AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

In 1963, Rubinstein and Taybi first described a malformation syndrome characterized by distinctive facies, mental retardation, broad thumbs, and broad great toes. 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), 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 encoding a binding protein for CREB protein (ie, CREBBP or CBP) has been associated with the phenotype of RSTS (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.

A number of institutionalized adults with mental retardation may carry a diagnosis of RSTS. In addition, up to 5% of patients with RSTS 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 RSTS have been reported with less retardation and more subtle clinical features. These patients have been referred to as having "incomplete RSTS."

Frequency

International

Estimated prevalence of RSTS 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 exist, 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 RSTS. 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 (2003) has provided guidelines for clinical management and surveillance for patients with RSTS.

Race

No known race predilection exists.

Sex

Males and females appear to be equally affected.

Age

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

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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%)
  • 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) 30-79 (average 51); more than 50% of patients have an IQ 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 also seen
• Skeletal abnormalities
• • Retarded osseous maturation (49%)
  • Vertebral and sternal abnormalities
  • Patellar dislocation
• Cardiac anomalies (33%)
• • Ventricular septal defect (VSD) and patent ductus arteriosus (PDA) most commonly seen
  • Atrial septal defect (ASD), coarctation of the aorta, pulmonic stenosis, and bicuspid aortic valve 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 encoding the CREB binding protein, or CBP, was cloned in 1995, and mutations in this gene have been found in some patients with RSTS. 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 deoxyribonucleic acid (DNA) repair, cell growth, differentiation, apoptosis, and tumor suppression.

Recently, molecular analysis has demonstrated a mutation detection rate of up to 56% in the CBP (CREBBP) gene in patients with RSTS. Approximately 10-12% of patients with RSTS 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 RSTS or a phenotype that resembles RSTS 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 will pick 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. Larger chromosomal rearrangements (eg, translocations, inversions) are found in less than 1% of patients with RSTS and they involve band 16p13.
• 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 RSTS 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 RSTS 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 RSTS 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Syndromes with broad thumbs and/or toes

Aarskog
Greig
Larsen
Pfeiffer (Craniosynostosis is major feature.)
Saethre-Chotzen (Craniosynostosis is major feature.)
Simpson-Golabi-Behmel
Weaver (Overgrowth is major feature.)

Syndromes with broad thumbs and/or toes, hypoplasia of the maxilla, and down-slanted palpebral fissures (no craniosynostosis)

Aarskog (X-linked, with hypertelorism, shawl scrotum, and variable developmental delay)

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Imaging Studies

• Determine imaging studies using a system-by-system approach based on clinical findings of the individual patient. For example, a patient with a congenital heart defect would require an involved cardiac investigation such as ECG and echocardiogram, while a patient with a seizure disorder would require EEG and brain imaging.
• Renal ultrasound may be appropriate, but few reports of anomalies exist.

Other Tests

• Chromosomal karyotype analysis
• FISH for chromosome band 16p13
• Mutation analysis of the CBP gene
• ECG for cardiac investigation for congenital heart disease
• Neurologic evaluation

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Wide variability exists in the phenotype; therefore, treatment is individualized based on the patient's findings. Typically, physical therapy, speech and feeding therapy, and special education are important adjuncts in infancy and early childhood.

Surgical Care

Wide variability exists in the phenotype; therefore, surgical treatment is individualized based on the patient's findings.

Consultations

• Cardiologist (evaluation for congenital heart disease)
• Neurologist

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug therapy currently is not a component of the standard of care for this syndrome (see Treatment).

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Typically, physical therapy, speech and feeding therapy, and special education are important adjuncts in infancy and early childhood.

Complications

• Cardiac arrhythmia is possible with use of succinylcholine.

Prognosis

• 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 from congenital heart disease are major causes of morbidity and mortality in the first years of life.
• Developmentally, milestones in these patients are delayed to such an extent that patients typically sit up at age 11 months and walk at age 30 months. First words typically are spoken at age 25 months, and affected individuals are toilet trained at approximately age 62 months. Approximately two thirds of patients older than 6 years can read, but they usually do not progress beyond a first-grade level.
• Survival rates, in general, are good, with frequent reports of adults with Rubinstein-Taybi syndrome (RSTS).

