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Last updated: 04/11/2024
Years published: 1992, 2000, 2003, 2009, 2021
NORD gratefully acknowledges Katy Phelan, PhD, FACMG, Florida Cancer Specialist & Research Institute, Fort Myers, Florida, Phelan-McDermid Foundation (Founder), Phelan-McDermid Scientific Advisory Board (Member) and Luigi Boccuto, MD, Clemson University, School of Nursing, College of Behavioral, Social and Health Sciences, Clemson University, Phelan-McDermid Scientific Advisory Board (Member) for assistance in the preparation of this report.
Ring chromosome 22 is a rare genetic condition that occurs when one chromosome 22 forms a circular or ring, structure. The ring forms after loss (deletion) of genetic material from both the short arm and long arm of chromosome 22. The size of the deletion is variable, ranging from less than 100kb to greater than 10Mb. The clinical features are also variable but typically include developmental delay, poor muscle tone (hypotonia), severe speech delay and minor physical features such as large ears and bulbous nose. The ring chromosome typically occurs de novo, meaning that it is a new event in the child and was not inherited. Chromosome studies and genetic counseling are indicated for parents of a child with a ring chromosome to determine if the ring was inherited and to provide important information about what the ring will mean for the development and medical care of their child. People with ring 22 are at risk of developing neurofibromatosis type 2 (NF2). Treatment is directed to the specific signs and symptoms that the affected person has.
The first indication that a child has ring chromosome 22 may be poor muscle tone (hypotonia). An infant may have trouble feeding, holding their head up and staying in a sitting position. As the child grows, other motor milestones such as crawling and walking will be delayed and the child may exhibit poor coordination, lack of balance and an unsteady gait. Moderate to profound intellectual disability is common, as is severely delayed or absent speech. Autism or autistic-like behavior is frequently seen. Mood disorders and other behavioral issues including aggression and hyperactivity have also been described.
Physical features of ring chromosome 22 are mild. They include bulbous nasal tip, broad nasal bridge, large ears and long eyelashes. Small head size (microcephaly) was reported as a common feature in early reports, but larger studies have found this to occur in less than 35% of individuals with ring 22. In about 10% of individuals, brain imaging studies show abnormalities of the central nervous system including dilation of the ventricles, atrophy (decrease in size) of the cerebellum and cerebrum, large cisterna magnum, meningiomas and brain tumors. Meningiomas and brain tumors may be indicative of neurofibromatosis type 2. Individuals with ring 22 are at risk of developing neurofibromatosis type 2 (NF2). NF2 is a genetic condition characterized by the growth of non-cancerous tumors in the nervous system. The gene for NF2 is on the long arm of chromosome 22, near the segment that is deleted in ring 22. In NF2, tumors may occur along the nerve that carries information from the inner ear to the brain leading to hearing loss, ringing in the ears and loss of balance. Since many individuals with ring 22 have limited speech, they may not be able to tell their parents or caregivers that they have these symptoms. Tumors can also occur elsewhere in the brain leading to additional complications. For this reason, individuals with ring 22 should be monitored for signs of NF2 beginning at age 10-12, as discussed in โRelated Disordersโ.
Ring chromosome 22 is formed when genetic material is lost (deleted) from both ends of chromosome 22 and the broken ends fuse to form a circular chromosome or ring. Chromosomes typically are rod-like structures that are found in the nucleus of our body cells. They are composed of genetic material (DNA) and proteins, and their function is to transmit genetic information from generation to generation. The normal chromosome number is 46, or 23 pairs of chromosomes, with one member of each pair inherited from the mother and the other from the father. The chromosomes numbered from 1 to 22, according to length from longest to shortest, are called autosomes. The remaining pair of chromosomes are the sex chromosomes which are XX in females and XY in males.
