Genetics of Rubinstein-Taybi Syndrome
- Author: David Flannery, MD, FAAP, FACMG; Chief Editor: Bruce Buehler, MD more...
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, 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). 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."
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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