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Silver-Russell syndrome

This is part of Rare diseases.

Diagnosis: Silver-Russell syndrome

Synonyms: Russell-Silver syndrome

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Publication date: 2014-12-10
Version: 2.0

ICD 10 code

Q87.1G

The disease

Silver-Russell syndrome is associated with restricted physical growth, but normal development of the head. Growth is impaired from early in the foetal stage and continues to be restricted during childhood so that adults with the condition are short. For many children with Silver-Russell syndrome puberty commences earlier than usual, which further affects their final height. One half of the body is often larger than the other (hemihypertrophy) and children usually have characteristic facial features.

The syndrome was named after two paediatricians, Henry Silver from America and Alexander Russell from Great Britain, who independently described the different symptoms in the early 1950s.

Occurrence

There is no definite information on how common Silver-Russell syndrome is. In Sweden, more than 50 people have been diagnosed but it is thought that there are many who have not had the diagnosis confirmed.

Cause

Several genetic mechanisms are thought to cause the syndrome. The common denominator for these mechanisms is an imbalance in the expression of certain genes which regulate growth.

Between 35 and 50 per cent of people with the syndrome have abnormalities in genes located on the short arm of chromosome 11 (11p15). Genes in this region are normally either active or inactive, with the copy from one of the parents being silenced - a process called genomic imprinting. Genomic imprinting is made possible by, among other things, methylation, in which genes on a chromosome become inactive as a result of chemical methyl groups binding to the DNA molecule. In Silver-Russell syndrome, the methylation of 11p15 is often impaired. Two imprinted genes thought to play important roles in Silver-Russell syndrome are IGF2 and H19. IGF2 is important in regulating cell growth during foetal development and is normally expressed from the father's chromosome while H19, which works as a IGF2 inhibitor, is methylated and inactivate. In Silver-Russell syndrome, the methylation of the H19 gene on the father's chromosome does not take place, leading to inhibition of the IGF2 gene and in turn to restricted growth. Sometimes there is a minor duplication of the segment of the chromosome inherited from the mother, which also results in the impaired expression of the IGF2 gene.

Approximately 7 to 10 per cent of children have another underlying genetic mutation. At conception they have received two copies of chromosome 7 from the mother and none from the father (uniparental disomy). This in turn affects the expression of two imprinted genes on chromosome 7, GRB10 (7p11.2-p12) and MEST (7q32).

Heredity

Usually Silver-Russell syndrome is caused by a new mutation. This means that the genetic mutation occurs in an individual for the first time and is not inherited from either parent. Consequently, parents with a child with a new mutation generally have only a slight risk of having another child with the disorder. The risk that the child will eventually pass the syndrome on is also regarded as low.

A few families have been described as having inheritance patterns which could be caused by mutations in a specific gene (monogenic inheritance pattern). In families where more than one individual has the syndrome, the risk of passing on the condition may therefore be increased, which should be taken into account during genetic counselling.

Symptoms

At birth the weight of children with Silver-Russell syndrome is low and they are also shorter than average. Growth is impaired from the early stages of pregnancy and can be observed in ultrasound scans from weeks 17 to 20. After birth the child’s weight and size increase only slowly. The body grows asymmetrically so that one half often becomes larger than the other. The legs may be of different lengths and the difference between them usually increases during the teenage years.

In early puberty there is a good growth spurt, but as puberty progresses growth suddenly halts. Without growth hormone treatment the final height of an adult woman is on average 140 centimetres and for a man, approximately 150 centimetres. In some children with Silver-Russell syndrome the onset of puberty is earlier than normal. This means that they have a comparatively short time when they can grow, and so they remain short in adulthood.

Children with Silver-Russell syndrome often share common facial characteristics. The head is frequently large in relation to the body, the face triangular and the two halves of the face may be of different sizes. The forehead is often broad and high while the chin and the lower jaw may be small and narrow (micrognatia). The whole face, particularly the lower jaw, may be depressed and the roof of the mouth is often raised. Hands and feet are usually small and the little finger crooked (clinodactyly).

Bite abnormalities are relatively common, in particular a pronounced overbite and a condition known as deep bite. There is frequently insufficient space for teeth, particularly in the lower jaw. The change from milk teeth to permanent teeth takes place about a year later than normal. The teeth can be rather narrow and short and there may sometimes be changes in the dental enamel, especially on milk teeth and permanent front teeth. Children with the condition need to eat often and may vomit frequently, which can increase the risk of dental caries.

Motor development is usually delayed and many children have weak musculature. Infants often have problems sucking, which can be partially explained by muscle weakness in combination with a raised palate. Other possible reasons for these problems are poor appetite, nausea and vomiting. Sometimes eating problems persist for many years. Delayed speech and speech difficulties are also common.

