Rubinstein–Taybi syndrome (RTS) is a rare type of microdeletion syndrome characterized by short stature, moderate to severe learning difficulties, distinctive facial features, and broad thumbs and first toes. Other features of the disorder vary among affected individuals. These characteristics are caused by a mutation or deletion in the CREBBP gene, located on chromosome 16, and/or the EP300 gene, located on chromosome 22.
This condition is sometimes inherited as an autosomal dominant pattern, but often as a de novo. It affects an estimated 1 in 125,000-300,000 births.
Signs and symptoms Rubinstein-Taybi Syndrome is characterized by intellectual disability, distinct facies, and atypical growth. Anatomical & musculoskeletal Typical facial characteristics include a small chin and small oral cavity.
Other characteristics, which may vary by genetic cause of the disorder, include the following:
Broad thumbs Broad first toes Clinodactyly of the 5th finger Radially-deviated thumbs Broad toes, which may cause difficulty walking and may be so severe in a minority of patients as to require surgical intervention. Small chin and small oral cavity Narrow, highly-arched palate, which can sometimes show clefting In some cases, a relatively large tongue, bifid tongue tip, short frenulum, and wide alveolar ridges occur. Almost all patients with the condition have dental abnormalities, which can be primary or secondary to other aspects of the condition.
Hypermobility is common in the hip, elbows, fingers, thumbs, knees, and kneecaps, which may lead to stiffness and a waddling gait.
Scoliosis happens regularly in the condition, developing in late childhood and puberty. Other spinal abnormalities occur at higher rates than in the general population.
Cardiopulmonary Congenital heart defects occur in about 30% of cases, among which the most common are patent ductus arteriosus, persistent foramen ovale, atrial septal defect, and ventricular septal defect.
Hypertension occurs in 10% of adults, and is caused by renal artery stenosis.
Mild respiratory distress is common in newborns, and upper respiratory infections are common over the lifespan. Lower respiratory infections are less common and, when present, often caused by the aforementioned gastroenterological problems.
Interstitial lung disease is rare, but can occur. Pulmonary functioning can be lowered due to scoliosis, and chronic sleep apnoea can cause pulmonary hypertension.
Dermatological Keloids are the primary skin issue experienced by patients with the condition, the risk for which can be amplified or reduced by patient-specific and environmental factors. Keloids cannot develop spontaneously except in genetic conditions, and RTS provides the highest risk of keloid development. However, cancer risk isn't elevated due to these keloids.
Pilomatricomas are also a risk of the disease. Puberty is often a triggering factor.
Ingrown nails, congenital generalized hypertrichosis that becomes less marked with age, melanocytic naevi, white papulae on the limbs and trunk, additional nipples, lentigines, and café-au-lait spots are other findings associated with the condition.
Developmental
Birth & growth During pregnancy, pre-eclampsia is highly common. Rates of pre-term and full-term birth match those found among the general population. While birth parameters are generally normal, there is a higher incidence of microcephaly and growth restriction than among the general population, possibly due to the higher preeclampsia rates.
Although size at birth is normal, children with the disorder will generally not grow as fast as their peers, and will generally fall to about 2 standard deviations below their peer's heights, weights, and head circumferences. Children affected by the disorder will not experience a growth spurt during puberty, leading to adult heights, weights, and head circumferences around 3 standard deviations below normal. Growth hormone (GH) deficiency is rare but possible, and can cause the child to go further below the growth patterns of typically developing children.
Milestones & intellectual disability Individuals with the condition often experience milestones at a later date than typically-developing peers, but both populations experience wide ranges.
Intellectual disability and autism are common. A 2009 study found that children with RTS were more likely to be overweight and to have a short attention span, motor stereotypies, and poor coordination. The study hypothesized that the identified CREBBP gene impaired motor skills learning. Other research has shown a link with long-term memory (LTM) deficit. Generally, self-injurious and aggressive behavior are found in similar rates to the wider population of individuals with autism and intellectual disability. Some children will experience anxiety, and the presence of emotional outbursts and over-friendliness may be higher in this population. Repetitive behavior and especially repeated questioning is common in children with the condition, for which a variety of causes have been hypothesized. Distractability, impulsivity, and overactivity have been noted.
Endocrinological A small number of newborns and young children with the condition will experience transient hypoglycemia, which can be well-managed. Hyperinsulinemic hypoglycemia is very rare, but can occur, especially if the disorder is caused by an EP300 variant.
Gastroenterological Neonatal breastfeeding difficulties are present in roughly three quarters of affected individuals because of swalling miscoordination, poor nipple grasp, hypotonia, and gastroesophogeal reflux disease (GERD). This leads to roughly 40% of babies requiring feeding support, up to and including PEG tubes. Very rarely, eosiniphilic estrophagitis may form.
There may be a higher rate of gastroentological complications among individuals with the disorder; namely, duodenal web and GI tract malrotation. Constipation is highly common.
