Growth Restriction, Relative Macrocephaly and Hemihypoplasia
- RUSSELL-SILVER SYNDROME (also written Silver-Russell syndrome) is an IMPRINTING DISORDER causing prenatal AND postnatal growth restriction. Diagnosis is primarily CLINICAL, using the Netchine-Harbison Clinical Scoring System (NH-CSS): small for gestational age, postnatal growth failure, relative macrocephaly at birth, body asymmetry, feeding difficulties or low BMI, and protruding forehead at age 1-3 years. At least FOUR of these SIX criteria indicate likely Russell-Silver syndrome; the system was 98% sensitive for patients with a demonstrated molecular abnormality (Azzi 2015).
- GET THE IMPRINTING DIRECTION RIGHT. The commonest mechanism is an EPIMUTATION - DEMETHYLATION (loss of methylation) of the telomeric imprinting centre ICR1 at 11p15 - which relaxes imprinting, produces BIALLELIC expression of the growth-suppressing H19 and DOWNREGULATES the growth-promoting IGF2 (Gicquel 2005). The second mechanism is MATERNAL UNIPARENTAL DISOMY OF CHROMOSOME 7, present in about 10% of affected individuals. Less IGF2 means less growth: the phenotype is restriction, not overgrowth.
- THE ASYMMETRY IS HEMIHYPOPLASIA: the affected side is SMALLER because it grows less, not because the other side overgrows. This is the exact mirror image of Beckwith-Wiedemann syndrome, which arises from OPPOSITE epigenetic alterations at the SAME 11p15 locus and produces hemihyperplasia (Shin 2021). The clinical consequence is a PROGRESSIVE limb-length discrepancy in a child who is already short.
- THE ORTHOPAEDIC WORKLOAD is limb-length discrepancy and spinal deformity. Scoliosis and/or kyphosis was found in 21% of 163 people with Russell-Silver syndrome, and 18% of those affected underwent corrective surgery (Yamaguchi 2015). For discrepancy, first-line care is a shoe raise; definitive surgery in the published guidance is LENGTHENING of the short side rather than reflex epiphysiodesis of the long side, because shortening the long limb spends stature that this child cannot afford - untreated adult height averages about 3.1 SD below the mean.
- PERIOPERATIVE SAFETY IS A SEPARATE DISCIPLINE. Prolonged fasting is explicitly to be avoided because of ketotic hypoglycaemia; elective surgery is to be avoided where possible because of hypoglycaemia, HYPOTHERMIA, difficult healing and DIFFICULT INTUBATION (GeneReviews). Children with Russell-Silver syndrome develop spontaneous hypoglycaemia if not fed frequently and regularly, and hypoglycaemia may be ASYMPTOMATIC (Azcona 2005). TESTING FOR GROWTH HORMONE DEFICIENCY BY FASTING IS CONTRAINDICATED.
- TUMOUR SURVEILLANCE IS NOT PART OF RUSSELL-SILVER CARE. The consensus surveillance schedule and the GeneReviews surveillance table cover growth, hypoglycaemia, nutrition, limb length, scoliosis, puberty and development - not tumour screening. The tumour-surveillance logic belongs to hemiHYPERplasia (overgrowth), and even there the measured incidence of abdominal neoplasm in isolated hemihyperplasia was only 1.2% (3 of 250), prompting a recommendation of genetic referral to identify high-risk subgroups rather than blanket imaging (Dempsey-Robertson 2012).
- “NH-CSS: 4 of 6 criteria = likely Russell-Silver syndrome; 98% sensitive for molecularly proven cases.
- “LOSS of methylation at paternal ICR1 → biallelic H19, DOWNregulated IGF2 → growth restriction (not overgrowth).
- “Asymmetry = hemihypoplasia (smaller side). Beckwith-Wiedemann = hemihyperplasia at the same locus, opposite direction.
- “Relative macrocephaly is RELATIVE: head circumference at least 1.5 SD above birth weight and/or length - the head is normal, the body is small.
- “A normal molecular test does NOT exclude the diagnosis (only about 60% are confirmed).
- “Never fast this child: ketotic hypoglycaemia, sometimes asymptomatic. First on the list, short starve, glucose-containing fluids.
- “No tumour surveillance programme - that belongs to hemihyperplasia, not hemihypoplasia.
Russell-Silver asymmetry is hemiHYPOplasia: the affected side is smaller because it grows less. Beckwith-Wiedemann syndrome arises from the opposite epigenetic alteration at the same 11p15 locus and produces hemiHYPERplasia. Two disorders, one locus, opposite directions - and therefore opposite surveillance logic.
Low muscle and fat mass plus poor appetite means accelerated starvation and ketotic hypoglycaemia, which may be asymptomatic. Prolonged fasting and avoidable elective surgery are on the explicit avoid-list, alongside hypothermia, difficult healing and difficult intubation. A standard nil-by-mouth order is a genuine hazard in this child.
Overview, Epidemiology & Historical Context
Russell-Silver syndrome is a congenital disorder of growth in which restriction begins before birth and continues after it. The child is born small for gestational age, fails to show catch-up growth, and grows along a low centile with a head that looks disproportionately large for a small, lean, asymmetric body. It is one of the classic imprinting disorders, and its defining teaching point for orthopaedic examinations is that it is the growth-restricted mirror image of Beckwith-Wiedemann syndrome at the same chromosomal locus.
- Two independent original descriptions. Silver and colleagues (1953) described a syndrome of congenital hemihypertrophy, shortness of stature and elevated urinary gonadotropins in Pediatrics. Russell (1954) described a syndrome of intra-uterine dwarfism recognizable at birth with cranio-facial dysostosis, disproportionately short arms, and other anomalies in the Proceedings of the Royal Society of Medicine. Both names persist; Silver-Russell syndrome dominates the endocrine and genetics literature and Russell-Silver syndrome the paediatric and orthopaedic literature. They are the same condition.
- A historical trap worth noticing. Silver's original title says hemihypertrophy. It is now understood that the asymmetry of this syndrome is hypoplasia of the affected side - the side that grows less - rather than hypertrophy of the other. GeneReviews states it plainly: limb-length asymmetry is caused by hypoplasia or hemihypoplasia with diminished growth of the affected side. The 1953 title is a historical artefact, not a description of the mechanism.
