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Russell-Silver syndrome (RSS) is a rare disorder characterized by intrauterine growth retardation and postnatal growth deficiency along with a handful of common physical characteristics and a range of other symptoms. The wide spectrum of phenotype findings vary both in incidence rate and severity from one individual to another. Besides prenatal and postnatal growth retardation, the most common characteristics are normal head circumference (appearing large for the body), a large forehead that protrudes out from the plane of the face, a triangular-shaped face, a pinky that is fixed or "locked" in a bent position (clinodactyly), lack of appetite/low BMI, and undergrowth of one side or limb(s) of the body (hemihypotrophy), resulting in unequal (asymmetric) growth. The majority of children with RSS fall within the normal range of intelligence, but are more likely to have motor and speech delays. Intervention at an early age (infancy) is critical. Some evidence indicates that there may be neurodevelopmental differences between the different genetic causes of RSS. RSS is genetically heterogeneous, meaning that different genetic abnormalities are believed to cause the disorder. Abnormalities affecting certain genes on chromosomes 7 or 11 have been found in up to 60% of RSS patients, leaving approximately 40% of patients where the underlying cause of RSS is not known.
This syndrome was independently identified by H.K. Silver in 1953 and A. Russell in 1954. In the early medical literature, the term Silver syndrome had been used to denote a child with low birth weight, overgrowth of one side (in fact, undergrowth) of the body (lateral asymmetry), and clinodactyly, whereas the term Russell syndrome had been used to denote a similar condition without asymmetry. However, most researchers now consider Russell-Silver syndrome one disease entity. The disorder is usually called Russell-Silver syndrome in the United States and Silver-Russell syndrome in Europe
The symptoms of RSS vary greatly from one individual to another. Some individuals may be mildly affected; others may have serious complications. The wide range of potential symptoms (clinical spectrum) can affect many different organ systems of the body.
It is important to note that affected individuals will not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. In most cases, with proper medical care, most children with RSS can live full, productive lives.
Almost all infants with RSS exhibit birth weight well below the 3rd percentile (<-2SD) even at full term, and after birth, the weight curve often continues to fall farther away from the normal curve. Parents will report poor appetite (some children never cry for food) and the struggle to get an RSS child to gain weight is one of their concerns. Special care is required to ensure adequate feeding and caloric intake.
An RSS child’s birth length is most commonly also below the 3rd percentile (<-2SD), but not always. Growth velocity for length/height continues to be slower than normal throughout infancy and childhood. The majority of RSS children are not growth hormone deficient, and research has found that their response to growth hormone therapy does not differ statistically between those who are deficient from those that are not. Most RSS children do have a delayed bone age at young ages, which continues in early childhood. But it is important to note that the delayed bone age of RSS children is not typical of constitutional growth delay - the delayed bone age is not predictive of a late growing period. Instead, RSS children typically experience a rapid acceleration of their bone age, often around age 8-9, and their once-delayed bone age becomes advanced. Motor development skills may be delayed due to diminished muscle tone (hypotonia) and large-head-size-for-body, especially in infancy and toddlerhood. Early intervention (physical and/or occupational therapy) is important and can usually be obtained free through a state’s "Birth-to-Three" program. Parents should ask their pediatrician for more information.
Most untreated individuals with RSS will not see an improvement in linear growth as they age. In rare cases, affected individuals may experience a"growth spurt" during adolescence. Some researchers believe that children who exhibit catch-up growth later during adolescence may have had different conditions and not RSS. Average final height in individuals with RSS is approximately 5 feet in males (152.4cm) and just under 5 feet in females.
