Clinical characteristics.

Silver-Russell Syndrome (SRS) is typically characterized by asymmetric gestational growth restriction resulting in affected individuals being born small for gestational age, with relative macrocephaly at birth (head circumference ≥1.5 SD above birth weight and/or length), prominent forehead usually with frontal bossing, and frequently body asymmetry. This is followed by postnatal growth failure, and in some cases progressive limb length discrepancy and feeding difficulties. Additional clinical features include triangular facies, fifth-finger clinodactyly, and micrognathia with narrow chin. Except for the limb length asymmetry, the growth failure is proportionate and head growth normal. The average adult height in untreated individuals is ~3.1±1.4 SD below the mean. The Netchine-Harbison Clinical Scoring System (NH-CSS) is a sensitive diagnostic scoring system. Clinical diagnosis can be established in an individual who meets at least four of the NH-CSS clinical criteria – prominent forehead/frontal bossing and relative macrocephaly at birth plus two additional findings – and in whom other disorders have been ruled out.

Diagnosis/testing.

SRS is a genetically heterogeneous condition. Genetic testing confirms clinical diagnosis in approximately 60% of affected individuals. Hypomethylation of the imprinted control region 1 (ICR1) at 11p15.5 causes SRS in 35%-50% of individuals, and maternal uniparental disomy (mUPD7) causes SRS in 7%-10% of individuals. There are a small number of individuals with SRS who have duplications, deletions or translocations involving the imprinting centers at 11p15.5 or duplications, deletions, or translocations involving chromosome 7. Rarely, affected individuals with pathogenic variants in CDKN1C, IGF2, PLAG1, and HMGA2 have been described. However, approximately 40% of individuals who meet NH-CSS clinical criteria for SRS have negative molecular and/or cytogenetic testing.

Management.

Treatment of manifestations: Multidisciplinary follow up and early, specific intervention are necessary for optimal management of affected individuals. Treatment may include growth hormone therapy. Hypoglycemia should be prevented or aggressively managed. Strategies for feeding disorders include nutritional and caloric supplements, medication for gastroesophageal reflux, therapy for oral motor problems and feeding aversion, cyproheptadine for appetite stimulation, and enteral tube feeding as needed. Lower-limb length discrepancy exceeding 2 cm requires intervention. In older children, distraction osteogenesis is recommended for most individuals. Physical, occupational, speech, and language therapy with an individualized education plan are used to treat delays. Psychological counseling can be used as needed to address psychosocial and body image issues. Severe micrognathia or cleft palate should be managed by a multidisciplinary craniofacial team. Males with cryptorchidism or hypospadias should be referred to a urologist. Males with micropenis and females with internal genitourinary anomalies benefit from referral to a multidisciplinary disorders of sex development center.

Surveillance: Monitoring of: growth velocity; blood glucose concentration and urine ketones for hypoglycemia in infants and as needed in older children; limb length at each well-child visit in early childhood for evidence of asymmetric growth; evaluation for scoliosis, signs of premature central puberty, dental crowding and malocclusion, and speech/language development.

Agents/circumstances to avoid: prolonged fasting in infants and young children because of the risk for hypoglycemia; elective surgery whenever possible due to risk of hypoglycemia, hypothermia, difficult healing, and difficult intubation.

Genetic counseling.

SRS has multiple etiologies and typically has a low recurrence risk. In most families, a proband with Silver-Russell syndrome (SRS) represents a simplex case (a single affected family member) and has SRS as the result of an apparent de novo epigenetic or genetic alteration (e.g., loss of paternal methylation at the 11p15 ICR1 H19/IGF2 imprinting center 1 or maternal uniparental disomy for chromosome 7). SRS may also occur as the result of a genetic alteration associated with up to a 50% recurrence risk (e.g., a copy number variant on chromosome 7 or 11 or an intragenic pathogenic variant in CDKN1C, IGF2, PLAG2, or HMGA2) depending on the nature of the genetic alteration and the sex of the transmitting parent. Accurate assessment of SRS recurrence therefore requires identification of the causative genetic mechanism in the proband.

