Rubinstein-Taybi syndrome is a rare genetic multisystem disorder that affects many organ systems of the body. The group of findings (constellation) associated with this syndrome include growth retardation and delayed bone age; mental retardation; distinctive abnormalities of the head and face (craniofacial dysmorphism), including widely spaced eyes (hypertelorism), a broad nasal bridge, and an abnormally large or "beak-shaped" nose; abnormally broad thumbs and great toes (halluces); and/or breathing and swallowing difficulties. In addition, most affected children experience delays in attaining developmental milestones (e.g., sitting, crawling, walking, talking, etc.) and/or delays in the acquisition of skills requiring coordination of muscular and mental activity (psychomotor retardation). Additional craniofacial abnormalities may include an abnormally small head (microcephaly); a highly-arched roof of the mouth (palate); an unusually small (hypoplastic) lower jaw (micrognathia); crossed eyes (strabismus); droopy eyelids (ptosis); downwardly slanting eyelid folds (palpebral fissures); and/or an extra fold of skin on either side of the nose that may cover the eyes' inner corners (epicanthal folds). In addition, many individuals with Rubinstein-Taybi syndrome may have malformations of the heart, kidneys, urogenital system, and/or skeletal system. In most cases, the skin is also affected. The range and severity of symptoms and physical findings may vary widely from case to case. Most cases of Rubinstein-Taybi syndrome occur randomly, for no apparent reason (sporadic).
Rubinstein-Taybi syndrome is a rare genetic multisystem disorder that typically affects many organ system of the body. The group of physical findings and symptoms associated with this syndrome include distinctive abnormalities of the fingers and toes; developmental delays, growth retardation, speech delays, and/or mental retardation; characteristic abnormalities of the head and face (craniofacial dysmorphism); breathing and swallowing difficulties; skeletal malformations; and/or urogenital abnormalities. In many cases, the skin, heart, and/or respiratory system may also be affected. Physical findings and symptoms associated with Rubinstein-Taybi syndrome vary greatly from case to case.
In most cases, infants with Rubinstein-Taybi syndrome have a distinctive findings associated with the hands and feet including thumbs and/or great toes that are abnormally broad as a result of unusual broadness of the bones in the tips of the thumbs and great toes (terminal phalanges). In addition, distal bones of the thumbs and great toes may also be angled improperly (misaligned) on a proximal bone that is abnormally shaped (delta phalanx). The fifth fingers may be permanently fixed in a bent position (clinodactyly).
In most cases, infants with Rubinstein-Taybi syndrome experience growth retardation and delayed bone age (below the 50th percentile) following birth (postnatally). Affected infants may fail to grow and gain weight at the expected rate (failure to thrive). Breathing and swallowing difficulties may occur and most affected individuals are prone to repeated respiratory infections. As affected infants age, they may continue to experience poor growth and eventually exhibit short stature (most below the third percentile). Children with Rubinstein-Taybi syndrome may later show a relative obesity for their height.
Most infants and children with Rubinstein-Taybi syndrome experience varying degrees of mental retardation, delays in the acquisition of skills requiring coordination of muscular and mental activities (psychomotor retardation), and delayed socialization. In some cases, affected infants and children may not reach certain developmental milestones (e.g., sitting, crawling, standing, walking, etc.) at a time when they would otherwise be expected. In most cases, infants with Rubinstein-Taybi syndrome experience a significant delay in developing expressive speech. In addition, affected infants may experience diminished muscle tone (hypotonia); abnormally exaggerated reflexes (hyperreflexia); a stiff, unsteady gait; infrequent bowel movements (constipation); and/or episodes of uncontrolled electrical disturbances in the brain (seizures). In some cases, affected individuals may have partial or complete absence of the thick band of nerve fibers that connects the left and right hemispheres of the brain (hypoplasia or agenesis of the corpus callosum). (For more information on this disorder, choose “Agenesis of Corpus Callosum” as your search term in the Rare Disease Database.)
Infants with Rubinstein-Taybi syndrome may have a wide variety of distinctive abnormalities of the head and facial (craniofacial) area. In most cases, affected infants have an abnormally large, “beak-shaped” or straight nose with a broad nasal bridge. In addition, affected infants may have a peculiar grimacing facial appearance when smiling and laterally downslanting eyelid folds (palpebral fissures). In some cases, the wall (septum) dividing the nostrils (nasal alae) may extend below the nostrils. Infants with Rubinstein-Taybi syndrome typically have an abnormally small head (microcephaly), below the 50th percentile, with an unusually prominent forehead (frontal bossing). In some cases, the soft, membrane-covered space near the forehead (where two of the fibrous joints [sutures] of the skull meet [anterior fontanelle]) may be abnormally wide and may close later than otherwise expected. In addition, there may also be a gap between certain bones of the skull (parietal foramina). In some cases, scalp hair patterning may be abnormal, demonstrating a distinctive “upsweep” in the forehead area and abnormal extension of the hairline onto the sides of the forehead and/or back of the head.
