Rubinstein-Taybi syndrome (RSTS)

• Rubinstein-Taybi syndrome (RSTS) is a rare genetic disorder that is characterized by varying degrees of intellectual disabilities (formerly known as mental retardation), distinct facial features, and broad thumbs and first toes. The disorder is often detected in newborns because the physical features are apparent at birth.
• There are many complications associated with RSTS, including heart and kidney defects, obesity, ear infections, and difficulty swallowing. Furthermore, patients with the disorder have an increased risk of developing cancerous and noncancerous tumors, as well as leukemia.
• Some cases of RSTS are inherited, but most are caused by random genetic mutations or chromosomal deletions during the development of the egg, sperm, or embryo. About 50% of people with RSTS either have mutations in specific genes or are missing a part of chromosome 16. The other 50% of RSTS cases occur for unknown reasons. Therefore, researchers believe that other genes may be involved in RSTS.
• RSTS is estimated to affect one out of 10,000-300,000 births. However, most researchers estimate that the incidence is about one out of 100,000-125,000 births. Males and females are equally affected, and it does not appear to affect any particular race or ethnicity more than others.
• Currently, there is no known cure for RSTS. However, treatment, such as special education and occupational therapy, can help people cope with the disorder. Many people with RSTS are able to live long, healthy lives, but a person's prognosis depends on whether or not life-threatening complications, such as cancer, occur.

• People with family histories of Rubinstein-Taybi syndrome (RSTS) have an increased risk of having children with the disorder. When the condition is inherited, it is passed down as an autosomal dominant condition. This means that if one parent has the disorder, there is a 50% risk that a child will have the disorder. If both parents have the disorder, there is a 75% chance that their child will have the disorder. However, most cases occur randomly without a family history of the disorder.
• General: Some cases of Rubinstein-Taybi syndrome are passed down among family members. However, most cases are caused by random genetic mutations or chromosomal deletions during the development of the egg, sperm, or embryo.
• Genetic mutations: Some people are born with abnormal (mutated) genes. Mutations in the CREBBP gene have been linked to RSTS. Normally, this gene provides the body with instructions on how to produce the CREB binding protein. This protein helps regulate many other genes. It is needed for normal fetal development because it controls cell growth and division and it triggers cells to develop specialized functions (a process called cell differentiation). When the CREBBP gene is mutated, the body is unable to produce enough CREB binding protein. As a result, symptoms of RSTS, including skeletal abnormalities of the face, develop. Researchers are performing studies to determine exactly how this mutation causes symptoms of RSTS.
• A minority of RSTS cases occur when a person has a mutated EP300 gene. Like the CREBBP gene, the EP300 gene helps regulate the activity of many other genes. The EP300 gene appears to play an important role in human development before and after birth. When mutations occur, symptoms of RSTS develop. Although RSTS patients with mutations in the CREBBP gene and EP300 gene appear to have similar symptoms, patients with EP300 mutations may experience milder skeletal abnormalities in the hands and feet than those with CREBBP mutations.
• Chromosome 16 deletion: Some people with Rubinstein-Taybi syndrome are missing part of chromosome 16. The part of the chromosome that is usually missing contains genes that are involved in human development, including the CREBBP gene and the EP300 gene. Because more than one gene is deleted, patients with chromosomal deletions generally experience the most severe symptoms and complications.
• Other: About half of RSTS cases occur for unknown reasons. In these instances, mutations in the CREBBP or EP300 gene are not present, and chromosome 16 is completely intact. Therefore, researchers believe that other, unidentified genes may cause RSTS.

