RUNX2-related metaphyseal dysplasia with maxillary hypoplasia: A rare skeletal disorder resembling SFRP4-related Pyle disease.

Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly (MDMHB) is an ultra-rare skeletal dysplasia caused by heterozygous intragenic RUNX2 duplications, comprising either exons 3 to 5 or exons 3 to 6 of RUNX2. In this study, we describe a 14-year-old Belgian boy with metaphyseal dysplasia with maxillary hypoplasia but without brachydactyly. Clinical and radiographic examination revealed mild facial dysmorphism, dental anomalies, enlarged clavicles, genua valga and metaphyseal flaring and thin cortices with an osteoporotic skeletal appearance. Exome sequencing led to the identification of a de novo heterozygous tandem duplication within RUNX2, encompassing exons 3 to 7. This duplication is larger than the ones previously reported in MDMHB cases since it extends into the C-terminal activation domain of RUNX2. We review previously reported cases with MDMHB and highlight the resemblance of this disorder with Pyle disease, which may be explained by intersecting molecular pathways between RUNX2 and sFRP4. This study expands our knowledge on the genotypic and phenotypic characteristics of MDMHB and the role of RUNX2 in rare bone disorders.

Impact of Mechanical Strain and Nicotinamide on RUNX2-Deficient Osteoblast Mimicking Cleidocranial Dysplasia.

Cleidocranial dysplasia (CCD) is a rare genetic defect caused by a heterozygous mutation of runt-related transcription factor 2 (RUNX2), which is important for osteoblast and skeletal development. RUNX2-deficiency causes extra- and intra-oral malformations that often require orthodontic treatment. Nicotinamide (NAM) affects bone remodelling processes. As these are crucial for orthodontic therapy, NAM could improve orthodontic treatment in CCD patients. This study investigates the effect of NAM in control and RUNX2-deficient osteoblasts under mechanical strain mimicking orthodontic treatment. First, the optimal NAM concentration and the differences in the expression profile of control and RUNX2-deficient osteoblasts were determined. Subsequently, osteoblasts were exposed to tensile and compressive strain with and without NAM, and the expression of genes critically involved in bone remodelling was investigated. NAM increased the expression of bone remodelling genes. RUNX2-deficient osteoblasts expressed more receptor activator of NFkB ligand (RANKL) and interleukin-6 (IL6), but less colony-stimulating factor-1 (CSF1). Most of the positive effects of NAM on bone remodelling genes were impaired by mechanical loading. In conclusion, NAM stimulated osteoblast differentiation by increasing the expression of RUNX2 and regulated the expression of osteoclastogenic factors. However, the positive effects of NAM on bone metabolism were impaired by mechanical loading and RUNX2 deficiency.

Peptidylarginine deiminase 2 plays a key role in osteogenesis by enhancing RUNX2 stability through citrullination.

Peptidylarginine deiminase (PADI) 2 catalyzes the post-translational conversion of peptidyl-arginine to peptidyl-citrulline in a process called citrullination. However, the precise functions of PADI2 in bone formation and homeostasis remain unknown. In this study, our objective was to elucidate the function and regulatory mechanisms of PADI2 in bone formation employing global and osteoblast-specific Padi2 knockout mice. Our findings demonstrate that Padi2 deficiency leads to the loss of bone mass and results in a cleidocranial dysplasia (CCD) phenotype with delayed calvarial ossification and clavicular hypoplasia, due to impaired osteoblast differentiation. Mechanistically, Padi2 depletion significantly reduces RUNX2 levels, as PADI2-dependent stabilization of RUNX2 protected it from ubiquitin-proteasomal degradation. Furthermore, we discovered that PADI2 binds to RUNX2 and citrullinates it, and identified ten PADI2-induced citrullination sites on RUNX2 through high-resolution LC-MS/MS analysis. Among these ten citrullination sites, the R381 mutation in mouse RUNX2 isoform 1 considerably reduces RUNX2 levels, underscoring the critical role of citrullination at this residue in maintaining RUNX2 protein stability. In conclusion, these results indicate that PADI2 plays a distinct role in bone formation and osteoblast differentiation by safeguarding RUNX2 against proteasomal degradation. In addition, we demonstrate that the loss-of-function of PADI2 is associated with CCD, thereby providing a new target for the treatment of bone diseases.

Functional consequences of C-terminal mutations in RUNX2.

