Clinical characteristics.

Silver-Russell Syndrome (SRS) is typically characterized by gestational growth restriction resulting in affected individuals being born small for gestational age, with relative macrocephaly at birth (head circumference ≥1.5 standard deviations [SD] above birth weight and/or length), prominent forehead with frontal bossing, and frequently body asymmetry. This is typically 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, growth failure is proportionate and head growth typically 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 imprinting control region 1 (ICR1) at 11p15.5 causes SRS in 35%-67% of individuals, and maternal uniparental disomy of chromosome 7 (upd(7)mat) 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 30%-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, including early referral to an endocrinologist. Treatment may include growth hormone therapy. Hypoglycemia should be prevented or aggressively managed. Strategies for feeding issues include nutritional and caloric supplementation, medication for gastroesophageal reflux, therapy for oral motor problems and oral aversion, cyproheptadine for appetite stimulation, and enteral tube feeding as needed. Lower limb length discrepancy exceeding 2 cm requires intervention. In the majority of affected older children, distraction osteogenesis is recommended. 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 a referral to a multidisciplinary disorders of sex development (DSD) center. Physical, occupational, speech, and language therapy with an individualized education plan are used to treat developmental delays. Psychological counseling can be used as needed to address psychosocial and body image issues.

Surveillance: Monitoring of growth velocity, blood glucose concentration, and urine ketones for hypoglycemia in infants and as needed in older children; evaluation of nutritional status and oral intake at each visit as well as managing tube feedings if needed; limb length assessment at each well child visit in early childhood for evidence of asymmetric growth; evaluation for scoliosis, signs of precocious puberty, genitourinary issues, dental crowding and malocclusion, and speech-language development at each visit.

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.

Risk to family members: In most families, a proband with SRS represents a simplex case (a single affected family member) and has SRS as a result of an apparent de novo epigenetic or genetic alteration. While the majority of families are presumed to have a very low recurrence risk, SRS can occur as the result of a genetic alteration associated with up to a 50% recurrence risk depending on the nature of the genetic alteration and the sex of the transmitting parent. Rare familial cases of SRS have been reported with several underlying mechanisms, including maternally inherited 11p15 duplications, maternally inherited CDKN1C gain-of-function pathogenic variants, paternally inherited IGF2 loss-of-function pathogenic variants, paternally inherited small deletions close to the boundaries of the ICR1, and paternally or maternally inherited deletions and intragenic pathogenic variants involving PLAG1 or HMGA2. Reliable SRS recurrence risk assessment therefore requires identification of the causative genetic mechanism in the proband.

Prenatal testing: Reliable prenatal testing for loss of paternal methylation at the 11p1.5 ICR1 H19/IGF2 region is not possible. Prenatal testing for the following SRS-related genetic mechanisms is possible provided the genetic mechanism has been demonstrated to be causative in an affected family member: upd(7)mat, SRS-related chromosomal abnormalities, intragenic CDKN1C, IGF2, HMGA2, or PLAG1 pathogenic variants, and deletions involving HMGA2 or PLAG1. The prenatal finding of a genetic alteration consistent with SRS cannot be used to reliably predict clinical outcome because children with SRS demonstrate varying responses to growth hormone, variable late catch-up growth, and variable developmental outcomes.

Suggestive Findings

SRS should be suspected in a proband with at least four of the following NH-CSS clinical criteria [Azzi et al 2015]:

• Small for gestational age (birth weight and/or length two or more standard deviations [SD] below the mean for gestational age)
• Postnatal growth failure (length/height two or more SD below the mean for age and sex at age 24 months)
• Relative macrocephaly at birth (head circumference more than 1.5 SD above birth weight and/or length)
• Frontal bossing or prominent forehead (forehead projecting beyond the facial plane on a side view at age one to three 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 two or more SD below the mean at age two years, or current use of a feeding tube or cyproheptadine for appetite stimulation

Rarely, individuals meeting three of the six criteria have had positive molecular confirmation of SRS.

Establishing the Diagnosis

The clinical diagnosis of SRS can be established in a proband based on clinical diagnostic criteria [Azzi et al 2015], or the molecular diagnosis can be established in a proband with suggestive findings and abnormal molecular genetic testing consistent with one of several molecular mechanisms (see Table 1 and Molecular Pathogenesis).