The majority of RSS children fall within the normal range of intelligence, but the published research is conflicting. Some evidence indicates that RSS children may be at risk for learning disabilities such as problems with processing or mathematics. But because most RSS children are born small-for-gestational-age (SGA), it is unknown whether any neurodevelopmental issues are more related to "RSS" versus being born SGA. Having a normal head circumference is a good predictor of normal intelligence but also means that an adequate amount of glucose is continually required or else hypoglycemia can occur, which is not good for neurological development. Some evidence also indicates that there may be neurodevelopmenal differences between the different genetic causes of RSS, with greater risk for the children whose RSS is caused by maternal uniparental disomy of chromosome 7. More research needs to be done in this area to control for variables such as head circumference and incidence of untreated hypoglycemia.
In many infants and children with RSS, all or part of one side of the body may be smaller than the other side (lateral asymmetry). This results from the underdevelopment of one side or structure of the body (hemihypotrophy). The extent and severity of asymmetry is extremely variable. In some cases, one entire side of the body may be affected. In most cases, asymmetry is found in just leg length or arm length. In such cases, affected individuals may experience some difficulties with balance and walking due to unevenly developed limbs. With any asymmetry of the body, the RSS child should be followed regularly by an orthopedist. Although, in the majority of cases, asymmetry is apparent at birth, it may not become evident until later during childhood. Some asymmetry may also improve with age.
Infants with RSS typically have characteristic craniofacial features. The most common finding is a "large-head-for-body." The RSS child’s head circumference is almost always far higher on the growth curve than either weight or length (called head sparing). In addition, due to an abnormally small triangular-shaped face, the head may also appear unusually large in comparison to the body. This appearance may cause a child with RSS to be mistakenly diagnosed with hydrocephalus (pseudohydrocephalus), a condition in which accumulation of excessive cerebrospinal fluid (CSF) in the skull causes pressure on the tissues of the brain. In addition, affected children may exhibit delayed closure of the soft, membrane-covered space near an infant's forehead where two of the fibrous joints (sutures) of the skull meet (anterior fontanelle). Another common facial feature is an abnormally prominent forehead (frontal bossing), where the forehead protrudes out from the plane of the face.
Other specific craniofacial features are less common, but can include a small, pointed chin; bluish discoloration of the whites of the eyes (blue sclera) early during infancy; eyes that may appear abnormally large; an unusually thin area where the lips meet the skin (vermilion border); an abnormally small, wide mouth; downturned corners of the mouth; an unusually small jaw (micrognathia); and a high, narrow roof of the mouth (palate). A variety of dental abnormalities have been reported including absence of teeth, abnormally small teeth (microdontia), and crowding of the teeth. As affected children age, characteristic facial features typically become less pronounced and less obvious.
Orthopedic physical findings associated with RSS may include pinkies that are fixed in a bent position (curving inward) and cannot be fully straightened (clinodactyly); fingers that are fixed in a bent position and cannot be fully straightened (camptodactyly); underdevelopment (hypoplasia) of certain bones of the fingers (middle phalanges); abnormal curvature of the spine (scoliosis); and/or absence of the small triangular bone at the base of the spine (coccyx) and/or the large triangular bone above the coccyx (sacrum). Some affected children may have webbing of the second and third toes (syndactyly). In rare cases, affected children may also experience hip and/or elbow dislocations.
RSS children have also been found to more frequently have small, coffee-colored spots (cafe-au-lait) on the skin. In most cases, these spots are usually found on the chest, stomach and/or arms or legs. These spots, too, are more difficult to find as the child gets older.
Hypoglycemia (recurrent episodes of unusually low blood sugar [glucose} levels) is a risk to infants and children with RSS, especially due to their large head-for-body-size. This condition is usually triggered when an affected infant does not eat for an extended period of time (fasting). During such episodes, affected infants may sweat profusely (hyperhidrosis) and breathe rapidly (tachypnea). Other symptoms associated with hypoglycemia include weakness, hunger, dizziness, and/or headaches. Children with RSS often have little subcutaneous fat and often have poor appetites, findings that may contribute to hypoglycemia. It is important to note that studies have found that RSS infants have been found to have had nighttime hypoglycemic episodes with little to no physical symptoms. All efforts to prevent any occurrence of hypoglycemia should be made and ketones in the morning urine can be a way to be alerted to the possibilities of such episodes. Excessive sweating (diaphoresis) has also been reported to occur in some children with RSS without the presence of hypoglycemia.
