Silver-Russell Syndrome: Background, Pathophysiology, Epidemiology

Sections

Sections Silver-Russell Syndrome
Overview
Presentation
- History
- Physical
- Causes
- Show All
DDx
Workup
Treatment
Guidelines
Medication
Follow-up
References

Overview

Background

Silver-Russell syndrome (SRS) originally was described by Silver and colleagues in 1953 and, soon afterwards, by Russell in 1954. The first reports were in children with characteristic facies, low birthweight, asymmetry, and growth retardation.

Over the past several years, more than 400 patients have been described, with phenotypes ranging from mild to classic. Most patients are found to have hypomethylation in the chromosome 11p15 imprinting center 1 (IC1); some patients have maternal uniparental disomy of chromosome 7, with the possibility of imprinting (eg, inheriting 2 copies of maternal chromosome 7, with no paternal contribution).^{[1, 2, 3]}

Pathophysiology

Growth failure is the primary abnormality. The American College of Radiology has established guidelines regarding growth disturbances.^[4]

Patients typically present with intrauterine growth retardation, difficulty feeding, failure to thrive, or postnatal growth retardation. Adequate catch-up growth often does not occur, and final adult height still is less than normal (≤ -3.6 standard deviations [SD]). See the image below.

Failure of growth in weight, length, and head circumference starting at birth, suggesting an organic etiology that occurred in utero.

Older children and adults do not manifest clinical features as clearly as infants or young children. Growth hormone insufficiency may be present. Abnormalities of spontaneous growth hormone (GH) secretion and subnormal responses to provocative growth hormone stimulation testing have been reported in a significant number of children with Silver-Russell syndrome. Facial dysmorphism is observed, with small triangular facies and normal head circumference. Because length usually is less than normal, the head appears disproportionately large. Intelligence may be normal, or the patient may have a learning disability. The limbs may be asymmetric, and camptodactyly (ie, fixed flexion of digits) or clinodactyly (ie, incurving) of one or more fingers may be present.

Frequency

International

More than 400 cases have been reported. Estimates of incidence range from as high as 1 case in 3,000 population to as low as 1 case in 100,000 population.

Mortality/Morbidity

Infants have failure to thrive, feeding difficulties, and fasting hypoglycemia. A retrospective study by Marsaud et al found digestive problems and malnutrition to be common in children with Silver-Russell syndrome. The study, in which 75 patients (median age 24.3 mo) were assessed, found malnutrition in 70% of them and gastrointestinal signs in 77% of them. The latter included feeding difficulties (65%), severe gastroesophageal reflux (55%), severe vomiting before age 1 year (50%), persistent vomiting from age 1 year (29%), and constipation (20%).^[5]

Sex

The male-to-female ratio is equal.

Age

Clinical features are easier to identify in infants and younger children, particularly the small triangular facies. These findings are more difficult to recognize in adults.