• General: The symptoms of Rubinstein-Taybi syndrome may vary among individuals. In general, patients have distinct physical characteristics and intellectual disabilities. Patients typically experience delays in cognitive and motor skill development.
• Physical characteristics: Physical characteristics may be present at birth, but they usually become more noticeable with age. People with RSTS are typically short in stature. Common features include broad big toes and thumbs, a small upper jaw with a narrow palate, a prominent beaked nose, low-set and/or malformed ears, downward-slanted eyes that may be spaced far apart, crowded teeth, large head (called macrocephaly), thick and arched eyebrows, long eyelashes, drooping eyelids, crossed eyes (strabismus), cataracts, tear duct obstruction, decreased muscle tone, excessive hair growth (called hirsutism), and undescended testicles (in males).
• Intellectual disabilities: Patients with RSTS experience varying degrees of intellectual disabilities. Researchers typically use intelligence quotient (IQ) tests to measure the severity of a person's intellectual disabilities. Individuals who have IQs in the 85-115 range are considered to have average intelligence.
• Patients with mild intellectual disabilities typically have IQs in the range of 52 to 69. From birth to age six, patients are able to develop normal social and communication skills, but motor coordination is slightly impaired. By late adolescence, patients are able to learn until about a sixth-grade level. They are generally able to learn appropriate social skills. Adults with mild intellectual disabilities are usually able to work and support themselves, although some patients may need help during times of social or financial stress.
• Patients with moderate intellectual disabilities typically have IQs in the range of 36 to 51. Children younger than six years old are able to talk or communicate with others, but social awareness, or understanding of social situations, is generally poor. Motor coordination is typically fair, but delayed and below average. Adolescents are able to learn some occupational and social skills. For instance, they may be able to learn how to travel alone in familiar places. Adults may be able to support themselves with jobs. They usually require guidance and assistance during mild social or financial stress.
• Patients with severe intellectual disabilities generally have IQs that range from 20 to 35. Young children who are up to six years of age can say a few words, but their speech is limited. Motor coordination is generally poor. Adolescents can usually talk or communicate with others. They are able to learn simple habits, such as how to brush their teeth. Adults typically require lifelong assistance and guidance with daily activities, such as cooking.
• Patients with profound intellectual disabilities have IQs of 19 or lower. Children younger than six years old have very little motor coordination and may require nursing care. Adolescents typically have limited motor and communication skills. Adults usually require lifelong nursing care.
• Motor skill development: Healthy children usually learn to walk when they are 9-15 months old, while children with RSTS are developmentally delayed. On average, children with RSTS learn how to walk when they are 2.5 years old.
• Speech problems: About 90% of patients with RSTS have speech and communication problems. Studies show that speech is one of the slowest developmental areas for children with RSTS. Some may be unable to talk at all, while others may only experience mild speech problems, such as slowed speech, difficulty pronouncing big words, or difficulty understanding complex sentences.

• Clinical evaluation: In general, Rubinstein-Taybi syndrome (RSTS) is diagnosed after a medical and physical examination. A doctor will look for the characteristic signs and symptoms of the disorder, such as varying degrees of intellectual disabilities (formerly known as mental retardation), distinct facial features, and broad thumbs and first toes. If RSTS is suspected, additional tests, such as X-rays of the thumbs and first toes, may be performed to confirm a diagnosis.
• Cytogenetic studies: Some, but not all, cases of RSTS can be diagnosed with cytogenetic studies, or tests that evaluate the structure of chromosomes. A sample of the patient's blood is analyzed to determine if part of chromosome 16 is deleted. If part of this chromosome is missing, a positive diagnosis is made. However, because not all cases are caused by deletions in chromosome 16, RSTS cannot be ruled out with just a chromosomal test.
• Prenatal testing: Currently, prenatal testing is not available for RSTS.

• General: Patients with Rubinstein-Taybi syndrome (RSTS) who have deletions in chromosome 16 generally experience the most severe complications. This is likely because several genes are in the deleted region.
• Constipation: Patients with RSTS typically experience chronic constipation.
• Ear problems: Because people with RSTS may have malformed ears, they have an increased risk of experiencing frequent ear infections and possibly hearing loss.
• Feeding difficulties: Children with RSTS may have difficulty swallowing and experience gastroesophageal reflux disease (GERD). GERD occurs when liquid from the stomach backs up (regurgitates) into the esophagus. This liquid may contain stomach acids and bile. In some cases, the regurgitated stomach liquid can cause inflammation (esophagitis), irritation, and damage to the esophagus. These digestive problems may make it difficult for the child to feed.
• Heart defects: Children with RSTS may be born with heart defects. An estimated 40% of patients have defects that are serious and require surgery. In addition, some people may experience irregular heart rhythms, called arrhythmia.
• Keloid formation: Patients with RSTS have an increased risk of developing keloids, which are raised, irregularly shaped scars that become larger over time. This type of scar occurs when excessive amounts of a structural protein (called collagen) are produced in the inner layer of skin (called corium) during connective tissue repair.
• Kidney problems: Some patients may have kidney or bladder problems, such as an absent or extra kidney.
• Nail problems: Patients with RSTS have an increased risk of developing fungal infections in the fingernails or toenails. They also have an increased risk of experiencing ingrown nails, which happens when part of the nail starts to grow into the skin surrounding the fingernail or toenail.
• Reactions to anesthesia: People with RSTS have an increased risk of experiencing aspiration when they are under general anesthesia. Aspiration occurs when a person vomits and then inhales the gastrointestinal juices into the lungs. Aspiration is very serious because it can cause life-threatening infections in the lungs. Therefore, tubes should be inserted in a patient's throat before anesthesia if he/she has RSTS.
• Respiratory tract infections: People with RSTS have an increased risk of developing respiratory tract infections or infections in the airways (such as the nose, throat, or lungs).
• Tumors and cancer: People with RSTS have an increased risk of developing noncancerous and cancerous tumors, including certain kinds of brain tumors. Patients also have an increased risk of developing a type of bone marrow cancer called leukemia.

