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.

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).

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.

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].

Treatment of Manifestations

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