- How common. Prevalence is not precisely known. It was long estimated at 1 in 30,000 to 1 in 100,000. The best population-based figure comes from a retrospective Estonian analysis of all molecularly and clinically diagnosed imprinting disorders from 1998 to 2016, which gave a minimum live-birth prevalence of 1 in 15,866 for Silver-Russell syndrome and concluded that the worldwide prevalence is likely underestimated and may be at least three times higher than expected (Yakoreva 2019). More than 1,000 individuals have been reported in the literature.
- Why the orthopaedic surgeon meets these children. Two referral routes dominate: a progressive limb-length discrepancy noticed when the child walks or when leg lengths are plotted at surveillance visits, and a spinal deformity found at routine examination. A third, less obvious route is preoperative: the anaesthetic and metabolic risk profile means the orthopaedic team is often the service that has to build the safe perioperative pathway.
Genetics & Pathophysiology - Getting the Direction Right
The 11p15 imprinted domain controls fetal growth. Gicquel and colleagues (2005) identified an epimutation - demethylation - in the telomeric imprinting centre region ICR1 of 11p15 in individuals with clinically typical Silver-Russell syndrome. This epigenetic defect is associated with, and probably responsible for, relaxation of imprinting and BIALLELIC expression of H19 with DOWNREGULATION of IGF2. IGF2 is the growth-promoting gene; H19 opposes growth. Removing methylation from the paternal ICR1 therefore switches the paternal allele towards the maternal (H19-expressing, IGF2-silent) pattern - and the fetus grows less. Maternal uniparental disomy of chromosome 7 accounts for approximately 10% of affected individuals.
Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome
- Silver-Russell syndrome is characterised by severe intrauterine AND postnatal growth retardation, dysmorphic facial features and body asymmetry.
- Maternal uniparental disomy of chromosome 7 occurs in approximately 10% of affected individuals - the condition is genetically heterogeneous.
- An epimutation - DEMETHYLATION - was identified in the telomeric imprinting centre region ICR1 of 11p15 in several individuals with clinically typical Silver-Russell syndrome.
- The epigenetic defect is associated with, and probably responsible for, relaxation of imprinting with BIALLELIC expression of H19 and DOWNREGULATION of IGF2.
- The 11p15 imprinted region, in addition to 7p11.2-p13 and 7q31-qter, is therefore involved in Silver-Russell syndrome.
- The same locus, two directions, two syndromes. Shin and colleagues (2021) put the relationship in one line: Beckwith-Wiedemann syndrome and Silver-Russell syndrome are opposite growth-affecting disorders caused by opposite epigenetic alterations at the same chromosomal locus, 11p15, to induce hemihyperplasia and hemihypoplasia, respectively. Because both are somatically mosaic, both show a wide spectrum of clinical phenotypes, and an isolated hemihypoplasia or hemihyperplasia can be the only manifestation.
- Frequency of each mechanism in clinically scored patients. In the prospective validation cohort of 69 patients, of the 60 classified as Likely Silver-Russell syndrome, 46 (76.7%) had a molecular abnormality: 11p15 ICR1 hypomethylation in 35 (58.3%) and maternal UPD7 in 11 (18.3%) (Azzi 2015). GeneReviews gives broader literature ranges of 35-67% for ICR1 loss of methylation and 7-10% for upd(7)mat, with genetic testing confirming the clinical diagnosis in approximately 60% of affected individuals overall.
- The rarer mechanisms matter for counselling. Duplications, deletions and translocations involving the 11p15.5 imprinting centres or chromosome 7 occur, and rare pathogenic variants in CDKN1C, IGF2, PLAG1 and HMGA2 have been described. Most probands are simplex cases from an apparent de novo epigenetic or genetic alteration with a very low recurrence risk, but Russell-Silver syndrome can result from a genetic alteration carrying up to a 50% recurrence risk, depending on the nature of the alteration and the sex of the transmitting parent - which is precisely why the orthopaedic surgeon refers to clinical genetics rather than reassuring the family personally.
- Approximately 30-40% of individuals who meet the clinical criteria have no identifiable molecular abnormality. Consequently the consensus is explicit that a 'normal' result from a molecular test does not exclude the diagnosis of SRS (Wakeling 2017). The clinical score leads; the molecular test confirms and subtypes.
Q: A candidate says Russell-Silver syndrome is caused by hypermethylation of ICR1. Correct them.
A: It is the opposite. Russell-Silver syndrome is caused by LOSS of methylation (demethylation, hypomethylation) of the telomeric imprinting centre ICR1 at 11p15, which relaxes imprinting, gives biallelic expression of H19 and downregulates IGF2. Less IGF2 signalling means less fetal and postnatal growth. Gain of methylation at ICR1 sits on the Beckwith-Wiedemann/hemihyperplasia side of the locus. The memory device is simple: loss of methylation, loss of IGF2, loss of growth.