Cleidocranial dysplasia (CCD) is a genetic disorder caused by mutations in the RUNX2 gene, affecting bone and teeth development. Previous studies focused on mutations in the RUNX2 RHD domain, with limited investigation of mutations in the C-terminal domain. This study aimed to investigate the functional consequences of C-terminal mutations in RUNX2. Eight mutations were analyzed, and their effects on transactivation activity, protein expression, subcellular localization, and osteogenic potential were studied. Truncating mutations in the PST region and a missense mutation in the NMTS region resulted in increased transactivation activity, while missense mutations in the PST showed activity comparable to the control. Truncating mutations produced truncated proteins, while missense mutations produced normal-sized proteins. Mutant proteins were mislocalized, with six mutant proteins detected in both the nucleus and cytoplasm. CCD patient bone cells exhibited mislocalization of RUNX2, similar to the generated mutant. Mislocalization of RUNX2 and reduced expression of downstream genes were observed in MSCs from a CCD patient with the p.Ser247Valfs*3 mutation, leading to compromised osteogenic potential. This study provides insight into the functional consequences of C-terminal mutations in RUNX2, including reduced expression, mislocalization, and aberrant transactivation of downstream genes, contributing to the compromised osteogenic potential observed in CCD.

Restoration of a Maxillary Anterior Defect With a Rotational Path Removable Partial Denture: Clinical Report of a Patient With Cleidocranial Dysplasia.

Cleidocranial dysplasia (CCD) is an uncommon genetic condition that affects teeth and bones, potentially leading to delayed ossification, dental abnormalities, and craniofacial changes, which can be treated through a combination of orthodontic and prosthodontic therapies. This case report describes the diagnostic evaluation, laboratory procedures, and prosthodontic treatment for a patient with CCD who had two missing maxillary anterior teeth. Following occlusal device therapy and the achievement of occlusal equilibration, restorative treatment was performed, consisting of a maxillary central incisor survey crown, rest seat preparations, and a lateral rotational path removable partial denture (RPD). The article highlights the value of this type of RPD as an alternative restoration for the replacement of missing anterior teeth.

Amyloid-mediated remineralization for tooth hypoplasia of cleidocranial dysplasia.

Introduction: Cleidocranial dysplasia (CCD) is an autosomal-dominant, heritable skeletal and dental disease, involving hypoplastic clavicles, defective ossification of the anterior fontanelle, dentin and enamel hypoplasia, and supernumerary teeth, which can seriously affect the oral and mental health of patients. Amyloid-like protein aggregation, which is established by lysozyme conjugated with polyethylene glycol (Lyso-PEG), forms a mineralized nanofilm layer on a healthy enamel surface. However, whether it can form a remineralization layer in dental tissues from CCD remains unclear. Methods: This study evaluated deciduous teeth from healthy individuals and a patient with CCD. Because pulp and dentin are functionally closely related, stem cells from human exfoliated deciduous teeth (SHED) from CCD patients and healthy individuals were collected to compare their biological properties. Results: The results found that deciduous teeth from patients with CCD exhibited dentin hypoplasia. In addition, the proliferative ability and osteogenic potential of SHED from patients with CCD were lower than those of control individuals. Finally, Lyso-PEG was applied to dentin from the CCD and control groups, showing a similar remineralization-induced effect on the dentin surfaces of the two groups. Conclusion: These results extend our understanding of the dentin and SHED of patients with CCD, exhibiting good caries-preventive capacity and good biocompatibility of Lyso-PEG, thus providing a novel dental therapy for CCD and patients with tooth hypoplasia.

Suspected Endodontic Failure in a Patient with Cleidocranial Dysplasia: A Case Report.

A patient's medical history and related dental manifestations can significantly contribute to confounding signs and symptoms leading to a diagnostic challenge. An 18-year-old female patient presented with persistent radiographic radiolucency associated with the apex of a previously treated tooth (tooth 9); asymptomatic apical periodontitis and endodontic failure were suspected. This report presents how a patient's condition of cleidocranial dysplasia had a profound effect on her dental history, which included the presence of multiple supernumerary teeth. Extensive surgical intervention during the patient's childhood was required to remove the supernumerary teeth, which resulted in an endodontic misdiagnosis in her adult life. After clinical and radiographic examination, the patient was diagnosed with a periapical scar. Periapical fibrous scars have a prevalence of between 2.5% and 12% and are a rare healing process with fibrous tissue after surgical and nonsurgical interventions. This report describes the diagnosis and pathophysiology of fibrous scars, including their risk factors and long-term monitoring approaches.

