Silver-Russell syndrome

Silver-Russell syndrome (SRS) is a genomic imprinting condition characterised by intrauterine growth restriction, poor postnatal growth, relatively large head size, prominent forehead, body asymmetry and feeding issues.

Clinical features of SRS include:

• intrauterine growth restriction, or a fetus that is small for gestational age;
• short stature with no postnatal ‘catch-up’ growth;
• relative macrocephaly (more than 1.5 standard deviations (1.5SD) above the patient’s height and weight), with a prominent forehead;
• body asymmetry;
• feeding difficulties;
• gastrointestinal problems, including gastroesophageal reflux, delayed gastric emptying and constipation;
• increased risk of hypoglycaemia due to lack of appetite and/or subcutaneous fat;
• normal intelligence (this is the case for most children with SRS, though delays in motor and/or speech development are common and affected children are more likely to have cognitive and behavioural issues due to maternal uniparental disomy (UPD) of chromosome 7);
• orthopaedic problems, such as scoliosis, hip dislocation and fifth finger clinodactyly;
• genitourinary problems in some boys, such as cryptorchidism and hypospadias; and
• absence of microcephaly (children with SRS are almost never microcephalic – occipitofrontal head circumference is typically at or below the third centile).

SRS is a genetically heterogeneous condition that may be caused by:

• hypomethylation at the imprinted 11p15.5 region (30%–60% of cases);
• maternal UPD of chromosome 7 (5%–10% of cases);
• copy number variants of the imprinted 11p15.5 region (rare); or
• pathogenic variants affecting the IGF2, HMGA2, PLAG1 or CDKN1C genes (fewer than 1% of cases).

Individuals with suspected SRS are assessed using the Netchine-Harbison clinical scoring system, which involves the following criteria:

• small for gestational age (birth weight and/or length is at least 2SD below the mean);
• postnatal growth failure (length and/or height is at least 2SD below the mean at 24 months);
• relative macrocephaly at birth (head circumference is more than 1.5SD above birth weight and/or length);
• frontal bossing or prominent forehead (forehead projecting beyond the facial plane on a side view as a toddler (one to three years of age));
• body asymmetry (limb length discrepancy more than 0.5cm, or less than 0.5cm with more than two other asymmetric body parts, one non-face); and
• feeding difficulties or body mass index at least 2SD below the mean at 24 months, or current use of a feeding tube or cyproheptadine for appetite stimulation.

If an individual meets at least three of these six criteria, and there is a clinical suspicion of SRS, genomic testing should be arranged.

Molecular investigation of suspected SRS should start with ‘R452 Silver Russell Syndrome and Temple Syndrome’, which includes methylation analysis of chromosome 11p15.5 and chromosome 7. This test also includes 14q32 methylation analysis for Temple syndrome, as this is an important differential for SRS. If R452 testing returns a normal result, ‘R453 Monogenic short stature’ panel testing should be considered.

For more information about testing, please see Presentation: Clinical suspicion of Silver-Russell syndrome.

In around 30%–40% of individuals with a suspected clinical diagnosis who meet criteria for molecular testing, no molecular cause can be established. A clinical diagnosis can still be made under certain conditions; however, it is important to rule out differential diagnoses by molecular testing before giving a diagnosis of clinical SRS because doing so may have important implications for management.

Genomic counselling for SRS is complex because the recurrence risk depends on the underlying genetic mechanism. This should, therefore, be established before advice is given.

In the majority of cases, SRS occurs in a single individual in a family as a result of a de novo genetic or epigenetic change (such as maternal uniparental disomy (UPD) of chromosome 7 or loss of paternal methylation at 11p15.5). In this case, the likelihood of recurrence in a subsequent child is low (less than 1%).

In a minority of cases, SRS may occur as a result of a copy number variant on chromosome 7 or 11, or due to a pathogenic variant in IGF2, HMGA2, PLAG1 or CDKN1C. Under these circumstances, the likelihood of recurrence in a subsequent child can be much higher – up to 1 in 2 (50%). The recurrence risk under these circumstances can be affected by which parent carries the genetic change, so advice should be sought from your local clinical genetics service, with each case considered on an individual basis.

Management of children and adults with SRS is complex and should be delivered through a multidisciplinary team. Detailed suggested approaches have been published by several authors, including an international consensus statement on the diagnosis and management of the condition.

For clinicians

• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• National Organization for Rare Disorders: Silver-Russell syndrome
• NHS England: National Genomic Test Directory
• Patient Info: Silver-Russell syndrome
• US National Library of Medicine: ClinicalTrials.gov database

References:

• Azzi S, Salem J, Thibaud N and others. ‘A prospective study validating a clinical scoring system and demonstrating phenotypical-genotypical correlations in Silver-Russell syndrome’. Journal of Medical Genetics 2015: volume 52, issue 7, pages 446–453. DOI: 10.1136/jmedgenet-2014-102979
• Wakeling E, Brioude F, Lokulo-Sodipe O and others. ‘Diagnosis and management of Silver–Russell syndrome: first international consensus statement’. Nature Reviews Endocrinology 2017: volume 13, pages 105–124. DOI: 10.1038/nrendo.2016.138

For patients

• Child Growth Foundation: Silver Russell syndrome
• Child Growth Foundation and Silver Russell Syndrome Global Alliance: Highlights and summary of ‘Diagnosis and management of Silver-Russell syndrome: First international consensus statement’ (PDF, 12 pages)
• Silver Russell Syndrome Global Alliance
• The Magic Foundation: Russell Silver syndrome