Note: Molecular genetic testing is recommended in all individuals with suspected SRS to provide accurate recurrence risk information.

Molecular Diagnosis

The molecular diagnosis of SRS can be established in a proband with one of the following identified on molecular genetic testing (see Table 1 and Molecular Pathogenesis):

• Abnormal methylation of chromosome 11p15.5. 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).
• Maternal uniparental disomy of chromosome 7 (upd(7)mat), which can occur by different mechanisms (see Molecular Pathogenesis).
• Pathogenic gain-of-function variants in CDKN1C
• Pathogenic loss-of-function variants in IGF2, PLAG1, or HMGA2

An international expert consensus algorithm for the molecular investigation of SRS has been published [Wakeling et al 2017], including first-tier, second-tier, and other molecular diagnostic testing approaches (see Figure 1). Third-tier testing using comprehensive genomic approaches has been proposed by the authors of this GeneReview and adapted from Wakeling et al [2017].

Figure 1.

Flowchart for investigation and diagnosis of Silver-Russell syndrome Adapted from Wakeling et al [2017]

• First-tier testing. Methylation analysis of 11p15.5 imprinting control regions (ICR1/ICR2) and upd(7)mat studies performed simultaneously.
  Note: (1) Detection of an abnormality is dependent on the mechanism of disease and testing methodology used (see Table 1). (2) Mosaicism has been reported; therefore, testing alternative tissues (e.g., buccal cells or skin fibroblasts) should be considered if testing of peripheral blood is normal.
• Second-tier testing. If methylation analysis of 11p15.5 ICR1/ICR2 and upd(7)mat 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 various multigene panels 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.
• Other testing options
  • SNP chromosomal microarray (CMA). Some individuals ultimately diagnosed with SRS will have a SNP CMA due to their significant growth abnormalities at birth or later or based on speech or other developmental delays. While this is not a first- or second-tier testing recommendation for individuals suspected to have SRS, CMA will identify chromosomal deletions, duplications, or isodisomy, including of chromosomes 7 or 11, that may establish the diagnosis of SRS (see Table 1).
  • Methylation analysis of chromosomes 11 and 16 to detect SRS due to upd(11)mat and upd(16)mat (see Differential Diagnosis). Methylation analysis of chromosomes 11 and 16 should be considered in individuals with clinical features of SRS who do not have hypomethylation of 11p15.5 ICR1/ICR2 or upd(7)mat [Luk et al 2016a, Pignata et al 2021].
• Third-tier testing. When the diagnosis of SRS is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Silver-Russell Syndrome

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Method	Pathogenic Variants/Alterations Detected		Proportion of SRS Alterations Detected 1
Methylation analysis 2	Chr 11	Loss of methylation at H19/IGF2 (paternal) 3	~35%-67% 4
		Somatic mosaicism for upd(11)mat 5, 6	Rare
		Duplication of 11p15.5 (maternal)	Unknown 7, 8
	Chr 7	upd(7)mat 9	~7%-10% 10
		Deletions, duplications, mosaic trisomy 7	Rare 11
Chromosomal microarray analysis (SNP based)	Chr 11	Duplication of 11p15.5 (maternal)	Unknown 7, 8
		Somatic mosaicism for upd(11)mat 5, 6	Rare 12
	Chr 7	Deletions, duplications of 7p, mosaic trisomy 7	Rare 11, 13, 14
		upd(7)mat	Maternal isodisomy 7 only 15
STR marker analysis	Chr 11	Somatic mosaicism for upd(11)mat 5, 6	Rare
	Chr 7	upd(7)mat 9, maternal mosaic trisomy 7	~7%-10% 10
Karyotype	Inversion or translocation of 11p15.5		Rare 5, 6
Sequence analysis 16 / gene-targeted deletion/ duplication analysis 17	CDKN1C (maternal transmission)		Rare 18
	IGF2 (paternal transmission)		Rare 19
	PLAG1		Rare 20
	HMGA2		Rare 21
Unknown			30%-40% 22

chr = chromosome; SNP = single-nucleotide polymorphisms; STR = short tandem repeat; upd(7)mat = maternal uniparental disomy of chromosome 7; upd(11)mat = maternal uniparental disomy of chromosome 11

1.

