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Rubinstein-Taybi Syndrome

Synonym: Broad Thumb-Hallux Syndrome

, MD.

Author Information

Initial Posting: ; Last Update: August 22, 2019.

Estimated reading time: 20 minutes

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 diagnosis 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.

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.

Figure 2.

Broad terminal phalanges (A) and broad, radially deviated thumbs (B)

Figure 3.

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, 2Proportion of Rubinstein-Taybi Syndrome Attributed to Pathogenic Variants in GeneProportion of Probands with a Pathogenic Variant 3 Detectable by Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
CREBBP50%-60% 6~80%~20% 7
EP3008%-10% 8>99%<1% 9
Unknown 10~30%NA
1.

Genes are listed in alphabetic order.

2.
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. 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.
7.
8.
9.
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)DisorderMOIClinical Features of Differential Diagnosis Disorder
Overlapping w/RSTSDistinguishing from RSTS
FGFR1
FGFR2
Pfeiffer syndrome & Apert syndrome (see FGFR-related craniosynostosis syndromes)ADBroad/angulated thumbs & halluces
  • Bicoronal craniosynostosis or cloverleaf skull
  • Distinctive facial features
TWIST1Classic Saethre-Chotzen syndromeADBroad/angulated thumbs & halluces
  • Coronal synostosis (unilateral or bilateral), facial asymmetry, ptosis, & characteristic appearance of the ear (small pinna w/prominent crus)
  • Syndactyly of digits 2 & 3 of the hand variably present
  • Mild-to-moderate DD & ID reported; normal intelligence is more common.
GLI3Typical Greig cephalopolysyndactyly syndrome (GCPS)ADBroad/angulated thumbs & halluces
  • Preaxial polydactyly or mixed pre- & postaxial polydactyly, widely spaced eyes, & macrocephaly
  • Individuals w/mild GCPS may have subtle craniofacial findings.
  • Individuals w/severe GCPS may have seizures, hydrocephalus, & ID.
HOXD13Brachydactyly type D
(OMIM 113200)
ADUnilateral or bilateral shortening of the distal phalanx of the thumbAbsence of other features (broad thumbs seen as an isolated finding)
SRCAP 1Floating-Harbor syndromeAD
  • Facial features (e.g., low-hanging columella)
  • Short thumbs & broad fingertips
  • Short stature
  • Normal OFC
  • Absence of downslanting palpebral fissures
  • Thumbs not usually deviated & halluces not broad

AD = autosomal dominant; DD = developmental delay; 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/ConcernEvaluationComment
NeurologicUltrasound of spinal canal in neonatal period to screen for tethered cordMRI of spinal canal should be performed in older children if symptomatic.
ConstitutionalMeasurement of growthPlot parameters on RSTS growth charts.
NeurodevelopmentalMultidisciplinary developmental &/or neuropsychological evaluationAssess: gross & fine motor, speech/language, cognitive, & vocational skills; behavior.
OphthalmologicOphthalmologic examinationEvaluate for strabismus, refractory errors, ptosis, nasolacrimal duct obstruction, cataracts, coloboma, nystagmus, glaucoma, & corneal abnormalities.
AudiologicHearing evaluationRecommended: auditory brain stem evoked response testing (see Hereditary Hearing Loss and Deafness Overview for details of evaluation)
PulmonaryEvaluation for obstructive sleep apnea by polysomnographyIf indicated by snoring, particular sleeping posture, night wakefulness, & excessive daytime sleepiness
CardiacEchocardiogramEvaluation by cardiologist for structural heart defects
Genitourinary
  • Renal ultrasound examination
  • Consider VCUG.
  • Assess for presence of cryptorchidism in males.
Refer to urologist for undescended testes by age 6-12 mos.
Gastrointestinal
  • Assess for gastroesophageal reflux as warranted.
  • Assess for constipation.
Upper GI study if symptoms of malrotation
OrthopedicAssess thumbs & halluces, joints, & spine.
Dental/OrthodonticDental & orthodontic evaluations
OtherConsultation w/clinical geneticist &/or genetic counselor

VCUG = voiding cystourethrogram

Treatment of Manifestations

Table 4.