- Russell-Silver syndrome
- Prenatal AND postnatal growth restriction; untreated adult height averages about 3.1 SD below the mean
- Beckwith-Wiedemann syndrome
- Overgrowth
- Russell-Silver syndrome
- LOSS of methylation at ICR1 (H19/IGF2:IG-DMR); biallelic H19, downregulated IGF2
- Beckwith-Wiedemann syndrome
- Opposite alterations at the same locus - including loss of methylation at ICR2, gain of methylation at ICR1, and paternal UPD of 11p15
- Russell-Silver syndrome
- Maternal uniparental disomy of chromosome 7 (about 10%)
- Beckwith-Wiedemann syndrome
- Maternally inherited loss-of-function CDKN1C variant
- Russell-Silver syndrome
- HemiHYPOplasia - affected side SMALLER (68% have limb and/or facial asymmetry)
- Beckwith-Wiedemann syndrome
- HemiHYPERplasia - affected side LARGER
- Russell-Silver syndrome
- RELATIVE macrocephaly: head circumference at least 1.5 SD above birth weight and/or length; head growth itself is normal
- Beckwith-Wiedemann syndrome
- Macroglossia, facial naevus flammeus; not relative macrocephaly of this type
- Russell-Silver syndrome
- Feeding difficulties 84-100%; ketotic hypoglycaemia from accelerated starvation
- Beckwith-Wiedemann syndrome
- Neonatal hyperinsulinaemic hypoglycaemia
- Russell-Silver syndrome
- NOT part of the recommended surveillance schedule
- Beckwith-Wiedemann syndrome
- Embryonal tumour surveillance is standard practice
- Russell-Silver syndrome
- Progressive limb-length discrepancy in an ALREADY SHORT child - lengthening favoured over epiphysiodesis
- Beckwith-Wiedemann syndrome
- Limb-length discrepancy in a child of normal or above-average stature - epiphysiodesis of the long side is straightforward
Clinical Recognition & the Netchine-Harbison Clinical Scoring System
The Netchine-Harbison Clinical Scoring System (NH-CSS) is the diagnostic instrument. It has six items, all of them obtainable from the birth record, the growth chart and a clinic examination - no imaging and no laboratory test:
- Small for gestational age - birth length and/or weight at or below -2 SDS
- Postnatal growth retardation - height at or below -2 SDS
- Relative macrocephaly at birth
- Body asymmetry
- Feeding difficulties and/or BMI at or below -2 SDS in toddlers
- Protruding forehead at the age of 1-3 years
Threshold: at least four of the six items. In the prospective validation study, subjects meeting at least four criteria were classified as Likely Silver-Russell syndrome, and the system was 98% sensitive for detecting patients with demonstrated molecular abnormalities (Azzi 2015). GeneReviews frames the same threshold with an added qualifier used in practice: clinical diagnosis can be established in an individual who meets at least four NH-CSS criteria - prominent forehead/frontal bossing and relative macrocephaly at birth plus two additional findings - and in whom other disorders have been ruled out.
The Orthopaedic Problem I: Body Asymmetry & Limb-Length Discrepancy
In Russell-Silver syndrome the discrepancy sits inside a short child with low muscle mass, poor bone regenerative quality and a metabolic vulnerability to fasting. Every decision therefore answers three questions in order: how big will the discrepancy be at maturity, can I afford to spend stature to correct it, and can this child safely tolerate the operation I am proposing. The first is arithmetic, the second is a judgement about a child whose untreated adult height averages about 3.1 SD below the mean, and the third is a perioperative plan - not an afterthought.
What you are measuring. The asymmetry is hypoplasia of the affected side with diminished growth of that side. Because the short side grows more slowly, the absolute discrepancy increases with growth - this is a progressive, not a static, deformity. GeneReviews accordingly places examination and measurement of limb length discrepancy in the recommended surveillance schedule, with limb-length assessment at each well-child visit in early childhood.
How to project it. The multiplier method is the standard arithmetic (Paley 2000). Its premise fits this disorder exactly: in a congenital or developmental discrepancy, the short limb grows at a rate proportional to the long limb, so the discrepancy at maturity can be calculated as the current discrepancy multiplied by the age- and sex-specific multiplier, from as few as one or two measurements. For progressive developmental discrepancies, the maturity discrepancy is the current discrepancy plus the growth inhibition multiplied by the growth remaining. The same multiplier also times an epiphysiodesis, and the predictions correlated well with the Moseley straight-line-graph method and with the actual discrepancy in validation groups managed by epiphysiodesis or lengthening.
Treat the projection with appropriate scepticism. In a consecutive series of 16 patients managed by percutaneous epiphysiodesis with transphyseal screws, the mean error between predicted and final discrepancy was 0.2 cm (Green-Anderson), 1.4 cm (Moseley) and -0.1 cm (Paley), but with high variability - the three models predicted within an average of 1.4 cm (Monier 2015). Project, but re-measure and re-project at every visit rather than committing to a single early number.
A molecular aid on the horizon. In the prospective series of 30 patients with isolated hemihyperplasia/hemihypoplasia who underwent surgery for discrepancy, the methylation difference between 11p15 DMR1 and DMR2 correlated moderately with the standardised predicted discrepancy at maturity in fat tissue (r = 0.53, p = 0.002) and skin (r = 0.50, p = 0.005), leading the authors to propose that epigenetic testing may help predict the discrepancy and aid treatment planning (Shin 2021). This is a correlation in a small surgical cohort, not a clinical tool.
Hypoplasia means the affected limb grows more slowly, so the discrepancy widens with every year of growth. Two errors follow. The first is treating a single early measurement as the final figure - always project to maturity with the multiplier and re-project at each visit. The second is missing the surgical window: internal femoral distraction is described as being done before completion of growth but close to final attainment of height, and any epiphysiodesis must be timed off growth remaining. A child reviewed annually with plotted leg lengths never loses that window; a child reviewed when the parents complain usually has.
Prospective study of epigenetic alterations responsible for isolated hemihyperplasia/hemihypoplasia and their association with leg length discrepancy
- Beckwith-Wiedemann syndrome and Silver-Russell syndrome are described as opposite growth-affecting disorders caused by opposite epigenetic alterations at the same 11p15 locus, inducing hemihyperplasia and hemihypoplasia respectively; both are somatically mosaic with a wide phenotypic spectrum.
- Paired blood-tissue samples were collected prospectively from 30 patients with isolated hemihyperplasia/hemihypoplasia who underwent surgery for leg-length discrepancy.
- Ten patients (33%) showed epigenetic alterations on MS-MLPA and bisulfite pyrosequencing - six Beckwith-Wiedemann-related and four Silver-Russell-related.
- In four of these ten patients the clinical diagnosis of hemihyperplasia versus hemihypoplasia was NOT compatible with the epigenetic alteration found.
- The methylation difference between DMR1 and DMR2 correlated moderately with the standardised predicted discrepancy at skeletal maturity using fat tissue (r = 0.53; p = 0.002) and skin tissue (r = 0.50; p = 0.005).
- The authors note that accurate differentiation between isolated hemihyperplasia and hemihypoplasia is important for TUMOUR SURVEILLANCE PLANNING and is often clinically difficult without epigenetic testing.
Correction of the axial and appendicular deformities in a patient with Silver-Russell syndrome
- Scoliosis and limb-length discrepancy are identified as the major orthopaedic abnormalities in Silver-Russell syndrome.