Over half the children with Silver-Russell syndrome are of normal intellect, although their profiles may be uneven and they may have learning difficulties in specific areas. Fewer than one third of individuals have a mild intellectual disability, and it can take them longer to acquire new skills and solve problems. Studies show that slightly over half of those affected have visual perception problems, meaning that they perceive and interpret three-dimensional visual impressions differently to their peers. These differences of perception can, among other things, make it more difficult to learn to read and write, which in turn affects progress at school. It is important to recognize these problems, so that teaching methods can be adapted and the correct support provided.

Diagnosis

The diagnosis is based on specific signs and observations. It is important that the correct diagnosis is made early, so that parents receive an explanation of why the child has problems eating and grows more slowly than other children.

For a diagnosis:

1. impaired foetal development
2. impaired growth after birth
3. small, triangular face and a relatively large head

The diagnosis is supported if:

4. the halves of the body are asymmetrical (the legs in particular being of different lengths)
5. the little finger is crooked

It is possible to identify the genetic defect in less than half of those with the syndrome. Initial genetic investigations should include tests for methylation-sensitive MLPA on 11p15, including the H19 gene, and the elimination of uniparental disomy on chromosome 7 (UPD7). A chromosome analysis may be considered in order to eliminate more unusual chromosomal abnormalities.

Treatment/interventions

There is as yet no cure for Silver-Russell syndrome, and efforts are directed at alleviating symptoms, compensating for disabilities and providing support. The need for different measures varies among individuals.

Children require contact with several different specialists including a paediatric endocrinologist, orthopaedic surgeon, nutritionist and dentist. It is important that investigations and treatment are coordinated by a paediatrician.

As the child has a low birth weight and often has problems sucking, feeds/meals should be frequent. As the child may not receive enough nutrition, a nasogastric tube may be inserted into the stomach for feeding purposes. Sometimes a surgical procedure is performed, where a tube is passed into a patient's stomach through the abdominal wall (PEG, percutaneous endoscopic gastrostomy). Parents must continually try to persuade children to eat, as many of them have poor appetites. Contact with a dietician is required. Where necessary a speech therapist can give advice on managing mealtimes and on ways of stimulating oral motor skills so that eating becomes more enjoyable for the child.

As growth usually continues to be poor during childhood it is important to check hormone production and to eliminate other possible causes of restricted growth, such as gluten intolerance or another chronic disease. If treatment with a growth hormone is considered, it should be started early. For several years children born with growth impairments and who are extremely short for their ages have been treated with growth hormones from the ages of two to four. If a growth hormone deficiency is identified, treatment starts at the earlier age.

If there are signs of early puberty, treatment to postpone pubertal development should be started so that the growth period lasts longer.

The difference between the lengths of the individual's legs often increases during the teen years. If this difference is significant, a surgical procedure in the bone's growth zone is carried out approximately one year before the individual has stopped growing. In this way growth in the longer leg is inhibited.

Dental examinations should be frequent and start at an early age. Augmented preventive care is important, especially if there is an increased risk of caries. The dental services should be familiar with the problems children with impaired growth can experience. Abnormalities in dental alignment may require dental braces.

In order to stimulate the child's development and help compensate for loss of function some children with the syndrome require early habilitation. A habilitation team includes professionals with special expertise in how disability affects everyday life, health and development. Help is available within the medical, educational, psychological, social and technical fields. Measures may include assessments, treatment, assistance with choice of aids, information about disabilities and counselling. Information is also available about support offered by public services as well as advice on adapting accommodation and other environments to the child’s needs. Parents and siblings can also receive support.

Habilitation focuses on existing needs, may vary over time and takes place in collaboration with individuals close to the child. It is important to monitor speech and language development. If it is delayed and there are speech problems a speech therapist can judge which type of treatment is appropriate. The physiotherapist in the team is responsible for an assessment of motor skills and for appropriate physical training for the children who require it. Approximately half of the children with the syndrome require specialist educational provision to facilitate the development of writing and reading skills. Children with a developmental disability may need to attend a special school.

There is close collaboration with the public services, which can offer different forms of support in everyday life depending on the degree of disability.

The parents should be offered psychological support, both at the time of diagnosis and later. Children and young people with the syndrome should themselves be offered continuous psychological support, adapted to their age and maturity. Meeting others in the same situation and sharing experiences with them can also be valuable.

Most adults require continued, specialist medical treatment and sometimes continued habilitation.

Practical advice

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National and regional resources in Sweden

There is a multi-disciplinary team for children with Silver-Russell syndrome at The Queen Silvia Children’s Hospital in Gothenburg. Contact Professor Jovanna Dahlgren. See under "Resource personnel." The specialist paediatric team includes an endocrinologist, orthopaedic surgeon, radiologist, dentist, ophthalmologist, physiotherapist, nurse, and neuropsychologist.

