Diagnosis and management of Silver–Russell syndrome: first international consensus statement

Journal name:
Nature Reviews Endocrinology
Volume:
13,
Pages:
105–124
Year published:
DOI:
doi:10.1038/nrendo.2016.138
Published online

Abstract

This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver–Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited. SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype. A 'normal' result from a molecular test does not exclude the diagnosis of SRS. The management of children with SRS requires an experienced, multidisciplinary approach. Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges. An early emphasis on adequate nutritional status is important, with awareness that rapid postnatal weight gain might lead to subsequent increased risk of metabolic disorders. The benefits of treating patients with SRS with growth hormone include improved body composition, motor development and appetite, reduced risk of hypoglycaemia and increased height. Clinicians should be aware of possible premature adrenarche, fairly early and rapid central puberty and insulin resistance. Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential. Long-term follow up is essential to determine the natural history and optimal management in adulthood.

At a glance

Figures

  1. Flow chart for investigation and diagnosis of SRS.
    Figure 1: Flow chart for investigation and diagnosis of SRS.

    Diagnostic questions are in blue boxes; recommended molecular tests are in beige boxes. Pink boxes: diagnosis not confirmed; green boxes: diagnosis of SRS confirmed. *Studies have excluded 11p15 LOM and upd(7)mat in patients with intrauterine growth retardation and postnatal growth retardation alone; some patients, particularly those with upd(7)mat or children under 2 years, score 3/6 (see text for details). Arrange CNV analysis before other investigations if patient has notable unexplained global developmental delay and/or intellectual disability and/or relative microcephaly. §Insufficient evidence at present to determine relationship to SRS, with the exception of tissue mosaicism for 11p15 LOM. ||Unless evidence of catch-up growth by 2 years. Previously known as idiopathic SRS. CNV, copy number variant; LOM, loss of methylation; NH-CSS, Netchine-Harbison clinical scoring system; SRS, Silver–Russell syndrome.

  2. The imprinted domains of chromosome 11p15 that are implicated in Silver-Russell syndrome.
    Figure 2: The imprinted domains of chromosome 11p15 that are implicated in Silver–Russell syndrome.

    a | Representation of the 11p15 region, showing both centromeric and telomeric domains. Only the imprinted genes that are implicated in the pathophysiology of Silver–Russell syndrome are represented. Blue boxes indicate paternally expressed genes (the growth promoter IGF2 and the long noncoding RNA (lncRNA) KCNQ1OT1). Red boxes indicate maternally expressed genes (the growth inhibitor CDKN1C, the ion channel KCNQ1 and the noncoding RNA H19). Ovals indicate differentially methylated regions (DMRs). Dark grey ovals indicate methylated DMRs. Beige ovals indicate unmethylated DMRs. b | Structure of the H19/IGF2 IG-DMR (intergenic differentially methylated region). This DMR contains short repetitive blocks of sequence and harbours seven binding sites for the zinc finger protein CTCF (green circles). Multiple enhancer elements (grey hexagons) distal to H19 are shared between H19 and IGF2, and are able to increase expression of either. Binding of CTCF to the unmethylated maternal DMR blocks interactions between the IGF2 promoter and enhancers downstream of H19, which results in maternal H19 expression. Conversely, methylation of ICR1 on the paternal allele prevents CTCF binding, enabling interaction between the IGF2 promoter and distal enhancers, and thus paternal IGF2 expression162, 163. Beige triangles indicate unmethylated CTCF binding sites. Dark grey triangles indicate methylated CTCF binding sites.

  3. Mutations and epimutations of the imprinted region at chromosome 11p15 associated with Silver-Russell syndrome.
    Figure 3: Mutations and epimutations of the imprinted region at chromosome 11p15 associated with Silver–Russell syndrome.

    The structure of the 11p15 region is represented as in Fig. 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 phenotype9. Less commonly, maternal duplication of the centromeric or both domains results in growth retardation due to increased dosage of CDKN1C; however, smaller copy number variants should be classified with caution due to the complex regulation of the region27. Rare familial cases have been associated with a maternal CDKN1C gain-of-function mutation (green cross)60 or a paternal IGF2 loss-of-function mutation (red cross)61.

Introduction

Silver–Russell syndrome (SRS, OMIM #180860, also known as Russell–Silver syndrome, RSS) is a rare, but well-recognized, condition associated with prenatal and postnatal growth retardation. The syndrome was first described by Silver et al.1 and Russell2, who independently described a subset of children with low birth weight, postnatal short stature, characteristic facial features and body asymmetry. Almost all patients with SRS are born small for gestational age (SGA; Box 1). The aetiology of intrauterine growth retardation and SGA is extremely heterogeneous. Children with SRS can be distinguished from those with idiopathic intrauterine growth retardation or SGA and postnatal growth failure by the presence of other characteristic features, including relative macrocephaly (defined as a head circumference at birth ≥1.5 SD score (SDS) above birth weight and/or length SDS), prominent forehead, body asymmetry and feeding difficulties3, 4, 5, 6.

Box 1: Definitions

Small for gestational age (SGA)

Weight and/or length less than −2 SDS for gestational age at birth, based on accurate anthropometry at birth (including weight, length and head circumference) and reference data from a relevant population106.

Intrauterine growth retardation

Also known as intrauterine growth restriction, this diagnosis is based on at least two ultrasonography measurements at least 2 weeks apart, with fetal weight below the 10th percentile for gestational age. Intrauterine growth retardation might or might not result in a baby born SGA161.

Silver–Russell syndrome (SRS)

A distinct syndromic growth disorder in which prenatal and postnatal growth failure are associated with other characteristic features, including relative macrocephaly at birth, protruding forehead in early life, body asymmetry and substantial feeding difficulties. Almost all children with SRS are born SGA. Postnatal catch-up growth is not seen in the majority of children with SRS.

Globally, estimates of the incidence of SRS range from 1:30,000 to 1:100,000 (Ref. 7). In 2015, a study in Estonia8 estimated an incidence of 1:70,000; however, only molecularly confirmed cases were included, which could have resulted in underdiagnosis. Overall, SRS is probably more common than some previous estimates have suggested, but the exact incidence remains unknown.

An underlying molecular cause can currently be identified in around 60% of patients clinically diagnosed with SRS4. The most common underlying mechanisms are loss of methylation on chromosome 11p15 (11p15 LOM; seen in 30–60% of patients) and maternal uniparental disomy for chromosome 7 (upd(7)mat; seen in ~5–10% of patients)4, 9, 10. However, the molecular aetiology remains unknown in a substantial proportion of patients.

Although considerable overlap exists in the clinical care of individuals born SGA and those with SRS, many management issues are specific to SRS. These include notable feeding difficulties, severe postnatal growth failure with no catch-up, recurrent hypoglycaemia, premature adrenarche, fairly early and rapid central puberty, insulin resistance and body asymmetry. Identification of the molecular cause in many patients has also raised questions about the management of individual molecular subtypes of SRS. As evidence from controlled trials is limited, a consensus meeting was organized to develop guidelines for the diagnosis and management of patients with SRS.

This Consensus Statement was produced on behalf of the COST Action BM1208 (European Network for Human Congenital Imprinting Disorders, http://www.imprinting-disorders.eu), European Society of Pediatric Endocrinology (ESPE), Pediatric Endocrine Society (PES), Asian Pacific Pediatric Endocrine Society (APPES) and Sociedad Latino-Americana de Endocrinología Pediátrica (SLEP).

Methods

41 task force members from 16 countries, chosen for their publication record and expertise in SRS, collaborated to develop this consensus statement. They included paediatric endocrinologists, clinical geneticists, molecular geneticists, a gastroenterologist and five non-voting representatives from a parent support group. Participants included representatives nominated by the council and clinical practice committees from four international paediatric endocrine societies. All participants signed a conflict of interest declaration, and the consensus was supported by academic funding, without pharmaceutical support. A Delphi-like consensus methodology was adopted11. A comprehensive literature search was conducted using PubMed and the search terms “Silver Russell syndrome” and “Russell Silver syndrome”. Additional relevant articles on SGA, differential diagnoses and growth hormone (GH) were also identified by PubMed searches when supplementary information was necessary. A comprehensive review of >600 articles formed the basis of discussion by three working groups. These groups focused on clinical diagnosis (working group 1: E.L.W., J.S., K.H.C., M.E., R.P.D., P.G.M., T.O., E.S., M.T. and I.K.T.), molecular testing (working group 2: F.B., J.B., K.G., M.K., D.M., G.E.M., S.R., Z.T., T.E. and D.J.G.M) and clinical management (working group 3: O.L.-S., S.M.O'C., J.H.D., A.P.M.C., B.D., E.G., A.G., A.C.S.H.-K., A.A.J., A.L., M.M., K.M., I.O.P., G.B., M.D.H. and I.N.), with 10, 10 and 16 members, respectively. Preparations for the consensus took place over 10 months, including two preparatory meetings and regular teleconference discussions between the working group members. At the final consensus meeting, propositions and recommendations were considered by participants and discussed in plenary sessions, enabling reformulation of the recommendations if necessary. Where published data were unavailable or insufficient, experts' clinical experiences and opinions were considered. Finally, all experts voted on the recommendations of each working group using the following system:

  1. Evidence or general agreement allow full agreement with the recommendation
  2. Evidence or general agreement are in favour of the recommendation
  3. Evidence or general agreement are weak for the recommendation
  4. There is not enough evidence or general agreement to agree with the recommendation

Depending on the proportion of votes received, the strength of the recommendation was recorded as follows:

+ 26–49% of the votes

++ 50–69% of the votes

+++ ≥70% of the votes

Clinical diagnosis

SRS is currently a clinical diagnosis based on a combination of characteristic features. Molecular testing can confirm the diagnosis in around 60% of patients4. Molecular testing enables stratification of patients with SRS into subgroups, which can lead to more tailored management. However, molecular investigations are negative in a notable proportion of patients with characteristic clinical features of SRS. For these patients, an established clinical diagnosis enables access to appropriate support groups, treatment (including GH) and further research into the underlying incidence, natural history and aetiology of the SRS phenotype.

However, the diagnosis of SRS can be difficult, as the condition varies widely in severity among affected individuals and many of its features are nonspecific4, 5, 6. Until now, no consensus has been reached on the clinical definition of SRS. Historically, this lack of consensus has probably led to underdiagnosis and overdiagnosis, particularly by clinicians unfamiliar with SRS.

Several clinical scoring systems for SRS have been proposed, which reflects the challenge in reaching a confident diagnosis4, 5, 12, 13, 14, 15. All the systems use similar criteria, but vary in the number and definition of diagnostic features required for diagnosis. The relative sensitivity and specificity of these scoring systems have been compared in patients with confirmed molecular diagnoses14, 15.

Netchine–Harbison clinical scoring system

The Netchine–Harbison clinical scoring system (NH-CSS; Table 1), which was proposed by Azzi and colleagues in 2015,15 is the only scoring system for the diagnosis of SRS that was developed using prospective data. Four of the six criteria are objective; protruding forehead and feeding difficulties remain subjective, but clear clinical definitions are given. Using the same cohort, the NH-CSS proved more sensitive (98%) than previous systems4, 14. The NH-CSS also had the highest negative predictive value (89%), which gives a high degree of confidence that patients who have less than four of the six clinical criteria for diagnosis are truly unaffected by SRS. The system is easy to use in a busy clinical setting. The NH-CSS is also flexible enough to use even if data are incomplete, which is important as the diagnosis is often made in infancy, before information about postnatal growth and BMI is available.

