eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Silver-Russell Syndrome

Author: Robert J Ferry Jr, MD, Chief, Division of Pediatric Endocrinology and Metabolism, Le Bonheur Children's Medical Center, University of Tennessee Health Science Center at Memphis, and St Jude Children's Research Hospital; Field Surgeon (Medical Corps), 162nd Area Support Medical Company, Army National Guard
Contributor Information and Disclosures

Updated: Jun 1, 2009

Introduction

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. 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).

Pathophysiology

Growth failure is the primary abnormality. The American College of Radiology have established guidelines regarding growth disturbances.1

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]).

Failure of growth in weight, length, and head cir...

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

[ CLOSE WINDOW ]
Failure of growth in weight, length, and head cir...

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.

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

History

Diagnostic criteria are not strictly established and were only recently proposed by a group whose homogeneous patients with Silver-Russell syndrome (SRS) generally had at least 4 of the following features:

  • Birthweight less than or equal to -2 standard deviations (SD) from the mean
  • Poor postnatal growth, less than or equal to -2 SD from the mean at diagnosis
  • Preservation of occipitofrontal circumference
  • Classic facial phenotype
  • Asymmetry
  • Low birthweight (£ -2 SD)
  • Feeding difficulties during infancy
  • Tendency for fasting hypoglycemia during infancy and early childhood
  • Tendency for increased sweating during infancy, particularly on the head and upper trunk
  • Developmental delay
  • Poor head control during infancy caused by relatively large size of head compared to a small body
  • Motor impairment caused by lack of muscle bulk and strength
  • Impairment of cognitive abilities (language, arithmetic) during childhood in about 50% of patients

Physical

  • Dysmorphic facies
    • Classic features include normal head circumference (head may appear large because of small body size), blue sclerae, small triangular facies, a high forehead that tapers to a small jaw, micrognathia, prominent nasal bridge, and down-turning corners of the mouth.
    • Mild dysmorphic facies include some features of the classic facies.
  • Growth and skeletal
    • Prenatal onset short stature (final height £ -3.6 SD)
    • Late closure of anterior fontanelle
    • Asymmetry, usually of the limbs
    • Hemihypertrophy
    • Clinodactyly of the fifth finger
    • Camptodactyly
    • Syndactyly of second and third toes
    • Sprengel deformity or other hand anomalies2
  • Genital anomalies
  • Radiographic findings, hand: Delayed bone age, ivory epiphyses of the distal phalanges, small middle phalanx of the fifth finger (80%), pseudoepiphyses at the base of the second metacarpal
  • Other (occasional)

Causes

  • Silver-Russell syndrome is both clinically and genetically a heterogeneous disorder, and the basic underlying defect is not known. Silver-Russell syndrome usually occurs sporadically and its etiology is not identified in most cases. Various molecular defects have been reported, mostly involving chromosomes 7 and 17. Defects have also been reported in chromosomes 1 and X. A few cases of autosomal dominant transmission have been described, including ring 2 chromosome, balanced translocation of band 17q25, and duplication of band 7p11.2-p13.
  • Approximately 10% of patients have proven uniparental disomy (UPD) and abnormal methylation. Imprinting may play a role in the clinical phenotype of Silver-Russell syndrome in these patients. UPD results from inheritance of both alleles from one parent and no allele from the other parent (ie, loss of the allele contributed by one of the parents). Multiple reports suggest that approximately 10% of patients may have maternal UPD of chromosome 7 (mUPD7). Heterodisomy (inheritance of both alleles from one parent) and isodisomy (inheritance of 2 copies of a single allele from one parent) are both demonstrated. Partial heterodisomy or isodisomy have also been shown. Findings also suggest that imprinting defects on chromosome 11 within the 11p15 region may also play a role in Silver-Russell syndrome.3
  • Imprinting involves the methylation of particular bases within an allele. The methylation pattern differs depending on whether the allele is obtained from the mother or from the father's genome. If the allele is methylated, then that gene selectively is turned off.
  • Assisted reproduction technologies (ART) may increase the risk of imprinting disorders such as Silver-Russell syndrome.4

More on Silver-Russell Syndrome

Overview: Silver-Russell Syndrome
Differential Diagnoses & Workup: Silver-Russell Syndrome
Treatment & Medication: Silver-Russell Syndrome
Follow-up: Silver-Russell Syndrome
Multimedia: Silver-Russell Syndrome
References
Further Reading
[ CLOSE WINDOW ]

References

  1. [Guideline] Zelop C, Fleischer AC, Andreotti RF, et al. Growth disturbance--risk of intrauterine growth restriction. ACR Appropriateness Criteria. 2007;[Full Text].

