NORD gratefully acknowledges Dr. Emma Wakeling, North West Thames Regional Genetic Service, London North West Hospitals NHS Trust, London, UK; Dr. Irène Netchine, Laboratoire d'Explorations Fonctionnelles Endocriniennes, Paris, France; Jennifer Salem, The MAGIC Foundation; and the Child Growth Foundation, for assistance in the preparation of this report.
Russell-Silver syndrome (RSS) is a rare disorder characterized by intrauterine growth restriction (IUGR), poor growth after birth, a relatively large head size, a triangular facial appearance, a prominent forehead (looking from the side of the face), body asymmetry and significant feeding difficulties. The wide spectrum of findings varies both in frequency and severity from one affected individual to another. The majority of individuals with RSS are of normal intelligence, but motor and/or speech delay is common.
RSS is genetically heterogeneous, meaning that different genetic abnormalities are known to cause the disorder. Abnormalities involving chromosomes 7 or 11 have been found in up to 60% of RSS patients. However, in approximately 40% of patients with a clinical diagnosis of RSS, the underlying cause is still not known.
Consensus guidelines have recently been published which give recommendations regarding the investigation, diagnosis and management of individuals with RSS. The management of children with RSS should start as early as possible and often requires the involvement of many different health professionals.
Russell-Silver syndrome was first described by Silver in 1953 and Russell in 1954. At first it was thought that they were describing two separate conditions; it took nearly 20 years for doctors to realize that they had seen different aspects of the same condition. 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 are mildly affected; others may have serious complications. The wide range of potential features can affect many different parts of the body. It is important to note that affected individuals will not have all of the symptoms discussed below. Affected individuals/ parents should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. With appropriate medical care, most individuals with RSS will live full, productive lives.
Growth and puberty: Almost all infants with RSS have a birth weight well below the 3rd percentile (<-2SD) even at full term. After birth, weight often continues to fall farther away from the normal range. Parents often report poor appetite (some children never cry for food) and the struggle to get an RSS child to gain weight is one of their main concerns. Special care is required to ensure adequate feeding and caloric intake.
Birth length is usually also below the 3rd percentile (<-2SD), but not always. Growth velocity for length/height continues to be slower than normal throughout infancy and childhood, with no ‘catch-up’ growth. 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 have a delayed bone age in early childhood. But it is important to note that the delayed bone age of RSS children is not typical of constitutional growth delay in that 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 bone age then becomes advanced.
There is only limited information regarding final height individuals with RSS who have not received growth hormone (GH) treatment, but in one study this was reported as approximately 5 feet in males (151 cm) and 4 feet 7 inches (140 cm) in females.
Asymmetry: In many children with RSS, all or part of one side of the body is smaller than the other (asymmetry). This results from the underdevelopment of one side of the body (hemihypotrophy). The extent and severity of asymmetry is extremely variable. In most cases, asymmetry is found in just leg length or arm length but, in some children, one entire side of the body is affected. Individuals may experience difficulties with balance and walking as a result. Any child with significant asymmetry should be followed regularly by an orthopedist. Although, in the majority of children, asymmetry is apparent at birth, it may not become evident until later during childhood. Asymmetry may also improve with age. Treatment with GH does not appear to increase the severity of asymmetry.
Craniofacial features: Characteristic craniofacial features are commonly seen in affected children, particularly in infancy and early childhood. The most common finding is a “large-head-for-body”. The head circumference is almost always far higher on the growth curve than either weight or length (called head sparing/ relative macrocephaly). This, along with the tendency for the jaw to be small (micrognathia), gives rise to the typical triangular facial shape seen in children with RSS. The relatively large head size may cause a child with RSS to be mistakenly diagnosed with hydrocephalus, 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 have delayed closure of the ‘soft spot’ (anterior fontanelle) on the top of the head where two of the fibrous joints (sutures) of the skull meet. Another common facial feature is an abnormally prominent forehead, where the forehead protrudes out when the face is viewed from the side. Other craniofacial features associated with RSS are less common, but can include bluish discoloration of the whites of the eyes (blue sclera) during infancy; a small mouth; downturned corners of the mouth; and a high, narrow roof of the mouth (palate).