Table 1: Netchine–Harbison clinical scoring system

Similarly to other clinical scoring systems, the NH-CSS has a low specificity (36%)15, which could result in false positive results when the diagnosis is just based on clinical findings. Relative macrocephaly at birth (defined as a head circumference at birth ≥1.5 SDS above birth weight and/or length SDS) and protruding forehead are the two features in the NH-CSS that best distinguish SRS from non-SRS SGA (see Supplementary information S1 (table))4, 15, 16, 17, 18. To maintain confidence in the clinical diagnosis if all molecular testing is normal, we recommend that only patients scoring at least four of six criteria, including both prominent forehead and relative macrocephaly, should be diagnosed as 'clinical SRS' (previously known as 'idiopathic SRS'); see the flow diagram for investigation and diagnosis of SRS (Fig. 1).

Figure 1: Flow chart for investigation and diagnosis of SRS.
Flow chart for investigation and diagnosis of SRS.

Diagnostic questions are in blue boxes; recommended molecular tests are in beige boxes. Pink boxes: diagnosis not confirmed; green boxes: diagnosis of SRS confirmed. *Studies have excluded 11p15 LOM and upd(7)mat in patients with intrauterine growth retardation and postnatal growth retardation alone; some patients, particularly those with upd(7)mat or children under 2 years, score 3/6 (see text for details). Arrange CNV analysis before other investigations if patient has notable unexplained global developmental delay and/or intellectual disability and/or relative microcephaly. §Insufficient evidence at present to determine relationship to SRS, with the exception of tissue mosaicism for 11p15 LOM. ||Unless evidence of catch-up growth by 2 years. Previously known as idiopathic SRS. CNV, copy number variant; LOM, loss of methylation; NH-CSS, Netchine-Harbison clinical scoring system; SRS, Silver–Russell syndrome.

Diagnosis in late childhood or adulthood

All scoring systems for SRS have been developed and validated in paediatric cohorts. However, an increasing number of adults with a historical diagnosis of SRS are being seen by clinicians, particularly regarding their concerns about passing the condition on to their offspring (personal experience of working groups 1 and 3). In these patients, a clinical diagnosis is frequently challenged by lack of early growth data. An attempt should be made to obtain photographs of the individual aged 1–3 years, especially of the face in profile, as well as measurements at birth and in the first 2 years. No current evidence exists to support an alternative approach to diagnosis in adults.

Additional clinical features

In addition to the clinical features in the NH-CSS, several others are recognized in association with SRS, as shown in Table 2 and Supplementary information S1 (table). These characteristics are not specific to SRS, and might be present in children born SGA who do not have SRS, but at a lower frequency than in patients with SRS. However, a few features occur at a much higher rate in children with SRS than in those with SGA4, 15, 16. These features include low muscle mass, crowded or irregular teeth, micrognathia, down-turned mouth, clinodactyly and excessive sweating.

Table 2: Additional clinical features of Silver–Russell syndrome

1 Recommendations

1.1 SRS should remain primarily a clinical diagnosis. Molecular testing is useful for the confirmation and stratification of diagnosis in SRS. Lack of a positive molecular result does not exclude the diagnosis of SRS. (A+++)

1.2 The flow chart (Fig. 1), based on the NH-CSS, should be adopted for the investigation and diagnosis of SRS. (A++)

1.3 In children aged <2 years, adolescents and adults, a reduced threshold for molecular testing might be required due to missing data. (A++)

Molecular diagnosis

Investigation and diagnosis

A positive molecular test result provides useful confirmation of the clinical diagnosis (Fig. 1). This result also enables stratification into a specific molecular subgroup that, in turn, can help guide appropriate management. However, many patients are referred for molecular testing with few, or atypical, features of SRS, which leads to low diagnostic yields and incurs unnecessary expense19. We, therefore, recommend the use of the flow chart in Fig. 1 to aid in the investigation and diagnosis of SRS.

Some patients, particularly those with upd(7)mat, have fewer typical clinical features of SRS than patients with 11p15 LOM4, 5, 13, 16, 20, 21. In the cohort reported by Azzi and co-workers15, one of the nine patients scoring three of six criteria (and therefore predicted 'unlikely to have SRS') had upd(7)mat. The threshold recommended in Fig. 1 for molecular testing (≥3 of six criteria) is, therefore, lower than that needed for a clinical diagnosis of SRS (≥4 of six criteria).

Conversely, in the same cohort, no positive molecular diagnoses were made in patients scoring less than three of six criteria15. Other studies have also excluded 11p15 LOM and upd(7)mat in patients born SGA with postnatal growth retardation but without additional features of SRS4, 10, 22. We, therefore, do not recommend testing for SRS in patients scoring less than three of six criteria. Of note, a small number of patients with body asymmetry have been reported to have 11p15 LOM without associated growth retardation, probably due to tissue mosaicism20, 21, 23. These patients would score fewer than three of six criteria, which is insufficient to justify a clinical diagnosis of SRS in these patients.

Chromosome 11p15

Both SRS and the overgrowth condition Beckwith–Wiedemann syndrome are associated with molecular abnormalities of chromosome 11p15.5, which contains two imprinted domains (Fig. 2). Imprinting of the telomeric domain, which is strongly implicated in SRS24, 25, is controlled by the paternally methylated imprinting control region H19/IGF2 IG-DMR (H19/IGF2 intergenic differentially methylated region, previously known as IC1, ICR1 and H19 DMR). The centromeric domain contains the maternally expressed growth repressor CDKN1C; the imprinting of this gene is controlled by the maternally methylated imprinting control region KCNQ1OT1 TSS-DMR (previously known as IC2, ICR2, LIT1 or KvDMR1). Figure 3 summarises the more common molecular changes at chromosome 11p15 associated with SRS. Hypomethylation of the H19/IGF2 IG-DMR results in reduced paternal IGF2 expression and increased maternal H19 expression, which leads to growth restriction9. Numerous copy number variants (CNVs) involving the 11p15.5 region have been reported; the phenotype is dependent on CNV size, location and parental origin24, 26 (see Supplementary information S2 (table)).

Figure 2: The imprinted domains of chromosome 11p15 that are implicated in Silver–Russell syndrome.
The imprinted domains of chromosome 11p15 that are implicated in Silver-Russell syndrome.

a | Representation of the 11p15 region, showing both centromeric and telomeric domains. Only the imprinted genes that are implicated in the pathophysiology of Silver–Russell syndrome are represented. Blue boxes indicate paternally expressed genes (the growth promoter IGF2 and the long noncoding RNA (lncRNA) KCNQ1OT1). Red boxes indicate maternally expressed genes (the growth inhibitor CDKN1C, the ion channel KCNQ1 and the noncoding RNA H19). Ovals indicate differentially methylated regions (DMRs). Dark grey ovals indicate methylated DMRs. Beige ovals indicate unmethylated DMRs. b | Structure of the H19/IGF2 IG-DMR (intergenic differentially methylated region). This DMR contains short repetitive blocks of sequence and harbours seven binding sites for the zinc finger protein CTCF (green circles). Multiple enhancer elements (grey hexagons) distal to H19 are shared between H19 and IGF2, and are able to increase expression of either. Binding of CTCF to the unmethylated maternal DMR blocks interactions between the IGF2 promoter and enhancers downstream of H19, which results in maternal H19 expression. Conversely, methylation of ICR1 on the paternal allele prevents CTCF binding, enabling interaction between the IGF2 promoter and distal enhancers, and thus paternal IGF2 expression162, 163. Beige triangles indicate unmethylated CTCF binding sites. Dark grey triangles indicate methylated CTCF binding sites.

Figure 3: Mutations and epimutations of the imprinted region at chromosome 11p15 associated with Silver–Russell syndrome.
Mutations and epimutations of the imprinted region at chromosome 11p15 associated with Silver-Russell syndrome.

The structure of the 11p15 region is represented as in Fig. 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 phenotype9. Less commonly, maternal duplication of the centromeric or both domains results in growth retardation due to increased dosage of CDKN1C; however, smaller copy number variants should be classified with caution due to the complex regulation of the region27. Rare familial cases have been associated with a maternal CDKN1C gain-of-function mutation (green cross)60 or a paternal IGF2 loss-of-function mutation (red cross)61.

Molecular testing must robustly and accurately measure DNA methylation of CpG dinucleotides at H19/IGF2 IG-DMR27. Assays involve either bisulfite analysis28, 29, 30 or enzymatic methods, such as methylation-specific multiplex ligation-mediated PCR amplification (MS-MLPA) or Southern blotting9, 31. The most common test in diagnostic use is MS-MLPA, which is economical on DNA, cost-effective and enables parallel analysis of copy number and DNA methylation31, 32. Hypomethylation of H19/IGF2 IG-DMR is frequently incomplete and low levels of hypomethylation might elude detection. Methylation patterns might vary between different tissues and cells (leucocytes, samples from a buccal swab and skin fibroblasts)21, 33, 34 and could explain cases of a negative molecular diagnosis using a blood sample.

Although copy number change can be detected by MS-MLPA, additional array analysis is useful for characterizing the size and gene content of any CNV identified.

Chromosome 7

Of individuals with SRS, ≤10% have upd(7)mat35, 36. The SRS phenotype of upd(7)mat is thought to result from altered expression of an imprinted growth-regulatory gene (or genes)37. In addition, the duplication of pre-existing pathogenic mutations by isodisomy can lead to the clinical expression of recessive disorders (such as cystic fibrosis) in patients with upd(7)mat38, 39, 40.

Candidate SRS regions have been suggested through identification of patients with segmental upd(7)mat or CNVs (see Supplementary information S3 (table)); the primary candidate SRS genes on chromosome 7 are currently GRB10 (7p12.1) and MEST (7q32)41, 42, 43, 44, 45, 46, 47, 48.

Microsatellite analysis was the first diagnostic test for upd(7)mat35, 36; however, this analysis cannot detect imprinting defects (epimutations) and requires DNA from at least one parent. DNA methylation analysis, including at least the imprinting control regions GRB10 alt-TSS-DMR and MEST alt-TSS-DMR, can identify upd(7)mat, epimutations, CNVs and segmental or whole-chromosome variations. DNA methylation analysis, for example by MS-MLPA, is economical on DNA, cost-effective and compatible with parallel analysis of 11p15 (Refs 30,49,50).

Additional testing

If testing of both 11p15 and chromosome 7 is negative, additional molecular testing can be considered.

CNVs. Over 30 different pathogenic CNVs have been described in patients with suspected SRS15, 51, 52, 53. Patients with these CNVs usually have more severe developmental delay and/or intellectual disability than is typically seen in SRS52, 53. Some patients fulfil the NH-CSS for diagnosis; others either do not meet the NH-CSS criteria, or insufficient data are given to use the criteria for their assessment. Although features of SRS can be present in individuals with a pathogenic CNV, clinical diagnosis of SRS is not helpful in these cases and management needs to be tailored specifically to the phenotypic consequences of the individual CNV.

While either array comparative genomic hybridization or single nucleotide polymorphism array can be used to detect CNVs, single nucleotide polymorphism array can also detect regions of segmental isodisomy54.

Chromosome 14q32 abnormalities. Molecular abnormalities at the paternally methylated imprinted locus on chromosome 14q32 include upd(14)mat, paternal microdeletions and hypomethylation of the DLK1/GTL2 IG-DMR (also referred to as MEG3-DMR, 14q32 DMR or IG-DMR). These result in Temple syndrome, which has clinical overlap with SRS55, 56, including being born SGA, postnatal growth retardation, hypotonia, delay in the development of motor skills and early puberty55.

