Heritable dentin defects such as dentinogenesis imperfecta (a intraoral, the amber dentin color and the severe wear are visible, and b radiographic features with obliterated pulp spaces, cervical constrictions, short roots), dentin dysplasia (c), intrapulpal calcifications (f) encountered in isolation or associated with other symptoms in SMOC2 mutation-associated rare disease (c dentin dysplasia, short roots with extreme microdontia in the primary dentition and oligodontia in the permanent dentition), hypophosphatemic X-linked rickets (d enlarged pulps), hypophosphatasia (e alveolar bone resorption; dentin and pulp chamber anomalies are present), and enamel renal syndrome (f intrapulpal calcifications are associated with absent enamel, retained teeth, and hyperplastic follicles)
They may also induce or be associated with subsequent enamel, dentin/enamel junction, or cementum/periodontium anomalies as dentinogenesis proceeds and occurs in coordination and interaction with amelogenesis and periodontium formation through epithelio-mesenchymal interactions.
These almost always genetically driven defects are seen in isolation or in association with other defects in syndromes. They mainly occur in conjunction with bone dysplasia, reflecting the similarities between dentin and bone formation, extracellular matrix chemical composition, and mineralization.
In this chapter, we will first describe the archetype of the genetic alterations of dentin formation in dentinogenesis imperfecta and dentin dysplasia type I and type II associated mainly with DSPP mutations . However, other rare diseases also display some kind of dentin dysplasia in their clinical synopsis.
We will then review dentin defects encountered in rare diseases related to genes encoding dentin and bone extracellular matrix proteins, such as bone dysplasia caused by mutations on collagen genes, rickets caused by mutations in small integrin-binding ligand N-linked glycoproteins (SIBLINGS), and hypophosphatasia caused by mutations in calcium-binding proteins such as alkaline phosphatase.
We will also review animal models presenting with dentinal defects.
11.2 Genetic Dentin Defects
11.2.1 Dentinogenesis Imperfecta
Dentinogenesis imperfecta is a group of inherited conditions that show autosomal dominant transmission and that encompass dentinogenesis imperfecta type II (DGI-II) or hereditary opalescent dentin (OMIM #125490) also named dentinogenesis imperfecta 1 (DGI-1) or Capdepont teeth, dentinogenesis imperfecta associated with progressive sensorineural hearing loss (OMIM # 605594) , and dentinogenesis imperfecta type III (DGI-III; OMIM # 125500) [5–7].
18.104.22.168 Dentinogenesis Imperfecta Type II
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].
22.214.171.124 Dentinogenesis Imperfecta Type III
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) . 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 . 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.
11.2.2 Dentin Dysplasia
There are two main varieties of dentin dysplasia, type I (DD-I, radicular) and type II (DD-II, coronal). Four distinct forms of dentin dysplasia type I and one form of dentin dysplasia type II are recognized. The enamel seems normal but wears off.
126.96.36.199 Type I or Radicular Dentin Dysplasia (OMIM #125400)
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.
188.8.131.52 Type II or Coronal Dentin Dysplasia (OMIM #125420)
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 .
11.2.3 Dentin Dysplasia and Rare Diseases
Radicular dentin dysplasia with short roots or aberrant dentin formation is seen in various syndromes.
11.2.4 Pulp Defects
It is noteworthy that dentin developmental defects will affect coronal and radicular pulp shape, size, and structure. Pulp may appear smaller or even absent in dentinogenesis imperfecta as dentin may be regarded as overproduced, for example, or pulp may appear larger in hypophosphatemic rickets phenomenon explained either by a delayed or reduced dentin formation. The shape of the pulp chamber or root pulpal spaces may be affected; a “thistle tube”-shaped appearance of the pulp, for example, is described in coronal dentin dysplasia. Intrapulpal calcifications  contribute also to reduce the pulp volume and testify the potential of pulp cells to produce mineralized dentin-like tissue.
Defects affecting the epithelial root sheath of Hertwig will also influence shape, size, structure of root, and root dentin formation.
11.3 Rare Diseases with Dentin Defects
Bone, dentin, and even cartilage extracellular matrix share common proteins. It is noteworthy that rare diseases affecting the composition of structural proteins like collagens or even those affecting the mineralization processes show combined skeletal and teeth defects . The extracellular matrix (ECM) is a complex entity composed of structural proteins (such as fibrillins, collagens, elastin), ground substance (proteoglycans), modifying enzymes (ADAMTS, PLOD, lysyloxidases (LOX), matrix metalloproteinases (MMPs)), and cytokines that regulate morphogenesis, growth, homeostasis, remodeling, and repair (transforming growth factor-beta (TGF-beta), bone morphogenetic protein (BMP)).
