Rubinstein-Taybi syndrome (RTS) is a rare, multi-system genetic condition affecting the skeletal structure, brain, and internal organs. First described in 1963, the syndrome is characterized by distinctive physical features combined with developmental and cognitive delays. RTS is present from birth, estimated to affect between one in 100,000 and one in 125,000 live births globally. It is considered a neurodevelopmental disorder, resulting in moderate to severe intellectual disability. The condition is caused by altered genes that regulate the activity of many other genes, disrupting normal development.
Defining Physical Characteristics
The physical features of RTS are often the first signs leading to recognition. The most recognized hallmark is the presence of broad or duplicated thumbs and great toes, which are often angulated or radially deviated. The severity of these distal limb differences varies.
Individuals commonly have a distinctive facial appearance that changes as they age. Characteristic features include a small head size, highly arched eyebrows, and long eyelashes. The nose is frequently prominent or “beaked,” and the nasal septum may hang lower than usual, known as a low-hanging columella.
Most individuals experience postnatal growth deficiency. While birth size is often normal, height, weight, and head circumference tend to drop rapidly in the first few months of life, leading to short stature. Other findings include dental abnormalities (crowded teeth and a high-arched palate) and issues with the eyes (strabismus or drooping eyelids).
Associated medical issues can affect various organ systems. Approximately one-third of individuals may have congenital heart defects, and kidney problems are reported. Males may present with undescended testicles, and there is an increased risk for developing noncancerous brain and skin tumors.
Developmental and Cognitive Profile
Intellectual disability is a consistent finding, typically ranging from moderate to severe, with the average intelligence quotient (IQ) falling between 30 and 70. This cognitive profile significantly affects learning and adaptive skills.
Motor skills are delayed, with children reaching milestones like sitting and walking later than peers. This delay is often accompanied by low muscle tone in infancy and a slightly unsteady or stiff walking gait later in life.
Speech and language delays are common, including difficulties in expressive language, vocal imitation, and symbolic play skills. Many individuals with RTS are described as having a generally happy and friendly disposition. However, some exhibit specific behavioral issues, including hyperactivity, repetitive behaviors, and features that overlap with autism spectrum disorder.
The Genetic Basis
Rubinstein-Taybi syndrome is classified as a chromatinopathy, caused by disrupted gene expression regulation. The condition is linked to pathogenic variants or deletions in one of two genes: CREBBP or EP300. CREBBP is implicated in the majority of cases, accounting for 55% to 75% of clinically diagnosed individuals.
Both CREBBP and EP300 provide instructions for making proteins that act as transcriptional coactivators and histone acetyltransferases. These proteins play a role in chromatin remodeling, altering DNA structure to turn genes on or off. Loss of one functional copy of either gene results in a reduced amount of the corresponding protein, disrupting the precise timing and level of gene expression required for normal development.
Approximately 99% of RTS cases result from a de novo mutation, meaning the genetic change is new and not inherited. This indicates the condition is sporadic. Only 8% to 10% of cases are caused by variants in the EP300 gene, which are often associated with a milder presentation.
Diagnosis and Management Approaches
Diagnosis is initially based on a clinical examination identifying the characteristic physical features. A medical professional looks for the combination of broad thumbs and great toes, specific facial characteristics, intellectual disability, and postnatal growth deficiency. The presence of these cardinal features suggests the diagnosis.
Confirmation is achieved through molecular investigations to identify a pathogenic variant in the CREBBP or EP300 genes. Genetic sequencing or techniques like Multiplex Ligation-dependent Probe Amplification (MLPA) detect point mutations or larger deletions. Even without an identified gene variant, a strong clinical presentation can still lead to a diagnosis, as the cause remains unknown in a minority of cases.
Management requires a comprehensive, multidisciplinary team approach due to the syndrome’s multi-system involvement. Early screening is implemented for associated health concerns, such as heart defects, kidney problems, and eye abnormalities. Surgical intervention may be considered for severe skeletal issues, like angulated thumbs or toes, to improve function.
Supportive therapies address developmental and cognitive delays. Educational support, often through specialized schooling, maximizes cognitive potential, and behavioral therapy helps manage issues like hyperactivity or repetitive behaviors. These therapies include:
- Physical therapy to improve gross motor skills.
- Occupational therapy for fine motor and daily living skills.
- Speech therapy to address communication challenges.