Cleidocranial dysplasia: Molecular genetic analysis and phenotypic‐based description of a Middle European patient group

Abstract

Cleidocranial dysplasia (CCD) (OMIM 119600) is a rare dysplasia of osseous and dental tissue. Characteristic features are typical facial and dental appearance plus morphologic anomalies. RUNX2 (OMIM 600211), the responsible gene for CCD, is considered to be a master gene for bone development and bone homeostasis. This study describes the genotype-phenotype correlation based on craniofacial features involving an interdisciplinary approach. Our patient cohort consisted of 31 CCD patients from 20 families; five patients from two families were unavailable for clinical examination. Since CCD mostly affects the craniofacial region, phenotypic characterization of each individual focused on craniofacial and dental aspects. After recording patient medical and family history, the phenotypic data was analyzed using homogeneity analysis (HOMALS), a statistical procedure for data reduction in categorical data analysis. The coding sequence of the RUNX2 gene was analyzed using PCR, direct sequencing, and restriction endonuclease digestion. Eight unpublished and four known heterozygous mutations in a total of 14/20 index patients (70%) were identified. In total, we detected 7 missense mutations, 5 frameshift mutations, and 2 nonsense mutations in 14 index patients (35%, 25%, 10%, respectively). The overall CCD phenotype varied from mild to fullblown expression. Using HOMALS, we were able to discriminate four groups of patients showing significant differences in phenotypic expressivity, thereby simplifying the grouping of our large patient cohort into clear distinguishable entities. Analysis of the mutation patterns revealed that mutational frequency and types of mutations found can be attributed to the gene's structure and function.

Cleidocranial Dysplasia with Normal Clavicles: A Report of a Novel Genotype and a Review of Seven Previous Cases

“…We have attempted to tabulate the phenotypic features of the 5 patients (including our patient) presenting with normal clavicles. Baumert et al [2005] proposed a classification system for CCD which we found useful for eliciting the features and assigning a score. We scored the patients for each variable to reach the cumulative score for genotype-phenotype correlation ( table 1 ).…”

“…c Patient 5 refers to the present study. Classification scheme given by Baumert et al [2005] was used in patients 1 -4. In all cases, shoulder mobility was zero (clavicles could not be approximated to midline).…”

Classical cleidocranial dysplasia in an adult, due to a novel frameshift pathogenic variant inRUNX2

“…It is a transcription factor involved in osteoblast differentiation from mesenchymal cells 5. Mutations in this gene are found in 60–70% of the participants clinically diagnosed with the condition and include missense, non-sense, deletions/insertions and splice site variations leading to premature termination 2 6 7…”

Intragenic microdeletion of RUNX2 is a novel mechanism for cleidocranial dysplasia

“…Numerous mutations in RUNX2 have been identified in patients with CCD (Otto et al 2002;Yoshida et al 2002;Zhou et al 1999). Most of the missense mutations were located in the runt region (Baumert et al 2005;Otto et al 2002;Yoshida et al 2002) involving heterodimerization and DNA binding with CBFb. This discrepancy in distribution could be explained by that the runt domain is highly conserved and is less resistant to single nucleotide changes.…”