Years published: 2023
NORD gratefully acknowledges Amanda J. Grieco, PhD, Wendy Chung, MD, PhD, Clinical and Molecular Geneticist, Kennedy Family Professor of Pediatrics and Medicine, Columbia University Medical Center, and CTNNB1 Connect and Cure for the preparation of this report.
CTNNB1 syndrome is an extremely rare genetic neurodevelopmental disorder caused by changes (pathogenic variants or mutations) in the CTNNB1 gene. Neurodevelopmental disorders are ones that impair or alter the growth and development of the brain and the central nervous system. Common signs and symptoms include varying degrees of intellectual disability (cognitive impairment), delays in reaching developmental milestones (developmental delays), speech delays, abnormal muscle tone, vision impairments, distinct facial features and behavioral problems. Less common features include feeding difficulties, abnormalities of body structure or function and growth abnormalities.
CTNNB1 syndrome is a collection of signs and symptoms that can vary between affected individuals. It is important to note that every individual is unique and how the disorder affects one person can be different from how it affects another.
Neurologic features are present in most individuals affected by CTNNB1 syndrome. A child’s progression through predictable developmental phases like sitting up and crawling may be delayed (developmental delays). Global developmental delays can affect intellectual development ranging from mild to severe and motor functions including muscle coordination to complete tasks like writing and walking. Speech delays and language disorders are common, but the degree of difficulty can range from speaking in simple sentences to communicating through signs, vocalization or manipulating objects.
Many individuals affected by CTNNB1 syndrome have altered muscle tone. Most babies have low muscle tone (hypotonia) in the torso which can affect motor developmental milestones and feeding ability. Later in childhood, most children experience abnormally high muscle tone (hypertonia) in the arms and legs, which causes prolonged muscle contractions and muscle tightness (spasticity) and can lead to difficulties with speech and movement like walking and stability. Many individuals experience involuntary contractions of the muscles (dystonia) that can cause abnormal body positions and repetitive or twisting movements.
Most people with CTNNB1 syndrome have vision difficulties. Some individuals have a problem seeing clearly (refractive errors) which can cause blurriness of objects that are up-close (farsighted) or at a distance (nearsighted). Focusing difficulties may occur from misalignment of the eyes where one eye aligns inward toward the nose or outward away from the nose while the other eye remains focused (strabismus). The back of the eye contains a nerve and blood vessel-rich lining (retina) which transmits visual images to the brain and makes it possible to see. Some individuals affected by CTNNB1 syndrome have a rare eye condition characterized by abnormal growth and development of the blood vessels in the retina (exudative vitreoretinopathy) which can lead to vision loss and more rarely, blindness. Rarely, the retina can detach from the back of the eye which can lead to blindness.
A variety of facial differences are common in individuals affected by CTNNB1 syndrome including a bulbous nose, a longer than usual vertical indentation that extends from the upper lip to the nose (philtrum) and a thin upper lip. Some individuals have sparse and thin hair and eyebrows and long eyelashes. Less common facial features include low set ears and eyes that are spaced closer than usual and a high roof of the mouth (palate).
Some individuals affected by CTNNB1 syndrome experience behavioral or psychiatric issues that can include anxiety, aggressive behavior, sleep difficulties, temper tantrums, attention problems and features suggestive of autism spectrum disorder.
Some individuals, especially babies, have feeding and gastrointestinal difficulties. Feeding challenges can include difficulty coordinating motor functions to breastfeed, chew food or swallow (dysphagia). Additionally, abnormal gastrointestinal motor functions can lead to frequent constipation, diarrhea and backflow of the contents of the stomach into the esophagus (gastroesophageal reflux).
Structural and growth abnormalities can occur in individuals affected by CTNNB1 syndrome. Infants may be born with a birth weight that is lower than expected based on sex (intrauterine growth restriction) and some children will continue to have difficulties gaining weight and growing in height. Infants may also be born with a head circumference that is smaller than expected based on age and sex (microcephaly) and may continue to have a smaller head compared to peers of the same age and sex as they grow. Occasionally, brain anomalies that can further contribute to developmental delays may occur including underdevelopment of the area of brain which connects the two cerebral hemispheres (hypoplasia of the corpus callosum) and an abnormal fluid space in the brain (ventriculomegaly). Rarely, as some children grow up, spinal anomalies that further affect motor functions can occur including abnormal restrictions on spinal cord movements (tethered spinal cord), abnormal growth of a fluid-filled pockets (cysts) in the spinal cord (syringomyelia) and an abnormal curvature of the spinal cord. A minority of children may be born with heart anomalies but may not experience any symptoms.
