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Last updated: 3/6/2025
Years published: 1994, 2001, 2003, 2011, 2014, 2017, 2021, 2025
NORD gratefully acknowledges Virginia C. Thurston, PhD, Senior Director, Parke Cytogenetics Laboratory, Co-Director Molecular Pathology, Atrium Health Charlotte, NC, for assistance in the preparation of this report.
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Ring chromosome 4 is a rare disorder that is typically characterized by loss (deletion) of genetic material from both ends of the 4th chromosome and joining of the chromosomal ends to form a ring. Associated symptoms and findings may vary greatly, depending on the location of lost genetic material and/or other factors. Some affected infants may have a low birth weight; growth delay; delays in the acquisition of skills requiring the coordination of mental and physical activities (psychomotor retardation); an abnormally small head (microcephaly); a broad, “beaked” nose and/or various additional physical differences that are present at birth (congenital anomalies). However, some people with ring chromosome 4 have been reported with normal psychomotor development and no major physical anomalies, but with growth delay only. Ring chromosome 4 is usually caused by spontaneous (de novo) errors very early in the development of the embryo that appear to occur randomly for unknown reasons (sporadically).
As noted above, associated symptoms and physical findings may be extremely variable from person to person. Some infants with ring chromosome 4 may have multiple characteristic features, such as low birth weight, feeding difficulties, failure to grow and gain weight at the expected rate (failure to thrive), developmental delays, malformations of the skull and facial (craniofacial) region, heart defects and/or other physical abnormalities. In addition, certain features may be similar to those seen in individuals with Wolf-Hirschhorn syndrome, which is a chromosomal disorder characterized by partial deletion (monosomy) of the short arm (p) of chromosome 4 (partial monosomy 4p) or features similar to those seen in individuals with partial deletion (monosomy) of the long arm (q) of chromosome 4 (partial monosomy 4q. (For further information on this disorder, please see the “Disorders with Similar Symptoms” section of this report below.) Other people with ring chromosome 4 may have few symptoms and be primarily affected by growth delays (failure to thrive), with no major physical anomalies.
In some infants and children, ring chromosome 4 may be associated with intellectual disability and delays in the development of physical, mental and behavioral skills that are typically acquired at particular stages (developmental milestones). For example, there are usually delays in language and speech development. However, others with ring chromosome 4 may have normal intelligence and normal psychomotor development.
Craniofacial malformations associated with ring chromosome 4 may include an unusually small head (microcephaly); a broad, rounded, or “beaked” nose; a small jaw (micrognathia) and/or malformed (dysplastic) ears. In some people, other craniofacial abnormalities may also be present, such as incomplete closure of the roof of the mouth (cleft palate), drooping of the upper eyelids (ptosis) and/or other findings.
Some affected individuals may also have abnormal bending or deviation of one or more fingers (clinodactyly); abnormal skin ridge patterns on the palms of the hands (palmar creases) and/or, in affected males, abnormal placement of the urinary opening on the underside of the penis (hypospadias). There have also been a few reports in which ring chromosome 4 is associated with underdevelopment of the kidneys at birth (congenital renal hypoplasia) or a missing kidney (renal agenesis). These conditions may lead to chronic renal failure or an impaired ability of the kidneys to excrete waste products through urine, regulate the balance of salt and water in the body and perform their other vital functions. In some people, ring chromosome 4 may also be associated with additional congenital anomalies.
In most affected individuals, ring chromosome 4 appears to result from loss (deletion) of genetic material from both ends of the 4th chromosome and a joining of the ends to form a ring. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p”, a long arm identified by the letter “q” and a narrowed region at which the two arms are joined (centromere). Chromosomes are further subdivided into bands that are numbered outward from the centromere. For example, “chromosome 4p16” refers to band 16 on the short arm of chromosome 4.
In individuals with ring chromosome 4, the variability of associated symptoms and findings may depend upon the location of genetic material lost from the 4th chromosome, the percentage of cells containing the chromosomal abnormality (see below*), the stability of the ring chromosome during subsequent cellular divisions (mitosis) and/or other factors. For example, reports indicate that affected individuals with deletions of chromosome 4q35 and 4p16 have similar symptoms and findings to those with deletions of 4q33 and 4p16. These findings suggest that certain features often seen in those with ring chromosome 4 appear to result from deletions of genetic material at 4p16. In some people, only some of their cells may contain ring chromosome 4, while other cells may have a normal chromosomal makeup (a finding known as “chromosomal mosaicism*”), potentially affecting the variability of associated symptoms and findings.
