AUTHOR INFORMATION

Section 1 of 11

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

Coauthored by Ainu Prakash-Cheng, MD, PhD †, Former Co-Director, Comprehensive Gaucher Disease Treatment Center, Department of Human Genetics, Mount Sinai School of Medicine; Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine

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

Edited by Elaine H Zackai, MD, Director of Clinical Genetics Center, Professor of Pediatrics, Department of Pediatrics, Division of Human Genetics and Molecular Biology, University of Pennsylvania, Children's Hospital of Philadelphia; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Robert Anthony Saul, MD, Senior Clinical Geneticist, Greenwood Genetic Center; Clinical Professor, Department of Pediatrics, University of South Carolina; Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Lawrence A Wetterau, MD
Editor's Email:	Elaine H Zackai, MD

eMedicine Journal, July 25 2006, VOLUME 7, Number 7

INTRODUCTION

Section 2 of 11

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. 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 SD). 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 SRS. Facial dysmorphism exists, 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 exist.

Frequency:

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

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

Section 3 of 11

History:

• Diagnostic criteria are not strictly established and only recently were proposed by a group whose homogeneous SRS patients generally had at least 4 of the following features:


• • Birthweight less than or equal to -2 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
  
  
  
• Genital anomalies


• • Hypospadias
  
  
  
  • Posterior urethral valves
  
  
  
• X-ray 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)


• • Cardiac defects
  
  
  
  • Malignancy (eg, craniopharyngioma, testicular seminoma, hepatocellular carcinoma, Wilms tumor)
  
  
  

Causes:

• SRS is both clinically and genetically a heterogeneous disorder, and the basic underlying defect is not known. SRS usually occurs sporadically and its etiology is not identified in most cases. A variety of 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 are 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 methylation. Imprinting may play a role in the clinical phenotype of SRS in these patients. UPD is the inheritance of both alleles from the same parent and none from the other parent. Multiple reports suggest that approximately 10% of patients may have maternal uniparental disomy of chromosome 7 (mUPD7). Heterodisomy (inheritance of both alleles from 1 parent) and isodisomy (inheritance of 2 copies of a single allele from 1 parent) are both demonstrated. Partial heterodisomy or isodisomy have also been shown. Recent findings also suggest that imprinting defects on chromosome 11 within the 11p15 region may also play a role in SRS.



• 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.

DIFFERENTIALS

Section 4 of 11

Fanconi Syndrome
Fetal Alcohol Syndrome

Other Problems to be Considered:

Dubowitz syndrome

WORKUP

Section 5 of 11

Lab Studies:

• Use chromosomal analysis and karyotyping to evaluate for other disorders.



• If SRS is suspected, obtain patient and parental blood to evaluate for uniparental disomy of chromosome 7. This can be done only in specialized molecular diagnostic labs.

Imaging Studies:

• Obtain a hand radiograph to determine bone age. Plain film hand x-ray findings include the following:



• • Delayed bone age
  
  
  
  • Ivory epiphyses of distal phalanges
  
  
  
  • Small middle phalanx of the fifth finger in 80% of SRS patients
  
  
  
  • Pseudoepiphyses at base of second metacarpal
  
  
  

TREATMENT

Section 6 of 11

Medical Care:

• Growth


• • Significant effort must be undertaken to optimize caloric intake.
  
  
  
  • Growth hormone therapy should be considered in a child with SRS who has not manifested adequate catch-up growth by age 2 years. Growth hormone was approved in the United States in 2001 by the US Food and Drug Administration for use in children born small for gestational age who have not yet manifested adequate catch-up growth by age 2 years. Recombinant human growth hormone (rhGH) is given via daily subcutaneous injections. Recommended dose is 0.48 mg/kg/week.
  
  
  
• Development


• • An early intervention program, including physical therapy, is beneficial.
  
  
  
  • Special education courses are needed when the child is older.
  
  
  

Surgical Care:

• Consider enteral feeding if the patient does not tolerate oral feeding and has severe failure to thrive. Nasogastric or percutaneous endoscopic gastrostomy (PEG) feeds are needed to facilitate growth and maintenance.

Consultations:

• Consult a clinical geneticist to differentiate SRS from etiologies of growth retardation, asymmetry, and other clinical findings.



• Consult a gastroenterologist or nutritionist to optimize caloric intake and enhance growth and feeding therapy.



• Developmental evaluation places the patient in Early Intervention, special education programs, physical therapy, and occupational therapy as early as possible.