Gastrointestinal intestinal abnormalities are common in children with RSS and may include inflammation of the tube that carries food from the mouth to the stomach (esophagitis), backflow (reflux) of the contents of the stomach or small intestines into the esophagus (gastroesophageal reflux), delayed gastric emptying (where ingested food takes longer than normal to digest causing the child to feel full) and failure to gain weight or grow at the expected rate for age and sex (failure to thrive). Some children with RSS simply never have a sensation of hunger during early childhood, while others may develop an aversion to food. Paradoxically, some children will overeat later on. Due to a low muscle mass, it is important to be cautious that these children do not put on too much fat mass. RSS children should be well nourished but stay thin.
Additional symptoms have been described in the medical literature with varying frequency, although most are considered uncommon. Such symptoms include severe craniofacial features such as the Pierre-Robin sequence, an assortment of abnormalities that may occur alone or as part of a syndrome. The Pierre-Robin sequence is characterized by an unusually small jaw (micrognathia), downward displacement or retraction of the tongue (glossoptosis), and incomplete closure of the roof of the mouth (cleft palate).
A variety of abnormalities affecting the organs of the reproduction and urinary systems (genitourinary abnormalities) have been reported including failure of one or both testes to descend into the scrotum (cryptorchidism) and abnormal placement of the urinary opening (meatus) on the underside of the penis (hypospadias) or absence of uterus (Rokitansky syndrome). Kidney (renal) abnormalities may also occur including enlarged kidneys; kidneys that are joined together (fused) at the base so that they resemble a horseshoe; and development of abnormal tissue in the urethra (posterior urethral valves), which may prevent urine from flowing out of the bladder and, subsequently, cause backup of urine (hydronephrosis) and damage to the kidneys. These genito-urinary abnormalities are also found at an increased risk for children who are born small-for-gestational-age and who do not have RSS.
RSS can result from several different genetic causes. Two causes have been found to result in the majority of RSS cases: 1) maternal disomy of chromosome 7 (where the child inherits both number 7 chromosomes from his mother instead of one from his mother and one from his father) and 2) abnormalities at an imprinted region on chromosome 11p15. The matUPD7 cause of RSS has been found in about 5-10% of RSS cases, and the 11p15 abnormalities in up to 50-60% of cases. However, this still leaves another 40% or so of children who are clinically diagnosed RSS but for whom the underlying genetic defect that causes RSS is unknown. The genetics underlying RSS are complex and specific reasons for the development of the symptoms of this disorder are not fully understood.
The changes affecting the genes associated with RSS may involve changes in the structure of a gene (genetic factors) or changes in the function or expression of a gene (epigenetics). Besides matUPD7 and the 11p15.5 abnormalities, additional chromosomal abnormalities affecting chromosomes 1, 7, 14, 15, 17, and 18 have been described as causing RSS or RSS-like syndromes.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 11p15.5" refers to band 15.5 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
A specific process that is associated with some cases of RSS is genetic imprinting. Everyone has two copies of every gene - one received from the father and one received from the mother. In most cases, both genes are "turned on" or active. However, some genes are preferentially silenced or "turned off" based upon which parent that gene came from (genetic imprinting). Genetic imprinting is controlled by chemical switches through a process called methylation. Proper genetic imprinting is necessary for normal development. Defective imprinting has been associated with several disorders.
Imprinted genes tend to be found clustered or grouped together. Several imprinted genes are found in a cluster on chromosome 11p15.5. The cluster is divided into two functional regions known as imprinting centers regions (ICR1 and ICR2). Researchers have identified several specific imprinted genes regulated by these imprinting centers. These genes play a critical role in the regulation of fetal growth. Abnormalities in this region have been shown to cause an overgrowth disorder known as Beckwidth-Wiedemann syndrome.
