruption, and short roots in molars were observed [39].

Osteogenesis imperfecta type XI (#610968) is caused by mutations in the FKBP10 gene (17q21.2) and is associated with dentinogenesis imperfecta.

Class III type craniofacial morphology with open bite and increased incidence of impacted permanent molars is often encountered in osteogenesis imperfecta [40].

Vertical underdevelopment of the dentoalveolar structures and the condylar process were identified as the main reasons for the relative mandibular prognathism in OI [41].

Osteogenesis imperfecta is therefore associated with dysplastic dentin that sometimes presents as dentinogenesis imperfecta [42].

The presence of dentinogenesis imperfecta is determined by the type of collagen mutation. The majority of patients with glycine mutations in a1(I) or a2(I) have clinically recognizable dentinogenesis imperfecta. Dentinogenesis imperfecta is absent in patients who have mutations in the amino-terminal end of the a1(I) or a2(I) triple helical domain [43].

Ehlers-Danlos syndromes (EDS) are a heterogeneous group of autosomal dominant and autosomal recessive disorders sharing joint hypermobility, skin extensibility, abnormal scarring, and tissue friability as hallmark diagnostic features [44]. More than XI forms are described. Type I (classical #130000) and type II (#130010) EDS are associated with mutations in COL1A1 and COL5A1 or COL5A2, respectively.

EDS type IV (#130050) is caused by COL3A1 mutations and is associated with periodontal disease and early loss of teeth.

Type VII EDS is linked to COL1A1, COL1A2 (#130060), and ADAMTS2 mutations (#225410).

EDS type VIII (%130080) is distinguished from other EDS subtypes by severe gingival recession and periodontitis leading to premature loss of permanent teeth and resorption of alveolar bone.

An analysis of the ultrastructure of teeth from patients affected by type VIIC Ehlers-Danlos syndrome (substitution of a codon for tryptophan by a stop codon in ADAMTS2) associated with multiple tooth agenesis and focal dysplastic dentin defects and of teeth from a patient affected by type I Ehlers-Danlos syndrome (COL1A1) demonstrated abnormal dentin formation [45].

Many case reports describe the presence of dentin dysplasia and abnormal dentin formation in various forms of Ehlers-Danlos syndrome [46, 47].

Mice deficient in the Zn transporter Slc39a13/Zip13 show changes in bone, teeth, and connective tissue reminiscent of the clinical spectrum of human Ehlers-Danlos syndrome (EDS). The Slc39a13 knockout (Slc39a13-KO) mice show defects in the maturation of osteoblasts, chondrocytes, odontoblasts, and fibroblasts [48].

Hypophosphatemic vitamin D-resistant rickets is characterized by rickets associated with short stature, bone defects such as bowing of the extremities, frontal bossing in the craniofacial area, and dental anomalies. At the biological level it implies hypophosphatemia (low amount of phosphate), normal calcemia, normal or low levels of vitamin D, normal levels of PTH, and increased activity of alkaline phosphatase in the serum and hypocalciuria in the urine.

Hypophosphatemic rickets can be inherited in an X-linked dominant (XLH) manner (OMIM #300550) due to PHEX (phosphate regulating endopeptidase homologue, Xp22.2-1) mutations [50]. The PHEX gene codes for a membrane-bound endoprotease (Zn-metalloendopeptidase proteolytic enzyme) which is predominantly expressed in osteoblasts and which regulates phosphates.

This form of rickets can also be transmitted as an autosomal dominant disease (ADHR #193100) due to FGF23 (12p13.3) mutations or as an autosomal recessive disease (ARHR #241520) with DMP1 mutations [51] or even as an X-linked recessive disease (#300554) due to mutations in the CLCN5 gene, which encodes a voltage-gated chloride ion channel [52]. PHEX regulates the function of fibroblast growth factor 23 (FGF23). The absence of functional PHEX leads to abnormal accumulation of ASARM (acidic serine- and aspartate-rich motif) peptide – a substrate for PHEX and a strong inhibitor of mineralization – derived from MEPE (matrix extracellular phosphoglycoprotein) and other matrix proteins. MEPE-derived ASARM peptide accumulates in tooth dentin of XLH patients where it may impair dentinogenesis [53].

