Mosaic Ring 20 Syndrome

Abstract

Background and Objectives

Ring 20 syndrome is a rare childhood-onset neurodevelopmental disorder caused by a postzygotic event leading to a structural change in the 20th chromosome. Next-generation sequencing (NGS) does not identify an abnormality in the most common mosaic form. Through a systematic review of the literature, we sought to identify clinically distinct characteristics that would trigger an order for a karyotype, which is the only definitive diagnostic test for this condition.

Methods

A systematic literature review was performed reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. PubMed and Web of Science were searched from inception through January 8, 2025. Included studies reported on mosaic ring 20 syndrome. Two independent reviewers screened studies based on predefined criteria and extracted data from each study, which were quantitatively combined.

Results

A total of 70 publications reporting on 148 patients were included. Our review clearly reveals a distinct set of signs that should alert the informed neurologist to order a karyotype analysis at the first evaluation because it is currently the only method to properly diagnose this condition. Over 90% of cases which mention the seizure type describe multiply recurrent nonconvulsive status epilepticus. Patients generally do not have dysmorphia and are developing normally over the average of 7 years before seizure onset. The diagnosis of mosaic ring 20 syndrome should be considered in the setting of childhood-onset treatment-resistant epilepsy, particularly in the absence of focal abnormalities on brain MRI abnormalities, distinctive EEG findings, and pathogenic variants on short-read NGS.

Discussion

The diagnosis of mosaic ring 20 syndrome is via karyotype analysis. The current lag time from seizure onset to definitive diagnosis is 7.7 years. More widespread recognition of the distinctive clinical features of mosaic ring 20 syndrome should help shorten the diagnostic delay for affected individuals.

Introduction

Ring 20 syndrome is a rare disorder characterized by a structural abnormality of the 20th chromosome.¹ One of the 2 chromosomes fuse, usually end to end, resulting in a ring appearance on karyotype analysis. Approximately one-fifth of the affected patients have subtelomeric microdeletions that can be diagnosed by chromosomal microarray (CMA) or next-generation sequencing (NGS) tests like whole-genome sequencing (WGS).¹ A postzygotic alteration is responsible for the ring appearance in the remaining patients. Thus, only a subset of cells is affected in a mosaic fashion. It is important that CMA or WGS does not identify any variants in these patients. For these individuals, a karyotype analysis, which is infrequently ordered because of reliance on NGS tests, is required for proper diagnosis.² As a result, diagnosis is often delayed; therefore, it is important to clearly define the clinical features characterizing mosaic ring 20 syndrome to promptly identify individuals who would benefit from karyotype analysis.

Methods

To synthesize the available evidence regarding the clinical features and treatment outcomes of mosaic ring 20 syndrome, we conducted a systematic review of case reports, case series, and clinical observational studies of mosaic ring 20 syndrome. Eligibility criteria included English-language studies describing mosaic ring 20 syndrome. Cases describing individuals with Ring 20 syndrome with deletions or translocations that would be identified by NGS tests were not included. In conjunction with a medical librarian (S.R.), a search strategy was developed using the following terms: “R (20) Syndrome” OR “Ring 20” OR “Ring Chromosome 20”. Searches were conducted in PubMed and Web of Science from inception through January 8, 2025. Four investigators (S.E., D.C., S.W., and W.D.J.) independently screened the titles and abstracts of all identified citations. The articles in full text were obtained for potentially relevant citation, which were reviewed for inclusion in the final analysis. Any conflicts were resolved by a third reviewer (J.S.B., W.D.J). This study is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. This study did not require institutional review board approval because it does not involve live human participants, only a review of published literature. Similarly, there is no reason to obtain informed consent of human participants. The principal author takes full responsibility for the data, analyses and interpretation, and conduct of the research and has full access to all the data; we have the right to publish any and all data, separate and apart from the guidance of any sponsor. Data not published within this article will be made available by request from any qualified investigator. All applicable ethical research principles have been followed.

Results

After removal of duplicates, 244 records were identified, of which 142 were retrieved for full-text review (Figure). An additional 72 studies were excluded upon full-text review, leaving 70 studies included in the final review. There were 148 analyzable cases (Table). There were 63 (42%) male and 85 (58%) female individuals. One hundred forty-four had seizures, with the only 2 cases with a prenatal diagnosis and 2 individuals reported before age 3 years, which is younger than the typical age at onset of seizures, lacking seizures. The average age at onset of seizures was 7.0 years. The average age at diagnosis of ring 20 was 14.7 years. The average interval between the first presentation and definitive diagnosis was 7.7 years. Of the 62 individuals with seizure frequency reported, 4 responded to therapy with antiseizure medications and were seizure free. Forty-five (72.6%; 95% CI 59.8%–83.1%) had seizures at least daily (many multiple times daily), 11 weekly (17.7%; CI 9.2–29.5%), and 2 (3%; CI 0.4–11.2%) monthly.