Suggestive Findings

Silver-Russell syndrome (SRS) should be suspected in individuals who meet the NH-CSS clinical criteria [Azzi et al 2015] as follows:

• Small for gestational age (birth weight and/or length ≥2 SD below the mean for gestational age)
• Postnatal growth failure (length/height ≥ SD below the mean at 24 months)
• Relative macrocephaly at birth (head circumference >1.5 SD above birth weight and/or length)
• Frontal bossing or prominent forehead (forehead projecting beyond the facial plane on a side view as a toddler [1–3 years])
• Body asymmetry (limb length discrepancy ≥0.5 cm, or <0.5 cm with ≥2 other asymmetric body parts)
• Feeding difficulties or body mass index ≤2 SD at 24 months or current use of a feeding tube or cyproheptadine for appetite stimulation

If an individual meets four of the six criteria, the clinical diagnosis is suspected and molecular confirmation testing is warranted. Some rare individuals meeting three of the six criteria have had a positive molecular confirmation for SRS.

Establishing the Diagnosis

The diagnosis of SRS is established in a proband who meets four of the six Netchine-Harbison clinical diagnostic criteria and who has findings on molecular genetic testing consistent with either hypomethylation on chromosome 11p15.5 or maternal uniparental disomy (UPD) for chromosome 7 (see Table 1).

Chromosome 11p15.5 imprinting cluster. SRS is associated with abnormal regulation of gene transcription in two imprinted domains on chromosome 11p15.5. Regulation may be disrupted by any one of numerous mechanisms. See Molecular Pathogenesis for a detailed description of the regulation of gene expression in this region.

Maternal UPD7 can occur by different mechanisms. See Molecular Pathogenesis.

An algorithm for investigation of the diagnosis of SRS was published by the International Expert Consensus [Wakeling et al 2017]. See Figure 1.

Figure 1.

Flow chart for investigation and diagnosis of Silver-Russell Syndrome This figure was adapted (legends not included) from Wakeling et al [2017], which was published under a Creative Commons Attribution 4.0 International License.

The recommended order of testing for SRS is the following:

• Methylation analysis of 11p15.5 ICR1/ICR2 and maternal UPD7 studies may be ordered simultaneously.
  Note: (1) Detection of an abnormality is dependent on the mechanism of disease and methodology used (see Table 1). (2) Mosaicism has been reported; therefore, testing of other tissues (e.g., buccal cells or skin fibroblasts) may be considered if leukocyte testing is normal.
• If methylation analysis of 11p15.5 ICR1/ICR2 and maternal UPD7 studies are normal, sequence analysis of IGF2, CDKN1C, PLAG1, and HMGA2 may be considered.
  Note: Some individuals ultimately diagnosed with SRS will have a SNP chromosomal microarray (CMA) based on their significant growth restriction noted at birth or later based on speech or other developmental delays. While this is not a first-tier testing recommendation for someone suspected of having SRS, it can uncover chromosome 7 or 11 abnormalities that establish the diagnosis (see Table 1).

If methylation analysis of 11p15.5 ICR1/ICR2 and UPD7 studies are normal, a multigene panel that includes sequence analysis of IGF2, CDKN1C, PLAG1, HMGA2, and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Silver-Russell Syndrome (SRS) is typically characterized by asymmetric gestational growth restriction resulting in affected individuals being born small for gestational age with relative macrocephaly at birth (head circumference ≥1.5 SD above birth weight and/or length), prominent forehead usually with frontal bossing, and frequently body asymmetry. This is followed by postnatal growth failure, and in some cases progressive limb length discrepancy and severe feeding difficulties in the first years of life. Additional clinical features include triangular facies, fifth-finger clinodactyly, and micrognathia with narrow chin. Except for the limb length asymmetry, the growth failure is proportionate with normal head growth. The average adult height in untreated individuals is ~3.1±1.4 SD below the mean.

SRS is an etiologically heterogeneous condition. In the recent international consensus statement for diagnosis and management of SRS [Wakeling et al 2017], the Netchine-Harbison Clinical Scoring System [Netchine et al 2007, Azzi et al 2015] was selected as the most sensitive of the compared diagnostic scoring systems.

