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 gender 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 at the most reasonable cost 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].