CTNNB1 syndrome is caused by changes (pathogenic variants or mutations) in the CTNNB1 gene. Genes provide instructions for creating (encoding) proteins that play a critical role in many functions of the body. When a variation in a gene occurs, the protein that is created may be faulty, inefficient, absent or overproduced. Depending upon the functions of the protein, this can affect many parts of the body.
Researchers are trying to understand if specific types of variants in the CTNNB1 gene may affect the specific clinical features that an individual experiences. This is called genotype-phenotype correlation and is currently being studied.
The CTNNB1 gene contains instructions for creating a protein called beta-catenin (β-catenin). Beta-catenin is found in cells throughout the body and plays an essential role in growth and development, especially in the brain. It helps strengthen connections between nerve cells (neurons) which allows for proper brain function, and it helps coordinate when other genes are read (expressed) which ensures the right proteins are produced at the right time for the body to develop properly. Individuals with CTNNB1 syndrome have a variant of the CTNNB1 gene which prevents the normal beta-catenin protein from being produced and consequently, can lead to a range of neurodevelopmental and health issues.
Variants in the CTNNB1 gene almost always occur as new (sporadic or de novo) mutations, which means they occurred randomly in that child without either parent having the gene variant. Since the disorder is usually not inherited from a parent, it’s estimated there is only a 1% risk of the gene variant reoccurring in another child from the same parents. When it does recur, it’s because one of the parents has some cells in their body (egg or sperm cells) that have the gene variant although the variant was not detected in the genetic test on blood or saliva.
If a person with a CTNNB1 syndrome were to have a child, they have a 50% chance to pass the CTNNB1 gene variant to each of their children, since the gene is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease.
CTNNB1 syndrome is believed to affect females and males in equal numbers. The exact number of people who have this disorder is unknown. According to CTNNB1 Connect & Cure, as of March 2023, there are 300 individuals around the world known to have CTNNB1 syndrome. Rare disorders like CTNNB1 syndrome often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. As molecular genetic testing becomes more widely used, it is estimated that approximately 3 individuals in every 100,000 births may be affected by CTNNB1 syndrome.
A diagnosis of CTNNB1 syndrome is based on characteristic clinical features, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. No formal clinical diagnostic criteria have been established for CTNNB1 syndrome. A diagnosis can only be made through molecular genetic testing.
Clinical Testing and Workup
Molecular genetic testing can detect variants in the CTNNB1 gene but is available only as a diagnostic service at specialized laboratories. Doctors will take a blood or saliva sample of individuals suspected of having CTNNB1 syndrome for a molecular genetic test called whole exome sequencing (WES). WES examines the parts of genes that provide instructions to create proteins called exons and evaluates all of the exons (exome) at the same time. WES can detect variants in the CTNNB1 gene or in other genes that may have overlapping clinical features. More recently, the CTNNB1 gene has been added to a molecular genetic test known as the intellectual disability next generation sequencing panel. This test only examines genes throughout the genome that have known associations with intellectual disabilities. This more targeted approach means the test can be less expensive.
Affected individuals may undergo additional tests to assess the extent of clinical features. Developmental examinations can help assess any developmental delays including motor function and speech or language delays. Neuropsychological assessments can help evaluate brain function and its impact on cognition and behaviors, particularly in individuals older than 12 months. An advanced imaging test called magnetic resonance imaging (MRI) may be recommended. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and body tissues. An MRI of the brain and spine can help detect abnormalities. Swallow tests are frequently needed to assess any feeding issues and eye exams can evaluate eye and vision function.
The treatment of CTNNB syndrome is directed toward the specific clinical features that are present. There are no standardized treatment protocols or guidelines, but the coordinated efforts of a team of specialists can help tailor treatments to the affected individual. Body systems that are or may be affected should be routinely evaluated. Regular monitoring by healthcare professionals can track symptoms as they change or develop over time and treatments can be appropriately adjusted to best support current needs.