These characteristic facial features typically become less noticeable with age.
A variety of dental abnormalities have been reported including absence of teeth, abnormally small teeth (microdontia), and crowding of the teeth.
Feeding difficulties: Gastrointestinal problems are common in children with RSS. These can include inflammation of the tube that carries food from the mouth to the stomach (esophagitis), backflow 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 children with RSS do not put on too much fat mass. There is also evidence that rapid weight gain in early childhood can lead to problems with the body’s metabolism and increased risk of high blood pressure and heart disease later on in life. RSS children should be well nourished but stay thin.
Hypoglycemia: Infants and children with RSS are at increased risk of hypoglycemia (recurrent episodes of unusually low blood sugar levels). This is likely to be due to their lack of subcutaneous fat and poor appetite. Hypoglycaemia is usually triggered when an affected infant does not eat for an extended period of time (fasting). Symptoms associated with hypoglycemia include weakness, hunger, dizziness, sweating and/or headaches. However, it is important to note that studies have found that infants with RSS have been found to have had night-time hypoglycemic episodes with little to no physical symptoms. Excessive sweating also occurs in some children with RSS without associated hypoglycemia.
Neurodevelopment: Motor development skills may be delayed due to low muscle tone (hypotonia) and relatively large head size, especially in infancy and toddlerhood. Delay in speech development is also common, particularly in those patients with maternal uniparental disomy of chromosome 7 (see ‘Causes’, below). Early intervention (physical, occupational and/or speech therapy) is important and parents should ask their pediatrician for more information.
The majority of children with RSS have normal intelligence. However, there is evidence for differences in frequency of learning and/or behavioral problems between the different genetic subtypes of RSS, with greater risk for children with maternal uniparental disomy of chromosome 7.
Additional features: Other features have been described in the medical literature with varying frequency.
Orthopedic problems associated with RSS include body asymmetry, curvature of the spine (scoliosis) and occasionally hip dislocation. Minor hand and/or foot anomalies are also common, including short and in-curving 5th fingers (clinodactyly), fingers that are fixed in a bent position and cannot be fully straightened (camptodactyly) and webbing of the second and third toes (syndactyly).
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 on the underside of the penis (hypospadias) or under-development of the uterus and upper part of the vagina (Rokitansky syndrome). Structural kidney (renal) abnormalities may also occur. Genitourinary abnormalities are also found at increased frequency in children who are born small-for-gestational-age and who do not have RSS.
Other congenital abnormalities reported less commonly in RSS include structural heart defects and cleft palate (an opening in the roof of the mouth). Congenital anomalies are more common in children with loss of methylation on chromosome 11p15 (see ‘Causes’ below)
In the last few years it has become possible to confirm the clinical diagnosis by genetic testing in approximately 60% of individuals with RSS. Two main genetic changes (involving chromosome 7 and chromosome 11) are currently known to cause RSS. These are specific to the condition and not seen in most children with IUGR and poor postnatal growth.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information (genes) for each individual. We 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.
Everyone has two copies of each gene – one inherited from the father and one inherited 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. Problems with imprinting have been associated with several disorders, including RSS.
Chromosome 11: 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 center regions (ICR1 and ICR2). Researchers have identified several imprinted genes regulated by these imprinting centers. These genes play a critical role in the regulation of fetal growth. Abnormalities in this region have also been shown to cause Beckwith-Wiedemann syndrome, an imprinting disorder which results in overgrowth.
About 30-60% of children with RSS have changes (loss of methylation/ hypomethylation) affecting the ICR1 region on chromosome 11 (11p15 LOM). This, in turn, affects the activity of two genes (maternally expressed H19 and paternally expressed IGF2) which are believed to play a role in the development of RSS. Further research is necessary to learn more about the role of these genes and the complex genetic mechanisms responsible for RSS.
