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

Abstract

We report an unusual combination of features comprising delayed tooth eruption and closure of the anterior fontanel as the sole presenting features in a child with cleidocranial dysplasia (CCD). Radiological survey revealed the presence of wormian bones in the skull, pseudoepiphysis at the base of the bilateral second metacarpal, and midline ossification defects at pubic symphysis in the presence of essentially normal clavicles. DNA sequencing of the RUNX2 gene detected a novel nonsense mutation in exon1 (c.166C>T; p.Q56X) in its glutamine-alanine (Q/A) repeat domain. The genotypes of all published cases of CCD with normal clavicles were reviewed. Additional dental and otolaryngological features were enlisted. Three cases with a milder dental phenotype and normal clavicles were associated with a mutation in the Q/A domain. Collectively, we found a novel CCD-causing nonsense mutation p.Q56X in the Q/A domain of the RUNX2 gene.

Functional analysis of novel RUNX2 mutations identified in patients with cleidocranial dysplasia

“…All patients in this study presented with the clinical symptoms typical of CCD, including short stature, hypoplastic clavicles, delayed closure of the anterior fontanel, large anterior fontanel, facial dysmorphism, and dental anomalies. Consistent with other reports, the phenotype was heterogeneous with the severity of the symptoms significantly varied even among affected members of the same family . In all 11 probands with CCD, we confirmed the clinical diagnosis at a molecular level, identifying eight different RUNX2 mutations.…”

“…Mildly affected individuals may present only dental abnormalities, while severely affected patients have more pronounced skeletal malformations, including narrow thorax with respiratory distress in the early infancy. In most of the cases, CCD is inherited from an affected parent, while in approximately 30% the disease occurs as a result of a de novo mutational event …”

“…In most of the cases, CCD is inherited from an affected parent, while in approximately 30% the disease occurs as a result of a de novo mutational event. 4,6 Numerous pathogenic variants in RUNX2 have been reported to cause CCD and the number of known causative mutations is still growing. 7 Since many pathogenic RUNX2 variants are missense substitutions, identification of such mutations along with the characterization of their functional consequences is important for both basic research and clinical practice, including genetic diagnostics and counseling.…”

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…”

Displasia cleidocraneal: reporte de un caso

“…The CCD can be present as a mutation in 60% of the cases, in a 10% it can be present as deletion, and in the remaining percentage of patients, no mutation of the gene has been found, which it is assumed that there is heterogenecity of loci, involving another genes 4 . The CCD is characterized by frontal and parietal prominence, brachycephaly, late closure of the cranial sutures, hypoplasia or clavicle aplasia (which it does not occur in all patients) and multiple dental anomalies 3,[5][6][7][8][9][10][11][12] . All these features tend to be vary, even among the members of the same family.…”