Last updated:
3/13/2024
Years published: 2024
NORD gratefully acknowledges William T. Gibson, MD, PhD, Senior Clinician Scientist, UBC and British Columbia Children’s Hospital Research Institute, for the preparation of this report.
Cohen-Gibson Syndrome is a neurodevelopmental disorder caused by disease-causing changes (pathogenic variants) in the EED gene. Affected children typically have developmental delays or intellectual disability, tall stature for age, large head size, large hands and feet and facial features that are unusual for their family background.
There is no curative treatment for Cohen-Gibson syndrome. Management focuses on supporting children and young adults as they acquire motor skills, oral communication skills and social skills. Patients with suspected Cohen-Gibson syndrome should be referred to a general pediatrician, and eventually to a clinical geneticist or pediatric neurologist. If a developmental pediatrician is available, detailed developmental assessment is advisable.
Developmental Delay and Intellectual Disability
Many individuals with Cohen-Gibson syndrome have developmental delays. When these delays do not resolve and intellectual disability results, it is typically mild intellectual disability. Some degree of speech and/or language delays (reading, writing) are seen in most patients. The proportion of patients who ultimately live independently as adults is not yet known, as most cases reported so far have been children.
Overgrowth
Tall stature, large hands and feet and large head size are features of generalized overgrowth. Obesity may or may not be a feature in any individual patient. X-rays often reveal “advanced bone age,” where the apparent age of the bones is greater than the patient’s age calculated based on their birth date. The growth spurt at puberty does not appear to be significantly different from average, based on the small number of older patients reported to date. Bone growth typically stops after puberty when the patients reach their final adult height.
Other
Variants in the EED gene have been reported in the tissue found in cancerous tumours, such as peripheral nerve sheath tumors. However, the degree to which patients who are born with pathogenic variants in EED in all of their cells (sometimes termed “germline pathogenic variants” or “germline constitutional variants”) is not clear. No specific cancer screening protocols are yet being recommended for patients with Cohen-Gibson syndrome. Nevertheless, patients with unexplained signs or symptoms that do not resolve (e.g. pallor, anemia, abdominal pain, masses in the abdomen, masses in the skin and just under the skin) should be referred to appropriate medical specialists.
Cohen-Gibson syndrome is caused by likely pathogenic or pathogenic variants (disease-causing changes) in a gene called EED (embryonic ectoderm development). The EED protein cooperates with several other proteins, including EZH2 and SUZ12, to form a protein bundle called PRC2 (polycomb repressive complex 2). The job of the PRC2 complex is to help cells put away genes that they don’t need to use – a process called chromatin compaction. Essentially, when the body’s stem cells need to convert into a specific organ, they need to put away all their stem cell genes, as well as all the genes they would use if they were turning into a different organ. In this way, muscle cells would put away all the “not-muscle” genes (such as genes specific to fat tissue, the eyes, bone, etc.) and leave the “muscle-only” genes turned on. Bone cells would put away all the “not-bone” genes (including the genes that self-renew stem cells) and leave the “bone-only” genes turned on. The PRC2 complex adds a modification to histone proteins in the nucleus of the cell to help these histone proteins pack themselves (and the DNA that is wrapped around them) together more tightly. If the PRC2 complex is not working at full efficiency, such as when a pathogenic variant is present in the EED gene, some genes remain turned “on” for longer, and this affects how the body tissues develop.
Since EED binds to EZH2 and SUZ12, scientists think that pathogenic variants in the EZH2 gene and SUZ12 gene have much the same effects on the PRC2 complex as do pathogenic variants in EED. This is likely the reason why the genetic diseases associated with EZH2 (Weaver syndrome) and SUZ12 (Imagawa-Matsumoto syndrome) have similar features to Cohen-Gibson syndrome (see “Disorders with Similar Symptoms” below).
Most people have two copies of the EED gene that both work normally. Their biological mother contributes one EED gene in the egg, and their biological father contributes one EED gene in the sperm. If one copy of the EED gene is missing (“deleted”) or changed in a way that its efficiency is reduced (“likely pathogenic” variant or “pathogenic” variant), a person will be born with Cohen-Gibson syndrome. Cohen-Gibson syndrome is considered to be an autosomal dominant condition, because only one variant copy of the gene is necessary to cause the disease. For autosomal dominant conditions, the risk for an affected person to pass on the dominant variant is 50% with each pregnancy. It is not clear whether there may be effects on male or female fertility from pathogenic variants in EED. Some cases of affected mothers having affected children are known. When a variant arises for the first time in the affected patient (i.e. both parents test negative for the variant), the patient’s variant is assumed to have arisen de novo, sometimes termed a “brand new” variant. In these situations, the risk for the patient’s parents to conceive a second affected child is often estimated as ~1%. In these people, the variant is assumed to be present in some proportion of the sperm or eggs, though not in all the cells of one of the parents. One of the parents is then thought of as having “mosaicism” for the variant, but if they have no signs or symptoms of it they are considered to be unaffected.
