Agenesis Of Permanent Teeth Research Articles

Mutations in AXIN2 Cause Familial Tooth Agenesis and Predispose to Colorectal Cancer

Wnt signaling regulates embryonic pattern formation and morphogenesis of most organs. Aberrations of regulation of Wnt signaling may lead to cancer. Here, we have used positional cloning to identify the causative mutation in a Finnish family in which severe permanent tooth agenesis (oligodontia) and colorectal neoplasia segregate with dominant inheritance. Eleven members of the family lacked at least eight permanent teeth, two of whom developed only three permanent teeth. Colorectal cancer or precancerous lesions of variable types were found in eight of the patients with oligodontia. We show that oligodontia and predisposition to cancer are caused by a nonsense mutation, Arg656Stop, in the Wnt-signaling regulator AXIN2. In addition, we identified a de novo frameshift mutation 1994-1995insG in AXIN2 in an unrelated young patient with severe tooth agenesis. Both mutations are expected to activate Wnt signaling. The results provide the first evidence of the importance of Wnt signaling for the development of dentition in humans and suggest that an intricate control of Wnt-signal activity is necessary for normal tooth development, since both inhibition and stimulation of Wnt signaling may lead to tooth agenesis. Our findings introduce a new gene for hereditary colorectal cancer and suggest that tooth agenesis may be an indicator of cancer susceptibility.

The human KROX-26/ZNF22 gene is expressed at sites of tooth formation and maps to the locus for permanent tooth agenesis (He-Zhao deficiency).

Tooth development is mediated by sequential and reciprocal interactions between dental epithelium and mesenchyme under the molecular control of secreted growth factors and responsive transcription factors. We have previously identified the transcription factor Krox-26 as a potential regulator of tooth formation in mice. The purpose of this study was to investigate a potentially similar role for the human KROX-26 orthologue. We cloned the KROX-26 gene and found its single mRNA transcript (2.4 kb) to be expressed in multiple adult tissues. During fetal development, KROX-26 is expressed in the epithelial component of the developing tooth organ during early bud and cap stages as well as in osteoblasts of craniofacial bone and the developing tongue. The KROX-26 gene was mapped to chromosome 10q11.21, a locus that has been associated with permanent tooth agenesis (He-Zhao deficiency). These results indicate a potential function for KROX-26 in the molecular regulation of tooth formation in humans.

Novel mutation in the paired box sequence of PAX9 gene in a sporadic form of oligodontia.

Tooth development is regulated through a series of reciprocal interactions between the dental epithelium and mesenchyme and requires protein products of a number of genes. It has been reported that selective tooth agenesis is associated with mutations in human MSX and PAX9 genes. Mutational analysis of the two genes was performed in 25 individuals with familial or sporadic form of permanent tooth agenesis. Single-stranded conformational polymorphism analysis revealed no mutations in the entire coding sequence of the MSX1 gene. In PAX9, a novel, heterozygous G151A transition in the sequence encoding the paired domain of the PAX9 protein was detected in a patient with agenesis of third molars, second premolars and incisors, but not in her parents, the remaining patients or 162 individuals with normal dentition. This is the first de novo mutation described in PAX9. Our results support the view that mutations in PAX9 could constitute a causative factor of oligodontia. We hypothesize that the G151A transition in PAX9 might be responsible for the sporadic form of tooth agenesis in this patient.

Dental characteristics in Williams syndrome: a clinical and radiographic evaluation

Williams syndrome is a rare congenital syndrome with distinctive craniofacial features, cardiovascular abnormalities, and behavior characteristics including mental retardation. The dental abnormalities have received scant attention in previous literature. The aim of this study was to describe dental characteristics in individuals with Williams syndrome. In a group of 41 individuals more than 10 years of age, 40.5% had agenesis of one or more permanent teeth and 11.9% had agenesis of 6 permanent teeth or more. The mesio-distal and labio-lingual dimensions of permanent tooth crowns were measured on 31 dental study casts from individuals older than 12 years. The mesio-distal and labio-lingual dimensions were significantly smaller compared with a reference sample. An analysis of tooth morphology was performed on the same dental study casts revealing altered tooth morphology. A high proportion of maxillary and mandibular incisors was tapered or screwdriver shaped. An evaluation of taurodontism on mandibular permanent molars was performed using a metric crown-body/root ratio. However, most of the molars rated as being taurodontic had short or extremely short total tooth lengths and could thus be rated taurodontic without meeting the classical definition. The results of this study indicate that although there is variation in dental development in individuals with Williams syndrome, agenesis of permanent teeth in combination with aberrations in tooth size and morphology may affect dental esthetics and complicate orthodontic and prosthodontic treatment.

