Rubinstein-Taybi Syndrome 1

A number sign (#) is used with this entry because Rubinstein-Taybi syndrome-1 (RSTS1) is caused by heterozygous mutation in the gene encoding the transcriptional coactivator CREB-binding protein (CREBBP; 600140) on chromosome 16p13.

Description

Rubinstein-Taybi syndrome is a multiple congenital anomaly syndrome characterized by mental retardation, postnatal growth deficiency, microcephaly, broad thumbs and halluces, and dysmorphic facial features. The facial appearance is striking, with highly arched eyebrows, long eyelashes, downslanting palpebral fissures, broad nasal bridge, beaked nose with the nasal septum, highly arched palate, mild micrognathia, and characteristic grimacing or abnormal smile. Affected individuals also have an increased risk of tumor formation (Rubinstein and Taybi, 1963; review by Hennekam, 2006).

Floating-Harbor syndrome (136140), which shows phenotypic overlap with Rubinstein-Taybi syndrome, is caused by mutation in the SRCAP gene (611421), a coactivator for CREBBP.

Genetic Heterogeneity of Rubinstein-Taybi Syndrome

Rubinstein-Taybi syndrome-1 (RSTS1) constitutes about 50 to 70% of patients with the disorder. Rubinstein-Taybi syndrome-2 (RSTS2; 613684) comprises about 3% of patients and is primarily due to de novo heterozygous mutation in the EP300 gene (602700) on chromosome 22q13 (Bartsch et al., 2010).

See also chromosome 16p13.3 deletion syndrome (610543), a severe form of Rubinstein-Taybi syndrome resulting from a contiguous gene deletion involving the CREBBP gene as well as other neighboring genes.

Clinical Features

Rubinstein and Taybi (1963) reported a syndrome characterized by mental retardation, broad thumbs and toes, and facial abnormalities. Rubinstein (1969) found parental age to be about average. Levy (1976) described juvenile glaucoma in RSTS and McKusick (1968) observed congenital glaucoma. Talon cusps were reported in nearly 90% of patients with Rubinstein-Taybi syndrome by Gardner and Girgis (1979) and Davis and Brook (1986). Bonioli and Bellini (1992) reported the association of RSTS with pheochromocytoma in a 7-year-old girl.

Hennekam et al. (1990) reported that among 45 RSTS patients in the Netherlands, all had broad halluces but only 39 had broad thumbs. Persistent fetal pads of the fingers, shawl scrotum, and frequent fractures were found in several patients. Constipation was a problem, and easily collapsible laryngeal walls caused difficulties in sleep and anesthesia. Hennekam and Van Doorne (1990) commented on short upper lip and pouting lower lip, a feature documented in many photographs by Hennekam et al. (1990). A high, slit-like palate was also noted. Lowry (1990) discussed the phenotypic overlap with the Saethre-Chotzen syndrome (101400).

Guion-Almeida and Richieri-Costa (1992) described agenesis of the corpus callosum, iris coloboma, and megacolon in a boy with RSTS. Kanjilal et al. (1992) described pulmonary hypertension, mitral valve regurgitation, and patent ductus arteriosus as well as hypoplastic right kidney in a 3-month-old child with delayed motor and mental development corresponding to that of a 1-month-old infant. Shashi and Fryburg (1995) described mediastinal vascular ring causing tracheoesophageal obstruction with respiratory symptoms and dysphagia in a child with RSTS. The patient had a remarkable improvement in swallowing ability after surgery and some decrease in the frequency of respiratory infections. Chun et al. (1992) had reported 1 case of RSTS among their large series of cases of vascular rings at Johns Hopkins.

Stevens and Bhakta (1995) evaluated cardiac abnormalities with a questionnaire survey. Of 138 patients in the study, 45 (32.6%) had a known cardiac abnormality; 27 patients had single defects, including atrial septal defect, ventricular septal defect, patent ductus arteriosus (see 607411), coarctation of the aorta, pulmonic stenosis, or bicuspid aortic valve. In 8 of these individuals the problem resolved spontaneously, while 8 required surgery. Complex congenital heart defects of 2 or more abnormalities were present in 16 patients; 2 of these patients had spontaneous resolution, while 7 required surgery. Surgery was planned in 5 additional patients. It is noteworthy that pulmonic stenosis was present in only 1 patient as an isolated finding.