Netchine-Harbison Clinical Scoring System (NH-CSS) [Azzi et al 2015]:

• Small for gestational age (birth weight and/or length ≤2 SD for gestational age)
• Postnatal growth failure (length/height ≥2 SD below the mean at 24 months)
• Relative macrocephaly at birth (head circumference >1.5 SD above birth weight and/or length)
• Frontal bossing or prominent forehead (Forehead projecting beyond the facial plane on a side view as a toddler [1–3 years])
• Body asymmetry (limb length discrepancy ≥0.5 cm, or <0.5 cm with ≥2 other asymmetric body parts)
• Feeding difficulties or BMI ≤2 SD at 24 months or current use of a feeding tube or cyproheptadine for appetite stimulation

Clinical diagnosis is made when an infant meets at least four of the clinical criteria, two of which must be relative macrocephaly at birth and frontal bossing. In older children and adults, the facial features can evolve and the prominent forehead can disappear. Therefore, in order to be able to use the NH-CSS in older children and adults, the prominence of the forehead needs to be assessed in childhood and profile photographs taken of the individual at around age two years.

Individuals with SRS typically have additional supportive clinical findings, including the following:

• Delayed closure of anterior fontanelle
• Triangular face
• Micrognathia
• Dental crowding
• Down-turned corners of the mouth
• High pitched voice
• Diminished muscle mass
• Shoulder dimples
• Hypoplastic elbow joints
• Fifth-finger clinodactyly and/or brachydactyly
• Scoliosis
• Excessive sweating
• Fasting hypoglycemia
• Speech delay
• Motor delay
• Genitourinary anomalies

Growth. The earliest manifestation of SRS is abnormal growth. Most children are born small for gestational age with birth weight and/or length ≥2 SD below the mean. Although growth velocity may be within the normal range, children with SRS rarely show significant catch-up growth. At age two years, most children with SRS remain >2 SD below the mean for length unless the parents are tall. Growth charts for European children with SRS have been published [Wollmann et al 1995]. Growth charts for North American children with the Wollmann data superimposed are available from the MAGIC Foundation (accessed 5-22-20).

In two European series of untreated adults with SRS, height ranged from 3.7 to 3.5 SD below the mean for males and 4.2 to 2.5 SD below the mean for females [Wollmann et al 1995, Binder et al 2013]. Except for the limb length asymmetry, the growth failure is proportionate, with normal head growth. Most children diagnosed clinically as having SRS who demonstrated catch-up growth in later childhood had conditions other than classic SRS [Saal et al 1985].

See Management for use of growth hormone therapy to influence growth in children with SRS. Note: Many children with SRS do not achieve normal stature even with administration of human growth hormone if rapid bone age advancement during puberty is not managed.

Other endocrinologic issues can include premature adrenarche, early puberty, and insulin resistance, which can contribute to a reduced final height even after treatment with growth hormone.

Skeletal abnormalities may include:

• Limb length asymmetry, caused by hemihypotrophy with diminished growth of the affected side;
• Fifth-finger clinodactyly and/or brachydactyly, among the most frequently described skeletal anomalies (albeit minor) in individuals with SRS;
• Scoliosis, which has been reported in some studies in up to 36% of individuals with SRS [Abraham et al 2004]. A more recent study identified scoliosis or kyphosis in 21% of individuals; 18% required corrective surgery [Yamaguchi et al 2015].

Neurodevelopment. Besides the growth issues, neurodevelopment is of great concern to parents. Evidence shows that children with this condition are at increased risk for developmental delay (both motor and cognitive) and learning disabilities.

In a review of a large cohort of children with SRS with either 11p15 methylation defects or maternal UPD7, developmental delay was seen in 34% of individuals, the majority of whom had mild delays. Developmental delays were more commonly seen in those with maternal UPD7 than in those with 11p15 methylation defects (65% vs 20%). Speech delays were common in both groups [Wakeling et al 2010]. Further studies of individuals with molecularly confirmed SRS and early appropriate clinical management are needed to give a more accurate cognitive prognosis.

Feeding disorders and hypoglycemia. Children with SRS have little subcutaneous fat and often have poor appetites, oral motor problems, and feeding disorders [Fuke et al 2013]. They are at risk for hypoglycemia, especially associated with any prolonged fast [Wakeling et al 2017]. In a study of children with SRS, contributing factors for hypoglycemia included reduced caloric intake, often secondary to poor appetite and feeding; reduced body mass; and, in several children, growth hormone deficiency [Azcona & Stanhope 2005]. While most children had clinical symptoms of hypoglycemia, several were asymptomatic.