Patients have been reported in which ring chromosome 4 is present with no detectable loss of genetic material (as based upon chromosomal analysis). Such cases are sometimes referred to as “ring syndrome,” a general term used to describe the presence of growth delay in the absence of major malformations due to a ring chromosome. Researchers suggest that such ring chromosomes originate with abnormal fusion of the ends (i.e., telomeres) of a particular chromosome (e.g., chromosome 4) and that “ring syndrome” results due to instability of the ring chromosome during subsequent cellular divisions.
In most people, ring chromosome 4 appears to be caused by spontaneous (de novo) errors very early in embryonic development. In such cases, the parents of the affected child usually have normal chromosomes and a relatively low risk of having another child with this chromosomal abnormality. However, chromosomal analysis and genetic counseling are typically recommended for parents of an affected child to help confirm or exclude the presence of certain chromosomal abnormalities in one of the parents, such as ring chromosome 4, potential mosaicism or a “balanced translocation” involving chromosome 4.
Translocations occur when regions of certain chromosomes break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. If a chromosomal rearrangement is balanced, meaning that it consists of an altered but balanced set of chromosomes, it is usually harmless to the person. However, translocations may be associated with an increased risk of abnormal chromosomal development in the person’s children.
There has been one report of two sisters with identical large ring chromosome 4 in most of the cells analyzed from each sister. The parents had normal chromosomes in their blood and skin. There were also three additional unaffected sisters. DNA analysis determined that both rings were maternal in origin. The presence of two siblings with maternal ring chromosome 4 and parents with normal chromosomes is thought to be due to gonadal mosaicism. Gonadal mosaicism is a type of mosaicism that occurs in the eggs or sperm of an individual in which some of the eggs or sperm have a normal genetic makeup and others have a different genetic makeup. In this case, the ring chromosome 4 was present in some of the mother’s eggs and not in other eggs.
Since ring chromosome 4 was originally described, more than 65 cases have been reported in the medical literature. Males and females appear to be affected relatively equally.
The disorder may be suspected based upon a thorough clinical evaluation and detection of characteristic physical findings. Ring chromosome 4 is diagnosed with a chromosomal analysis. Specialized tests may also be performed to help detect and/or characterize certain abnormalities that may be associated with the disorder.
Ring chromosome 4 may be diagnosed before birth (prenatally) by specialized tests such amniocentesis and/or chorionic villus sampling (CVS). With amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta. Chromosomal analysis performed on these samples may show the presence of ring chromosome 4.
Treatment
The treatment of ring chromosome 4 is directed toward the specific symptoms that are apparent in each individual. In some people, physicians may recommend surgical repair of certain malformations associated with the disorder. The specific surgical procedures performed will depend upon the severity and location of the anatomical abnormalities, their associated symptoms and other factors.
Early intervention may be important in ensuring that affected children reach their potential. Special services that may be beneficial include special education, speech therapy and/or other medical, social and/or vocational services.
Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
http://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Jones KL, et al. Smith’s Recognizable Patterns of Human Malformation. 7th ed. Philadelphia, PA: W.B. Saunders Company; 2013:38-41.
Schinzel A. Catalogue of Unbalanced Chromosome aberrations in Man. 2nd ed. New York, NY: Walter de Gruyter; 2001:191-193.
Behrman RE, et al., eds. Nelson Textbook of Pediatrics. 15th ed. Philadelphia, PA: W.B. Saunders Company; 1996:317.
Gorlin RJ, et al., eds. Syndromes of the Head and Neck. 3rd ed. New York, NY: Oxford University Press; 1990:46-48.
Buyse ML. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications, Inc.; 1990:336-37.
JOURNAL ARTICLES
Phillips, EA et al. Clinical and molecular characterization of an almost complete ring chromosome 4 in two sisters, with recurrence due to gonadal mosaicism. Clin. Dysmorph. 2021; 30:173-176.
Paz-y-Mino C. et al. Clinical, cytogenetic, and molecular findings in a patient with ring chromosome 4: case report and literature review. BMC Med. Genomics. 2019; 12:167
Burgemeister, AL, et al. 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. Part A. 2016; 173A:727-732.
Dominguez, MG. et. al. Variegated-like mosaicism and ring syndrome in a r(4) boy. Appraisal of 38 patients with a fairly complete ring 4. Genet. Counsel. 2010; 21:411-422.
Soysal Y; et al. Characterization of double ring chromosome 4 mosaicism associated with bilateral hip dislocation, cortical dysgenesis, and epilepsy. Am J Med Genet. Part A. 2009; 149A(12):2782-7
Chen CP, Hsu CY, Tzen CY, et al. Prenatal diagnosis of mosaic ring chromosome 4. Prenat Diagn. 2007; 27(5):485-7.
