Rubinstein-Taybi Syndrome (RTS) is a rare genetic disorder characterized by a specific combination of physical abnormalities, developmental delays, and mild to moderate intellectual disability. The syndrome affects multiple body systems and is present from birth, though symptoms vary in severity among affected individuals. It was formally identified and described in 1963 by Dr. Jack Rubinstein, a pediatrician, and Dr. Hooshang Taybi, a radiologist. RTS is an uncommon condition, estimated to occur in approximately 1 out of every 100,000 to 125,000 live births worldwide.
The Genetic Causes
The underlying cause of Rubinstein-Taybi Syndrome is a genetic change affecting genes that are centrally involved in regulating the activity of many other genes. The condition is primarily linked to pathogenic variants in the CREBBP gene, which accounts for about 50% to 60% of all diagnosed cases. The CREBBP gene provides instructions for making the CREB-binding protein (CBP), a powerful transcriptional coactivator.
A smaller percentage of cases, around 3% to 8%, are caused by mutations in the EP300 gene, which is closely related to CREBBP and produces a similar protein, p300. A pathogenic change in either of these genes results in the cell producing only half the normal amount of the functional protein. This reduced functionality disrupts the complex regulation of cell growth, division, and development before and after birth, leading to the multi-system features observed in the syndrome.
Most cases arise from a spontaneous, new (de novo) mutation, meaning the genetic change was not inherited from either parent. The inheritance pattern is autosomal dominant because a change in only one copy of the gene in each cell is sufficient to cause the disorder. In rare instances, an affected parent may pass the gene variant to their child, carrying a 50% chance of inheritance. For about 30% of individuals, the specific genetic cause remains unknown.
Characteristic Physical and Developmental Features
The syndrome is defined by a collection of specific physical characteristics, with one of the most distinctive being abnormalities of the hands and feet. Individuals with RTS typically have broad or abnormally angled thumbs and broad first toes, which often prompts medical investigation. These skeletal features are often accompanied by short stature and microcephaly, which is a smaller-than-average head size.
Facial features are also highly characteristic and tend to become more pronounced as the individual ages. These features include highly arched eyebrows, long eyelashes, and eyes that may slant downward. A convex nasal bridge, a low-hanging columella (the tissue separating the nostrils), and a high-arched palate are also common findings. Some individuals may also experience eye abnormalities such as droopy eyelids (ptosis) and frequent eye infections due to tear duct blockage.
Developmentally, a wide range of intellectual disability is seen, typically falling in the mild to moderate range, with the average intelligence quotient (IQ) often between 35 and 50. Developmental delays are nearly universal, affecting motor skills like walking and sitting, as well as speech and communication. Low muscle tone, or muscular hypotonia, contributes significantly to delays in achieving these early motor milestones.
While many individuals with RTS are described as having a friendly and happy disposition, behavioral challenges such as anxiety, hyperactivity, or mood swings can also occur. The syndrome is also associated with a number of medical complications:
- Congenital heart defects.
- Kidney abnormalities.
- Skeletal problems, such as scoliosis and joint hyperextensibility.
- A slightly increased risk of developing certain tumors, particularly non-cancerous brain tumors and leukemia.
Diagnosis and Confirmation
The initial diagnosis of Rubinstein-Taybi Syndrome is typically based on a thorough clinical evaluation of the characteristic physical features. A healthcare provider, often a pediatrician or geneticist, will look for the combination of distinctive facial features, short stature, and the hallmark broad thumbs and great toes. The presence of developmental delay and intellectual disability further supports the suspected diagnosis.
To definitively confirm the condition, molecular genetic testing is required, especially when the clinical features are not entirely clear. This testing involves analyzing the individual’s DNA, usually from a blood sample, to identify a pathogenic variant or deletion in the CREBBP or EP300 genes. Techniques like targeted sequencing or chromosomal microarray analysis can detect these genetic changes.
Genetic testing provides a medical confirmation of the clinical diagnosis, identifying a specific gene mutation in roughly 70% of individuals who present with the typical features. However, a lack of an identified mutation in CREBBP or EP300 does not entirely rule out the diagnosis, as about 30% of clinically diagnosed cases have no known genetic cause yet identified. In these instances, the diagnosis relies on the presence of a strong constellation of the syndrome’s characteristic physical signs.
Coordinated Care and Management Strategies
Managing Rubinstein-Taybi Syndrome requires a proactive, multidisciplinary approach that addresses the broad spectrum of physical and developmental needs. Since the condition affects multiple body systems, care is coordinated among various medical and therapeutic specialists. A developmental pediatrician or geneticist often serves as the central point for overseeing this complex care plan.
Early Intervention and Therapy
Early intervention programs, including physical, occupational, and speech therapy, are started as soon as possible to address developmental delays and low muscle tone. Physical therapy helps improve gross motor skills, while occupational therapy focuses on fine motor skills and daily living activities like feeding and self-care. Speech therapy is particularly important for communication delays, sometimes incorporating nonverbal methods.
Health Surveillance
Regular health surveillance is organized to monitor for potential complications associated with the syndrome. This includes annual hearing and eye examinations, as well as routine cardiac evaluations to check for heart defects. Orthopedic specialists may be involved to manage skeletal issues, such as the anomalies of the thumbs and toes, and to monitor for scoliosis. Surgical intervention may be considered for severe orthopedic malformations.
Specialized Care
Dental care is also a focus, as individuals with RTS often have crowded teeth, high arched palates, and an accessory cusp on some teeth, requiring the attention of a pediatric dentist. Behavioral and educational support is structured to fit the individual’s specific intellectual needs, and specialists may assist with managing common behavioral issues like anxiety or hyperactivity. Furthermore, surgeons must be aware that individuals with RTS have an increased tendency to form keloids and hypertrophic scars following skin trauma or surgical procedures.