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eMedicine Journal
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Pediatrics
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Genetics And Metabolic Disease
Rubinstein-Taybi Syndrome Synonyms, Key Words, and Related Terms: Rubinstein-Taybi syndrome, RSTS, Rubinstein syndrome, distinctive facies, prominent nose, mental retardation, broad thumbs, broad great toes, OMIM #180849, cyclic adenosine monophosphate, cAMP, cAMP response element binding, CREB, OMIM #600140, OMIM #602700, growth retardation, feeding difficulties, failure to thrive, respiratory infections, congenital heart disease, developmental delay |
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 | AUTHOR INFORMATION | Section 1 of 11    |
Authored by Sulagna C Saitta, MD, PhD, Assistant Professor of Pediatrics, Division of Human Genetics, Children's Hospital of Philadelphia
Sulagna C Saitta, MD, PhD, is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, and American Society of Human Genetics
Edited by Elaine H Zackai, MD, Director of Clinical Genetics Center, Professor of Pediatrics, Department of Pediatrics, Division of Human Genetics and Molecular Biology, University of Pennsylvania, Children's Hospital of Philadelphia; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Robert Anthony Saul, MD, Senior Clinical Geneticist, Greenwood Genetic Center; Clinical Professor, Department of Pediatrics, University of South Carolina; Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center
| Author's Email: | Sulagna C Saitta, MD, PhD |  |
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| Editor's Email: | Elaine H Zackai, MD |
eMedicine Journal, April 18 2006, VOLUME 7,
Number 4
| INTRODUCTION | Section 2 of 11  |
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:
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 11 |
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:
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.
| DIFFERENTIALS | Section 4 of 11 |
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 11 |
Imaging Studies:
Other Tests:
| TREATMENT | Section 6 of 11 |
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:
| MEDICATION | Section 7 of 11 |
Drug therapy currently is not a component of the standard of care for this syndrome (see Treatment).
| FOLLOW-UP | Section 8 of 11 |
Further Outpatient Care:
Complications:
Prognosis:
| MISCELLANEOUS | Section 9 of 11 |
Medical/Legal Pitfalls:
| TEST QUESTIONS | Section 10 of 11 |
CME Question 1: An infant presents with failure to thrive, high arched palate, prominent beaked nasal bridge, and broad thumbs and great toes. Which of the following consultations or evaluations is the most immediately relevant for patient care and prognosis?
A: Gastroenterologist to evaluate for malabsorption
B: Hematologist to evaluate for bone marrow suppression
C: Cardiologist to evaluate for congenital heart defect
D: Dermatologist for evaluation of café au lait spots
E: Endocrinologist to evaluate for parathyroid hormone dysfunction
The correct answer is C: These features suggest Rubinstein-Taybi syndrome (RSTS), which is associated with small stature and growth and not malabsorption per se. Approximately a third of patients have congenital cardiac defects (typically ventricular septal defect or patent ductus arteriosus), which would have significant clinical implications. Bone marrow suppression, café au lait spots, and parathyroid dysfunction are not usually associated with RSTS.
CME Question 2: An infant presents with failure to thrive, high arched palate, prominent beaked nasal bridge, and broad thumbs and great toes. Which of the following is the definitive diagnostic test?
A: Fluorescence in situ hybridization (FISH) for band 16p13
B: Uniparental disomy studies
C: Mutation analysis of the cyclic adenosine monophosphate (cAMP) response element binding (CREB) protein or CBP gene
D: High resolution karyotype
E: E. None of the above
The correct answer is E: Microdeletions of band 16p13, which can be detected by FISH, and mutations of the CREB binding protein gene (CBP) gene located in this region, have been described for about 20-25% of patients with Rubinstein-Taybi syndrome (RSTS). A very small number of patients with RSTS have translocations involving 16p13 that are detectable on a karyotype. While the consideration of these tests in any patient with suggestive clinical features (for diagnostic, recurrence risk, and potential prenatal counseling) is important, the vast majority (80%) do not have detectable mutations in this region of the genome. The diagnosis is primarily based on clinical findings. Uniparental disomy (when both copies of a given chromosome come from the same parent) does not appear to be a mechanism involved in this syndrome.
Pearl Question 1 (T/F): The clinical findings most consistently seen in Rubinstein-Taybi syndrome (RSTS) are distinct in infancy.
The correct answer is False: The facial characteristics (eg, prominent nose, broad thumb, broad great toe) may not be distinct in infancy and can evolve over time.
Pearl Question 2 (T/F): The prognosis for a child diagnosed with Rubinstein-Taybi syndrome (RSTS) can be variable.
The correct answer is True: Although characteristic features exist for RSTS, such as the characteristic facies and broad digits, the clinical presentation is widely variable. It is, therefore, critical to prognosticate using a system-by-system approach based on the clinical findings. For example, a child with congenital heart disease and seizure disorder has more severe involvement than a child without these findings.
Pearl Question 3 (T/F): The genetic workup for a suspected case of Rubinstein-Taybi syndrome (RSTS) involves obtaining a karyotype.
The correct answer is True: Any patient with multiple malformations should have chromosomal analysis looking for rearrangements and/or aneuploidy. Fluorescence in situ hybridization (FISH) and mutation analysis of cyclic adenosine monophosphate (cAMP) response element binding (CREB) protein, or CBP, would be warranted with the caveat that, so far, only 20-25% of clinically diagnosed patients have detectable genetic alterations.
Pearl Question 4 (T/F): The recurrence risk for an unaffected individual who has a child with Rubinstein-Taybi syndrome (RSTS) is 50%.
The correct answer is False: The condition occurs sporadically, and the recurrence risk, although not zero, is very low (close to 1%). Given normal fertility, a person who has RSTS would have a 50% chance of transmitting the disease to each offspring, consistent with autosomal dominant inheritance.
| BIBLIOGRAPHY | Section 11 of 11 |
| NOTE: |
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