Rubinstein-Taybi Syndrome: Characteristics, Causes, and Treatment
Rubinstein-Taybi syndrome (RTS) is a genetic disorder prevalent in every 1 in 125,000 births. The disorder is characterized by a spectrum of congenital anomalies, growth deficiencies, motor skills deficits, intellectual disability, and behavioral abnormalities. Individuals with RTS are also at a higher risk for the development of various medical conditions. Despite numerous deficiencies, individuals with RTS typically exhibit social strengths and have a relatively normal life expectancy. The etiology of RTS is only partially known, and the CREBBP gene and EP300 gene have been identified as genes that are micro-deleted or mutated to cause RTS. These genes are associated with memory, cognitive functioning, motor skills learning, and cell growth, providing a partial explanation of the disease process and the presentations seen in this disorder. The abnormalities in specific areas of the brain of individuals with RTS could also provide a partial explanation of the disease process. Each case of RTS is unique, thus treatment is significantly individualized based on need. Treatment options include medical monitoring and treatments, physiotherapy, psychosocial treatment, and vocational and educational services. Care should be as comprehensive as possible to address all of the needs of the individual with RTS, as well as the needs of their caregivers and family.
Keywords: Rubinstein-Taybi syndrome (RTS), abnormalities, CREBBP gene, CREB-binding proteins (CBP)
Rubinstein-Taybi Syndrome: Characteristics, Causes, and Treatment
Rubinstein-Taybi syndrome (RTS) is a genetic disorder characterized by a spectrum of congenital anomalies, growth deficiencies, motor skills deficits, intellectual disability, and behavioral abnormalities (Ajmone et al., 2018). RTS was first described by Jack Rubinstein and Hooshang Taybi in 1963, hence the labeling of the syndrome (Hallam & Bourtchouladze, 2006). It is a rare disorder, occurring in one in every 125,000 births (Ajmone et al., 2018), and affects males and females relatively equally (Hallam & Bourtchouladze, 2006). The following will outline the characteristics of RTS, the currently identified causes of RTS, the potential disease process of RTS, and treatment options for individuals with RTS.
There are currently no diagnostic criteria for RTS (Hennekam, 2006), but there are various dysmorphic features and skeletal abnormalities that are characteristic of and are used to identify cases of RTS (Ajmone et al., 2018). In addition, individuals with RTS experience postnatal growth deficiency and express motor deficiencies in comparison to normally developing peers (Cazalets et al., 2017). Furthermore, there are cognitive deficiencies and behavioral abnormalities associated with RTS (Cazalets et al., 2017).
Physical Abnormalities and Medical Issues
There are multiple structural and functional anomalies that occur during intrauterine development in individuals with RTS, which become visible to diagnose postnatal (Waite et al., 2015). Distinctive facial features of RTS include an undersized jaw (micrognathia), arched eyebrows, a down-slanted opening between the eyelids (palpebral fissures), increased distance between the eyes (hypertelorism), and externally abnormally shaped (dysplastic) and low-set ears (Ajmone et al., 2018; Cazalets et al., 2017). Additional distinctive facial features include a prominent beaked nose, a low hanging nasal base (columella), a high palate (roof of the mouth), a thin upper lip, cusp-like projections (talon cusps) at the permanent incisors, and a grimacing smile (Ajmone et al., 2018; Cazalets et al., 2017; Hennekam, 2006). Other abnormalities include small head circumference (microcephaly), enlarged hallux toes (the big toe), broad and bent (angulated) thumbs, and a short stature (Ajmone et al., 2018; Cazalets et al., 2017).
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Individuals with RTS often have additional congenital anomalies unrelated to facial features, such as heart defects, renal malformations, and skin anomalies (Cazalets et al., 2017). These potential additional anomalies can lead to medical complications and increase the risk of developing certain medical conditions. For example, there is increased risk of overgrowth of scar tissue (keloid formation), an increased risk of tumors and cancer, and an increased likelihood of the development of defects at the base of the skull and cerebellum (Chiari malformation) in individuals with RTS (Ajmone et al., 2018; Cazalets et al., 2017; Hennekam, 2006). Neonatal feeding difficulties, neonatal respiratory difficulties, obstructive sleep apnea, hearing loss, severe constipation, and childhood/adolescent obesity are also medical issues associated with RTS (Galera et al., 2009; Stevens, 2019).
