RESUMO
Tooth agenesis and orofacial clefts represent the most common developmental anomalies and their co-occurrence is often reported in patients as well in animal models. The aim of the present systematic review is to thoroughly investigate the current literature (PubMed, EMBASE) to identify the genes and genomic loci contributing to syndromic or non-syndromic co-occurrence of tooth agenesis and orofacial clefts, to gain insight into the molecular mechanisms underlying their dual involvement in the development of teeth and facial primordia. Altogether, 84 articles including phenotype and genotype description provided 9 genomic loci and 26 gene candidates underlying the co-occurrence of the two congenital defects: MSX1, PAX9, IRF6, TP63, KMT2D, KDM6A, SATB2, TBX22, TGFα, TGFß3, TGFßR1, TGFßR2, FGF8, FGFR1, KISS1R, WNT3, WNT5A, CDH1, CHD7, AXIN2, TWIST1, BCOR, OFD1, PTCH1, PITX2, and PVRL1. The molecular pathways, cellular functions, tissue-specific expression and disease association were investigated using publicly accessible databases (EntrezGene, UniProt, OMIM). The Gene Ontology terms of the biological processes mediated by the candidate genes were used to cluster them using the GOTermMapper (Lewis-Sigler Institute, Princeton University), speculating on six super-clusters: (a) anatomical development, (b) cell division, growth and motility, (c) cell metabolism and catabolism, (d) cell transport, (e) cell structure organization and (f) organ/system-specific processes. This review aims to increase the knowledge on the mechanisms underlying the co-occurrence of tooth agenesis and orofacial clefts, to pave the way for improving targeted (prenatal) molecular diagnosis and finally to reflect on therapeutic or ultimately preventive strategies for these disabling conditions in the future.
Assuntos
Anodontia/genética , Encéfalo/anormalidades , Fenda Labial/genética , Fissura Palatina/genética , Estudos de Associação Genética , Anodontia/fisiopatologia , Encéfalo/fisiopatologia , Fenda Labial/fisiopatologia , Fissura Palatina/fisiopatologia , Regulação da Expressão Gênica/genética , Ontologia Genética , Genótipo , Humanos , Especificidade de Órgãos , Fenótipo , Biossíntese de Proteínas/genéticaRESUMO
The physiology of masseter muscles is known to change in response to functional demands, but the effect on the satellite cell (SC) population is not known. In this study, the hypothesis is tested that a decreased functional demand of the masseter muscle causes a reduction of SCs. To this end, twelve 5-week-old male Sprague-Dawley rats were put on a soft diet (SD, n = 6) or a hard diet (HD, n = 6) and sacrificed after 14 days. Paraffin sections of the superficial masseter and the m. digastricus (control muscle) were stained with haematoxylin and eosin for tissue survey and with anti-myosin heavy chain (MHC) for slow and fast fibres. Frozen sections of both muscles were double-stained for collagen type IV and Pax7. Slow MHC fibres were equally distributed in the m. digastricus but only localized in a small area of the m. masseter. No differences between HD or SD for the m. digastricus were found. The m. masseter had more SCs per fibre in HD than in SD (0.093 ± 0.007 and 0.081 ± 0.008, respectively; P = 0.027). The m. masseter had more fibres per surface area than the m. digastricus in rats with an SD group (758.1 ± 101.6 and 568.4 ± 85.6, P = 0.047) and a HD group (737.7 ± 32.6 and 592.2 ± 82.2; P = 0.007). The m. digastricus had more SCs per fibre than the m. masseter in the SD group (0.094 ± 0.01 and 0.081 ± 0.008; P = 0.039). These results suggest that reduced masseter muscle function is related to a lower number of SCs. Reduced muscle function might decrease microdamage and hence the requirement of SCs in the muscle fibres.