11.3.1 Bone Dysplasia and Collagens
Collagens are important components of bone extracellular matrix. Their alterations lead to a variety of genetic diseases.
184.108.40.206 Osteogenesis Imperfecta
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 .
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 .
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 .
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 .
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 .
Vertical underdevelopment of the dentoalveolar structures and the condylar process were identified as the main reasons for the relative mandibular prognathism in OI .
Osteogenesis imperfecta is therefore associated with dysplastic dentin that sometimes presents as dentinogenesis imperfecta .
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 .
220.127.116.11 Ehlers-Danlos Syndromes
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 . 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 .
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 .
11.3.2 Rickets-Related Diseases
Rickets is responsible for abnormalities in the formation and mineralization of skeletal bone, resulting in bone growth defects and malformations. The phenotype of the rare diseases belonging to this group includes dental anomalies in their clinical synopsis .
18.104.22.168 Hypophosphatemic Rickets
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 . 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  or even as an X-linked recessive disease (#300554) due to mutations in the CLCN5 gene, which encodes a voltage-gated chloride ion channel . 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 .
1,25 vitamin D regulates DMP-1 expression through a VDR-dependent mechanism, possibly contributing to local changes in bone/tooth mineral homeostasis .
DMP1 has a protective antiapoptotic role for odontoblasts and ameloblasts, and the dentin defects might be enhanced by increased Pi level .
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.
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 . 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 .
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 .
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 . 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 .
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 .
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 . 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 . 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  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  rescued the skeletal and dentin defects and restored normal root formation mainly via a reduction of PP(i), a potent inhibitor of mineralization . The replacement of alkaline phosphatase also corrected the periodontal/cementum anomalies . This enzyme replacement therapy is currently under clinical trial .
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 . 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 .
11.3.3 Other Syndromes
Other syndromes combine in their clinical synopsis dentin, bone or cartilage defects, and/or other symptoms.
22.214.171.124 Goldblatt Syndrome or Spondylometaphyseal Dysplasia with Dentinogenesis Imperfecta (OMIM 184260)
126.96.36.199 Elsahy-Waters Branchio-Skeleto-Genital Syndrome (OMIM 211380)
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 .
188.8.131.52 Microcephalic Osteodysplastic Primordial Dwarfism, Type II, MOPD2 (OMIM #210720)
184.108.40.206 Immunoosseous Dysplasia, Schimke Type
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 . The dental anomalies are hypodontia, microdontia, bulbous crown, and short roots .
220.127.116.11 Kenny-Caffey Syndrome
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) . Short roots are a frequent dental feature associated with teeth agenesis and microdontia . (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 .
18.104.22.168 Congenital Insensitivity to Pain and Anhidrosis
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 .
11.3.4 Ion Channels and Transporters
Root dysplasia (CLCN7 (chloride channel 7) – osteopetrosis OMIM #166600, #611490; KCNJ2 (potassium channel family J member 2) – Andersen syndrome OMIM #170390) and dentin dysplasia (CLCN5 (chloride channel 5) – X-linked recessive hypophosphatemic rickets; Dent disease 1 OMIM #300009) are seen in various channelopathies .
11.3.5 Lipids in Dentinogenesis and Rare Diseases
Phospholipids play an important role during dentinogenesis and amelogenesis and in the formation and mineralization of dental tissues [95, 96]. Sphingomyelin degradation is a key factor involved in dentin and bone mineralization .
Krabbe disease (OMIM #245200) is a galactosylceramide lipidosis and leukodystrophy caused by homozygous or compound heterozygous mutations in the galactosylceramidase gene GALC. Anomalies of dental mineralized tissues are present at the clinical and ultrastructural level and include enamel hypoplasia, dendritic inclusions of amorphous material inside the mantle dentin, and lysosomal storage inclusions in all the cells of the dental pulp. The myelin sheaths of dental peripheral nerves display severe degenerative changes [98–101].
Osteogenesis imperfecta associated with dentinogenesis imperfecta is observed in a mouse model, named fro/fro (fragilitas ossium), deficient for Smpd3, a gene that encodes neutral sphingomyelin phosphodiesterase 3 .
11.3.6 Enamel Proteins, Dentin Defects, and Rare Diseases
Dentinogenesis and amelogenesis are interrelated. Amelogenin is also expressed/secreted by odontoblasts, and DSP and DPP are expressed by ameloblasts during enamel-dentin junction formation [103, 104]. Enamel and dentin defects are encountered in various rare diseases including amelogenesis imperfecta .