Ring Chromosome 4

Ring chromosome 4 is a chromosomal arrangement where the long arm and short arm of a singular chromosome 4 are joined together. This causes the entire chromosome to be in a circular, or ring, structure rather than linear. This joining process often results in the deletion, and potentially duplication, of some genetic material. The clinical picture of ring chromosome 4 can be variable, which is largely due to the variance in overall size and location of any deletions or duplications.¹ The most common features include low birth weight, small stature, microcephaly, hypoplastic thumbs, and occasionally WolfHirschhorn syndrome.¹ All individuals with ring chromosome 4 have some clinical symptoms present, even if no deletion or duplication of genetic material occurs.² The nature of a ring chromosome itself can be enough to cause severe growth restriction and, occasionally, minor anomalies with relatively normal facial experience, as well as mild to moderate intellectual delays.² It is thought that this occurs due to the structure of the ring chromosome being unstable during mitosis, resulting in a higher rate of cellular death during development.³ Those with ring chromosome 4 consistently have symmetric growth restriction throughout the prenatal and postnatal periods.¹

Additionally, various congenital differences can be seen after birth. This may include hypoplastic kidneys, ventricular septal defect, atrial septal defect, patent ductus arteriosus, and hypospadias.¹,⁴ Skeletal anomalies including contractures, clubfeet, overlapping toes, clinodactyly, rocker-bottom feet, toe deviations, polydactyly, and, most commonly, hypoplastic thumbs have all been seen.¹,⁴

Should the formation of a ring chromosome 4 result in a deletion of 4p16.3, an individual will often have characteristics of Wolf-Hirschhorn syndrome. This includes developmental or intellectual delays, growth restriction, microcephaly, seizures, and hypotonia.⁵ Less commonly, congenital differences including congenital heart defects, cleft palate/lip, hypospadias, renal anomalies, and skeletal anomalies can all occur.⁵ Wolf-Hirschhorn often causes a unique set of facial features including a wide bridge of the nose that continues to the forehead, widely spaced eyes, short philtrum, downturned corners of the mouth, and micrognathia.⁶ Not all individuals with a deletion of 4p16.3 due to ring chromosome 4 will present with all the typical features of Wolf-Hirschhorn syndrome.⁵

References

¹Bone K.M. et al. Ring chromosome 4. In: P.Li & T.Liehr (eds.), “Human Ring Chromosomes”, Springer, 2024, 93-112.

²Phillips EA, Caluseriu O, Schlade-Bartusiak K, et al. (2021). Clinical and molecular characterization of an almost complete ring chromosome 4 in two sisters, with recurrence due to gonadal mosaicism. Clin Dysmorphol. 30(4):173–176.

³Burgemeister AL, Daumiller E, Dietze-Armana I, et al. (2017). Continuing role for classical cytogenetics: Case report of a boy with ring syndrome caused by complete ring chromosome 4 and review of literature. Am J Med Genet A. 173(3):727–732.

⁴Kishi Y, Ikeda H. (2018). A case of thumb polydactyly which ulnar thumb has no active motion in ring chromosome 4. J Hand Surg Asian Pac Vol. 23(4):566–570.

⁵Paththinige CS, Sirisena ND, Kariyawasam UG, et al (2016). Ring chromosome 4 in a child with multiple congenital abnormalities: A case report and review of the literature. Case Rep Genet. 2016:4645716.

⁶Paz-Y-Miño C, Proaño A, Verdezoto SD, et al (2019). Clinical, cytogenetic, and molecular findings in a patient with ring chromosome 4: case report and literature review. BMC Med Genomics. 12(1):167.

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