Structurally, chromosomes have a long arm (q) and a short arm (p) which are separated by a constriction known as the centromere. The long arm is below the centromere and the short arm is above the centromere. Depending on the length of the chromosome arm, it is divided into regions, bands and sub-bands. A class of chromosomes referred to as โacrocentricโ chromosomes have the centromere very near the top of the chromosome, making the short arms very short. Chromosome 22 is an acrocentric chromosome. Structures known as โsatellitesโ are attached to the short arms of acrocentric chromosomes by narrow โstalksโ. The short arms, stalks and satellites are comprised of repetitive genetic material. Deletion of the repetitive material is not clinically significant when the ring chromosome forms because this material is present on the other acrocentric chromosomes (chromosomes 13, 14, 15, 21, and the second copy of chromosome 22). It is the loss of the distal long arm of chromosome 22 that leads to the clinical features of ring 22. In ring 22, the most common breakpoint for the deletion on the long arm (q) of chromosome 22 is in region 1, band 3 โ written as 22q13.
The clinical features associated with ring chromosome 22 are variable for numerous reasons. The amount of material deleted from the long arm of 22 varies from individual to individual, causing the features to vary. In addition, the ring 22 is unstable during the division of the body cells, called mitosis. At the beginning of mitosis, each chromosome consists of a single strand of chromatin which subsequently replicates to form two sister chromatids. Initially, the sister chromatids are paired and joined at the centromere. As mitosis proceeds, the sister chromatids separate. Mitosis ultimately results in the formation of two identical daughter cells. However, the ring chromosome is unstable during mitosis and may be lost in the daughter cells. This results in daughter cells with only one copy of chromosome 22, called monosomy 22. Another feature of mitosis is sister chromatid exchange. While the sister chromatids are paired, they can exchange genetic material. In normally formed chromosomes, the sister chromatids are exchanging genetically identical sequences. With ring chromosomes, however, sister chromatid exchange can result in double rings, rings with two centromeres (dicentric), interlocked rings, or other structural anomalies. Partial duplication or triplication of the ring may resemble a genetic condition known as โcat-eye syndromeโ. (Please see โRelated Disordersโ for more information on the cat-eye syndrome.)
Ring 22 usually occurs as a new, or de novo, event that is not inherited from one of the parents. Both parents have normal chromosomes and their risk of having a second child with ring 22 is no greater than the general population. In rare cases, one of the parents carries the ring chromosome in a small population of cells while most of the cells have a normal chromosome constitution. This is called โchromosome mosaicismโ. Because most of the parental cells do not carry the ring, the parent does not show features of ring 22. However, the parent has a risk of having another child with ring 22. Genetic counseling and chromosome analysis are recommended for the parents of a child with ring 22 to determine if one of the parents carries the ring and to provide accurate risk information.
There have also been exceptional cases in which a parent carries a ring chromosome in all their cells. In these cases, the deletion of chromosome 22 is very small and the parent often shows mild features or no features of ring 22. Because of the instability of the ring as discussed previously in this section, the child may show more features of ring 22 than the parent. A parent with a ring 22 has a theoretical risk of 50% for passing the ring to the offspring. Genetic counseling is recommended to discuss this risk.
Ring chromosome 22 is a rare genetic condition with over 60 cases in the medical literature since 1968. Males and females are equally likely to be affected.
There are two common methods used when a chromosome disorder is suspected. One is chromosomal microarray (CMA) and the other is next-generation sequencing (NGS). These are called molecular genetic tests because they diagnose conditions at the level of the DNA molecule. Two techniques are sometimes used to confirm the results of CMA and NGS. One is FISH (fluorescence in situ hybridization) which is a targeted method to determine if a segment of DNA is present or absent. FISH can be performed on uncultured cells or on chromosomes derived from cultured cells. The other technique is chromosome analysis which relies on counting the number of chromosomes in a subset of cells and examining chromosome structure to determine if an abnormality is present. Chromosome analysis (sometimes called karyotyping) is the only method that permits visualization of the ring chromosome at the microscope.
