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. Characteristic craniofacial features include 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-related 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. A heterozygous pathogenic variant in CREBBP or EP300 identified by molecular genetic testing 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.

Pregnancy management: Preeclampsia or placental abnormalities have been reported in some pregnancies with RSTS.

Genetic counseling.

RSTS is inherited in an autosomal dominant manner. Most individuals diagnosed with RSTS have the disorder as the result of a de novo pathogenic variant and are the only affected member of their families. Rarely, an individual diagnosed with RSTS has the disorder as the result of a CREBBP or EP300 pathogenic variant inherited from a heterozygous or mosaic parent. Each child of an individual with RSTS has a 50% chance of inheriting the RSTS-related pathogenic variant. Once the RSTS-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for RSTS are possible.

Suggestive Findings

Rubinstein-Taybi syndrome (RSTS) should be suspected in individuals with the following characteristic clinical and neuroimaging findings and family history.

Major features

• 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.
• Most 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. Absence of the pubertal growth spurt adds to the reduced final height for males and females.
• Microcephaly is present within the first few months of life and typically persists into 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-related RSTS have normal intellect.

Neuroimaging findings. The most common feature on brain imaging is a dysmorphic or dysplastic corpus callosum (73.6%).

Family history. Because Rubinstein-Taybi syndrome is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Rarely, the family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations).

Establishing the Diagnosis

The diagnosis of RSTS is established in a proband with the aforementioned suggestive findings. Identification of one of the following on molecular genetic testing can confirm the diagnosis especially if clinical features are inconclusive (see Table 1):

• A heterozygous pathogenic (or likely pathogenic) variant in CREBBP or EP300 (65%-70% of affected individuals) [Fergelot et al 2016, Pérez-Grijalba et al 2019]
• A heterozygous deletion of chromosome 16p13.3 (CREBBP) or 22q13.2 (EP300) (10% of affected individuals) [Negri et al 2015, Pérez-Grijalba et al 2019]

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include gene-targeted 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 other inherited disorders with similar features are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Rubinstein-Taybi syndrome (RSTS) is a multisystem disorder characterized by short stature, variable structural abnormalities, characteristic facial appearance, broad thumbs and halluces, and variable degrees of intellectual disability. The most consistent craniofacial features are microcephaly, highly arched eyebrows, downslanted palpebral fissures, convex nasal ridge, low-hanging columella, and grimacing smile. The thumbs and halluces are broad and often angulated [Hennekam et al 1990, Stevens et al 1990].

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 issues, poor weight gain, recurrent infections, and severe constipation.

To date, at least 600 individuals have been identified with a pathogenic variant in CREBBP or EP300 [Fergelot et al 2016, Pérez-Grijalba et al 2019, Cross et al 2020, Douzgou et al 2022]. The following description of the phenotypic features associated with this condition is based on these reports.

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. A higher incidence of microcephaly and growth restriction has been noted in infants with EP300 pathogenic variants, possibly related to the increased incidence of preeclampsia.

While body mass index is normal for males at age 21, it is increased for females at this age. Many adults develop obesity of unclear etiology [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, congenital glaucoma, and corneal and retinal 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 commonly occurs 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 problems due to facial anatomy and laryngo-, tracheo-, and bronchomalacia and anesthesia complications. These include arrhythmias and obstructive symptoms occurring post extubation. Aspiration, asthma, and recurrent upper respiratory infections may also occur. Interstitial lung disease has also been reported in several individuals [Bradford et al 2022].

Cardiac. Approximately one third of affected individuals have 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 of the renal system, are very common. Other genitourinary complications include hypospadias, vesicoureteral reflux, nephrolithiasis, and urinary tract infections. Most boys have undescended testes.

Gastrointestinal. Feeding problems, gastroesophageal reflux, and constipation are very common. Intestinal malrotation should be suspected if there is bilious vomiting, recurrent abdominal pain, failure to pass stool, or bloody stools [Stevens 2015]. Anorectal malformations have also been reported [Belanger Deloge et al 2023].