1,25 vitamin D regulates DMP-1 expression through a VDR-dependent mechanism, possibly contributing to local changes in bone/tooth mineral homeostasis [52].

DMP1 has a protective antiapoptotic role for odontoblasts and ameloblasts, and the dentin defects might be enhanced by increased Pi level [54].

Beside enamel hypomineralization and delayed tooth eruption, the dental defects affect dentin, which is seen as globular and hypocalcified and presents many clefts and tubular defects. Abnormal large pulp chambers with pulp horns extending into the dentin and reaching the dentin-enamel junction are exposed directly to the oral cavity via the enamel defects and lead to pulpitis and pulp necrosis with recurrent abscesses and periapical pathology [55–58]. The cementum is also abnormal.

Treatment of hypophosphatemic rickets allows normal dentin development and mineralization [59, 60].

The discovery of mutations in FAM20C provides a putative new mechanism in human subjects for dysregulated FGF23 levels, hypophosphatemia, hyperphosphaturia, dental anomalies, intracerebral calcifications, and osteosclerosis of the long bones in the absence of rickets [61]. The teeth in an individual with a FAM20C mutation initially appeared to be normal but had been removed due to periapical abscesses. Clinical and histopathological examination of the teeth revealed enlarged pulp chambers, elongated pulp horns up to the enamel-dentin junction, and globular defects in the hypomineralized dentin. The enamel was hypoplastic. The roots were partly resorbed [61].

FAM20C knockout mice manifest hypophosphatemic rickets. The KO mice exhibit small malformed teeth, severe enamel defects, and very thin dentin, less cementum than normal, and overall hypomineralization in the dental mineralized tissues. DMP1 and DSPP are downregulated in the odontoblasts of these mice [62].

MEPE (matrix extracellular phosphoglycoprotein) (4q22.1) another SIBLING protein side to osteopontin (OPN) named secreted phosphoprotein-1 (SPP1), dentin matrix protein-1 (DMP1), bone sialoprotein (IBSP; 147563), and dentin sialophosphoprotein (DSPP) are also phosphorylated by FAM20C [63]. ASARM peptide, derived from MEPE, accumulates in the absence of functional PHEX and inhibits the odontogenic differentiation of dental pulp stem cells and impairs mineralization in tooth models of X-linked hypophosphatemia, thus explaining some of the dentin defects observed in X-linked hypophosphatemia [53].

Hypophosphatasia is an inherited disorder caused by a large panel of mutations in the ALPL gene (1p36.12) leading to a deficiency in the tissue-nonspecific alkaline phosphatase protein (TNAP) [64–66]. The modes of inheritance are autosomal dominant or autosomal recessive with often compound heterozygous mutations. Dominant negative effects of mutations complicate genetic counseling [67–69].

In the serum, reduced levels of alkaline phosphatase are detected, whereas in the urine, increased levels of phosphoethanolamine, calcium, and inorganic pyrophosphate (PPi) are present. Clinical features observed in the four clinical forms (infantile including the perinatal lethal form (#241500), childhood (#241510), adult (#146300), odontohypophosphatasia (#146300)), defined by the age of onset of the disease, range from complete absence of mineralization of the skeleton to premature loss of primary and eventually permanent teeth as an isolated feature. The main clinical features of this progressive disease are failure to thrive, severe rickets, bone deformities, short stature, craniosynostosis, seizures, gastrointestinal and renal problems, and spontaneous or fatigue fractures leading to mobility impairment [70].