Assuntos
Músculo Masseter/fisiologia , Células Satélites de Músculo Esquelético/fisiologia , Animais , Contagem de Células , Colágeno Tipo IV/metabolismo , Dieta , Masculino , Músculo Masseter/citologia , Músculo Masseter/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Músculos do Pescoço/citologia , Músculos do Pescoço/metabolismo , Fator de Transcrição PAX7/metabolismo , Ratos Sprague-DawleyRESUMO
In the literature many different mutations of the WNT10A-gene have been described in relation to the prevalence of tooth agenesis. Such mutations can result in strongly divergent phenotypes. Clinically a single phenotype can lead to either simple hypodontia or to comprehensive syndromatic disorders. Both the Schöpf-Schulz-Passarge syndrome (SPSS) and odonto-onycho-dermal dysplasia (OODD) as well as isolated tooth agenesis have been associated with mutations of this gene. If the WNT10A-gene were to be included in DNA-tests, it has been predicted that 70% of the cases of isolated hypodontia could be explained by a WNT10A-gene mutation. An analysis of all reported cases in the research literature shows that patients with a mutation in both alleles always show a phenotype. More than half of them also have, in addition to hypodontia, clinical disorders in other ectodermal tissue. When only one allele is affected, there is a 41.3% chance that he or she will be asymptomatic.
RESUMO
Solitary Median Maxillary Central Incisor syndrome is a rare condition (prevalence 1:50,000), with the characteristic dental feature of a solitary central incisor in the maxilla, positioned exactly in the midline. This single incisor is symmetrical and can be present in the deciduous as well as in the permanent dentition. The syndrome can occur as a mild form of the broad holoprosencephaly-spectrum, but can also be associated with other characteristics. The etiology is still largely unknown, but the syndrome is probably based especially on genetic causes. Early recognition of the syndrome is of great importance for establishing the diagnosis, for additional investigation, for possible treatment of associated anomalies and for the correct advice concerning the risk of inheritance of severe congenital birth defects, related to holoprosencephaly. Dentists and orthodontists can play an important role in this regard and should therefore be able to recognise the clinical features of this condition and know how to refer a patient for further diagnostic counselling.
Assuntos
Holoprosencefalia/complicações , Incisivo/anormalidades , Anormalidades Dentárias/etiologia , Anormalidades Múltiplas , Holoprosencefalia/diagnóstico , Humanos , Maxila , Síndrome , Anormalidades Dentárias/genéticaRESUMO
In the tooth eruption mechanism, various disturbances can appear as a result of gene mutations, a consequence of which can be that tooth eruption does not occur. There are 5 syndromes which involve the complete failure of several or even all teeth to erupt, specifically: cleidocranial dysplasia, Gardner's syndrome, osteopetrosis, mucopolysaccharidosis and GAPO syndrome. Some are very rare and will seldom be encountered in a dental practice, but they show how vulnerable the tooth eruption mechanism is. Dentists are generally the ones who identify a tooth eruption problem in a patient. Since syndromes can be associated with other disorders, additional investigation by a clinical geneticist is always important when a syndrome is suspected.
Assuntos
Erupção Dentária/genética , Erupção Dentária/fisiologia , Dente não Erupcionado/genética , Alopecia/genética , Alopecia/fisiopatologia , Anodontia/genética , Anodontia/fisiopatologia , Displasia Cleidocraniana/genética , Displasia Cleidocraniana/fisiopatologia , Síndrome de Gardner/genética , Síndrome de Gardner/fisiopatologia , Transtornos do Crescimento/genética , Transtornos do Crescimento/fisiopatologia , Humanos , Mucopolissacaridoses/genética , Mucopolissacaridoses/fisiopatologia , Atrofias Ópticas Hereditárias/genética , Atrofias Ópticas Hereditárias/fisiopatologia , Osteopetrose/genética , Osteopetrose/fisiopatologiaRESUMO
Bisphosphonates are used in the treatment of various diseases which are associated with a disturbance of the balance between bone apposition and degradation. The most important complication of bisphosphonate use is osteonecrosis of the jaw. Certain components of an orthodontic treatment plan, such as the extraction of 1 or more teeth, are important risk factors in developing this complication. In addition to the desired effects on the bone metabolism, bisphosphonates may delay tooth eruption and inhibit or block orthodontic tooth movement. Nevertheless, case studies suggest that orthodontic treatment is possible despite the use of bisphosphonates. However, it is recommended to avoid orthodontic treatment unless this is strictly indicated.