[Analysis of clinical phenotypes and genetic variants in two children with sporadic cleidocranial dysplasia].

OBJECTIVE: To explore the clinical phenotypes and genetic diagnosis of 2 sporadic cases for cleidocranial dysplasia. METHODS: The clinical data of two cases of CCD admitted to the Third Affiliated Hospital of Zhengzhou University on December 16, 2021 and December 9, 2021 were analyzed retrospectively, and the whole exome sequencing (WES), chromosome microarray analysis and copy number variation sequencing were performed. RESULTS: The main ultrasonographic findings of the fetus had included poorly calcified skull bones, budging of parieto-occipital area, compression and deformation of skull, and loss of nasal bone. The infant's clinical phenotypes included delayed closure of anterior fontanelle, recurrent respiratory tract infection, growth retardation, and clavicular hypoplasia. By WES analysis, the fetus was found to harbor a heterozygous c.911_914delinsTTT variant of the RUNX2 gene, whilst the infant was found to harbor a heterozygous c.1008delT variant of the RUNX2 gene. Both variants were verified by Sanger sequencing to have occurred de novo. CONCLUSION: For sporadic cases featuring cleidocranial dysplasia, prenatal ultrasonography is particularly important. Hypoplastic clavicle, skull calcification and nasal bone absence are the main features. Diagnosis should also be suspected for infants featuring growth retardation, recurrent respiratory tract infections and clavicular dysplasia. The identification of the c.911_914delinsTTT and c.1008delT variants of the RUNX2 gene has facilitated genetic counseling and prenatal diagnosis, and also expanded the mutational spectrum of the RUNX2 gene.

Inhibition of miR338 rescues cleidocranial dysplasia in Runx2 mutant mice partially via the Hif1a-Vegfa axis.

Haploinsufficiency of Runt-related transcription factor-2 (RUNX2) is responsible for cleidocranial dysplasia (CCD), a rare hereditary disease with a range of defects, including delayed closure of the cranial sutures and short stature. Symptom-based treatments, such as a combined surgical-orthodontic approach, are commonly used to treat CCD patients. However, there have been few reports of treatments based on Runx2-specific regulation targeting dwarfism symptoms. Previously, we found that the miR338 cluster, a potential diagnostic and therapeutic target for postmenopausal osteoporosis, could directly target Runx2 during osteoblast differentiation in vitro. Here, we generated miR338-/-;Runx2+/- mice to investigate whether inhibition of miR338 could rescue CCD defects caused by Runx2 mutation in vivo. We found that the dwarfism phenotype caused by Runx2 haploinsufficiency was recovered in miR338-/-;Runx2+/- mice, with complete bone density restoration and quicker closure of fontanels. Single-cell RNA-seq analysis revealed that knockout of miR338 specifically rescued the osteoblast lineage priming ability of bone marrow stromal cells in Runx2+/- femurs, which was further confirmed by Osterix-specific conditional knockout of miR338 in Runx2+/- mice (OsxCre; miR338 fl/fl;Runx2+/-). Mechanistically, ablation of the miR338 cluster in Runx2+/- femurs directly rescued the Hif1a-Vegfa pathway in Runx2+/- osteoblasts, as proven by gene expression profiles and ChIP and Re-ChIP assays. Collectively, our data revealed the genetic interaction between Runx2 and the miR338 cluster during osteoblast differentiation and implied that the miR338 cluster could be a potential therapeutic target for CCD.

A novel single-base deletion of the RUNX Family Transcription Factor 2 gene associated with cleidocranial dysplasia.

Cleidocranial dysplasia (CCD) is a rare, autosomal dominant hereditary disorder characterized by skeletal malformations and dental abnormalities. The purpose of this study was to explore the functional role of a novel mutation in the pathogenesis of CCD. Genomic DNA was extracted from peripheral blood mononuclear cells collected from family members of a Chinese patient with CCD. An analysis of their RUNX Family Transcription Factor 2 (RUNX2) gene sequences was performed by PCR amplification and Sanger sequencing. The function of the mutant RUNX2 was studied by bioinformatics, real-time PCR, western blotting, and subcellular localization analysis. Sanger sequencing identified a novel single-base deletion (NM_001024630.4:c.132delG;NP_001019801.3: Val45Trpfs* 99) in the RUNX2 gene present in the Chinese patient with CCD. In vitro, functional studies showed altered protein localization and increased expression of mutant RUNX2 mRNA and mutant Runt-related transcription factor 2 (RUNX2). Luciferase reporter assay demonstrated that the novel RUNX2 mutations significantly increased the transactivation activity of RUNX2 on the osteocalcin gene promoter. In conclusion, we identified a patient with sporadic CCD carrying a novel deletion/frameshift mutation of the RUNX2 gene and performed screening and functional analyses to determine the cause of the CCD phenotype. This study provides new insights into the pathogenesis of CCD.3.