Orthopedic. In addition to angulated thumbs and duplicated halluces, orthopedic issues include dislocated patellae, lax joints, spine curvatures, Legg-Perthes disease, increased fracture risk, and cervical vertebral abnormalities.

Neurologic. The most common intracranial malformation involves abnormal structure of the corpus callosum. Occasional craniospinal and posterior fossa abnormalities including Chiari malformation, Dandy-Walker 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 (most commonly on the upper incisors of the secondary dentition).

Skin. Keloids may occur with only minimal trauma to the skin. Pilomatrixomas (sometimes multiple) are relatively common [Boot et al 2018]. Ingrown nails are common, especially in the partially duplicated thumbs and halluces.

Recurrent infection is reported in some individuals; infections include otitis media, pneumonia, and other respiratory infections. There are reports of individuals with humoral or cellular immunodeficiency.

Tumors. There are early reports of various benign and malignant tumors in individuals with RSTS including neuroblastoma, rhabdomyosarcoma, medulloblastoma, and hematologic malignancies. A 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 recommendations for additional surveillance for malignancy before the age of 40 years.

Endocrine. Persistent hyperinsulinemic hypoglycemia has been reported in a few children with RSTS, primarily in those with EP300 pathogenic variants [Welters et al 2019].

Puberty. Puberty and sexual development are typically 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 [Stevens et al 1990]. 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 of affected individuals in one study was 51 and in another study 36 [Stevens et al 1990, Hennekam et al 1992]. IQ scores range from 25 to 79. Performance IQ is usually higher than verbal IQ [Stevens et al 1990, Hennekam et al 1992]. Some individuals with EP300-related RSTS have normal intellect [Fergelot et al 2016].

In one study of adults with RSTS, families reported a decline in developmental 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, overfriendliness, increased pain threshold, 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.

Brain MRI findings. The most common feature on brain imaging is a dysmorphic or dysplastic corpus callosum (73.6%) with or without minor dysplasia of the cerebellar vermis, periventricular posterior white matter hyperintensity, and other less common anomalies. Other infrequent findings include Chiari malformation, Dandy-Walker malformation, and underdeveloped pituitary gland.

Prognosis. More than 90% of individuals with RSTS survive into adulthood [Milani et al 2015].

It is unknown whether life span in RSTS is abnormal. One reported individual is alive at age 67 years [Stevens et al 2011], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Phenotype Correlations by Gene

EP300 pathogenic variants cause a phenotype that resembles CREBBP-related RSTS. However, except for the low-hanging columella, the facial features in EP300-related RSTS are less marked. Keloids are also less frequent. Maternal preeclampsia, intrauterine growth restriction, and microcephaly are more common in individuals with EP300 pathogenic variants. 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

The type and location of pathogenic variants in CREBBP and EP300 do not correlate with specific physical features, malformations, cognition, or behavior. An exception is missense variants between the end of exon 30 and the beginning of exon 31 in both CREBBP and EP300. This phenotype is distinct from RSTS and is known as Menke-Hennekam syndrome (see Genetically Related Disorders).

EP300. In one study examining many variants, no correlation was found between overall phenotype severity and the type of pathogenic variant or location of the pathogenic variant relative to the HAT domain or exon 31. Similar observations were made between genotype and severity of intellectual disability and presence of major organ difference [Cohen et al 2020].

CREBBP. Deletions of variable sizes involving CREBBP have been reported in many individuals with RSTS to date. Stef et al [2007] and Pérez-Grijalba et al [2019] 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 pathogenic missense variants.

Spena et al [2015] noted that pathogenic variants outside the histone acetyltransferase domain may be associated with a mild phenotype. Pérez-Grijalba et al [2019] did not find a correlation of pathogenic variant type, location, or involvement of the HAT domain with disease severity. Somatic mosaicism may result in a milder phenotype [Gervasini et al 2007, Chiang et al 2009].

Mosaic microdeletions of CREBBP have been reported by Gervasini et al [2007] and Schorry et al [2008]; these individuals tended to have a less severe phenotype than those with nonmosaic deletions.

