Rubinstein–Taybi syndrome (RTS) is a rare genetic
condition characterized by short stature, moderate to severe learning difficulties, distinctive facial features, and broad thumbs and first toes.
Other features of the disorder vary among affected individuals. These characteristics are caused by a mutation or deletion in the ''
CREBBP'' gene, located on chromosome 16, and/or the ''
EP300
Histone acetyltransferase p300 also known as p300 HAT or E1A-associated protein p300 (where E1A = adenovirus early region 1A) also known as EP300 or p300 is an enzyme that, in humans, is encoded by the ''EP300'' gene. It functions as histone ace ...
'' gene, located on chromosome 22.
This condition is sometimes inherited as an
autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
pattern, but often as a de novo. It affects an estimated 1 in 125,000-300,000 births.
Presentation
Facial features (A), left hand and feet showing broad thumb and big toes (B, C) and X-ray of both hands showing short broad thumbs (D). (Limb Malformations & Skeletal Dysplasia)
Rubinstein–Taybi syndrome presents itself from birth, and is usually hallmarked by delayed physical and cognitive growth.
Typical features of the disorder include:
* Broad thumbs and broad first toes and
clinodactyly of the 5th finger
*
Intellectual disability
Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...
* Small height, low bone growth, small head
*
Cryptorchidism in males
* Unusual
facies involving the eyes, nose, and
palate
*
Anesthesia
Anesthesia (American English) or anaesthesia (British English) is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia (relief from or prev ...
may be dangerous in these patients: "According to the medical literature, in some cases, individuals with Rubinstein–Taybi syndrome may have complications (e.g., respiratory distress and/or irregular heart beats or
cardiac arrhythmias) associated with a certain muscle relaxant (
succinylcholine) and certain anesthesia. Any situations requiring the administration of anesthesia or succinylcholine (e.g., surgical procedures) should be closely monitored by skilled professionals (Anesthesiologists)." Primary literature suggests the children may have a higher rate of cardiac physical and conduction abnormalities which may cause unexpected results with cardioactive medications. A further editorial reply in the ''British Journal of Anaesthesia'' discusses changes in the face and airway structure making it more difficult to secure the airway under anaesthesia, however, complications appeared in a minority of cases, and routine methods of airway control in the operating room appears to be successful. They recommended close individual evaluation of Rubinstein–Taybi patients for anaesthetic plans.
A 2009 study found that children with RTS were more likely to be overweight and to have a short
attention span, motor
stereotypies, and poor coordination. The study hypothesized that the identified CREBBP gene impaired motor skills learning. Other research has shown a link with long-term memory (LTM) deficit.
RTS is diagnosed when a
heterozygous pathogenic variant of the CREBBP gene is identified in the individual. It exhibits an
autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
inheritance pattern, but some documented cases show heterozygous individuals exhibiting
germline mosaicism. This condition affects men and women equally, and is often misdiagnosed with other diseases or
developmental disabilities
Developmental disability is a diverse group of chronic conditions, comprising mental or physical impairments that arise before adulthood. Developmental disabilities cause individuals living with them many difficulties in certain areas of life, espe ...
.
Genetics
Rubinstein–Taybi syndrome, in many cases, is a
microdeletion syndrome involving chromosomal segment 16p13.3 and is characterized by
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
s in the ''
CREBBP''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
Varying amounts of material are deleted from this section of the chromosome and account for the spectrum of physiological symptoms.
The ''CREBBP'' gene makes a protein that helps control the activity of many other genes. The protein, called
CREB-binding protein, plays an important role in regulating
cell growth
Cell most often refers to:
* Cell (biology), the functional basic unit of life
* Cellphone, a phone connected to a cellular network
* Clandestine cell, a penetration-resistant form of a secret or outlawed organization
* Electrochemical cell, a de ...
and
division and is essential for normal
fetal development. If one copy of the ''CREBBP'' gene is deleted or mutated, cells make only half of the normal amount of CREB binding protein. A reduction in the amount of this protein disrupts normal development before and after birth, leading to the signs and symptoms of Rubinstein–Taybi syndrome.
Mutations in the ''
EP300
Histone acetyltransferase p300 also known as p300 HAT or E1A-associated protein p300 (where E1A = adenovirus early region 1A) also known as EP300 or p300 is an enzyme that, in humans, is encoded by the ''EP300'' gene. It functions as histone ace ...
'' gene, located on chromosome 22q13.2, are responsible for a small percentage of cases of Rubinstein–Taybi syndrome.
[ These mutations result in the loss of one copy of the gene in each cell, which reduces the amount of p300 protein by half. Some mutations lead to the production of a very short, nonfunctional version of the p300 protein, while others prevent one copy of the gene from making any protein at all. Although researchers do not know how a reduction in the amount of p300 protein leads to the specific features of Rubinstein–Taybi syndrome, it is clear that the loss of one copy of the EP300 gene disrupts normal development.
CREBBP and p300 are the respective protein products of the paralogous genes ''CREBBP'' and ''EP300''. Both of these related proteins, prototypical members of the p300-CBP coactivator family, have a bromodomain and a ]histone acetyltransferase
Histone acetyltransferases (HATs) are enzymes that acetylation, acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-N-acetyllysine, ε-''N''-acetyllysine. DNA is wrapped around his ...
domain and are able to bind to various gene-specific transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
s as well as general transcription factors. Cell lines derived from RTS patients exhibit diminished acetylation of multiple histone proteins, particularly histone 2A and histone 2B, suggesting that this disease has its origins in problems with the regulatory mechanisms of transcription. The functions of CREBBP and p300 broadly overlap but do have co-activator–specific effects on gene expression. The proteins may also facilitate transcriptional elongation.