Altered phenotypes due to genetic interaction between the mouse phosphoinositide biosynthesis genes Fig4 and Pip4k2c.

Loss-of-function mutations of FIG4 are responsible for neurological disorders in human and mouse that result from reduced abundance of the signaling lipid PI(3,5)P2. In contrast, loss-of-function mutations of the phosphoinositide kinase PIP4K2C result in elevated abundance of PI(3,5)P2. These opposing effects on PI(3,5)P2 suggested that we might be able to compensate for deficiency of FIG4 by reducing expression of PIP4K2C. To test this hypothesis in a whole animal model, we generated triallelic mice with genotype Fig 4-/-, Pip4k2c+/-; these mice are null for Fig 4 and haploinsufficient for Pip4k2c. The neonatal lethality of Fig 4 null mice in the C57BL/6J strain background was rescued by reduced expression of Pip4k2c. The lysosome enlargement characteristic of Fig 4 null cells was also reduced by heterozygous loss of Pip4k2c. The data demonstrate interaction between these two genes, and suggest that inhibition of the kinase PIPK4C2 could be a target for treatment of FIG4 deficiency disorders such as Charcot-Marie-Tooth Type 4J and Yunis-Varón Syndrome.

Multidisciplinary prosthetic rehabilitation of an adult patient with cleidocranial dysplasia by using a rapid external distraction device: A clinical report.

The multidisciplinary treatment of a 41-year-old man with cleidocranial dysplasia is described. A rapid external distraction device was used to reposition the maxilla before the prosthodontic rehabilitation.

Heterozygous pathogenic variants involving CBFB cause a new skeletal disorder resembling cleidocranial dysplasia.

BACKGROUND: Cleidocranial dysplasia (CCD) is a rare skeletal dysplasia with significant clinical variability. Patients with CCD typically present with delayed closure of fontanels and cranial sutures, dental anomalies, clavicular hypoplasia or aplasia and short stature. Runt-related transcription factor 2 (RUNX2) is currently the only known disease-causing gene for CCD, but several studies have suggested locus heterogeneity. METHODS: The cohort consists of eight subjects from five unrelated families partially identified through GeneMatcher. Exome or genome sequencing was applied and in two subjects the effect of the variant was investigated at RNA level. RESULTS: In each subject a heterozygous pathogenic variant in CBFB was detected, whereas no genomic alteration involving RUNX2 was found. Three CBFB variants (one splice site alteration, one nonsense variant, one 2 bp duplication) were shown to result in a premature stop codon. A large intragenic deletion was found to delete exon 4, without affecting CBFB expression. The effect of a second splice site variant could not be determined but most likely results in a shortened or absent protein. Affected individuals showed similarities with RUNX2-related CCD, including dental and clavicular abnormalities. Normal stature and neurocognitive problems were however distinguishing features. CBFB encodes the core-binding factor ß subunit, which can interact with all RUNX proteins (RUNX1, RUNX2, RUNX3) to form heterodimeric transcription factors. This may explain the phenotypic differences between CBFB-related and RUNX2-related CCD. CONCLUSION: We confirm the previously suggested locus heterogeneity for CCD by identifying five pathogenic variants in CBFB in a cohort of eight individuals with clinical and radiographic features reminiscent of CCD.

Conservative orthodontic and multidisciplinary approaches for patients with cleidocranial dysplasia in late adolescence or young adulthood.

This case series describes conservative orthodontic and multidisciplinary approaches for treating two patients diagnosed with cleidocranial dysplasia in late adolescence and young adulthood. Most of the impacted permanent teeth erupted spontaneously within 3 to 4 years after surgical extraction of the deciduous and supernumerary teeth. The remaining unerupted permanent teeth were facilitated with traction or extracted followed by implantation or restoration. Repositioning of the maxilla and mandible via orthognathic surgery was also applied to correct skeletal and occlusal discrepancies and lead to satisfying results.