Miller and Rubinstein (1995) noted that patients with RSTS have an increased risk of tumor formation. Among over 700 patients, 17 had malignant tumors and 19 had benign tumors. Twelve of the tumors were located in the nervous system, including oligodendroglioma, medulloblastoma, neuroblastoma, and meningioma. Other tumor types included rhabdomyosarcoma and leukemias, among others. Miller and Rubinstein (1995) suggested that about 5% of RSTS patients develop a neoplasm, which is similar to the frequency of neoplasm in neurofibromatosis type I (162200).

Bonioli et al. (1993) described the association of RSTS with slipped capital femoral epiphysis in a 10-year-old girl. Stevens (1997) described 11 patients with RSTS and patellar dislocation. The age at diagnosis of patellar dislocation ranged from birth to 16 years. Chronic dislocations were present in 10 patients, and 8 of 11 had bilateral patellar dislocation. Surgical stabilization of the patella was required in 8 patients; most achieved a good outcome with surgical repair. All families reported that the patellar dislocations impaired developmental skills, which improved after surgery. Other joint abnormalities, including congenital dislocations and laxity of joints, were described in 7 of the 11 patients.

Ihara et al. (1999) suggested that premature thelarche (breast development) may not be uncommon in girls with RSTS. They reported breast development at age 6 years in a girl who had been found at the age of 6 months to have a neuroblastoma on a nationwide neuroblastoma screening program and had been surgically treated with a favorable clinical course. Among 12 girls with RSTS, Kurosawa et al. (2002) observed 2 with premature thelarche, and a third with premature thelarche and genital bleeding.

Naimi et al. (2006) reported 3 unrelated patients with RSTS who had recurrent upper and lower respiratory infections and otitis media associated with defective antibody response to polysaccharide antigens. One of the 3 also had decreased numbers of T cells. One patient responded well to IgG therapy. The authors suggested that some patients with RSTS may have a primary immunodeficiency, which may explain the increased rate of respiratory infections in these patients.

Bloch-Zupan et al. (2007) reported detailed orodental features of 40 patients with RSTS ranging in age from 4 to 30 years. Nondental oral findings included small mouth, thin upper lip, micrognathia, retrognathia, narrow maxilla, high-arched and narrow palate, wide alveolar ridges, and enlarged tonsils. Dental anomalies included anomalies of tooth number, talon cusps, screwdriver permanent incisors, enamel hypoplasia/discoloration, enamel wear, tooth crowding, and crossbite. Many patients had gastroesophageal reflux, which may have contributed to enamel wear. Timing of tooth eruption was usually normal. Bloch-Zupan et al. (2007) noted that dental anomalies may aid in the diagnosis of RSTS.

Caksen et al. (2009) reported an 8-month-old boy with genetically confirmed RSTS who presented with varicella meningoencephalitis. The authors postulated a primary immune deficiency in this child.

Stevens et al. (2011) reported the results of a questionnaire-based study of 61 adults with RSTS ranging in age from 18 to 67 years (average, 28.5 years). The average height in men was 158.5 cm and in women 150.1 cm. Many were overweight (25%), obese (33%), or morbidly obese (8%). The most commonly reported medical problems were visual difficulties (79%), including need for glasses (80%), strabismus (33%), glaucoma (11%), and cataracts (7%). Other problems included keloids (57%), eating problems (53%), spinal curvature (49%), joint laxity (46%), and dental problems (80%). All had moderate mental retardation, but most achieved some independence for self-care and many were in supported work situations. Most (69%) lived with their parents, but others lived in group homes (21%) or supervised apartments (5%). Many had behavioral problems, such as poor attention span and autistic features, and worsening of behavior over time was reported in about 37%. Very few of the participants were seeing a geneticist as an adult.

Beets et al. (2014) provided growth charts for individuals with Rubinstein-Taybi syndrome, which were based on individuals with a molecularly proven diagnosis.

