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Silver-Russell syndrome

This is part of Rare diseases.

Diagnosis: Silver-Russell syndrome

Synonyms: Russell-Silver syndrome


Publication date: 2011-03-16
Version: 1.1

ICD 10 code

Q87.1G

The disease

Symptoms of Silver-Russell syndrome include restricted growth, caused by reduced levels of growth factors. Growth is impaired early in foetal development and continues during childhood. For many children with the syndrome puberty commences earlier than usual, which affects their final height as adults. One half of the body is often larger than the other and the facial skeleton may show signs of abnormality.

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 about how common Silver-Russell syndrome is in Sweden. In Denmark approximately 80 children and adults with the syndrome have been identified. In Sweden, although the population is twice as large, fewer than 50 people have been diagnosed and it is presumed that many cases in Sweden have not been diagnosed.

Cause

Several genetic mechanisms are thought to cause the syndrome. Recent research indicates that the common denominator is an imbalance in certain genes which regulate growth. At conception, between seven and ten per cent of affected children receive two copies of chromosome 7 from the mother and none from the father (uniparental disomy). This in turn affects genes which are normally active exclusively on chromosomes from either the father or the mother – a process called genomic imprinting. Genomic imprinting is a vital process and comes about when genes on a chromosome become inactive due to methylation. Two imprinted genes thought to play important roles in Silver-Russell syndrome are GRB10 (7p11.2-p12) and MEST (7q32).

The short arm of chromosome 11 (11p15) is also of importance for growth and contains several imprinted genes, including H19. In certain cases of Silver-Russell syndrome, the methylation process of one of the copies of this gene, inherited via the father’s chromosome, is impaired. Even a minor duplication of a chromosome segment on chromosome 11, inherited from the mother, is believed to be enough to trigger the syndrome. It is estimated that approximately 35 per cent of those who have the syndrome have a genetic mutation on chromosome 11.

Heredity

Silver-Russell syndrome is usually 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 do not have an increased risk of having another child with the disorder. It is unlikely that the child will pass on the syndrome.

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

Symptoms

The birth weight of children with Silver-Russell syndrome is low and these neonates are also shorter than average. Growth is impaired from the early stages of pre-natal development and can be observed in ultrasound scans from weeks 17 to 20 of the pregnancy. 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.

During puberty the growth spurt is limited. 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 growth period and remain short when they reach adulthood. If there are signs of early puberty, treatment to delay its progress is necessary.

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, including 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 small and short and there may sometimes be changes in the dental enamel, especially on milk teeth and permanent front teeth. The need to eat often, and frequent vomiting, can increase the risk of dental caries.

Motor development is usually delayed and many children have weak musculature. Neonates 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 and nausea, leading to vomiting. Sometimes eating problems persist for many years. Delayed speech and certain speech difficulties are also common.

Most of the people with the syndrome have normal intellectual development, although there are wide variations. Less than one third of individuals have a mild intellectual disability. Studies show that slightly over half of those affected have problems affecting their three-dimensional perception. These problems of perception can, among other things, make it more difficult to learn to read and write, which in turn affects progress at school.

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 others.

There are three criteria for 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. Genetic investigations should include chromosome analysis or genomic microarray-CGH analysis, an elimination of UPD7 and methylation studies of gene H19. These analyses are performed by, or in collaboration with, departments of clinical genetics where further information is available if required.

Treatment/interventions

Children require contact with several different specialists including a paediatric endocrinologist, orthopaedic surgeon 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 have to 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 (percutaneous endoscopic gastrostomy). Parents must continually try to encourage children to eat, as many of them have poor appetites. Where necessary a speech therapist can give advice on managing mealtimes, and on stimulating oral motor skills. Stimulating oral motor skills is especially important if the child receives most of his/her nutrition via a feeding tube. For speech, language and communication training contact with a speech therapist may be appropriate.

As growth usually continues to be poor during childhood it is important to monitor hormone production and to eliminate other possible causes of impaired growth, such as gluten intolerance or another chronic disease. If treatment with growth hormone is required it should be started early. For several years in Sweden children born with growth impairment, and who remain extremely short, have been treated with growth hormones from the age of four. Sometimes premature puberty is postponed or halted so that growth may continue as long as possible. The difference between the lengths of the individual’s legs often increases during the teen years. If this difference is significant, a simple surgical procedure in the growth zone (metaphysis) is carried out a year or more before the individual has stopped growing. In this way growth in the longer leg is inhibited.

Dental examinations should start when the child is very young, and take place frequently. Augmented levels of preventive care are important, especially if there is an increased risk of caries. The dental services should also be familiar with the problems children with impaired growth can experience, as treatment with growth hormone may be prescribed. 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 provided within the medical, educational, psychological, social and technical fields. Measures may include assessments, treatment, assistance with choice of aids, information about disabilities and counselling. They also include information about support offered by the local authority as well as advice on the way accommodation and other environments can be adapted to the child’s needs. Parents and siblings may also receive support.

Support and treatment focus on existing needs, may vary over time and take place in collaboration with individuals close to the child. There is also close collaboration with the local authority, which can offer different forms of support depending on the degree of disability. Meeting others in the same situation and sharing experiences with them can be valuable.

It may be necessary to continue medical treatment and habilitation into adulthood.