In some cases, affected infants may have unusually long eyelashes and/or abnormally full, thick eyebrows that may be highly arched. In addition, affected infants may have abnormalities of the eyes including eyes that appear widely spaced (apparent hypertelorism); crossed eyes (strabismus); upper eyelids that droop (ptosis); and/or extra folds of skin on either side of the nose that may cover the eyes’ inner corners (epicanthal folds). In some cases, light may not pass correctly through the eye (refractive error), causing vision abnormalities such as nearsightedness (myopia). In addition, the clear portion of the eye through which light passes (cornea) may be abnormally shaped, leading to problems with depth perception (astigmatism). In some cases, there may be blockage in one or both of the channels (nasolacrimal ducts) through which tears pass into the nasal cavities. In rare cases, affected infants may have increased fluid pressure within the eyes (glaucoma); clouding (opacity) of the lenses of the eyes (cataracts); small corneal opacities; clefting defects, usually resulting in an abnormal “keyhole” shape to the colored portion of the eye (iris coloboma); and/or rapid, involuntary eye movements (nystagmus).
In many cases, in infants with Rubinstein-Taybi syndrome, the outer portions of the ears (pinna) may be misshapen (dysplastic) and/or abnormally low-set or rotated with abnormal depressions or lines. Affected infants may experience frequent (recurrent) ear infections that may lead to hearing impairment. In most cases, abnormalities of the mouth and jaw may be present including an abnormally small mouth; a short, thin upper lip; a “pouting” lower lip; a highly arched roof of the mouth (palate); an underdeveloped upper jaw bone (maxilla); and/or an abnormally small lower jaw (micrognathia) that is displaced farther back than otherwise expected (retrognathia). In many cases, affected infants have irregularly shaped, abnormally crowded teeth, resulting in upper and lower jaws that do not meet properly (malocclusion). Affected individuals may have abnormally enlarged portions (talon cusps) of the posterior aspect of the permanent upper incisor teeth, and/or an unusually large tongue (macroglossia). The soft tissue structure that hangs in the back of the throat may also be divided (bifid uvula). Macroglossia may contribute to respiratory and swallowing difficulties during infancy. In addition, in some cases, affected individuals may appear to be frowning or upset when they smile (grimacing smile).
In some cases, in addition to abnormally broad thumbs and toes, children with Rubinstein-Taybi syndrome may have additional abnormalities affecting the thumbs and toes. Such abnormalities may include toes that overlap, unusually shaped bones of the feet (metatarsals), and/or abnormally duplicated bones (proximal or distal phalanges) of the great toes (halluces). In rare cases, affected infants may have webbing (syndactyly) of the toes, an extra toe (postaxial polydactyly). In addition, infants with Rubinstein-Taybi syndrome may have flat feet (pes planus); a single, deep crease across the palms of the hands (simian crease); and/or deep crease along the bottom of the foot between the first and second toes. In addition, unusual characteristic findings involving the skin ridge patterns on the hands and feet (dermatoglyphics) may also be present (e.g., a double pattern on the thumb; an increase in the number of finger tip arch patterns; a distinctive large complex pattern on the thenar/first interdigital area; an ulnar loop on the hypothenar area; the atd angle on the palm may be increased due to a distal axial triradius, a double pattern on the great toe; and a distorted long distal loop or double loops on by the great toes [hallucal area]). In some cases, there may be prominent pads on the fingertips (persistent fetal fingertip pads).
In some cases, there may be additional skeletal abnormalities including abnormal side-to-side (scoliosis) or front-to-back (kyphosis) curvature of the spine; abnormal depression of the bone forming the center of the chest (sternum); known as “funnel chest” or pectus excavatum; abnormalities of vertebrae and the pelvis; and/or malformations of ribs. In some cases, the passage through the bone at the base of the skull (foramen magnum) through which the spinal cord enters the spinal column may be abnormally large. In addition, individuals with Rubinstein-Taybi syndrome may have incomplete closure of bones in the spinal column surrounding the spinal cord (spina bifida occulta). (For more information on this disorder, choose “Spina Bifida” as your search term in the Rare Disease Database.) The lower end of the spinal cord may be abnormally tied down (tethering) and, rarely, protrusion of the spinal cord and the membranes (meninges) that surround the spinal cord (myelomeningocele) may occur.