See Molecular Genetics for information on variants/alterations detected.

2.

Assays developed to be methylation sensitive such as multiplex ligation probe analysis (MS-MLPA), quantitative PCR (MS-qPCR), or Southern blotting (mainly historical testing) allow detection of epigenetic and genomic alterations of 11p15.5. Methylation-sensitive assays can diagnose SRS resulting from DNA methylation alterations, deletions, and duplications, or uniparental disomy (UPD). Interpretation of methylation data should consider results of copy number testing because copy number variants that alter the relative dosage of parental contributions (e.g., paternal duplication) are associated with abnormal methylation status. Note that MLPA testing may be followed by microarray testing to define breakpoints of deletions or duplications. Other methods to confirm maternal UPD at 11p15.5 include short tandem repeat (STR) analysis or SNP analysis [Keren et al 2013].

3.

A small number of individuals have hypomethylation of only H19 or IGF2 [Bartholdi et al 2009].

4.

False negatives may occur because of mosaicism as 11p15.5 hypomethylation occurs post fertilization. Testing tissues from a second source (e.g., buccal cells or fibroblasts) should be performed.

5.

Bullman et al [2008]

6.

Luk et al [2016a]

7.

Fisher et al [2002], Eggermann et al [2005], Schönherr et al [2007]

8.

Heide et al [2018]

9.

Both isodisomy and heterodisomy [Bernard et al 1999, Price et al 1999] as well as segmental maternal UPD [Hannula et al 2001, Eggermann 2008] have been reported. Mosaicism has been observed in cases of upd(7)mat and other chromosome 7 rearrangements; therefore, testing of an alternate tissue source may be appropriate [Reboul et al 2006]. Prenatal diagnosis of mosaic trisomy 7 was confirmed postnatally by microsatellite analysis [Abdelhedi et al 2014].

10.

Hannula et al [2001], Kim et al [2005], Abu Amero et al [2008], Eggermann et al [2012b]

11.

Courtens et al [2005], Flori et al [2005], Font-Montgomery et al [2005]

12.

Luk et al [2016b] described one group of 28 individuals with SRS, of which 3.6% who had mosaic upd(11)mat.

13.

A de novo duplication of 7p11.2-p13 on the maternal allele containing GRB10, GFBP1, and GFBP3 has been reported [Monk et al 2000].

14.

A de novo deletion of 7q32.2 on the paternal allele including MEST has been reported [Carrera et al 2016]. Further, a small paternally inherited 79-kb deletion of 7q32.2 was detected involving MEST in an individual with SRS [Vincent et al 2022].

15.

Note: SNP array analysis will detect maternal UPD only in those with isodisomy; 28.8% of upd(7)mat (2%-3% of all individuals with SRS) are a result of isodisomy [Chantot-Bastaraud et al 2017].

16.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, partial-, whole-, or multigene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

17.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

18.

Several reports, including one four-generation family segregating a CDKN1C gain-of-function pathogenic variant [Brioude et al 2013, Sabir et al 2019, Binder et al 2020, Li et al 2023]. In all reported familial cases to date, there was a maternally inherited substitution of arginine at amino acid 279 (p.Arg279).

19.

One family with SRS and a paternally transmitted IGF2 loss-of-function variant has been reported by Begemann et al [2015], and a few others have been reviewed by Tümer et al [2018]. Several individuals with IGF2 pathogenic variants have been reported [Masunaga et al 2020].

20.

Heterozygous loss-of-function PLAG1 variants were identified in affected individuals from two families and one additional individual [Abi Habib et al 2018, Inoue et al 2020].

21.

Heterozygous loss-of-function HMGA2 variants were identified in two individuals [Abi Habib et al 2018, Hübner et al 2020].

22.

Approximately 40% of individuals with at least four of the six Netchine-Harbison clinical diagnostic criteria will have nondiagnostic laboratory studies.

Clinical Description

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

To date, more than 1,000 individuals have been diagnosed with SRS [Wollmann et al 1995, Wakeling et al 2017, Fuke et al 2021, Lokulo-Sodipe et al 2022, Mackay et al 2022]. The following description of the phenotypic features associated with this condition is based on these reports.

