About russell syndrome

What is russell syndrome?

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

What are the symptoms for russell syndrome?

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 

What are the causes for russell syndrome?

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 (LOM)/ 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.

Approximately 1% of individuals with RSS have been shown to have variants (mutations) in genes in the IGF2 pathway (IGF2, HMGA2, PLAG1) or CDKN1C. Single gene variants are most often seen in rare familial cases of 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 RSS: 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.

Around 25-30% of children with RSS due to 11p15 LOM also have LOM at other imprinting regions on ICR2 and/or other chromosomes. This is known as multi-locus imprinting disturbance (MLID). The clinical significance of this finding is not yet well understood.

What are the treatments for russell syndrome?

Treatment in RSS is directed toward the specific symptoms that are apparent in each individual.

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 issues can lead to problems with self-image in some children, adolescents and adults. Referral for psychosocial support may be beneficial in those experiencing issues with self-image, peer relationships and other social interactions.

RSS in adulthood: Research about the long-term health of adults with RSS is limited and most adults with RSS are not routinely followed up. It is well recognized that being SGA at birth with accelerated gain in weight for length, particularly in early life, increases the risk of metabolic problems in adulthood. A recent study of individuals with RSS aged ≥18 years recorded impaired glucose tolerance (predisposing to diabetes) in 25%, high blood pressure in 33% and high cholesterol levels in 52%. In adults with RSS, other health problems (such as muscle and joint pains) have been highlighted but there remains uncertainty as to whether such problems are seen more frequently when compared to adults without RSS. Overall, however, most adults with RSS will have a normal quality of life, educational attainment and normal fertility.

Genetic counseling: Genetic counseling is recommended 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 families, 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.

What are the risk factors for russell 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. Recent data suggests that around 1 in 15,000 children will have RSS.

Video related to russell syndrome