Silver-Russell Syndrome 

Updated: Feb 11, 2019
Author: Sunil Kumar Sinha, MD; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG 

Overview

Background

Silver-Russell syndrome (SRS) originally was described by Silver and colleagues in 1953 and, soon afterwards, by Russell in 1954.[1, 2]  Silver-Russell syndrome is characterized by intrauterine and postnatal growth retardation leading to a small-for-gestational-age (SGA) infant at birth, feeding difficulties during infancy, short stature, body asymmetry, characteristic triangular facies with prominent forehead, and several other anomalies.

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 two copies of maternal chromosome 7, with no paternal contribution).[3, 4, 5, 6]

Pathophysiology

Growth failure is the primary abnormality. The American College of Radiology has established guidelines regarding growth disturbances.[7]

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 circ 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.

Epidemiology

Frequency

International

Estimates of incidence range from as high as 1 case in 3000 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%).[8]

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.

 

Presentation

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 four 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

  • 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

See the list below:

  • 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

See the list below:

  • 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 anomalies[9]

Genital anomalies

See the list below:

  • Hypospadias

  • Posterior urethral valves

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)

See the list below:

  • Cardiac defects

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

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. To date, genetic and epigenetic alteration can be detected in only half of cases with typical features. Various molecular defects have been reported, mostly involving chromosomes 7 and 11. Defects have also been reported in chromosomes 1, 15, 17 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.[10]

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 reproductive technologies (ARTs) may increase the risk of imprinting disorders such as Silver-Russell syndrome.[11]  A study by Hattori et al found the frequency of Silver-Russell syndrome to be 8.91-fold greater in association with ART.[12] The investigators also determined that DNA methylation variations were more numerous and widespread in Silver-Russell syndrome patients conceived through ART than in those who were spontaneously conceived. A literature review by Cortessis et al indicated that the summary odds ratio for the development of Silver-Russell syndrome in the context of ART is 11.3.[13]

 

DDx

Diagnostic Considerations

See the list below:

  • Bloom syndrome
  • Nijmegen breakage syndrome
  • IGF1R mutation or deletion
  • Mulibrey nanism
  • 3‐M syndrome
  • IMAGe syndrome

Differential Diagnoses

 

Workup

Approach Considerations

Even with recent advancements in molecular diagnosis, Silver-Russell syndrome remains a clinical diagnosis based on a combination of characteristic features and a scoring system. To date, about 40% of cases of suspected Silver-Russell syndrome remain unexplained by currently offered molecular investigations.

Several scoring systems exist in the literature, but a published international consensus statement on the clinical diagnosis, investigation, and management of Silver-Russell syndrome endorsed the Netchine-Harbison clinical scoring system (NH-CSS), based on favorable sensitivity (98%) and negative predictive (89%) values.[14]  The NH-CSS scoring system is based on six clinical criteria, including the following:

  • Degree of SGA
  • Postnatal growth failure
  • Relative macrocephaly at birth
  • Protruding forehead
  • Body asymmetry
  • Feeding difficulty and/or low body mass index (BMI)

The presence of at least four of these six factors was classified as "likely" Silver-Russell syndrome by Azzi et al, while a determination of "unlikely" Silver-Russell syndrome was reached if three or fewer factors were found during study.[15]

Laboratory Studies

An NH-CSS–based diagnostic flow chart published in a 2017 international consensus statement on the diagnosis and management of Silver-Russell syndrome recommended 11p15 loss of methylation (LOM) and UPD(7)mat as the initial molecular studies in likely Silver-Russell syndrome. If these are negative, additional diagnostic testing may be required, including copy number variant (CNV) and/or chromosome 14q32 analysis, with subsequent UPD(14)mat, UPD(16)mat, UPD(20)mat, and CDKN1C or IGF2 mutation analysis.[14]

Imaging Studies

Obtain a hand radiograph to determine bone age. Plain film hand radiographic findings include the following:

  • Delayed bone age

  • Ivory epiphyses of distal phalanges

  • Small middle phalanx of the fifth finger in 80% of patients with Silver-Russell syndrome

  • Pseudoepiphyses at base of second metacarpal

 

Treatment

Approach Considerations

A medical home with a multidisciplinary care facility is ideal for patients with Silver-Russell syndrome. Usually, a team may include clinical genetic counselors; dietitians and gastroenterologists, for feeding issues and failure to thrive; endocrinologists for short stature and puberty; speech therapists for delay; and orthopedists for scoliosis, but it can be tailored according to the patient's specific symptoms and needs.  