Diaphoresis in early childhood may be associated with hypoglycemia, although diaphoresis may often occur in the absence of hypoglycemia in children with SRS [Stanhope et al 1998].

Gastrointestinal disorders are common and problems include gastroesophageal reflux disease, esophagitis, food aversion, vomiting, constipation and failure to thrive. One large study documented gastrointestinal problems in 77% of children, and 55% of children had severe gastroesophageal reflux, which may have an atypical presentation without vomiting in this group of children [Marsaud et al 2015]. Reflux esophagitis should be suspected in children with either food aversion or aspiration.

Craniofacial anomalies are common. Some individuals with SRS have Pierre Robin sequence and cleft palate. Within a group of individuals with SRS, Wakeling et al [2010] found cleft palate or bifid uvula in 7% of those with 11p15.5 methylation defects and in no individuals with maternal UPD7. Those individuals with Pierre Robin sequence should be monitored for obstructive apnea.

Dental and oral abnormalities are common. Microdontia, high-arched palate, and dental crowding secondary to the relative micrognathia and small mouth have been reported [Orbak et al 2005, Wakeling et al 2010]. Overbite and dental crowding appear to be the most common orofacial manifestation [Hodge et al 2015]

Poor oral hygiene in the presence of dental crowding can lead to increased risk for dental caries.

Genitourinary problems have been observed. The most common anomalies are hypospadias and cryptorchidism in males [Bruce et al 2009, Wakeling et al 2017]. Mayer-Rokitansky-Kuster-Hauser syndrome (associated with underdeveloped or absent vagina and uterus with normal appearance of the external genitalia) has been reported in females [Bruce et al 2009, Abraham et al 2015]. Renal anomalies are not common; however, horseshoe kidney and renal dysplasia have been reported [Wakeling et al 2010].

Heart defects are uncommon, but have been reported in larger studies [Wakeling et al 2010] and smaller case series [Ghanim et al 2013]. The prevalence of heart defects may be as high as 5.5% [Ghanim et al 2013].

Genotype-Phenotype Correlations

Using methylation-sensitive restriction enzymes HpaII or NotI to measure the degree of methylation of H19, Bruce et al [2009] developed a scale of extreme H19 hypomethylation, moderate H19 hypomethylation, normal H19 methylation, and maternal UPD7 (normal H19 methylation). They determined that children with SRS with extreme H19 hypomethylation (i.e., ≥6 SD below the mean or <9% methylation) were more likely to have more severe skeletal manifestations (including radiohumeral dislocation, syndactyly, greater limb asymmetry, and scoliosis) than children with SRS with moderate hypomethylation and those with maternal UPD7.

A study by Wakeling et al [2010] compared clinical features of children with SRS caused by 11p15.5 ICR1 IGF2/H19 methylation defects to those with maternal UPD7. They found fifth-finger clinodactyly and congenital anomalies were more frequent in children with 11p 15.5 ICR1 hypomethylation than in those with maternal UPD7, whereas learning difficulties and speech disorders were more frequent in children with maternal UPD7 than in those with ICR1 hypomethylation.

Children with SRS with maternal UPD7 had more gain in height with growth hormone therapy compared to children with 11p15.5 epimutations, possibly because children with 11p15.5 methylation abnormalities showed elevated levels of insulin-like growth factor I (product of IGF1) and therefore a degree of IGF1 resistance; children with SRS with maternal UPD7 had response characteristics similar to other children who were small for gestational age [Binder et al 2008].