  2. Lahiri A, Lester R. Hand anomalies in Russell Silver syndrome. J Plast Reconstr Aesthet Surg. Apr 2009;62(4):462-5. [Medline].

  3. 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. Oct 15 2008;146A(20):2691-7. [Medline].

  4. Amor DJ, Halliday J. A review of known imprinting syndromes and their association with assisted reproduction technologies. Hum Reprod. Dec 2008;23(12):2826-34. [Medline].

  5. [Best Evidence] 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. Dec 2008;112(6):1227-34. [Medline].

  6. Azcona C, Stanhope R. Hypoglycaemia and Russell-Silver syndrome. J Pediatr Endocrinol Metab. Jul 2005;18(7):663-70. [Medline].

  7. Chernausek SD. Treatment of short children born small for gestational age: US perspective, 2005. Horm Res. 2005;64 Suppl 2:63-6. [Medline].

  8. Christoforidis A, Maniadaki I, Stanhope R. Managing children with Russell-Silver syndrome: more than just growth hormone treatment?. J Pediatr Endocrinol Metab. Jul 2005;18(7):651-2. [Medline].

  9. 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].

  10. Davies PS, Valley R, Preece MA. Adolescent growth and pubertal progression in the Silver-Russell syndrome. Arch Dis Child. Feb 1988;63(2):130-5. [Medline].

  11. Duncan PA, Hall JG, Shapiro LR, Vibert BK. Three-generation dominant transmission of the Silver-Russell syndrome. Am J Med Genet. Feb 1990;35(2):245-50. [Medline].

  12. Eggermann T, Meyer E, Ranke MB, et al. Diagnostic proceeding in Silver-Russell syndrome. Mol Diagn. 2005;9(4):205-9. [Medline].

  13. Eggermann T, Wollmann HA, Kuner R, et al. Molecular studies in 37 Silver-Russell syndrome patients: frequency and etiology of uniparental disomy. Hum Genet. Sep 1997;100(3-4):415-9. [Medline].

  14. Gicquel C, Le Bouc Y. Hormonal regulation of fetal growth. Horm Res. 2006;65 Suppl 3:28-33. [Medline].

  15. Gicquel C, Rossignol S, Cabrol S. Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome. Nat Genet. Sep 2005;37(9):1003-7. [Medline].

  16. Graham JM Jr, Rimoin DL. Abnormal body size and proportion. In: Emery and Rimoin's Principle and Practice of Medical Genetics. Vol 1. 1997:737-52.

  17. Jones KL. Russell-Silver syndrome. In: Smith's Recognizable Patterns of Human Malformation. 5th ed. 1997:96-9.

  18. Kotzot D, Schmitt S, Bernasconi F, et al. Uniparental disomy 7 in Silver-Russell syndrome and primordial growth retardation. Hum Mol Genet. Apr 1995;4(4):583-7. [Medline].

  19. Lacassie Y, Arriaza MI, Vargas A, La Motta I. Ring 2 chromosome: ten-year follow-up report. Am J Med Genet. Jul 16 1999;85:117-22. [Medline].

  20. Lai KY, Skuse D, Stanhope R, Hindmarsh P. Cognitive abilities associated with the Silver-Russell syndrome. Arch Dis Child. Dec 1994;71(6):490-6. [Medline].

  21. Langlois S, Yong SL, Wilson RD, et al. Prenatal and postnatal growth failure associated with maternal heterodisomy for chromosome 7. J Med Genet. Nov 1995;32:871-5. [Medline].

  22. 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. Apr 2004;13(2):95-8. [Medline].

  23. 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. Jul 1993;44(1):53-5. [Medline].

  24. Monk D, Bentley L, Hitchins M, et al. Chromosome 7p disruptions in Silver Russell syndrome: delineating an imprinted candidate gene region. Hum Genet. Oct 2002;111(4-5):376-87. [Medline].

  25. Monk D, Wakeling EL, Proud V, et al. Duplication of 7p11.2-p13, including GRB10, in Silver-Russell syndrome. Am J Hum Genet. Jan 2000;66(1):36-46. [Medline].