Medical Care

Growth

Significant effort must be undertaken to optimize caloric intake during evaluation of growth. Careful monitoring of linear growth after optimizing caloric intake is critical for early diagnosis of catch-up growth failure by 2 years of age and early intervention with recombinant human growth hormone (rhGH) for maximizing final adult height. Without treatment, mean adult height may be 151.2 cm (59.5 in) in males and 139.9 cm (55.1 in) in females.[16]

GH was approved in the United States in 2001 by the US Food and Drug Administration for use in children born SGA who have not yet manifested adequate catch-up growth by age 2 years. GH is given via daily subcutaneous injections. The recommended starting dose is 0.24 mg/kg/wk, but the dose can be titrated up to 0.48 mg/kg/wk, according to the response. A study by Smeets et al demonstrated that in SGA children who underwent GH treatment, patients with Silver-Russell syndrome achieved height gains similar to those in subjects without Silver-Russell syndrome. Height gain tended to be greater in Silver-Russell syndrome patients with mUPD7 than in those with 11p15 defects. Greater height gain was also seen in children with idiopathic Silver-Russell syndrome.[17]

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

See the list below:

  • Consult a clinical geneticist to differentiate Silver-Russell syndrome 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 rhGH in an infant nearing age 2 years who has not manifested adequate catch-up growth. Other endocrine issues that need close monitoring include premature adrenarche and precocious puberty. 

  • Consult an ophthalmologist to identify refractive errors and other abnormalities of vision commonly associated with Silver-Russell syndrome.

  • Consult a neurologist if there is any concern that myoclonus dystonia, commonly seen in mUPD7, is present. 

  • Monitor scoliosis and consult an orthopedist, especially if the child is on growth hormone therapy. 

Diet

See the list below:

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

 

Guidelines

Guidelines Summary

In 2017, an international consensus statement was published on the clinical diagnosis, investigation, and management of Silver-Russell syndrome. The statement, produced by a task force consisting of 41 members from 16 countries, including pediatric endocrinologists, clinical geneticists, and molecular geneticists, contained, but was not limited to, the following recommendations[14] :

  • Silver-Russell syndrome should remain primarily a clinical diagnosis; molecular testing is useful for the confirmation and stratification of the diagnosis, but lack of a positive molecular result does not exclude the diagnosis
  • First-line molecular testing should include DNA methylation analysis of the H19/insulinlike growth factor–2 (IGF2) intergenic differentially methylated region (IG-DMR) and the KCNQ1OT1 transcription start site (TSS)–DMR
  • First-line molecular testing should include analysis of DNA methylation at the GRB10 alt-TSS-DMR and the MEST alt-TSS-DMR
  • In case of a positive test result at either 11p15 or chromosome 7, discrimination between epimutation, copy number variant (CNV), and uniparental disomy (UPD) should be considered to estimate recurrence risk
  • An alternative syndromic diagnosis and specific investigation for this diagnosis should be particularly considered in patients with any of the following: additional features atypical of Silver-Russell syndrome, family history of growth failure, and/or consanguinity
  • For nutritional goals in the first years of life, nutritional repletion is recommended (although low muscle mass makes typical body mass index targets excessive in this population), with awareness of the possible hazards of rapid postnatal catch-up leading to subsequent increased metabolic risk
  • Ask for and/or screen early for gut dysmotility (gastroesophageal reflux, delayed gastric emptying, and constipation) in all children
  • Diagnose and treat any oromotor and/or sensory issues that affect oral intake of food
  • In patients with severe feeding failure who are unresponsive to standard care, anatomic or functional disorders of the gastrointestinal tract, such as malrotation, should be excluded
  • Avoid enteral feeding by nasogastric or gastrostomy tube in a child capable of eating when there is adequate nutritional repletion
  • In cases of extreme feeding difficulties or gastroesophageal reflux, consider enteral feeding by gastrostomy tube (with or without fundoplication) or low-profile transgastric jejunostomy as a last resort to protect against hypoglycemia and/or malnutrition
  • Glucagon is not recommended to correct hypoglycemia, because of poor glycogen stores and limited ability for gluconeogenesis
  • Provide parents with an emergency guidance plan for illnesses
  • Teach parents how to recognize signs of hypoglycemia, measure ketones, determine the “safe fasting time” for their child, prevent hypoglycemia using complex carbohydrates, and avoid fasting outside a controlled environment
  • If the response to growth hormone is poor, reevaluate the underlying diagnosis, growth hormone dose, IGF1 response, adherence to therapy, and other confounding systemic problems
  • Monitor for signs of premature adrenarche, fairly early and accelerated central puberty, and insulin resistance
  • In patients with maternal UPD for chromosome 7, check for symptoms of myoclonus dystonia at each clinical appointment and refer the patients early to a pediatric neurologist if required
  • Monitor children with maternal UPD for chromosome 7 for signs of verbal or oromotor dyspraxia and/or signs of autistic spectrum disorders
  • Routinely examine all patients with Silver-Russell syndrome for scoliosis
 

