Rubinstein-Taybi Syndrome
Summary
Clinical characteristics.
Rubinstein-Taybi syndrome (RSTS) is characterized by distinctive facial features, broad and often angulated thumbs and halluces, short stature, and moderate-to-severe intellectual disability. The characteristic craniofacial features are downslanted palpebral fissures, low-hanging columella, high palate, grimacing smile, and talon cusps. Prenatal growth is often normal, then height, weight, and head circumference percentiles rapidly drop in the first few months of life. Short stature is typical in adulthood. Obesity may develop in childhood or adolescence. Average IQ ranges between 35 and 50; however, developmental outcome varies considerably. Some individuals with EP300-RSTS have normal intellect. Additional features include ocular abnormalities, hearing loss, respiratory difficulties, congenital heart defects, renal abnormalities, cryptorchidism, feeding problems, recurrent infections, and severe constipation.
Diagnosis/testing.
The diagnosis of RSTS is established in a proband with characteristic clinical features. Identification of a heterozygous pathogenic variant in CREBBP or EP300 confirms the diagnosis if clinical features are inconclusive.
Management.
Treatment of manifestations: Early intervention programs, special education, vocational training to address developmental disabilities, referral to behavioral specialists / psychologists, and support groups / resources for family members; standard treatment for eye abnormalities, hearing loss, sleep apnea, cardiac anomalies, renal anomalies, cryptorchidism, and dental anomalies; aggressive management of gastroesophageal reflux and constipation; surgical repair of significantly angulated thumbs or duplicated halluces.
Surveillance: Monitoring of growth and feeding, especially in the first year of life; annual eye and hearing evaluations; routine monitoring for cardiac, renal, and dental anomalies.
Genetic counseling.
RSTS is inherited in an autosomal dominant manner. RSTS typically occurs as the result of a de novo pathogenic variant in the family; most individuals represent simplex cases (i.e., the only affected member in a family). In most instances, the parents of an individual with RSTS are not affected. When the parents are clinically unaffected, sibs are still presumed to be at increased risk for RSTS because of the possibility of a mild phenotype in a heterozygous parent or parental somatic and/or germline mosaicism. The empiric recurrence risk for sibs is less than 1%. Individuals with RSTS rarely reproduce. The risk to offspring is 50%. Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
Diagnosis
Suggestive Findings
Rubinstein-Taybi syndrome (RSTS) should be suspected in individuals with the following characteristic clinical findings:
- Craniofacial appearance (see Figure 1)
- Downslanted palpebral fissures
- Convex nasal ridge with low-hanging columella
- High palate
- Grimacing smile
- Talon cusps (an accessory cusp-like structure on the lingual side of the tooth), usually occurring on the maxillary incisors of the permanent dentition
Figure 1.
Typical facial appearance in individuals with RSTS. Note arched brows, downslanted palpebral fissures, low-hanging columella, and grimacing smile.
Other features (see Figure 2 and Figure 3)
Figure 2.
Broad terminal phalanges (A) and broad, radially deviated thumbs (B)
Figure 3.
Broad, partially duplicated halluces
- The thumbs and halluces are almost always broad and often angulated.
- The distal phalanges of the fingers may appear broad.
- The proximal phalanges may be abnormally shaped. Radiographs of the hands and feet in individuals with RSTS are unusual but not necessarily diagnostic.
- Almost all males have undescended testes.
- Structural abnormalities of the urinary tract are common.
- Congenital heart defects of various types occur in approximately one third of individuals.
Growth
- While prenatal growth is often normal, height, weight, and head circumference percentiles rapidly drop in the first few months of life. Short stature is typical in adulthood.
- Obesity may develop, particularly in adolescence or adulthood.
Intellectual disability. The average IQ ranges between 35 and 50; however, developmental outcome varies considerably. Some individuals with EP300-RSTS have normal intellect [Fergelot et al 2016].
Establishing the Diagnosis
The diagnosis of RSTS is established in a proband with the above Suggestive Findings. Identification of a heterozygous pathogenic variant in CREBBP or EP300 by molecular genetic testing can confirm the diagnosis if clinical features are inconclusive (see Table 1).
Molecular genetic testing approaches can include gene-targeted testing (serial single-gene testing, multigene panel, chromosomal microarray analysis) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of RSTS is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with short stature and/or intellectual disability are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of RSTS, molecular genetic testing approaches can include single gene testing or use of a multigene panel. Chromosomal microarray analysis can be useful in some situations:
- Serial single-gene testing. Sequence analysis detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis of CREBBP first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis of CREBBP to detect intragenic deletions or duplications. If no pathogenic variant is found, perform sequence analysis of EP300. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis of EP300.