The premature loss of teeth before 3 years of age for primary teeth shed with an intact root in the absence of periodontal disease is a common pathognomonic diagnostic sign whatever the clinical form [71]. The number of teeth lost and their type is also indicative of the severity of the disease, with incisors and canines being lost more frequently compared to primary molars. When confronted by this clinical presentation, it is important to refer the patient to the pediatrician or geneticist for further investigations.

TNAP is present during enamel, dentin, and cement formation [72]. Its deficiency will lead to absent acellular cement and periodontal anomalies in the ligament and alveolar bone leading to the premature loss of teeth and gradual defective dentinogenesis manifesting through small dentinal walls, large pulp chambers, and enamel defects.

Alkaline phosphatase knockout mice recapitulate the metabolic and skeletal defects of infantile hypophosphatasia [73] and demonstrate dentin mineralization defects as well as disturbed root dentinogenesis. The administration of a bioengineered recombinant alkaline phosphatase enzyme targeted to bone and mineralized tissues [74] rescued the skeletal and dentin defects and restored normal root formation mainly via a reduction of PP(i), a potent inhibitor of mineralization [75]. The replacement of alkaline phosphatase also corrected the periodontal/cementum anomalies [76]. This enzyme replacement therapy is currently under clinical trial [77].

Another molecule, PHOSPHO1, a soluble phosphatase with phosphoethanolamine and phosphocholine phosphatase activities, phosphoethanolamine and phosphocholine being present in matrix vesicles, is responsible for initiating hydroxyapatite crystal formation inside matrix vesicles and has functional roles complementary to TNAP during ossification [78]. In wild-type mice, Phospho1 and TNAP co-localize to odontoblasts at early stages of dentinogenesis, coincident with the early mineralization of mantle dentin. Nonredundant roles for both Phospho1 and TNAP in dentin mineralization are demonstrated by the spectrum of severity of dentin mineralization abnormalities in knockout mouse models [79].

This chondrodysplasia is characterized by severe shortness of stature and osteoporosis without fractures [80–82] combined with dentinogenesis imperfecta.

This syndrome is characterized by moderate mental retardation, hypospadias, and characteristic craniofacial morphology, which includes brachycephaly, facial asymmetry, exotropia, hypertelorism/telecanthus, broad nose, concave nasal ridge, underdeveloped midface, prognathism, and radicular dentin dysplasia [83].

This condition is caused by mutations in the pericentrin (PCNT) gene (21q22.3) [84, 85]. Severe dental anomalies (microdontia, tooth shape anomalies, dentin dysplasia with opalescent and rootless teeth) and hypoplastic alveolar bone are observed in this syndrome [86, 87].

This bone dysplasia (OMIM #242900) is an autosomal recessive disorder linked to SMARCAL1 (2q35) gene mutations and presents with spondyloepiphyseal dysplasia, T-cell deficiency, and focal segmental glomerulosclerosis. SMARCAL1 encodes the matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 protein [88]. The dental anomalies are hypodontia, microdontia, bulbous crown, and short roots [89].

Kenny-Caffey syndrome is an osteosclerotic bone dysplasia combining hypocalcemia, short stature, eye defects, and dental anomalies.

Two types of Kenny-Caffey syndromes have been described: (a) type 1, the autosomal recessive form (OMIM #24460), is due to mutations in the gene encoding tubulin-specific chaperone E (TBCE) [90]. Short roots are a frequent dental feature associated with teeth agenesis and microdontia [91]. (b) Autosomal dominant type 2 (#127000) is caused by mutation in the family with sequence similarity 111, member A gene (FAM111A), and defective dentition has been reported in some patients [92].

This rare inherited disorder (OMIM #256800) is caused by mutations in the neurotrophic tyrosine kinase receptor, type 1, NTRK1, and presents with unexplained fever, the inability to sweat, repeated traumatic injuries, mental retardation, and self-mutilating behavior. NTRK1 is the receptor for nerve growth factor NGF. Severe defects in peripheral nerve fibers formation are observed. Dental anomalies range from missing teeth to hypomineralization with dentin, cement, and periodontal ligament anomalies [93].