Researchers have shown that opposite abnormalities affecting genes in this region may play a role in the development of RSS. Researchers estimate that 35-60% of cases of RSS are due to errors, specifically hypomethylation, affecting the IC1 region on chromosome 11. Two genes, maternally expressed H19 and paternally expressed IGF2 are believed to plays roles in the development of RSS, either through over- or under expression. Further research is necessary to learn more about these genes and the complex genetic mechanisms responsible for RSS.
Approximately 10 percent of cases of RSS are caused by genetic imprinting errors that occur because of a specific chromosomal abnormality known as uniparental disomy of chromosome 7. As mentioned above, with uniparental disomy, a person receives both copies of a chromosome (or part of a chromosome) from one parent instead of receiving one from each parent. One cause of RSS occurs when both copies of chromosome 7 are received from the mother (maternal uniparental disomy). As a result, there are too many active maternally-expressed genes in this region and not enough paternally-expressed genes. Maternal uniparental disomy occurs after fertilization (post-zygotic) so the risk of recurrence in subsequent pregnancies is extremely low but seems to be enhanced by maternal age.
In rare cases, familial occurrence of RSS has been noted. In these rare cases, RSS may be inherited as an autosomal dominant or recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. In RSS, these cases usually occur as a result of a spontaneous genetic change (i.e., new mutation) and are not inherited from the parents.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Such causes of RSS (i.e. dominant genetic disorders or recessive genetic disorders) are very rare. Indeed, most cases of RSS are secondary to epigenetic modification (i.e. loss of methylation at the 11p15 ICR1) and are sporadic.
RSS appears to affect males and females in equal numbers. More than 400 cases have been reported in the medical literature. In the past, many infants with intrauterine growth retardation and normal head circumference were incorrectly diagnosed with RSS. Other cases (because of the difficulty in diagnosis) may go unrecognized and undiagnosed or misdiagnosed, making it difficult to determine the true frequency of the disorder in the general population. Estimates as to the incidence of RSS vary, ranging from 1 in 3,000 live births to 1 in 100,000. Some researchers believe the incidence rate is 1 in 75,000-100,000 but the incidence is unknown.
Symptoms of the following disorders can be similar to those of RSS. Comparisons may be useful for a differential diagnosis.
Growth delays prior to birth (intrauterine growth retardation) may occur in a number of different congenital disorders; all of these disorders are included in the differential diagnosis of RSS. These disorders can include Mulibrey nanism, and many chromosomal disorders such as mosaic Turner syndrome, diploid/triploid mixoploidy, deletion 12p14 and deletion 15q26.3. Although these disorders have signs and symptoms that are similar to RSS, they usually have other physical features that may differentiate them from RSS. A key differentiator is often macrocephaly (RSS) versus microcephaly. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
Three M syndrome is an extremely rare genetic disorder characterized by low birth weight, short stature (dwarfism), characteristic abnormalities of the head and facial (craniofacial) area, distinctive skeletal malformations, and/or other physical abnormalities. The name "three M" refers to the last initials of three researchers (J.D. Miller, V.A. McKusick, P. Malvaux) who were among the first to identify the disorder. Characteristic craniofacial malformations typically include a long, narrow head (dolichocephaly), an unusually prominent forehead (frontal bossing), and a triangular-shaped face with a prominent, pointed chin, large ears, and/or abnormally flat cheeks. In addition, in some affected children, the teeth may be abnormally crowded together; as a result, the upper and lower teeth may not meet properly (malocclusion). Skeletal abnormalities associated with the disorder include unusually thin bones, particularly the shafts of the long bones of the arms and legs (diaphyses); abnormally long, thin bones of the spinal column (vertebrae); and/or distinctive malformations of the ribs and shoulder blades (scapulae). Affected individuals may also have additional abnormalities including permanent fixation of certain fingers in a bent position (clinodactyly), unusually short fifth fingers, and/or increased flexibility (hyperextensibility) of the joints. The range and severity of symptoms and physical features may vary from case to case. Intelligence appears to be normal. Three M syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose "three M" as your search term in the Rare Disease Database.)
