Rubinstein–Taybi syndrome

Rubinstein–Taybi syndrome
Other names	Broad thumb-hallux syndrome or Rubinstein syndrome[1]
Child with Rubinstein–Taybi syndrome
Specialty	Medical genetics
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.^[2] 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.^[3]

People with this condition have an increased risk of developing noncancerous and cancerous

Presentation

Rubinstein–Taybi syndrome presents itself from birth, and is usually hallmarked by delayed physical and cognitive growth.^{[citation needed]}

Typical features of the disorder include:

• Broad thumbs and broad first toes and clinodactyly of the 5th finger^[4]
• Mental disability
• Small height, low bone growth, small head
• Cryptorchidism in males
• Unusual facies involving the eyes, nose, and palate
• 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)."^[5] Primary literature suggests the children may have a higher rate of cardiac physical and conduction abnormalities which may cause unexpected results with cardioactive medications.^[6] 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.^[7]

It 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.^{[citation needed]}

Genetics

Rubinstein–Taybi syndrome, in many cases, is a microdeletion syndrome involving chromosomal segment 16p13.3 and is characterized by mutations in the CREBBP gene.^[11][12] Varying amounts of material are deleted from this section of the chromosome and account for the spectrum of physiological symptoms.^[13]

The CREBBP gene makes a protein that helps control the activity of many other genes. The protein, called

Mutations in the EP300 gene, located on chromosome 22q13.2, are responsible for a small percentage of cases of Rubinstein–Taybi syndrome.^[3] 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.^{[citation needed]}

CREBBP and p300 are the respective protein products of the

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.[3]

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.^[20]

Medical Issues

Typical medical issues that occur in individuals with RTS include: visual difficulties, keloids, difficulty eating, significant gastro-oesophageal reflux, feeding difficulties, constipation, hypotonia, heart abnormalities, spinal curvature, joint problems, hypohidrosis, bladder incontinence, urinary tract abnormalities, including kidney problems, hearing loss, chronic nail fungus, urinary tract infections, sleep apnea, patellar dislocation, heart problems, frequent infections, anesthesia complications, neurologic abnormalities due to tethered cord, hypothyroidism, tumour and cancer, orthopedic problems, auditory impairment, dental and speech problems. These symptoms are often accompanied by cognitive-developmental impairment. ^[21][22][23]

Common dental problems include: crowded teeth, extra teeth, talon cusps, and excessive tooth decay. Older children and adults may require braces. ^[23]

Behavioural Issues

Behavioural characteristics for individuals with RTS include: being easily upset, eating excessively, having difficulty with peers, being unaware of common dangers, acting inappropriately in public, making odd movements or noises, being overly friendly, having unreasonable anxiety or fears, performing self-injury, difficulty sleeping, becoming agressive, having difficulty separating from the caregiver, and being overly shy. ^[23] Developmental delay often results in learning difficulties. ^[21]

Adults with RTS

In 2011, a study of 61 RTS adults (32 males, 29 females) in the USA found that most of the adults (69%) were living with their parents, but some lived in homes (21%) or supervised apartments (5%). Seventy-three percent of families arranged for guardianship after their children reached adulthood.

Eighteeen participants had IQ testing as adults; the average reported score was 49, with a range from 24 to 80. Out of 57 adults, 18 (32%) were noted to have a decrease in abilities over time. Seventy percent were said to be able to read and write to some degree; most were estimated by their families to have skills at the 'second grade' (age 7) to 'third grade' (age 8) levels.

Difficulties with speech was common. Forty-one percent were conversational, using sentences. Thirty percent used short phrases. Twelve percent used signs only, and 5% used a combination of words and signs, and 3% used a speech-assisted device.

Of the independence skills achieved upon reaching adulthood, 84% were feeding themselves, 72% were dressing themselves, 62% could use the toilet, 44% could shower, 43% could make their bed, 28% could use a telephone, 20% could do their laundry, 11% could prepare food, 8% could use public transportation and none could manage money.

Fifty-nine percent received vocational job training, usually through the school system, and 50% of the group were employed as adults, receiving financial compensation.

Ten percent were involved in dating and none were married or had children. ^[23]

Treatment

There is no existing treatment that reverses or cures RTS. There are, however, ways to manage and reduce symptoms for patients. Patients with RTS suffer from a diverse breadth of symptoms, however it is important to emphasise that not every patient will suffer from many or all of these symptoms, and not every patient will experience the same symptoms, meaning they differ from patient to patient. Due to there being a wide range of symptoms, RTS patients are referred to specialists that focus on each specific symptom. There is not a specialist for RTS. For example, patients will go to an orthopedic surgeon and physical therapy for skeletal and growth abnormalities, like scoliosis but will go to a cardiologist if they suffer from heart abnormalities or a dentist if they suffer from dental abnormalities. Individuals suffering from cognitive developments usually are part of special education programs and speech therapy. The specialists the individuals go to match the symptoms the individuals have. 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. ^[22]

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 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.^{[citation needed]}

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.^{[citation needed]}

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.^{[citation needed]}

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 CREBP 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.^{[citation needed]}

See also

• Nasodigitoacoustic syndrome
• List of cutaneous conditions

References

External links

Wikimedia Commons has media related to Rubinstein-Taybi syndrome.

• GeneReview/UW/NIH entry on Rubinstein-Taybi syndrome
• Rubinstein-Taybi syndrome due to 16p13.3 microdeletion on ORPHAnet
• RTS Support Group An Information Booklet