Healthcare professionals that may be part of the care team can include pediatricians and physicians who specialize in diagnosing and treating developmental neurological disorders (neurologists), disorders of the eyes (ophthalmologists), digestive system (gastroenterologists), musculoskeletal system (orthopedist) and heart (cardiologists). Additionally, rehabilitation therapists (physical, occupational and speech therapists), psychiatrists and other healthcare professionals may be needed to plan treatments and administer therapies.
Feeding and swallowing issues should be evaluated regularly at clinic visits and appropriately addressed by rehabilitation therapists. Feeding therapy may help resolve motor function and coordination difficulties or provide helpful feeding techniques like chilling or thickening food. In some patients, a nasogastric tube (NG-tube) or gastrostomy tube (G-tube) to deliver food directly to the stomach may be appropriate. Close monitoring for constipation and diarrhea may be needed.
A developmental assessment should be performed, and appropriate rehabilitation therapies may be instituted. Mobility and motor functions can be addressed by physical and occupational therapy. In some children, orthopedic devices for proper positioning or durable medical devices for mobility assistance may be required. Increased muscle tone abnormalities may benefit from muscle relaxant therapies. Behavioral concerns may be addressed through applied behavior analysis (ABA) or by a developmental pediatrician. Eye abnormalities and vision changes should be evaluated regularly. Individuals with abnormal growth and development of blood vessels in the retina (exudative vitreoretinopathy) may require laser therapy, while eye misalignment or blurred vision should be addressed to prevent further vision complications.
Speech therapy may be required, and some affected individuals may benefit from the use of sign language and various communication devices or modalities. Additional medical, social or vocational services including specialized learning programs may be necessary, including an individualized learning plan (IEP) and 504 plan that are updated regularly.
Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is also often recommended.
Ongoing research is focused on understanding CTNNB1 syndrome better to develop targeted medications and therapies. Current research priorities and ways to participate can be found at (https://www.curectnnb1.org/research/funded-research/) and (https://www.simonssearchlight.org/research/what-we-study/ctnnb1/).
Drs. Michelle Jacob and Jonathan Alexander at Tufts University are studying the molecular and functional changes of CTNNB1 syndrome in laboratory mice affected by variants of the CTNNB1 gene. They are also investigating medications that may increase the amount of functional beta-catenin protein to normal levels and, consequently, may lead to improved cognitive and motor functions in humans. (https://www.curectnnb1.org/news/ctnnb1-syndrome-collaboration-with-dr-jacobs-from-tufts-university-in-the-news/)
Simon Searchlight CTNNB1 syndrome patient registries are collecting natural history data on clinical features and progress of the disorder to discover trends across patients and help design future clinical trials. (https://www.simonssearchlight.org/research/what-we-study/ctnnb1/)
Dr. Wendy Chung at Boston Children’s Hospital with the patient registries at Simons Searchlight is generating human neurons in the laboratory setting that are derived from the cells of CTNNB1 syndrome affected individuals. These neurons can be used to better understand the effects of variants of the CTNNB1 gene on the function of the beta-catenin protein and allow for preclinical drug testing for new therapies.
Researchers at the University of Sydney and Children’s Medical Research Institute in collaboration with the National Institute of Chemistry Slovenia have started the Accelerating Development of Gene Therapies for CTNNB1 Program. The program’s goal is to introduce a corrected CTNNB1 gene into human cells that can produce a correct beta-catenin protein and improve the disorder. https://clinicaltrials.gov/ct2/show/study/NCT04812119?cond=ctnnb1&draw=2&rank=1)
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 website.
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
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
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/
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Kayumi S, Pérez-Jurado L, Palomares M et al. Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants. Genet Med. 2022;24(11):2351-2366. https://www.sciencedirect.com/science/article/pii/S1098360022008978
Miroševič S, Khandelwal S, Sušjan P, et al. Correlation between phenotype and genotype in CTNNB1 syndrome: a systematic review of the literature. Int J Mol Sci. 2022;23(20):12564. https://pubmed.ncbi.nlm.nih.gov/36293418/
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