  26. Moore GE, Abu-Amero S, Wakeling E, et al. The search for the gene for Silver-Russell syndrome. Acta Paediatr Suppl. Dec 1999;433:42-8. [Medline].

  27. Preece MA, Price SM, Davies V, et al. Maternal uniparental disomy 7 in Silver-Russell syndrome. J Med Genet. Jan 1997;34(1):6-9. [Medline].

  28. 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. Nov 1999;36(11):837-42. [Medline].

  29. 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. Oct 1996;155(10):851-7. [Medline].

  30. Ramirez-Duenas ML, Medina C, Ocampo-Campos R, Rivera H. Severe Silver-Russell syndrome and translocation. Clin Genet. Jan 1992;41(1):51-3. [Medline].

  31. 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].

  32. Rossignol S. Silver-Russell syndrome and its genetic origins. J Endocrinol Invest. 2006;29(1 Suppl):9-10. [Medline].

  33. 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.

  34. 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. Nov 2000;15(8):790-1.

  35. Shuman C, Weksberg R, Nedelescu R. Chromosome 7 uniparental disomy in Russell-Silver Syndrome. Am J Hum Genet. 1996;59S:A284(1648).

  36. Silver HK, Kiyasu W, George J. Syndrome of congenital hemihypertrophy, shortness of stature and elevated urinary gonadotropins. Pediatrics. 1953;12:368-75.

  37. Spence JE, Perciaccante RG, Greig GM, et al. Uniparental disomy as a mechanism for human genetic disease. Am J Hum Genet. Feb 1988;42(2):217-26. [Medline].

  38. 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. Dec 1992;51(6):1396-405. [Medline].

  39. Stanhope R, Albanese A, Azcona C. Growth hormone treatment of Russell-Silver syndrome. Horm Res. 1998;49 Suppl 2:37-40. [Medline].

  40. Tanner JM, Lejarraga H, Cameron N. The natural history of the Silver-Russell syndrome: a longitudinal study of thirty-nine cases. Pediatr Res. Aug 1975;9(8):611-23. [Medline].

  41. 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. Aug 2002;39(8):582-5. [Medline]. [Full Text].

  42. 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. Sep 1989;45(3):373-80. [Medline].

  43. Wakeling EL, Abu-Amero S, Price SM, et al. Genetics of Silver-Russell syndrome. Horm Res. 1998;49 Suppl 2:32-6. [Medline].

  44. 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. Dec 1995;154(12):958-68. [Medline].

  45. 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. Aug 2000;67(2):476-82. [Medline]. [Full Text].

[ CLOSE WINDOW ]

Further Reading

  • A recent study compared fetal and neonatal growth curves in detecting growth restriction. 5

[ CLOSE WINDOW ]

Keywords

Silver-Russell syndrome, SRS, Russell-Silver syndrome, Silver-Russell dwarfism, Silver syndrome, growth retardation, intrauterine growth retardation, facial dysmorphism, learning disability, camptodactyly, clinodactyly, fasting hypoglycemia, triangular facies, low birthweight, developmental delay, poor head control, language impairment, craniopharyngioma, testicular seminoma, hepatocellular carcinoma, Wilms tumor, hypospadias, assisted reproduction technologies, treatment, diagnosis

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Robert J Ferry Jr, MD, Chief, Division of Pediatric Endocrinology and Metabolism, Le Bonheur Children's Medical Center, University of Tennessee Health Science Center at Memphis, and St Jude Children's Research Hospital; Field Surgeon (Medical Corps), 162nd Area Support Medical Company, Army National Guard
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, Lawson-Wilkins Pediatric Endocrine Society, Society for Pediatric Research, and Texas Pediatric Society
Disclosure: Nutropin Speakers Bureau Honoraria Speaking and teaching; Genotropin Speakers Bureau Honoraria Speaking and teaching; Eli Lilly & Co. Grant/research funds Independent contractor; MacroGenics, Inc. Grant/research funds Independent contractor; Ipsen, S.A. (formerly Tercica, Inc.) Grant/research funds Independent contractor

Medical Editor

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 American Society of Human Genetics
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Robert Anthony Saul, MD, Clinical Professor, Department of Pediatrics, University of South Carolina; Senior Clinical Geneticist, Greenwood Genetic Center
Robert Anthony Saul, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, and American College of Physician Executives
Disclosure: Nothing to disclose.

CME Editor

Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine
Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine
Disclosure: Baxter Honoraria Consulting

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.