Assuntos
Conservadores da Densidade Óssea/efeitos adversos , Difosfonatos/efeitos adversos , Doenças Maxilomandibulares/induzido quimicamente , Ortodontia , Osteonecrose/induzido quimicamente , Mobilidade Dentária/induzido quimicamente , Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Humanos , Doenças Maxilomandibulares/prevenção & controle , Osteonecrose/prevenção & controle , Osteoporose/tratamento farmacológico , Fatores de Risco , Mobilidade Dentária/prevenção & controleRESUMO
The aim of this study was to determine the amount of deviation in nasolabial shape in patients with a cleft compared with an average non-cleft face, and to assess whether this difference is related to nasolabial aesthetics. Three-dimensional stereophotogrammetric images of 60 patients with a unilateral cleft were used. To quantify shape differences, four average non-cleft faces were constructed from stereophotogrammetric images of 141 girls and 60 boys. Three-dimensional shape differences were calculated between superimposed cleft faces and the average non-cleft face for the same sex and age group. Nasolabial aesthetics were rated with the modified Asher-McDade Aesthetic Index using a visual analogue scale (VAS). Mean VAS scores ranged from 51.44 to 60.21 for clefts, with lower aesthetic ratings associated with increasing cleft severity. Shape differences were found between cleft faces and the average non-cleft face. No relationship was found for the VAS, age, and sex, except that a lower VAS was related to a higher nose and lip distance between the superimposed cleft and average non-cleft faces for nasal profile (P= 0.02), but the explained variance was low (R2=0.066). In conclusion, except for nasal profile, nasolabial aesthetics were not influenced by the extent of shape differences from the average non-cleft face.
Assuntos
Fenda Labial , Fissura Palatina , Estética Dentária , Feminino , Humanos , Imageamento Tridimensional , Masculino , NarizRESUMO
OBJECTIVE: To determine the relationship between trisomies 13, 18, and 21 and craniofacial malformations detected by prenatal sonography. DESIGN: During a 29-year period (1976 through 2004), prenatal sonographic findings of 69 fetuses with trisomy 13; 171 fetuses with trisomy 18; 302 fetuses with trisomy 21; and 17 fetuses with other trisomies were evaluated retrospectively, after fetal karyotype identification. Sonographic findings were compared with autopsy results in 209 patients (trisomy 13, n=39; trisomy 18, n=64; and trisomy 21, n=106). RESULTS: For trisomy 13, cleft deformities were detected prenatally in 65.2%, and of the 39 cases with pathological information, 76.9% were found to have a cleft deformity. Ocular and orbital abnormalities were found in 28%. Malformations of the jaws and abnormal profiles were more frequently diagnosed postnatally than prenatally. For trisomy 18, abnormal profiles (41.5%) and ear abnormalities (5.3%) were the most noticeable ultrasound markers, next to abnormalities of the neurocranium (36.8%) and cranial bone configuration (21.6%). Dysmorphisms of the eye, ear, or nose were detected more frequently in autopsy cases. For trisomy 21, ultrasound showed an aberrant shape of the skull in 14.2% of fetuses. In general, the ocular-orbital and nasal abnormalities in fetuses with trisomy 18 or 21 were more evident in pathological examination than in prenatal ultrasound imaging. CONCLUSIONS: Facial anomalies are common in the major trisomies, and their prenatal sonographic identification should be improved. The above-mentioned facial anomalies provide sufficient reason to consider performing cytogenic evaluation.