Incomplete Rubinstein-Taybi Syndrome

Cotsirilos et al. (1987) described 2 sibs and their mother with a syndrome that they reported as similar to Rubinstein-Taybi syndrome. All 3 individuals, who appeared to be of normal intelligence, had broad terminal phalanges of the thumbs and the great toes, antimongoloid slant of the palpebral fissures, and characteristic facial appearance with beaked nose. Four sibs of the mother as well as 2 other members of the kindred were said to have broad thumbs. There were no instances of male-to-male transmission. Autosomal or X-linked dominant inheritance was suggested. Bonioli and Bellini (1989) reported a family in which 4 relatives of a full-blown case of Rubinstein-Taybi syndrome had broad thumbs, apparently inherited as a dominant trait with incomplete penetrance.

Bartsch et al. (2002) reported a girl with a mild variant of RSTS. Her face was round and slightly dysmorphic with intermittent exotropia, subtle ptosis, a beaked nose, and dorsally rotated ears. Her hands showed broad thumbs with brachytelephalangism, and her feet had broad big toes. Although she had low intellectual function, she was not mentally retarded. Genetic analysis revealed a missense mutation in the CREBBP gene (600140.0005), confirming that the phenotype is consistent with 'incomplete' RSTS. Bartsch et al. (2002) concluded that mild alleles or modifying factors can lead to incomplete RSTS, and suggested that the Rubinstein-like syndrome described by Cotsirilos et al. (1987) and Bonioli and Bellini (1989) can be equated with incomplete RSTS.

Bartsch et al. (2010) reported a 3-generation German family with incomplete RSTS, including a 12-year-old female proband, her mother, and the maternal grandmother. The proband had mild dysmorphic features, such as high-arched eyebrows, elongated face, prominent nose, high-arched palate, short broad thumbs, and broad halluces. She had a short attention span, dyslexia, dyscalculia, reading difficulties, and needed special teaching in language and mathematics. Her mother had similar facial features, was mildly obese, and had normal intelligence. The grandmother reportedly had a similar appearance and had not finished school.

Inheritance

The vast majority (about 99%) of cases of Rubinstein-Taybi syndrome occur sporadically resulting from de novo heterozygous mutations; vertical transmission is extremely rare but has been reported (summary by Bartsch et al., 2010).

Padfield et al. (1968) studied 17 patients with RSTS and found none of 50 sibs affected. Pfeifer (1968) described the syndrome in only 1 of presumably monozygotic twins. Baraitser and Preece (1983), on the other hand, reported the Rubinstein syndrome in all 4 members of 2 pairs of monozygotic twins.

Der Kaloustian et al. (1972) described affected brother and sister from consanguineous parents. However, whereas the facies was characteristic, broad first digits were absent clinically and questionable radiographically. Gillies and Roussounis (1985) reported 2 families: in one, 2 sibs were affected; in the other, the uncle of the index case was affected and other members of the family were judged to show varying degrees of expression of the disorder.

Stevens et al. (1990) found no second cases among the 91 sibs of 50 probands.

Hennekam et al. (1989) described this disorder in mother and son, consistent with autosomal dominant inheritance. The mother's IQ was estimated to be about 65.

Garcia et al. (1992) and Marion et al. (1993) reported 2 different cases of mother and daughter with RSTS. In one of these families, the mother had attended special education classes and had dropped out of school in the eleventh grade.

Hennekam et al. (1990) reviewed data on 502 cases. In 12 of 13 proven or possible monozygotic twins, both children were affected. Two patients had reproduced, with 1 affected and 2 normal offspring. They found 1 recurrence among 708 sibs of 502 probands. From this information and the scarcity of affected sibs reported in the literature, they suggested that the recurrence risk figure for sibs is on the order of 0.1%, lower than the figure of 1.0% suggested by Berry (1987) for use in genetic counseling. The recurrence risk for offspring of affected persons may be 50%. Hennekam et al. (1990) favored an autosomal dominant mutation as the most likely cause. Robinson et al. (1993) reported another set of monozygotic twins concordant for RSTS. Preis and Majewski (1995) reported monozygotic twin sisters concordant for RSTS diagnosed at the age of 10 weeks. They commented that the typical features of the syndrome increasingly developed in early infancy toward the total 'Gestalt' by the age of 2 years.