In approximately one third of the cases showing RTS symptoms, neither the ''CREBBP'' gene, nor the ''EP300'' gene appear to be the cause of the disease.[
A mouse ]model
A model is an informative representation of an object, person, or system. The term originally denoted the plans of a building in late 16th-century English, and derived via French and Italian ultimately from Latin , .
Models can be divided in ...
has been identified in order to perform experimental research procedures. The mice exhibited the same clinical RTS symptoms seen in humans, and the ''model'' has become a foundation for future research.
Diagnosis
RTS can be diagnosed through clinical features and can be confirmed through genetic testing. However, 30% of cases do not have a known genetic basis.[Char R, Miller R, Riddle I, Sabido A, Schloemer C, Schorry E, Stevens C*, Wiley S.
]
Understanding Rubinstein-Taybi Syndrome: A Guide for Families and Professionals.
' Cincinnati, OH, University of Cincinnati Center for Excellence in Developmental Disabilities (UCCEDD), Division of Developmental and Behavioral Pediatrics, Cincinnati Children’s Hospital Medical Center (CCHMC). 2019.
*Department of Pediatrics, University of Tennessee College of Medicine, Chattanooga, Tennessee
Treatment
There is no existing treatment that reverses or cures RTS. There are, however, ways to manage and reduce symptoms for patients. Due to there being a wide range of symptoms, RTS patients are referred to specialists that focus on each specific symptom. Individuals suffering from cognitive developments usually are part of special education programs and speech therapy. Regular check-ups and monitoring are needed for cardiac, dental, auditory, and renal abnormalities. Genetic counseling is also recommended for affected individuals and their families.
History
Rubinstein–Taybi syndrome was first unofficially mentioned in a French orthopedic medical journal in 1957 by Greek physicians' doctors
Michail, Matsoukas, and Theodorou
The medical journal reported a case concerning a seven-year-old boy with radically deviated/arched thumbs, long nose, muscular hypotonia, along with physical and mental underdevelopment. At this point in time the case study mentioned by the Greek physicians was considered to be an anomaly due to the fact that there had not been any other reported cases of children with these specific physical and mental characteristics. The doctors accredited with discovering the syndrome and therefore bear its name-sake were unaware of this journal at the time of their discovery. However, it is acknowledged that the 1957 case reported in the French journal of orthopedic medicine is most likely the first reported case of RTS.
Dr. Jack Herbert Rubinstein, an American pediatrician reported assessing a three-year-old girl with unusual facial and digital findings in 1958. Similarly, that same year Rubinstein had evaluated another child with similar characteristics, this time a seven-year-old boy. Having sensed a striking similarity between these two unrelated cases Rubinstein tried distributing photos and information concerning these two cases to other clinics in the U.S. from 1959 to 1960. Rubinstein graduated from Harvard Medical School and worked as the director of the Hamilton County Diagnostic Clinic for the Mentally Retarded. He has worked in behavioral and developmental pediatrics for many years prior to the discovery of this new syndrome.
In 1961
Dr. Hooshang Taybi
an Iranian-American pediatric radiologist, reported having assessed a three-year-old boy that appeared to have the same syndrome as described by Rubinstein. During the summer of 1963, Dr. Taybi reported having evaluated seven children with such characteristics as broad thumbs and great toes, "unusual" facial features, and intellectual disabilities – these findings went on to appear in the ''American Journal of Diseases of Children'' documenting these characteristics as a syndrome. Dr. Hooshang Taybi was graduated from Tehran University School of Medicine and worked for the Ministry of Health. Later in his career, he taught and practiced pediatric radiology in Oklahoma and Indiana. He had identified three new syndromes with his colleagues, among them is Rubinstein–Taybi syndrome.
In 1992, the first genetic abnormalities that act as markers for Rubinstein-Taybi syndrome were identified. These abnormalities are said to affect either chromosome 16 or chromosome 22. The specific chromosome impacted by a mutation determines the type of Rubinstein–Taybi syndrome that may occur. A mutation of the ''CREBBP'' gene on chromosome 16 gives rise to the first form of RTS (most common). While a mutation of the ''EP300'' gene on chromosome 22 is characteristic of the second form of RTS.
See also
* Nasodigitoacoustic syndrome
* List of cutaneous conditions
Many skin conditions affect the human integumentary system—the organ system covering the entire surface of the Human body, body and composed of Human skin, skin, hair, Nail (anatomy), nails, and related muscle and glands. The major function o ...
References
External links
GeneReview/UW/NIH entry on Rubinstein-Taybi syndrome
Rubinstein-Taybi syndrome due to 16p13.3 microdeletion
on ORPHAnet
RTS Support Group
An Information Booklet
{{DEFAULTSORT:Rubinstein-Taybi syndrome
Transcription factor deficiencies
Conditions of the skin appendages
Congenital disorders
Autosomal dominant disorders
Syndromes with craniofacial abnormalities
Syndromes with short stature
Syndromes with dysmelia