• General: Currently, there is no known cure for Rubinstein-Taybi syndrome (RSTS). However, many treatments and therapies may help patients cope with the disorder. It is important that patients regularly visit their doctors in order to treat and help prevent serious complications of the disorder.
• Antibiotics: If a patient develops a bacterial respiratory tract infection, antibiotics may be prescribed.
• Antibiotics may also be prescribed to treat an ear infection if the child is younger than six months old or has two or more ear infections within 30 days or fluid remains behind the eardrum. The American Academy of Pediatrics and the American Academy of Family Physicians recommend the use of high doses and short courses of amoxicillin (Amoxil®, Trimox®) or amoxicillin combined with clavulanate potassium (Augmentin®) in individuals (including children) with otitis media. Erythromycin antibiotics (Eryped® or Erytab®) may also be used. However, most ear infections go away without treatment in just a few days, and antibiotics will not help an infection caused by a virus.
• Antifungals: Patients with fungal nail infections often take antifungals, such as terbinafine (Lamisil®), fluconazole (Diflucan®), or itraconazole (Sporanox®). Treatment generally lasts about six to 12 weeks. However, results will not be apparent until the new nail has completely replaced the old, infected nail. This may take anywhere from four to six months. Once treatment is over, individuals should try not to expose the nails to warm, moist environments because this may cause the infection to return.
• Behavioral therapy: Behavioral therapy may also be beneficial. Several different types of behavioral therapy are available to help RSTS patients improve their communication and social skills, as well as their learning abilities and adaptive behaviors. For instance, applied behavior analysis (ABA) is a type of therapy used to improve the patient's behavior and to teach skills to help the person handle specific situations. The therapist uses positive reinforcement, which means the patient is rewarded when he/she behaves appropriately. ABA is highly structured and it usually requires 15-40 hours of therapy per week. The therapist usually works one-on-one with the patient and collaborates with the parents/caregivers, teachers, and others in the patient's life to provide treatment that is individualized to meet the patient's needs. Evidence suggests that behavioral therapy is most effective if it is started early in life.
• Cancer treatment: If a patient has a cancerous tumor, chemotherapy or radiation therapy may need to be performed before and/or after surgery.
• Patients with RSTS also have an increased risk of developing a type of bone marrow cancer called leukemia. In general, there are five major approaches to the treatment of leukemia. These include using chemotherapy to kill leukemia cells with strong anti-cancer drugs, interferon therapy to slow the reproduction of leukemia cells and promote the immune system's anti-leukemia activity, radiation therapy to kill cancer cells by exposure to high-energy radiation, stem cell transplantation (SCT) to enable treatment with high doses of chemotherapy and radiation therapy, and surgery to remove an enlarged spleen or to install a venous access device (large plastic tube) to give medications and withdraw blood samples.
• Early intervention programs: Patients with RSTS typically experience developmental delays in terms of cognitive and motor skills. For instance, children with RSTS usually do not start walking until they are about 2.5 years old. Therefore, caregivers should ask the doctors of RSTS patients about early intervention programs. These specialized programs expose children to appropriate sensory, motor, and cognitive activities. These programs typically involve special educators and therapists who help babies and young children develop their language, social, motor, and self-help skills.
• Keloid removal: Steroid injections with cortisone may help reduce the appearance of keloids. The medication is usually injected once a month until optimal results are reached. Although this treatment can help flatten out keloids, steroids sometimes cause the skin to redden.
• Cryotherapy can also help flatten keloids. This therapy uses liquid nitrogen to freeze the keloids. However, sometimes this therapy causes the keloids to become darker in color.
• Laser therapy can help flatten keloids and make them appear less red. Although this treatment is safe and causes minimal pain, several treatments may be needed.
• Keloids can also be surgically removed. However, surgery can also trigger an even larger keloid to develop. Sometimes doctors inject steroids or apply pressure dressings to the wound after surgery. Radiation has also been used after surgery.