Analysis of clinical phenotypes and genetic variants in two children with sporadic cleidocranial dysplasia / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical phenotypes and genetic diagnosis of 2 sporadic cases for cleidocranial dysplasia.@*METHODS@#The clinical data of two cases of CCD admitted to the Third Affiliated Hospital of Zhengzhou University on December 16, 2021 and December 9, 2021 were analyzed retrospectively, and the whole exome sequencing (WES), chromosome microarray analysis and copy number variation sequencing were performed.@*RESULTS@#The main ultrasonographic findings of the fetus had included poorly calcified skull bones, budging of parieto-occipital area, compression and deformation of skull, and loss of nasal bone. The infant's clinical phenotypes included delayed closure of anterior fontanelle, recurrent respiratory tract infection, growth retardation, and clavicular hypoplasia. By WES analysis, the fetus was found to harbor a heterozygous c.911_914delinsTTT variant of the RUNX2 gene, whilst the infant was found to harbor a heterozygous c.1008delT variant of the RUNX2 gene. Both variants were verified by Sanger sequencing to have occurred de novo.@*CONCLUSION@#For sporadic cases featuring cleidocranial dysplasia, prenatal ultrasonography is particularly important. Hypoplastic clavicle, skull calcification and nasal bone absence are the main features. Diagnosis should also be suspected for infants featuring growth retardation, recurrent respiratory tract infections and clavicular dysplasia. The identification of the c.911_914delinsTTT and c.1008delT variants of the RUNX2 gene has facilitated genetic counseling and prenatal diagnosis, and also expanded the mutational spectrum of the RUNX2 gene.

Detection and diagnosis of cleidocranial dysplasia by panoramic radiography: a retrospective study.

BACKGROUND: Cleidocranial dysplasia (CCD) is a rare and underdiagnosed congenital disorder in dentistry. The purpose of this study was to illustrate and quantify the maxillofacial bone abnormalities detected on panoramic radiographs from a relatively large retrospective case series and to provide a series of diagnostic references for dentists to indicate the presence of disease and help in making an early and accurate diagnosis. METHODS: The dental panoramic radiographs of thirty CCD patients aged 11 to 45 years (18 males and 12 females) were examined retrospectively. The dentition states, including supernumerary teeth and impacted teeth, were recorded. Twelve quantified measurements were adopted to determine the abnormalities of maxillofacial bones, including the degree of the zygomatic arch downward bend, bicondylar breadth, ramal height, mandibular height, mandibular aspect ratio, mandibular body height, condylar height, coronoid height, distance between the coronoid process and the condyle, bigonial width, gonial angle and best-fit gonial circle diameter. The Wilcoxon rank-sum test was used to compare the findings of the CCD patients with those of their matched controls (n = 300). RESULTS: Supernumerary teeth were detected in 27 patients (90.0%), and all 30 patients presented impacted teeth. Compared to the matched controls, the CCD patients had a significantly larger degree of zygomatic arch downward bend (ZAD), a larger diameter of the best-fit gonial circle (BGC), and a shorter distance between the coronoid process and the condyle (DCC) in panoramic radiographs (P < 0.001). According to the reference cutoff values established from the 5th or 95th percentile of the measurements in the control group, ZAD higher than 6.90 mm, DDC less than 22.37 mm and BGC higher than 52.41 mm were significantly associated with the CCD features identified. Other panoramic measurements were not significantly different between the two groups. CONCLUSIONS: Panoramic radiographs had great value in the diagnosis of CCD. In this study, we identified some dental and maxillofacial features on panoramic radiographs from a relatively large retrospective case series of CCD. A series of reliable quantitative indicators were provided for dentists that can indicate the presence of disease and improve the diagnostic specificity.

Chloroquine corrects enlarged lysosomes in FIG4 null cells and reduces neurodegeneration in Fig4 null mice.

