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Clinical Description Cleidocranial dysplasia (CCD) spectrum disorder is a skeletal dysplasia representing a clinical continuum ranging from classic CCD (triad of delayed closure of the cranial sutures, hypoplastic or aplastic clavicles, and dental abnormalities), to mild CCD, to isolated dental anomalies without other skeletal features [Golan et al 2000]. Most individuals are diagnosed because they have classic features. CCD spectrum disorder affects most prominently those bones derived from intramembranous ossification, such as the cranium and the clavicles, although bones formed through endochondral ossification can also be affected. Cooper et al [2001] recorded the natural history of 90 probands and 56 first- and second-degree relatives; findings highlight the clinical variability of this condition within affected members of the same family who harbor the same pathogenic variant. Roberts et al [2013] reviewed their experience with more than 100 affected individuals in South Africa. Classic CCD. The most prominent clinical findings in individuals with classic CCD are listed in Suggestive Findings and include: abnormally large, wide-open fontanelles at birth that may remain open throughout life; clavicular hypoplasia resulting in narrow, sloping shoulders that can be opposed at the midline; and abnormal dentition Further medical problems identified in individuals with CCD spectrum disorder include short stature, skeletal/orthopedic findings, dental complications, ENT complications, endocrine findings, and mild developmental delay. Molecular Pathogenesis RUNX2 encodes runt-related transcription factor 2 (RUNX2), a transcription factor involved in osteoblast differentiation and skeletal morphogenesis. RUNX2 is essential for osteoblast differentiation during intramembranous ossification as well as chondrocyte maturation during endochondral ossification [Zheng et al 2005]. RUNX2 contains an N-terminal stretch of consecutive polyglutamine and polyalanine repeats known as the Q/A domain, a runt domain, and a C-terminal proline/serine/threonine-rich (PST) activation domain. The runt domain is a 128-amino-acid polypeptide motif originally described in the Drosophila runt gene that has the unique ability to independently mediate DNA binding and protein heterodimerization [Zhou et al 1999]. The majority of RUNX2 pathogenic variants in individuals with classic CCD affect the runt domain and most are predicted to abolish DNA binding [Lee et al 1997, Mundlos et al 1997, Otto et al 2002]. Pathogenic missense variants cluster at arginine 225 (p.Arg225) of RUNX2, a critical residue for RUNX2 function. In vitro studies have shown that pathogenic missense variants at p.Arg225 interfere with nuclear accumulation of RUNX2. Hypomorphic RUNX2 alleles with partial loss of protein function, c.90dupC and c.598A>G, are associated with mild CCD, isolated dental anomalies, and significant intrafamilial variability. Mechanism of disease causation. Loss of function RUNX2-spRead less