- A 7-year-old girl with the full phenotype underwent seven operations between the ages of 7 and 13 years.
- Pemberton osteotomy treated right hip dislocation due to developmental dysplasia of the hip; spinal fusion from T3 to L5 corrected the scoliosis.
- A Taylor Spatial Frame with percutaneous distal femoral corticotomy, plus proximal tibial and foot correction, reduced a 15 cm limb-length discrepancy to 5 cm.
- The patient walked with a below-knee orthosis and a 5 cm shoe raise.
- The authors warn that limb lengthening in Silver-Russell syndrome carries a high recurrence risk because of muscular hypotonia, overtubulation of the long bones and poor bone regenerative quality.
The Orthopaedic Problem II: Spinal Deformity
Spinal deformity is common enough in Russell-Silver syndrome that it must be actively looked for at every review, and the only dedicated prevalence study puts real numbers on it.
Spinal Deformity in Russell-Silver Syndrome
- Cross-sectional analysis of 163 people with Russell-Silver syndrome identified through a national foundation, with radiographic review of coronal and sagittal Cobb angles in those reporting deformity.
- 24 of 163 (14%) reported scoliosis, 5 (3.1%) kyphosis and 6 (3.8%) both - an overall spinal deformity prevalence of 21%.
- Mean age at diagnosis of the deformity was 8 years (range 1-43 years).
- Six respondents reported bracing; three of those braced went on to surgery, and a further three had corrective surgery planned.
- The authors conclude that people with Russell-Silver syndrome have a high prevalence of spinal deformity (21%) and that a significant number undergo corrective surgery (6 of 34; 18%).
- This was the first study to evaluate the prevalence of scoliosis and kyphosis in this population.
How this changes the clinic.
- Screen early and repeatedly. Mean age at diagnosis of 8 years means deformity is appearing in mid-childhood, not just at the adolescent growth spurt. GeneReviews places evaluation for scoliosis at each visit.
- Level the pelvis before you call it a structural curve. With a progressive limb-length discrepancy present in a majority of these children, a coronal curve must be reassessed with the short side blocked. A curve that disappears on sitting or with the pelvis levelled is postural; a curve that persists, with a rib hump on forward bending, is structural.
- Brace early. The GeneReviews management position is that scoliosis and kyphosis should be monitored and early bracing is recommended, with the acknowledgement that many individuals will need corrective surgery.
- Watch the sagittal plane too. Kyphosis, alone or with scoliosis, accounted for roughly a third of the deformity in the Yamaguchi cohort (11 of 35 deformity reports involved kyphosis). Do not run a coronal-plane-only screening programme.
- Plan fusion around the metabolic and airway risk. Spinal fusion in this population is a long operation in a small, lean, hypotonic child with micrognathia - exactly the patient in whom hypoglycaemia, hypothermia, difficult intubation and difficult healing are the documented hazards. The published staged case required a T3-L5 fusion as one of seven operations (Al Kaissi 2015).
- Consider the neuraxis if the picture is atypical. A low conus medullaris has been reported in Russell-Silver syndrome: a 2-year-old with the full phenotype had the conus at the inferior border of L3 on magnetic resonance imaging, with detrusor-sphincter dyssynergia and detrusor overactivity on urodynamics, and was followed for suspected tethered cord. The authors note that although tethered cord is not a common finding in this syndrome, it is worth considering precisely to avoid scoliosis and other long-term complications (Gabor 2016). An atypical curve, a neurological sign, bladder dysfunction or a cutaneous midline marker warrants magnetic resonance imaging on the usual principles.
Feeding Failure, Hypoglycaemia & Nutritional Management
GeneReviews lists prolonged fasting in infants and young children because of the risk for hypoglycaemia, and elective surgery whenever possible because of the risk of hypoglycaemia, hypothermia, difficult healing and difficult intubation, as agents and circumstances to avoid. The corresponding management rule is frequent feeding, avoidance of prolonged fasting between feeds - not more than 4 hours in infants - and complex carbohydrates, with monitoring for urinary ketones after prolonged fasting. Testing for growth hormone deficiency by fasting is contraindicated because it can induce hypoglycaemia.
Hypoglycaemia and Russell-Silver syndrome
- Twenty-four children with Russell-Silver syndrome under 4 years of age with clinical or documented biochemical hypoglycaemia were admitted for 48 hours for a 24-hour cortisol/glucose profile, with a diagnostic fast in those who did not develop spontaneous hypoglycaemia.
- Mean age at assessment was 2.2 ± 0.8 years (range 1.1-3.9 years); 10 of 24 had previously documented hypoglycaemia.
- Seven of 12 patients tested were growth hormone insufficient after a glucagon test.
- Feeding pattern was described as 'poor and picky eaters' in all; seven required nasogastric tube feeding. Mean spontaneous energy intake was 56 ± 19.6 kcal/kg/day (range 38-90).
- Nocturnal sweating was the commonest symptom (23.96%), followed by irritability (11.46%), tantrums (7.29%), pallor and shakiness (3.13%).
- The glucose profile showed hypoglycaemia in seven children but only FOUR were symptomatic - hypoglycaemia can be silent.
- No child was cortisol deficient and no metabolic or hormonal abnormality other than growth hormone insufficiency was detected at the time of hypoglycaemia; mean fasting period was 11.8 ± 4 hours (range 3-18 h).
- The authors conclude that children with Russell-Silver syndrome are prone to spontaneous hypoglycaemia especially if not fed frequently and regularly, most likely from accelerated starvation and/or growth hormone insufficiency.
Prevalence and management of gastrointestinal manifestations in Silver-Russell syndrome
- Seventy-five children (median age 24.3 months, range 5.1-135.2) with Silver-Russell syndrome; 65 had 11p15 hypomethylation and 10 had maternal UPD7.
- Malnutrition, defined as weight-for-expected-weight-for-height below 80%, was present in 70% of children.
- Gastrointestinal signs were present in 77%, including severe vomiting before age 1 year in 50%, persistent vomiting from age 1 year in 29%, and constipation in 20%.
- Severe gastro-oesophageal reflux was diagnosed in 55% of children by 24-hour oesophageal pH-metry.