Both CMA and NGS can show deletions at a much higher resolution than chromosome analysis. They are not targeted techniques like FISH and can look at all the genetic material at the same time. Both techniques can determine how much genetic material has been lost. While CMA and NGS will detect that a segment of chromosome 22 is deleted, they will not show that a ring chromosome is present. This is critical information because individuals with ring 22 are at increased risk of developing NF2 while individuals with a simple deletion of chromosome 22 are not. It is important that anyone diagnosed with a deletion of 22q13 by CMA or NGS have a follow-up chromosome study to determine if a ring chromosome is present.
It is a frequent misunderstanding that if NGS does not show a pathogenic variant of the NF2 gene, an individual with ring 22 is not at risk for NF2. This is wrong, because the mechanism for developing NF2 in people with ring 22 does not rely on the presence of a pathogenic variant of NF2 that causes NF2. It is a two-hit phenomenon. The presence of the ring is the first hit. The second hit could develop at any time during the lifetime of an individual with ring 22. In a survey of individuals with PMS and ring 22, the average age for diagnosis of NF2 was 25 years. Surveillance for symptoms of NF2 is essential in people with ring 22.
Surveillance for symptoms of NF2 should begin between the ages of 10 and 12. A cranial MRI should be performed and continued annually until at least the fourth decade of life. A spinal MRI should be considered every 3 to 5 years, or as indicated if symptoms occur. Hearing evaluations, including brain stem auditory evoked response (BAER) testing, complete eye exams and skin examinations should be performed annually. If a diagnosis of NF2 is made, the extent of the disease should be established by cranial MRI, hearing evaluation including BAER testing, eye evaluation, skin examination, and consideration of spinal MRI. The evaluation and treatment of individuals with NF2 may be best undertaken at an NF2 center experienced at managing this condition.
CMA, NGS, and chromosome analysis can be performed before birth or after birth. Before birth, a fetal ultrasound showing intrauterine growth delay, decreased fetal movements or fetal structural anomalies may prompt genetic studies. The studies can be performed on chorionic villi or cells from amniotic fluid. Chorionic villus sampling tests a sample of placental tissue between 10 to 12 weeks of pregnancy. Amniocentesis is performed between 16 and 18 weeks of pregnancy by obtaining a sample of the fluid that surrounds the fetus. Fetal cells floating in the amniotic fluid are studied. After birth, genetic studies can be performed on a blood sample from an individual suspected of having a chromosome abnormality.
Therapies should be designed to address the needs of each individual. Early intervention programs are available for babies and young children with developmental delays. These may include physical therapy, occupational therapy, speech therapy and other therapies as the child develops. Behavior therapies may be more intense in children with autism or autistic-like features. Adaptive sports, such as swimming and horseback riding, may help improve muscle tone, coordination and balance.
Treatments should also be directed to the childโs needs. Since most of the children have restricted communication skills, the parents and caregivers must be particularly vigilant to determine if there are any changes in the individualโs behavior or appearance that could indicate a developing health issue. In children with known medical problems, specialists should be consulted to address the problem. For example, a pediatric cardiologist for a child with a heart defect or a neurologist for a child with persistent hypotonia.
A clinical geneticist and a genetic counselor should be consulted. The continued care of the individual will require a team approach. In addition to routine pediatric or primary care visits, hearing and eye evaluations, skin examinations, neurologic assessments will be needed. Other specialists and health care professionals may be required depending on the medical problems of the individual with ring 22. Patients diagnosed with NF2 should have a consultation at a center experienced in treating NF2.
Information on current clinical trials is posted on the Internet at www.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:
Toll-free: (800) 411-1222
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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, in the main, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
INTERNET
Phelan-McDermid syndrome; PHMDS. Entry # 606232. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Last Edit Date 11/07/2022. Available at: https://www.omim.org/entry/606232. Accessed April 11, 2024.
NF2. Entry #101000. in Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Last Edit Date 4/11/2021. Available at: https://www.omim.org/entry/10100. Accessed April 11, 2024.