Prevalence

The prevalence is unknown and was previously estimated at 1:30,000-1:100,000 (A Toutain, Orphanet). A recent retrospective study conducted in Estonia estimated the minimum prevalence of SRS at birth as 1:15,886 [Yakoreva et al 2019].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Silver-Russell syndrome (SRS), the following evaluations are recommended if they have not already been completed:

• Assessment and plotting of growth curves. See the MAGIC Foundation.
• Physical examination for evaluation of possible limb length asymmetry, genitourinary anomalies, scoliosis, precocious or early-onset puberty, and oral and craniofacial abnormalities
• Consultation with a pediatric endocrinologist
• Consultation with a pediatric gastroenterologist and dietician
  • For children suspected of having gastroesophageal reflux disease (GERD), evaluation for esophagitis including video swallow studies, gastric emptying studies pH probe, and endoscopy.
  • Intestinal malrotation has been reported in children with SRS and needs to be ruled out in those who have feeding disorders, constipation and delayed gastric emptying.
• Screening assessment of neurocognitive development, speech and language, and muscle tone
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

SRS leads to a wide spectrum of abnormal physical characteristics and functional abnormalities. Multidisciplinary follow up and early, specific, interventions are necessary for optimal management of individuals with SRS. The multidisciplinary team should be composed of pediatric subspecialists including an endocrinologist, gastroenterologist, dietician, clinical geneticist and genetic counselor, craniofacial team, orthopedic surgeon, neurologist, speech and language therapist, and psychologist

Growth and use of growth hormone. Children with any condition associated with body differences and/or short stature are often sensitive about body image. These factors can play a significant role in self-image, peer relationships, and socialization. Thus, early referral to a pediatric endocrinologist is essential for children with SRS.

• Growth hormone therapy in children with intrauterine growth restriction of all causes has significantly improved growth and final height, especially in those children who do not experience catch-up growth [Dahlgren et al 2005, Jensen et al 2014, Zanelli & Rogol 2018]. Specifically, children with SRS have benefited from growth hormone supplementation [Toumba et al 2010, Binder et al 2013].
  • Smeets et al [2016] found that height gain in children with SRS treated with growth hormone was similar to that in children who did not have SRS, although final heights were less in the SRS population because their heights were lower at the initiation of treatment [Smeets et al 2016].
  • The goals of GH treatment are, of course, to improve growth velocity but also to improve body composition (especially lean body mass), psychomotor development, and appetite; to reduce the risk of hypoglycaemia; and to optimize linear growth [Wakeling et al 2017].
  • A study by Rizzo et al [2001] demonstrated significant increase in height in children with SRS treated with growth hormone, but without a change in body or limb asymmetry
  • Such treatment is best undertaken in a center with experience in managing growth disorders.
• Growth hormone deficiency. Treatment with human growth hormone is necessary in the presence of documented growth hormone deficiency. However, growth hormone deficiency is not common in SRS [Wakeling et al 2017].
  • Treatment with growth hormone in SRS is indicated and not altered even in the presence of growth hormone deficiency.
  • Testing for growth hormone deficiency by fasting is contraindicated because of the risk for inducing hypoglycemia [Wakeling et al 2017].
• Bone age advancement and puberty. Monitoring for signs of premature adrenarche, fairly early and accelerated central puberty, and insulin resistance is very important in individuals with SRS. Personalized treatment with GnRH analogs for at least two years in children with evidence of central puberty (starting no later than age 12 years in girls and age 13 years in boys) can be considered to preserve adult height potential [Wakeling et al 2017].

Hypoglycemia should be prevented and aggressively managed if present.

• Monitoring for urinary ketones after prolonged fasting (including when infants start sleeping through the night) or excess physical activity or with illness
• Frequent feeding; avoidance of long fasting between feeds (in infants: ≤4 hours)
• Use of complex carbohydrates

Gastrointestinal disorders should be treated early and adequately. It is critical that attention to growth and nutrition begin in infancy. Infants with SRS usually have poor muscle mass and often have feeding difficulties in addition to inherent growth disturbance. In one study gastrointestinal issues, feeding disorders, and/or malnutrition were seen in 70% of individuals [Marsaud et al 2015]. Therefore, aggressive feeding measures are often required, but there must be careful monitoring to avoid too rapid a rate of postnatal weight catch up, which has been associated with subsequent increased metabolic risk.

Recommended strategies include:

• Use of nutritional and caloric supplements;
• Treatment of gastroesophageal reflux with appropriate medications, including proton pump inhibitors and H-2 histamine blockers;
• Speech or occupational therapy for oral motor problems and feeding aversion;
• The use of cyproheptadine, an appetite stimulant which has been shown to have a positive effect on weight and growth velocity [Lemoine et al 2018];
• Use of enteral feeding with gastrostomy or jejunostomy to address extreme cases of feeding aversion and/or gastroesophageal reflux with or without fundoplication limited to extreme cases where other measures have been unsuccessful [Wakeling et al 2017]. With non-volitional feeding, too rapid and excessive weight gain must be avoided.