- A multigene panel that includes CREBBP, EP300, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
- Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including CREBBP and EP300) that cannot be detected by sequence analysis.Note: (1) Since a significant proportion of CREBBP pathogenic variants are large deletions, RSTS may be diagnosed by CMA performed without prior consideration of a diagnosis of RSTS. (2) Allelic disorders associated with contiguous gene deletions involving CREBBP and limited phenotypic overlap with RSTS have been reported (see Genetically Related Disorders). For individuals with features of RSTS as well as these related disorders, chromosomal microarray analysis (CMA) should be performed first.
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by short stature and/or intellectual disability, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is another option. Exome sequencing is most commonly used; genome sequencing is also possible.
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Rubinstein-Taybi Syndrome
| Gene 1, 2 | Proportion of Rubinstein-Taybi Syndrome Attributed to Pathogenic Variants in Gene | Proportion of Probands with a Pathogenic Variant 3 Detectable by Method | |
|---|---|---|---|
| Sequence analysis 4 | Gene-targeted deletion/duplication analysis 5 | ||
| CREBBP | 50%-60% 6 | ~80% | ~20% 7 |
| EP300 | 8%-10% 8 | >99% | <1% 9 |
| Unknown 10 | ~30% | NA | |
- 1.
Genes are listed in alphabetic order.
- 2.
See Table A. Genes and Databases for chromosome locus and protein.
- 3.
See Molecular Genetics for information on allelic variants detected in these genes.
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods (see Genetically Related Disorders).
- 6.
Coupry et al [2002], Bartsch et al [2005], Bentivegna et al [2006], Schorry et al [2008]
- 7.
Stef et al [2007], Spena et al [2015]
- 8.
Negri et al [2015], Fergelot et al [2016]
- 9.
Fergelot et al [2016]
- 10.
RSTS may be caused by pathogenic variants in another gene(s) in up to 30% of individuals [Bartsch et al 2005].
Clinical Characteristics
Clinical Description
Rubinstein-Taybi syndrome (RSTS) is frequently recognized at birth or in infancy because of the striking facial features and characteristic hand and foot findings. Problems in early life include respiratory difficulties, feeding problems, poor weight gain, recurrent infections, and severe constipation. Moderate intellectual disability is typical.
Growth. Although prenatal growth is usually normal, growth deficiency begins in the first year of life. There is typically an absence of a growth spurt in adolescence. While BMI is normal for males at age 21, it is increased for females at this age. Many adults develop obesity [Stevens et al 2011]. Average height for adult males is 162.6 cm and for adult females is 151.0 cm [Beets et al 2014]. Beets et al [2014] published growth charts for RSTS.
Eye findings include strabismus, refractory errors, ptosis, nasolacrimal duct obstruction, cataracts, coloboma, nystagmus, glaucoma, and corneal abnormalities.
Hearing loss. Recurrent or refractory middle ear disease can result in conductive hearing loss. Sensorineural hearing loss may also be seen.
Respiratory. Obstructive sleep apnea is often a considerable problem and may be caused by the combination of a narrow palate, micrognathia, hypotonia, obesity, and easy collapsibility of the laryngeal walls. There are reported incidences of intubation and anesthesia complications. Aspiration, asthma, and recurrent upper respiratory infections may also occur.
Cardiac. Approximately one third of affected individuals have a variety of congenital heart defects (e.g., atrial septal defect, ventricular septal defect, patent ductus arteriosus, coarctation of the aorta, pulmonary stenosis, bicuspid aortic valve, pseudotruncus arteriosus, aortic stenosis, vascular ring, conduction abnormalities).
Genitourinary. Renal abnormalities, including hydronephrosis and duplications, are very common. Other genitourinary complications include hypospadias, vesicoureteral reflux, nephrolithiasis, and urinary tract infections. Almost all boys have undescended testes.
Gastrointestinal. Feeding problems, gastroesophageal reflux, and constipation are common. Malrotation should be suspected if there is bilious vomiting, recurrent abdominal pain, failure to pass stool, or bloody stools [Stevens 2015].
Orthopedic. In addition to angulated thumbs and duplicated halluces, orthopedic issues include dislocated patellae, lax joints, spine curvatures, Legg-Perthes disease, slipped capital femoral epiphysis, and cervical vertebral abnormalities.
Neurologic. Occasional craniospinal and posterior fossa abnormalities including Chiari malformation, syringomyelia, os odontoideum, and cervical cord compression have been reported [Marzuillo et al 2013]. There may also be spinal cord tethering or lipoma. Seizures or abnormal EEG findings can occur.