- Feeding difficulties were described in 65%, with dietary enrichment indicated in 49% and enteral nutrition by gastrostomy indicated in 22%.
- The authors conclude that systematic exploration and management of digestive signs and malnutrition are crucial to improve nutritional status BEFORE initiating growth hormone therapy.
Practical nutritional and metabolic management the orthopaedic team should know exists.
- Aggressive feeding measures are routine, including nasogastric tubes and, less frequently, gastrostomy. In a Swedish national cohort of 46 children with Silver-Russell syndrome followed for a median of 9 years, feeding problems and gastrointestinal symptoms were reported in 91% (vomiting 57%, constipation 46%), were most prevalent in infancy and decreased in the toddler years; 19 children relied on enteral feeding and 13 received a percutaneous endoscopic gastrostomy, after which BMI increased significantly at 2 years (p = 0.005) (Muz 2025).
- Beware rapid catch-up. The consensus warns that 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 (Wakeling 2017). Feeding is optimised, not maximised.
- Monitor ketones, not just glucose. The recommended surveillance is to monitor for ketotic hypoglycaemia (urine ketones and blood glucose) during infancy and in older children with macrocephaly, lean body habitus and poor appetite, and to monitor urine ketones when feed frequency is being reduced, during acute illness or fever with reduced feeding, and in older children at times of increased physical activity.
- Reduced muscle mass (56%) and little subcutaneous fat are the mechanism. There is no glycogen and fat buffer to cross a normal fast. This is accelerated starvation, which is why the child ketoses early and why intravenous glucose - not simply "keep nil by mouth and re-book" - is the answer when feeding is interrupted.
Growth Hormone, Puberty & Adult Height
Growth hormone deficiency is not common in Russell-Silver syndrome, but treatment with growth hormone is indicated regardless of the presence or absence of documented deficiency. The consensus lists the benefits as improved body composition, motor development and appetite, reduced risk of hypoglycaemia, and increased height - a list in which only one item is stature. Critically, testing for growth hormone deficiency by fasting is contraindicated because of the hypoglycaemia risk.
Height and body mass index in molecularly confirmed Silver-Russell syndrome and the long-term effects of growth hormone treatment
- Seventy-one individuals (40 female) with molecularly confirmed Silver-Russell syndrome aged 13 years or older; median age 22.0 years (range 13.2-69.7).
- Molecular subtypes: H19/IGF2:IG-DMR loss of methylation in 80.3% (57/71), upd(7)mat in 16.9% (12/71) and IGF2 variant in 2.8% (2/71).
- Growth hormone treatment had been given to 77.5% (55/71).
- Total height gain was greater in treated individuals (median 1.53 SDS versus 0.53 SDS, p = 0.007); they were shorter at initiation (-3.46 SDS versus -2.91 SDS, p = 0.04) but reached comparable final heights (-2.22 SDS versus -2.74 SDS, p = 0.7).
- Treated individuals had lower adult BMI SDS (median -1.10 versus 1.66, p = 0.002) and lower BMI gain (2.01 versus 3.58, p = 0.006) despite similar early BMI SDS.
- The authors conclude the results support the use of growth hormone in Silver-Russell syndrome for increasing height SDS, with lower adult BMI possibly reflecting improved metabolic health even after discontinuation.
Early Growth Hormone Treatment Enhances Growth and Nutritional Status in Silver-Russell Syndrome
- Seventy-seven prepubertal children with molecularly proven Silver-Russell syndrome, analysed over the first 2 years of recombinant growth hormone therapy; mean age at initiation 3.7 years (range 1.4-10.3).
- Mean height gain was 0.8 SDS after 1 year and 1.3 SDS after 2 years.
- Ideal weight-for-height, reflecting nutritional status, rose from a mean of 81% at initiation to 84% at 1 year (p < .001) and 86% at 2 years (p < .001).
- The proportion of children below a weight-for-height of 75% fell from 22.1% at initiation to 7.8% after 2 years.
- Starting therapy before the age of 4 years was associated with greater height gain at 2 years: 1.5 versus 1.1 SDS (p = .012).
- The authors conclude that early initiation, before age 4 years, further optimises height gain.
Adrenarche in Silver-Russell Syndrome: Timing and Consequences
- Sixty-two patients (34 boys) with Silver-Russell syndrome, documented age at adrenarche and a positive Netchine-Harbison clinical score, median follow-up 12.8 years.
- Boys reached adrenarche at a median age of 9.2 years and pubarche at 11.7 years; girls reached adrenarche at 8.1 years and pubarche at 9.8 years.
- Premature adrenarche occurred in 13% of patients - more frequent than in the general population.
- Early adrenarche was associated with early initiation of recombinant human growth hormone (p = 0.0024 in boys; p = 0.0195 in girls) but NOT with the Netchine-Harbison clinical score (p > 0.25).
- Response to growth hormone (median dose 50 µg/kg/day) and adult height (n = 43) were NOT compromised by early adrenarche.
The puberty problem, stated for the surgeon. These children are prone to premature adrenarche, fairly early and rapid central puberty and insulin resistance, and rapid bone-age advancement during puberty can erase the height gained. The consensus response is that gonadotropin-releasing hormone analogue treatment can delay progression of central puberty and preserve adult height potential; GeneReviews frames it as personalised treatment for at least two years in children with evidence of central puberty, starting no later than age 12 years in girls and 13 years in boys. For the orthopaedic surgeon this is not endocrine trivia: bone age, not birthday, governs the timing of every growth-modulating procedure, and in this syndrome bone age can run ahead.
Perioperative & Anaesthetic Considerations
GeneReviews names them together: elective surgery is to be avoided where possible because of the risk of hypoglycaemia, hypothermia, difficult healing and difficult intubation. Read as a checklist, those four risks dictate the whole plan: glucose strategy, active warming, wound and regenerate expectations, and a difficult-airway plan.
- First on the list. Minimise fasting time; a child who ketoses after a fast within the ordinary preoperative range should not be scheduled last.
- Clear carbohydrate fluids up to the permitted limit, then intravenous dextrose-containing maintenance fluid from the end of the clear-fluid window rather than a dry fast.