Skeletal abnormalities. The most common orthopedic problem is limb length discrepancy, which often can be several centimeters and involve upper and/or lower extremities. Functionally, this is most significant for lower extremity asymmetry because of the impact on gait. Lower limb length discrepancy exceeding 2 cm can lead to compensatory scoliosis and thus requires intervention. Initial treatment can include the use of a shoe lift. In older children, limb lengthening with distraction osteogenesis has become a more widely applied procedure. When single segment limb lengthening is sufficient, the limb lengthening is generally done prior to completion of growth but close to final height with femoral internal distracters [Goldman et al 2013]. For young children with leg length discrepancy greater than 4 cm, lengthening is done in the lower segment (tibia) with external fixators [Goldman et al 2013].

Scoliosis and kyphosis are a common problem in SRS [Yamaguchi et al 2015]. The relationship of lower limb length asymmetry to scoliosis is not clear, but many children with limb length asymmetry will develop a compensatory scoliosis. Treatment with monitoring and bracing initially is indicated. Many individuals will need corrective surgery [Yamaguchi et al 2015].

Neurodevelopment

• For infants with hypotonia, referral to an early-intervention program and physical therapy
• For children with evidence of delay, referral for early intervention, speech and language therapy, and occupational and physical therapy as indicated.
• For school-age children, working with the school system to address learning disabilities through appropriate neuropsychological testing and an individualized educational plan, including therapeutic interventions as indicated
• Referral for psychological counseling as needed to address psychosocial and body image issues

Craniofacial anomalies. For those children with severe micrognathia, cleft palate, or complex dental relationships, management by a multidisciplinary cleft palate and craniofacial team is recommended. Early dental care, orthodontia for dental crowding, and maxillofacial surgery may be needed for older children once growth is completed.

Otherwise, dental hygiene and dental crowding can be appropriately managed in a routine manner by pediatric dentists and orthodontists.

Genitourinary abnormalities. Cryptorchidism and hypospadias is best managed by a pediatric urologist.

Males with micropenis and females with internal genitourinary anomalies (some are born with Mayer-Rokitansky-Kuster-Hauser syndrome) benefit from referral to a multidisciplinary disorders of sex development (DSD) center.

Surveillance

Monitoring guidelines of children with SRS has been well outlined in the international consensus statement for diagnosis and management of SRS [Wakeling et al 2017].

The following are appropriate:

• Monitoring of growth with special attention to growth velocity and excessive weight gain
• Monitoring of urine ketones and blood glucose for ketotic hypoglycemia is of major importance especially in infancy and in older children with a large head circumference, lean body habitus, and poor appetite. Monitoring urine ketones to prevent hypoglycemia should be peformed in infants when frequency of feeding is being reduced, in all children who are acutely ill with decreased feeding or have fevers, and in older children at times of increased physical activity.
• At each well-child visit in early childhood, examination and measurement of limb length discrepancy. Infant lengths should be measured for both legs, both lengths recorded, and the longer entered on a growth curve. For measuring height in older children, an appropriate-sized lift sufficient to level the hips should be placed under the foot of the shorter lower extremity.
• Examination for presence or scoliosis at each visit
• Monitoring for early and aggressive adrenarche and early onset of central puberty because of the risk of rapid bone age advancement and reduced final height despite a long course of GH therapy
• Close monitoring for developmental delays, especially motor and speech and language development

Agents/Circumstances to Avoid

Avoid prolonged fasting in infants and young children because of the risk for hypoglycemia.

Avoid elective surgery whenever possible. If surgery is unavoidable, physicians must be aware of the risk for hypoglycemia, hypothermia, difficult healing, and difficult intubation (due to abnormal tooth distribution and small mandible, which affect airway visualization and intubation process).