Dental. Dental problems include crowding of teeth, malocclusion, multiple caries, hypodontia, hyperdontia, natal teeth, and talon cusps on the upper incisors of the secondary dentition.
Skin. Keloids may occur with only minimal trauma to the skin. Pilomatrixomas have been reported [Boot et al 2018].
Recurrent infection is reported in some individuals and includes otitis media, pneumonia, and other respiratory infections. There are reports of individuals with humoral or cellular immunodeficiency.
Tumors. Various benign and malignant tumors have been reported in individuals with RSTS including neuroblastoma, rhabdomyosarcoma, medulloblastoma, and hematologic malignancies. A recent study of Dutch individuals with RSTS did not confirm an increased risk for malignancies. However, the incidence of meningiomas and pilomatrixomas was significantly elevated [Boot et al 2018]. There are currently no standard screening protocols for tumors.
Puberty. Puberty and sexual development are normal.
Development and intellect. Delayed development is typical in children with RSTS. In one study, the average age of walking was 30 months, first words 25 months, and toilet training 62 months. Speech delay occurs in 90% of children and some remain largely nonverbal. Waite et al [2016] noted deficits in verbal and visuospatial working memory.
The average IQ in one study was 51 and in another study was 36. IQ scores range from 25 to 79. Performance IQ is usually higher than verbal IQ. Some individuals with EP300-RSTS have normal intellect [Fergelot et al 2016].
In one study of adults with RSTS, families reported a decline in abilities over time in 32%, including decreased social interaction, more limited speech, and worsening stamina and mobility [Stevens et al 2011].
Behavior. Impulsivity, distractibility, instability of mood, and stereotypies are frequently observed [Verhoeven et al 2010]. Other abnormal behaviors include attention problems, hyperactivity, self-injurious behaviors, and aggressive behaviors. Approximately 62% of adults with RSTS were reported to have autistic-like behaviors and one third had unreasonable fears or anxiety [Stevens et al 2011]. There may be an insistence on sameness and repetitive questioning [Waite et al 2015]. Crawford et al [2017] noted higher levels of panic attack, agoraphobia, and obsessive-compulsive disorder.
Phenotype Correlations by Gene
EP300 pathogenic variants cause a phenotype that resembles CREBBP-RSTS. However, with the exception of the low-hanging columella, the facial features in EP300-RSTS are less marked. Although the thumbs and halluces are broad, angulation is very uncommon. Intellectual disability is variable but is usually less severe and occasionally normal [Fergelot et al 2016].
Genotype-Phenotype Correlations
CREBBP. Stef et al [2007] did not observe a difference in phenotype based on CREBBP deletion size. Rusconi et al [2015] described 14 individuals with CREBBP deletions ranging from single exons to the whole gene and flanking regions. They noted that individuals with deletions extending beyond CREBBP did not always have a more severe phenotype than individuals with CREBBP missense variants. Spena et al [2015] noted that pathogenic variants outside the histone acetyltransferase domain may be associated with a mild phenotype. Somatic mosaicism may result in a milder phenotype [Gervasini et al 2007, Chiang et al 2009].
See Genetically Related Disorders for a discussion of contiguous gene deletions involving CREBBP.
Mosaic microdeletions have been noted by Gervasini et al [2007] and Schorry et al [2008]; these individuals tended to have a less severe phenotype than those with non-mosaic deletions.
Prevalence
Hennekam et al [1990b] reported a birth prevalence of 1:100,000 to 1:125,000 for RSTS in the Netherlands. RSTS appears to be pan ethnic.
Differential Diagnosis
For individuals with the distinctive facial features and hand and foot abnormalities, the diagnosis of Rubinstein-Taybi syndrome (RSTS) is usually straightforward.
Broad/angulated thumbs and halluces may be seen in the FGFR-related craniosynostosis syndromes (e.g., Pfeiffer syndrome, Apert syndrome), in Saethre-Chotzen syndrome, and in Greig cephalopolysyndactyly syndrome. The presence of craniosynostosis and the difference in facial features should differentiate these disorders (see Table 2).
Table 2.
