Genetics of Rubinstein-Taybi Syndrome 

  • Author: David Flannery, MD, FAAP, FACMG; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Nov 24, 2009
 

Background

In 1963, Rubinstein and Taybi first described a malformation syndrome characterized by distinctive facies, mental retardation, broad thumbs, and broad great toes as are seen in the images below.[1]

Facial abnormalities (eg, hypoplastic maxilla, proFacial abnormalities (eg, hypoplastic maxilla, prominent beaked nose, antimongoloid palpebral fissures) and broad thumbs in a child with Rubinstein-Taybi syndrome (RSTS). Prominent beaked nose, low-set ears, and broad thuProminent beaked nose, low-set ears, and broad thumbs in a child with Rubinstein-Taybi syndrome (RSTS). Broad great toes in a child with Rubinstein-Taybi Broad great toes in a child with Rubinstein-Taybi syndrome (RSTS).

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.

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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."

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Epidemiology

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 case per 600 in institutionalized individuals.

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Contributor Information and Disclosures
Author

David Flannery, MD, FAAP, FACMG  Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia

David Flannery, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics and American College of Medical Genetics

Disclosure: Nothing to disclose.

Specialty Editor Board

Elaine H Zackai, MD  Professor of Pediatrics, Professor of Obstetrics and Gynecology, Professor of Pediatrics in Human Genetics, University of Pennsylvania School of Medicine; Director, Clinical Genetics Center, University of Pennsylvania; Senior Physician and Director of Clinical Genetics, The Children's Hospital of Philadelphia

Elaine H Zackai, MD is a member of the following medical societies: American Cleft Palate/Craniofacial Association, American College of Medical Genetics, and American Society of Human Genetics

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Pharmacy Editor, eMedicine

Disclosure: Nothing to disclose.

Robert Anthony Saul, MD  Clinical Professor, Department of Pediatrics, University of South Carolina; Senior Clinical Geneticist, Greenwood Genetic Center

Robert Anthony Saul, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, and American College of Physician Executives

Disclosure: Nothing to disclose.

Daniel Rauch, MD, FAAP  Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine

Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine

Disclosure: Baxter Honoraria Consulting

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

References

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  2. Foley P, Bunyan D, Stratton J, Dillon M, Lynch SA. Further case of Rubinstein-Taybi syndrome due to a deletion in EP300. Am J Med Genet A. May 2009;149A(5):997-1000. [Medline].

  3. [Guideline] 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].

  4. Hosek J, Borkova A. [The Rubinstein-Taybi syndrome or a broad thumb-hallux syndrome]. Cas Lek Cesk. 2008;147(3):136-40. [Medline].

  5. Balci S, Ergun MA, Yuksel-Konuk EB, Bartsch O. Rubinstein-Taybi syndrome with normal FISH result and CREBBP gene analysis: a case report. Turk J Pediatr. May-Jun 2008;50(3):265-8. [Medline].

  6. Marangi G, Leuzzi V, Orteschi D, et al. Duplication of the Rubinstein-Taybi region on 16p13.3 is associated with a distinctive phenotype. Am J Med Genet A. Sep 15 2008;146A(18):2313-7. [Medline].

  7. Galera C, Taupiac E, Fraisse S, et al. Socio-Behavioral Characteristics of Children with Rubinstein-Taybi Syndrome. J Autism Dev Disord. Apr 7 2009;[Medline].

  8. Altintas F, Cakmakkaya S. Anesthetic Management of a child with Rubenstein-Taybi syndrome. Paediatr Anaesth. 2004;14(7):610-611. [Medline].

  9. 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].

  10. 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].

  11. 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].

  12. [Guideline] Cunniff C. Prenatal screening and diagnosis for pediatricians. Pediatrics. Sep 2004;114(3):889-94. [Medline].

  13. 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].

  14. 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].

  15. Jones KL. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: WB Saunders; 1996.

  16. 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.

  17. 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].

  18. 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].

  19. 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].

  20. 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].

  21. 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].

  22. Rubinstein JH. The broad thumb syndrome - progress report 1968. Birth Defects Orig Art Ser. 1969;V(2):25-41.

  23. Rubinstein-Taybi Syndrome. OMIM. Available at http://www.ncbi.nlm.nih.gov.

  24. Stevens CA, Bhakta MG. Cardiac abnormalities in the Rubinstein-Taybi syndrome. Am J Med Genet. Nov 20 1995;59(3):346-8. [Medline].

  25. Stirt JA. Succinylcholine in Rubinstein-Taybi syndrome. Anesth. 1982;57(5):429. [Medline].

  26. 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].

  27. 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].

 
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Facial abnormalities (eg, hypoplastic maxilla, prominent beaked nose, antimongoloid palpebral fissures) and broad thumbs in a child with Rubinstein-Taybi syndrome (RSTS).
Prominent beaked nose, low-set ears, and broad thumbs in a child with Rubinstein-Taybi syndrome (RSTS).
Broad great toes in a child with Rubinstein-Taybi syndrome (RSTS).
 
 
 
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