Chromosome 7: About 5-10% of individuals with RSS have been found to have both copies of chromosome 7 from their mother, rather than one from each parent. This is called maternal uniparental disomy of chromosome 7 (upd(7)mat). The exact way in which this affects growth and development is not fully understood, though this is likely to be due to increased activity of maternally-expressed gene(s) and/or under-activity of paternally-expressed gene(s) on chromosome 7.
Clinical SRS: The genetics underlying RSS are complex and the specific reasons for the development of the symptoms of this disorder are not fully understood. Currently, genetic test results are normal in about 40% of children who have a clinical diagnosis of RSS. More work is needed to try to identify the underlying cause in this group of children.
Other imprinting disorders: Rarely, other disorders of genomic imprinting can result in clinical features of RSS. Additional testing for these conditions may be considered in children with overlapping features. For example, changes affecting an imprinted region on chromosome 14q32 result in a condition known as Temple syndrome. Children with this condition commonly have IUGR, poor postnatal growth, low muscle tone, delay in development of motor skills and early puberty- all features which can be seen in RSS. Asymmetry is rarely a feature in Temple syndrome.
RSS occurs in all populations and affects males and females in equal numbers. In the past, many infants with IUGR and relatively large head circumference were incorrectly diagnosed with RSS. Because of the difficulty in diagnosis, other cases may go unrecognized and undiagnosed or misdiagnosed, making it difficult to determine the true frequency of the disorder in the general population. However, this is estimated to be between 1 in 30,000 and 1 in 100,000.
The diagnosis of RSS is based on clinical findings. Because many of the symptoms are nonspecific, making a diagnosis of RSS remains difficult. Consensus guidelines for investigation and diagnosis of RSS have recently been published, based on the Netchine-Harbison clinical scoring system for RSS: http://www.nature.com/nrendo/journal/v13/n2/full/nrendo.2016.138.html
Testing for known genetic causes of RSS (chromosome 7 and 11) can confirm the clinical diagnosis in up to 60% of individuals. Knowing the underlying genetic cause can also help guide treatment as some problems are more common in association with abnormalities of chromosome 7 or 11.
Treatment in RSS is directed toward the specific symptoms that are apparent in each individual. Recommendations for management are described in detail in the published consensus guidelines: http://www.nature.com/nrendo/journal/v13/n2/full/nrendo.2016.138.html
Early diagnosis and intervention can help improve growth and ensure that affected children reach their highest potential.
Treatment may require the coordinated efforts of a team of specialists. Pediatricians, doctors who specialize in treating disorders of the skeleton (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 be involved developing a comprehensive treatment plan. Parents may also wish to be referred for genetic counselling if they are planning to have further children.
Growth and puberty: Failure to thrive is very common in children with RSS, due to a combination of feeding difficulties and gastrointestinal problems, such as reflux. In the first 2 years of life the main goal is to ensure adequate intake of calories. This in turn will allow growth, avoid malnutrition and help maintain blood sugar levels. In some cases, feeding tubes may be necessary to assist feeding. Initially a nasogastric tube (a thin tube that runs from the nose to the stomach through the esophagus) may be used. If feeding difficulties are severe and persistent, a gastrostomy tube (inserted directly into the stomach through a small incision in the abdomen wall) may be needed.
It is, however, important not to overfeed an RSS infant (which can occur quickly, especially with feeding tubes). Babies born small-for-gestational-age should remain lean (but not underweight) due to high risk of medical problems related to insulin resistance and metabolic syndrome. It is important to monitor weight-for-height. Increasing the calories of a child with RSS can result in a brief spurt of length/height growth which often then levels off. The child then simply becomes more overweight rather than gaining any further height.