Male infants with Rubinstein-Taybi syndrome may also have abnormalities of the genitourinary tract including failure of one or both testes to descend into the scrotum (cryptorchidism), an abnormal fold of skin extending around the base of the penis (shawl scrotum), and/or misplacement of the urinary opening, such as on the underside of the penis (hypospadias). In addition, affected infants may have underdeveloped (hypoplastic) or absent kidney(s), repeated infections of the urinary tract, abnormal deposits of mineral salts in the kidneys (nephrolithiasis or kidney stones), unusual accumulation of urine in the kidney (hydronephrosis), and/or backflow (reflux) of urine into the tubes (ureters) that normally bring urine to the bladder. In some cases, duplication of the kidneys and/or ureters may also be present.
In some cases, individuals with Rubinstein-Taybi syndrome may have abnormalities of the skin. Affected individuals may have one or more pink or dark red irregularly shaped patches of skin (capillary hemangioma or nevus flammeus) on the forehead, back of the neck (nape), and/or back. Affected individuals may also have small, coffee-colored spots on the skin (cafe au lait spots). In addition, affected individuals may experience overgrowth of scar tissue at the site of a cut, injury, or surgical incision (keloid formation) or occurring spontaneously. This excess tissue may be raised and firm with irregular edges. In some cases, affected individuals may have excess body hair (hirsutism) and/or ingrown finger or toenails.
Approximately 25 percent of infants with Rubinstein-Taybi syndrome may have an associated heart defect that is present at birth (congenital heart defect). According to the medical literature, patent ductus arteriosus may be the most common congenital heart defect present in infants with Rubinstein-Taybi syndrome. Patent ductus arteriosus is a condition in which the passage (ductus) between the blood vessel that leads to the lungs (pulmonary artery) and the major artery of the body (aorta) fails to close after birth. This results in “recirculation” of blood from the aorta and the pulmonary artery through the lungs. Infants with Rubinstein Taybi Syndrome may also have extra heart sounds (heart murmurs), abnormal narrowing of the opening between the pulmonary artery and the right ventricle of the heart (pulmonary stenosis), narrowing of the aorta (aortic coarctation), and/or ventricular septal defects (VSDs) and/or atrial septal defects (ASDs). (For more information on these disorders, choose the exact name of the heart defect as your search term in the Rare Disease Database.)
The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. Affected infants have an abnormal opening in the ventricular septum, atrial septum, or both.
The symptoms associated with a ventricular septal defect or atrial septal defect vary from case to case, depending upon the size and location of such septal defects. A small ventricular septal defect may close on its own (spontaneously) or become less significant as the child matures and grows. A moderately-sized defect may affect the ability of the heart to pump blood efficiently to the lungs and the rest of the body (congestive cardiac failure). Symptoms associated with cardiac failure may include an abnormally rapid rate of breathing (tachypnea), wheezing, unusually fast heartbeat (tachycardia), enlarged liver (hepatomegaly), and/or failure to grow at the expected rate (failure to thrive). A large ventricular septal defect can cause life-threatening complications during infancy. Most children with an atrial septal defect exhibit no symptoms. However, in some cases, associated symptoms may include abnormal thinness, mild growth delays, and an increased susceptibility to repeated respiratory infections. In rare cases, severely affected children may experience breathlessness, easy fatigability with exercise, and/or irregular heartbeats (arrhythmias). (For more information on these disorders, choose “ventricular septal defects” or “atrial septal defects” as your search terms in the Rare Disease Database.)
In some cases, affected individuals may also have abnormalities of the respiratory system. The lungs may be abnormally divided into small extra sections (lung lobulation) and/or the walls of the voice box (larynx) may be weak and easily collapsible, potentially resulting in swallowing and breathing difficulties (e.g., temporary cessation of normal breathing rhythm during sleep [sleep apnea]).
In some cases, children with Rubinstein-Taybi syndrome appear to be more prone to developing certain malignancies (e.g., nasopharyngeal rhabdomyosarcoma, neurilemoma, leukemia, etc.) than the general population.
In some cases, additional abnormalities may be present. Affected individuals may experience the backward flow of fluid from the stomach into the esophagus (gastroesophageal reflux), leading to a burning sensation in the chest and/or inhalation (aspiration) into the lungs. In addition, individuals with Rubinstein-Taybi syndrome may have extra (supernumerary) nipples, widely spaced nipples, and/or a portion of the intestine may protrude through an abnormal opening in the muscular wall of the abdomen into the groin area (inguinal hernia). In rare cases, other physical features and symptoms have been reported in the medical literature; however, their significance and relationship to Rubinstein-Taybi syndrome has yet to be determined.