Figure. PRISMA Flow Diagram.

Table.

Summary Data for Patients With Mosaic Ring 20 Syndrome^a

Number = 148, (%)	M 63 (42), F 85 (58)
Average age at onset	7.0 y
Average age at diagnosis of ring 20	14.7 y
Average delay in diagnosis	7.7 y
Nonconvulsive status epilepticus (%)	Yes 99/108 (91.7), No 9/108 (8.3)
Seizure frequency (%)	Daily 45/62 (72.6), weekly 11/62 (17.7)
	Monthly 2/62 (3.2), none 4/62 (6.4)
Drug-resistantb (%)	Yes 95/105 (90.5), no 10/105 (9.5)
Intellectual disabilityc (%)	Yes 53/117 (45.3)
Behavioral change, (%)	Yes 56/76 (73.7)

^aNot all cases mention each variable.

^bDefined as nonresponse to 2 or more medications.

^cSevere, or if tested, IQ below 70.

Sufficient details regarding seizure patterns were available in 108 of the 144 individuals with seizures to make the following assessments. Multiple types were described. Staring episodes, often lasting hours, were noted in 44 of 108 (40.7%; CI 31.4–50.6%), sleep-associated arousals with fear in 45 of 108 (41.7%; 95% CI 32.3%–51.5%), focal motor seizures in 28 of 108 (25.8%; CI 20.0–35.2%), and generalized tonic-clonic seizures in 14 of 108 (13.0%; 95% CI 7.3%–20.8%). Nonconvulsive status epilepticus (NCSE) was noted in 99 of 108 (91.7%; 95% CI 84.8%–96.1%). Seizures were reported to be intractable to medications in 95 of 105 patients (90.5%’ 95% CI 83.2%–95.3%). Of those who were not reported to be intractable, 4 had no data presented regarding seizure treatment; 2 responded to lamotrigine monotherapy; 1 to valproic acid monotherapy; 1 to oxcarbazepine monotherapy; 1 to lamotrigine and valproic acid combination; and 1 to ethosuximide, valproic acid, lamotrigine combination therapy.^{e1,e2,e7,e17,e19}

Sufficient details regarding EEG patterns were available in 125 of the 144 cases with seizures to make the following assessments. Interictal epileptiform discharges were reported on the EEGs of 94 of 125 (75.2%; 95% CI 66.7%–82.5%) patients. Fifty-six patients (56/125; 44.8%; CI 35.9%–54.0%) were described as having frontal or bifrontal predominant epileptiform discharges. Twenty-two (22/125; 17.6%; 95% CI 11.4%–25.4%) had bifrontal epileptiform discharges. Interictal discharges were frontotemporal in 20 of 125 (16.0%; 95% CI 10.1%–23.6%) and generalized in 8 of 125 (6.4%; 95% CI 2.8%–12.2%). Rarely were interictal discharges described as being exclusively temporal. Among the 125 cases that described EEG findings, 28 (22.4%; 95% CI 15.4%–30.7%) cases described a theta-delta or theta-predominant slowing, often described as rhythmic or sharply contoured. Variable ictal EEG patterns were described among the cases. Electrographic patterns of lateralized frontal spike wave, lateralized and generalized fast activity, generalized spike wave, and rhythmic slowing were described.

When reviewing the articles in detail, no dysmorphia was seen in 84 of 104 individuals (80.8%; 95% CI 71.9%–87.8%). Of the 20 with some dysmorphic signs noted, there were a variety of features that did not fit a syndromic pattern, including a supernumerary thumb, frontal bossing, epicanthal folds, or a low nasal bridge. No consistent comorbid disorders were reported in other organ systems outside the nervous system. Neuroimaging information was available for 115 cases. There were no focal abnormalities. One hundred individuals had normal scans, and the 15 with reported findings were mostly mild cortical atrophy. Even in those experiencing years of seizures occurring multiple times per day, there was a lack of hippocampal sclerosis seen.

One hundred seventeen reports mentioned intellectual functioning. Fifty-three of 117 individuals (45.3%; 95% CI 36.12–54.8) were said to have severe impairment or, when tested, had IQs of less than 70. Fifty-six of the 76 individuals with behavioral issues reported (73.7%; 95% CI 62.3–83.1) had behavioral abnormalities. They included mood liability, hyperactivity, reckless behavior, and aggression.