Bartsch et al. (2010) reported a German family in which the female proband, her mother, and her maternal grandmother all had incomplete RSTS associated with a heterozygous mutation in the CREBBP gene (T910A; 600140.0008). The 12-year-old proband had a more severe phenotype despite her mother and maternal grandmother carrying the same mutation. The findings were consistent with autosomal dominant inheritance of RSTS and indicated that in cases of inherited RSTS, affected children tend to have a more severe phenotype. Bartsch et al. (2010) reported a second German family in which 3 sisters had RSTS with facial abnormalities, broad thumbs and great toes, and developmental delay. They were diagnosed at ages 11, 6, and 5 years, respectively. One developed a slow growing ganglioglioma of the brain at age 2. The father had broad thumbs and attended basic secondary school and worked as an unskilled laborer; he was clinically suspected of having mild or incomplete RSTS. Genetic analysis identified a heterozygous splice site mutation in the CREBBP gene in the 3 girls, and somatic mosaicism for the mutation in the father. Based on their patients and a review of the literature of familial occurrence of RSTS, Bartsch et al. (2010) estimated a recurrence risk of 0.5 to 1.0% for parents of an affected child.

Cytogenetics

The dermatoglyphic changes described by Giroux and Miller (1967) suggested a chromosomal abnormality. In 8 cases of RSTS, Wulfsberg et al. (1983) could demonstrate no abnormality by high resolution cytogenetics, but Berry (1987) reviewed the etiogenetic basis and concluded that microdeletion is most likely.

Imaizumi and Kuroki (1991) observed a sporadic case of Rubinstein-Taybi syndrome with de novo reciprocal translocation t(2;16)(p13.3;p13.3). Noting that Bazacliu et al. (1973) had reported a patient with RSTS and a deletion of chromosome 2, Imaizumi and Kuroki (1991) suggested that the RSTS gene may be at 2p13.3 rather than at 16p13.3. During a systematic chromosomal survey of 7 unrelated patients with Rubinstein-Taybi syndrome, Tommerup et al. (1991, 1992) found an apparently balanced de novo reciprocal translocation, t(7;16)(q34;p13.3), in an affected boy. The breakpoint in chromosome 16 involved the same subband p13.3 as was observed in a 2;16 translocation by Imaizumi and Kuroki (1991). Lacombe et al. (1992) provided confirmation for the assignment of the RSTS gene to 16p13.3. A 2-month-old girl with typical features showed a de novo pericentric inversion of one chromosome 16; her karyotype was 46,XX,inv(16)(p13.3;q13).

In a large collaborative study, Breuning et al. (1993) investigated the region of 16p13.3 where 2 distinct reciprocal translocations occurred in patients with a clinical diagnosis of RSTS. The breakpoints lay between the cosmids N2 and RT1. Using 2-color fluorescence in situ hybridization, Breuning et al. (1993) demonstrated that the signal from RT1 was missing from 1 chromosome 16 in 6 of 24 patients with RSTS. The parents of 5 of these patients did not show a deletion of RT1, indicating a de novo rearrangement. They estimated that RSTS is caused by submicroscopic interstitial deletions within 16p13.3 in approximately one-fourth of patients.

By molecular studies, Hennekam et al. (1993) found a copy of chromosome 16 from each parent in all 19 patients with RSTS studied. Uniparental disomy was also excluded for 5 other chromosome arms known to be imprinted in mice. Clinical features were essentially the same in patients with or without visible deletions, with a possible exception for the incidence of microcephaly, angulation of thumbs and halluces, and partial duplication of the halluces ('big toes'). Masuno et al. (1994) screened 25 Japanese patients with RSTS for microdeletions using high-resolution GTG banding and fluorescence in situ hybridization with a cosmid probe (RT1, D16S237). In 1 patient, a microdeletion was demonstrated by in situ hybridization, but none was detected by high-resolution banding.

Diagnosis

Wallerstein et al. (1997) used the RT1 probe to screen 64 patients with clinical evidence of RSTS; 7 (11%) had a deletion. Another patient had a translocation involving the region without evidence of deletion. The features of coloboma, growth retardation, nevus flammeus, and hypotonia had a positive predictive value for the presence of an RT1 deletion. The authors commented that because of the relatively low frequency of deletions in RSTS, the RT1 probe is useful in diagnostic confirmation but has limited use as a screening tool.