Clinical Presentation

Eggermann T, Spengler S, Gogiel M, Begemann M, Elbracht M. Epigenetic and genetic diagnosis of Silver-Russell syndrome. Expert Rev Mol Diagn. 2012 Jun. 12(5):459-71. [Medline].
Chiesa N, De Crescenzo A, Mishra K, Perone L, Carella M, Palumbo O, et al. The KCNQ1OT1 imprinting control region and non-coding RNA: new properties derived from the study of Beckwith-Wiedemann syndrome and Silver-Russell syndrome cases. Hum Mol Genet. 2012 Jan 1. 21(1):10-25. [Medline]. [Full Text].
Fuke T, Mizuno S, Nagai T, Hasegawa T, Horikawa R, Miyoshi Y, et al. Molecular and clinical studies in 138 Japanese patients with Silver-Russell syndrome. PLoS One. 2013. 8(3):e60105. [Medline]. [Full Text].
[Guideline] Zelop C, Fleischer AC, Andreotti RF, et al. Growth disturbance--risk of intrauterine growth restriction. ACR Appropriateness Criteria. 2007. [Full Text].
Marsaud C, Rossignol S, Tounian P, et al. Prevalence and management of gastrointestinal manifestations in Silver-Russell syndrome. Arch Dis Child. 2015 Apr. 100(4):353-8. [Medline].
Lahiri A, Lester R. Hand anomalies in Russell Silver syndrome. J Plast Reconstr Aesthet Surg. 2009 Apr. 62(4):462-5. [Medline].
South ST, Whitby H, Maxwell T, Aston E, Brothman AR, Carey JC. Co-occurrence of 4p16.3 deletions with both paternal and maternal duplications of 11p15: modification of the Wolf-Hirschhorn syndrome phenotype by genetic alterations predicted to result in either a Beckwith-Wiedemann or Russell-Silver phenotype. Am J Med Genet A. 2008 Oct 15. 146A(20):2691-7. [Medline].
Amor DJ, Halliday J. A review of known imprinting syndromes and their association with assisted reproduction technologies. Hum Reprod. 2008 Dec. 23(12):2826-34. [Medline].
[Guideline] Wakeling EL, Brioude F, Lokulo-Sodipe O, et al. Diagnosis and management of Silver-Russell syndrome: first international consensus statement. Nat Rev Endocrinol. 2017 Feb. 13 (2):105-24. [Medline]. [Full Text].
Marconi AM, Ronzoni S, Bozzetti P, Vailati S, Morabito A, Battaglia FC. Comparison of fetal and neonatal growth curves in detecting growth restriction. Obstet Gynecol. 2008 Dec. 112(6):1227-34. [Medline]. [Full Text].
Spengler S, Begemann M, Binder G, Eggermann T. Testing of Buccal Swab DNA Does Not Increase the Detection Rate for Imprinting Control Region 1 Hypomethylation in Silver-Russell Syndrome. Genet Test Mol Biomarkers. 2011 May 25. [Medline].
Andersson Gronlund M, Dahlgren J, Aring E, et al. Ophthalmological findings in children and adolescents with Silver-Russell syndrome. Br J Ophthalmol. 2011 May. 95(5):637-41. [Medline].
Azcona C, Stanhope R. Hypoglycaemia and Russell-Silver syndrome. J Pediatr Endocrinol Metab. 2005 Jul. 18(7):663-70. [Medline].
Azzi S, Steunou V, Rousseau A, et al. Allele-specific methylated multiplex real-time quantitative PCR (ASMM RTQ-PCR), a powerful method for diagnosing loss of imprinting of the 11p15 region in Russell Silver and Beckwith Wiedemann syndromes. Hum Mutat. 2011 Feb. 32(2):249-58. [Medline].
Begemann M, Spengler S, Kanber D, et al. Silver-Russell patients showing a broad range of ICR1 and ICR2 hypomethylation in different tissues. Clin Genet. 2011 Jul. 80(1):83-88. [Medline].
[Guideline] Chauhan SP, Gupta LM, Hendrix NW, Berghella V. Intrauterine growth restriction: comparison of American College of Obstetricians and Gynecologists practice bulletin with other national guidelines. Am J Obstet Gynecol. 2009 Apr. 200(4):409.e1-6. [Medline].
Christoforidis A, Maniadaki I, Stanhope R. Managing children with Russell-Silver syndrome: more than just growth hormone treatment?. J Pediatr Endocrinol Metab. 2005 Jul. 18(7):651-2. [Medline].
Cutfield WS, Lindberg A, Rapaport R, et al. Safety of growth hormone treatment in children born small for gestational age: the US trial and KIGS analysis. Horm Res. 2006. 65 Suppl 3:153-9. [Medline].
Davies PS, Valley R, Preece MA. Adolescent growth and pubertal progression in the Silver-Russell syndrome. Arch Dis Child. 1988 Feb. 63(2):130-5. [Medline].
Duncan PA, Hall JG, Shapiro LR, Vibert BK. Three-generation dominant transmission of the Silver-Russell syndrome. Am J Med Genet. 1990 Feb. 35(2):245-50. [Medline].
Eggermann T, Begemann M, Binder G, Spengler S. Silver-Russell syndrome: genetic basis and molecular genetic testing. Orphanet J Rare Dis. 2010 Jun 23. 5:19. [Medline]. [Full Text].
Eggermann T, Begemann M, Spengler S, et al. Genetic and epigenetic findings in Silver-Russell syndrome. Pediatr Endocrinol Rev. 2010 Dec. 8(2):86-93. [Medline].
Eggermann T, Wollmann HA, Kuner R, et al. Molecular studies in 37 Silver-Russell syndrome patients: frequency and etiology of uniparental disomy. Hum Genet. 1997 Sep. 100(3-4):415-9. [Medline].
Gicquel C, Le Bouc Y. Hormonal regulation of fetal growth. Horm Res. 2006. 65 Suppl 3:28-33. [Medline].
Gicquel C, Rossignol S, Cabrol S. Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome. Nat Genet. 2005 Sep. 37(9):1003-7. [Medline].
Graham JM Jr, Rimoin DL. Abnormal body size and proportion. Emery and Rimoin's Principle and Practice of Medical Genetics. 1997. Vol 1: 737-52.
Jones KL. Russell-Silver syndrome. Smith's Recognizable Patterns of Human Malformation. 6th ed. Philadelphia: Elsevier Saunders; 2006. 92-4.