In cohorts of patients with SRS, a small number of patients have been found to have Temple syndrome: 1 of 127 patients57, 2 of 85 patients56 and 1 of 26 patients15. However, the true incidence of 14q32 abnormalities in patients meeting the NH-CSS criteria for diagnosis remains unknown.

upd(20)mat and upd(16)mat. Patients with both upd(20)mat and upd(16)mat have occasionally been detected among cohorts of patients investigated for prenatal and postnatal growth failure or SRS15, 57, 58. However, in a study published in 2015, none of eight patients with upd(20)mat had relative macrocephaly or asymmetry59, two important criteria of the NH-CSS, which means that these patients might have eluded formal clinical diagnosis of SRS.

CDKN1C and IGF2 mutations. CDKN1C and IGF2 are the coding genes on chromosome 11p15 that are responsible for the growth anomalies in SRS and Beckwith–Wiedemann syndrome. Maternally transmitted SRS was described in a four-generation family with a CDKN1C gain-of-function mutation60, and paternally transmitted SRS in a family with an IGF2 loss-of-function mutation61. However, no additional mutations have been reported to date in sporadic or familial cases of SRS60, 62, 63. Sequence analysis of either gene might be considered, particularly in familial cases of SRS where the inheritance pattern is consistent; however, coding variants in these genes are rare60, 62, 63.

Multi-locus imprinting disturbance. A significant proportion (15–38%) of individuals with 11p15 LOM have multi-locus imprinting disturbance (MLID)33, 57, 64, 65, 66. High-density methylation arrays have revealed methylation changes involving both (maternally and paternally) imprinted and non-imprinted loci67, 68. However, despite welcome advances in genome-wide methylation screening67, 69, 70, standardization is required to ensure accurate description of MLID and comparison between cohorts.

The effect of MLID on clinical phenotype remains unclear. No difference in growth parameters was found at birth or at 2 years of age between patients with 11p15 LOM with and without MLID64. Although developmental delay and congenital anomalies were reported in patients with MLID, this finding might have been affected by ascertainment bias57.

In principle, MLID might be caused by trans-acting genetic mutations that affect the acquisition or maintenance of imprints, but in practice, very few have been identified71, 72.

Overall, the effect of MLID on clinical phenotype and its relevance for genetic counselling remain uncertain. Further information is needed before recommending testing for MLID outside the research setting.

2 Recommendations

2.1 Molecular genetic testing should be performed by a health professional experienced in the field of imprinting disorders. Consistent and logical nomenclature should be adopted in publications and in test reporting. (A+++)

2.2 First-line molecular testing should include DNA methylation analysis of the H19/IGF2 IG-DMR and KCNQ1OT1 TSS-DMR. (A+++)

2.3 First-line molecular testing should include analysis of DNA methylation at the GRB10 alt-TSS-DMR and the MEST alt-TSS-DMR. (A+++)

2.4 In case of a positive test result at either 11p15 or chromosome 7, discrimination between epimutation, CNV and upd should be considered to estimate recurrence risk. (A+++)

2.5 After exclusion of changes in 11p15 and chromosome 7, a clinical decision should be sought about the direction of further testing. Depending on the clinical features and family history of the patient, further testing might include CNV analysis and DNA methylation analysis at chromosome 14q32. Testing might also be considered for very rare molecular anomalies, including upd(20)mat, upd(16)mat and mutations in CDKN1C and IGF2, as well as analysis of further tissues to detect somatic mosaicism. (A++)

2.6 When an underlying pathogenic CNV is identified, the diagnosis should focus on this finding, even if features of SRS are present. (A+)

(Epi)genotype–phenotype correlation

The frequency of individual features in specific SRS subgroups (11p15 LOM, upd(7)mat and clinical SRS) and patients with SGA but not SRS, where data are available, are shown in Supplementary information S1 (table). Genotype–phenotype studies of patients with SRS indicate considerable overlap in clinical phenotype between (epi)genotypes, and these are generally clinically indistinguishable. However, some features are more common in particular molecular subgroups4, 13, 15, 16, 17, 20, 73.

Patients with 11p15 LOM tend to have a lower birth length and weight, more frequent body asymmetry and more frequent congenital anomalies than patients with upd(7)mat15, 20. Neurocognitive problems are more frequent in patients with upd(7)mat than in those with 11p15 LOM or clinical SRS15, 16, 20 (see later section on neurocognitive problems).

Patients with 11p15 duplication encompassing H19/IGF2 IG-DMR and KCNQ1OT1 TSS-DMR have an SRS phenotype, but usually without asymmetry and with an increased likelihood of developmental delay53. Of 15 patients reported to have a 11p15 duplication encompassing H19/IGF2 IG-DMR and KCNQ1OT1 TSS-DMR, four were noted to have hearing loss74.

Differential diagnosis

The differential diagnosis of children with short stature of prenatal onset includes many syndromic diagnoses and chromosomal rearrangements75 (Tables 3,4). Particular features should prompt consideration of diagnoses other than SRS. These include relative microcephaly (head circumference SDS below height and weight SDS), notable global developmental delay or intellectual disability (without a related explanation such as documented hypoglycaemia), absence of severe feeding difficulties and/or the presence of additional congenital anomalies, facial dysmorphism or other features atypical of SRS. Disproportionate short stature is suggestive of skeletal dysplasia. Photosensitive skin rash or recurrent bronchopulmonary infections should prompt investigation for chromosome breakage disorders. As SRS is generally sporadic, a family history of growth failure and/or consanguinity might suggest an alternative underlying diagnosis76. The clinical features of the most important and/or likely differential diagnoses are summarized in Tables 3,4.

Table 3: Differential diagnosis of Silver–Russell syndrome in patients with relative microcephaly
Table 4: Differential diagnosis of Silver–Russell syndrome in patients with relative normocephaly or macrocephaly

A correct diagnosis can have extremely important implications for management. Response to GH treatment, if given, varies depending on the underlying syndromic diagnosis. For instance, GH treatment is contraindicated in patients with chromosome breakage disorders, such as Bloom syndrome, due to the associated risk of malignancy77. GH treatment in patients with SHORT syndrome has been reported to precipitate insulin resistance and subsequent type 2 diabetes mellitus78. An incorrect diagnosis of SRS leading to the recommendation of GH treatment could, therefore, have adverse consequences in these patients.

Three patients (one with no history of fractures) have been reported with clinical features of SRS but a molecular diagnosis of osteogenesis imperfecta, with a COL1A1 mutation79, 80. Both SRS and osteogenesis imperfecta can cause prenatal onset of growth failure, relative macrocephaly, large fontanelle, blue sclerae and body asymmetry. Both diagnoses should, therefore, be considered in patients with features overlapping both conditions.

3 Recommendations

3.1 An alternative syndromic diagnosis, and specific investigation for this diagnosis, should be particularly considered in patients with any of the following: additional features atypical of SRS, family history of growth failure and/or consanguinity. (A+++)

3.2 Patients with features of SRS overlapping with osteogenesis imperfecta should have a skeletal survey to look for additional evidence for osteogenesis imperfecta, with consideration of COL1A1/2 gene testing. (A++)

Management

SRS leads to a wide spectrum of abnormal physical characteristics and functional abnormalities. Multidisciplinary follow up and early, specific, intervention are necessary for optimum management of this group of patients.

4 Recommendation

4.1 Patients with SRS should receive multidisciplinary care in a centre of expertise in SRS in coordination with their local centre. The multidisciplinary team should be composed of paediatric subspecialists such as an endocrinologist (coordinator), gastroenterologist, dietician, clinical geneticist, craniofacial team, orthopaedic surgeon, neurologist, speech and language therapist and psychologist. (A+++)

Early feeding and nutritional support

The typical neonate with SRS has length SDS below weight SDS; but after birth, due to poor appetite, feeding difficulties and gastrointestinal problems, weight SDS drops below the length SDS4, 17, 73, 81. Over time, progressive failure to thrive can result in a calorie-related length deficit4, 15, 82.

Feeding difficulties and failure to thrive are considerably more frequent in patients with SRS than in children with SGA but not SRS4, 17. Failure to thrive in children with SRS is probably due to a combination of factors, including feeding difficulties (poor appetite, oromotor issues and the resulting low caloric intake) as well as functional and structural gastrointestinal problems. Digestive problems or malnutrition occur in over 70% of patients with SRS82, including severe gastrooesophageal reflux in 55%, which often results in persistent vomiting after the age of 1 year. Constipation is also common, particularly after age 2 years82. Cyproheptadine used as an appetite stimulant improves weight gain in other paediatric conditions83, 84; however, specific studies of its use in SRS are needed before it can be recommended in these patients.

The main therapeutic goals for the first 2 years of life in patients with SRS are nutritional support, prevention of hypoglycaemia and recovery of any calorie-related length or height deficit, which should be addressed before initiation of GH therapy (see following sections on prevention of hypoglycaemia and GH therapy). However, careful monitoring is needed, especially during nonvolitional feeding, because rapid catch-up weight gain in children born SGA has been associated with an increased risk of metabolic and cardiovascular disease in later life85.

Children with SRS have an abnormal body composition with low muscle mass, and are typically light for their length or height3, 15, 86, 87. From our experience, the target for healthy nutritional status is narrow, and is dependent on individual innate muscle mass and even slight overnourishment (for example, weight >90% of ideal weight for length or height) can rapidly increase relative fat mass. Suggested targets for children aged 2–4 years preparing for GH therapy are: weight 75–85% of the 50th centile weight for length or height and/or BMI 12–14 kg/m2, using height measurements on the longer side if notable leg length discrepancy is found (see following section on GH therapy). A weight below 70% of the ideal weight for length or height compromises growth velocity, despite GH treatment. For children >4 years old, the optimal target BMI will depend on their muscle mass. Two groups of patients are exceptions to this observation. Firstly, in patients with 11p15 LOM who have a very low muscle mass and considerable body asymmetry, a lower BMI might be adequate (11–12 kg/m2). Secondly, for patients with upd(7)mat with near normal muscle mass, a higher BMI might be acceptable (14–15 kg/m2).

5 Recommendations

5.1 For nutritional goals in the first years of life, we recommend nutritional repletion* with awareness of possible hazards of rapid postnatal catch-up leading to subsequent increased metabolic risk. (A+++)

5.2 Ask for and/or screen early for gut dysmotility (gastrooesophageal reflux, delayed gastric emptying and constipation) in all children. (A+++)

5.3 Diagnose and treat any oromotor and/or sensory issues that affect oral intake of food. (A+++)

5.4 In patients with severe feeding failure who are unresponsive to standard care, anatomical or functional disorders of the gastrointestinal tract, such as malrotation, should be excluded. (A+++)

5.5 Avoid enteral feeding by nasogastric or gastrostomy tube in a child capable of eating where there is adequate nutritional repletion. (A+++)

5.6 In cases of extreme feeding difficulties or gastrooesophageal reflux, consider enteral feeding by gastrostomy tube (with or without fundoplication) or low-profile transgastric jejunostomy as a last resort to protect against hypoglycaemia and/or malnutrition. (A+++)

5.7 In the case of enteral feeding, prevent excessive weight gain in both volitionally and nonvolitionally fed children. (A++)

*Low muscle mass makes typical BMI targets excessive in this population. Targets currently used in some centres include: Waterlow score 75–85% (Ref. 88); weight-for-length SDS −2 to −1 in first year of life; BMI target SDS between −2 to −1 after first year of life.