Growth. The earliest manifestation of SRS is abnormal growth. Most children are born small for gestational age with birth weight and/or length two or more 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 affected children remain two or more SD below the mean for length unless parents are tall.

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 limb length asymmetry, 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 SRS [Saal et al 1985].

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.

Growth and use of growth hormone (GH). 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.

The goals of GH treatment are multifaceted, including improving growth velocity, body composition (especially lean body mass), psychomotor development, and appetite, as well as reducing the risk of hypoglycemia and optimizing overall linear growth [Wakeling et al 2017]. GH therapy in children with intrauterine growth restriction of all causes has been shown to significantly improve growth and final height, especially in 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 GH supplementation [Toumba et al 2010, Binder et al 2013], although final heights were less in individuals with SRS because their heights were lower at the initiation of treatment [Smeets et al 2016].

Note: Many children with SRS do not achieve normal stature even with administration of human GH if rapid bone age advancement during puberty is not managed (see Management).

GH deficiency. Treatment with human GH is necessary in the presence of documented GH deficiency. However, GH deficiency is not common in SRS [Wakeling et al 2017].

• Testing for GH deficiency by fasting is contraindicated because of the risk for inducing hypoglycemia [Wakeling et al 2017].
• Treatment with GH in SRS is indicated regardless of the presence or absence of GH deficiency.

Feeding disorders and hypoglycemia. Children with SRS have little subcutaneous fat and often have a poor appetite, oral motor issues, and feeding disorders [Fuke et al 2013]. They are at risk for hypoglycemia, especially associated with prolonged fasting [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 difficulties; reduced body mass; and, in several children, GH deficiency [Azcona & Stanhope 2005]. While most children had clinical symptoms of hypoglycemia, including diaphoresis, several were asymptomatic.

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

Gastrointestinal disorders should be treated early and adequately. It is critical that attention to growth and nutrition begin in infancy. Aggressive feeding measures are often required, including use of nasogastric tubes or, less frequently, gastrostomy tube placement (see Management).

Skeletal abnormalities include the following:

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

Bone age advancement and puberty. Monitoring for signs of premature adrenarche, early and accelerated central puberty, and insulin resistance is very important in individuals with SRS. Personalized treatment with gonadotropin-releasing hormone (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] (see Management).

Craniofacial anomalies are common. Some individuals with SRS have Pierre Robin sequence and cleft palate. Wakeling et al [2010] found cleft palate or bifid uvula, which is often associated with submucous cleft palate, in 7% of those with 11p15.5 methylation defects and none in individuals with upd(7)mat. Individuals with suspected Pierre Robin sequence should be monitored for obstructive apnea.

Dental and oral abnormalities are common. Microdontia, high-arched palate, and dental crowding secondary to 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 manifestations [Hodge et al 2015]. Poor oral hygiene in the presence of dental crowding can lead to increased risk for dental caries.

Neurodevelopment. Children with SRS are at increased risk for developmental delays including motor, cognitive, and speech delays as well as learning disabilities.

In a review of a large cohort of children with SRS with either 11p15 methylation defects or upd(7)mat, developmental delay was seen in 34% of individuals; the majority had mild delays. Developmental delays were more commonly seen in those with maternal upd(7)mat than those with 11p15 methylation defects (65% vs 20%). Speech delays were common in both groups [Wakeling et al 2010].

A study surveying adults with SRS reported that 64.5% had motor delays and 38.7% had speech delay, with most of the subjects having attended mainstream education and 21.2% receiving special education support. For individuals older than 21 years, 40% obtained university degrees [Lokulo-Sodipe et al 2020]. In a study looking at executive function in adolescents and adults with SRS, mean full scale IQ studies were normal for individuals with SRS due to 11p15 loss or methylation and upd(7)mat (IQs were 101.75 and 101.00, respectively) and equivalent to controls [Burgevin et al 2023]. Further studies of individuals with molecularly confirmed SRS and early medical management are needed to provide a more accurate cognitive prognosis.

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 and include patent ductus arteriosus, ventricular septal defects, tetralogy of Fallot, and total anomalous pulmonary venous return [Wakeling et al 2010, Ghanim et al 2013]. Routine cardiovascular evaluation is not needed unless clinically indicated.