Growth hormone (GH) therapy is recommended for children with RSS for a number of reasons: to improve body composition (especially lean body mass), motor development and appetite, to reduce the risk of hypoglycemia and to optimize growth. GH 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 numbers of children with RSS, the FDA studies of SGA combined children with RSS into the overall pool of subjects. If a child with RSS is not born SGA, the child may qualify for GH therapy coverage under the FDA approval for idiopathic short stature. Many studies have now shown that GH therapy 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 few RSS children who are GH deficient. As a result, GH stimulation testing is no longer recommended for an RSS child unless GH deficiency is suspected. A low starting dose of GH is recommended and has to be adapted to growth velocity. IGF-1 levels (which are routinely measured during GH therapy) are high in children with RSS, especially in those with 11p15 LOM.
Prior to puberty, children typically enter an early stage of sexual maturation known as adrenarche. In children with RSS, bone age starts to advance at around 7 or 8 years, when they enter adrenarche. This may happen even earlier, especially if there is a period of rapid weight gain. Children may then enter puberty, which accelerates bone age even further. If not diagnosed and treated, this can lead to a reduced final height, even if treated with GH. From mid-childhood, children with RSS need to be monitored closely by a pediatric endocrinologist to look for early signs of adrenarche and puberty. If necessary, puberty can be delayed by using a medicine known as gonadotropin-releasing hormone analogue (GnRHa).
Feeding difficulties: It is important to consider the possibility of underlying gastrointestinal problems and to treat these effectively as early as possible.
Gastroesophageal reflux can result in arching of the back and/or a tendency to bring feeds back up; it can also be “silent”, with almost no physical symptoms. Acid reflux can be helped by providing smaller, more frequent meals and upright positioning of babies so gravity can help prevent food from flowing back up into the esophagus. Medications such as H2 blockers or proton pump inhibitors may also be prescribed. 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 providing smaller, more frequent meals can help improve delayed gastric emptying. Constipation is also common in RSS and can cause a child to feel full so they do not want to eat.
Hypoglycaemia: Hypoglycemia is treated by standard guidelines, including frequent feeding, dietary supplementation and the use of complex carbohydrates such as corn starch. To avoid low blood sugar levels, children with RSS should never go without food for long periods (even for medical procedures) and should go to the emergency room for glucose infusion when they are ill and unable to eat food by mouth. It is helpful for parents to be taught to measure ketones in the urine as an early warning sign, particularly when a child is unwell.
Neurodevelopment: Some children with RSS may need additional support with development and learning. Early intervention is important to ensure that they reach their potential. Special services that may be beneficial include physical therapy, occupational therapy, and other medical, social, and/or vocational services. An individual education plan (IEP) may be developed to support children in school if special services are required; a 504 plan can ensure that the child receives access to an equal education by adapting their learning environment.
Speech problems are common (especially in children with upd(7)mat) and speech and language therapy may be recommended. An audiological examination should also be performed to rule out hearing loss as the cause of speech problems.
Additional problems: Braces and oral surgery may be needed to correct dental problems, such as crowding of the teeth.
Difficulties can sometimes arise with walking due to limb asymmetry. Special braces and shoes may help improve balance and gait. In a small number of cases, surgical intervention may eventually be required; this is usually performed when growth has ceased.
Cryptorchidism can sometimes resolve spontaneously, although some boys require surgical treatment. Hypospadias requires surgery, ideally by an experienced pediatric surgeon. Kidney (renal) abnormalities are treated along standard guidelines.
Psychological support: Short stature and other medical conditions can lead to issues with self-image in some children. Psychological counseling can help children manage issues with self-image and peer relationships and other social interactions.
Genetic counseling: Genetic counseling may be of benefit for affected individuals and their families. In most families, only one child is affected and the chance of parents having another baby with RSS is likely to be very low. Similarly, the chance of an individual with RSS having an affected child themselves is also likely to be very low. However, in rare famiies, familial occurrence of RSS has been noted and the risk of recurrence can be as high as 50%. Genetic investigation is therefore important before parents are advised about recurrence risk.
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