Genetic Pattern, Orthodontic and Surgical Management of Multiple Supplementary Impacted Teeth in a Rare, Cleidocranial Dysplasia Patient: A Case Report

Background: Cleidocranial dysplasia (CCD) is a rare, autosomal dominant skeletal dysplasia with a prevalence of one per million births. The main causes of CCD are mutations in the core-binding factor alpha-1 (CBFA1) or runt-related transcription factor-2 (RUNX2), located at the 6p21 chromosomal region. RUNX2 plays important roles in osteoblast differentiation, chondrocyte proliferation and differentiation, and tooth formation. The disease is characterized by clavicular aplasia or hypoplasia, Wormian bones, delayed closure of cranial suture, brachycephalic head, maxillary deficiency, retention of primary teeth, inclusion of permanent teeth, and multiple supernumerary teeth. Materials and Methods: A 22-year-old girl suffering from cleidocranial dysplasia with short stature, narrow shoulders, craniofacial manifestations (short face, broad forehead, etc.) and dental anomalies (different lower dental elements under eruption, supernumerary and impacted multiple teeth, etc.) was examined at our service (Complex Operative Unit of Odontostomatology of Policlinico of Bari). RX Orthopantomography (OPG) and cone beam computed tomography (CBCT) were requested to better assess the position of the supernumerary teeth and their relationships with others and to evaluate the bone tissue. Results: Under eruption was probably caused by dental interferences with supernumerary teeth; hence, extractions of supernumerary upper canines and lower premolars were performed under general anaesthesia. Surgery outcome was excellent with good tissue healing and improvements in the therapeutic possibilities with future orthodontics. Conclusions: The objective of this article is to give an update about radiological, clinical, and molecular features of CCD and to alert the health team about the importance of establishing an early diagnosis and an appropriate treatment in these patients to prevent impacted teeth complications and to offer them a better quality of life.

Survival of dental implants in patients with bone dysplasia: A systematic review

Objective: This study used published studies to assess the survival rate of dental implants placed in patients with bone dysplasia of the maxillofacial region.Material and methods: An electronic search without a specified date range was performed using the MEDLINE, PubMed, EMBASE, Web of Science, and Cochrane databases. No gender or age restrictions were applied.Results: Eighteen publications were found that met the study’s criteria, reporting data on 18 patients with bone dysplasia including cleidocranial dysplasia (CDD), fibrous dysplasia (FD), florid cemento-osseous dysplasia (FCOD), and odonto-maxillary segmental dysplasia (SOMD), who received a total of 130 implants, an average of 7.2 implants/patient (range 1 to 16). The mean age of the patients was 36.7 years (range 15 to 70 years). For implants placed in bone dysplasia, the survival rates were 100% for patients with CDD (n = 8), FD (n = 5), SOMD (n = 2), FCOD with implants inserted far from the lesions (n = 2) and 0% for dental implants inserted within FCOD (n = 1). The mean follow-up was 38.2 months (min 6, max 60).Conclusions: Dental implants placed in patients with dysplastic bone lesions show high survival rates, similar to those in the general population for CDD, FD, and SOMD. For FCOD, the failure rate was 100%.

Identification of a familial cleidocranial dysplasia with a novel RUNX2 mutation and establishment of patient-derived induced pluripotent stem cells

Cleidocranial dysplasia (CCD) is an autosomal dominant hereditary disease associated with the gene RUNX2. Disease-specific induced pluripotent stem cells (iPSCs) have emerged as a useful resource to further study human hereditary diseases such as CCD. In this study, we identified a novel CCD-specific RUNX2 mutation and established iPSCs with this mutation. Biopsies were obtained from familial CCD patients and mutation analyses were performed through Sanger sequencing and next generation sequencing. CCD-specific human iPSCs (CCD-hiPSCs) were established and maintained under completely defined serum, feeder, and integration-free condition using a non-integrating replication-defective Sendai virus vector. We identified the novel mutation RUNX2_c.371C>G and successfully established CCD-hiPSCs. The CCD-hiPSCs inherited the same mutation, possessed pluripotency, and showed the ability to differentiate the three germ layers. We concluded that RUNX2_c.371C>G was likely pathogenic because our results, derived from next generation sequencing, are supported by actual clinical evidence, familial tracing, and genetic data. Thus, we concluded that hiPSCs with a novel CCD-specific RUNX2 mutation are viable as a resource for future studies on CCD.

