Prenatal diagnosis of cleidocranial dysplasia: Case report on two cases with a negative family history.

Introduction: Cleidocranial dysplasia (CCD) is a rare autosomal dominant skeletal dysplasia that presents with abnormalities in the craniofacial region, teeth, and clavicles and is linked to RUNX2 mutation. Prenatal diagnoses of CCD have rarely been reported, and most of these cases have a positive family history. Here we report two prenatally diagnosed CCD cases without a positive family history. We conducted a literature review to summarize the prenatal sonographic findings of CCD. Case reports: Case 1 (a 26-year-old woman): ultrasound at 13 weeks showed a thickened nuchal translucency with absent nasal bones and poor ossifications in the cranium and vertebrae. Genetic testing confirmed a frame shift deletion of RUNX2. Case 2 (a 27-year-old woman): ultrasound at 32 weeks showed potential fetal skeletal dysplasia, with inadequate skull ossification, mild ossified bilateral clavicles, and RUNX2 frameshift deletion mutation. Both cases were diagnosed with CCD and the parents chose pregnancy termination. Conclusion: These cases underscore the importance of sonographic examination for prenatal CCD diagnosis with a negative family history. By reviewing previous cases, we concluded that combining NB hypoplasia, clavicle and skull hypoplasia, and shortened long bones may be effective for early screening for CCD. Prenatal diagnosis is crucial for guiding medical decisions.

Three-dimensional evaluation of dental characteristics in patients with Cleidocranial dysplasia.

BACKGROUND: Cleidocranial dysplasia (CCD) is an autosomal dominant hereditary disorder. Besides skeletal abnormalities, CCD is often associated with dental complications, such as multiple supernumerary teeth and permanent teeth impaction or delayed eruption. METHODS: Supernumerary teeth of axial, sagittal and coronal CBCT view was characterized in detail and 3D image reconstruction was performed. Number and location of teeth, morphology of supernumerary teeth, positional relationship between supernumerary and adjacent permanent teeth, direction of supernumerary teeth in CCD patients were analyzed. RESULTS: The mean age of the 3 CCD patients in this study was 16.7 years. Among 36 supernumerary teeth, the majority of them were identified as apical side located and lingual side located. Normal orientation was the most common type in this study, followed by sagittal orientation, and horizontal orientation. Horizontal orientation teeth were all distributed in the mandible. Supernumerary teeth exhibited significantly shorter crown and dental-root lengths, as well as smaller crown mesiodistal and buccolingual diameters (P < 0.01). There was no difference in the number of supernumerary teeth between the maxilla and mandible, and the premolars region had the largest number of supernumerary teeth and the incisor region had the smallest number. CONCLUSIONS: This study compares number and location of teeth, morphology of supernumerary teeth, positional relationship between supernumerary and adjacent permanent teeth and direction of supernumerary teeth, this study also provides a reference for the comprehensive evaluation of CCD patients before surgery.

Familial Cleidocranial Dysplasia: A Diagnostic Challenge.

Cleidocranial dysplasia (CCD) is a rare genetic disorder affecting primarily the cranium, clavicle, and dental tissues. The expression of this disorder can vary widely in severity, even within the same family. Here we present a case report of an affected mother and son with classical manifestations of the disease.

New Genetic Variants of RUNX2 in Mexican Families Cause Cleidocranial Dysplasia.

Cleidocranial dysplasia (CCD) is an autosomal dominant skeletal dysplasia characterized by persistent open skull sutures with bulging calvaria, hypoplasia, or aplasia of clavicles permitting abnormal opposition of the shoulders; wide public symphysis; short middle phalanx of the fifth fingers; and vertebral, craniofacial, and dental anomalies. It is a rare disease, with a prevalence of 1-9/1,000,000, high penetrance, and variable expression. The gene responsible for CCD is the Runt-related transcription factor 2 (RUNX2) gene. We characterize the clinical, genetic, and bioinformatic results of four CCD cases: two cases within Mexican families with six affected members, nine asymptomatic individuals, and two sporadic cases with CCD, with one hundred healthy controls. Genomic DNA analyses of the RUNX2 gene were performed for Sanger sequencing. Bioinformatics tools were used to predict the function, stability, and structural changes of the mutated RUNX2 proteins. Three novel heterozygous mutations (c.651_652delTA; c.538_539delinsCA; c.662T>A) and a previously reported mutation (c.674G>A) were detected. In silico analysis showed that all mutations had functional, stability-related, and structural alterations in the RUNX2 protein. Our results show novel mutations that enrich the pool of RUNX2 gene mutations with CCD. Moreover, the proband 1 presented clinical data not previously reported that could represent an expanded phenotype of severe expression.

