| Rubinstein–Taybi syndrome | |
| Synonyms: | Broad thumb-hallux syndrome or Rubinstein syndrome |
| Causes: | mutation or deletion in the CREBBP gene, located on chromosome 16, and/or the EP300 gene, located on chromosome 22. |
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.[1] 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 gene, located on chromosome 22.[2]
This condition is sometimes inherited as an autosomal dominant pattern, but often as a de novo. It affects an estimated 1 in 125,000-300,000 births.
thumb|right|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:
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.[7] Other research has shown a link with long-term memory (LTM) deficit.[8] [9]
RTS is diagnosed when a heterozygous pathogenic variant of the CREBBP gene is identified in the individual. It exhibits an autosomal dominant 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 disabilities that result in delayed mental development.
Rubinstein–Taybi syndrome, in many cases, is a microdeletion syndrome involving chromosomal segment 16p13.3 and is characterized by mutations in the CREBBP gene.[10] [11] Varying amounts of material are deleted from this section of the chromosome and account for the spectrum of physiological symptoms.[12]
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 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.[13]
Mutations in the EP300 gene, located on chromosome 22q13.2, are responsible for a small percentage of cases of Rubinstein–Taybi syndrome.[2] 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 domain and are able to bind to various gene-specific transcription factors as well as general transcription factors.[14] Cell lines derived from RTS patients exhibit diminished acetylation of multiple histone proteins, particularly histone 2A and histone 2B,[15] suggesting that this disease has its origins in problems with the regulatory mechanisms of transcription.[16] The functions of CREBBP and p300 broadly overlap but do have co-activator–specific effects on gene expression.[17] The proteins may also facilitate transcriptional elongation.[18]
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.[2]
A mouse model 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.[19]
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.[20]
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 hadn't 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 characteristics such 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 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.