Silver–Russell syndrome (SRS, OMIM #180860, also known as Russell–Silver syndrome, RSS) is a rare, but well-recognized, imprinting disorder with prenatal and postnatal growth retardation. SRS is currently a clinical diagnosis and is defined based on a clinical scoring system ¹: Table 1.

However, many conditions can clinically overlap with SRS, such as Temple Syndrome ². It is critical to make an accurate diagnosis, because for some of these conditions, some treatments may be contraindicated, such as growth hormone replacement in Bloom or Mulibrey syndrome for example. Differential diagnoses of SRS have been recently reviewed, with some specific traits besides Fetal Growth Restriction (FGR). In cases of FGR, head circumference and early feeding difficulties are cornerstone traits to distinguish between these various conditions. Furthermore, relative macrocephaly will expose to a high risk of hypoglycemia, which should be carefully monitored ³. Molecular testing can confirm the diagnosis in around 60% of patient and enables stratification of patients with SRS into subgroups, which can lead to more tailored management. Insulin-like growth factor 2 (a major fetal growth factor) has been implicated in the pathophysiology of SRS, as the principle molecular mechanism underlying the disease is loss of methylation of the 11p15 region, including the imprinted insulin-like growth factor 2 gene. Maternal uniparental disomy of chromosome 7 and recently identified rare molecular defects (including PLAG1, HAMGA2 and IGF2 genetic defects) have also been reported in patients with SRS ⁴.  A ‘normal’ result from a molecular test does not exclude the diagnosis of SRS. The first Consensus Statement on Silver Russell Syndrome has been held in 2015, on behalf of the COST Action BM1208 (European Network for Human Congenital Imprinting Disorders, http://www.imprinting-disorders.eu), ESPE, PES, APPES and SLEP with the participation of five representatives from a parent support group from different countries. It has been first published in 2016 ³. For dissemination, a patient « friendly » document has been generated and has been or will shortly be translated into seven languages (https://silverrussellsyndrome.org/). This consensus summarizes recommendations for clinical diagnosis and  molecular investigation and management of patients with SRS. 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. 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, sleep apnea 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 ³.

1. Azzi S, Salem J, Thibaud N, Chantot-Bastaraud S, Lieber E, Harbison MD*, Netchine I. A prospective study validating a clinical scoring system and demonstrating phenotypicalgenotypical correlations in Silver-Russell syndrome. Journal of medical genetics. 2015;52:446-53.[Pubmed]

2. Geoffron S, Abi Habib W, Chantot-Bastaraud S, Dubern B, Steunou V, Azzi S, Afenjar A, Busa T, Pinheiro Canton A, Chalouhi C, Dufourg MN, Esteva B, Fradin M, Geneviève D, Heide S, Isidor B, Linglart A, Morice Picard F, Naud-Saudreau C, Oliver Petit I, Philip N, Pienkowski C, Rio M, Rossignol S, Tauber M, Thevenon J, Vu-Hong TA, Harbison MD, Salem J, Brioude F, Netchine I, Giabicani E. J Clin Endocrinol Metab. 2018;103(7):2436-46. doi: https://doi.org/10.1210/jc.2017-02152.

3. Wakeling EL, Brioude F, Lokulo-Sodipe O, O'Connell SM, Salem J, Bliek J, Canton APM, Chrzanowska KH, Davies JH, Dias RP, Dubern B, Elbracht M, Giabicani E, Grimberg A,Gronskov K, Hokken-Koelega ACS, Jorge AA, Kagami M, Linglart A, Maghnie M,Mohnike K, Monk D, Moore GE, Murray PG, Ogata T, Petit IO, Russo S, Said E, Toumba, M, Tumer Z, Binder G, Eggermann T, Harbison MD, Temple IK, Mackay DJG, Netchine I. Diagnosis and management of Silver-Russell syndrome: first international consensus statement. Nature Reviews Endocrinology. 2017;13:105-24, 2017. https://www.nature.com/articles/nrendo.2016.138.

4. Abi Habib W, Brioude, F, Edouard T, Bennett JT, Lienhardt-Roussie A, Tixier F, SalemJ, Yuen T, Azzi S, Le Bouc Y, Harbison MD, Netchine I. Genetic disruption of the oncogenic HMGA2–PLAG1–IGF2 pathway causes fetal growth restriction. Genetics in Medicine. 2018;20:250-8. doi: https://doi.org/10.1038/gim.2017.105.