eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Rubinstein-Taybi Syndrome

Author: David Flannery, MD, FAAP, FACMG, Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia
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Updated: Apr 18, 2006

Introduction

Background

In 1963, Rubinstein and Taybi first described a malformation syndrome characterized by distinctive facies, mental retardation, broad thumbs, and broad great toes.¹ Deletions in band 16p13 have been described in association with this disorder, and mutations in the cyclic adenosine monophosphate (cAMP) response element binding (CREB) protein gene (OMIM #600140) that maps to this region have also been demonstrated. More recently, mutations in the EP300 gene (OMIM #602700),² a similar transcriptional coactivator located on chromosome 22q13, have also been found in patients with a Rubinstein-Taybi syndrome (RSTS) phenotype.

Pathophysiology

A region of chromosome band 16p13 that includes a gene that encodes a binding protein for CREB protein (ie, CREBBP or CBP) has been associated with the phenotype of Rubinstein-Taybi syndrome (OMIM #180849). Feeding difficulties are common in infancy and, together with the genetically based growth retardation characteristic of this syndrome, often result in a clinical picture of failure to thrive. Respiratory infections and complications due to congenital heart disease are major causes of morbidity and mortality in the first years of life. Developmentally, the milestones in these patients are significantly delayed.

Numerous institutionalized adults with mental retardation may carry a diagnosis of Rubinstein-Taybi syndrome. In addition, as many as 5% of patients with Rubinstein-Taybi syndrome have an increased risk of tumors, including medulloblastoma, neuroblastoma, meningioma, rhabdomyosarcoma, and leukemias, relating most likely to the role of the gene in signal transduction. Milder variants of Rubinstein-Taybi syndrome have been reported with less retardation and more subtle clinical features. These patients have been referred to as having "incomplete Rubinstein-Taybi syndrome."

Frequency

International

Estimated prevalence of Rubinstein-Taybi syndrome is as high as 1 per 10,000 live births. This syndrome has been estimated to be present in approximately 1 per 600 institutionalized individuals. Very few cases of sibling recurrences are noted, and only a handful of parent-to-child transmissions have been reported; however, concordance rates are very high in monozygotic twins. The disease is thought to occur sporadically, with recent discoveries of genetic mutations in CBP and EP300. These all appear to be new mutations with no apparent parental age factor involved.

Mortality/Morbidity

In general, survival rates are good, with frequent reports of adults with Rubinstein-Taybi syndrome. Respiratory infections and complications from congenital heart disease are major causes of morbidity and mortality in the first years of life. Instability of the craniovertebral junction at C1-C2, hypoplasia of the dens, and fusion of the cervical vertebrae have been described as potentially life-threatening malformations. Issues with perioperative management, including collapsible airway and susceptibility to succinylcholine, have also been described. Wiley has provided guidelines for clinical management and surveillance for patients with Rubinstein-Taybi syndrome.³

Race

No known race predilection is noted.

Sex

Males and females appear to be equally affected.

Age

Rubinstein-Taybi syndrome  is often detected in the newborn period when the characteristic physical features are noted (eg, prominent nose, broad thumb, broad great toe). It is also reported to have a frequency as high as 1 per 600 in institutionalized individuals.

Clinical

History

Rubinstein-Taybi syndrome (RSTS) is often detected in the newborn period based on the presence of characteristic features such as prominent nose, broad thumb, or broad great toe.

Physical

Selected physical findings and their relative frequencies are as follows:

