AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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

International

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  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Other Problems to be Considered

Dubowitz syndrome

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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.

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Ainu Prakash-Cheng, MD, PhD to the development and writing of this article.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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Article Last Updated: Jul 25, 2006