PubMed · 3679513
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P J Patel, V M Osundwa, A R Saleh Al-Frayh. 1987. Cleidocranial dysostosis.. https://pubmed.ncbi.nlm.nih.gov/3679513/
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OBJECTIVES: The aim of this study was to determine the clinical and radiological presentation of cleidocranial dysplasia (CCD) in our patient group and to compare them with other reported cases by a systematic review (SR) of the literature. METHODS: The study comprises two elements, a complete series of all diagnosed patients at the Center for Craniofacial Genetics at the University of Regensburg, Germany, and a SR. Relevant literature was identified by electronic databases, review of citation lists and hand searching of key journals. The principal selection criterion was that the study should contain as many pertinent cases as possible. The presented signs and symptoms were assigned to the following categories: "supernumerary teeth", "failure of eruption", "hypoplastic maxilla" and "clavicular sign". Additionally, the family history was taken into account. RESULTS: From the 410 English, German or French articles, 40 single case presentations and 17 multiple case studies remained that met the selection criteria. This report reviews the data of 283 patients with CCD including our own patient cohort of 24 individuals. Dental signs such as supernumerary teeth and eruption failure were expressed in over 93.5%. Skeletal symptoms such as hypoplastic maxilla and the clavicular sign were exhibited in over 84.3%. The prevalence of spontaneous mutations differs slightly when comparing the single case studies (72.0%) with our patient data (58.3%). The fraction of spontaneous mutations in multiple case studies was 5.0%. CONCLUSION: The diagnosis of CCD can be difficult when typical features are not clearly expressed. Since the multiple case studies concentrated on specific clinical aspects, an overall ranking including all associated findings was not possible. Owing to their prevalence, we recommend referencing to the described list of clinical signs as major symptoms for the pathognomy in CCD, since they are infrequent in other conditions and in the general population. To categorize the expression of CCD, more interdisciplinary studies are necessary. Nevertheless, a subjective classification is possible according to the related restrictions in the patients' quality of life.
Cleidocranial dysplasia (CCD) is an autosomal dominant heritable skeletal disease caused by heterozygous mutations in the osteoblast-specific transcription factor RUNX2. We have performed mutational analysis of RUNX2 on 24 unrelated patients with CCD. In 17 patients, 16 distinct mutations were detected in the coding region of RUNX2: 4 frameshift, 3 nonsense, 6 missense, and 2 splicing mutations, in addition to 1 polymorphism. The missense mutations were all clustered within the Runt domain, and their protein products were severely impaired in DNA binding and transactivation. In contrast, two RUNX2 mutants had the Runt domain intact and remained partially competent for transactivation. One criterion of CCD, short stature, was much milder in the patients with the intact Runt domain than in those without. Furthermore, a significant correlation was found between short stature and the number of supernumerary teeth. On the one hand, these genotype-phenotype correlations highlight a general, quantitative dependency, by skeleto-dental developments, on the gene dosage of RUNX2, which has hitherto been obscured by extreme clinical diversities of CCD; this gene-dosage effect is presumed to manifest on small reductions in the total RUNX2 activity, by approximately one-fourth of the normal level at minimum. On the other hand, the classic CCD phenotype, hypoplastic clavicles or open fontanelles, was invariably observed in all patients, including those with normal height. Thus, the cleidocranial bone formation, as mediated by intramembranous ossification, may require a higher level of RUNX2 than does skeletogenesis (mediated by endochondral ossification), as well as odontogenesis (involving still different complex processes). Overall, these results suggest that CCD could result from much smaller losses in the RUNX2 function than has been envisioned on the basis of the conventional haploinsufficiency model.
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