Prevention of hypoglycaemia

Young children with SRS, particularly under age 5 years, have low muscle and liver mass, a disproportionately large brain-for-body size and feeding difficulties, all of which increase their risk of fasting hypoglycaemia and its potential neurocognitive consequences. The incidence of hypoglycaemia in these children is approximately 27%20, with a high frequency of spontaneous, asymptomatic nocturnal hypoglycaemia89.

Monitoring of levels of urinary ketones is usually effective in pre-empting hypoglycaemia related to fasting, activity or illness. This measurement can be used to determine the 'safe fasting time' for a child, which will change with age. Night time hypoglycaemia can be prevented by adding either high molecular weight glucose polymer (for infants under 10 months) or uncooked corn starch (for older infants and children particularly at risk) to the last evening feed. Dental hygiene is important as complex carbohydrates can promote cavities90. Severe, non-fasting and non-ketotic hypoglycaemia should always be identified and investigated further.

For episodes of preoperative fasting or febrile illness, intravenous glucose (10% dextrose) might be required. Children with SRS might need longer periods of gut rest than children with SGA but not SRS before oral or enteral feeding because of their gut dysmotility and intrinsic feeding defects. Before discharge, it is advisable to achieve an absence of ketonuria following at least 12 h of feeding, without intravenous support. When hypoglycaemia remains a problem, early GH therapy should be considered91, 92 (see following section on GH therapy).

6 Recommendations

6.1 Monitoring for ketonuria at home is useful to determine which children need intervention for impending hypoglycaemia. (A++)*

6.2 Develop a plan with the child's local paediatrician and emergency room for rapid admission and intravenous dextrose treatment when the child is ill. (A++)

6.3 Admit children with SRS to hospital early in the course of an illness associated with ketonuria or hypoglycaemia and do not discharge them until they are metabolically stable and can be adequately fed. (A++)

6.4 Glucagon is not recommended to correct hypoglycaemia, because of poor glycogen stores and limited ability for gluconeogenesis. (A+++)

6.5 Provide parents with an emergency guidance plan for illnesses. (A+++)

6.6 Teach parents how to recognize signs of hypoglycaemia, measure ketones, determine the 'safe fasting time' for their child, prevent hypoglycaemia using complex carbohydrates and avoid fasting outside a controlled environment. (A+++)

6.7 In severe cases of fasting hypoglycaemia, where other causes have been excluded and if other alternatives are ineffective, consider:

  • Early start of GH therapy to support glucose sources (increase in muscle mass and gluconeogenesis) (A++)
  • Placement of a gastrostomy tube or jejunostomy tube. (A++)

*Children with a history of hypoglycaemia who do not have an appropriate ketone response will require formal fasting studies.

Surgery and anaesthesia

Any surgery should be carefully planned due to the increased risk of fasting hypoglycaemia in patients with SRS93. As a result of their diminished weight-for-height ratio, low BMI and large head, young patients with SRS are at risk of hypothermia in a cool operating room94. Many children with SRS also have abnormal tooth distribution and a small mandible, which affects airway visualization and intubation95. Finally, young children with SRS who are malnourished might not heal well following surgery96.

7 Recommendations

7.1 Review issues related to SRS with the anaesthetist and surgeon in advance. (A+++)

7.2 Consider admission the night before surgery for early administration of intravenous dextrose before surgery to avoid ketonuria and hypoglycaemia. (A++)

7.3 Schedule first on the surgical list where possible. (A++)

7.4 Monitor blood glucose and administer intravenous dextrose during and after surgery. Do not discharge until ketonuria is absent and the child can sustain themselves on oral or enteral feeding. (A++)

7.5 Follow the intraoperative temperature maintenance protocol appropriate for the patient's size, not age. (A+++)

7.6 Delay elective surgery until the child is adequately nourished. (B+)

7.7 Be aware of the high risk of malnutrition after surgery and follow appropriate guidelines. (A+)

Growth hormone treatment

Data on adult height in untreated patients with SRS are limited; however, SRS is associated with a significant reduction in adult height (around −3 SDS; Supplementary information S4 (table)) (Ref. 3). SRS is an indication for growth-promoting GH treatment under the SGA registered licence. It is worth noting that SRS was the only syndrome to be included in the clinical trials of GH in short children born SGA that led to the US FDA and the European Medicines Agency (EMA) SGA indications for GH therapy in 2001 and 2003, respectively97, 98, 99, 100, 101. The results of these clinical trials, therefore, validate the use of GH for patients with SRS.

Overall, clinical trials of GH treatment in patients with SGA (in which patients with SRS were included) demonstrated a satisfactory growth response and an increase in predicted adult height of 7–11 cm at pharmacological doses of GH97, 98, 99, 100, 102. However, the response in patients with SRS was not investigated until a Dutch longitudinal study analysed the response to GH in 62 children with a clinical diagnosis of SRS using the NH-CSS compared with 227 short, non-syndromic children born SGA. Overall, the study showed a similar response to GH in patients with SRS compared with non-SRS children born SGA (mean total height gains of 1.30 SDS and 1.26 SDS, respectively); however, the final adult height attained in patients with SRS was lower (mean adult height −2.17 SDS versus −1.65 SDS for non-SRS children born SGA)87. Although the mean height at the start of GH treatment in patients with SRS was statistically significantly lower than in those without SRS, it was shown that patients with all SRS subtypes benefited from GH treatment, with a trend towards increased height gain in patients with upd(7)mat or clinical SRS. In addition, some interim100, 102 and long-term103, 104 studies have focused on the response to GH specifically in patients with SRS, albeit without a control group of non-SRS short children born SGA. Strong predictors of the short-term and long-term responses to GH were age and height SDS at the start of GH treatment (both inversely related)103, 104, 105. However, the study by Rakover et al.105 of 33 patients with SRS lacked data on adult height. Mean total height gain ranged from +1.2 to +1.4 SDS for GH doses of 35–70 µg/kg per day, which is similar to that achieved in patients with non-syndromic SGA97, 103, 104. In 2007, an SGA consensus statement advocated early treatment with GH for children born SGA, including those with SRS, who had severe growth retardation (height SDS ≤2.5; age 2–4 years; dose 35–70 µg/kg per day)106.

Additional potential benefits of GH treatment are increases in appetite, lean body mass and muscle power, which can result in improved mobility86, 107. In patients with Prader–Willi syndrome, another imprinting disorder, GH treatment started in infancy results in increased lean body mass and motor development, as well as decreased fat mass108, 109; consequently, GH treatment is now recommended from infancy in this condition. Children with SRS who are <2 years old typically present with low muscle mass and hypotonia, similarly to patients with Prader–Willi syndrome15, and could also benefit from early GH treatment. Further studies are necessary to investigate this option in patients with SRS.

Classic GH deficiency is neither a common nor a relevant cause of short stature in SRS, nor is it predictive of the response to GH treatment in children born SGA103, 105, 110. Furthermore, given the risk of hypoglycaemia associated with fasting required for GH testing, testing children with SRS might carry added risks.

For most children with SRS, an increase in height velocity of ≥3 cm per year is the lower limit of an effective response range106. The growth response depends on the patient's age, GH dose, height deficit, rate of weight gain and confounding problems such as intercurrent illness and scoliosis.

Levels of insulin-like growth factor 1 (IGF1) in response to GH treatment in patients with SRS are difficult to interpret. Children with 11p15 LOM have significantly higher IGF1 levels than children with upd(7)mat and other children born SGA, which suggests an element of IGF1 resistance in patients with 11p15 LOM73, 111. Basal serum levels of IGF1 in the upper quartile of the normal age-related range or higher can be expected in children with SRS, especially those with 11p15 LOM73. In children with 11p15 LOM, serum levels of insulin-like growth factor-binding protein 3 (IGFBP3) are also elevated111. IGF1 levels might rise significantly above the reference range in children with SRS on standard doses of GH87, 111. Further studies are needed to understand how best to use IGF1 and IGFBP3 serum levels to monitor GH doses in children with SRS and IGF1 resistance.

Comprehensive reviews on the use of GH in children born SGA have concluded that GH treatment seems to be safe and effective112. Adverse effects due to GH treatment are no more frequent in children with SRS than in those with non-syndromic SGA87, 113 and no specific precautions are advised.

8 Recommendations

8.1 Defer GH treatment until caloric deficits are addressed. (A++)

8.2 Avoid GH stimulation testing. (A++)

8.3 Goals of GH treatment are to improve body composition (especially lean body mass), psychomotor development and appetite, to reduce the risk of hypoglycaemia, and to optimise linear growth. (A++)

8.4 Treat with GH as soon as possible; starting at age 2–4 years is adequate for the majority of patients; however, due consideration should be given to the exceptions listed below*. (A++)

8.5 Start GH at a dose of approximately 35 µg/kg per day. Use the lowest dose that results in catch-up growth. (A+++)

8.6 Terminate GH therapy when height velocity is <2 cm per year over a 6-month period and bone age is >14 years (female patients) or >17 years (male patients). (A++)

8.7 If response to GH is poor, re-evaluate the underlying diagnosis, GH dose, IGF1 response, adherence to therapy and other confounding systemic problems. (A+++)

8.8 Monitor circulating levels of IGF1 and IGFBP3 at least yearly during GH treatment. (A++)

*GH treatment does not have a specific indication for SRS and is prescribed under the SGA indication (height SDS −2.5; age >2–4 years; dose 35–70 µg/kg per day)106. Exemptions from the current SGA licensed indication used in some centres include starting GH therapy below the age of 2 years in case of: severe fasting hypoglycaemia; severe malnutrition, despite nutritional support, which will lead to gastrostomy if no improvement is seen; and severe muscular hypotonia.

Bone age advancement and puberty

The published literature on the natural history of bone age progression in patients with SRS is limited. Early bone age delay is followed by rapid advancement typically at around 8–9 years of age3, 81, 113 but sometimes much younger, especially in nonvolitionally overfed children. Onset of puberty is usually within the normal range (8–13 years in girls and 9–14 years in boys)114 but at the younger end of the spectrum3, 73, 87, 115. Adrenarche can be early and aggressive in comparison with children born with non-SRS SGA, particularly in those with 11p15 LOM116.

Our experience is that in patients with SRS and early adrenarche, the onset of central puberty might be earlier and the tempo faster than expected. In the past few decades, population studies analysing the timing of normal puberty observed a mean age of puberty onset of 9.7–10.0 years in girls114. As a group, girls with SRS seem to start central puberty at a mean age of 9.1 years (I. Netchine, unpublished work). This early puberty further accelerates bone age maturation, which leads to an attenuated pubertal growth spurt and compromised adult height. Children with upd(7)mat are likely to progress to central puberty at an even younger age than patients with SRS and 11p15 LOM (mean starting age 8.5 years in girls and 9.5 years in boys) (I. Netchine, unpublished work). A rapid increase in BMI might also exacerbate the tendency to early adrenarche and central puberty117, 118, 119.