Moreover, neurological problems and brain abnormalities have been seen in individuals with RTS (Lee et al., 2015). Neurologically, seizures occur in approximately 26% of this population and electroencephalographic (EEG) abnormalities occur in approximately 66% of this population (Ajmone et al., 2018). Moreover, magnetic resonance imagining (MRI) of individuals with RTS has demonstrated thinning of the corpus callosum, widening of the area between the brain and its protective layers (subarachnoid space), and delayed myelination (Lee et al., 2015). This data indicates that there are structural abnormalities within the brain that are likely contributing to the expression of atypical characteristics associated with RTS.
Psychomotor development is delayed in children with RTS (Milani et al., 2015), as these individuals typically have impaired motor skills learning (Galera et al., 2009). In addition to this developmental delay, motor capacities are often reduced for individuals with RTS (Cazalets et al., 2017). One of the most common motor issues in individuals with RTS is poor coordination (Hennekam, 2006). In comparison to typically developing children, children with RTS exhibit a reduction in motor performance, especially in motor skills requiring a high level of visuomotor coordination (Cazalets et al., 2017).
Cognitive Deficiencies and Behavioral Abnormalities
Individuals with RTS typically have diagnosable intellectual disabilities (ID) ranging from mild to profound, but are of moderate severity on average (Ajmone et al., 2018). Intelligence quotient (IQ) assessments on individuals with RTS have found an average IQ between 35 and 50 (Hennekam, 2006). Generally, nonverbal performance IQ is higher than verbal IQ in individuals with RTS (Ajmone et al., 2018). Furthermore, approximately 90% of individuals with RTS exhibit short attention span and limited concentration (Ajmone et al., 2018; Galera et al., 2009).
Children with RTS generally do not exhibit significantly different internal or external behavioral problems compared to same age peers (Galera et al., 2009). Although socio-behavioral difficulties are not typical of individuals with RTS, these individuals still express some abnormal behaviors in comparison to same age peers (Cazalets et al., 2017; Galera et al., 2009). For instance, repetitive behaviors that are often seen in individuals with neurodevelopmental disorders, such as Autism Spectrum Disorder (ASD), are also seen in individuals with RTS (Cazalets et al., 2017; Waite et al., 2015). These behaviors include repetitive questioning, adherence to routines, and body stereotypy (Waite et al., 2015). Mood swings and obsessive-compulsive disorder (OCD) are also observed in individuals with RTS, generally in adulthood (Milani et al., 2015).
While there are numerous deficiencies and abnormalities associated with RTS, these individuals usually have social skills, as evidence by a marked ability to develop and maintain excellent social contact (Hennekam, 2006). Children with RTS are often friendly, smiling, happy, easy-going, and readily accept social interactions (Galera et al., 2009; Hennekam, 2006). Interestingly, social deficits that are characteristic of other similar neurodevelopmental disorders are not present in individuals with RTS.
RTS is an autosomal dominant genetic disease, thus the abnormal gene is only needed from one parent for the child to develop the disorder (Cazalets et al., 2017). Despite the current knowledge and research, the etiology of RTS has only been partially identified (Ajmone et al., 2018). Chromosomal micro-deletions and molecular mutations on specific genes have been discovered to partially explain the genetic cause of RTS (Bartsch et al., 2005). Given the identification of multiple genes that can cause RTS, it is considered a genetically heterogeneous disorder (Cazalets et al., 2017). Additionally, these genetic mutations are typically new occurrences (de novo), as data indicates that there is a rare recurrence of RTS in siblings (Hallam & Bourtchouladze, 2006).
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One mutation that has been identified is in the CREBBP gene on chromosomal region 16p13.3, which accounts for approximately 55% of cases of RTS (Ajmone et al., 2018; Bartsch et al., 2005). The CREBBP gene provides instructions for making CREB-binding proteins (CBP), which play a role in memory formation and cognitive dysfunction, including motor skills learning (Hallam & Bourtchouladze, 2006). CBP also plays a critical role in biological cell growth, division, and maturation (Hallam & Bourtchouladze, 2006). Researchers identified that isolated loss of histone acetyl transferase (HAT) activity of the CBP subsequently results in RTS (Hennekam, 2006). Another mutation that has been identified is in the EP300 gene on chromosomal region 22q13, which accounts for approximately 8% of cases of RTS (Ajmone et al., 2018). The EP300 gene provides instructions for making E1A-binding proteins such as p300, which also plays a role in biological cell growth, division, and maturation (Hennekam, 2006).
Non-genetic, environmental causes of RTS have not been identified to date, but potential environmental causes cannot yet be ruled out given that the exact etiology of RTS has not been established (Hallam & Bourtchouladze, 2006). Two specific genetic mutations have only been indicated in approximately 63% of cases of RTS, thus more research is needed to determine whether RTS has an entirely genetic etiology or co-factorial causes.