Treatment of Manifestations in Individuals with Rubinstein-Taybi Syndrome

Manifestation/ConcernTreatmentConsiderations/
Other
Developmental & behavioral concerns
  • Early intervention programs, special education, & vocational training to address developmental disabilities
  • Behavior management strategies incl referral to behavioral specialist / psychologist & consideration of medication if needed
Refer family to support groups & other resources.
Ocular manifestationsStandard treatment as per ophthalmologist
Hearing lossStandard treatment as per audiologist
Obstructive sleep apneaTreatment as per pulmonologist
Cardiac anomaliesStandard treatment as per cardiologist
Renal anomaliesStandard treatment as per nephrologist &/or urologist
CryptorchidismStandard treatment as per urologist
Gastroesophageal reflux &/or constipation
  • Standard medical management of gastroesophageal reflux & constipation
  • Consider tube feeding as needed for failure to thrive.
Significantly angulated thumbs or duplicated hallucesSurgical repair as per orthopedist
Dental anomaliesStandard treatment as 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/ConcernEvaluationFrequency
GrowthMonitor weight & linear growth w/RSTS growth charts.Frequently during 1st yr of life & at regular checkups
Ocular manifestationsOphthalmologic evaluationAnnually or as necessary
Hearing lossAudiologic evaluation
  • Annually
  • More frequent if patient has history of recurrent otitis media
Dental anomaliesDental & orthodontic evaluationBeginning 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Rubinstein-Taybi syndrome (RSTS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

Offspring of a proband. Each child of an individual with RSTS has a 50% chance of inheriting the RSTS-related pathogenic variant [Cotsirilos et al 1987, Hennekam et al 1989, Marion et al 1993, Petrij et al 2000, Bartsch et al 2010].

Other family members. The risk to other family members of a proband depends on the genetic status of the proband's parents: if a parent has the pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have had a child with RSTS.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the RSTS-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for RSTS are possible.

A priori low-risk pregnancies. RSTS is not usually diagnosed by prenatal ultrasound. However, routine prenatal ultrasound examination may identify findings such as growth restriction, polyhydramnios, broad thumbs, and brain abnormalities that raise the possibility of RSTS in a fetus not known to be at increased risk [Van-Gils et al 2019].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Rubinstein-Taybi Syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Rubinstein-Taybi Syndrome (View All in OMIM)

180849RUBINSTEIN-TAYBI SYNDROME 1; RSTS1
600140CREB-BINDING PROTEIN; CREBBP
602700E1A-BINDING PROTEIN, 300-KD; EP300
613684RUBINSTEIN-TAYBI SYNDROME 2; RSTS2

The CREBB-binding protein (CREBBP) is ubiquitously expressed and is involved in transcriptional coactivation of many different transcription factors. It has intrinsic histone acetyltransferase (HAT) activity and acts as a scaffold to stabilize additional protein interactions with the transcription complex via chromatin remodeling. CREBBP regulates the expression of many genes affecting cellular pathways such as cell growth control, cellular differentiation, apoptosis, and tumor suppression [Negri et al 2016]. Germline pathogenic variants in CREBBP may lead to a truncated CREB-binding protein or one with an amino acid substitution. Pathogenic variants in the HAT domain interfere with the acetylation of histones, which is an important step in transcription activation. CREBBP also acetylates p53, a tumor suppressor pathway known to be deregulated in many human cancers.

EP300 encodes the p300 transcriptional coactivator protein, which shares 63% homology with CREBBP at the amino acid level. It functions as HAT, regulating transcription via chromatin remodeling and playing an important role in cell proliferation and differentiation. Pathogenic variants result in truncated p300 protein or absence of allele expression, which may lead to loss of HAT activity.

Mechanism of disease causation. The mechanism of disease causation is largely unknown. However, two models considered are haploinsufficiency and dominant-negative inhibition [Park et al 2014].

References

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Chapter Notes

Author Notes

The Rubinstein-Taybi Syndrome Program at Cincinnati Children's is one of the country's leading programs for the care of children with RSTS and provides expert confirmation of diagnosis as well as the latest treatments and support.

Revision History

  • 22 August 2019 (sw) Comprehensive update posted live
  • 7 August 2014 (me) Comprehensive update posted live
  • 20 August 2009 (cd) Revision: sequence analysis, deletion/duplication analysis, and prenatal diagnosis available clinically for EP300 mutations
  • 16 April 2009 (me) Comprehensive update posted live
  • 26 June 2007 (cd) Revision: sequence analysis and mutation scanning available clinically
  • 2 October 2006 (me) Comprehensive update posted live
  • 20 December 2005 (cs) Revision: EP300 mutations found to cause some cases of RSTS
  • 13 September 2004 (cd) Revision: testing
  • 22 July 2004 (me) Comprehensive update posted live
  • 30 August 2002 (tk,me) Review posted live
  • 5 April 2002 (cs) Original submission
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