See Genetically Related Disorders for a discussion of other copy number abnormalities involving CREBBP.

Prevalence

The birth prevalence RSTS in the Netherlands has been estimated to be between 1:100,000 and 1:125,000 [Hennekam et al 1990].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with RSTS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

There is no cure for RSTS.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

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-related RSTS and 2/59 of those with CREBBP-related RSTS [Fergelot et al 2016]. In another study, 4/12 individuals with EP300-related RSTS had pregnancies complicated by preeclampsia or placental abnormalities including one report of uteroplacental malperfusion. Polyhydramnios was noted in two pregnancies [Cohen et al 2020].

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.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with RSTS have the disorder as the result of a de novo pathogenic variant and are the only affected member of their families.
• Rarely, an individual diagnosed with RSTS has the disorder as the result of a CREBBP or EP300 pathogenic variant inherited from a heterozygous or mosaic parent.
  • Because of variable clinical expression, there is a small chance that a parent with normal intelligence is heterozygous for a CREBBP or EP300 pathogenic variant [Bartsch et al 2010, López et al 2016]. There should be a higher clinical suspicion of parental heterozygosity for an EP300 pathogenic variant (i.e., vs a CREBBP pathogenic variant) in an apparently asymptomatic parent because EP300 is associated with a milder RSTS phenotype [López et al 2016].
  • Parental somatic and germline mosaicism has been reported [Chiang et al 2009, Bartsch et al 2010, Tajir et al 2013, Lin et al 2021].
• Recommendations for the evaluation of parents of a proband include clinical examination for physical findings associated with RSTS and, if a molecular diagnosis has been established in the proband, testing for the CREBBP or EP300 pathogenic variant identified in the proband.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [Chiang et al 2009, Bartsch et al 2010, Tajir et al 2013, Lin et al 2021].* Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
    * If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected [Chiang et al 2009, Bartsch et al 2010].
• The family history of some individuals diagnosed with RSTS may appear to be negative because of failure to recognize the disorder in affected family members. Therefore, an apparently negative family history cannot be confirmed unless a molecular diagnosis has been established in the proband and molecular genetic testing of the parents has established that neither parent is heterozygous for the pathogenic variant identified in the proband.

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

• If a parent of the proband is affected and/or is known to have the CREBBP or EP300 pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known CREBBP or EP300 pathogenic variant that cannot be identified in the leukocyte DNA of either parent, the most likely explanation is that the proband has a de novo pathogenic variant. However, the recurrence risk to sibs is still greater than that of the general population because of the possibility of parental somatic and/or germline mosaicism. Somatic and germline mosaicism have been reported in the parents of individuals with RSTS [Chiang et al 2009, Bartsch et al 2010, Tajir et al 2013].
• If the parents have not been tested for a causative pathogenic variant but are apparently asymptomatic, 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%.

Offspring of a proband. Each child of an individual with RSTS has a 50% chance of inheriting the RSTS-related pathogenic variant [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, the parent's 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/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the RSTS-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing 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. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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 Rubinstein-Taybi syndrome (RSTS) and provides expert confirmation of diagnosis as well as the latest treatments and support.

Brittany Simpson, MD (moc.liamg@4321nospmisnb), is actively involved in clinical research regarding individuals with RSTS. Dr Jane Waite (ku.ca.notsa@etiaw.j) in the United Kingdom is collecting data on the behavioral phenotype in RSTS. They would be happy to communicate with persons who have any questions regarding diagnosis of RSTS or other considerations.

Dr Simpson is also interested in hearing from clinicians treating families affected by RSTS in whom no causative pathogenic variant has been identified through molecular genetic testing of the genes known to be involved in RSTS.

Contact Dr Simpson to inquire about review of CREBBP and EP300 variants of uncertain significance.

Revision History

• 9 November 2023 (gm) Comprehensive update posted live
• 22 August 2019 (sw) Comprehensive update posted live
• 7 August 2014 (me) Comprehensive update posted live
• 16 April 2009 (me) Comprehensive update posted live
• 2 October 2006 (me) Comprehensive update posted live
• 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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