Monosomy 22. Orphanet. Orphanet: Monosomy 22. Accessed April 11, 2024.
Neurofibromatosis type 2. Orphanet. Last update June 2009. Orphanet: Full NF2-related schwannomatosis Accessed April 11, 2024.
Ring Chromosome 22 Facebook page: https://www.facebook.com/groups/ring22/ Accessed April 11, 2024.
22q13 Deletion โ Phelan McDermid Syndrome Family Support Group Facebook page: https://www.facebook.com/groups/22Q13PMS Accessed April 11, 2024.
TEXTBOOKS
Gersen SL et al. Eds. The Principles of Clinical Cytogenetics. 3rd ed. New York: Springer. 2013. P124, 262.
Gardner RJM, et al. eds. Chromosome abnormalities and genetic counseling. 4th ed. New York: Oxford University Press. 2012. 307.
Schinzel A. Catalogue of Unbalanced Chromosome Aberrations in Man. 2nd ed. Berlin, New York: De Gruyter; 2001:860-844.
REVIEW ARTICLES
Ziats CA, et al. Neurofibromatosis type2 in Phelan-McDermid syndrome: Institutional experience and review of the literature. Eur J Med Gen 2020;63:10402. https://doi.org/10.1016/j.ejmg.2020.104042
MacLean JE, et al. Ring chromosome 22 and autism: report and review. Am J Med Genet 2000;90:382-385.
JOURNAL ARTICLES
Kashevarova AA, et al. Compound phenotype in a girl with r(22), concomitant microdeletion 22q13.32- q13.33 and mosaic monosomy 22. Molec Cytogen 2018;11:26-35.
Kurtas N, et al. Chromothripsis and ring chromosome 22: a paradigm of genomic complexity in the Phelan-McDermid syndrome (22q13 deletion syndrome). J Med Genet. 2018;55:269-277.
Lyons-Warren AM, et al. Clinical Reasoning: A common cause for Phelan-McDermid syndrome and neurofobromatosis type 2: one ring to bind them. Neurol 2017;89(17):e205-e209.
Guilherme RS, et al. Clinical, cytogenetic, and molecular characterization of six patients with ring chromosomes 22, including one with concomitant 22q11.2 deletion. Am J Med Genet A. 2014;164A:1659โ1665.
Zirn B, et al. Ring chromosome 22 and neurofibromatosis type II: proof of two-hit model for the loss of the NF2 gene in the development of meningioma. Clin Genet 2010;81(1):82-87.
Evans DGR, et al. Management of the patient and family with neurofibromatosis 2: a consensus confernence statement. Br J Neurosurg 2005;19(1):5-12.
Jeffries AR, et al. Molecular and phenotypic characterization of ring chromosome 22. Am J Med Genet A. 2005;137:139โ147.
Tsilchorozidou T, et al. Constitutional rearrangements of chromosome 22 as a cause of neurofibromatosis 2. J Med Genet 2004;41:529-534.
Ishmael HA, et al. Five new subjects with ring chromosome 22. Clin Genet 2003;63(5):410-414.
Wilson HL, et al. Molecular characterization of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms. J Med Genet 2003;40(8):575-584.
De Mas P, et al. Molecular characterisation of a ring chromosome 22 in a patient with severe language delay: a contribution to the refinement of the subtelomeric 22q deletion syndrome. J Med Genet 2002;39:e17 https://www.jmgjnl.com/cgi/content/full/39/4/e17
Frizzley JK, et al. Ring 22 duplication/deletion mosaicism: clinical, cytogenetic, and molecular characterisation. J Med Genet 1999;16:237-241.
Tommerup N, et al: Ring chromosome 22 and neurofibromatosis. Clin Gen 1992; 42:171-177.
Hunter AG, et al. Phenotypic correlations in patients with ring chromosome 22. Clin Genet 1977;12:239-349.
Weleber RG, et al. Ring G chromosome a new G deletion syndrome? Am J Dis Child 1968;115: 489โ49
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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).
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