A novel de novo variant in the RUNX2 gene causes cleidocranial dysplasia in a Malian girl.

Key Clinical Message: Cleidocranial dysplasia (CCD) is a rare genetic skeletal disorder with only few cases reported in Africa, mostly based on clinical and radiological findings. We report the first case in Mali, caused by a novel de novo variant in the RUNX2 gene. Abstract: Cleidocranial dysplasia (CCD) is a rare autosomal dominant skeletal dysplasia characterized by an aplastic/hypoplastic clavicles, patent sutures and fontanels, dental abnormalities and a variety of other skeletal changes. We report a novel de novo variant in the RUNX2 gene causing a severe phenotype of CCD in a Malian girl.

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.

Cleidocranial Dysplasia: A Rare Case Report.

Cleidocranial dysplasia (CCD) is a rare hereditary disease of unknown etiology which was previously known as cleidocranial dysostosis. It usually follows an autosomal dominant mode of transmission with no predilection of genre or ethnic group. It is caused by a mutation of RUNX2, characterized by generalized dysplasia of the bones and teeth. Affected individuals have short stature, atypical facial features, and skeletal anomalies affecting mainly the skull and clavicle. The dental manifestations are mainly delayed exfoliation of the primary teeth and delayed eruption of the permanent teeth, with multiple impacted supernumeraries, and the absence of cellular cementum. The frequency of this disorder is 1 per million individuals. Here we report a rare case of CCD in a 23 year old female patient having most of the characteristic features of this syndrome.

Dental characteristics of patients with four different types of skeletal dysplasias.

OBJECTIVE: Skeletal dysplasia (SD) comprises more than 450 separate disorders. We hypothesized that their dental features would be distinctive and investigated the tooth characteristics of four patients with different SDs. MATERIAL AND METHODS: Four SD patients with molecularly confirmed diagnoses, Pt-1 acromicric dysplasia, Pt-2 hypophosphatasia and hypochondroplasia, Pt-3 cleidocranial dysplasia, and Pt-4 achondroplasia, were recruited. A tooth from each patient was evaluated for mineral density (micro-computerized tomography), surface roughness (surface profilometer), microhardness, mineral contents (energy-dispersive X-ray), and ultrastructure (scanning electron microscopy and histology), and compared with three tooth-type matched controls. RESULTS: Pt-1 and Pt-3 had several unerupted teeth. Pt-2 had an intact-root-exfoliated tooth at 2 years old. The lingual surfaces of the patients' teeth were significantly smoother, while their buccal surfaces were rougher, than controls, except for Pt-1's buccal surface. The patients' teeth exhibited deep grooves around the enamel prisms and rough intertubular dentin. Pt-3 demonstrated a flat dentinoenamel junction and Pt-2 had an enlarged pulp, barely detectable cementum layer, and ill-defined cemento-dentinal junction. Reduced microhardnesses in enamel, dentin, and both layers were observed in Pt-3, Pt-4, and Pt-1, respectively. Pt-1 showed reduced Ca/P ratio in dentin, while both enamel and dentin of Pt-2 and Pt-3 showed reduced Ca/P ratio. CONCLUSION: Each SD has distinctive dental characteristics with changes in surface roughness, ultrastructure, and mineral composition of dental hard tissues. CLINICAL RELEVANCE: In this era of precision dentistry, identifying the specific potential dental problems for each patient with SD would help personalize dental management guidelines.

Expression of FBXW11 in normal and disease-associated osteogenic cells.

The ubiquitin-proteasome system (UPS) plays an important role in maintaining cellular homeostasis by degrading a multitude of key regulatory proteins. FBXW11, also known as b-TrCP2, belongs to the F-box family, which targets the proteins to be degraded by UPS. Transcription factors or proteins associated with cell cycle can be modulated by FBXW11, which may stimulate or inhibit cellular proliferation. Although FBXW11 has been investigated in embryogenesis and cancer, its expression has not been evaluated in osteogenic cells. With the aim to explore FBXW11gene expression modulation in the osteogenic lineage we performed molecular investigations in mesenchymal stem cells (MSCs) and osteogenic cells in normal and pathological conditions. In vitro experiments as well as ex vivo investigations have been performed. In particular, we explored the FBXW11 expression in normal osteogenic cells as well as in cells of cleidocranial dysplasia (CCD) patients or osteosarcoma cells. Our data showed that FBXW11 expression is modulated during osteogenesis and overexpressed in circulating MSCs and in osteogenically stimulated cells of CCD patients. In addition, FBXW11 is post-transcriptionally regulated in osteosarcoma cells leading to increased levels of beta-catenin. In conclusion, our findings show the modulation of FBXW11 in osteogenic lineage and its dysregulation in impaired osteogenic cells.