- Measure, do not observe. In the documented profiles, only 4 of 7 hypoglycaemic episodes were symptomatic. Check capillary glucose on arrival, before induction, intraoperatively for any case of significant length, and in recovery. Check urinary or blood ketones if the fast has been prolonged or the child is unwell.
- Restart feeding early and deliberately. Prolonged postoperative nil-by-mouth, patient-controlled opioid nausea and an unrecognised ileus are the common routes back into hypoglycaemia on the ward.
- Never use a fasting test for growth hormone deficiency in this child - it is contraindicated.
Multidisciplinary Care & When to Refer
There is no cure; care is supportive, multidisciplinary and lifelong, and the consensus is explicit that management requires an experienced, multidisciplinary approach. The named specialties are endocrinology, gastroenterology, dietetics, clinical genetics and genetic counselling, the craniofacial team, orthopaedic surgery, neurology, speech and language therapy and psychology.
Apply the Netchine-Harbison criteria; document birth weight and length SDS, current height SDS, head circumference relative to birth weight/length, asymmetry, feeding history and forehead morphology. Refer to clinical genetics for molecular testing - methylation analysis of the 11p15.5 imprinting control regions and upd(7)mat studies performed simultaneously as first-tier tests - and remember that a normal result does not exclude the diagnosis. Refer to paediatric endocrinology early: the height benefit of growth hormone is greater when started before age 4 years.
Nutrition and hypoglycaemia dominate. Feeds not more than 4 hours apart in infants, complex carbohydrates, urinary ketone monitoring when feed frequency is reduced or during illness, and active management of reflux and constipation. Dietetic and gastroenterology input; nasogastric or gastrostomy feeding where indicated. Measure both legs at each well-child visit and enter the longer limb on the growth curve.
Growth hormone treatment and its monitoring. Serial limb-length measurement with projection to maturity; shoe raise as first-line treatment. Spinal examination at every visit with the pelvis levelled - mean age at diagnosis of deformity is 8 years. Developmental, speech and educational support. Early referral to the craniofacial team for severe micrognathia, cleft palate or complex dental anomalies; routine paediatric dental and orthodontic care for crowding.
Watch for early adrenarche and early, rapid central puberty; gonadotropin-releasing hormone analogue treatment may be used to preserve adult height potential. This is the decision window for limb-length surgery: bone age and growth remaining, not chronological age, determine timing of lengthening or any epiphysiodesis. Brace progressive spinal deformity early; plan fusion with the full perioperative protocol. Address body-image and psychosocial issues with psychological support.
The consensus states that long-term follow-up is essential to determine the natural history and optimal management in adulthood. Ongoing concerns include residual short stature (adults remain roughly 2 SD below the mean even after growth hormone), insulin resistance and metabolic risk, gastrointestinal symptoms, and untreated or residual orthopaedic deformity. Adult anaesthetic risk persists - including the reported risk of carbon dioxide narcosis in chronic respiratory failure.
Refer to clinical genetics when: an unexplained body asymmetry presents without a diagnosis (to distinguish hemihypoplasia from hemihyperplasia and settle the surveillance question); the clinical score is positive; or a family asks about recurrence risk, which is usually very low but can be up to 50% with certain genetic alterations.
Refer to endocrinology when: the diagnosis is suspected at any age, and urgently in the under-4s, where early growth hormone gives the larger height gain; or when signs of early adrenarche or rapid pubertal progression appear and the growth window is closing.
Refer to orthopaedics (or keep in orthopaedic follow-up) when: the discrepancy is measurable and progressing; any spinal asymmetry is found; there is hip instability or an abnormal gait; or an elective procedure is being considered anywhere in the body, because the perioperative protocol is the orthopaedic team's routine business.
Guidelines, Registries & Global Practice
Russell-Silver syndrome is one of the better-governed rare disorders in this section of the curriculum, because it has a genuine international consensus statement. Wakeling and colleagues (2017) published the first international consensus statement on the diagnosis and management of Silver-Russell syndrome in Nature Reviews Endocrinology, summarising recommendations for clinical diagnosis, investigation and management. Its structural messages are quoted throughout this page: the diagnosis is primarily clinical with molecular testing confirming and subtyping it; a normal molecular result does not exclude the diagnosis; management requires an experienced, multidisciplinary approach; and evidence from controlled trials remains limited. The consensus also supplies the surveillance framework reproduced in GeneReviews, and its named management issues are growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges - two of the eight are explicitly orthopaedic.
The peer-reviewed GeneReviews chapter (Saal, Harbison and Netchine; last revised January 2025) operates as the working manual worldwide, and is written in part by the authors of the clinical scoring system. It carries the molecular testing algorithm adapted from the consensus - first-tier simultaneous 11p15.5 ICR1/ICR2 methylation analysis and upd(7)mat studies, with second-tier and comprehensive genomic approaches beyond that - together with the management and surveillance tables cited here.
What does not exist is equally important. There is no disease-specific orthopaedic guideline, no randomised trial of any orthopaedic intervention, and no international registry for this syndrome. The orthopaedic evidence base is one cross-sectional prevalence survey for spinal deformity, one staged single- patient surgical description, one prospective molecular-orthopaedic cohort in mixed hemi-asymmetry, and general limb-length-discrepancy methodology imported from the wider literature. Statements in this page about operative technique are therefore drawn from the cited descriptive guidance and case material, not from comparative evidence.
Globally, care is delivered by multidisciplinary teams wherever growth disorders are managed, and the population data are consistent with substantial under-ascertainment: a third of both Silver-Russell and Beckwith-Wiedemann cases in the Estonian population study met diagnostic criteria but tested negative for genetic abnormalities, and the authors concluded the worldwide prevalence of Silver-Russell syndrome is likely at least three times higher than expected (Yakoreva 2019). The access-limited steps are molecular methylation testing, growth hormone availability, and paediatric limb-reconstruction capability - which is why the clinical scoring system, requiring nothing more than a birth record, a growth chart and a tape measure, remains the single most valuable tool in this condition anywhere in the world.
Mnemonics & Memory Aids
RUSSELL
Hook:RUSSELL: Relative macrocephaly, UPD7, Small for dates, Smaller side, Eating difficulty, Loss of methylation, Leg length and spine.