In most cases, Rubinstein-Taybi syndrome occurs randomly, with no apparent cause (sporadic). In some cases, a positive family history has been identified that has suggested possible autosomal dominant inheritance. According to the medical literature, the range and severity of symptoms may vary greatly among affected family members (kindreds).
The gene responsible for Rubinstein-Taybi syndrome has been located on the short arm (p) of chromosome 16 (16p13.3). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males, and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”. Chromosomes are further subdivided into bands that are numbered. For example, “chromosome 16p13.3″ refers to band 13.3 on the short arm of chromosome 16.
Researchers have suggested that some cases of Rubinstein-Taybi syndrome may be caused by a small genetic change (point mutation or deletion [interstitial]) in a gene that is involved in the regulation of a particular protein, CREB binding protein [CBP]. Mutations affecting the CBP gene (generalized dysregulation of gene expression) may be the underlying cause of Rubinstein-Taybi syndrome and may be the reason that affected individuals may be at increased risk for certain malignancies (e.g., nasopharyngeal rhabdomyosarcoma, neurilemoma, leukemia, etc.). Approximately one tenth to one fourth of cases of Rubinstein-Taybi syndrome may be due to missing portions of the gene (submicroscopic deletions).
Rubinstein-Taybi syndrome is a rare disorder that affects males and females in equal numbers. Drs. Rubinstein and Taybi first identified this syndrome in 1963; however, a child with this syndrome was described in the medical literature as early as 1957. Since 1963, more than 730 cases have been reported in the medical literature. The exact incidence of Rubinstein-Taybi syndrome is unknown. Estimates for the general population range from one in 300,000 to one in 720,000 individuals. In the Netherlands, the estimate ranges from one in 100,000 to one in 1250,000 individuals.
Rubinstein-Taybi syndrome may be suspected at birth based upon a thorough clinical evaluation and identification of characteristic physical findings (e.g., growth retardation [low percentile for length, weight, and head circumference], characteristic facial features, particularly a straight or “beak-like” nose; broad thumbs and great toes; narrow, highly-arched palate; etc.). The diagnosis may be further confirmed by x-ray studies that may reveal characteristic malformations of the bones of the hands and feet.
In approximately 15-20 percent of cases, cytogenetic and molecular study of the CREB binding protein gene region of chromosome 16 can help confirm diagnosis.
X-ray studies and/or other tests may also be conducted to detect and/or confirm the degree of certain craniofacial, dental, skeletal, cardiac, and/or other abnormalities that may occur in association with the disorder. For example, imaging tests (e.g., CT scan, MRI, etc.) may reveal characteristic malformations of the brain (e.g., agenesis of the corpus callosum). In addition, an electroencephalogram (EEG) may be conducted to help monitor the electrical activities of the brain.
Because of the possibility of associated congenital heart defects, a thorough cardiac evaluation may be beneficial. Tests conducted may include x-ray studies, electrocardiogram (EKG), echocardiogram, and cardiac catheterization. X-ray studies may reveal pulmonary stenosis and/or malformations of other heart structures. An EKG, which records the transmission of the heart's electrical impulses, may reveal abnormal electrical patterns. During an echocardiogram, ultrasonic waves are directed toward the heart, enabling physicians to study cardiac function and motion. During cardiac catheterization, a small hollow tube (catheter) is inserted into a large vein and threaded through the blood vessels leading to the heart. This procedure allows physicians to determine the rate of blood flow through the heart, measure the pressure within the heart, and/or thoroughly identify anatomical abnormalities.
The treatment of Rubinstein-Taybi syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists who may need to systematically and comprehensively plan an affected child's treatment. Such specialists may include pediatricians, physicians who diagnose and treat heart abnormalities (cardiologists), skeletal abnormalities (orthopedists), hearing problems (audiologists), urinary tract abnormalities (urologists), kidney malformations (nephrologists), as well as, dental specialists, physical therapists, speech pathologists, dietitians, and/or other health care professionals.
Specific therapies for the treatment of Rubinstein-Taybi syndrome are symptomatic and supportive. Affected individuals may require early intervention to prevent and/or monitor respiratory and feeding difficulties. Because individuals with Rubinstein-Taybi syndrome may have an increased susceptibility to repeated respiratory infections, physicians may closely monitor affected individuals, recommend preventive measures, and immediately institute appropriate treatment (e.g., antibiotics) should such infections occur. In severe cases of such infections, hospitalization may be required. In some cases, physicians may recommend anticonvulsants to treat seizures.