Assuntos
Cromossomos Humanos 13-15/genética , Cromossomos Humanos 16-18/genética , Cromossomos Humanos 21-22 e Y/genética , Anormalidades Craniofaciais/diagnóstico por imagem , Anormalidades Craniofaciais/genética , Anormalidades Maxilofaciais/diagnóstico por imagem , Anormalidades Maxilofaciais/genética , Trissomia/patologia , Ultrassonografia Pré-Natal , Adulto , Amniocentese , Autopsia , Cromossomos Humanos 13-15/diagnóstico por imagem , Cromossomos Humanos 16-18/diagnóstico por imagem , Cromossomos Humanos 21-22 e Y/diagnóstico por imagem , Anormalidades Craniofaciais/patologia , Feminino , Marcadores Genéticos , Idade Gestacional , Humanos , Recém-Nascido , Cariotipagem , Masculino , Idade Materna , Anormalidades Maxilofaciais/patologia , Fenótipo , Estudos Retrospectivos , Crânio/anormalidadesRESUMO
Valproic acid (VPA) is an anti-epileptic drug known to cause congenital craniofacial abnormalities, including orofacial clefts (OFC). The exact mechanisms by which VPA leads to craniofacial skeletal malformations are poorly understood. In this study, we investigated the effects of VPA on cartilage and bone formation in the zebrafish larval head during 1-13 hpf (early) and 25-37 hpf (late) development in which cranial neural crest cells (CNCCs) arise and then proliferate and differentiate, respectively. Double-staining for cartilage and bone at 5 dpf revealed that VPA reduced cartilage and bone formation in a dose-dependent manner after both early or late exposure. Several different CNCC-derived cartilage and bone elements were affected in both groups. In the early group (100 µM VPA), the posterior head length and the ethmoid plate were reduced in length (both p < 0.01), while mineralization of 4 out of 9 bone elements was often lacking (all p < 0.01). In the late group (100 µM VPA), also the posterior head length was reduced as well as the length of the ceratohyals (both p < 0.01). Similar to early exposure, mineralization of 3 out of 9 bone elements was often lacking (all p < 0.01). These results indicate that both CNCC formation (early) and differentiation (late) are hampered by VPA treatment, of which the consequences for bone and cartilage formation are persistent at 5 dpf. Indeed, we also found that the expression of several genes related to cartilage and bone was upregulated at 5 dpf. These data indicate a compensatory reaction to the lack of cartilage and bone. Altogether, VPA seems to induce craniofacial malformations via disturbed CNCC function leading to defects in cartilage and bone formation.
Assuntos
Cartilagem/anormalidades , Crânio/anormalidades , Ácido Valproico/farmacologia , Proteínas de Peixe-Zebra/genética , Animais , Cartilagem/efeitos dos fármacos , Cartilagem/crescimento & desenvolvimento , Cartilagem/patologia , Diferenciação Celular/efeitos dos fármacos , Condrogênese/efeitos dos fármacos , Condrogênese/genética , Fenda Labial/induzido quimicamente , Fenda Labial/genética , Fenda Labial/fisiopatologia , Fissura Palatina/induzido quimicamente , Fissura Palatina/genética , Fissura Palatina/fisiopatologia , Embrião não Mamífero , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Cabeça/anormalidades , Cabeça/fisiopatologia , Humanos , Larva/efeitos dos fármacos , Larva/genética , Larva/crescimento & desenvolvimento , Crista Neural/efeitos dos fármacos , Crista Neural/crescimento & desenvolvimento , Crista Neural/patologia , Crânio/crescimento & desenvolvimento , Ácido Valproico/efeitos adversos , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimentoAssuntos
Catarata/congênito , Defeitos dos Septos Cardíacos/genética , Defeitos dos Septos Cardíacos/patologia , Microftalmia/genética , Microftalmia/patologia , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Catarata/genética , Catarata/patologia , Códon sem Sentido/genética , Feminino , Humanos , Lactente , Mutação de Sentido Incorreto/genética , Adulto JovemAssuntos
Assistência Odontológica para Crianças/tendências , Dente não Erupcionado/genética , Criança , Pré-Escolar , Previsões , Humanos , Erupção Dentária/genética , Erupção Dentária/fisiologia , Erupção Ectópica de Dente/genética , Erupção Ectópica de Dente/reabilitação , Dente não Erupcionado/diagnósticoRESUMO
Craniofacial development is tightly regulated and therefore highly vulnerable to disturbance by genetic and environmental factors. Fibroblast growth factors (FGFs) direct migration, proliferation and survival of cranial neural crest cells (CNCCs) forming the human face. In this study, we analyzed bone and cartilage formation in the head of five dpf fgf8ati282 zebrafish larvae and assessed gene expression levels for 11 genes involved in these processes. In addition, in situ hybridization was performed on 8 and 24â hours post fertilization (hpf) larvae (fgf8a, dlx2a, runx2a, col2a1a). A significant size reduction of eight out of nine craniofacial cartilage structures was found in homozygous mutant (6-36%, P<0.01) and heterozygous (7-24%, P<0.01) larvae. Also, nine mineralized structures were not observed in all or part of the homozygous (0-71%, P<0.0001) and heterozygous (33-100%, P<0.0001) larvae. In homozygote mutants, runx2a and sp7 expression was upregulated compared to wild type, presumably to compensate for the reduced bone formation. Decreased col9a1b expression may compromise cartilage formation. Upregulated dlx2a in homozygotes indicates impaired CNCC function. Dlx2a expression was reduced in the first and second stream of CNCCs in homozygous mutants at 24â hpf, as shown by in situ hybridization. This indicates an impairment of CNCC migration and survival by fgf8 mutation.