• Laxatives: Laxatives are medicines taken orally or rectally to relieve and prevent constipation. Oral laxatives come in many different forms, including liquids, tablets, wafers, gums, or powders that are dissolved in water. Rectal laxatives include suppositories and enemas. There are many different types of laxatives available for the treatment of constipation. Laxatives include stool softeners and bulk forming, stimulant, osmotic, lubricating, and saline agents.
• Medical history and other medications an individual is taking may limit laxative options. Laxatives can interact with many medications, including blood thinners, antibiotics, diabetes drugs, and anti-seizure medications. If laxatives are used frequently over a period of weeks or months, they can decrease the colon's natural ability to contract and actually worsen constipation. In severe cases, overuse of laxatives can damage nerves, muscles, and tissues of the large intestine. Children younger than six years of age should not take laxatives without a doctor's recommendation. If pregnant or breastfeeding, seek a doctor's advice before using laxatives.
• Occupational therapy: Patients may benefit from occupational therapy. During sessions, a therapist helps the child learn skills to help him/her perform basic daily tasks, such as feeding, dressing, and communicating with others. Some patients work with therapists who specialize in disorders and disabilities. Parents and caregivers can ask their children's pediatricians for recommended therapists.
• Physical therapy: Physical therapy may help patients improve their physical strength and motor coordination. For example, since babies with RSTS usually have decreased muscle tone, a physical therapist may be able to help babies learn how to roll over, sit up, and walk. A variety of techniques, including exercises, stretches, traction, electrical stimulation, and massage, are used during physical therapy sessions.
• Special education: Patients with RSTS must have access to education that is tailored to their specific strengths and weaknesses. According to the Individuals with Disabilities Education Act, all children with disabilities, including those with RSTS, must receive free and appropriate education. According to the law, members of the patient's school should consult with the patient's parents or caregivers to design an individualized education plan. The school faculty should document the child's progress in order to ensure that the child's needs are being met.
• Educational programs vary among patients. In general, most experts believe that children with disabilities should be educated alongside their non-disabled peers. The idea is that non-disabled students will help the patient learn appropriate behavioral, social, and language skills. Therefore, some RSTS patients are educated in mainstream classrooms. Other patients attend public schools but take special education classes. Others attend specialized schools that are designed to teach children with disabilities.
• Speech-language therapy: Because 90% of RSTS patients have speech difficulties, which may make it difficult to communicate with others, speech-language therapy is often used. During speech-language therapy, a qualified speech-language professional (SLP) works with the patient on a one-to-one basis in order to help the patient improve speech, language, and communication skills. These programs may also help children with feeding problems. Programs are tailored to the patient's individual needs.
• Speech pathologists use a variety of exercises to improve the patient's communication skills. Exercises typically start off simple and become more complex as therapy continues. For instance, the therapist may ask the patient to name objects, tell stories, or explain the purpose of an object.
• On average, patients receive five or more hours of therapy per week for three months to several years. Doctors typically recommend that treatment is started early to ensure the best possible prognosis for the child.
• Surgery: Surgery may be performed to repair the thumbs and/or first toes. This may help improve the patient's ability to grasp objects. However, not all patients require surgery.
• If males have undescended testicles, a surgery (called orchiopexy) may be performed to bring the testicles down into the scrotum. The testicles are then stitched into place. This procedure is typically performed when the child is six months to two years old. It has been shown to help reduce the risk of infertility.
• Other patients made need surgery to repair heart defects.
• Some patients with RSTS develop noncancerous or cancerous tumors. These tumors may need to be surgically removed.