• Facial abnormalities (may not be distinct in infancy; can evolve over time)
  • Hypoplastic maxilla with narrow palate (100%)
  • Prominent beaked nose (90%)
  • Down-slanting palpebral fissures (88%)
  • Low-set and/or malformed ears (84%)
  • Strabismus (69%)
  • Large anterior fontanel (41%)
  • Microcephaly (35%)
  • Malpositioned or crowded teeth, high palate, short upper lip, and protuberant lower lip also seen
• Digit abnormalities
  • Broad great toes (100%)
  • Broad thumbs with radial angulation (87%)⁴
  • Broadness of other fingers (87%)
  • Persistent fetal finger pads (31%)
  • Syndactyly and polydactyly also seen
• Abnormalities of growth and development
  • Mental retardation with intelligence quotient (IQ) of 30-79 (average 51): More than 50% of patients have an IQ of less than 50.
  • Speech difficulty (90%)
  • Hypotonia (67%)
  • EEG abnormalities (30%)
  • Growth retardation (postnatal onset growth deficiency)
    • Average male height - 153 cm
    • Average female height - 147 cm
  • Feeding problems
• Skeletal abnormalities
  • Retarded osseous maturation (49%)
  • Vertebral and sternal abnormalities
  • Patellar dislocation
• Cardiac anomalies (33%)
  • Ventricular septal defect (VSD) and patent ductus arteriosus (PDA) are most common.
  • Atrial septal defect (ASD), coarctation of the aorta, pulmonic stenosis, and bicuspid aortic valve are also seen.
• Other symptoms and findings
  • Cryptorchidism (78% of males)
  • Hirsutism (75%)
  • Keloid formation
  • Cardiac arrhythmia with use of succinylcholine
  • Laryngeal wall collapsibility
  • Sleep and anesthesia problems

Causes

The gene that encodes the CREB binding protein, or CBP, was cloned in 1995, and mutations in this gene have been found in some patients with Rubinstein-Taybi syndrome. CBP has significant histone acetyltransferase activity and "opens" the chromatin structure so that transcription factors can enter and regulate gene expression. This protein is involved in different signaling pathways and in basic cellular functions, such as DNA repair, cell growth, differentiation, apoptosis, and tumor suppression.

Molecular analysis has demonstrated a mutation detection rate of as much as 56% in the CBP (CREBBP) gene in patients with RSTS.⁵ Approximately 10-12% of patients with Rubinstein-Taybi syndrome have deletions of CBP, and a smaller percentage have complex cytogenetic rearrangements involving the region of chromosome 16p that contains the gene. In addition, approximately 3% of patients with true Rubinstein-Taybi syndrome or a phenotype that resembles Rubinstein-Taybi syndrome show mutations in the EP300 gene, underscoring the genetic heterogeneity of the disorder.

• Chromosomal microdeletions (8-12%), which range from 50-650 kb, all cause partial or complete deletion of CBP. No other genes in this area are thought to contribute to the phenotype. The more commonly used RT-1 probe on the 3' end picks up only 50% of microdeletions. Therefore, the use of 5 cosmids covering the entire gene for fluorescence in situ hybridization (FISH) in order to identify more proximal deletions is recommended.⁵ Larger chromosomal rearrangements (eg, translocations, inversions) are found in less than 1% of patients with Rubinstein-Taybi syndrome and they involve band 16p13.⁶
• Point mutations (single base changes) in CBP account for the remainder of detectable mutations. Most of these mutations result in a truncated protein. No major phenotypic differences exist between patients with large deletions and those with point mutations. This fact is consistent with clinical manifestations due to haploinsufficiency (ie, half-normal levels) of the gene product. This is also consistent with autosomal dominant inheritance patterns and a 50% transmission risk for a patient with Rubinstein-Taybi syndrome if fertility is normal.
• The relatively low percentage (20%) of patients without deletions who have demonstrable mutations involving CBP may be due to an inability to identify all alterations that could be present in the gene or in its upstream or downstream regulatory regions. Alternatively, the low percentage of individuals with clinical features of Rubinstein-Taybi syndrome who have an alteration of band 16p13 or CBP may reflect genetic heterogeneity and other loci that could be involved in the etiology of the phenotype.
• Genetic null heterozygous (+/-) mutant mouse models (which are deleted for large parts of one of the two copies of the CBP gene) have been generated that display a phenotype compatible with Rubinstein-Taybi syndrome including the following characteristics: growth retardation, retarded osseous maturation, hypoplastic maxilla with narrow palate, cardiac anomalies (eg, VSD, ASD, bicuspid aortic valve), and skeletal abnormalities, as well as significant disturbances in long-term memory (LTM). Homozygously deleted mice demonstrate in utero fatality at embryonic day 9.5-10.5. Another, smaller truncated CBP (+/-) null mutant mouse has been described that exhibits growth retardation, skeletal abnormalities, large anterior fontanel, and holes in the xiphoid process. However, both of these models have limitations in their phenotypes compared to what has been seen in human patients.

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