The window for effective GH treatment seems to be shorter in patients with SRS than in non-SRS patients with SGA. In a study comparing a cohort of patients with SRS and a cohort of patients born SGA but without SRS, puberty started significantly earlier in the former (at 10.2 years versus 11.2 years in girls with SRS and non-SRS SGA, respectively, and at 11.4 years versus 12.0 years in boys with SRS and non-SRS SGA, respectively)87. Furthermore, a steeper decline in height SDS from the onset of puberty until adult height was seen in patients with SRS, which contributed to a lower adult height and a larger distance to target height than in non-SRS patients with SGA. However, in 17 patients with SRS in this study, puberty was postponed for 2 years with gonadotropin-releasing hormone analogue (GnRHa) due to a low predicted adult height. The effect of GnRHa on final height has been analysed in a cohort of patients with SGA, including patients with SRS120, 121. This analysis suggested that the combination of GnRHa, started at the initiation of puberty and continued for at least 2 years, along with GH treatment, improves adult height in patients born SGA with a poor adult height prognosis. A retrospective study of GnRHa treatment specifically in patients with SRS did not detect an effect of GnRHa on adult height, but this therapy was used in only 16 of 37 patients and was not standardized104. Further studies are required to specifically look at its effects in patients with SRS.

Aromatase catalyses the rate-limiting step in the conversion of androstenedione to oestrone and testosterone to oestradiol. In patients with adrenarche with advancing bone age, but without central puberty, third-generation aromatase inhibitors (such as anastrozole) might be helpful in preventing rapid bone maturation, but are currently not licensed for growth disorders122. An 18-month double-blind clinical trial is currently underway to study the efficacy and tolerance of treatment with anastrozole to slow bone maturation related to pathological adrenarche in patients with SRS and Prader–Willi syndrome123.

9 Recommendations

9.1 Monitor for signs of premature adrenarche, fairly early and accelerated central puberty, and insulin resistance. (A+++)

9.2 Monitor and anticipate acceleration of bone age especially from mid childhood. (A++)

9.3 Consider personalized treatment with GnRHa for at least 2 years in children with evidence of central puberty (starting no later than age 12 years in girls and age 13 years in boys) to preserve adult height potential. (A++)

Long-term metabolic complications

Individuals born with a low birth weight are at increased risk of adult health problems including coronary heart disease124, 125, 126, hypertension, dyslipidaemia, insulin resistance and obesity (the metabolic syndrome)127, 128, 129, 130. Studies of children born SGA indicate that those who have rapid or disproportionate catch-up in weight are at particularly high risk119, 131, 132.

Insulin resistance in young, pre-pubertal, children with SRS can be atypical and difficult to detect in the fasting state; however, impaired glucose tolerance can be confirmed on formal oral glucose tolerance testing133, 134. Insulin resistance becomes more classic in the pubertal or post-pubertal age groups with elevation in fasting levels of glucose and insulin, and possibly the development of type 2 diabetes mellitus135, 136.

Overall, GH therapy seems to have positive metabolic effects in children born SGA137, but specific data on such effects in SRS are lacking. Many studies of long-term GH treatment in children born SGA have shown positive outcomes, including increased lean body mass, reduced fat mass, decreased blood pressure and an improved lipid profile107, 120, 137, 138, which might last after discontinuation of therapy138, 139.

In a study of 110 children born SGA treated with GH, those with the highest baseline levels of IGF1 were the least insulin sensitive. Gains in height and IGF1 response were positively associated with insulin secretion140. In SRS, children with 11p15 LOM seem to be at a higher metabolic risk than children who have upd(7)mat and other children born SGA due to poor muscle mass and raised levels of IGF1 (Refs 15,16,73,87). Further research is, therefore, required on the long-term effects of GH therapy on body composition and metabolic parameters in SRS and its various genotypes.

10 Recommendations

10.1 Avoid excessive or rapid weight gain to prevent increased insulin resistance, which is associated with early and rapidly advancing adrenarche, early central puberty, and, in girls, a future risk of developing polycystic ovary syndrome. (A++)

10.2 Raise awareness among gastroenterologists, dieticians, neonatologists, paediatricians and primary health-care providers of the importance of not overfeeding this group of children. (A+++)

10.3 Advise parents, grandparents and care-givers about the risk of insulin resistance associated with intrauterine growth retardation and overfeeding. (A+++)

10.4 Screen for physical and biochemical indicators of insulin resistance during GH treatment, especially in children with low muscle mass and high baseline levels of IGF1. (A+)

10.5 In patients with clinical signs of insulin resistance, consider formal assessment of insulin sensitivity with a 2-h oral glucose tolerance test including measurement of insulin and C-peptide levels (A++)

10.6 Advocate a healthy diet and lifestyle in older children and young adults with particular emphasis on protein calorie balance and regular exercise to avoid disproportionate weight gain, particularly after discontinuation of GH treatment. (A+++)

Neurocognitive problems

Motor and speech delay are common in children with SRS4, 16, 17, 18, 20 (Table 2). Motor delay might be related to reduced muscle bulk and fairly large head size. Verbal dyspraxia and more global developmental delay or learning difficulties, usually mild, have been described in some children with SRS, particularly those with upd(7)mat12, 15, 16, 20, 141. Autistic spectrum disorder has also been reported more frequently in this subgroup than in the other subgroups of SRS15. Myoclonus dystonia in patients with upd(7)mat is probably associated with altered expression of the paternally expressed SGCE on chromosome 7q21 (Refs 20,40,142,143).

11 Recommendations

11.1 Refer infants and children with SRS for a developmental assessment when necessary to ensure appropriate intervention as early as possible. (A+++)

11.2 In patients with upd(7)mat, check for symptoms of myoclonus dystonia at each clinical appointment and refer early to a paediatric neurologist if required. (A+++)

11.3 Monitor children with upd(7)mat for signs of verbal or oromotor dyspraxia and/or signs of autistic spectrum disorders. (A+++)

11.4 Inform parents about increased risk of speech, oromotor and learning disabilities (especially in those with upd(7)mat). (A+++)

11.5 Follow up school-age children for any learning difficulties, psychosocial challenges and/or cognitive delay, to enable appropriate intervention. (A+++)

Orthopaedic problems

Orthopaedic problems seen in association with SRS include limb or body asymmetry, scoliosis, hip dysplasia and hand and/or foot anomalies (Table 2).

Limb asymmetry can affect the arms, legs or both. In seven patients with clinically diagnosed SRS, limb length discrepancy was not significantly affected by GH treatment144. Limb lengthening surgery performed to equalize limb lengths in patients with SRS has shown positive results145.

Scoliosis has been reported in 9–36% of individuals with SRS20, 146, 147. The causal relationship to leg length asymmetry is not clear146, 147. Associated back pain has been reported inconsistently5, 146. GH therapy might be associated with worsening of existing scoliosis; however, causality has not been established148. A study in a large group of children with Prader–Willi syndrome (an imprinting disorder with clinical features that overlap with those of SRS: growth failure; infant hypotonia; early feeding difficulties; and an increased risk of scoliosis) has clearly shown that GH therapy does not influence onset and progression of scoliosis149; however, specific studies are required to determine whether GH therapy modifies the risk of scoliosis in patients with SRS.

12 Recommendations

12.1 Where necessary, refer to a paediatric orthopaedic surgeon for collaborative management of body asymmetry, limb length discrepancy and scoliosis. (A+++)

12.2 Routinely examine all patients with SRS for scoliosis. (A+++)

12.3 Before initiation of GH therapy, refer patients with scoliosis to the orthopaedic team and monitor while receiving GH. (A+++)

12.4 Evaluate leg length asymmetry regularly and consider orthopaedic management if necessary. (A++)

Maxillofacial abnormalities

SRS is characterized by craniofacial disproportion, which results in a triangular-shaped face95. Delayed dental eruption, microdontia, absence of secondary teeth and blunted condyles have all been reported in patients with SRS150, 151, 152.

In our experience, the upper jaw arch is frequently narrow and crowded, but crowding might be severe in the lower arch, with displacement of lower incisors into a lingual position. Micrognathia is frequent, with lack of mandibular growth, which results in a small, pointed chin and an overbite. Children with notable facial asymmetry might have a crossbite that impairs normal chewing. Velopharyngeal insufficiency with or without a submucous cleft is quite common in patients with 11p15 LOM SRS20. Otitis media is frequent in young children with SRS7 and seems to be improved by orthodontic treatment20.

Orthodontic intervention in children with SRS can help normalize oropharangeal function and facial appearance. An experienced craniofacial team, including orthodontists, plastic surgeons and ear, nose and throat surgeons is ideal. Multiple orthodontic techniques have been used successfully153. Currently, rapid palatal expansion is the most effective technique to change the shape of the face154.

Many patients with SRS report excessive daytime fatigue, snoring and/or disrupted sleep. However, data are very limited regarding sleep problems, including sleep disordered breathing, in association with SRS. A retrospective study identified mild sleep disordered breathing in 74% of patients with SRS (not exacerbated with GH therapy)155. Further studies are necessary.

13 Recommendations

13.1 Develop a referral relationship with a maxillofacial team or orthodontist who has experience caring for patients with SRS. (A++)

13.2 Refer patients to the maxillofacial team for assessment after eruption of primary dentition when necessary. (A++)

13.3 Encourage early orthodontic intervention and compliance with follow-up. (A+)

13.4 Screen for symptoms of sleep disordered breathing (such as snoring, apnoeas, excessive daytime fatigue, disrupted sleep and agitation). (A++)

13.5 Refer patients with suspected sleep disordered breathing to the appropriate specialist for evaluation of obstructive sleep apnoea. (A++)

Other congenital anomalies

Congenital anomalies have been described in a minority of patients with SRS, particularly those with 11p15 LOM (see Supplementary information S1 (table)). Genital abnormalities, including cryptorchidism and hypospadias, occur frequently in boys16, 20. Mayer–Rokitansky–Kuster–Hauser syndrome in female patients is characterized by congenital hypoplasia or aplasia of the uterus and upper part of the vagina16, 18, 156, 157. Structural renal anomalies18, 20 and congenital heart defects4, 18, 20, 158 have also been reported.

14 Recommendations

14.1 Investigate genital abnormalities in boys. (A+++)

14.2 Investigate girls with primary amenorrhoea for Mayer–Rokitansky–Kuster–Hauser syndrome. (A+++)

Adulthood

Very little information exists in the literature regarding the long-term natural history of SRS. The majority of individuals with SRS are not routinely followed up, and the small numbers of adults reported have few medical problems. However, it is well recognized that being SGA at birth with accelerated gain in weight for length, particularly during early life, increases the risk of metabolic problems in adulthood119, 132, 159 (see previous discussion). Medical problems reported in adult patients with 11p15 LOM include hypertension, dilated cardiomyopathy, type 2 diabetes mellitus, hypercholesterolaemia, fatty liver infiltration, elevated glucose levels and raised HbA1c levels135, 136, 160; however, these reports might not be representative of the population as a whole.

15 Recommendations

15.1 Consider medical follow-up of adolescents and young adult patients with SRS or develop collaboration with a general or internal medicine team for follow-up. (A+++)

15.2 Avoid losing contact with adult patients with SRS, to facilitate their participation in, and potential benefit from, future clinical research. (A+++)

Genetic counselling

Accurate genetic counselling depends on the underlying molecular cause. 11p15 LOM is associated with a low recurrence risk (with parents of a child with SRS being unlikely to have another affected child). The offspring risk is also low (meaning that individuals with SRS are unlikely to pass the condition on to their children). However, empirical figures are not available. Only three sibships with 11p15 LOM are reported in the literature13, 20, and the underlying mechanism is unknown in all three.

The potential for a familial trans-acting gene mutation suggests that the recurrence risk in patients with SRS and MLID could be higher than in other patients with SRS; however, evidence to support this supposition does not yet exist.