The Novel Gene Locus for Agenesis of Permanent Teeth (He-Zhao deficiency) Maps to Chromosome 10q11.2

He-Zhao deficiency has been recently characterized with a distinct form of agenesis of permanent teeth that is different from other previously reported disorders of tooth agenesis. This inherited abnormality suggests that some gene(s) associated with the development of permanent teeth may mutate. In this study, we map the gene locus to chromosome 10q11.2. The DNA pooling method combined with two-point and multi-point linkage analysis has been successfully applied. The maximum LOD (Zmax) scores for two-point and multi-point analyses are 13.29 (on marker D10S196) at recombination fraction (theta) = 0 and 18.09 (between markers D10S1772 and D10S1766), respectively. Haplotype analysis confined the locus within an interval of 5.5 cM flanked by markers D10S604 and D10S568. This study has demonstrated a novel gene locus responsible for He-Zhao deficiency and provides a good likelihood for the discovery of one of the genes determining permanent tooth formation and development.

Oro‐dental and craniofacial anomalies in LEOPARD syndrome

'LEOPARD syndrome' is a syndrome affecting many systems or organs. The main anomalies are summarized in the acronym LEOPARD in which each letter corresponds to the damage of a given organ. In the presented case, there are oro-dental and craniofacial anomalies. The relationship between the LEOPARD syndrome and the given anomalies and the possibilities of the management and the follow-up of the diseased are studied. The clinical case presented is a 4-year-old boy with LEOPARD syndrome showing retardation of dental development, delayed development and possible agenesis of permanent teeth, and craniofacial anomalies (osseous hypodevelopment). The bibliographical study shows that LEOPARD syndrome is due to damage of the neural crest cells. Thus, the dental and craniofacial anomalies arise since neural crest cells participate in the formation of the teeth and some craniofacial bones. Therefore, dental and craniofacial anomalies might be expected in some cases of the disease. The therapeutic management of the lesions, and the follow-up of the patient would be done by a multidisciplinary team.

Congenital absence of permanent teeth in a six-generation Chinese kindred

We report on rare, heritable, permanent tooth agenesis in a large Chinese kindred. The congenital absence of permanent teeth except the first and second accessory teeth was observed in 52 individuals through six successive generations in the kindred comprising 328 members. Clinical assessments were carried out, and inheritance mode and spousal influence of the anomaly on their offspring were analyzed. Consequently, the anomaly was transmitted in an autosomal dominant fashion with incomplete penetrance (P = 0.88), and no significant clinical manifestations other than the oligodontia were found. A geographical or environmental effect on the affected individuals was obviously eliminated, because any who are related to the kindred but live under the same conditions are fully healthy. The disorder we describe, therefore, differs from any previously reported oligodontia/anodontia syndromes. The oligodontia ranged from a few teeth to the whole set of teeth, and usually occurred at a period from age 7 or 8 years, the time when primary teeth are normally replaced by permanent teeth, to the forties. Roentgenography of the affected persons indicated that only the first and/or second accessory teeth with tooth buds developed as permanent teeth. In fact, the diphyodontic germination sometimes occurred in the oral cavity of the affected individuals. Am. J. Med. Genet. 90:193–198, 2000. © 2000 Wiley-Liss, Inc.

Congenital absence of permanent teeth in a six-generation Chinese kindred

We report on rare, heritable, permanent tooth agenesis in a large Chinese kindred. The congenital absence of permanent teeth except the first and second accessory teeth was observed in 52 individuals through six successive generations in the kindred comprising 328 members. Clinical assessments were carried out, and inheritance mode and spousal influence of the anomaly on their offspring were analyzed. Consequently, the anomaly was transmitted in an autosomal dominant fashion with incomplete penetrance (P = 0.88), and no significant clinical manifestations other than the oligodontia were found. A geographical or environmental effect on the affected individuals was obviously eliminated, because any who are related to the kindred but live under the same conditions are fully healthy. The disorder we describe, therefore, differs from any previously reported oligodontia/anodontia syndromes. The oligodontia ranged from a few teeth to the whole set of teeth, and usually occurred at a period from age 7 or 8 years, the time when primary teeth are normally replaced by permanent teeth, to the forties. Roentgenography of the affected persons indicated that only the first and/or second accessory teeth with tooth buds developed as permanent teeth. In fact, the diphyodontic germination sometimes occurred in the oral cavity of the affected individuals.

