Genetics of Rubinstein-Taybi Syndrome Clinical Presentation

  • Author: David Flannery, MD, FAAP, FACMG; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Mar 9, 2012
 

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.

Next

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%)
  • 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
Previous
Next

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 Rubinstein-Taybi syndrome.[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 are noted 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.
Previous
Proceed to Workup
 
 
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; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Robert Anthony Saul, MD  Clinical Professor, Department of Pediatrics, University of South Carolina School of Medicine; 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.

Additional Contributors

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Sulagna C Saitta, MD, PhD, to the original writing and development of this article.

References

  1. Rubinstein JH, Taybi H. Broad thumbs and toes and facial abnormalities. Am J Dis Child. 1963;105:588-608.

  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].

 
Previous
Next
 
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).
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.