Practical advice

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National and regional resources in Sweden

The Queen Silvia Children’s Hospital in Gothenburg, Sweden has a multidisciplinary team for children with Silver-Russell syndrome under the leadership of Associate Professor Jovanna Dahlgren. See under, “Resource personnel.” The specialist paediatric team includes an endocrinologist, orthopaedic surgeon, radiologist, ophthalmologist, physiotherapist, nurse, speech therapist and neuropsychologist. Contact with a social worker can also be provided if required.

Expertise in orofacial problems is available at Mun-H-Center, Institute of Odontology, Medicinaregatan 12A, SE-413 90 Gothenburg, Sweden. Tel: +46 31 750 92 00, fax: +46 31 750 92 01, email mun-h-center@vgregion.se, www.mun-h-center.se.

Resource personnel

Associate professor Jovanna Dahlgren, Paediatric Growth Research Center, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 51 63, 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 people 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

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@telia.com, www.fkv.se.

RBU, The Swedish National Association for Disabled Children and Young People, St Eriksgatan 44, Stockholm. Mailing address: Box 8026, SE-104 20 Stockholm, Sweden. Tel: +46 8 677 73 00, fax: +46 8 677 73 09, email: info@riks.rbu.se, www.rbu.se.

Courses, exchanges of experience for personnel

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Research and development (R&D)

The Silver-Russell team in Gothenburg has developed a care programme. The team is also continuing to correlate research findings. For further information, see under, “Resource personnel.”

Information material

An information leaflet on Silver-Russell syndrome that summarises the information in this database text is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2010-4-20.) Address: SE-120 88 Stockholm, Sweden. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.

Newsletter from Ågrenska, nr 290 (2007) and nr 317 (2008). 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, www.agrenska.se The newsletter is also available on www.agrenska.se.

Information (in Danish) on Sjaeldne Handicap, Silver-Russells syndrom. Order from: Center for Små Handicapgrupper, Bredgade 25 F, 5 sal, DK-1260 Copenhagen, Denmark. Tel: +45 339 140 20, fax: +45 339 140 19, email: csh@csh.dk, www.csh.dk.

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.

Bailey W, Popowich B, Lee Jones K. Monozygotic twins discordant for the Russell-Silver syndrome. Am J of Medical Genetics 1995; 58: 101-105.

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, Peltonen J, Kere J, Lipsanen-Nyman M. Clinically distinct epigenetic subgroups in Silver-Russell syndrome: the degree of H19 hypomethylation associates with phenotype severity and genital and skeletal anomalies. J Clin Endocrinol Metab 2009; 94: 579-587.

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 2009; sep 14. Epub ahead of print.

Dahlgren J, Albertsson Wikland K. Final height in children born small for gestational age treated with growth hormone. Pediatr Res 2005; 57: 216-222.

Eggermann T, Schönherr N, Meyer E, Obermann C, Mavany M, Eggermann K et al. Epigenetic mutations of 11p15 in Silver-Russell syndrome are restricted to the telomeric imprinting domain. J Med Genet 2006; 43: 615-616.

Feuk L, Kalervo A, Lipsanen-Nyman M, Skaug J, Nakabayashi K, Finucane B et al. Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia. Am J Hum Genet 2006; 79: 965-972.

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.

Johnston LB, Dahlgren J, Leger J, Gelander L, Savage MO, Czernichow P et al. Association between insulin-like growth factor 1 (IGF-1) polymorphisms, circulating IGF-1, and pre- and postnatal growth in two European small for gestational age populations. J Clin Endocrinol Metabol 2003; 88: 4805-4810.

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.

Kotilainen J, Holtta P, Mikkonen T, Arte S, Sipila I, Pirinen S. Craniofacial and dental characteristics of Silver-Russell Syndrome. Am J of Medical Genetics 1995; 56: 229-236.

Moore GE, Abu-Amero S, Wakeling E, Hitchins M, Monk D, Stainer P et al. The search for the gene for Silver-Russell syndrome. Acta Paediatr Suppl 1999; 433: 42-48.

Rakover Y, Dietsch S, Ambler GR, Chock C, Thomsett M, Cowell CT. Growth hormone therapy in Silver Russell Syndrome: 5 years experience of the Australian and New Zealand Growth database (OZGROW). Eur J Pediatr 1996; 155: 851-857.

Russell A. A syndrome of “intrauterine” dwarfism recognizable at birth with craniofacial dysostosis, disproportionately short arms and other anomalities. Proc R Soc Med 1954; 47: 1040-1044.

Schönherr N, Meyer E, Roos A, Schmidt A, Wollmann HA, Eggermann T. The centrometic 11p15 imprinting centre is also involved in Silver-Russell syndrome. J Med Genet 2007; 44: 59-63.

Silver HK, Kiyasu W, George J, Deamer WC. Syndrome of congenital hemihypertrophy, shortness of stature and elevated urinary gonadotropins. Pediatrics 1953; 12: 368-375.

Wollmann HA, Kirchner T, Enders H, Preece MA, Ranke MB. Growth and symptoms in Silver-Russell syndrome: review on the basis of 386 patients. Eur J Pediatr 1995; 154: 958-968.

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, then Titles)
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 Kerstin Albertsson-Wikland, The Queen Silvia Children’s Hospital, Gothenburg, Sweden.

The material has been revised by Associate professor and paediatric endocrinologist Jovanna Dahlgren, The Queen Silvia Children’s Hospital, Gothenburg, Sweden.

The relevant organisations 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: 2011-03-16
Version: 1.1
Publication date of the Swedish version: 2010-06-16

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se

 

About the database

This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.