Caroline Crachami, the Sicilian dwarf (1815–1824): Was she really nine years old at death?

Caroline Crachami (C.C.) considered to have had the Seckel syndrome was one of the most extreme cases of dwarfism ever recorded. Reputedly born in Sicily in 1815, she attracted much attention when exhibited in England before her death on 3 June 1824. Although she is said to have been 9 years old at death, published descriptions give her a dental age varying from 2 to 7 years. Examination of her skull in the Royal College of Surgeons of England demonstrated a more or less erupted complete deciduous dentition, with no erupted permanent teeth. Radiographs showed agenesis of several permanent teeth. It was concluded that the dental age of C.C. was 3 years (± 6 months). Perikymata were evident in the surface enamel encircling the crown of the partially exposed maxillary left first permanent molar. Their distribution and spacing were normal, with no evidence of developmental retardation. The distance between the periradicular bands in the root near the cement-enamel junction was also normal. We conclude that the dental age of C.C. was similar to her chronological age and that at death she was about 3 and not 9 years old. The reason that she was said to be nearly 9 when exhibited in England we believe was related to financial considerations, as people would be generally less impressed with a dwarf only 3 years old. The new age we give C.C. has implications on the diagnosis of her medical condition. Am. J. Med. Genet. 76:343–348, 1998. © 1998 Wiley-Liss, Inc.

Caroline Crachami, the Sicilian dwarf (1815-1824): Was she really nine years old at death?

Caroline Crachami (C.C.) considered to have had the Seckel syndrome was one of the most extreme cases of dwarfism ever recorded. Reputedly born in Sicily in 1815, she attracted much attention when exhibited in England before her death on 3 June 1824. Although she is said to have been 9 years old at death, published descriptions give her a dental age varying from 2 to 7 years. Examination of her skull in the Royal College of Surgeons of England demonstrated a more or less erupted complete deciduous dentition, with no erupted permanent teeth. Radiographs showed agenesis of several permanent teeth. It was concluded that the dental age of C.C. was 3 years (+/- 6 months). Perikymata were evident in the surface enamel encircling the crown of the partially exposed maxillary left first permanent molar. Their distribution and spacing were normal, with no evidence of developmental retardation. The distance between the periradicular bands in the root near the cement-enamel junction was also normal. We conclude that the dental age of C.C. was similar to her chronological age and that at death she was about 3 and not 9 years old. The reason that she was said to be nearly 9 when exhibited in England we believe was related to financial considerations, as people would be generally less impressed with a dwarf only 3 years old. The new age we give C.C. has implications on the diagnosis of her medical condition.

Prevalence of tooth agenesis and peg-shaped maxillary lateral incisor associated with palatally displaced canine (PDC) anomaly

Fifty-eight nonsyndromic North American white orthodontic patients with palatal displacement of one or both maxillary canine teeth were studied for associated tooth agenesis and peg-shaped maxillary lateral incisors. Agenesis of permanent teeth was identified by x-ray film analysis. Conical crown-size reduction (peg-shape anomaly) of the maxillary lateral incisor (I2) was determined by direct observation. Increases in absence of third molars and second premolars associated with the palatally displaced canine (PDC) anomaly were statistically very highly significant compared with normative data for tooth-agenesis prevalence. In contrast, the prevalence of I2 agenesis in the PDC sample showed no difference statistically compared with reference values. Reasons for this posterior site-specific suppression of tooth formation are not clear. The I2 peg-shape anomaly exceeded a 10-fold elevation in expression in the PDC sample, a very highly significant increase from normal prevalence. The findings are consistent with a hypothesis that the anomalies of tooth agenesis, tooth-size reduction, and PDC are biologic covariables in a complex of genetically related dental disturbances. (Am J Orthod Dentofac Orthop 1996;110:441-3.)