Other Genes of Interest in the Differential Diagnosis of Rubinstein-Taybi Syndrome (RSTS)
| Gene(s) | DiffDx Disorder | MOI | Clinical Features of DiffDx Disorder | |
|---|---|---|---|---|
| Overlapping w/RSTS | Distinguishing from RSTS | |||
| FGFR1 FGFR2 | Pfeiffer syndrome & Apert syndrome (see FGFR-related craniosynostosis syndromes) | AD | Broad/angulated thumbs & halluces |
|
| TWIST1 | Classic Saethre-Chotzen syndrome | AD | Broad/angulated thumbs & halluces |
|
| GLI3 | Typical Greig cephalopolysyndactyly syndrome (GCPS) | AD | Broad/angulated thumbs & halluces |
|
| HOXD13 | Brachydactyly type D (OMIM 113200) | AD | Unilateral or bilateral shortening of the distal phalanx of the thumb | Absence of other features (broad thumbs seen as an isolated finding) |
| SRCAP 1 | Floating-Harbor syndrome | AD |
|
|
AD = autosomal dominant; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; MOI = mode of inheritance; OFC = occipital frontal circumference
- 1.
Floating-Harbor syndrome is caused by a pathogenic variant in SRCAP, which encodes an SNF2-related chromatin-remodeling factor that serves as a coactivator for CREB-binding protein. This likely accounts for the phenotypic overlap with RSTS.
Keipert syndrome is characterized by broad thumbs and halluces but is distinguished by hearing loss and characteristic facial features. The genetic basis of Keipert syndrome is unknown (OMIM 255980).
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Rubinstein-Taybi syndrome (RSTS), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended [Wiley et al 2003].
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with Rubinstein-Taybi Syndrome
| System/Concern | Evaluation | Comment |
|---|---|---|
| Neurologic | Ultrasound of spinal canal in neonatal period to screen for tethered cord | MRI of spinal canal should be performed in older children if symptomatic. |
| Constitutional | Measurement of growth | Plot parameters on RSTS growth charts. |
| Neurodevelopmental | Multidisciplinary developmental &/or neuropsychological eval | Assess: gross & fine motor, speech/language, cognitive, & vocational skills; behavior. |
| Ophthalmologic | Ophthalmologic exam | Evaluate for strabismus, refractory errors, ptosis, nasolacrimal duct obstruction, cataracts, coloboma, nystagmus, glaucoma, & corneal abnormalities. |
| Audiologic | Hearing eval | Recommended: auditory brain stem evoked response testing (see Hereditary Hearing Loss and Deafness Overview for details of eval) |
| Pulmonary | Eval for obstructive sleep apnea by polysomnography | If indicated by snoring, particular sleeping posture, night wakefulness, & excessive daytime sleepiness |
| Cardiac | Echocardiogram | Eval by cardiologist for structural heart defects |
| Genitourinary |
| Refer to urologist for undescended testes by age 6-12 mos. |
| Gastrointestinal |
| Upper GI study if symptoms of malrotation |
| Orthopedic | Assess thumbs & halluces, joints, & spine. | |
| Dental/Orthodontic | Dental & orthodontic evals | |
| Other | Consultation w/clinical geneticist &/or genetic counselor |
VCUG = voiding cystourethrogram
Treatment of Manifestations
Table 4.
Treatment of Manifestations in Individuals with Rubinstein-Taybi Syndrome
| Manifestation/Concern | Treatment | Considerations/ Other |
|---|---|---|
| Developmental & behavioral concerns |
| Refer family to support groups & other resources. |
| Ocular manifestations | Standard treatment per ophthalmologist | |
| Hearing loss | Standard treatment per audiologist | |
| Obstructive sleep apnea | Treatment per pulmonologist | |
| Cardiac anomalies | Standard treatment per cardiologist | |
| Renal anomalies | Standard treatment per nephrologist &/or urologist | |
| Cryptorchidism | Standard treatment per urologist | |
| Gastroesophageal reflux &/or constipation |
| |
| Significantly angulated thumbs or duplicated halluces | Surgical repair per orthopedist | |
| Dental anomalies | Standard treatment per dentist &/or orthodontist |
Prevention of Secondary Complications
Individuals with RSTS can be difficult to intubate because of the easy collapsibility of the laryngeal wall. An anesthesiologist comfortable with managing complex pediatric airway problems should therefore administer general anesthesia when needed. Individuals with RSTS may require earlier intubation and later extubation than other individuals undergoing similar procedures.
Surveillance
Table 5.
Recommended Surveillance for Individuals with Rubinstein-Taybi Syndrome
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Growth | Monitor weight & linear growth w/RSTS growth charts. | Frequently during 1st yr of life & at regular checkups |
| Ocular manifestations | Ophthalmologic eval | Annually or as necessary |
| Hearing loss | Audiologic eval |
|
| Dental anomalies | Dental & orthodontic eval | Beginning at age 1 yr; continue every 6 mos or as per dentist/orthodontist |
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Pregnancy Management
Preeclampsia was reported in 12/52 mothers whose fetus had EP300-RSTS and 2/59 of those with CREBBP-RSTS [Fergelot et al 2016].
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.