Genotype-Phenotype Correlations

Several genotype-phenotype correlations have been observed in individuals with SRS.

Using methylation-sensitive restriction enzymes to measure the degree of methylation of H19 within the 11p15.5 region, Bruce et al [2009] developed a scale of extreme H19 hypomethylation, moderate H19 hypomethylation, normal H19 methylation, and upd(7)mat (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 upd(7)mat.

A study by Wakeling et al [2010] compared clinical features of children with SRS caused by 11p15.5 imprinting control region 1 (ICR1) IGF2/H19 methylation defects to those with maternal upd(7)mat. They found that fifth finger clinodactyly and congenital anomalies including cleft palate, congenital heart defects, genital anomalies in males, and renal anomalies were more frequent in children with 11p15.5 ICR1 hypomethylation than those with upd(7)mat, whereas learning difficulties and speech disorders were more frequent in children with upd(7)mat than ICR1 hypomethylation.

In another study, children with SRS due to upd(7)mat attained more linear growth (or height) with GH therapy compared to children with 11p15.5 ICR1 hypomethylation, possibly because children with 11p15.5 methylation abnormalities showed elevated levels of insulin-like growth factor 1 (IGF-1, the product of IGF1) and therefore a degree of IGF-1 resistance. Children with SRS due to upd(7)mat had IGF-1 response patterns similar to other children who were small for gestational age and did not have SRS [Binder et al 2008].

A series of children with SRS with 11p15.5 loss of methylation (LOM), upd(7)mat, and SRS with no identified epigenetic or genetic variants showed genotype-phenotype correlations comparable to children with SRS reported in earlier publications. There were more individuals who were small for gestational age in the 11p15.5 LOM group and SRS group with no identified epigenetic/genetic etiology compared to those with upd(7)mat. Triangular face and frontal bossing were more common in individuals with 11p15.5 LOM and no epigenetic/genetic etiology cases compared to those with upd(7)mat. Facial and limb asymmetry were more common in individuals with 11p15.5 LOM compared to the upd(7)mat and SRS with no epigenetic/genetic abnormalities groups [Luk et al 2016b].

Another study comparing individuals with SRS due to 11p15.5 LOM to individuals with SRS due to upd(7)mat showed similar body weight at diagnosis (3 and 3.2 SD below the mean, respectively), but heights were greater in individuals with 11p15.5 LOM (3.0 SD below the mean) compared to those with upd(7)mat (3.8 SD below the mean). Asymmetry was seen in 76% of individuals with 11p15.5 LOM vs 50% of individuals with upd(7)mat. Most cases in both groups had normal neurocognitive development (86% of individuals with 11p15.5 LOM and 80% of individuals with upd(7)mat). Triangular facies were reported in 89% of individuals with 11p15.5 LOM vs 50% of those with upd(7)mat. Also of note, clinodactyly was more frequently reported in individuals with 11p11.5 LOM (68%) compared to those with upd(7)mat (20%). Genital anomalies were seen in 19% of individuals with 11p15.5 LOM and none of the individuals with upd(7)mat [Lin et al 2021].

Penetrance

Penetrance for SRS is estimated to be 100% for males and females. Sex-limited penetrance is observed in individuals with CDKN1C- or IGF2-related SRS.

Prevalence

The prevalence of SRS is unknown and was previously estimated at 1:30,000-100,000 (A Toutain, Orphanet). A 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 and needs in an individual diagnosed with SRS, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for SRS. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists including an endocrinologist, gastroenterologist, dietician, clinical geneticist and genetic counselor, craniofacial team, orthopedic surgeon, neurologist, speech-language therapist, and psychologist (see Table 6).

Surveillance

Surveillance guidelines for children with SRS are outlined in Wakeling et al [2017].

Agents/Circumstances to Avoid

Avoid prolonged fasting in infants and young children because of the risk of inducing hypoglycemia. For this reason, testing for GH deficiency by fasting is contraindicated [Wakeling et al 2017].

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 micrognathia, which can affect airway visualization and the 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

The following recurrence risk information pertains to individuals who have Silver-Russell syndrome (SRS) without other imprinting disorders, such as multilocus imprinting disturbances (MLID) (see Differential Diagnosis for more information on MLID).