RESUMO
Although the molecular cascades that control craniofacial development are still largely unknown, the generation of mutant animal models and the identification of gene mutations that cause human craniofacial syndromes have recently given significant insight into how the unique structure of the head develops. Craniofacial structures are formed from the prechordal mesoderm, the craniofacial ectoderm as well as the neural crest cells which develop on the dorsal side of the neural tube. Normal craniofacial morphology as well as normal (in number and in morphology) tooth organs develop as a consequence of complex interactions between these embryonic tissues. A series of inductive and reciprocal signals between the epithelium and mesenchyme determine the growth, the form and the ultimate differentiation of tissues and organs. Genetic research has shown the involvement of numerous developmental genes encoding a variety of transcription factors, growth factors and receptors. Mutations have been associated with, among others, non-syndromal forms of cleft palate, agenesis of tooth organs and abnormalities in the cranial bones.
Assuntos
Ossos Faciais/embriologia , Odontogênese/genética , Odontogênese/fisiologia , Transdução de Sinais , Crânio/embriologia , Animais , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Movimento Celular , Modelos Animais de Doenças , Ectoderma/embriologia , Ectoderma/crescimento & desenvolvimento , Ossos Faciais/crescimento & desenvolvimento , Humanos , Mesoderma/embriologia , Mesoderma/crescimento & desenvolvimento , Crista Neural/embriologia , Crista Neural/crescimento & desenvolvimento , Crânio/crescimento & desenvolvimentoRESUMO
Non-syndromal orofacial clefts are congenital anomalies with a high incidence of heterogeneous origin. The condition is usually multifactorially determined, caused by interaction between multiple genetic and environmental factors. So far, only a few causal factors have been identified. Even in genetically identical individuals like monozygotic twins, the orofacial cleft is usually not fully concordant. As an illustration of non-syndromal orofacial clefts, monozygotic twin brothers with orofacial clefts which are not fully concordant are presented.
Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Criança , Pré-Escolar , Fenda Labial/etiologia , Fissura Palatina/etiologia , Doenças em Gêmeos , Meio Ambiente , Predisposição Genética para Doença , Humanos , Masculino , Gêmeos MonozigóticosRESUMO
Four patients with a Class II/1 malocclusion were treated. Despite their common malocclusion, the 4 patients had a different skeletal and dentofacial structure, which resulted in four different treatments. Whether treatment is indicated and which treatment is preferable depends on many factors, such as expected jaw growth, the possibility of jaw adaptation, the motivation of the patient and his or her parents and psychological factors. In the case of children and young adolescents a Class II/1 malocclusion can be treated with orthopaedic appliances, in which case natural growth and adaptation mechanisms of the face and jaw are exercised in the correction. In treating these 4 patients, both functional and extra-oral orthopaedic appliances were used.
Assuntos
Má Oclusão Classe II de Angle/reabilitação , Ortodontia Corretiva/instrumentação , Ortodontia Corretiva/métodos , Aparelhos Ativadores , Adolescente , Criança , Oclusão Dentária , Humanos , Masculino , Aparelhos Ortodônticos , Resultado do TratamentoRESUMO
In dentistry 3 aspects may lead to an improvement in the quality of life: pain reduction, aesthetic adjustments, and improvement of masticatory performance. Only the improvement of masticatory performance can be assessed objectively. Althougn orthodontists often claim that they improve masticatory performance, they seldom initiate treatment on the basis of functional limitations. Patients also often express the expectation that orthodontic treatment will improve their oral functions. Chewing is dependent on various anatomical, physiological and physical factors. The combination of all of these factors can reduce food particles to a greater or lesser extent. The magnitude of food reduction is known as masticatory performance. The masticatory performance is related to quality of life since it influences food selection, the quality of digestion, and the experience or enjoyment of eating. The smaller food particles are the easier will be the subsequent enzymatic food digestion during the later phases of digestion. Because it is clear that malocclusions cause functional limitations, it is concluded that orthodontists should integrate functional goals in their treatments in order to improve the quality of life of their patients.
