Silver-Russell Syndrome

Silver-Russell syndrome is an imprinting disorder characterised by intrauterine and postnatal growth restriction, relative macrocephaly at birth, prominent forehead, body asymmetry and feeding difficulties. Diagnosis is clinical, supported by molecular testing.

It is rare, with an estimated incidence of 1 in 30 000 to 100 000. The commonest molecular cause is loss of methylation at imprinting centre 1 on chromosome 11p15 (H19/IGF2), found in about 30 to 60%. Maternal uniparental disomy of chromosome 7 accounts for about 5 to 10%, and rarer causes include CDKN1C, IGF2, HMGA2 and PLAG1 variants. A proportion remain without a molecular diagnosis.

Final height without treatment is usually about 3 to 4 z-scores under the mean. Cognitive outcomes are mostly normal, though speech and learning difficulties are more common.

Pathophysiology.

Loss of methylation at imprinting centre 1 reduces expression of the growth promoting gene IGF2, which lowers foetal and postnatal growth. Maternal uniparental disomy of chromosome 7 affects genes at 7p and 7q that influence growth.

Asymmetry arises from mosaic distribution of the epigenetic change. Poor feeding, small stomach and fasting hypoglycaemia contribute to poor growth.

• Small for gestational age (birth length and weight under the 3rd centile), with poor postnatal growth.
• Relative macrocephaly at birth (head circumference z-score at least 1.5 higher than the birth weight or length z-score), prominent forehead, triangular face, small chin and downturned mouth.
• Body asymmetry (limb length difference), fifth finger clinodactyly, and feeding difficulties with low body mass index.
• Fasting hypoglycaemia in infancy, sweating, constipation, reflux, delayed motor and speech development, and early adrenarche and puberty.

Red flags.

• Symptomatic or recurrent hypoglycaemia.
• Severe feeding difficulty with failure to thrive.
• Marked leg length difference, scoliosis, or atypical features suggesting another diagnosis.

• Clinical diagnosis using a combined clinical score of six features: small for gestational age, postnatal growth failure, relative macrocephaly at birth, prominent forehead, body asymmetry and feeding difficulties. Four or more features, with prominent forehead and relative macrocephaly, support the diagnosis.
• Molecular testing in order: methylation analysis of 11p15 (imprinting centres 1 and 2), then testing for uniparental disomy of chromosome 7, then genetic panel or exome testing for CDKN1C, IGF2, HMGA2 and PLAG1.
• Glucose monitoring, nutritional assessment, bone age, spine radiography, and endocrine assessment.

Differential diagnosis. Constitutional small stature, other causes of small for gestational age (intrauterine infection, placental insufficiency), 3-M syndrome, Mulibrey nanism, Bloom syndrome, Fanconi anaemia, IGF1 resistance, Noonan syndrome and chromosome anomalies (maternal uniparental disomy of 14, Temple syndrome).

• Nutrition: high energy feeds, frequent meals, early dietitian review, and gastrostomy for severe feeding problems. Avoid prolonged fasting, and give complex carbohydrate (uncooked cornstarch) at bedtime if there is fasting hypoglycaemia. Keep glucose over 2.6 mmol/L.
• Growth hormone: recombinant growth hormone at 0.035 mg/kg/day SC (about 35 micrograms/kg/day), started from 2 to 4 years of age, which improves height. Monitor IGF-1 and glucose, as growth hormone may unmask hyperglycaemia, and review for scoliosis.
• Treat early puberty with a gonadotrophin releasing hormone analogue if needed, with monitoring of bone age.
• Orthopaedic review for leg length discrepancy (shoe raise or surgery) and scoliosis.
• Speech therapy, occupational therapy and educational support. Dental review for crowding.

Monitoring. Growth, glucose, blood pressure, puberty, bone age and scoliosis. Metabolic follow up in adulthood for insulin resistance.

Referral and escalation. Refer to clinical genetics and paediatric endocrinology, with dietetic and feeding input.