SPARE-FThe Six Netchine-Harbison Criteria (four of six required)
Hook:SPARE-F: Small, Postnatal failure, Asymmetry, Relative macrocephaly, Eating difficulty, Forehead. Four of six SPARE-F items and you should be testing for Russell-Silver syndrome.
WARM-SUGARThe Perioperative Checklist
Hook:WARM-SUGAR: warm the child, plan the airway, restart feeds, measure the sugar, short starve, urinary ketones, no fasting growth hormone test, anticipate poor healing, record the protocol.
MCQ Practice Points
- Diagnosis is clinical. The Netchine-Harbison Clinical Scoring System has six items and the threshold is at least four; it was 98% sensitive for patients with demonstrated molecular abnormalities (Azzi 2015). GeneReviews adds that the four should include prominent forehead and relative macrocephaly at birth plus two additional findings, with other disorders ruled out.
- The imprinting direction. LOSS of methylation (demethylation) at the telomeric ICR1 of 11p15 produces relaxation of imprinting, biallelic H19 expression and DOWNREGULATION of IGF2 (Gicquel 2005). Maternal UPD of chromosome 7 accounts for about 10%.
- Mechanism frequencies in scored patients: ICR1 hypomethylation 58.3%, upd(7)mat 18.3% of Likely cases, with 76.7% molecularly positive overall (Azzi 2015); GeneReviews quotes literature ranges of 35-67% and 7-10% and overall confirmation in approximately 60%.
- A normal molecular test does NOT exclude the diagnosis - roughly 30-40% of clinically diagnosed patients have no identifiable abnormality.
- Relative macrocephaly means head circumference at least 1.5 SD above birth weight and/or length - the head growth itself is normal.
- The asymmetry is hemihypoplasia (affected side smaller, 68% have limb and/or facial asymmetry) - the opposite epigenetic alteration at the same 11p15 locus to Beckwith-Wiedemann hemihyperplasia (Shin 2021).
- Disproportionate short stature EXCLUDES the diagnosis and suggests a skeletal dysplasia.
- Spinal deformity: 21% (scoliosis 14%, kyphosis 3.1%, both 3.8%) in 163 people, mean age at diagnosis 8 years, with 18% of those affected (6 of 34) undergoing corrective surgery (Yamaguchi 2015).
- Limb-length discrepancy: shoe lift first; limb lengthening with distraction osteogenesis in older children, internal femoral distractors before completion of growth but close to final height, and tibial lengthening with external fixators for young children with a discrepancy over 4 cm. Expect high recurrence risk from muscular hypotonia, overtubulation of long bones and poor bone regenerative quality (Al Kaissi 2015).
- Untreated adult height averages about 3.1 ± 1.4 SD below the mean - the reason epiphysiodesis of the long side is a deliberate, quantified decision rather than a reflex.
- Feeding and metabolism: gastrointestinal signs 77%, malnutrition 70%, severe reflux on pH-metry 55%, gastrostomy indicated 22% (Marsaud 2015). Hypoglycaemia is from accelerated starvation, and only 4 of 7 documented episodes were symptomatic (Azcona 2005).
- Growth hormone is indicated regardless of growth hormone status; fasting tests for deficiency are contraindicated. Treated individuals gained 1.53 versus 0.53 SDS and reached comparable final height despite starting shorter (Lokulo-Sodipe 2022); starting before age 4 gave 1.5 versus 1.1 SDS at two years (Giabicani 2026).
- Premature adrenarche in 13%, with early, rapid central puberty - bone age, not chronological age, governs growth-modulating surgery (Binder 2017).
- Perioperative: avoid prolonged fasting and avoidable elective surgery because of hypoglycaemia, hypothermia, difficult healing and difficult intubation.
- NO tumour surveillance in Russell-Silver syndrome. In isolated hemihyperplasia the measured abdominal neoplasm incidence was 1.2% (3 of 250), prompting genetics-directed risk stratification rather than blanket imaging (Dempsey-Robertson 2012).
- Prevalence: minimum live-birth prevalence 1 in 15,866 in the Estonian population study, with the worldwide figure likely underestimated (Yakoreva 2019).
Clinical Decision Scenarios
Practise clinical reasoning and management decisions out loud
“A 5-year-old boy is referred with a 2 cm leg-length discrepancy. He was born at term weighing 2.1 kg, has never caught up in height, has a triangular face with a prominent forehead, fifth-finger clinodactyly and a head that looks large for his body. His mother says he has always been a poor eater. What is the diagnosis, how do you confirm it, and what is your orthopaedic plan?”
“You are listing a 4-year-old with molecularly confirmed Russell-Silver syndrome (11p15 ICR1 loss of methylation) for an examination under anaesthesia and hip arthrogram. The anaesthetist asks what they need to know. What do you tell them, and what do you write in the plan?”
“A 3-year-old is referred with a 1.5 cm leg-length discrepancy and a visibly smaller right leg and hemithorax. The referring clinician has arranged three-monthly abdominal ultrasound and alpha-fetoprotein measurement 'for hemihypertrophy surveillance'. Comment.”