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.

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.

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.

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.

Different Requirements of CBFB and RUNX2 in Skeletal Development among Calvaria, Limbs, Vertebrae and Ribs.

RUNX proteins, such as RUNX2, regulate the proliferation and differentiation of chondrocytes and osteoblasts. Haploinsufficiency of RUNX2 causes cleidocranial dysplasia, but a detailed analysis of Runx2+/- mice has not been reported. Furthermore, CBFB is required for the stability and DNA binding of RUNX family proteins. CBFB has two isoforms, and CBFB2 plays a major role in skeletal development. The calvaria, femurs, vertebrae and ribs in Cbfb2-/- mice were analyzed after birth, and compared with those in Runx2+/- mice. Calvarial development was impaired in Runx2+/- mice but mildly delayed in Cbfb2-/- mice. In femurs, the cortical bone but not trabecular bone was reduced in Cbfb2-/- mice, whereas both the trabecular and cortical bone were reduced in Runx2+/- mice. The trabecular bone in vertebrae increased in Cbfb2-/- mice but not in Runx2+/- mice. Rib development was impaired in Cbfb2-/- mice but not in Runx2+/- mice. These differences were likely caused by differences in the indispensability of CBFB and RUNX2, the balance of bone formation and resorption, or the number and maturation stage of osteoblasts. Thus, different amounts of CBFB and RUNX2 were required among the bone tissues for proper bone development and maintenance.

Cleidocranial dysplasia-A case report of incidentally found and lately diagnosed disorder.

Cleidocranial dysplasia (CCD) is a rare autosomal dominant disorder with facial, dental, and skeletal impairments. Affected individuals have varying degrees of skull, shoulder, dental, spine, and facial impairments. Early diagnosis and timely intervention help in minimization of complications, planning of pregnancy, and better quality of life.

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.

Manejo odontológico integral de una paciente con disostosis cleidocraneal. Reporte caso / Integral dental management of a patient with cleidocraneal dysplasia. Case report

Introducción: la disostosis cleidocraneal (CCD) es una enfermedad genética rara que compromete el desarrollo óseo normal, causada por la alteración en el gen RUNX2 del cromosoma 6p (brazo corto). Sus consecuencias incluyen alteraciones óseas por anomalías en la osificación intramembranosa que, a su vez, conllevan a modificaciones en el desarrollo de huesos craneales, claviculares, a múltiples efectos sobre el número, erupción y recambio dental, y a dificultades funcionales, además de cambios en la conducta psicosocial por el deterioro en la calidad de vida. Objetivo: describir el manejo integral de una paciente con disostosis cleidocraneal, a través de la revisión de caso clínico y el reporte de hallazgos en su mejoramiento, como consecuencia de tratamientos quirúrgicos, rehabilitación y el apoyo interdisciplinario, aspecto de gran importancia para este tipo de pacientes. Caso clínico: paciente femenina de 31 años con diagnóstico de CCD que asistió a la Unidad Estomatológica de la Universidad de Cartagena ­ Colombia, y fue remitida desde Genética por presentar inconformidad funcional y dolor leve durante la masticación de los alimentos por movilidad dental severa en dientes antero-inferiores; además, manifestó permanencia de órganos dentarios deciduos, la cual fue tratada en fases. Al tratamiento se le dio un enfoque multidisciplinar, lo que mejoró, de forma sustancial, la autopercepción e interrelación de la paciente en la sociedad.

Background: Cleidocranial dysostosis (CCD) is a rare genetic disease that compromises normal bone development, caused by the alteration in the RUNX2 gene of chromosome 6p (short arm), which causes bone alterations due to abnormalities in intramembranous ossification that leads to alterations in the development of cranial and clavicular bones and multiple efects on the number, eruption and dental turnover, which leads to functional difculties, in addition to behavior and alterations in psychosocial behavior and the deterioration of their quality of life, Objective: To describe the comprehensive management of a patient with cranial Cleido dysostosis, through a clinical case review, reporting among the fndings the improvement of the patient through surgical treatments, rehabilitation and interdisciplinary support, of great importance for this type of patient. Clinical case: A 31-year-old female patient with a diagnosis of CCD, who attended the Stomatology Unit of the University of Cartagena - Colombia, referred by the treating geneticist, due to functional discomfort and mild pain during chewing food due to severe dental mobility. in anterior-inferior teeth, also showing permanence of deciduous dental organs, which was treated in phases in which a multidisciplinary approach was given to its management, which substantially improved its self-perception and its interrelation in society.