Discussion

This systematic review identifies several characteristic clinical features of mosaic ring 20 syndrome. In reviewing 148 reported cases of mosaic ring 20 syndrome,^e1-e70 a clinically recognizable combination of childhood-onset epilepsy with recurrent nonconvulsive status epilepticus and with characteristic, seizure type, frequency, and electroencephalographic findings has emerged.

The average age at seizure onset in individuals with mosaic ring 20 syndrome is 7.0 years. Multiple seizure types are possible; however, mosaic ring 20 syndrome is often characterized by prolonged seizures manifested as fluctuating mental status, lasting more than 15–20 minutes each. Other compatible findings include night terrors, normal brain anatomic imaging, no clear syndromic dysmorphia, and interictal EEG findings, which often show frontal predominant interictal discharges. Finally, such patients are drug resistant.

Our findings suggest that when a neurologist is evaluating a child with new-onset epilepsy who by history has prolonged (many minutes to hours) episodes of fluctuating mental status (NCSE), mosaic ring 20 syndrome should be strongly considered. Episodes of NCSE are typically recurrent in mosaic ring 20. Notably, these prolonged seizures should not be dismissed as a postictal finding but taken as a potential indicator of NCSE, especially if recurrent in nature. Children fitting this clinical scenario should have karyotype testing until other genetic diagnostic technologies are developed that can detect mosaic ring 20. This test must be run on 50 to 100 mitoses to best evaluate for low levels of mosaicism.³ Variable ictal EEG patterns were seen among patients. This is distinct from many other epilepsy syndromes, for example, childhood absence epilepsy or juvenile absence epilepsy, which has classical EEG findings and serves as defining features to the identification of these syndromes. Although variable ictal/interictal patterns were seen among patients with ring 20 syndrome, certain localizations were uncommon, specifically a temporal onset.

Because mosaic ring 20 syndrome can be missed if a karyotype is not ordered, it is likely that its incidence and prevalence are underestimated. Despite having a recognizable clinical phenotype, individuals with mosaic ring 20 syndrome experience a diagnostic delay of 7.7 years on average. Timely recognition of this clinical phenotype is paramount, and sending a karyotype analysis in these individuals early in the workup can prevent a prolonged diagnostic odyssey. With the advent of short-read NGS techniques including targeted sequence capture and whole-exome and WGS, karyotype analysis has become an infrequent component of the workup of children with newly diagnosed epilepsy. Moreover, even the recent consensus guidelines on genetic testing and counseling for the unexplained epilepsies relies heavily on NGS testing.⁴ Karyotype analysis is an important targeted testing modality that must be considered for all individuals with clinical features potentially consistent with mosaic ring 20 syndrome. Until karyotype is more routinely considered as a targeted testing option for children with undiagnosed epilepsy, we suspect that the true incidence of mosaic ring 20 syndrome will remain elusive. As more individuals with mosaic ring 20 syndrome are diagnosed, it is likely that further research into the pathophysiology and treatment of individuals with this rare genetic epilepsy will occur, with the ultimate hope that improved research will lead to improvements in quality of life for patients with mosaic ring 20 syndrome and their families. For instance, in the future, functional neuroimaging may serve as another noninvasive diagnostic tool to identify patients with mosaic ring 20 syndrome. In addition, functional connectivity may be measured by methods such as resting-state fMRI, EEG, and magnetoencephalography. Specifically, as understanding of the seizure networks of these patients is gained by PET, SPECT, and new EEG and MRI technologies, the hope is that they identify characteristic patterns. These tools may help to identify these patients earlier, provide insights into the pathophysiology of this disorder, and evaluate the outcome of therapies.^5-7

Glossary

CMA

chromosomal microarray

NCSE

nonconvulsive status epilepticus

NGS

next-generation sequencing

WGS

whole genome sequencing

Author Contributions

S. Woodson: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data. W.D. James: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data. R. Roth: drafting/revision of the manuscript for content, including medical writing for content. J.S. Barbieri: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data. S. Ershadi: major role in the acquisition of data. D. Cheng: major role in the acquisition of data M.P. Fitzgerald: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data.

Study Funding

The authors report no targeted funding.

Disclosure

John S. Barbieri has received consulting fees from Honeydew Care and Sanofi Pasteur for work unrelated to the current submission. All other authors report no conflicts of interest. Go to Neurology.org/NG for full disclosures.