Chromosomal instability disorders such as Fanconi anemia, Bloom syndrome, and Nijmegen breakage syndrome may have similar symptoms to RSS. In individuals with these disorders, the chromosomes within their cells are unstable and break and rearrange easily (chromosome instability), damaging deoxyribonucleic acid (DNA) found within cells. DNA is the carrier of the genetic code and damage to DNA is a normal daily occurrence. In most people, damage to DNA is repaired. However, in affected individuals, breaks and rearrangements occur more often and their bodies are slow or fail to repair the damage. These disorders are commonly associated with intrauterine growth deficiency and short stature as well as additional symptoms including limb abnormalities and an abnormal sensitivity to light (photophobia). (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.)
Fetal alcohol syndrome (FAS) is a characteristic pattern of mental and physical birth defects that results due to maternal use of alcohol during pregnancy. The range and severity of associated abnormalities may vary greatly from case to case. However, characteristic features may include growth delays before and after birth (prenatal and postnatal growth retardation); malformations of the skull and facial (craniofacial) region; brain abnormalities; and/or additional physical findings. FAS may also be associated with varying degrees of mental retardation, learning abnormalities, and/or behavioral problems that, in some cases, may occur in the absence of obvious physical abnormalities. (For more information on this disorder, choose "fetal alcohol syndrome" as your search term in the Rare Disease Database.)
A rare disorder described in a handful of cases is sometimes referred to as X-linked Russell-Silver syndrome or Partington syndrome. Affected individuals experience prenatal growth retardation. Additional symptoms included a triangular facial appearance, café-au-lait spots and areas of skin lacking color (achromatic) on the trunk and limbs.
A diagnosis of RSS is based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic features, especially growth retardation before and after birth in children with normal head circumference. Because many of the symptoms are nonspecific, obtaining a diagnosis of RSS remains difficult.
Growth retardation may be diagnosed before birth (prenatally) by ultrasound. During ultrasound, reflected sound waves are used to create an image of the developing fetus.
Testing for known genetic causes of RSS such as abnormalities affecting specific areas of chromosomes 7 and 11 are available on a clinical basis.
The treatment of RSS is directed toward the specific symptoms that are apparent in each individual. Many therapies follow routine, established guidelines for the condition. Early diagnosis and prompt therapy can help improve growth and ensure that affected individuals reach their highest potential.
Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in treating disorders of the skeleton (orthopedists), orthopedic surgeons, physicians who specialize in disorders of the glands and hormones (endocrinologists), dental specialists, physicians who specialize in the gastrointestinal tract (gastroenterologists), psychologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child's treatment.
Growth can be improved in children with RSS by ensuring proper feeding and intake of calories. Aggressively feeding children with RSS can help to avoid malnutrition and low blood sugar. In some cases, feeding tubes may be necessary to assist feeding and ensure proper nutrition and growth. A nasogastric tube (a thin tube that runs from the nose to the stomach through the esophagus) may be used. In other cases, a tube that is inserted directly into the stomach through a small incision in the abdomen wall may be used. It is important not to overfeed an RSS infant (which can occur quickly especially with feeding tubes) because RSS babies can quickly become "fluffy" with visible subcutaneous fat). Due to high risk for medical problems related to insulin resistance and metabolic syndrome, babies born small-for-gestational-age should remain lean but not underweight. Lastly, it is important to monitor an RSS child’s weight-for-height. Increasing the calories of an RSS toddler or child can result in a brief spurt of length/height growth but often then levels off, and the toddler or child simply becomes more overweight rather than improving the height in any additional manner.