Petrij et al. (2000) reported diagnostic analysis of 194 patients with RSTS. Of these, 86 had previously been reported. A total of 157 individuals were tested by FISH, 23 by protein truncation test and 14 by both methods for microdeletions and truncating mutations in CBP. Fourteen of 171 (8.2%) patients had microdeletions, and truncating mutations were found in 4 of 37 (10.8%) cases. Eighty-nine of the 171 were tested using 5 cosmid probes: RT1, RT100, RT102, RT191, RT203 and RT166. Eight microdeletions were found in this group, of which 4 were not deleted for RT1/RT100. Petrij et al. (2000) concluded that the use of all 5 probes is essential to detect all microdeletions in patients with clinical features of RSTS, and stated that microdeletions and truncating mutations in CBP account for approximately 20% of mutations in individuals with the RSTS phenotype.

In 6 (28.6%) of 21 RSTS patients in whom no point mutations had been identified, Stef et al. (2007) used comparative genomic hybridization on microarrays and quantitative multiplex fluorescent-PCR to identify deletions involving the CREBBP gene. The deletions ranged in size from 3.3 kb to 6.5 Mb; 1 patient had a deleterious duplication containing exon 16. No phenotypic differences were observed, except for 1 patient with a 6.5-Mb deletion, who had a severe phenotype and died at 34 days of life. Stef et al. (2007) concluded that CREBBP dosage anomalies constitute a common cause of the disorder and recommended high-resolution gene dosage studies of the CREBBP gene in candidate patients.

Gervasini et al. (2007) used FISH and microsatellite analysis to screen 42 Italian RSTS patients, and identified deletions ranging in size from 150 kb to 2.6 Mb in 6 patients. Three of the patients were low-level mosaics, with the deletion present in less than 30% of lymphocytes and in less than 20% of epithelial cells analyzed. The authors stated that the clinical presentation was typical in all cases, but more severe in the 3 patients with constitutional deletions, and suggested that there may be underdiagnosis of a few cases of mild RSTS.

Clinical Management

Stirt (1982) warned of the risk of cardiac arrhythmia with use of succinylcholine in the Rubinstein-Taybi syndrome.

Wiley et al. (2003) provided recommendations for specific surveillance and interventions to guide clinicians caring for individuals with RSTS.

Hennekam (2006) provided a review of RSTS, including a diagnostic strategy, clinical management, and genetic counseling.

Molecular Genetics

Petrij et al. (1995) showed that the breakpoints at 16p13.3 demonstrated in patients with RSTS are all restricted to a region that contains the gene for the human CREB-binding protein (CREBBP; 600140), a nuclear protein participating as a coactivator in cAMP-regulated gene expression. In patients with RSTS, Petrij et al. (1995) identified heterozygous point mutations in the CREBBP gene (600140.0001, 600140.0002), suggesting that the loss of one functional copy of the CREBBP gene underlies the developmental abnormalities in RSTS. Petrij et al. (1995) suggested that the unusual incidence of neoplasms in RSTS, as well as the propensity to form keloids, may be explained by the role proposed for CREBBP in cAMP-regulated cell immortalization. The X-linked alpha-thalassemia/mental retardation syndrome (301040) is another example of multiple congenital malformations with mental retardation caused by a generalized dysregulation of gene expression. In that case, the mutation is located in the gene encoding X-linked helicase-2 (300032).

Roelfsema et al. (2005) screened the entire CREBBP gene for mutations in 92 patients with RSTS and found 36 mutations. By using multiple ligation-dependent probe amplification, they found not only several deletions but also the first reported intragenic duplication in a patient with RSTS. Both CREBBP and EP300 (602700) function as transcriptional coactivators in the regulation of gene expression through various signal transduction pathways. Both are potent histone acetyltransferases. A certain level of CREBBP is essential for normal development, as indicated by the fact that inactivation of 1 allele causes RSTS. There is a direct link between loss of acetyltransferase activity and RSTS, which indicates that the disorder is caused by aberrant chromatin regulation. Roelfsema et al. (2005) searched for mutations in the EP300 gene in patients with RSTS, identified 3 mutations (602700.0003-602700.0005), and stated that these were the first mutations found in EP300 as the basis of a congenital disorder.