Diagnosis (clinical first)
- Netchine-Harbison Clinical Scoring System: 6 items, need at least 4; 98% sensitive for molecularly proven cases (Azzi 2015)
- The six: small for gestational age (length and/or weight at or below -2 SDS); postnatal height at or below -2 SDS; relative macrocephaly at birth; body asymmetry; feeding difficulty or BMI at or below -2 SDS; protruding forehead at 1-3 years
- Relative macrocephaly = head circumference at least 1.5 SD above birth weight and/or length; head growth itself is normal
- Disproportionate short stature EXCLUDES the diagnosis - do a skeletal survey for a dysplasia
- Growth failure is otherwise proportionate; untreated adult height about 3.1 ± 1.4 SD below the mean
Genetics
- LOSS of methylation (demethylation) at telomeric ICR1, 11p15 → relaxed imprinting → biallelic H19 → DOWNREGULATED IGF2 (Gicquel 2005)
- Maternal UPD chromosome 7 in about 10%
- In scored patients: ICR1 hypomethylation 58.3%, upd(7)mat 18.3%; 76.7% of Likely cases molecularly positive (Azzi 2015)
- Overall confirmation about 60% - a NORMAL molecular test does NOT exclude the diagnosis
- First-tier testing: 11p15.5 ICR1/ICR2 methylation analysis AND upd(7)mat studies simultaneously
- Rare: CDKN1C, IGF2, PLAG1, HMGA2 variants; recurrence risk usually very low but can be up to 50% - refer to genetics
Orthopaedic
- Asymmetry is hemiHYPOplasia - affected side SMALLER and growing slower, so discrepancy is PROGRESSIVE (68% have asymmetry)
- Measure BOTH legs at every early-childhood visit; plot the LONGER limb; project with the multiplier method (Paley 2000)
- Shoe raise first; measure standing height with a lift that levels the pelvis
- Lengthening favoured: internal femoral distractors before completion of growth but close to final height; tibial external fixator for young child with discrepancy over 4 cm
- Epiphysiodesis of the long side spends stature in an already-short child - a quantified joint decision with endocrinology, not a reflex
- Expect high recurrence after lengthening: muscular hypotonia, overtubulated long bones, poor bone regenerate (Al Kaissi 2015)
- Spinal deformity 21% (scoliosis 14%, kyphosis 3.1%, both 3.8%), mean diagnosis age 8 years, 18% of affected had surgery (Yamaguchi 2015); brace early; level the pelvis before calling a curve structural
Feeding, metabolism, growth hormone
- Feeding difficulty 84-100%; GI signs 77%; malnutrition 70%; severe reflux on pH-metry 55%; gastrostomy indicated 22% (Marsaud 2015)
- Ketotic hypoglycaemia from accelerated starvation; reduced muscle mass in 56%; only 4 of 7 documented episodes symptomatic (Azcona 2005)
- Feeds not more than 4 hours apart in infants; complex carbohydrates; monitor urine ketones
- Growth hormone indicated regardless of GH status; benefits include body composition, motor development, appetite, reduced hypoglycaemia, height
- Treated 1.53 vs 0.53 SDS height gain, equal final height despite shorter start (Lokulo-Sodipe 2022); before age 4: 1.5 vs 1.1 SDS at 2 years (Giabicani 2026)
- Premature adrenarche 13%; early rapid central puberty; GnRH analogue to preserve height potential - BONE AGE governs surgical timing (Binder 2017)
Perioperative and surveillance
- Avoid: prolonged fasting; avoidable elective surgery - hypoglycaemia, HYPOTHERMIA, difficult healing, DIFFICULT INTUBATION
- First on the list, short starve, dextrose-containing maintenance, MEASURE glucose and ketones - do not rely on symptoms
- Micrognathia + 64% craniofacial anomalies → difficult-airway plan; adult case with CO2 narcosis, ETCO2 above 90 mmHg (Hibino 2024)
- Fasting testing for growth hormone deficiency is CONTRAINDICATED
- Surveillance covers growth, ketotic hypoglycaemia, nutrition, limb length, scoliosis, puberty, genitourinary, dental, speech - NO tumour screening
- Tumour surveillance belongs to hemihyperplasia; isolated hemihyperplasia incidence 1.2% (3/250) → genetics-directed stratification, not blanket imaging (Dempsey-Robertson 2012)
- Clinical assignment of bigger vs smaller side was WRONG in 4 of 10 molecularly positive patients - refer unexplained asymmetry to genetics (Shin 2021)
Tumour Surveillance: What the Evidence Actually Says
The recommended surveillance for Russell-Silver syndrome covers growth parameters, ketotic hypoglycaemia (urine ketones and blood glucose), nutritional status and feeding, limb-length measurement, scoliosis, puberty including early adrenarche, genitourinary issues, dental crowding and speech and language. There is no tumour-screening element - no periodic abdominal ultrasound and no serum alpha-fetoprotein programme.
Tumour surveillance is the logic of hemiHYPERplasia and overgrowth - Beckwith-Wiedemann syndrome and isolated hemihyperplasia - not of hemihypoplasia. Russell-Silver syndrome sits on the reduced-IGF2 side of the locus. Applying overgrowth surveillance to a growth-restricted child is a conceptual error that examiners specifically probe.
Incidence of abdominal tumors in syndromic and idiopathic hemihypertrophy/isolated hemihyperplasia
- Ten-year review of all patients diagnosed with hemihypertrophy at a paediatric centre, examining diagnostic criteria, imaging findings and associated syndromes.
- One of 10 patients with syndromic hemihyperplasia - a child with Beckwith-Wiedemann syndrome - developed a hepatoblastoma, a 10% tumour incidence in that group.
- Three of 250 children (1.2%) with isolated idiopathic hemihyperplasia developed an abdominal neoplasm: one adrenal carcinoma and two Wilms tumours.
- The incidence in isolated hemihyperplasia was LOWER than in earlier reported studies.
- On the basis of the 1.2% incidence, the current literature and available molecular genetic testing, the authors recommend referral to a clinical geneticist to identify higher-risk subgroups more likely to benefit from routine imaging surveillance, rather than universal imaging.
- Recommendations for tumour surveillance exist but there is no consensus on frequency or duration of screening.
How to answer the surveillance question correctly, in three steps.
- State the direction. Russell-Silver syndrome is a growth-restriction disorder with hemihypoplasia; the recommended surveillance schedules for it contain no tumour screening.
- State where the tumour logic does apply - Beckwith-Wiedemann syndrome and isolated hemihyperplasia - and note that even there the measured incidence in isolated hemihyperplasia was 1.2% (3 of 250), which led the authors to recommend genetic referral to stratify risk rather than universal imaging, with no consensus on the frequency or duration of screening.
- Add the essential caveat. An isolated asymmetry may be the presenting feature of either syndrome, and clinical assignment is unreliable: in the prospective molecular series, the clinical diagnosis of hemihyperplasia versus hemihypoplasia was incompatible with the epigenetic finding in 4 of the 10 molecularly positive patients, and the authors note that accurate differentiation matters precisely because of tumour-surveillance planning (Shin 2021). So the safe orthopaedic position is: an unexplained hemi-asymmetry is a referral to clinical genetics before it is a decision about surveillance.
References
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