Cohen-Gibson syndrome is very rare, and the true incidence and prevalence of the condition is unknown. As of 2024, fewer than 10 patients with this disorder have been reported in the medical literature. There does not seem to be a specific global superpopulation or subpopulation that is affected more frequently than others. Because the features of Cohen-Gibson syndrome overlap with those seen in Weaver syndrome, Imagawa-Matsumoto syndrome and other overgrowth conditions (see below), the diagnosis is best confirmed by finding a variant in EED that is classified by a genetic testing lab as likely pathogenic or pathogenic. Large DNA sequencing studies that have aggregated data from hundreds of thousands of healthy people and people with a variety of diseases have found that about 1 in 500 people have a detectable rare variant of unknown significance (VUS) in EED; since the prevalence of Cohen-Gibson syndrome cannot plausibly be 2 persons per 1,000 population, most variants in EED will not cause Cohen-Gibson syndrome.
Confident diagnosis of Cohen-Gibson syndrome requires clinical examination by a physician as well as clinical-grade DNA testing that identifies a likely pathogenic or pathogenic variant in the EED gene that affects the EED protein. Testing results from labs that are not accredited to provide clinical-grade testing should not be used for diagnosis, since both “false positive” and “false negative” results would result in an incorrect diagnosis.
There is currently no cure for Cohen-Gibson syndrome and there are no licensed medications that target the cause at the level of the EED protein. Supportive care remains the cornerstone of management. Multiple specialist visits in the early years are often required.
Neurodevelopment
If possible, infants and toddlers (aged 0-3 years) should be enrolled in early intervention programs to assist with developmental milestones (e.g. crawling, walking and feeding). A formal assessment by a developmental pediatrician is likely to be useful prior to enrollment in school. In the United States, there are federally funded early intervention programs in every state. Many Canadian provinces also offer funded early intervention programs for infants and toddlers. Where possible, developmental supports should continue into the preschool age group, and an individualized education plan (IEP) or similar writeup should be prepared to assist teachers and one-to-one educational assistants.
Periodic updates to the initial developmental pediatrics assessment are advisable, where possible, since the development of each child may proceed at different rates in different skill sets (e.g. gross motor, fine motor, speech). Language support in the form of speech therapy and, where necessary, assistive communication devices, can narrow the developmental gap between patients and their age-matched peers.
In the United States, a variety of supports are available, including an IEP (individualized education plan), a 504 plan (which prohibits discrimination based on disability), Developmental Disabilities Administration (DDA) enrollment and Supplemental Security Income (SSI). Families should speak with their child’s care providers about the supports available in their area.
Neurologic Symptoms
Low muscle tone (“hypotonia”) is frequent in childhood. Joint contractures may or may not be related to high muscle tone (“hypertonia,” or “spasticity” when severe). Patients may benefit from occupational therapy (e.g. for fine motor skills), physiotherapy (for strength-building and to address joint contractures) or pediatric physiatry (physical and rehabilitation medicine). See also below “Musculoskeletal Issues.”
Seizures have been described in one patient so far. Routine EEG is not recommended for all patients at this time, but should of course be done if there is a suspicion of seizures. Seizure treatment should follow standard protocols – there is not yet specific evidence that one particular class of anti-seizure medications works best in patients with Cohen-Gibson syndrome.
Musculoskeletal Issues
Joint contractures may affect the small joints of the fingers and toes, but may also affect larger joints such as the elbows, hips and knees. Orthopedic assessment for flat feet and other issues such as gait abnormalities may be beneficial, and orthotic inserts or orthopedic shoes may be designed with the patient’s needs in mind. Specific mention should be made of the possibility of instability of the cervical spine. One patient required surgery to relieve spinal cord compression near the base of the skull after the sudden onset of walking difficulties during a gymnastics class. Though routine X-rays or CT scan of the cervical spine are not yet recommended, physicians should be willing to investigate sudden-onset symptoms thoroughly. Spine curvatures such as scoliosis and kyphosis are managed according to standard protocols.
Mental Health/Behavior
Any child with a neurodevelopmental disorder should be considered to be at increased risk for mental health issues, including anxiety and depression. Children with socialization and/or behavioral difficulties should receive an assessment for autism spectrum disorder.
Glucose Control/Endocrine
Low blood glucose (hypoglycemia) may or may not be related to poor feeding or inappropriately high insulin levels. Blood glucose should be checked if there are feeding difficulties in the newborn period. The risk for childhood-onset or adult-onset diabetes is unknown.
Vision and Hearing
Crossed eyes (strabismus) and refractive errors including nearsightedness (myopia) are common. Routine vision screening and eye exams should be guided by signs and symptoms. Speech delays should prompt age-appropriate hearing screening.
Sleep
An irregular sleep-wake cycle and or daytime sleepiness should prompt a sleep study. Sleep apnea is not a major feature of Cohen-Gibson syndrome but is treatable when identified.