Loss-of-function mutations of FIG4 impair the biosynthesis of PI(3,5)P2 and are responsible for rare genetic disorders including Yunis-Varón Syndrome and Charcot-Marie-Tooth Disease Type 4 J. Cultured cells deficient in FIG4 accumulate enlarged lysosomes with hyperacidic pH, due in part to impaired regulation of lysosomal ion channels and elevated intra-lysosomal osmotic pressure. We evaluated the effects of the FDA approved drug chloroquine, which is known to reduce lysosome acidity, on FIG4 deficient cell culture and on a mouse model. Chloroquine corrected the enlarged lysosomes in FIG4 null cells. In null mice, addition of chloroquine to the drinking water slowed progression of the disorder. Growth and mobility were dramatically improved during the first month of life, and spongiform degeneration of the nervous system was reduced. The median survival of Fig4 null mice was increased from 4 weeks for untreated mutants to 8 weeks with chloroquine treatment (p < 0.009). Chloroquine thus corrects the lysosomal swelling in cultured cells and ameliorates Fig4 deficiency in vivo. The improved phenotype of mice with complete loss of Fig4 suggests that chloroquine could be beneficial FIG2 in partial loss-of-function disorders such as Charcot-Marie-Tooth Type 4 J.

[Analysis of clinical phenotype and genetic variant in a Chinese pedigree affected with cleidocranial dysplasia].

OBJECTIVE: To analyze the clinical features and pathogenic variant in a Chinese pedigree affected with cleidocranial dysplasia (CCD). METHODS: Clinical data of 8 patients from the pedigree was collected, including physical examination and X-ray images of head, face, spine, limbs, and mouth. Peripheral blood samples were collected from 6 affected members for the extraction of genomic DNA. The proband and other 3 patients were subjected to trio-whole exome sequencing. Candidate variant was verified by Sanger sequencing of the other 2 affected members from the pedigree. RESULTS: This pedigree has included 22 members (8 affected) from four generations. Genetic testing revealed that the proband has harbored a novel pathogenic variant of the RUNX2 gene [NM_001024630: c.1268_1277del (p.P425Afs*56)], which was inherited from her mother and carried by all affected members in the pedigree. The same variant was not detected among the unaffected members, suggesting co-segregation with the phenotype. CONCLUSION: The c.1268_1277del (p.P425Afs*56) variant of the RUNX2 gene probably underlay the pathogenesis of CCD in this pedigree. Genetic testing has facilitated the definite diagnosis and enabled prenatal diagnosis.

A Novel lncRNA Mediates the Delayed Tooth Eruption of Cleidocranial Dysplasia.

Delayed eruption of permanent teeth is a common symptom of cleidocranial dysplasia (CCD). Previous studies have focused on the anomaly of osteogenesis resulting from mutations in the Runt-related transcription factor-2 gene (RUNX2). However, deficiencies in osteoclastogenesis and bone resorption, and the epigenetic regulation mediated by long non-coding (lnc)RNAs in CCD remain to be elucidated. Here, a novel osteoclast-specific lncRNA (OC-lncRNA) was identified during the osteoclast differentiation of RAW 264.7 cells transfected with a RUNX2 mutation expression cassette. We further confirmed that OC-lncRNA positively regulated osteoclastogenesis and bone resorption. The OC-lncRNA promoted the expression of CXC chemokine receptor type 3 (CXCR3) by competitively binding to microRNA (miR)-221-5p. The CXCR3-CXC-motif chemokine ligand 10 (CXCL10) interaction and nuclear factor-κB constituted a positive feedback that positively regulated osteoclastogenesis and bone resorption. These results demonstrate that OC-lncRNA-mediated osteoclast dysfunction via the OC-lncRNA-miR-221-5p-CXCR3 axis, which is involved in the process of delayed tooth eruption of CCD.

RUNX2 Nonsense Mutation Associated with Cleidocranial Dysplasia with Unusual Dental Features.

Purpose: The purpose of this case report is to describe a RUNX2 nonsense mutation associated with cleidocranial dysplasia (CCD) with unusual dental features. The patient was a 12-year-old Brazilian girl who sought dental care due to over-retention of primary teeth and absence of erupted permanent teeth. Clinical and radiographic examinations revealed multiple impacted permanent teeth, a prominent cingulum of the permanent impacted maxillary incisors and enamel defects (hypoplasia and hypomineralization) in addition to skeletal abnormalities. No supernumerary teeth were present. The diagnostic hypothesis of CCD was raised and the patient was refer- red to the genetic medical service, where the diagnosis was cofirmed. After RUNX2 genetic screening, including polymerase chain reaction and sequencing of both DNA strands, a heterozygous nonsense mutation was identified in exon 2 (c.193 C>T [Q65X]). This article reports unusual dental features in a patient with CCD.