Using high resolution array comparative genomic hybridization (array CGH) targeting exons, Tsai et al. (2011) identified a de novo 5- to 6-kb deletion on chromosome 16p13.3 encompassing exons 27 and 28 of the CREBBP gene in a male infant with classic clinical features of RSTS.

Genotype/Phenotype Correlations

Using FISH and 3 cosmid probes, Bartsch et al. (1999) studied 45 Rubinstein-Taybi syndrome patients from Germany, the Czech Republic, Austria, and Turkey and found 4 deletions. This gave a frequency of deletions of 8.9%; when pooled with the data from previous studies, a frequency of 11% was found. All deletions were interstitial; 3 spanned the CREB-binding protein gene and 1 was smaller. The findings of Bartsch et al. (1999) suggested a more severe phenotype in these deletion cases. The mean age at presentation was 0.96 years in patients with a deletion as opposed to 11.12 years in those without. Bartsch et al. (1999) suggested that the 2 patients who died in infancy had a contiguous gene deletion syndrome.

Using a combination of FISH and multiple ligation-dependent probe amplification (MLPA) analysis, Rusconi et al. (2015) identified 14 different and novel CREBBP deletions in 14 of 171 patients with a clinical diagnosis of RSTS. The deletions, which accounted for 23% of detected CREBBP mutations in this cohort, ranged in size from 930 bp encompassing single exons to 1.35 Mb encompassing the whole gene and neighboring genes. Genotype/phenotype correlations indicated that patients with larger deletions did not always have a more severe phenotype than those with smaller deletions or point mutations, suggesting that the idea of a contiguous gene deletion syndrome in such patients, as proposed by Bartsch et al. (2006) (see 610543), may not be accurate.

Hendrich and Bickmore (2001) reviewed human disorders which share in common defects of chromatin structure or modification, including the ATR-X spectrum of disorders (301040), ICF syndrome (242860), Rett syndrome (312750), Rubinstein-Taybi syndrome, and Coffin-Lowry syndrome (303600).

Schorry et al. (2008) identified pathogenic mutations in the CREBBP gene in 52 (56%) of 93 patients meeting clinical diagnostic criteria for RSTS. Ten patients had single amino acid changes, 36 had truncating or splice site mutations, and 6 had microdeletions. The mutations were distributed throughout the gene. There were few phenotypic differences observed between patients grouped by different types of mutations, other than a trend toward increased severity of cognitive impairment and autistic features in patients with larger deletions.

Population Genetics

Padfield et al. (1968) estimated that the frequency of Rubinstein syndrome was 1 per 300-500 in institutionalized patients with mental retardation over age 5 years.

Beets et al. (2014) stated that the birth prevalence of Rubinstein-Taybi syndrome is 1 in 100,000-125,000.

Nomenclature

Although the acronym RTS is sometimes used for Rubinstein-Taybi syndrome, the use of this acronym for 2 other syndromes, Rothmund-Thomson syndrome (268400) and Rett syndrome, may lead to confusion; hence, use of the symbol RSTS is recommended.

Animal Model

Oike et al. (1999) generated a mouse model of RSTS by an insertional mutation in the Cbp gene. Heterozygous mice that had truncated Cbp protein (residues 1 to 1084) containing the CREB-binding domain showed clinical features of RSTS, such as growth retardation (100%), retarded osseous maturation (100%), hypoplastic maxilla with narrow palate (100%), cardiac anomalies (15%), and skeletal abnormalities (7%). The authors concluded that the mutant truncated Cbp protein acted in a dominant-negative fashion to generate the RSTS phenotype in mice. Mutant mice performed poorly in passive avoidance and fear-conditioning tests, suggesting deficiency in long-term memory. Short-term memory appeared to be normal.

History

Roy et al. (1968) suggested multifactorial inheritance in RSTS.

Since the CREB-binding protein is a critical coactivator for thyroid hormone receptors, Olson and Koenig (1997) hypothesized that thyroid hormone resistance might occur in RSTS. To assess the function of the thyroid axis in RSTS, they measured free thyroxine (T4) and thyroid-stimulating hormone (TSH; see 188540) in 12 affected subjects. Free T4 and TSH levels were normal in all 12 subjects, indicating that overt thyroid hormone resistance is not a typical feature of RSTS.