Laleye A, et al. Wolf Hirshhorn syndrome in a case of ring chromosome 4: phenotype and molecular cytogenetic findings. Genet Couns. 2006; 17(1):35-40
Balci S, Engiz O, Akta D, et al. Ring chromosome 4 and Wolf-Hirschhorn syndrome (WHS) in a child with multiple anomalies. Am J Med Genet A. 2006;140(6):628-32.
Blackett, PR; Li, S; Mulvihill, JJ. Ring chromosome 4 in a patient with early onset type 2 diabetes, deafness, and developmental delay. Am J Med Genet A. 2005; 137(2):213-6.
Lee MH, Park SY, Kim YM, et al. Molecular cytogenetic characterization of ring chromosome 4 in a female having a chromosomally normal child. Cytogenet Genome Res. 2005;111(2):175-8.
Kocks, A; et al. Partial deletion of 4p and 4q in a fetus with ring chromosome 4: phenotype and molecular mapping of the breakpoints. Journal of Medical Genetics 2002; 39(5):E23.
Sigurdardottir S, et al. Clinical, cytogenetic, and fluorescence in situ hybridization findings in two cases of “complete ring” syndrome. Am J Med Genet. 1999;87:384-90.
Vermeesch JR; et al. A mosaic extra ring chromosome 4 in a female patient with postnatal overgrowth. Genet Couns 1999; 10(2):195-6.
Robertson SP et. al. The 4q syndrome: delineation of the minimal critical region to within 4q31, Clin Genet. 1998;53:70-73.
Anderson CE, et al. Ring chromosome 4 mosaicism coincidence of oligomeganephronia and signs of Seckel syndrome. Am J Med Genet. 1997;72:281-85.
Hou JW and Wang TR. Amelia, dextrocardia, asplenia, and congenital short bowel in deleted ring chromosome 4. J Med Genet. 1996; 33(10):879-81.
Lurie, I W. Further study of genetic interactions: loss of short arm material in patients with ring chromosome 4 changes developmental pattern of del(4)(q33). Am J Med Genet. 1995;56(3):308-11.
Park SH, et al. Oligomeganephronia associated with 4p deletion type chromosomal anomaly. Pediatr Pathol. 1993;13:731-40.
Pezzolo A, et al. Presence of telomeric and subtelomeric sequences at the fusion points of ring chromosomes indicates that the ring syndrome is caused by ring instability. Hum Genet. 1993;92:23-27.
Freyberger G; Wamsler C; Schmid M. Ring chromosome 4 in a child with mild dysmorphic signs. Clin Genet. 1991;39(2):151-5.
Halal, F and Vekemans, M. Ring chromosome 4 in a child with duodenal atresia. Am J Med Genet.1990; 37(1):79-82.
Giuffre L, et al. Ring chromosome 4 in twins. Pediatr Med Chir. 1987;9:349-50.
Gutkowska A, et al. Ring chromosome 4: 46,XY, r(4) (p16q35) in a boy. Klin Padiatr. 1985;197:294-96.
Kosztolanyi G. Ring chromosome 4: Wolf syndrome and unspecific developmental anomalies. Acta Paediatr Hung. 1985;26:157-65.
Haspeslagh M, et al. Severe limb malformations in 4p deletion. Clin Genet. 1984;25:353-56.
Finley WH; Finley SC; Chonmaitree T; Koors JE; Chandler WC. Ring 4 chromosome with terminal p and q deletions. Am J Dis Children. 1981; 135(8):729-31.
Young, R S; Zalneraitis, E L. Neurological and neuropathological findings in ring chromosome 4. J Med Genet. 1980; 17(6):487-90.
del Mazo J, et al. Partial deletion of 4p16 band in a ring chromosome and Wolf Syndrome. Hum Genet. 1978;44:105-08.
Perez-Castillo A, et al. Ring chromosome 4 and Wolf syndrome. Hum Genet. 1977;37:87-91.
McDermott, A; Voyce, M A; Romain, D. Ring chromosome 4. J Med Genet. 1977; 14(3):228-32.
Surana RB; Bailey JD; Conen PE. A ring-4 chromosome in a patient with normal intelligence and short stature. Journal of Medical Genetics.1971; 8(4):517-21.
Carter R; Baker E; Hayman D. Congenital malformations associated with a ring 4 chromosome. J Med Genet.1969; 6(2):224-7.
INTERNET
Ring chromosome 4. Genetic and Rare Diseases Information Center (GARD). https://rarediseases.info.nih.gov/diseases/1339/ring-chromosome-4 Accessed Feb 25, 2025.
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
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