Growth hormone therapy (GHT) is recommended for children with RSS who wish to improve their childhood height and adult height. Growth hormone therapy was approved by the Food and Drug Administration (FDA) in 2001 for children who were born small-for-gestational-age (SGA) and who have not displayed adequate catch up growth by the age of 2. Due to the small population size of Russell-Silver syndrome, the FDA studies of SGA combined RSS children into an overall pool of subjects. If an RSS child is not born SGA, the child may qualify for growth hormone therapy coverage under the FDA approval for idiopathic short stature. Many, many studies have now shown that GHT significantly improves childhood growth and final adult height. Furthermore, these studies indicate that RSS children who are not growth deficient respond in similar ways to the RSS children who are growth hormone deficient. As a result, growth hormone stimulation testing is no longer recommended for an RSS child unless growth hormone deficiency is suspected. A low starting dose of GH is recommended and has to be adapted to growth velocity. IGF-1 levels are often high, especially for the RSS children with 11p15 ICR1 loss of methylation.
However, most of the RSS patients advance their bone age around 6 or 7, when they enter adrenarche, especially if this is a period of rapid weight gain. Children can then enter into central puberty. If not diagnosed and treated, this can lead to a small final height even if treated with GH.
Early intervention is important in ensuring that children with RSS reach their potential. Special services that may be beneficial to affected children may include special social support, physical therapy, occupational therapy, and other medical, social, and/or vocational services. An individual education plan (IEP) may be developed to assist children in school if special services are required, or a 504 plan which can ensure that the child receives access to an equal education through accommodations in their learning environment.
Short stature and other medical conditions can lead to issues with self-image in some affected children. Psychological counseling can help children manage issues with self-image and peer relationships and other social interactions.
Aggressive management of gastrointestinal symptoms is recommended in RSS children. Gastroesophageal reflux can involve symptoms such as arching of the back and spitting up, but it can also be "silent reflux" with almost no physical symptoms. Therapies can range from having the child eat smaller, more frequent meals, to positioning infants so gravity can help prevent food from flowing back into the esophagus, to providing medications such as H2 blockers or proton pump inhibitors, and lastly, in rare cases of severe gastroesophageal reflux, (especially when a gastrostomy tube is being placed), a surgical procedure known as fundoplication may be necessary. During this surgical procedure the upper curve of the stomach (fundus) is wrapped around the lower portion of the esophagus. This procedure strengthens the valve (sphincter) between the esophagus and stomach and helps prevent acid reflux. Decreasing the quantity of foods high in fat and increasing the number of small, frequent meals can help improve delayed gastric emptying. Constipation is another GI issue faced by RSS children, which can cause a child to feel full so he doesn’t want to eat. Many over-the-counter home remedies can be tried, and the product Miralax has also been found to be helpful.
In affected individuals who experience dental abnormalities, braces and oral surgery may be used to treat and correct these abnormalities. Speech and language therapy may be recommended for affected children with speech problems, and is very frequent, especially for children with mUPD7. An audiological exam should be performed to rule out hearing loss as the cause of speech problems.
In some cases, if affected individuals experience difficulties with walking due to unevenly developed limbs, special braces and shoes may be used to help improve balance and gait. In some cases, surgical intervention may eventually be required; such surgery is usually performed when growth has ceased.
In males, cryptorchidism may resolve spontaneously, although some males may require hormonal or surgical treatment. Hypospadias requires surgery and a pediatric surgeon experienced in this delicate surgery is recommended. Kidney (renal) abnormalities are treated along standard guidelines.
Hypoglycemia is treated by standard guidelines, which can include frequent feeding, dietary supplementation and the use of complex carbohydrates such as corn starch. To avoid such problems, RSS children should never fast (even for medical procedures) and they should go to the emergency room for glucose infusion when they are ill and unable to eat food by mouth (remember, for these children, we are preventing hypoglycemia not just dehydration).
Genetic counseling may be of benefit for affected individuals and their families. Other treatment 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:
Toll-free: (800) 411-1222
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For information about clinical trials sponsored by private sources, contact:
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FROM THE INTERNET
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Report last updated: 2013/04/10 00:00:00 GMT+0