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 [cardiac arrythmias]) associated with a certain muscle relaxant (succinlycholine) and certain anesthesia. Any situations requiring the administration of anesthesia or succinlycholine (e.g., surgical procedures) should be closely monitored by skilled professionals (anesthesiologists).
Orthopedic techniques, orthopedic surgery, physical therapy, and/or other supportive techniques may help treat certain skeletal abnormalities potentially associated with Rubinstein-Taybi syndrome, such as scoliosis. In some cases, surgery may be performed on the hands and/or feet, particularly when there are extra (supernumerary) phalanges, or the phalanges are malformed. Surgery may also be performed to correct other skeletal malformations, certain congenital heart defects, genital abnormalities, and/or dental abnormalities. Dental abnormalities associated with Rubinstein-Taybi syndrome may also be treated through the supportive techniques. In some causes, the dentists who specialize in the alignment of teeth (orthodontists) may need to be consulted.
Language/speech therapy and augmentative and/or alternative communication techniques may be recommended for individuals with Rubinstein-Taybi syndrome who demonstrate delays in the development of expressive language. Appropriate supportive techniques may be recommended to treat individuals with hearing impairment.
Some individuals with this disorder may be more prone to certain malignancies than the general population. Physicians may closely monitor an affected individual to ensure early detection and appropriate treatment.
Early intervention is important to ensure that children with Rubinstein-Taybi syndrome reach their potential. Special services that may be beneficial to affected children may include special remedial education, special social support, and other medical, social, and/or vocational services.
Families may benefit from contacting parent support groups. Genetic counseling will also be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
Rubinstein JH. Rubinstein-Taybi Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:726-7.
Jones KL, ed. Smith’s Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W. B. Saunders Co: 1997:18-9, 92-93, 412.
Champion RH, et al., eds. Textbook of Dermatology. 5th ed. Cambridge, MA: Blackwell Scientific Publications; 1992:366.
Buyce ML, ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990:1502-04.
Gorlin RJ, et al., eds. Syndromes of the Head and Neck, 3rd ed. New York, NY: Oxford University Press; 1990:309-11.
Wiley S, et al., Rubinstein-Taybi syndrome medical guidelines. Am J Med Genet. 2003;119A:101-10.
van Genderen MM, et al. Ocular features in Rubinstein-Taybi syndrome: investigation of 24 patients and review of the literature. Br J Ophthalmol. 2000;84:1177-84.
Cantani A, et al. Rubinstein-Taybi syndrome. Review of 732 cases and analysis of the typical traits. Eur Rev Med Pharmacol Sci. 1998;2:81-87.
Wallerstein R, et al. Submicroscopic deletions at 16p13.3 in Rubinstein-Taybi syndrome: frequency and clinical manifestations in a North American population. J Med Genet. 1997;34:203-06.
Hendrix JD, et al. Rubinstein-Taybi syndrome associated with multiple flamboyant keloids. Cutis. 1996;57:346-48.
McGaughran JM, et al. Rubinstein-Taybi syndrome with deletions of FISH probe RT1 at 16p13.3: two UK patients. J Med Genet. 1996;33:82-83.
Critchley LA, et al. Anaesthesia in an infant with Rubinstein-Taybi syndrome. Anaesthesia. 1995;50:37-38.
Petrij F, et al. Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature. 1995;376:348-51.
Miller RW, et al. Tumors in Rubinstein-Taybi syndrome. Am J Med Genet. 1995;56:112-15.
Stevens CA, et al. Cardiac abnormalities in the Rubinstein-Taybi syndrome. Am J Med Genet. 1995;59:346-48.
Sener RN. Rubinstein-Taybi syndrome: cranial MR imaging findings. Comput Med Imaging Graph. 1995;19:417-18.
Brei TJ, et al., Glaucoma and findings simulating glaucoma in the Rubinstein-Taybi syndrome. J Pediatr Ophthalmol Strabismus. 1995;32:248-52.
Cambiaghi S, et al. Multiple pilomatricomas in Rubinstein-Taybi syndrome: a case report. Pediatr Dermatol. 1994;11:21-25.
Rubinstein JH. Broad thumb-hallux (Rubinstein-Taybi) syndrome 1957-1988. American Journal of Medical Genetics Supplement. 1990;6:3-16.
FROM THE INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 180849, Last Update: 7/26/96; Entry No: 122470; Last Update: 10/4/96.