Genetics of Rubinstein-Taybi Syndrome

Three main genetic etiologies for RSTS have been identified, accounting for approximately half of all cases. They include the following[7, 8, 9] :

• 16p13 deletion syndrome - A submicroscopic, proximal deletion on chromosome 16p13.3, which includes the CREB-binding protein ( CBP) gene, DNASE1, and TRAP1
• Rubenstein-Taybi syndrome 1 (RSTS-1) - A point mutation or deletion in  CBP (OMIM 180849); 50% of cases ^[5]
• Rubenstein-Taybi syndrome 2 (RSTS-2) - A point mutation or deletion in EP300 (OMIM 602700);  3% of cases ^[4]

Mutation of the CBP gene has been detected in approximately 50% of affected individuals with RSTS. Mutations in EP300 on 22q13.2 account for a small number of cases. Epigenetic alterations have been suggested as a possible cause for the remaining cases, as approximately 50% of individuals with clinical features consistent with RSTS do not have a detectable deletion or mutation in CBP or EP300.

A study by Enomoto et al demonstrated the allelic heterogeneity of RSTS. The analysis, as performed in 19 patients, was aimed at CRP and EP300. In two patients, non-coding regions contained genetic alterations, including, in one individual, “a deep 229-bp intronic deletion” that produced a splicing error. In two more patients, with an EP300 variant, abnormal neural tube development, a rare clinical finding, occurred. Another rare finding, “anorectal atresia with a cloaca,” existed in a patient with a CRP variant.[10]

Frequency

International

Beets et al stated that the birth prevalence of RSTS is 1 in 100,000-125,000.[6]

Mortality/Morbidity

Respiratory infections and complications from congenital heart disease are major causes of morbidity and mortality in the first years of life. Instability of the craniovertebral junction at C1-C2, hypoplasia of the dens, and fusion of the cervical vertebrae have been described as potentially life-threatening abnormalities. Issues with perioperative management, including collapsible airway and susceptibility to succinylcholine, have also been described. Wiley et al have provided guidelines for the clinical management and surveillance of patients with RSTS.[11]

Race

No known race predilection has been noted.

Sex

Males and females appear to be equally affected.

Age

RSTS is often identified in the newborn period when the characteristic physical features are noted (eg, prominent nose, broad thumb, broad great toe).

Patients with RSTS can have a normal lifespan. Major causes of morbidity and mortality in the first years of life include the following:

• Respiratory infections
• Complications from congenital heart disease
• Instability of the craniovertebral junction at C1-C2
• Hypoplasia of the dens
• Fusion of the cervical vertebrae
• Perioperative management - Collapsible airway, susceptibility to succinylcholine

See the following:

• Rubinstein-Taybi Syndrome: Genetics Home Reference

Patients show multiple congenital anomalies, including intellectual disabilities, growth deficiency (postnatal), microcephaly, broad thumbs and first toes, and dysmorphic facial features. Patients have a striking facial appearance, characterized by highly arched eyebrows, long eyelashes, abnormally slanting palpebral fissures, broad nasal bridge, beaked nose, and mandibular abnormalities, including mild micrognathia.[12, 13, 3]

Selected physical findings

Facial abnormalities

These include the following:

• Abnormal maxilla with narrow palate

• Prominent beaked nose

• Down-slanting palpebral fissures

• Low-set and/or malformed ears

• Strabismus 

• Large anterior fontanel 

• Microcephaly 

• Malpositioned or crowded teeth, high palate, short upper lip, and protuberant lower lip are also seen

Digit abnormalities

These include the following:

• Broad great toes

• Broad thumbs with radial angulation

• Broadness of other fingers

• Persistent fetal finger pads

• Syndactyly and polydactyly

Abnormalities of growth and development

These include the following:

• Mental retardation with intelligence quotient (IQ) of 30-79 (average 51) - More than 50% of patients have an IQ of less than 50

• Speech difficulty

• Hypotonia

• Electroencephalographic abnormalities (even in the absence of seizures)

• Growth retardation (postnatal-onset growth deficiency; Rubinstein-Taybi syndrome [RSTS]–specific charts are available) - Average male height: 153 cm; average female height: 147 cm

• Feeding problems - Gastroesophageal reflux

Skeletal abnormalities

These include the following:

• Retarded osseous maturation

• Vertebral and sternal abnormalities

• Patellar dislocation

Cardiac anomalies

These include the following:

• Ventricular septal defect (VSD) and patent ductus arteriosus (PDA) are most common

• Atrial septal defect (ASD), coarctation of the aorta, pulmonic stenosis, and bicuspid aortic valve