Appropriateness of standard cephalometric norms for the assessment of dentofacial characteristics in patients with cleidocranial dysplasia

Objectives: Cleidocranial dysplasia (CCD) is a rare skeletal syndrome affecting craniofacial and dental development. As a consequence, conventional cephalometric landmarks may not be valid for CCD patients, and the appropriateness of norms used for the general population should be critically discussed. Methods: Five patients 9 to 22 year-old (three females, two males) with CCD were included. Lateral-cephalograms, orthopantomographies, and intra oral photos were retrospectively analysed. Lateral-cephalograms of fifty normal controls (ten for each CCD patient) matched for age and sex were selected from an online database. Cephalometric measurements of each CCD patients were compared with average values of matched controls using Wilcoxon signed-rank test for paired values (α = 0.05). Results: In CCD patients, a shortening of the cranial base was present (ΔSN = −17.1 mm, p = 0.043). Thus, the mandible (ΔSNPg =+9.5°, p = 0.043) and the maxilla (ΔSNA =+11.2°, p = 0.043) showed protrusion compared to the cranial base, despite a reduced maxillary (ΔCo-A = −15.1 mm, p = 0.043) and mandibular (ΔCo-Gn −15.2 mm, p = 0.080) length. The mandibular divergence was reduced (ΔSN/GoGn = −6.4°, p = 0.043), a negative overjet was present (ΔOverbite = −2.9 mm, p = 0.043), and the interincisal angle was increased (ΔInterincisalAngle =+13.7°, p = 0.043), mainly due to retro-inclination of lower incisors. Conclusions: Standard cephalometric norms for the assessment of horizontal jaw position may not be applicable to CCD patients because of a reduced anterior cranial base length compared to normal subjects. Vertical relationships may not be affected, and mandibular hypodivergency was confirmed.

An Exploration of Mutagenesis in a Family with Cleidocranial Dysplasia without RUNX2 Mutation

Cleidocranial dysplasia (CCD) is an autosomal dominant inheritable skeletal disorder characterized by cranial dysplasia, clavicle hypoplasia, and dental abnormalities. Mutations involving Runt-related transcription factor 2 (RUNX2) are currently the only known molecular etiology for CCD but are not identified in all CCD patients. No RUNX2 abnormality can be detected in about 20–30% of patients, and the molecular cause remains unknown. The present study includes a family case with typical features of CCD. RUNX2 mutation was first screened by sequencing analysis, and no mutation was detected. Copy number alterations of the RUNX2 gene were then measured by quantitative PCR and multiplex ligation-dependent probe amplification (MLPA). No copy number variation in RUNX2 could be detected. We performed whole-exome sequencing (WES) to identify the underlying genetic mutations. Unexpectedly, no abnormalities could be detected in genes related to the RUNX2 signaling pathway. Therefore, it was supposed that other new unknown gene variations might contribute to the CCD phenotype. We focused on Immunoglobulin superfamily member 10 (IGSF10), a gene related to bone development. An IGSF10 frameshift mutation (c.6001_6002delCT, p.Leu2001Valfs*24) was detected by WES. Sanger sequencing verified that this mutation was only detected in the patient and her affected mother but not in her unaffected father. Bioinformatics studies demonstrated that this mutation could change the 3D structure of the IGSF10 protein and severely damage its function. In addition, alkaline phosphatase (ALP) activity and the ability to form mineralized nodules were inhibited by IGSF10 knockdown compared with normal controls. The expression of bone sialoprotein (BSP) was significantly reduced by IGSF10 knockdown, but not that of other osteogenic markers. Our results provide new genetic evidence that IGSF10 mutation might contribute to CCD.