Other Systems
Echocardiogram should be considered if heart murmurs are present. If pigmented nevi (“moles”) are present, these should be monitored for changes in size, border, color, symmetry and elevation above the skin.
Genetic Counseling
A genetic counselor can interpret the results of clinical DNA testing and assess reproductive risks. Because Cohen-Gibson syndrome is typically caused by de novo variants, the reproductive risks for parents of an affected person to have a second affected child are thought to be low (~1%). Testing of parents for the patient’s likely pathogenic/pathogenic variant can clarify these reproductive risks. If a variant of unknown significance (VUS) is identified in the EED gene, testing for this variant in the parents can help to reclassify the variant as likely pathogenic or likely benign.
Family Supports
Families may need respite care for children, adolescents and adult family members with special needs. Home support workers and/or social workers may be able to assist in identifying locally available resources.
There are currently no clinical trials being conducted for Cohen-Gibson syndrome. Professor Gibson’s Lab at the University of British Columbia is running an ongoing registry study to follow the natural history of children and adults with Cohen-Gibson syndrome and other epigenetic disorders. For more information contact: https://bcchr.ca/wgibson.
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:
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: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Griffiths S, Loveday C, Zachariou A, Behan LA, Chandler K, Cole T, D’Arrigo S, Dieckmann A, Foster A, Gibney J, Hunter M, Milani D, Pantaleoni C, Roche E, Sherlock M, Springer A, White SM, Tatton-Brown K, et al. EED and EZH2 constitutive variants: a study to expand the Cohen-Gibson syndrome phenotype and contrast it with Weaver syndrome. Am J Med Genet A. 2019;179:588–94. doi: 10.1002/ajmg.a.61066. [PubMed]
Smigiel R, Biernacka A, Biela M, Murcia-Pienkowski V, Szmida E, Gasperowicz P, Kosinska J, Kostrzewa G, Koppolu AA, Walczak A, Wawrzuta D, Rydzanicz M, Sasiadek M, Ploski R. Novel de novo mutation affecting two adjacent amino acids in the EED gene in a patient with Weaver syndrome. J Hum Genet. 2018;63:517–20. doi: 10.1038/s10038-017-0391-x. [PubMed]
Cooney E, Bi W, Schlesinger AE, Vinson S, Potocki L. Novel EED mutation in patient with Weaver syndrome. Am J Med Genet A. 2017;173:541–5. doi: 10.1002/ajmg.a.38055. [PubMed]
Imagawa E, Higashimoto K, Sakai Y, Numakura C, Okamoto N, Matsunaga S, Ryo A, Sato Y, Sanefuji M, Ihara K, Takada Y, Nishimura G, Saitsu H, Mizuguchi T, Miyatake S, Nakashima M, Miyake N, Soejima H, Matsumoto N. Mutations in genes encoding polycomb repressive complex 2 subunits cause Weaver syndrome. doi: 10.1002/humu.23200. Hum Mutat. 2017;38:637–48. doi: 10.1002/humu.23200. [PubMed]
Tatton-Brown K, Loveday C, Yost S, Clarke M, Ramsay E, Zachariou A, Elliott A, Wylie H, Ardissone A, Rittinger O, Stewart F, Temple IK, Cole T, Mahamdallie S, Seal S, Ruark E, Rahman N, et al. Mutations in epigenetic regulation genes are a major cause of overgrowth with intellectual disability. Am J Hum Genet. 2017;100:725–36. doi: 10.1016/j.ajhg.2017.03.010. [PMC free article] [PubMed]
Cohen AS, Gibson WT. EED-associated overgrowth in a second male patient. J Hum Genet. 2016;61:831–4. doi: 10.1038/jhg.2016.51. [PubMed]
Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. doi: 10.1038/ng.3469. [PMC free article] [PubMed]
Cohen AS, Tuysuz B, Shen Y, Bhalla SK, Jones SJ, Gibson WT. A novel mutation in EED associated with overgrowth. J Hum Genet. 2015;60:339–42. doi: 10.1038/jhg.2015.26. [PubMed]
Lee W, Teckie S, Wiesner T, Ran L, Prieto Granada CN, Lin M, Zhu S, Cao Z, Liang Y, Sboner A, Tap WD, Fletcher JA, Huberman KH, Qin LX, Viale A, Singer S, Zheng D, Berger MF, Chen Y, Antonescu CR, Chi P. PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nat Genet. 2014; 46(11):1227-32. doi: 10.1038/ng.3095. [PMC free article][PubMed]
Margueron R, Justin N, Ohno K, Sharpe ML, Son J, Drury WJ III, Voigt P, Martin SR, Taylor WR, De Marco V, Pirrotta V, Reinberg D, Gamblin SJ. Role of the polycomb protein EED in the propagation of repressive histone marks. Nature. 2009;461:762–7. doi: 10.1038/nature08398. [PMC free article] [PubMed]
INTERNET
Cohen ASA, Gibson WT. EED-Related Overgrowth. 2019 Apr 11. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK540017/ Accessed Feb 13, 2024.
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