Other symptoms and findings

These include the following:

• Cryptorchidism (very common in males)

• Hirsutism

• Keloid formation

• Cardiac arrhythmias

• Laryngeal wall collapsibility

• Sleep and anesthesia problems

In a study by Ajmone et al of 23 patients with RSTS, brain magnetic resonance imaging (MRI) revealed that 73.6% of the cohort had dysmorphia of the corpus callosum, with or without the presence of other anomalies, such as minor dysmorphia of the cerebellar vermis and hyperintensity of the posterior periventricular white matter. In addition, whole-spine MRI scans indicated a greater tendency for patients with RSTS to have a low-lying conus medullaris without thickening of the filum terminale.[14]

The following tests are used in the diagnosis and monitoring of Rubinstein-Taybi syndrome (RSTS):

• Microarray
• Whole exome sequencing (WES) 
• Targeted sequencing of  CBP and EP300
• Electroencephalogram - Strongly consider even in the absence of seizures
• Measurement of growth and plotting of parameters on published syndrome-specific growth charts ^[6] ​
• Ophthalmologic examination
• Hearing evaluation in newborn period and auditory brain stem evoked response testing 
• Regular dental evaluations
• Echocardiogram
• Monitoring for constipation 
• Monitoring for cryptorchidism in males
• Specialty orthopedic assessment of thumbs and toes
• Ongoing scoliosis evaluation
• Monitoring for obstructive sleep apnea
• Tethered cord evaluation - Neonatal ultrasonography of the spinal canal in all patients; magnetic resonance imaging (MRI) in symptomatic older patients

 

These include the following:

• Ongoing scoliosis and spinal abnormalities evaluation
• MRI if indicated by neuroexamination ^[15]
• Echocardiogram or cardiology evaluation
• Chest radiograph if pulmonary symptoms
• Tethered cord evaluation - Neonatal ultrasonography of the spinal canal in all patients; MRI in symptomatic older patients

These include the following:

• Chromosomal karyotype analysis

• Fluorescence in situ hybridization (FISH) for chromosome band 16p13[16]

• Mutation analysis of the CBP gene

• Electrocardiogram for cardiac investigation for congenital heart disease

• Neurologic evaluation

Wide variability is noted in Rubinstein-Taybi syndrome (RSTS); therefore, treatment is individualized based on patient findings. Typically, physical therapy, speech and feeding therapy, and special education are important adjuncts in infancy and early childhood. Regular dental exams and symptomatic treatment of infections are also part of care for RSTS.

As with medical care, surgical treatment is individualized based on patient findings.

Symptomatic treatment as needed.

Outpatient care includes the following[17] :

• Growth measurement and plotting of parameters on published syndrome-specific growth charts ^[6]
• Ophthalmologic examination
• Hearing evaluation in newborn period and auditory brain stem evoked-response testing 
• Dental evaluations
• Echocardiogram or assessment by cardiologist for structural heart defects
• Monitoring for constipation
• Monitoring for cryptorchidism in males
• Specialty orthopedic assessment of thumbs and toes
• Scoliosis evaluation
• Monitoring for obstructive sleep apnea
• Tethered cord evaluation - Neonatal ultrasonography of the spinal canal in all patients; MRI in symptomatic older patients

These include the following:

• Anesthesia respiratory compromise
• Intellectual disabilities
• Fine motor challenges from deviated thumbs
• Difficulty wearing shoes
• Tumor risk
• Infections
• Cardiac arrhythmia - Possible with use of succinylcholine.

A study from the Netherlands, by Boot et al, of 87 individuals with RSTS found the incidence of benign meningiomas and pilomatricomas in this cohort to be significantly greater than in the overall Dutch population. However, the report did not find evidence for a greater incidence of malignant tumors in RSTS, although the investigators cautioned that because the cohort was small, the study could not completely rule out the possibility of a greater tendency for malignancies to develop in this syndrome.[18]

Feeding difficulties are common in infancy and, together with the genetically based growth retardation characteristic of this syndrome, often result in a clinical picture of failure to thrive.

Respiratory infections and complications from congenital heart disease are major causes of morbidity and mortality in the first years of life.

Developmentally, milestones in these patients are delayed to such an extent that patients typically sit up at age 11 months and walk at age 30 months. First words typically are spoken at age 25 months, and affected individuals are toilet trained at about age 62 months. Approximately two thirds of patients older than 6 years can read, but they usually do not progress beyond a first-grade level. However, survival rates, in general, are good, with frequent reports of adults with RSTS.