The genes that have been identified as micro-deleted and mutated in RTS are genes associated with memory, cognitive functioning, and motor skill learning. Provided this information, it is evident that these mutations can likely result in the cognitive and motor deficits previously indicated. Additionally, the physical abnormalities and growth deficiencies seen in RTS can partially be explained by the dysfunction of CBP and p300, as this protein is involved in cell growth and maturation (Hallam & Bourtchouladze, 2006). Moreover, identification of affected structures can provide further relational information between biological abnormalities and motor and cognitive deficiencies. For example, delayed myelination of white matter is associated with delayed acquisition of developmental motor and cognitive milestones (Pujol et al., 2004). Delayed myelination has been found in children with RTS, thus providing another explanation for the cognitive and motor deficits prior indicated. Another example for consideration is that the corpus callosum integrates information between the left and right cerebral cortices (Kalat, 2016), thus the thinning of the corpus callosum seen in individuals with RTS may delay the integration of information, ultimately resulting in some of the developmental, motor, and cognitive deficits demonstrated by individuals with RTS. Furthermore, the intact social skills of individuals with RTS are indicative the there are some different biological processes occurring in RTS compared to other neurodevelopmental disorders, even though numerous symptomatic similarities have been found. It is noteworthy that there is a significant lack of information regarding RTS, therefore these are plausible, but not confirmed, potential explanations of the disease processes of RTS.
Given that there are various biopsychosocial problems associated with RTS that may or may not manifest for an individual with RTS, treatment is typically unique to the individual, depending on the presenting issues. Despite the wide range of issues for individuals with RTS, life expectancy is normal (Hennekam, 2006) and over 90% of these individuals survive into adulthood (Milani et al., 2015). Treatment typically targets various aspects of the disease, thus many individuals with RTS need comprehensive care including medical treatment, physiotherapy, psychosocial treatment, and vocational and educational services and accommodations.
Significant monitoring of a child with RTS is needed in the early years of life to manage physical anomalies and developmental difficulties (Stevens, 2019). Caregivers should especially focus on feeding problems and constipation in the first year (Hennekam, 2006). Primary care doctors and any necessary specialists should regularly examine children with RTS to continually maintain health and manage potential medical complications often associated with RTS (Stevens, 2019). Specialists may include an ophthalmologist for ocular issues, audiologist for hearing issues, cardiologist for heart defects, urologist for renal malformations, a dentist for dental anomalies, and a pulmonologist for obstructive sleep apnea (Stevens, 2019). Growth and dietary monitoring in later childhood and adolescence are additionally recommended to prevent overfeeding and overweight (Galera et al., 2009). Medications have not been identified to treat RTS specifically, as the physical characteristics are congenital and generally not curable. Medications may be prescribed and surgery may be needed to treat other associated health problems on an individual basis (Hennekam, 2006). Regarding surgeries, it is typically difficult to intubate individuals with RTS, thus anesthesiologists who can manage complex airway problems are necessary in order to prevent secondary complications (Stevens, 2019). Moreover, physiotherapies, such as physical therapy, could be beneficial in helping children with RTS improve development of motor skills and address motor deficiencies (Cazalets et al., 2017). For instance, a physiotherapist could help a child improve their attention and visuomotor skills (Cazalets et al., 2017).
Psychosocial, Vocational, and Educational
Early intervention is essential for children with RTS (Stevens, 2019). It is recommended that children are assessed early and appropriately placed in special education classrooms or school that can accommodate their needs (Hennekam, 2006; Stevens, 2019). Speech therapy may be beneficial (Stevens, 2019), but alternatives may be needed if speech therapy is not resulting in enhanced communication. For example, given that nonverbal IQ is higher than verbal IQ for individuals with RTS, teaching them and communicating with them in sign language may help them communicate more efficiently. Additionally, if emotional and behavioral issues are identified (i.e. mood swings, OCD), referrals to a behavioral specialists, psychologist, and support groups are appropriate (Stevens, 2019). Vocational training is also recommended to address developmental and cognitive disabilities, especially as the individual ages and enters adulthood (Stevens, 2019).
There are also clinical considerations for the family of individuals with RTS. Professionals should consider the impact of caregiving and the associated stressors, as well as the impact that caregiving for one child has on other siblings. Professionals should also provide quality information in layperson language to help parents provide optimal care and support to their child with RTS (Stevens, 2019). Genetic counseling may also be helpful for families of individuals with RTS, especially to provide a genetic risk assessment if they plan on having another child (Stevens, 2019). Overall, RTS is a disorder that results in a multitude of medical, developmental, cognitive issues, thus treatment should be as comprehensive and individualized as possible to help enhance the quality of life of individuals living with RTS.
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