In most families, a proband with SRS represents a simplex case (a single affected family member) and has SRS as a result of an apparent de novo epigenetic or genetic alteration. While the majority of families are presumed to have a very low recurrence risk, SRS can occur as the result of a predisposing genetic alteration associated with up to a 50% recurrence risk depending on the nature of the genetic alteration and the sex of the transmitting parent. Reliable SRS recurrence risk assessment therefore requires identification of the causative genetic mechanism in the proband.

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). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Loss of paternal methylation at the 11p1.5 ICR1 H19/IGF2 regions. Reliable prenatal testing for loss of paternal methylation at the 11p1.5 ICR1 H19/IGF2 region is not possible, since studies show that differentially methylated regions are not firmly established by the gestational age at which chorionic villus sampling (CVS) is performed (10-12 weeks' gestation) [Paganini et al 2015]. Additionally, there are 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(7)mat can be diagnosed prenatally. Maternal isodisomy 7 can be diagnosed with a SNP CMA. Maternal heterodisomy 7 can be diagnosed by analyzing fetal SNP CMA and comparing it to SNP CMA of both parents.

Chromosomal abnormalities. If a causative chromosomal abnormality (e.g., an unbalanced translocation involving 11p15.5, a paternal deletion, or a maternal duplication of chromosome 11p15.5 including CDKN1C) or a maternal duplication or paternal deletion involving 7q32.2 that includes MEST 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 CDKN1C, IGF2, HMGA2, or PLAG1 pathogenic variant or deletion involving HMGA2 or PLAG1. A known maternally inherited CDKN1C gain-of-function pathogenic variant, paternally inherited IGF2 loss‑of‑function pathogenic variant, or parental intragenic pathogenic variant or deletion involving HMGA2 or PLAG1 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)

Imprinted genes often occur in clusters that include a regulatory imprinting control region (ICR). 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]. 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 the noncoding transcript H19. In SRS, hypomethylation of the ICR1 leads to biallelic H19 expression and biallelic silencing of IGF2, resulting in growth restriction; this accounts for approximately 35%-67% of affected individuals [Gicquel et al 2005, Abu-Amero et al 2010, Wakeling et al 2017].

See Figure 2 for an outline of the molecular changes associated with 11p15.5-related SRS.

Figure 2.

Paternal hypomethylation of the imprinting control region 1 (ICR1; also called H19/IGF2 IG-DMR, or intergenic differentially methylated region) results in loss of paternal IGF2 expression and gain of maternal H19 expression, which leads to a growth restriction (more...)

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

• Hypomethylation at the ICR1 on the paternal chromosome is detected in 35%-67% of individuals with SRS. Because the ICR1 regulates methylation of IGF2 and H19, differential analysis showed that in most cases both 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 close to the boundaries of the ICR1 on the paternal allele [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 deletions and duplications are detectable by SNP microarray [Begemann et al 2012, Eggermann et al 2012a] (see Table 1).
• Rare familial cases of SRS have been reported with underlying mechanisms including the following:
  • Maternally inherited 11p15 duplication
  • Maternally inherited CDKN1C gain‑of-function pathogenic variants
  • Paternally inherited IGF2 loss‑of‑function pathogenic variants
  • Small paternally inherited deletions adjacent to the 11p15.5 ICR1.

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].

Author Notes

Howard M Saal, MD, FACMG, is Director of Clinical Genetics at Cincinnati Children's Hospital Medical Center. He directs the Cleft and Craniofacial Center and the Skeletal Dysplasia Clinic. Dr Saal is actively involved in clinical research regarding individuals with growth disorders, skeletal dysplasias, bone mineralization disorders, and orofacial cleft and craniofacial disorders. He is happy to communicate with persons who have any questions regarding the diagnosis of Silver-Russell syndrome or other related considerations. He can be contacted at gro.cmhcc@laas.drawoh.

Revision History

• 9 May 2024 (gm) Comprehensive update posted live
• 21 October 2019 (ha) Comprehensive update posted live
• 2 June 2011 (me) Comprehensive update posted live
• 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

Published Guidelines / Consensus Statements

• American College of Medical Genetics Statement on diagnostic testing for uniparental disomy. Available online. 2001. Accessed 10-7-21.
• 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. [PubMed]
• 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. [PubMed]
• 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]

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