• Consult a pediatric endocrinologist to consider the use of recombinant human growth hormone (rhGH) in an infant nearing age 2 years who has not manifested adequate catch-up growth.

Diet:

• Patients should have a nutritional evaluation to provide optimal calories for growth. As stated previously, nasogastric or PEG feeding may be required.

MEDICATION

Section 7 of 11

rhGH has been shown to substantially improve linear growth in patients with SRS. Additional long-term studies and continued efforts to optimize dosing regimens are required before benefits on final adult height can be fully assessed.

FOLLOW-UP

Section 8 of 11

Further Inpatient Care:

• The patient may require hospitalization for enteral tube feeding.

Further Outpatient Care:

• The patient may need home-health services for enteral tube feeding follow-up at home.



• Early intervention programs and special education classes are beneficial.



• Feeding, physical, and occupational therapy are beneficial.

Prognosis:

• The prognosis is relatively good.



• Some patients may have a learning disability.

Patient Education:

• Educate the family regarding the growth and development of these children.

MISCELLANEOUS

Section 9 of 11

Special Concerns:

• Genetic counseling


• • Most studies demonstrate that the siblings of children with SRS do not have the disorder. Therefore, risk for recurrence is expected to be minimal.
  
  
  
  • In some of the cases seen to date, the children of patients with SRS do not have the disorder.
  
  
  

TEST QUESTIONS

Section 10 of 11

CME Question 1: Which of the following is the most likely reason that infants with possible Silver-Russell syndrome present for medical care?

A: Infections
B: Failure to thrive, poor feeding
C: Unusual facies
D: Developmental delay
E: Asymmetry of the limbs

The correct answer is B: Children with Silver-Russell syndrome have difficulty feeding during infancy and have poor growth during childhood. Birthweight and length are less than -2 SD.

CME Question 2: Which of the following is the most common etiology of Silver-Russell syndrome?

A: Unknown, sporadic
B: Autosomal dominant
C: Autosomal recessive
D: Uniparental disomy
E: Ring chromosomes

The correct answer is A: Most cases of Silver-Russell syndrome are sporadic. Uniparental disomy has been identified in about 10% of cases.

Pearl Question 1 (T/F): Typical facies of patients with Silver-Russell syndrome include a triangular small face and a normal-sized head relative to the body.

The correct answer is False: Although the facies are small and triangular shaped, the head circumference is normal and appears disproportionately large relative to a small body.

Pearl Question 2 (T/F): Maternal uniparental disomy is the inheritance of alleles from the mother only.

The correct answer is True: This can be either heterodisomy, in which both alleles from the mother are inherited, or isodisomy, in which 2 copies of a single allele from the mother are inherited.

Pearl Question 3 (T/F): Growth hormone therapy should not be considered in patients with Silver-Russell syndrome.

The correct answer is False: Growth hormone therapy may be helpful in increasing the final height of patients with Silver-Russell syndrome and should be considered in those who have not achieved adequate catch-up growth by age 2 years.

Pearl Question 4 (T/F): Imprinting is the methylation of specific bases within the gene on the DNA, thus rendering that gene inactive.

The correct answer is True: 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.

BIBLIOGRAPHY

Section 11 of 11

• Azcona C, Stanhope R: Hypoglycaemia and Russell-Silver syndrome. J Pediatr Endocrinol Metab 2005 Jul; 18(7): 663-70[Medline].
• Chernausek SD: Treatment of short children born small for gestational age: US perspective, 2005. Horm Res 2005; 64 Suppl 2: 63-6[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, 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].
• Eggermann T, Meyer E, Ranke MB, et al: Diagnostic proceeding in Silver-Russell syndrome. Mol Diagn 2005; 9(4): 205-9[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. In: Emery and Rimoin's Principle and Practice of Medical Genetics. Vol. I. 1997: 737-752.
• Jones KL: Russell-Silver syndrome. In: Smith's Recognizable Patterns of Human Malformation. 5th ed. 1997: 96-9.
• 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].
• 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].
• 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, 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].
• 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].
• Moore GE, Abu-Amero S, Wakeling E, et al: The search for the gene for Silver-Russell syndrome. Acta Paediatr Suppl 1999 Dec; 433: 42-8[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].

eMedicine Journals > Pediatrics > Genetics And Metabolic Disease > Silver-Russell Syndrome

Please email us with any comments you have on our new chapter format.

Author Information | Introduction | Clinical | Differentials | Workup | Treatment | Medication | Follow-up | Miscellaneous | Test Questions | Bibliography