Note
: Currently, there is a lack of scientific data on the use of integrative therapies for the treatment or prevention of Rubinstein-Taybi syndrome (RSTS). However, some therapies have been used for constipation, a possible complication of Rubinstein-Taybi syndrome. The integrative therapies listed below should be used only under the supervision of a qualified healthcare provider and should not be used in replacement of other proven therapies.

• Aloe
  : Dried latex from the inner lining of the aloe leaf (Aloe vera, Aloe barbadensis) has traditionally been used as an oral laxative. There is strong scientific evidence in support of the laxative properties of aloe latex, based on the well-established cathartic properties of anthroquinone glycosides (found in aloe latex). A combination herbal remedy containing aloe was found to be an effective laxative, although it is not clear if this effect was due to aloe or to other ingredients in the product. Further study is needed to establish dosing and to compare the effectiveness and safety of aloe with other commonly used laxatives. Caution is advised when taking aloe supplements, as adverse effects including diarrhea and drug interactions are possible. Aloe supplements should not be used if pregnant or breastfeeding, unless otherwise directed by a doctor. Do not use for more than three days without consulting a doctor.
• Phosphates
  : Phosphates are the naturally occurring form of the element phosphorus. In the body, phosphate is the most abundant intracellular (in the cell) anion (negatively charged particle). Occasional constipation is an approved use of phosphates in adults and children, both in oral form and as an enema (for example, Fleet Enema®). Sodium phosphate taken orally or as an enema may be used for bowel cleansing in preparation for surgery, imaging studies, or endoscopy (for example, Fleet Phospho-soda®, Fleet Enema®). Phosphates appear to increase peristalsis (movement of the gastrointestinal tract) and cause an entry of fluids into the intestine. Aluminum phosphate is used orally to neutralize gastric acid.
  • Flaxseed
    : Flaxseed (Linum usitatissimum), not flaxseed oil, is a rich source of the essential fatty acid alpha-linolenic acid. Early studies in humans suggest that flaxseed can be used as a laxative. However, more information is needed to compare the effectiveness and dosing to more commonly used agents. Do not use for longer than three days without consulting a doctor.
  • Psyllium
    : Psyllium is derived from the husks of the seeds of Plantago ovata or Plantago isphagula. Psyllium contains a high level of soluble dietary fiber and is the chief ingredient in many commonly used bulk laxatives, including products such as Metamucil® and Serutan®. Psyllium has long been used as a chief ingredient in bulk forming laxatives. Generally, an increase in stool weight, an increase in bowel movements per day, and a decrease in total gut transit time has been observed in most studies. Use psyllium with caution, as psyllium may cause medications to not be absorbed properly. Do not use for more than three days without consulting a doctor.
    • Art therapy
      : Art therapy involves the application of a variety of art modalities including drawing, painting, clay, and sculpture. Art therapy enables the expression of inner thoughts or feelings when verbalization is difficult or not possible. It is not clear if play with modeling clay is an effective therapeutic intervention in children with constipation and encopresis (fecal soiling of clothes). In one study, play with modeling clay was associated with improvement in five of six children, but was limited by a lack of a control group.
    • Barley
      : Barley (Hordeum vulgare) is a cereal used as a staple food in many countries. It is commonly used as an ingredient in baked products and soup in Europe and the United States. Barley has been used traditionally as a treatment for constipation, due to its high fiber content. However, there is limited scientific evidence in this area. Further research is necessary in order to establish safety and dosing. Do not use for more than three days without consulting a doctor.
    • Cascara
      : Cascara (Rhamnus purshiana), also known as cascara sagrada, is widely accepted as a mild and effective treatment for chronic constipation. However, limited data is available. Caution is advised when taking cascara supplements, as adverse effects, including diarrhea and drug interactions, are possible. Cascara supplements should not be used if pregnant or breastfeeding, unless otherwise directed by a doctor. Do not use for more than three days without consulting a doctor.
    • Massage
      : Various forms of therapeutic superficial (on the surface) tissue manipulation have been practiced for thousands of years across cultures. Chinese use of massage dates to 1600 BC, and Hippocrates made reference to the importance of physicians being experienced with "rubbing" as early as 400 BC. Touch is fundamental to massage therapy and is used by therapists to locate painful or tense areas, to determine how much pressure to apply, and to establish a therapeutic relationship with clients. A small number of human trials report that abdominal massage may be helpful in patients with constipation. Overall, these studies are not well-designed or reported. Better quality research is necessary before a definitive conclusion can be reached.
    • Probiotics
      : Probiotics are beneficial bacteria (sometimes referred to as "friendly germs") that help to maintain the health of the intestinal tract and aid in digestion. They also help keep potentially harmful organisms in the gut under control. Most probiotics come from food sources, especially cultured milk products. Probiotics can be consumed as capsules, tablets, beverages, powders, yogurts, and other foods. The use of probiotics with constipation has had mixed results. One study combining probiotics with food showed a beneficial effect on gastrointestinal symptoms in patients with chronic constipation. However, another study did not show effectiveness in young children. More studies are needed to determine what forms of probiotics and which pathways of administration might be effective in constipation. Probiotics may cause diarrhea, but are otherwise considered safe.
    • Rhubarb
      : Rhubarb (Rheum palmatum) has been used by Chinese herbalists for thousands of years for various health conditions. Although rhubarb has been used in multiple cultures as a laxative, clinical research is limited. Positive effects on constipation when using a combination of rhubarb and Glauber's salt (sodium sulfate) has been reported in the scientific literature.

• Currently, there is no known method of prevention against Rubinstein-Taybi syndrome. If one parent has the disorder, there is a 50% risk that their child will have the disorder. If both parents have the disorder, there is a 75% chance that their child will have the disorder. However, most cases occur randomly without a family history of the disorder. Also, prenatal testing is not currently available for RSTS.
• An early diagnosis and prompt treatment can help ensure that patients maximize their intellectual potential. It is also important that patients regularly visit their doctors in order to treat and help prevent serious complications of the disorder.