Hypnological Sleep can be affected by the facial abnormalities and increased laryngeal wall collapsibility. Sleep disorders are frequent, occurring moreso in children than adults. The risk of sleep disorders in children can be increased by more abnormal facial features, hypotonia, and adenotonsilar hypertrophy.
Immunological While most individuals with the condition do not experience recurrent infections, other aspects of the condition, like gastric reflux, can cause immunological difficulties, and immune system dysfunctions have been reported in some individuals with the condition.
Neurological & spinal Individuals commonly have corpus callosum malformations, followed in decreasing order of frequency by white matter abnormalities, cerebeller vermis malformations, and small/absent olfactory bulbs. Other brain malformations, including glandular, are uncommon but do occur, as is also true for spinal malformations.
While individuals often have abnormal EEG findings, clinical manifestations of epilepsy occur infrequently.
Oncological Newer studies have reversed older studies' findings that younger individuals with the condition have higher rates of cancer; data for older individuals is incomplete. However, benign tumors present at higher rates.
Opthalmalogical Ocular abnormalities and reduced vision are present at a higher rate in this population. There is a higher incidence of watery eye due to congenital issues in this population. Glaucoma is rare; it can be unilateral or bilateral and can be associated with anterior segment anomalies such as iris coloboma or ectopia lentis that can cause tearing, blepharospasm, photophobia, and enlargement of the eye manifesting as megalocornea and rapidly increasing myopia. Coloboma is reported in 10% of individuals and can affect any or all of following structures: iris, choroid, retina, or optic nerve.
Up to a quarter of individuals with RTS will have cataracts, generally in the first two months of life but sometimes later on which are often congenital.
Retinal abnormalities are frequent in this population.
Visual impairment occurs in a fifth of patients, often caused by the anatomical abnormalities associated with the condition. In severe cases, infantile nystagmus may follow from decresed sensory input from the eyes starting at birth. Refractive errors and strabismus occur in half to three quarters of individuals, and their severity may change rapidly.
Otolaryngological Recurrent middle ear infections can be caused by airway difficulties, which are themselves caused by the GORD and unique facial structures. This may cause conductive, sensorineural, and mixed hearing loss.
Urinogenitary 23% of individuals with RTS have urinary tract anomalies, including horseshoe kidney, renal duplication, renal agenesis, renal dysplasia, hydronephrosis, nephrolithiasis and vesicoureteral reflux. Renal artery stenosis can cause hypertension in children with the condition.
Shawl scrotum formation is common. 59% of men have cryptorchidism on one or both sides. Hypospadias in both sexes and labia minora fusion are rarer. Uterine malfunctions are rare. Female patients may have hypermenorrhagia or metrorhaggia.
Genetics
Rubinstein–Taybi syndrome, in many cases, is a microdeletion syndrome involving chromosomal segment 16p13.3 and is characterized by mutations in the CREBBP gene. Varying amounts of material are deleted from this section of the chromosome and account for the spectrum of physiological symptoms.
The CREBBP gene makes a protein that helps control the activity of many other genes. The protein, called CREB-binding protein, plays an important role in regulating cell growth and division and is essential for normal fetal development. If one copy of the CREBBP gene is deleted or mutated, cells make only half of the normal amount of CREB binding protein. A reduction in the amount of this protein disrupts normal development before and after birth, leading to the signs and symptoms of Rubinstein–Taybi syndrome.
Mutations in the EP300 gene, located on chromosome 22q13.2, are responsible for a small percentage of cases of Rubinstein–Taybi syndrome. These mutations result in the loss of one copy of the gene in each cell, which reduces the amount of p300 protein by half. Some mutations lead to the production of a very short, nonfunctional version of the p300 protein, while others prevent one copy of the gene from making any protein at all. Although researchers do not know how a reduction in the amount of p300 protein leads to the specific features of Rubinstein–Taybi syndrome, it is clear that the loss of one copy of the EP300 gene disrupts normal development.
CREBBP and p300 are the respective protein products of the paralogous genes CREBBP and EP300. Both of these related proteins, prototypical members of the p300-CBP coactivator family, have a bromodomain and a histone acetyltransferase domain and are able to bind to various gene-specific transcription factors as well as general transcription factors. Cell lines derived from RTS patients exhibit diminished acetylation of multiple histone proteins, particularly histone 2A and histone 2B, suggesting that this disease has its origins in problems with the regulatory mechanisms of transcription. The functions of CREBBP and p300 broadly overlap but do have co-activator–specific effects on gene expression. The proteins may also facilitate transcriptional elongation.
In approximately one third of the cases showing RTS symptoms, neither the CREBBP gene, nor the EP300 gene appear to be the cause of the disease.
A mouse model has been identified in order to perform experimental research procedures. The mice exhibited the same clinical RTS symptoms seen in humans, and the model has become a foundation for future research. Diagnosis