Rare familial cases of SRS have been reported with underlying mechanisms including: maternally inherited 11p15 duplication24, 26 (see Supplementary information S2 (table)); maternally inherited CDKN1C gain-of-function mutations60; and paternally inherited IGF2 loss-of-function mutations61. In these families, the risk of recurrence might be as high as 50%24, 26, 60, 61. Investigation for underlying CNVs in patients with 11p15 LOM is, therefore, important. upd(7)mat is associated with a low recurrence and offspring risk (if the karyotype of the patient is normal)50. Data are limited regarding the risk of parents of children with clinically diagnosed SRS having another child with SRS; however, the overall risk is probably low. Similarly, the offspring risk for individuals with clinically diagnosed SRS is likely to be low.

16 Recommendation

16.1 Genetic counselling should be performed by a health professional experienced in the field of imprinting disorders. As the recurrence risk associated with CNVs is dependent on their size, location and parental origin, these should be taken into consideration during counselling for the family. (A+++)

Conclusions

Children with SRS and their families face challenges from birth to adulthood. In addition to the problems associated with being born SGA, clinicians treating patients with SRS need to be aware of syndrome-specific management issues. These include substantial feeding difficulties, severe postnatal growth failure with no catch-up, recurrent hypoglycaemia, premature adrenarche, fairly early and rapid puberty, insulin resistance, body asymmetry, orthodontic issues, sleep disordered breathing and the potential for other congenital anomalies.

Presented here are the first international consensus guidelines for the diagnosis and management of SRS, based on published evidence and expert opinion. A summary of all 72 recommendations, including a flow chart for the investigation and diagnosis of SRS, is available as supplementary information online (see Supplementary information S5).

These management recommendations apply to all patients clinically diagnosed with SRS, both with and without a molecularly confirmed diagnosis. However, identification of the underlying molecular subtype can guide treatment with regard to specific risk factors. Management should involve a multi-disciplinary approach and close parental guidance. A practical checklist for use in routine clinical follow up of these patients is proposed in Table 5.

Table 5: Checklist for management of patients with Silver–Russell syndrome

As published data specific to SRS are limited, many questions remain (Box 2). International collaboration and further research is urgently needed to better inform the investigation and management of patients with SRS in the future.

Box 2: Future research directions for SRS

Clinical

• Incidence and/or prevalence

• Frequency of associated features (for example, scoliosis, sleep disordered breathing, developmental delay, behavioural issues)

• Frequency and associated phenotype of molecular subtypes, including:

- 11p15, upd(7)mat

- MLID

- 14q32 abnormalities, upd(20)mat, upd(16)mat

• Clinical overlap with other imprinting disorders

Molecular

• Development of testing methodology

• Identification of additional molecular causes in patients with clinically diagnosed SRS

• Prenatal testing: methodology, ethical implications

Management

• Use of cyproheptadine as an appetite stimulant

• Optimal timing of GH use

• Interpretation of IGF1 levels

• Role of aromatase inhibitors to control bone age advancement

• GnRH analogue inhibition of central puberty

• Control of postnatal weight gain

• Limb lengthening

SRS in adulthood

• Natural history, including risk of the metabolic syndrome

• Quality of life indicators

• Reproductive issues (assisted reproductive technology, recurrence risk associated with MLID)

GH, growth hormone; GnRH, gonadotropin-releasing hormone; IGF1, insulin-like growth factor 1; MLID, multi-locus imprinting disturbance; SRS, Silver–Russell syndrome.

References

  1. Silver, H. K., Kiyasu, W., George, J. & Dearner, W. C. Syndrome of congenital hemihypertrophy, shortening of stature and elevated urinary gonadotropins. Pediatrics 12, 368373 (1953).
  2. Russell, A. A syndrome of intra-uterine dwarfism recognizable at birth with cranio-facial dysostosis, disproportionately short arms, and other anomalies (5 examples). Proc. R. Soc. Med. 47, 10401044 (1954).
  3. Wollmann, H. A., Kirchner, T., Enders, H., Preece, M. A. & Ranke, M. B. Growth and symptoms in Silver–Russell syndrome: review on the basis of 386 patients. Eur. J. Pediatr. 154, 958968 (1995).
  4. Netchine, I. et al. 11p15 imprinting center region 1 loss of methylation is a common and specific cause of typical Russell–Silver syndrome: clinical scoring system and epigenetic-phenotypic correlations. J. Clin. Endocrinol. Metab. 92, 31483154 (2007).
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Acknowledgements

This consensus was organised by the European Network of Human Congenital Imprinting Disorders (EUCID.net) with the support of COST (European Cooperation in Science and Technology, BM1208), European Society of Paediatric Endocrinology (ESPE), Asia Pacific Paediatric Endocrine Society (APPES), Sociedad Latinoamericana de Endocrinología Pediátrica (SLEP), Pediatric Endocrine Society (PES) and other expert participants. The consensus was financially supported by the above societies and networks and did not receive funding from pharmaceutical companies. The authors would like to acknowledge the assistance of Jenny Child and Nick Child (Child Growth Foundation), Nonjia Rosen (Association Libre d'Informations sur la Croissance des Enfants 'Silver Russell'), Bénédicte Perrotin (Association FrançaIses des Familles ayant un enfant atteint du Syndrome Silver Russell (SSR) ou né Petit pour l'Age Gestationnel (PAG) et leurs amis: AFIF-SSR-PAG) and Dayna Carney (MAGIC foundation) in preparing this manuscript. Oluwakemi Lokulo-Sodipe was funded by the UK National Institute for Health Research - Research for Patient Benefit programme PB-PG-1111-26003 – VTC.

Author information

Affiliations

  1. North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, Watford Road, Harrow HA1 3UJ, UK.

    • Emma L. Wakeling
  2. AP-HP, Hôpitaux Universitaires Paris Est (AP-HP) Hôpital des Enfants Armand Trousseau, Service d'Explorations Fonctionnelles Endocriniennes, 26 avenue du Dr Arnold Netter, 75012 Paris, France.

    • Frédéric Brioude,
    • Eloise Giabicani &
    • Irène Netchine
  3. Centre de Recherche Saint Antoine, INSERM UMR S938, 34 rue Crozatier, 75012 Paris, France.

    • Frédéric Brioude,
    • Eloise Giabicani &
    • Irène Netchine
  4. Sorbonne Universities, UPMC UNIV Paris 06, 4 place Jussieu, 75005 Paris, France.

    • Frédéric Brioude,
    • Eloise Giabicani &
    • Irène Netchine
  5. Human Development and Health, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK.

    • Oluwakemi Lokulo-Sodipe,
    • I. Karen Temple &
    • Deborah J. G. Mackay
  6. Wessex Clinical Genetics Service, Princess Anne Hospital, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK.

    • Oluwakemi Lokulo-Sodipe &
    • I. Karen Temple
  7. Department of Paediatrics and Child Health, Cork University Hospital, Wilton, Cork T12 DC4A, Ireland.

    • Susan M. O'Connell
  8. MAGIC Foundation, 6645 W. North Avenue, Oak Park, Illinois 60302, USA.

    • Jennifer Salem
  9. Academic Medical Centre, Department of Clinical Genetics, Laboratory for Genome Diagnostics, Meibergdreef 15, 1105AZ Amsterdam, Netherlands.

    • Jet Bliek
  10. Unidade de Endocrinologia Genetica, Laboratorio de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Arnaldo, 455 5° andar sala 5340 (LIM25), 01246–000 São Paulo, SP, Brazil.

    • Ana P. M. Canton &
    • Alexander A. Jorge
  11. Department of Medical Genetics, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04–730 Warsaw, Poland.

    • Krystyna H. Chrzanowska
  12. Department of Paediatric Endocrinology, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK.

    • Justin H. Davies
  13. Institutes of Metabolism and Systems Research, Vincent Drive, University of Birmingham, Birmingham B15 2TT, UK.

    • Renuka P. Dias
  14. Centre for Endocrinology, Diabetes and Metabolism, Vincent Drive, Birmingham Health Partners, Birmingham B15 2TH, UK.

    • Renuka P. Dias
  15. Department of Paediatric Endocrinology and Diabetes, Birmingham Children's Hospital NHS Foundation Trust, Steelhouse Lane, Birmingham B4 6NH, UK.

    • Renuka P. Dias
  16. AP-HP, Hôpitaux Universitaires Paris Est (AP-HP) Hôpital des Enfants Armand Trousseau, Nutrition and Gastroenterology Department, 26 avenue du Dr Arnold Netter, 75012 Paris, France.

    • Béatrice Dubern
  17. Trousseau Hospital, HUEP, APHP, UPMC, 75012 Paris, France.

    • Béatrice Dubern
  18. Insitute of Human Genetics, Technical University of Aachen, Pauwelsstr. 30, D-52074 Aachen, Germany.

    • Miriam Elbracht &
    • Thomas Eggermann
  19. Perelman School of Medicine, University of Pennsylvania, The Children's Hospital of Philadelphia, 3401 Civic Center Boulevard, Suite 11NW30, Philadelphia, Pennsylvania 19104, USA.

    • Adda Grimberg
  20. Applied Human Molecular Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Gl. Landevej 7, 2600 Glostrup, Copenhagen, Denmark.

    • Karen Grønskov &
    • Zeynep Tümer
  21. Erasmus University Medical Center, Pediatrics, Subdivision of Endocrinology, Wytemaweg 80, 3015 CN, Rotterdam, Netherlands.

    • Anita C. S. Hokken-Koelega
  22. Department of Molecular Endocrinology, National Research Institute for Child Health and Development, 2-10-1 Ohkura, Setagayaku, Tokyo 157–8535, Japan.

    • Masayo Kagami
  23. APHP, Department of Pediatric Endocrinology, Reference Center for Rare Disorders of the Mineral Metabolism and Plateforme d'Expertise Paris Sud Maladies Rares, Hospital Bicêtre Paris Sud, 78 Rue du Général Leclerc, 94270 Le Kremlin-Bicêtre, France.

    • Agnes Linglart
  24. IRCCS Istituto Giannina Gaslini, University of Genova, Via Gerolamo Gaslini 5, 16147 Genova, Italy.

    • Mohamad Maghnie
  25. Otto-von-Guericke University, Department of Pediatrics, Leipziger Street 44, 39120 Magdeburg, Germany.

    • Klaus Mohnike
  26. Imprinting and Cancer Group, Cancer Epigenetic and Biology Program, Bellvitge Biomedical Research Institute, Gran via 199–203, Hospital Duran i Reynals, 08908, Barcelona, Spain.

    • David Monk
  27. Fetal Growth and Development Group, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.

    • Gudrun E. Moore
  28. Centre for Paediatrics and Child Health, Institute of Human Development, Royal Manchester Children's Hospital, Oxford Road, Manchester M13 9WL, UK.

    • Philip G. Murray
  29. Department of Pediatrics, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431–3192, Japan.

    • Tsutomu Ogata
  30. Pediatric Endocrinology, Genetic, Bone Disease & Gynecology Unit, Children's Hospital, TSA 70034, 31059 Toulouse, France.

    • Isabelle Oliver Petit
  31. Instituto Auxologico Italiano, Cytogenetic and Molecular Genetic Laboratory, via Ariosto 13 20145 Milano, Italy.

    • Silvia Russo
  32. Department of Anatomy & Cell Biology, Centre for Molecular Medicine & Biobanking, Faculty of Medicine & Surgery, University of Malta, Msida MSD2090, Malta.

    • Edith Said
  33. Section of Medical Genetics, Department of Pathology, Mater dei Hospital, Msida MSD2090, Malta.

    • Edith Said
  34. IASIS Hospital, 8 Voriou Ipirou, 8036, Paphos, Cyprus.

    • Meropi Toumba
  35. The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.