Kotzot D, Schmitt S, Bernasconi F, et al. Uniparental disomy 7 in Silver-Russell syndrome and primordial growth retardation. Hum Mol Genet. 1995 Apr. 4(4):583-7. [Medline].
Lacassie Y, Arriaza MI, Vargas A, La Motta I. Ring 2 chromosome: ten-year follow-up report. Am J Med Genet. 1999 Jul 16. 85:117-22. [Medline].
Lai KY, Skuse D, Stanhope R, Hindmarsh P. Cognitive abilities associated with the Silver-Russell syndrome. Arch Dis Child. 1994 Dec. 71(6):490-6. [Medline].
Langlois S, Yong SL, Wilson RD, et al. Prenatal and postnatal growth failure associated with maternal heterodisomy for chromosome 7. J Med Genet. 1995 Nov. 32:871-5. [Medline].
[Guideline] Lee PA, Chernausek SD, Hokken-Koelega AC, Czernichow P. International Small for Gestational Age Advisory Board consensus development conference statement: management of short children born small for gestational age, April 24-October 1, 2001. Pediatrics. 2003 Jun. 111(6 Pt 1):1253-61. [Medline].
Li CC, Chodirker BN, Dawson AJ, Chudley AE. Severe hemihypotrophy in a female infant with mosaic Turner syndrome: a variant of Russell-Silver syndrome?. Clin Dysmorphol. 2004 Apr. 13(2):95-8. [Medline].
Lin SY, Lee CN, Hung CC, et al. Epigenetic profiling of the H19 differentially methylated region and comprehensive whole genome array-based analysis in Silver-Russell syndrome. Am J Med Genet A. 2010 Oct. 152A(10):2521-8. [Medline].
Midro AT, Debek K, Sawicka A, et al. Second observation of Silver-Russel syndrome in a carrier of a reciprocal translocation with one breakpoint at site 17q25. Clin Genet. 1993 Jul. 44(1):53-5. [Medline].
Monk D, Bentley L, Hitchins M, et al. Chromosome 7p disruptions in Silver Russell syndrome: delineating an imprinted candidate gene region. Hum Genet. 2002 Oct. 111(4-5):376-87. [Medline].
Monk D, Wakeling EL, Proud V, et al. Duplication of 7p11.2-p13, including GRB10, in Silver-Russell syndrome. Am J Hum Genet. 2000 Jan. 66(1):36-46. [Medline].
Preece MA, Price SM, Davies V, et al. Maternal uniparental disomy 7 in Silver-Russell syndrome. J Med Genet. 1997 Jan. 34(1):6-9. [Medline].
Price SM, Stanhope R, Garrett C, et al. The spectrum of Silver-Russell syndrome: a clinical and molecular genetic study and new diagnostic criteria. J Med Genet. 1999 Nov. 36(11):837-42. [Medline].
Rakover Y, Dietsch S, Ambler GR, et al. Growth hormone therapy in Silver Russell syndrome: 5 years experience of the Australian and New Zealand Growth database (OZGROW). Eur J Pediatr. 1996 Oct. 155(10):851-7. [Medline].
Ramirez-Duenas ML, Medina C, Ocampo-Campos R, Rivera H. Severe Silver-Russell syndrome and translocation. Clin Genet. 1992 Jan. 41(1):51-3. [Medline].
Rizzo V, Traggiai C, Stanhope R. Growth hormone treatment does not alter lower limb asymmetry in children with Russell-Silver syndrome. Horm Res. 2001. 56(3-4):114-6. [Medline].
Rossignol S. Silver-Russell syndrome and its genetic origins. J Endocrinol Invest. 2006. 29(1 Suppl):9-10. [Medline].
Russell A. A syndrome of "intrauterine dwarfism" recognisable at birth with craniofacial dysostosis, disproportionately short arms and other abnormalities (5 examples). Proc Royal Soc Med. 1954. 47:1040-4.
Schlegel D, Arcona A, Morgan J, Hatt C. Silver-Russell syndrome: a case study of neuropsychological deficits in a 8-year-old male. Arch Clin Neuropsychol. 2000 Nov. 15(8):790-1.
Shuman C, Weksberg R, Nedelescu R. Chromosome 7 uniparental disomy in Russell-Silver Syndrome. Am J Hum Genet. 1996. 59S:A284(1648).
Silver HK, Kiyasu W, George J. Syndrome of congenital hemihypertrophy, shortness of stature and elevated urinary gonadotropins. Pediatrics. 1953. 12:368-75.
Spence JE, Perciaccante RG, Greig GM, et al. Uniparental disomy as a mechanism for human genetic disease. Am J Hum Genet. 1988 Feb. 42(2):217-26. [Medline].
Spotila LD, Sereda L, Prockop DJ. Partial isodisomy for maternal chromosome 7 and short stature in an individual with a mutation at the COL1A2 locus. Am J Hum Genet. 1992 Dec. 51(6):1396-405. [Medline].
Stanhope R, Albanese A, Azcona C. Growth hormone treatment of Russell-Silver syndrome. Horm Res. 1998. 49 Suppl 2:37-40. [Medline].
Tanner JM, Lejarraga H, Cameron N. The natural history of the Silver-Russell syndrome: a longitudinal study of thirty-nine cases. Pediatr Res. 1975 Aug. 9(8):611-23. [Medline].
van Haelst MM, Eussen HJ, Visscher F, et al. Silver-Russell phenotype in a patient with pure trisomy 1q32.1-q42.1: further delineation of the pure 1q trisomy syndrome. J Med Genet. 2002 Aug. 39(8):582-5. [Medline]. [Full Text].
Voss R, Ben-Simon E, Avital A, et al. Isodisomy of chromosome 7 in a patient with cystic fibrosis: could uniparental disomy be common in humans?. Am J Hum Genet. 1989 Sep. 45(3):373-80. [Medline].
Wakeling EL, Abu-Amero S, Price SM, et al. Genetics of Silver-Russell syndrome. Horm Res. 1998. 49 Suppl 2:32-6. [Medline].
Wollmann HA, Kirchner T, Enders H, et al. Growth and symptoms in Silver-Russell syndrome: review on the basis of 386 patients. Eur J Pediatr. 1995 Dec. 154(12):958-68. [Medline].
Yoshihashi H, Maeyama K, Kosaki R, et al. Imprinting of human GRB10 and its mutations in two patients with Russell-Silver syndrome. Am J Hum Genet. 2000 Aug. 67(2):476-82. [Medline]. [Full Text].