Site-specificity of tooth agenesis in subjects with maxillary canine malpositions.

Tooth agenesis (hypodontia) was studied in two samples of nonsyndromic subjects possessing either maxillary canine-first premolar transposition (Mx.C.P1; N=43, M9:F34) or palatal displacement of the maxillary canine (PDC; N=58, M21:F37). Agenesis of permanent teeth was identified by x-ray film analysis. Significantly elevated tooth-agenesis frequencies were noted in both samples. Statistically significant differences between the Mx.C.P1 and PDC samples were found in locations of absent teeth, indicating site-specificity of tooth agenesis associated with these canine malpositions. In Mx.C.P1, agenesis of third molars (M3) occurred at a near-normal rate (19%) while maxillary lateral incisor (I2) agenesis showed a thirteen-fold increase (26%). In PDC, the prevalence rate for associated M3 agenesis was 40%, twice the normal rate, while I2 agenesis was 3%, a slight elevation of no statistical significance. These new findings may warrant a hypothesis of anteroposterior site-specific shift in the occurrence of tooth agenesis, associated genetically or epigenetically with distinct anomalies of maxillary canine position and possibly other abnormalities.

Congenital, Genetic, and Endocrinologic Influences on Dental Occlusion

Employment of studies on individuals who have experienced congenital, genetic, and endocrinologic influences on dental occlusion affords an opportunity to study and observe current concepts of occlusal and centric relationships in the general population. In Down's syndrome one rarely finds a satisfactory occlusal relationship as well as a so-called centric relationship. Patients who are educable and trainable have no problem with mastication despite the occurrence of minor or major occlusal disharmonies and a complete absence of centric relationship. When permanent tooth agenesis occurs, one finds a significantly different pattern of occlusal relationship from that found in the general population. There is an unusually high incidence of Class II occlusal disharmonies with accompanying closed bites. In pituitary dwarfism different segments of the dentofacial complex are differentially retarded, resembling the postcranial skeleton. The teeth, on the other hand, although retarded in emergence, formation, and alignment, are advanced in respect to skeletal age and jaw formation and demonstrate an independence of epithelial growth by growth hormone secretion. Congenital X-linked ectodermal dysplasia is accompanied by partial and complete agenesis of teeth. The affected individuals, because of tooth agenesis, are essentially edentulous. When making dentures for these individuals there is no precise guideline for occlusal relationships or centric relationship. When dentures are constructed approximations for occlusal and so-called centric relationship are established. In no single case in my experience has the patient had any difficulty in adapting to the dentures. When the dentures are made for young children they must be remade as many times as is necessary to accommodate the anteroposterior growth of the maxilla and mandible. The osseous defects in Morquio's syndrome are severe and grotesque, yet the craniofacial complex is relatively free from any gross abnormalities. The cranial and facial size and proportions are at or near normal values (with the possible exception of cranial length). All of the patients studied showed a slight protrusion of the premaxillary region yet the occlusion was functional and acceptable in appearance. The cases of Duchenne muscular dystrophy all manifested varying degrees of open bite. Although there was no apparent occlusal relationship of the teeth in any of these individuals, they had no problem with mastication. As one examines the occlusal relationship of individuals affected by congenital, genetic, and endocrinologic influences it becomes apparent that our present standards of evaluating occlusal and so-called centric relationships require re-examination. Many years ago Angle stated in the introduction of his text, Malocclusion of the Teeth, “that no two normal human dentures have been created that were exactly alike.” Angle did not realize that the ideal rarely or never exists in nature, yet the term normal and ideal are profusely used in dental literature today. The concept of ideal occlusion has permeated the whole field of dentistry, not only in orthodontics but also in fixed and removable prosthodontics. When one examines large numbers of young children one rarely finds a so-called ideal occlusion in the primary, mixed, or permanent dentitions. What one finds is an occlusion that is not static and that changes with the growth and development of the child. The congenital, genetic, and endocrinologic disorders described in this article demonstrate the independence of these influences upon growth and development of the dentofacial complex and occlusal relationships. With the general growth and development of the dentofacial complex, in the above disorders environmental factors play an important role in the accentuation of the occlusal disharmonies. It becomes obvious that statisfactory occlusal relationships as well as centric relationships are not observed in the above disorders, yet it has no apparent effect on mastication and the nutritional status of these individuals.