    • Meropi Toumba
  36. University Children's Hospital, Pediatric Endocrinology, Hoppe-Seyler-Strasse 1, 72070 Tuebingen, Germany.

    • Gerhard Binder
  37. Mount Sinai School of Medicine, 5 E 98th Street #1192, New York, New York 10029, USA.

    • Madeleine D. Harbison

Contributions

E.L.W., F.B., O.L.-S., S.M.O'C., J.S., E.G., A.C.S.H.-K., P.G.M., M.T., G.B., T.E., M.D.H., I.K.T., D.J.G.M. and I.N. researched data for the article, made substantial contributions to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission. J.B., A.P.M.C., J.H.D., R.P.D., B.D., M.E., K.G., A.A.J., M.K., M.M., K.M., G.E.M., T.O., I.O.P., S.R. and E.S. made substantial contributions to discussion of the content and reviewed and/or edited the manuscript before submission. K.H.C., A.L., D.M. and Z.T. researched data for the article, made substantial contributions to discussion of the content and reviewed and/or edited the manuscript before submission. A.G. made substantial contributions to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission. F.B., O.L.S., S.M.O'C. and J.S. are co-second authors. G.B. T.E., M.D.H. and I.K.T. were co-chairs of the working groups and co-ordinating authors with major contributions. D.J.G.M. and I.N. are co-last authors.

Competing interests statement

J.H.D. has received a travel bursary from Merck. B.D. has received honoraria from Fresenius Kiabi. A.G. has received financial support in respect of membership of the steering committee, Pfizer International Growth study (KIGS) database. A.H.-K. has received independent research funding for investigator-initiated and responsible studies, from Novo Nordisk Netherlands and Pfizer. A.L. has received consultancy fees from Sandoz-Alexion. K.M. has received research funding from Pfizer for SRS registry. P.M. has received consultancy fees from Novo Nordisk. S.O'C. has received speaker's fee from Pfizer Healthcare. G.B. has received consultancy fees from Novo Nordisk and Pfizer, as well as honoraria from Pfizer. The other authors declare no competing interests.

Corresponding authors

Correspondence to:

Author details

  • Emma L. Wakeling

    Emma L. Wakeling is a Consultant in Clinical Genetics (MA (Oxon), FRCP, PhD), for the North West Thames Regional Genetic Service, London North West Hospitals NHS Trust, Harrow, UK. Her PhD thesis covered genomic imprinting and Silver–Russell syndrome: candidate genes on chromosome 7. Her interests include clinical genetics, particularly growth disorders and Silver–Russell syndrome (SRS), as evidenced by 45 PubMed publications including key publications on epigenotype–phenotype correlations in SRS.

  • Frédéric Brioude

    Frédéric Brioude is Associate Professor and Pediatric Endocrinologist at Armand Trousseau Hospital, Paris, France. He focuses on the clinical care and molecular diagnosis of Silver–Russell syndrome (SRS) and Beckwith–Wiedemann syndrome. He is a Member of the French Society for Pediatric Endocrinology and Diabetology. He has 20 PubMed publications, including papers on the discovery of CDKN1C mutations in SRS and a clinical study of multi-locus imprinting disturbance.

  • Oluwakemi Lokulo-Sodipe

    Oluwakemi Lokulo-Sodipe is a Paediatrician with an interest in endocrinology. Dr Lokulo-Sodipe's PhD study, titled 'The Study of Adults and Adolescents with Russell-Silver syndrome' was supervised by Professor Temple and was funded by the UK National Institute for Health Research – Research for Patient Benefit programme PB-PG-1111-26003 – VTC.). Dr Lokulo-Sodipe's experience is in management of children with Silver–Russell syndrome (SRS) through specialist clinics with Professors Netchine and Harbison. Dr Lokulo-Sodipe has published papers relating to Temple syndrome, which has clinical features that overlap with SRS.

  • Susan M. O'Connell

    Susan M. O'Connell works at the Department of Paediatrics and Child Health, Cork University Hospital, Ireland. She is a Consultant Paediatric Endocrinologist and Clinical Senior Lecturer at University College Cork. Her MD study (2009) was on follow-up growth of SGA children. Her research interests include growth and imprinting disorders. She has 54 PubMed publications, including North European small for gestational age study (NESGAS) findings.

  • Jennifer Salem

    Jennifer B. Salem is Research Director, RSS/SGA Research & Education Fund, The MAGIC Foundation, USA. Her focus is on expanding research and educational tools related to Silver–Russell syndrome and small for gestational age growth failure for the benefit of physicians and families worldwide. As well as fundraising for, advising and presenting to families, curating a patient database and supporting translational research, she has written educational materials for physicians and patients, including co-authoring the major resource: RSS/SGA – A Comprehensive Guide: Understanding aspects of children diagnosed with Russell–Silver syndrome or born small-for-gestational-age (2009, ISBN No. 978-615-23362-8). She has 2 PubMed publications.

  • Jet Bliek

    Jet Bliek is Laboratory Lead, Academic Medical Center Department of Clinical Genetics, University of Amsterdam, Netherlands. Her interests include basic and clinically applied research on the genetic aetiology of Beckwith–Wiedemann syndrome and associated childhood tumours; genomic imprinting; innovation of DNA-diagnostics for imprinting disorders; mechanisms of genomic imprinting; and epigenetic gene regulation in clinical conditions including trauma, child abuse and neglect and fetal alcohol syndrome. She has 44 publications including development and validation of novel diagnostic methods and epigenotype–phenotype correlations in imprinting disorders.

  • Ana P. M. Canton

    Ana Pinheiro Machado Canton is a post-doctorant (clinical fellow) in Paediatric Endocrinology, Paediatric Departament of Clinical and Biological Investigations in Endocrinology, Hospital Armand Trousseau, Saint-Antoine Research Center, Paris, France. Her research interests are in genetics and epigenetics of growth and pubertal disorders, including small for gestational age, Silver–Russell syndrome (SRS) and SRS-like conditions.

  • Krystyna H. Chrzanowska

    Krystyna Chrzanowska is a Paediatrician and Consultant in Clinical Genetics, Full Professor and Head of the Genetic Counseling Unit, Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland. Her special interest is in clinical and molecular aspects of dysmorphic syndromes, chromosomal instability syndromes (notably Nijmegen and Warsaw breakage syndromes) and imprinting disorders including Silver–Russell syndrome. She has over 130 original publications (89 in PubMed), review articles and book contributions.

  • Justin H. Davies

    Justin Davies is a Consultant in Paediatric Endocrinology and Diabetes, University Hospital Southampton, and senior lecturer in child health, University of Southampton, UK. His research interest is in childhood bone disorders and diseases affecting body composition in children. He is service lead for paediatric endocrinology and has initiated a national multidisciplinary specialist service for Silver–Russell syndrome. He has over 50 publications on a wide range of childhood endocrine and imprinting disorders and is Chair-Elect of the British Society for Paediatric Endocrinology and Diabetes.

  • Renuka P. Dias

    Renuka P. Dias is a Consultant in Paediatric Endocrinology, Birmingham Children's Hospital NHS Foundation Trust, UK. Her research interests include genetic aetiology, growth, body composition, cognition and long-term metabolic profiles of children and adolescents with imprinting disorders or born small for gestational age, including those with Silver–Russell syndrome (SRS). She has 15 PubMed publications, including papers on the development and assessment of a SRS clinical scoring system.

  • Béatrice Dubern

    Béatrice Dubern is an Associate Professor of Pediatric Nutrition and Gastroenterology, Hôpital Armand-Trousseau, Paris, France; Gastroenterologist and Nutritionist of the French reference center for Silver–Russell syndrome (coordinator Professor I. Netchine). Her research focus is on genetic aetiology, growth, body composition and long-term complications of obese children and adolescents, and on digestive manifestations and nutritional management of children born small for gestational age including those with Silver–Russell syndrome and Prader–Willi syndrome. She has 47 major PubMed publications on these topics.

  • Miriam Elbracht

    Miriam Elbracht is a clinical geneticist (Fachärztin für Humangenetik) at Institute of Human Genetics, RWTH Aachen University Hospital, Aachen, Germany. She is senior physician at the Institute of Human Genetics at RWTH Aachen University Hospital, with responsibilities for patient care and university education and tasks. She is a close collaborator of Professor Thomas Eggermann regarding scientific, clinical and academic studies on imprinting disorders. She has 22 PubMed publications including papers on the differential diagnoses of Silver–Russell syndrome.

  • Eloise Giabicani

    Eloise Giabicani is an Assistant Professor in Pediatric Endocrinology, Armand Trousseau Hospital, Paris, France. Her career is focused on diagnosis, clinical care and research on Silver–Russell syndrome, growth disorders and precocious puberty.

  • Adda Grimberg

    Adda Grimberg is an Associate Professor of Pediatrics, Perelman School of Medicine, University of Pennsylvania, USA, and Scientific Director, Diagnostic and Research Growth Center, The Children's Hospital of Philadelphia, USA. Her research focus, attested by 48 publications, is on the growth hormone (GH)/insulin-like growth factor 1 (IGF1) axis and clinical issues related to child growth, including disparities in the evaluation and management of growth faltering in primary care. She is Chair of the task force charged with drafting new guidelines for GH and rhIGF1 use in children and adolescents for the Pediatric Endocrine Society and is a representative of the Pediatric Endocrine Society for the SRS Clinical Consensus.

  • Karen Grønskov

    Karen Grønskov is a Senior Scientist, Clinical Genetic Clinic, Kennedy Center, Rigshospitalet, University of Copenhagen, Denmark. Her research interests include identification of (epi)genetic mechanisms involved in eye development and diseases such as oculocutanoeous albinism, retinal dystrophies, microphthalmia, optic atrophy, glaucoma and aniridia, as well as genetic causes of imprinting disorders including Beckwith–Wiedemann and Silver–Russell syndromes. She is a Working group leader in COST Action BM1208 – EUCID.net on imprinting disorders. She has 58 publications, including papers on genetic rearrangements and mutations underlying imprinting disorders.

  • Anita C. S. Hokken-Koelega

    Anita C. S. Hokken-Koelega is a Professor of Pediatric Endocrinology, Head of Pediatric Endocrinology and head of Dutch Expert Center for Rare Growth Disorders (including Silver–Russell syndrome), Erasmus University Medical Center Rotterdam and Sophia Children's Hospital, Rotterdam, Netherlands, and Director of the Dutch Growth Research Foundation, Netherlands. Her research interests include genetic aetiology, growth, body composition, cognition and long-term metabolic profile of children and adolescents born small for gestational age, including those with Silver–Russell syndrome and Prader–Willi syndrome, and the short-term and long-term effects of growth hormone treatment on these parameters. She has over 280 research publications in these fields.

  • Alexander A. Jorge

    Alexander Augusto de Lima Jorge is Associate Professor of Medicine at The University of Sao Paulo (USP), School of Medicine, and Principal Investigator of the Genetic-Endocrinology Unit of the Endocrinology Division, Brazil. He is responsible for a growth disorders outpatient clinic (400 patients per year, including 30–40 patients with Silver–Russell syndrome). He is a member and delegate of the Latin American Society of Pediatric Endocrinology. His research interest is in genetic causes of growth disorders, and he has 91 publications. He is a representative of Sociedad Latino-Americana de Endocrinología Pediátrica (SLEP) for the SRS Clinical Consensus.