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Cardiac arrhythmia with use of succinylcholine
• Laryngeal wall collapsibility
• Sleep and anesthesia problems

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Altintas F, Cakmakkaya S. Anesthetic Management of a child with Rubenstein-Taybi syndrome. Paediatr Anaesth. 2004;14(7):610-611. [Medline].
• Bartsch O, Schmidt S, Richter M, et al. DNA sequencing of CREBBP demonstrates mutations in 56% of patients with Rubinstein-Taybi syndrome (RSTS) and in another patient with incomplete RSTS. Hum Genet. 2005;117(5):485-493. [Medline].
• Cantani A, Gagliesi D. Rubinstein-Taybi syndrome. Review of 732 cases and analysis of the typical traits. Eur Rev Med Pharmacol Sci. Mar-Apr 1998;2(2):81-7. [Medline].
• Coupry I, Monnet L, Attia AA, et al. Analysis of CBP (CREBBP) gene deletions in Rubinstein-Taybi syndrome patients using real-time quantitative PCR. Hum Mutat. 2004;23(3):278-284. [Medline].
• Hennekam RC, Lommen EJ, Strengers JL, et al. Rubinstein-Taybi syndrome in a mother and son. Eur J Pediatr. Feb 1989;148(5):439-41. [Medline].
• Hennekam RC, Stevens CA, Van de Kamp JJ. Etiology and recurrence risk in Rubinstein-Taybi syndrome. Am J Med Genet Suppl. 1990;6:56-64. [Medline].
• Jones KL. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: WB Saunders;1996.
• Jones KL, Jones MC. A Clinical Approach to the Dysmorphic Child in Emery and Rimoin's Principles and Practices of Medical Genetics. 3rd ed. New York, NY: Churchill;1996.
• Marion RW, Garcia DM, Karasik JB. Apparent dominant transmission of the Rubinstein-Taybi syndrome. Am J Med Genet. May 15 1993;46(3):284-7. [Medline].
• OMIM (Online Mendelian Inheritance in Man), subject #180849. Rubinstein-Taybi Syndrome. Available at http://www.ncbi.nlm.nih.gov.
• Oike Y, Hata A, Mamiya T, et al. Truncated CBP protein leads to classical Rubinstein-Taybi syndrome phenotypes in mice: implications for a dominant-negative mechanism. Hum Mol Genet. Mar 1999;8(3):387-96. [Medline]. [Full Text].
• Petrij F, Giles RH, Dauwerse HG, et al. Rubinstein-Taybi syndrome caused by mutations in the transcriptional co- activator CBP. Nature. Jul 27 1995;376(6538):348-51. [Medline].
• Petrij F, Dauwerse HG, Blough RI, et al. Diagnostic analysis of the Rubinstein-Taybi syndrome: five cosmids should be used for microdeletion detection and low number of protein truncating mutations. J Med Genet. Mar 2000;37(3):168-76. [Medline].
• Roelfsema JH, White SJ, Ariyurek Y, et al. Genetic heterogeneity in Rubinstein-Taybi syndrome: mutations in both the CBP and EP300 genes cause disease. Am J Hum Genet. 2005;76(4):572-580. [Medline]. [Full Text].
• Rubinstein JH, Taybi H. Broad thumbs and toes and facial abnormalities. Am J Dis Child. 1963;105:588-608.
• Rubinstein JH. The broad thumb syndrome - progress report 1968. Birth Defects Orig Art Ser. 1969;V(2):25-41.
• Stevens CA, Bhakta MG. Cardiac abnormalities in the Rubinstein-Taybi syndrome. Am J Med Genet. Nov 20 1995;59(3):346-8. [Medline].
• Stirt JA. Succinylcholine in Rubinstein-Taybi syndrome. Anesth. 1982;57(5):429. [Medline].
• Wiley S, Swayne S, Rubinstein JH, et al. Rubinstein-Taybi syndrome medical guidelines. Am J Med Genet A. Jun 1 2003;119(2):101-10. [Medline].
• Wood MA, Kaplan MP, Park A, et al. Transgenic mice expressing a truncated form of CREB-binding protein (CBP) exhibit deficits in hippocampal synaptic plasticity and memory storage. Learn Mem. 2005;12(2):111-119. [Medline]. [Full Text].
• Yamamoto T, Kurosawa K, Masuno M, et al. Congenital anomaly of cervical vertebrae is a major complication of Rubinstein-Taybi syndrome. Am J Med Genet. 2005;135(2):130-133. [Medline].

Article Last Updated: Apr 18, 2006