Assuntos
Má Oclusão/complicações , Mastigação/fisiologia , Digestão/fisiologia , Ingestão de Alimentos/fisiologia , Humanos , Tamanho da Partícula , Qualidade de VidaRESUMO
Common variants in interferon regulatory factor 6 ( IRF6) have been associated with nonsyndromic cleft lip with or without cleft palate (NSCL/P) as well as with tooth agenesis (TA). These variants contribute a small risk towards the 2 congenital conditions and explain only a small percentage of heritability. On the other hand, many IRF6 mutations are known to be a monogenic cause of disease for syndromic orofacial clefting (OFC). We hypothesize that IRF6 mutations in some rare instances could also cause nonsyndromic OFC. To find novel rare variants in IRF6 responsible for nonsyndromic OFC and TA, we performed targeted multiplex sequencing using molecular inversion probes (MIPs) in 1,072 OFC patients, 67 TA patients, and 706 controls. We identified 3 potentially pathogenic de novo mutations in OFC patients. In addition, 3 rare missense variants were identified, for which pathogenicity could not unequivocally be shown, as all variants were either inherited from an unaffected parent or the parental DNA was not available. Retrospective investigation of the patients with these variants revealed the presence of lip pits in one of the patients with a de novo mutation suggesting a Van der Woude syndrome (VWS) phenotype, whereas, in other patients, no lip pits were identified.
Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Fatores Reguladores de Interferon/genética , Anormalidades Múltiplas/genética , Cistos/genética , Predisposição Genética para Doença/genética , Humanos , Lábio/anormalidades , Mutação/genética , Mutação de Sentido Incorreto/genética , Análise de Sequência de DNARESUMO
BACKGROUND: KBG syndrome is a rare disorder characterized by intellectual disability and associated with macrodontia of the upper central incisors, specific craniofacial findings, short stature and skeletal anomalies. Genetic corroboration of a clinical diagnosis has been possible since 2011, upon identification of heterozygous mutations in or a deletion of the ANKRD11 gene. METHODS: We summarized the height data of 14 adults and 18 children (age range 2-16 years) with a genetically confirmed diagnosis of KBG syndrome. Two of these children were treated with growth hormones. RESULTS: Stature below the 3rd centile or -1.88 standard deviation score (SDS) was observed in 72% of KBG children and in 57% of KBG adults. Height below -2.50 SDS was observed in 62% of KBG children and in 36% of KBG adults. The mean SDS of height in KBG children was -2.56 and in KBG adults -2.17. Two KBG children on growth hormone therapy increased their height by 0.6 and 1 SDS within 1 year, respectively. The former also received a gonadotropin-releasing hormone agonist due to medical necessity. CONCLUSION: Short stature is prevalent in KBG syndrome, and spontaneous catch-up growth beyond childhood appears limited. Growth hormone intervention in short KBG children is perceived as promising.
Assuntos
Doenças do Desenvolvimento Ósseo/complicações , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Deficiência Intelectual/complicações , Anormalidades Dentárias/complicações , Anormalidades Múltiplas , Criança , Fácies , Transtornos do Crescimento/complicações , Humanos , Masculino , Resultado do TratamentoRESUMO
Hemifacial microsomia (HFM) is a congenital disorder marked by facial asymmetry. Whether facial asymmetry accounts for asymmetrical dental development is unknown. There are few data on dental development relative to mandibular development or severity of HFM, or on development over time. We hypothesized that when mandibular development was severely disturbed, local dental development was also affected. We compared dental development scores between affected and non-affected mandibular sides in patients with HFM (n = 84) and compared these data with those collected from Dutch control children (n = 451). Logistic functions were constructed for dental age over time for all four Pruzansky/Kaban types. The results showed a tendency toward delayed dental development in Pruzansky/Kaban types IIb and III at younger ages. The temporary delay of tooth formation in patients with severe forms of HFM and the distribution of agenic teeth suggest an interaction between mandibular and dental development.