  • Masayo Kagami

    Masayo Kagami is Chief of Clinical Endocrine Research Division, Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Japan. Dr Kagami's research interests include growth failure and imprinting disorders, including the first description of Kagami–Ogata syndrome and epigenotype–phenotype correlations in Silver–Russell syndrome-like syndromes. She has 37 publications, including major contributions to clinical and molecular description of chr14-related imprinting disorders.

  • Agnes Linglart

    Agnès Linglart is a Professor of Paediatrics (specialized in paediatric endocrinology and metabolic bone diseases), Department of Paediatric Endocrinology and Diabetology, Kremlin Bicêtre (APHP) Hospital, Le Kremlin-Bicêtre Paris, France. She is an international expert in imprinting disorders, in particular in GNAS-related diseases. She is Leader of the reference centre of rare diseases of calcium–phosphorus metabolism INSERM U1169, Paris Sud Paris Saclay University. She is President of the National French Society of Pediatric Endocrinology and Diabetology. She is Chair of the EuroPHP network and working group leader in COST Action BM1208 – EUCID.net on imprinting disorders. She has 78 PubMed publications, with a focus on genetics, epigenetics, diagnosis and care of GNAS-related disorders.

  • Mohamad Maghnie

    Mohamad Maghnie is Head of Clinical Pediatrics and Endocrine Unit, Giannina Gaslini Institute, University of Genoa, Italy. He is President of the Italian Society for Paediatric Endocrinology and Diabetology (ISPED) and co-author of the Yearbook of Paediatric Endocrinology (2004–2009). His research interests include the aetiology of growth abnormalities, the investigation and treatment of growth hormone deficiency, and the management of paediatric pituitary disorders, with over 155 PubMed scientific publications in these fields.

  • Klaus Mohnike

    Klaus Mohnike is an Extraordinary Professor at the Department of Pediatrics, Otto-von-Guericke-University Magdeburg, Germany: Central-German Network for Rare Diseases (Mitteldeutsches Netzwerk für seltene Erkrankungen, MKSE), and Deputy Chairman, Bundesverband Kleinwüchsige Menschen und ihre Familien (BKMF e.V.). His specialism is in metabolism and endocrinology with over 130 PubMed publications across a broad range of disorders.

  • David Monk

    David Monk is a Principal Investigator of the Imprinting and Cancer group in the Cancer Epigenetic and Biology Program, Institut d'Investigació Biomedica de Bellvitge, Hospital Duran i Reynals, Barcelona, Spain. His PhD studies were on Silver–Russell syndrome (SRS), specifically characterisation of chr7 microduplications in SRS probands and methylation-based screening to identify imprinted genes. His career focus is on imprinted genes in human development, including imprinting disorders, nonsyndromic growth failure and cancer. He is a Working Group Leader in COST Action BM1208 – EUCID.net on imprinting disorders. He has 75 publications, including characterization of SRS imprinted genes and genome-wide characterizations of imprinting.

  • Gudrun E. Moore

    Gudrun Elisabeth Moore is Professor of Clinical & Molecular Genetics, UCL Institute of Child Health, University College London, UK. She is Director of the International Resource for Pregnancy Complications, Baby Bio Bank. Her career focus is on genomic imprinting, with over 150 publications on imprinted genes and their relevance to normal growth and development, and (epi)genetic characterization of imprinting disorders.

  • Philip G. Murray

    Philip Murray is an NIHR Clinical Lecturer in Paediatric Endocrinology, University of Manchester, and Consultant Paediatric Endocrinologist at the Royal Manchester Children's Hospital, Manchester, UK. He is a clinical and academic paediatric endocrinologist with 22 publications attesting to research interests in the diagnosis and pathogenesis of short stature disorders focusing on children born small for gestational age. He is a participant in the Silver–Russell syndrome consensus meeting as representative of clinical practice committee, European Society of Pediatric Endocrinology (ESPE), and contributor of the differential diagnosis tables.

  • Tsutomu Ogata

    Tsutomu Ogata is Professor, Department of Pediatrics, Hamamatsu University School of Medicine, Japan; Visiting Director, Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Japan. Professor Ogata is President of the Japanese Society for Pediatric Endocrinology. His career spans research interests (with over 300 publications) in imprinting disorders, growth failure, disorders of sex development and congenital malformation syndromes. He is a representative of the Asian Pacific Pediatric Endocrine Society (APPES) for the SRS Clinical Consensus.

  • Isabelle Oliver Petit

    Isabelle Oliver Petit is at the Children's Hospital, Centre Hospitalier Universitaire, Toulouse, France. She is an experienced clinician in the Department of Paediatric Endocrinology, Genetic, Bone Disease and Gynaecology, and for the Rare Disease national reference centre for Prader–Willi syndrome. Her research interests are in growth disorders, growth hormone treatment in childhood diseases, rare genetic diseases with small for gestational age and endocrine diseases in paediatric oncology. She is the French clinical coordinator for NESTEGG (Network of European Studies of genes in Growth).

  • Silvia Russo

    Silvia Russo is Group Leader, Cytogenetic and Molecular Genetic Laboratory, Istituto Auxologico Italiano, I.R.C.C.S., Milano, Italy. She is Group Leader for diagnostic and research activities of rare Mendelian diseases and imprinting disturbances (Beckwith–Wiedemann, Silver–Russell syndrome (SRS), Angelman syndrome, Prader–Willi syndrome, Cornelia de Lange X-linked Mental Retardation, including Fragile X and Rett Syndrome) and susceptibility to multifactorial pathologies, in particular autism. She is interested in diagnosis and translational research in SRS, in close collaboration with clinical colleagues. She is a founding Member of the Italian National SRS Association. She uses genomic tools (exome sequences, SNParray) to investigate origins of imprinting disorders. She has 80 publications focusing on translational research and diagnosis of (epi)genetic disorders.

  • Edith Said

    Edith Said is a Consultant Medical Geneticist & Head of Section of Clinical Genetics & Cytogenetics, Mater dei Hospital, Malta, and Resident Academic Senior Lecturer, Department of Anatomy and Cell Biology, University of Malta. Her special interest is in clinical genetics and dysmorphology, cryptic chromosomal rearrangements and imprinting disorders. She is responsible for paediatric genetic clinics with over 750 consultations a year, at least a third of which are related to growth disorders. She has over 30 original publications, including 10 in PubMed.

  • Meropi Toumba

    Meropi Toumba is a Consultant in Pediatrics and Pediatric Endocrinology, IASIS Hospital, Paphos, Cyprus; Scientific Associate, Cyprus Institute of Neurology and Genetics, with a special interest in small for gestational age (SGA) and Silver–Russell syndrome (SRS). Dr Toumba underwent specialist training in Paediatrics (Hippokration General Hospital, Aristotelion University, Thessaloniki, Greece) and Paediatric Endocrinology (Great Ormond Street Hospital for Sick Children, London, UK). She has received an ESPE Clinical Fellowship to study Silver–Russell syndrome (SRS) with Dr Richard Stanhope at GOSH, London, UK. She is a visiting clinician at MAGIC foundation convention, USA. Dr Toumba has 22 PubMed publications, including papers on the metabolic status of SGA children and GH treatment in SRS.

  • Zeynep Tümer

    Zeynep Tümer is Professor and Chief of R&D, Applied Human Molecular Genetics, Kennedy Center, Rigshospitalet, University of Copenhagen, Denmark. She has 20 years' experience in classic and molecular cytogenetic analysis. She has been leader of microarray diagnostic facilities at the Kennedy Center since 2008 and leader of cytogenetics (Medical Genetics Clinic, ICMM, KU) for 4 years. Her main research interest is use of genomic technology (including array and next-generation sequencing strategies) to define genetic and/or epigenetic mechanisms of brain and/or neurological disorders such as Menkes disease, Tourette syndrome, intellectual disabilities, developmental and congenital disorders. She is a Board member of European Society of Human Genetics (ESHG) and Working Group Leader in COST Action BM1208 – EUCID.net on imprinting disorders. She has over 160 peer-reviewed publications spanning a broad range of human genetic disorders.

  • Gerhard Binder

    Gerhard Binder is Associate Professor, University of Tübingen, and Head of Paediatric Endocrinology, University Children's Hospital, Tübingen, Germany. He is Head of the German Working Group on Growth. His career focus is on diagnosis and management of growth disorders in children, with over 140 publications across these topics.

  • Thomas Eggermann

    Thomas Eggermann is head of laboratory at the Institute of Human Genetics, RWTH Aachen, Germany, and is vice-chair of the German Society of Human Genetics and chair of the COST Action BM1208 – EUCID.net. He provides national and international leadership in molecular diagnosis and translational research on genetic and epigenetic disorders with particular interest in imprinting disorders, and has over 230 publications across these fields.

  • Madeleine D. Harbison

    Madeleine Harbison is Assistant Professor of Pediatrics in the Genetic Endocrinology, Adrenal and Steroid Disorders Group, Mount Sinai School of Medicine, New York, USA, and Assistant Attending Physician at the Department of Pediatrics, Mount Sinai Hospital, New York, USA. She is a pioneer in clinical diagnosis and care of patients with Silver–Russell syndrome. She has 20 PubMed publications.

  • I. Karen Temple

    I. Karen Temple is Professor of Medical Genetics in the Faculty of Medicine, University of Southampton; Honourary Consultant in Clinical Genetics at University Hospital Southampton; Director of the Academic Unit of Human Development and Health, University of Southampton, UK, and Co-lead of the Wessex Genome Medicine centre. She is Past President of the Clinical Genetics Society; Working Group Leader in COST Action BM1208 – EUCID.net on imprinting disorders; and instigator of UK national specialist service for imprinting disorders. Her career interests are in genetics, epigenetics and clinical characterization of childhood developmental disorders, as evidenced by over 180 research publications, including descriptions of transient neonatal diabetes mellitus (TNDM) and Temple syndrome (TS14).

  • Deborah J. G. Mackay

    Deborah J. G. Mackay is Professor of Medical Epigenetics, Faculty of Medicine, University of Southampton, UK. Her research interests are in identification of genetic and epigenetic causes of imprinting disorders, including definition of the archetypal multi-locus imprinting disorder, and identification of causative mutations in ZFP57 and NLRP5. She is a Working Group Leader in COST Action BM1208 – EUCID.net on imprinting disorders. She has over 80 publications in research and diagnosis of human imprinting disorders.

  • Irène Netchine

    Irène Netchine is Professor of Physiology at Pierre & Marie Curie School of Medicine, Armand Trousseau Children's Hospital, Paris, France; coordinator of the Departments of Paediatric Endocrinology and the Molecular Diagnosis Laboratory concerning growth disorders, and an INSERM research team leader. She is a research pioneer in Silver–Russell syndrome (SRS) with 60 PubMed publications, and her current research interests include the role of the insulin-like growth factor (IGF) system in intrauterine growth retardation and imprinting anomalies leading to fetal growth disorders. She is an instigator of the French multidisciplinary clinical services for SRS and Beckwith–Wiedemann syndrome; Vice-chair of COST Action BM1208 – EUCID.net on imprinting disorders; ESPE research unit coordinator; and the Chair of the first Silver–Russell International Consensus.

Supplementary information

PDF files

  1. Supplementary information S1 (table) (232 KB)

    Frequency of clinical features in patients with SRS and SGA

  2. Supplementary information S2 (table) (232 KB)

    Genetic variants on chromosome 11p15

  3. Supplementary information S3 (table) (152 KB)

    Genetic variants on chromosome 7

  4. Supplementary information S4 (table) (128 KB)

    Adult height data in SRS patients untreated with GH

  5. Supplementary information S5 (1.34 MB)

    Summary of recommendations

Additional data