Mun-H-Center is a centre of excellence providing expertise in orofacial problems and a national resource centre providing information on rare diseases and available aids. Mun-H-Center, Institute of Odontology, Gothenburg, Sweden. Tel: +46 31 750 92 00, email: mun-h-center@vgregion.se, www.mun-h-center.se.

Resource personnel

Professor Jovanna Dahlgren, Paediatric Growth Research Centre, The Queen Silvia Children's Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00, email: jovanna.dahlgren@vgregion.se.

Courses, exchanges of experience, recreation

Ågrenska is a national competence centre for rare diseases and its families' programme arranges stays for children and young people with rare diseases and their families. Ågrenska is open to families from the whole of Sweden and focuses particularly on the needs of children and young people with rare diseases. Information is available from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se, www.agrenska.se.

Organizations for the disabled/patient associations etc.

The Association of People with Short Stature in Sweden - DHR, Eneby-Näs Framnäs Hage, SE-590 40 Kisa, Sweden. Tel: +46 494 421 41, email fkv@live.se, www.fkv.se.

Courses, exchanges of experience for personnel

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Research and development

At the Queen Silvia Children's Hospital in Gothenburg there is a unit of the Swedish Rare Disease Centre (CSD), which includes the Silver-Russell team.

The team has developed a care programme and is monitoring all children with Silver-Russell syndrome in the Swedish Västra Götaland region. It is also correlating results of growth hormone treatments of people with the condition, and examining how hormonal balance affects sensitivity to insulin. Contact Jovanna Dahlgren. See under, "Resource personnel."

Information material

Short summaries of all the database texts are available as leaflets, in Swedish only. These leaflets may be ordered or printed out. (See under "Mer hos oss" in the right hand column.)

Newsletters from Ågrenska, no. 290 (2007) and no. 317, (2008). (In Swedish only.) Order from: Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se. The newsletter is also available on www.agrenska.se.

Literature

Abu-Amero S, Monk D, Apostolidou S, Stainer P, Moore G. Imprinted genes and their role in human fetal growth. Cytogenet Genome Res 2006; 113: 262-270.

Akawi NA, Ali BR, Hamamy H, Al-Hadidy A, Al-Gazali L. Is autosomal recessive Silver-Russell syndrome a separate entity or is it part of the 3-M syndrome spectrum? Am J Med Genet A 2011; 155A: 1236-1245.

Andersson Grönlund M, Dahlgren J, Aring E, Kraemer M, Hellström A. Ophthalmological findings in children and adolescents with Silver-Russell syndrome. Br J Ophthalmol 2011; 95: 637-641.

Berman A, Kjellberg H, Dahlgren J. Craniofacial morphology and dental age in children with Silver-Russell syndrome. Orthod Craniofac Res 2003; 6: 54-62.

Binder G, Seidel AK, Weber K, Haase M, Wollmann HA, Ranke MB et al. IGF-II serum levels are normal in children with Silver-Russells syndrome who frequently carry epimutations at the IGF2 locus. J Clin Endocrin Metabol 2006; 10: 1210.

Bliek J, Terhal P, van den Bogaard MJ, Maas S, Hamel B, Salieb-Beugelaar G et al. Hypomethylation of the H19 gene causes not only Silver-Russell syndrome (SRS) but also isolated asymmetry or an SRS-like phenotype. Am J Hum Genet 2006; 78: 604-614.

Bruce S, Hannula-Jouppi K, Puoskari M, Fransson I, Simola KO, Lipsanen-Nyman M et al. Submicroscopic genomic alterations in Silver-Russell syndrome and Silver-Russell-like patients. J Med Genet 2010; 47: 816-822.

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Ghanim M, Rossignol S, Delobel B, Irving M, Miller O, Devisme L et al. Possible association between complex congenital heart defects and 11p15 hypomethylation in three patients with severe Silver-Russell syndrome. Am J Med Genet A 2013; 161: 572-577.

Gicquel C, Rossignol S, Cabrol S, Houang M, Steunou V, Barbu V et al. Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome. Nat Genet 2006; 37: 1003-1007.

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Kim Y, Kim SS, Kim G, Park S, Park IS, Yoo HW. Detection of maternal uniparental disomy at the two imprinted genes on chromosome 7, GRB10 and PEG1/MEST, in a Silver-Russell syndrome patient using methylation-specific PCR assays. Clin Genet 2005; 67: 267-269.

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Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: silver-russell syndrome

GeneReviews (University of Washington)
www.genetests.org (select GeneReviews)
Search: russell-silver syndrome

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Professor emerita Kerstin Albertsson-Wikland.

The material has been revised by Professor Jovanna Dahlgren,The Queen Silvia Children's Hospital, Gothenburg, Sweden.

The relevant organizations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Publication date: 2014-12-10
Version: 2.0
Publication date of the Swedish version: 2014-06-05

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

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