Silver–Russell syndrome

Silver–Russell syndrome (SRS), also called Silver–Russell dwarfism, is a rare congenital growth disorder. In the United States it is usually referred to as Russell–Silver syndrome (RSS), and Silver–Russell syndrome elsewhere. It is one of 200 types of dwarfism and one of five types of primordial dwarfism.

Silver–Russell syndrome
Other namesSilver–Russell dwarfism
A somewhat triangular head and delicate facial features are typical characteristics of Silver–Russell syndrome.
SpecialtyMedical genetics 

Silver–Russell syndrome occurs in approximately one out of every 50,000 to 100,000 births. Males and females seem to be affected with equal frequency.[1]

Signs and symptoms

Although confirmation of a specific genetic marker is in a significant number of individuals, there are no tests to clearly determine if this is what a person has. As a syndrome, a diagnosis is typically given for children upon confirmation of the presence of several symptoms listed below.[2]

Symptoms are intrauterine growth restriction (IUGR) combined with some of the following:

  • Often small for gestational age (SGA) at birth (birth weight less than 2.8 kg)
  • Feeding problems: the baby is uninterested in feeding and takes only small amounts with difficulty
  • Hypoglycemia
  • Excessive sweating as a baby, especially at night, and a greyness or pallor of the skin. This may be a symptom of hypoglycemia
  • Triangular face with a small jaw and a pointed chin that tends to lessen slightly with age. The mouth tends to curve down
  • A blue tinge to the whites of the eyes in younger children
  • Head circumference may be of normal size and disproportionate to a small body size
  • Wide and late-closing fontanelle
  • Clinodactyly
  • Body asymmetry: one side of the body grows more slowly than the other
  • Continued poor growth with no "catch up" into the normal centile lines on growth chart
  • Precocious puberty (occasionally)
  • Low muscle tone
  • Gastroesophageal reflux disease
  • A striking lack of subcutaneous fat
  • Constipation (sometimes severe)

The average adult height for patients without growth hormone treatment is 4'11" for males and 4'7" for females.[3]

Cause

Its exact cause is unknown, but present research points toward a genetic and epigenetic component, possibly following maternal genes on chromosomes 7 and 11.[4]

It is estimated that approximately 50% of Silver–Russell patients have hypomethylation of H19 and IGF2.[5] This is thought to lead to low expression of IGF2 and over-expression of the H19 gene.[6]

In 10% of the cases the syndrome is associated with maternal uniparental disomy (UPD) on chromosome 7.[4] This is an imprinting error where the person receives two copies of chromosome 7 from the mother (maternally inherited) rather than one from each parent.

Other genetic causes such as duplications, deletions and chromosomal aberrations have also linked to Silver–Russell syndrome.[6]

Interestingly, Silver–Russell patients have variable hypomethylation levels in different body tissues, suggesting a mosaic pattern and a postzygotic epigenetic modification issue. This could explain the body asymmetry of the SRS phenotype.[7]

Like other imprinting disorders (e.g. Prader–Willi syndrome, Angelman syndrome, and Beckwith–Wiedemann syndrome), Silver–Russell syndrome may be associated with the use of assisted reproductive technologies such as in vitro fertilization.[8]

Diagnosis

For many years the diagnosis of Silver–Russell syndrome was clinical. However, this led to overlaps with syndromes with similar clinical features such as Temple syndrome and 12q14 microdeletion syndrome.[9] In 2017, an international consensus was published – detailing the steps clinicians should take to diagnose Silver–Russell syndrome.[10] It is now recommended to test for 11p15 loss of methylation and mUPD7 first. If they are negative, then testing for mUPD16, mUPD20 should take place. Testing for 14q32 should also be considered, to rule out Temple syndrome as a differential diagnosis. If these tests come back inconclusive, then a clinical diagnosis should be made.[10]

It is recommended that the Netchine-Harbison clinical scoring system (NH-CSS) is used to group the clinical features together in a point based score.[10]

Treatment

The caloric intake of children with SRS must be carefully controlled in order to provide the best opportunity for growth.[2] If the child is unable to tolerate oral feeding, then enteral feeding may be used, such as the percutaneous endoscopic gastrostomy.

In children with limb-length differences or scoliosis, physiotherapy can alleviate the problems caused by these symptoms. In more severe cases, surgery to lengthen limbs may be required. To prevent aggravating posture difficulties children with leg length differences may require a raise in their shoe.

Growth hormone therapy is often prescribed as part of the treatment of SRS. The hormones are given by injection typically daily from the age of 2 years old through teenage years. It may be effective even when the patient does not have a growth hormone deficiency. Growth hormone therapy has been shown to increase the rate of growth in patients[11] and consequently prompts 'catch up' growth. This may enable the child to begin their education at a normal height, improving their self-esteem and interaction with other children. Several studies have shown that growth hormone therapy significantly improves childhood growth and final adult height.[12] There are some theories suggesting that the therapy also assists with muscular development and managing hypoglycemia.

