6p21.1 Deletion

Deletions that include the p21.1 segment on the short arm of chromosome 6 can result in a rare condition called Cleidocranial dysplasia (CCD). Characterized by various skeletal malformations, CCD is caused by loss of function mutations in RUNX2, which is located within the 6p21.1 region¹. RUNX2 plays key roles in the overall organization, assembly, and activation of regulatory factors responsible for skeletal gene expression². This includes odontogenesis, cartilage development, cranial skeletal system development, and skeletal system morphogenesis².

CCD can result in various skeletal malformations of the skull, teeth, and broader skeletal system. Hypoplasia or aplasia of the clavicles is a key feature¹. Skull deformities may include increased circumference, large fontanels, open sutures, and multiple Wormian bones¹. Dental anomalies can include prolonged retention of deciduous teeth, delay in eruption of permanent teeth, and multiple supernumerary teeth¹. Broader skeletal manifestations such as short stature, bell shaped thorax, pelvic hypoplasia, scoliosis, and kyphosis are all commonly seen¹,³.

There can be some variability in how individuals present and there is an unclear genotype-phenotype correlation in those who have differing RUNX2 mutations². However, dental problems and some degree of clavicular hypoplasia seem to be consistent among all individuals with CCD¹. It is also common for an individual’s fontanels to remain open until adulthood¹.

Although most cases of CCD are caused by mutations within RUNX2 gene or its surrounding regulatory elements, approximately 13% of cases are due to microdeletions that encompass RUNX2 or its untranslated regions²,⁴. It is important to note, however, that deletions of 6p21.1 that do not include the RUNX2 gene will not present with clinical features of CCD. Additionally, those who have deletions that expand beyond RUNX2 in 6p21.1 may have additional clinical features present⁵.

References

¹Franceschi R, Maines E, Fedrizzi M, et al. (2015). Familial cleidocranial dysplasia misdiagnosed as rickets over three generations. Pediatr Int. 57(5):1003–1006.

²Mijovic M, Cuturilo G, Ruml Stojanovic J, et al. (2026). A Novel 4.2 kb deletion of the 3’UTR of RUNX2 gene causes cleidocranial dysplasia: Further delineation of the role of the 3′ UTR. Balkan J Med Genet. 28(2): 107–112.

³Zhang J, Li YZ, Chen WQ, et al. (2022). Genome sequencing identified a novel exonic microdeletion in the RUNX2 gene that causes cleidocranial dysplasia. Clin Chim Acta. 528: 6–12.

⁴Zhang Y, Duan X. (2022). A Novel 90-kbp Deletion of RUNX2 Associated with Cleidocranial Dysplasia. Genes (Basel) 13(7):1128.

⁵Izumi K, Yahagi N, Fujii Y, et al. (2006). Cleidocranial dysplasia plus vascular anomalies with 6p21.2 microdeletion spanning RUNX2 and VEGF. Am J Med Genet A. 140(4): 398–401.

Chromosome Disorder Outreach Inc. medical geneticist and medical advisor Dr. Iosif Lurie M.D. Ph.D examines newly published research studies to locate the most important and relevant for our members. Synopses of these articles are then posted to our website’s research pages. Review and formatting by Lydia Bentley, MS CGC. For more information on any article please contact info@chromodisorder.org