RSTS is a rare genetic disorder which may affect many organ systems of the body. Features include distinctively broad and/or angled fingers and toes, developmental delays, growth delays, speech delays, intellectual disability, characteristic abnormalities of the head and face (craniofacial dysmorphism), breathing and feeding difficulties (dysphagia), and urogenital abnormalities. In some people, the skin, heart, and/or respiratory system may also be affected. Symptoms associated with RSTS vary greatly from person to person.
Most infants with RSTS have 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, the 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 fixed in a bent position (clinodactyly).
Growth and Development
While prenatal growth is often normal, in most infants with RSTS parameters for height, weight, and head circumference fall below the fifth percentile during infancy. Affected infants fail to grow and gain weight at the expected rate (failure to thrive). Although weight gain can be very slow in infancy, children with RSTS may later show a relative obesity for their height. Feeding difficulties (dysphagia) may occur and many affected individuals are prone to repeated respiratory infections. As infants age, they may continue to experience poor growth and exhibit short stature (most below the third percentile).
Most infants and children with RSTS experience varying degrees of intellectual disability (average IQ between 36-51), delays in the acquisition of skills requiring coordination of muscular and mental activities (psychomotor delays), and delayed socialization. Most affected infants and children do not reach certain developmental milestones (e.g., sitting, crawling, standing, walking, etc.) at a time when they would otherwise be expected. Most children with RSTS experience a significant delay in expressive speech. In addition, there may be diminished muscle tone (hypotonia), abnormally exaggerated reflexes (hyperreflexia), a stiff, unsteady gait, infrequent bowel movements (constipation), and seizures.
Infants with RSTS have several distinctive head and facial (craniofacial) features. Most affected infants have a 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 downslanting eyelid openings (palpebral fissures). In some children, the wall (septum) dividing the nostrils may extend below the nostrils (low hanging columella). Infants with RSTS typically have a small head (microcephaly), below the 5th percentile.
Abnormalities of the mouth and jaw may be present including an abnormally small mouth, a short, thin upper lip, a highly arched roof of the mouth (palate), an underdeveloped upper jaw bone (maxilla), and an abnormally small lower jaw (micrognathia) that is displaced farther back than otherwise expected (retrognathia). Many affected infants have irregularly shaped, abnormally crowded teeth, resulting in upper and lower jaws that do not meet properly (malocclusion). Affected individuals may have a boney protuberance on the lingual aspect of the upper front teeth (talon cusps). The soft tissue structure that hangs in the back of the throat may also be divided (bifid uvula). In addition, some affected individuals may appear to be frowning or upset when they smile (grimacing smile).
In addition to abnormally broad thumbs and toes, some children with RSTS may have toes that overlap, unusually shaped bones of the feet (metatarsals), and/or abnormally duplicated bones (proximal or distal phalanges) of the great toes (halluces).
Affected individuals may experience overgrowth of scar tissue at the site of a cut, injury, or surgical incision (keloid formation) or this may occur spontaneously.
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).
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, malformations of ribs, and recurrent dislocation of the knee caps. The lower end of the spinal cord may be abnormally tied down (tethering).
Male infants with RSTS may 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, infants with RSTS may have underdeveloped (hypoplastic) or absent kidney(s), repeated infections of the urinary tract, 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.
Approximately one third of infants with RSTS 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 RSTS. Infants with RSTS 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). The symptoms associated with a ventricular septal defect or atrial septal defect vary from case to case, depending upon the size and location of the defect. (For more information on these disorders, choose the exact name of the heart defect as your search term in the Rare Disease Database.)
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]).
Individuals with RSTS often exhibit a short attention span, decreased tolerance for noise and crowds, impulsivity, and moodiness. Autistic behaviors are common.
Some children with RSTS appear to be more prone to developing certain malignancies (including meningioma, pilomatixoma, rhabdomysarcoma, pheochromocytoma, neuroblastoma, medulloblastona, oligodendroglioma, leioyosarcoma, seminoma, odontoma, choristoma, and leukemia) than the general population.
Individuals with RSTS can be difficult to intubate because of the easily collapsibility of the laryngeal wall. An anesthesiologist comfortable with managing complex pediatric airway problems should administer general anesthesia when needed.
In most affected children, RSTS occurs as the result of a new (de novo) genetic mutation that is not present in or carried by the parents. In these cases, the risk of having a second affected child is less than 1%.
RSTS may also be inherited in an autosomal dominant pattern, meaning that if a person has RSTS each of his/her children has a 50% chance of having RSTS.
The most common gene responsible for RSTS (CREBBP) is located on the short arm (p) of chromosome 16 (16p13.3). Pathogenic variants in the CREBBP gene have been identified in 50%-60% of individuals with RSTS. Mutations in the EP300 gene have been identified in 3%-8% of individuals with RSTS. This gene is located on chromosome 22 (22q13.2).
RSTS is a rare disorder that affects males and females in equal numbers. The exact incidence of RSTS is unknown, although a study in the Netherlands estimates the incidence to be between one in 100,000 to one in 125,000 individuals.
The diagnosis of RSTS is primarily based on physical (clinical) features, including a downward to the eyes (downslanted palpebral fissures), a low-hanging nasal septum (columella), a high palate, a grimacing smile, cusp-like structures (talon cusps) on the front teeth, and/or broad and angulated thumbs and great toes.
The diagnosis may be further supported through x-ray studies revealing malformations of the bones of the hands and feet characteristic to RSTS. Genetic testing (FISH or sequence analysis) may confirm RSTS, including pathogenic variants in the CREBBP gene (identified in 50%-60% of affected individuals) or in the EP300 gene (identified in 3%-8% of RSTS individuals).
The management of RSTS is directed toward the specific symptoms of each individual. Management may require the coordinated efforts of a team of specialists, including 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. Growth parameters should be regularly plotted on an RSTS-specific growth chart. There should be yearly eye and hearing evaluations and routine monitoring for cardiac, dental, and renal abnormalities.
Orthopedic surgery, physical therapy, and/or other supportive techniques may help treat certain skeletal abnormalities potentially associated with RSTS, such as scoliosis. In some cases, surgery may be performed on the hands and/or feet, particularly when there are extra (supernumerary) fingers and/or toes, or when the fingers are severely misaligned.
Affected individuals may require early intervention to prevent and/or monitor respiratory and feeding difficulties. Special education programs, vocational training, speech, and/or behavioral therapy may also be recommended.
Families may benefit from contacting parent support groups. Genetic counseling is available as well.
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