Eponym

It is named for Henry Silver and Alexander Russell.[13][14][15]

References
  1. Gilbert, Patricia (1996). "Silver-Russell Syndrome". The A-Z Reference Book of Syndromes and Inherited Disorders (second ed.). pp. 271–273. doi:10.1007/978-1-4899-6918-7_71. ISBN 978-0-412-64120-6.
  2. "Russell-Silver Syndrome". patient.info.
  3. Wollmann, H. A.; Kirchner, T; Enders, H; Preece, M. A.; Ranke, M. B. (1995). "Growth and symptoms in Silver-Russell syndrome: Review on the basis of 386 patients". European Journal of Pediatrics. 154 (12): 958–68. doi:10.1007/bf01958638. PMID 8801103. S2CID 21595433.
  4. "Silver-Russell Syndrome; SRS". OMIM.
  5. Bartholdi, D; Krajewska-Walasek, M; Ounap, K; Gaspar, H; Chrzanowska, K H; Ilyana, H; Kayserili, H; Lurie, I W; Schinzel, A; Baumer, A (2008). "Epigenetic mutations of the imprinted IGF2-H19 domain in Silver-Russell syndrome (SRS): Results from a large cohort of patients with SRS and SRS-like phenotypes" (PDF). Journal of Medical Genetics. 46 (3): 192–7. doi:10.1136/jmg.2008.061820. PMID 19066168. S2CID 29211777.
  6. Eggermann, Thomas; Begemann, Matthias; Binder, Gerhard; Spengler, Sabrina (2010). "Silver-Russell syndrome: genetic basis and molecular genetic testing". Orphanet Journal of Rare Diseases. 5 (1): 19. doi:10.1186/1750-1172-5-19. ISSN 1750-1172. PMC 2907323. PMID 20573229.
  7. Ishida, Miho (April 2016). "New developments in Silver–Russell syndrome and implications for clinical practice". Epigenomics. 8 (4): 563–580. doi:10.2217/epi-2015-0010. ISSN 1750-1911. PMC 4928503. PMID 27066913.
  8. Butler, M. G. (2009). "Genomic imprinting disorders in humans: A mini-review". Journal of Assisted Reproduction and Genetics. 26 (9–10): 477–86. doi:10.1007/s10815-009-9353-3. PMC 2788689. PMID 19844787.
  9. Spengler, S.; Schonherr, N.; Binder, G.; Wollmann, H. A.; Fricke-Otto, S.; Muhlenberg, R.; Denecke, B.; Baudis, M.; Eggermann, T. (2009-09-16). "Submicroscopic chromosomal imbalances in idiopathic Silver-Russell syndrome (SRS): the SRS phenotype overlaps with the 12q14 microdeletion syndrome" (PDF). Journal of Medical Genetics. 47 (5): 356–360. doi:10.1136/jmg.2009.070052. ISSN 0022-2593. PMID 19762329. S2CID 30653418.
  10. Wakeling, Emma L.; Brioude, Frédéric; Lokulo-Sodipe, Oluwakemi; O'Connell, Susan M.; Salem, Jennifer; Bliek, Jet; Canton, Ana P. M.; Chrzanowska, Krystyna H.; Davies, Justin H. (2016-09-02). "Diagnosis and management of Silver–Russell syndrome: first international consensus statement". Nature Reviews Endocrinology. 13 (2): 105–124. doi:10.1038/nrendo.2016.138. ISSN 1759-5029. PMID 27585961. S2CID 13729923.
  11. Rakover, Y.; Dietsch, S.; Ambler, G. R.; Chock, C.; Thomsett, M.; Cowell, C. T. (1996). "Growth hormone therapy in Silver Russell Syndrome: 5 years experience of the Australian and New Zealand Growth database (OZGROW)". European Journal of Pediatrics. 155 (10): 851–7. doi:10.1007/BF02282833. PMID 8891553. S2CID 11550940.
  12. Silver-Russell Syndrome (2.0 ed.). United Kingdom: Child Growth Foundation. March 2021. p. 19. Retrieved 9 April 2022.
  13. synd/2892 at Who Named It?
  14. Russell, A (1954). "A syndrome of intra-uterine dwarfism recognizable at birth with cranio-facial dysostosis, disproportionately short arms, and other anomalies (5 examples)". Proceedings of the Royal Society of Medicine. 47 (12): 1040–4. PMC 1919148. PMID 13237189.
  15. Silver, H. K.; Kiyasu, W; George, J; Deamer, W. C. (1953). "Syndrome of congenital hemihypertrophy, shortness of stature, and elevated urinary gonadotropins". Pediatrics. 12 (4): 368–76. PMID 13099907.
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