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

In most families, a proband with Silver-Russell syndrome (SRS) represents a simplex case (a single affected family member) and has SRS as the result of an apparent de novo epigenetic or genetic alteration (e.g., loss of paternal methylation at the H19/IGF2 imprinting center 1 or maternal uniparental disomy for chromosome 7). SRS may also occur as the result of a genetic alteration associated with an up to 50% recurrence risk (e.g., a copy number variant on chromosome 7 or 11 or an intragenic pathogenic variant in CDKN1C, IGF2, PLAG2, or HMGA2) depending on the nature of the genetic alteration and the sex of the transmitting parent. Accurate assessment of SRS recurrence therefore requires identification of the causative genetic mechanism in the proband.

Risk to Family Members

Related Genetic Counseling Issues

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Loss of paternal methylation at the 11p1.5 ICR1 H19/IGF2 regions. Reliable testing for loss of paternal methylation at the 11p1.5 ICR1 H19/IGF2 regions is not possible, since studies show that differentially methylated regions are not firmly established by the gestational age (10-12 weeks) at which chorionic villus sampling (CVS) is performed [Paganini et al 2015]. Additionally, there have been no validated studies establishing reliable testing for differential methylation patterns in amniocytes. Since the majority of epigenetic pathogenic variants can be mosaic, reliable prenatal testing becomes even more challenging [Eggermann et al 2016].

Maternal uniparental disomy (UPD). Maternal UPD7 can be diagnosed prenatally. Maternal isodisomy 7 can be diagnosed with SNP chromosomal microarray (CMA). Maternal heterodisomy 7 can be diagnosed by analyzing fetal SNP CMA and comparing it to SNP CMA of both parents.

Chromosome anomalies. If a causative chromosome anomaly (e.g., an unbalanced translocation involving 11p15.5, a paternal microdeletion, or a maternal microduplication of chromosome 11p15.5 including CDKN1C) has been identified in the proband, prenatal testing with SNP CMA on fetal cells obtained by CVS or amniocentesis is possible. Preimplantation genetic testing can also be offered with a known chromosome anomaly depending on the size of the duplication or deletion.

Intragenic pathogenic variants. A known familial maternally inherited CDKN1C pathogenic variant, paternally inherited IGF2 pathogenic variant, or parental pathogenic variant in PLAG1 or HMGA2 can be diagnosed using preimplantation genetic testing or prenatally with samples obtained from CVS or amniocentesis [Eggermann et al 2016, Abi Habib et al 2018].

Note: The preimplantation genetic diagnosis or prenatal finding of a genetic alteration consistent with SRS cannot be used to reliably predict clinical outcome [Eggermann et al 2016]: children with SRS demonstrate varying responses to growth hormone, variable late catch-up growth, and variable developmental outcomes.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Chromosome 11p15.5-Related Silver-Russell Syndrome (SRS)

The importance of imprinted genes at chromosome 11p15.5 for fetal growth is known [DeChiara et al 1990, Fitzpatrick et al 2002, Eggermann et al 2009].

Imprinted genes often occur in clusters that include a regulatory imprinting control region (ICR). At one of the 11p15.5 imprinted clusters, parent-specific differential methylation of imprinting control region 1 (ICR1) regulates reciprocal expression of IGF2 – which encodes a growth factor crucial for fetal development – and H19, a noncoding transcript. In SRS, hypomethylation of ICR1 leads to biallelic H19 expression and biallelic silencing of IGF2, resulting in growth restriction, and accounts for approximately 30%-60% of affected individuals [Gicquel et al 2005, Abu-Amero et al 2010, Wakeling et al 2017].

See Figure 2 for a diagram of the molecular changes associated with 11p15.5-related Silver-Russell syndrome. Note that ICR1 is also known as H19/IGF2 IG-DMR (intergenic differentially methylated region).

Figure 2.

Paternal hypomethylation of H19/IGF2 IG-DMR results in loss of paternal IGF2 expression and gain of maternal H19 expression, which leads to a growth restriction phenotype [Gicquel et al 2005, Wakeling et al 2017]. Rarely, maternal duplication of the centromeric (more...)