A Novel 90-kbp Deletion of RUNX2 Associated with Cleidocranial Dysplasia.

Cleidocranial dysplasia (CCD) is a rare autosomal dominant skeletal dysplasia caused by runt-related transcription factor 2 (RUNX2) mutations. In addition to the regular missense, small or large fragment deletions are the common mutation types of RUNX2. This study aimed to find the rules of deletions in RUNX2. The clinical information of one Chinese CCD family was collected. Genomic DNA was extracted for whole-exome sequencing (WES). Bioinformatics analyzed the pathogenicity of the variants. Polymerase chain reaction (PCR) and Sanger sequencing were carried out using specific primers. RT-PCR and Q-PCR were also used to detect the mRNA level of RUNX2. The CCD studies related with deletions in RUNX2 from 1999 to 2021 from HGMD and PubMed were collected and analyzed for the relationship between the phenotypes and the length of deleted fragments. The proband presented typical CCD features, including delayed closure of cranial sutures, clavicle dysplasia, abnormal teeth. WES, PCR with specific primers and Sanger sequencing revealed a novel heterozygous 90-kbp deletion in RUNX2 (NG_008020.2 g.103671~193943), which caused a substitution (p.Asn183Ile) and premature termination (p.Asp184*). In addition, the mRNA expression of RUNX2 was decreased by 75.5% in the proband. Herein, 31 types of deletions varying from 2 bp to 800 kbp or covering the whole gene of RUNX2 were compared and the significant phenotypic difference was not found among these deletions. The CCD phenotypes were related with the final effects of RUNX2 mutation instead of the length of deletion. WES has the defects in identifying large indels, and direct PCR with specific primers and Sanger sequencing could make up for the shortcoming.

Osteoarthritis in a fifty-year-old patient with unfused skeleton due to undiagnosed coexisting cleidocranial and spondyloepiphyseal dysplasia - Case report.

Background: Skeletal dysplasia's cause significant neurological symptoms and disrupt the development of many bones and cartilages in the body. Skeletal dysplasia, although a common presentation in paediatric population, rarely presents in older age group. Case presentation: This case presents a unique incidental finding of skeletal dysplasia in a fifty-year-old male patient who presented with osteoarthritis. Eventual workup uncloaked the presence of cleidocranial dysplasia and spondyloepiphyseal dysplasia. The patient in this case had both dysplasias at the same time. Discussion: Cleidocranial dysplasia and Spondyloepiphyseal dysplasia are two uncommon autosomal dominant dysplasia's that are often diagnosed in early life and can have serious consequences, including death. It is critical to diagnose a child early in life. Radiology findings from a thorough skeletal examination aid in the early detection of numerous dysplasia's, which helps improving quality of life and allowing for effective treatment. Conclusion: The novelty of our presented case lies in the rare presentation of CCD and SED occurring concurrently at an older age with accompanying collateral abnormalities usually emerging more commonly in infants. Early diagnosis is thus essential for optimal management.

Craniofacial Phenotypes and Genetics of DiGeorge Syndrome.

The 22q11.2 deletion is one of the most common genetic microdeletions, affecting approximately 1 in 4000 live births in humans. A 1.5 to 2.5 Mb hemizygous deletion of chromosome 22q11.2 causes DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS). DGS/VCFS are associated with prevalent cardiac malformations, thymic and parathyroid hypoplasia, and craniofacial defects. Patients with DGS/VCFS manifest craniofacial anomalies involving the cranium, cranial base, jaws, pharyngeal muscles, ear-nose-throat, palate, teeth, and cervical spine. Most craniofacial phenotypes of DGS/VCFS are caused by proximal 1.5 Mb microdeletions, resulting in a hemizygosity of coding genes, microRNAs, and long noncoding RNAs. TBX1, located on chromosome 22q11.21, encodes a T-box transcription factor and is a candidate gene for DGS/VCFS. TBX1 regulates the fate of progenitor cells in the cranial and pharyngeal apparatus during embryogenesis. Tbx1-null mice exhibit the most clinical features of DGS/VCFS, including craniofacial phenotypes. Despite the frequency of DGS/VCFS, there has been a limited review of the craniofacial phenotypes of DGC/VCFS. This review focuses on these phenotypes and summarizes the current understanding of the genetic factors that impact DGS/VCFS-related phenotypes. We also review DGS/VCFS mouse models that have been designed to better understand the pathogenic processes of DGS/VCFS.