Medication

Medication Summary

Recombinant human growth hormone (rhGH) has been shown to substantially improve linear growth in patients with Silver-Russell syndrome (SRS).

 

Follow-up

Further Outpatient Care

See the list below:

  • 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.

Further Inpatient Care

See the list below:

  • Patients with Silver-Russell syndrome (SRS) may require hospitalization for enteral tube feeding.

Prognosis

See the list below:

  • 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. In addition, educate caregivers to recognize the signs and symptoms of hypoglycemia; prolonged fasting should be avoided if hypoglycemia is a concern.

 

Questions & Answers

Overview

What is Silver-Russell syndrome (SRS)?

What is the pathophysiology of Silver-Russell syndrome (SRS)?

What is the prevalence of Silver-Russell syndrome (SRS)?

What is the mortality and morbidity associated with Silver-Russell syndrome (SRS)?

What are the sexual predilections of Silver-Russell syndrome (SRS)?

At what age are the clinical features of Silver-Russell syndrome (SRS) most evident?

Presentation

What are the diagnostic criteria for Silver-Russell syndrome (SRS)?

Which dysmorphic findings are characteristic of Silver-Russell syndrome (SRS)?

Which growth and skeletal findings are characteristic of Silver-Russell syndrome (SRS)?

Which genital anomalies are characteristic of Silver-Russell syndrome (SRS)?

Which radiographic findings are characteristic of Silver-Russell syndrome (SRS)?

How frequently are cardiac defects or malignancies associated with Silver-Russell syndrome (SRS)?

What causes Silver-Russell syndrome (SRS)?

DDX

Which conditions are included in the differential diagnoses of Silver-Russell syndrome (SRS)?

What are the differential diagnoses for Silver-Russell Syndrome?

Workup

How is Silver-Russell syndrome (SRS) diagnosed?

What is the role of lab studies in the workup of Silver-Russell syndrome (SRS)?

What is the role of imaging studies in the workup of Silver-Russell syndrome (SRS)?

Treatment

Which specialists make up the multidisciplinary care team needed to treat Silver-Russell syndrome (SRS)?

How is Silver-Russell syndrome (SRS) treated?

What is the role of surgery in the treatment of Silver-Russell syndrome (SRS)?

Which specialist consultations are beneficial to patients with Silver-Russell syndrome (SRS)?

Which dietary modifications are used in the treatment of Silver-Russell syndrome (SRS)?

Guidelines

What are the guidelines for the diagnosis and treatment of Silver-Russell syndrome (SRS)?

Medications

Which medications are used in the treatment of Silver-Russell syndrome (SRS) treatment?

Follow-up

What is included in the monitoring and long-term care of patients with Silver-Russell syndrome (SRS)?

When is inpatient care indicated for the treatment of Silver-Russell syndrome (SRS)?

What is the prognosis of Silver-Russell syndrome (SRS)?

What is included in patient education about Silver-Russell syndrome (SRS)?