Abnormal methylation at 11p15.5 can occur through several mechanisms:

• Hypomethylation at ICR1 on the paternal chromosome is detected in 30%-60% of individuals with SRS. Because ICR1 regulates methylation of IGF2 and H19, differential analysis showed that in most cases both of these genes are hypomethylated.
  Note: (1) Because 11p15.5 hypomethylation at the paternal ICR1 is usually a postzygotic event, most individuals with SRS have a somatic distribution of abnormal methylation patterns (see Table 1 for testing implications). About 1% of the individuals with 11p15.5 ICR1 hypomethylation have a deletion of part of the ICR1. In these rare cases, there is a genetic cause identified for this epigenetic anomaly [Abi Habib et al 2017]. (2) A small number of individuals with SRS have selective hypomethylation of only H19 or only IGF2 [Bartholdi et al 2009].
• A small number of individuals with SRS have a duplication involving the maternal 11p15.5 region. Larger duplications, which can involve translocations and inversions, are detectable by cytogenetic analysis [Fisher et al 2002, Eggermann et al 2005], and microdeletions and duplications are detectable by SNP microarray [Begemann et al 2012, Eggermann et al 2012] (Table 1).
• Rare familial cases of SRS have been reported with underlying mechanisms including:
  • Maternally inherited 11p15 duplication;
  • Maternal inherited CDKN1C gain‑of-function pathogenic variants;
  • Paternally inherited IGF2 loss‑of‑function variants;
  • 11p15.5 ICR1 small deletions.
  In these families, the risk of recurrence can be as high as 50%. Investigation for underlying CNVs in individuals with 11p15.5 loss of methylation is, therefore, important [Abi Habib et al 2017, Wakeling et al 2017, Heide et al 2018].

Published Guidelines / Consensus Statements

• American College of Medical Genetics Statement on diagnostic testing for uniparental disomy. Available online. 2001. Accessed 10-7-21. [PMC free article: PMC3111049] [PubMed: 11388763]
• Eggermann K, Bliek J, Brioude F, Algar E, Buiting K, Russo S, Tümer Z, Monk D, Moore G, Antoniadi T, Macdonald F, Netchine I, Lombardi P, Soellner L, Begemann M, Prawitt D, Maher ER, Mannens M, Riccio A, Weksberg R, Lapunzina P, Grønskov K, Mackay DJ, Eggermann T. EMQN best practice guidelines for the molecular genetic testing and reporting of chromosome 11p15 imprinting disorders: Silver-Russell and Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2016;24:1377–87. [PMC free article: PMC5027690] [PubMed: 27165005]
• Eggermann T, Brioude F, Russo S, Lombardi MP, Bliek J, Maher ER, Larizza L, Prawitt D, Netchine I, Gonzales M, Grønskov K, Tümer Z, Monk D, Mannens M, Chrzanowska K, Walasek MK, Begemann M, Soellner L, Eggermann K, Tenorio J, Nevado J, Moore GE, Mackay DJ, Temple K, Gillessen-Kaesbach G, Ogata T, Weksberg R, Algar E, Lapunzina P. Prenatal molecular testing for Beckwith-Wiedemann and Silver-Russell syndromes: a challenge for molecular analysis and genetic counseling. Eur J Hum Genet. 2016;24:784–93. [PMC free article: PMC4867462] [PubMed: 26508573]
• Wakeling EL, Brioude F, Lokulo-Sodipe O, O'Connell SM, Salem J, Bliek J, Canton AP, Chrzanowska KH, Davies JH, Dias RP, Dubern B, Elbracht M, Giabicani E, Grimberg A, Grønskov K, Hokken-Koelega AC, Jorge AA, Kagami M, Linglart A, Maghnie M, Mohnike K, Monk D, Moore GE, Murray PG, Ogata T, Petit IO, Russo S, Said E, Toumba M, Tümer Z, Binder G, Eggermann T, Harbison MD, Temple IK, Mackay DJ, Netchine I. Diagnosis and management of Silver-Russell syndrome: first international consensus statement. Nat Rev Endocrinol. 2017;13:105–24. [PubMed: 27585961]

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Revision History

• 21 October 2019 (ha) Comprehensive update posted live
• 2 June 2011 (me) Comprehensive update posted live
• 9 March 2007 (hs) Revision: methylation analysis for H19 clinically available
• 7 September 2006 (me) Comprehensive update posted live
• 5 March 2004 (me) Comprehensive update posted live
• 2 November 2001 (me) Review posted live
• February 2001 (hs) Original submission