Media Gallery

Failure of growth in weight, length, and head circumference starting at birth, suggesting an organic etiology that occurred in utero.

of 1

Author

Sunil Kumar Sinha, MD

Sunil Kumar Sinha, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, Endocrine Society, Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Luis O Rohena, MD Chief, Medical Genetics, San Antonio Military Medical Center; Assistant Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Assistant Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Additional Contributors

Elaine H Zackai, MD Professor of Pediatrics, Professor of Obstetrics and Gynecology, Professor of Pediatrics in Human Genetics, University of Pennsylvania School of Medicine; Director, Clinical Genetics Center, University of Pennsylvania; Senior Physician and Director of Clinical Genetics, The Children's Hospital of Philadelphia

Elaine H Zackai, MD is a member of the following medical societies: American Cleft Palate-Craniofacial Association, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Acknowledgements

Robert J Ferry Jr, MD Le Bonheur Chair of Excellence in Endocrinology, Professor and Chief, Division of Pediatric Endocrinology and Metabolism, Department of Pediatrics, University of Tennessee Health Science Center

Robert J Ferry Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, American Medical Association, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, and Texas Pediatric Society

Disclosure: Eli Lilly & Co Grant/research funds Investigator; MacroGenics, Inc Grant/research funds Investigator; Ipsen, SA (formerly Tercica, Inc) Grant/research funds Investigator; NovoNordisk SA Grant/research funds Investigator; Diamyd Grant/research funds Investigator; Bristol-Myers-Squibb Grant/research funds Other; Amylin Other; Pfizer Grant/research funds Other; Takeda Grant/research funds Other

Margaret M McGovern, MD, PhD Professor and Chair of Pediatrics, Stony Brook University, New York

Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics and American Society of Human Genetics

Disclosure: Genzyme Grant/research funds PI

Ainu Prakash-Cheng, MD, PhD† Former Co-Director, Comprehensive Gaucher Disease Treatment Center, Department of Human Genetics, Mount Sinai School of Medicine

Lawrence A Wetterau, MD Assistant Professor, Section of Endocrinology, Children's Hospital Central California.

Lawrence A Wetterau is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Lawson-Wilkins Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Sections Silver-Russell Syndrome
Overview
Presentation
- History
- Physical
- Causes
- Show All
DDx
Workup
Treatment
Guidelines
Medication
Follow-up
References

Silver-Russell Syndrome

Background

Pathophysiology

Epidemiology

Frequency

Mortality/Morbidity

Sex

Age

About

Membership

Apps

WebMD Network

Editions

What to Read Next on Medscape

Silver-Russell Syndrome

Background

Pathophysiology

Epidemiology

Frequency

Mortality/Morbidity

Sex

Age

References

Tables

Contributor Information and Disclosures

What would you like to print?

Find Us On

About

Membership

Apps

WebMD Network

Editions

What to Read Next on Medscape

Related Conditions and Diseases

Medscape Consult

News & Perspective

Tools

Most Popular Articles

Recommended