Definition

This is an inherited syndrome featuring:

• Intrauterine growth restriction and low birthweight
• Asymmetrical somatic growth
• Overall growth retardation
• Characteristic facial abnormalities

It was first described by Silver and co-workers in 1953,^[1] then independently by Russell in 1954.^[2]

Epidemiology

Incidence

This is very rare.

• Reported cases since the discovery of the syndrome number in the hundreds but it may be underdiagnosed.
• Estimates of incidence vary from 1 in 3,000 births to 1 in 100,000.^[3]

Risk factors

Maternal age greater than 35 years.^[4]

Genetics

The condition occurs sporadically and, in most cases, no genetic cause can be clearly identified.

• There have been families with autosomal dominant transmission including ring 2 chromosome, balanced translocation of 17q2 and duplication of sections of 7p.^[5]
• There is research linking chromosome 11 to growth abnormalities.^[6]
  • About 10% have uniparental disomy of chromosome 7 (usually maternal).^[7]
  • Genomic imprinting (differing expression of a gene depending on the parent from whom it was inherited and the degree of DNA methylation) and placental mosaicism play a role in the manifestations of the condition.^[8]
• There are x-linked varieties of the condition.^[9]

Presenting features

In general the features of the syndrome are most pronounced in young children and become less obvious as the patient ages.

The face is characteristically small and triangular, but the head circumference is usually normal for age. This, combined with short stature, gives the appearance of having a large head.

• Growth:
  • Birth weight less than 2 standard deviation (SD) from mean.
  • Poor postnatal growth - less than 2 SD from mean at diagnosis.
  • Normal occipitofrontal circumference despite growth retardation.
  • Asymmetrical patterns of growth.
• Facies:
  • Normal head circumference, but characteristic small, triangular face.
  • Blue sclerae.
  • High forehead tapering to micrognathic jaw.
  • Prominent nasal bridge and down-turned corners of mouth.
• Gastrointestinal/metabolic:
  • Feeding difficulties during infancy, including gastro-oesophageal reflux, oesophagitis, food aversion and failure to thrive.^[10]
  • Tendency to fasting hypoglycaemia during infancy/early childhood.^[11]
• Developmental abnormalities:
  • Poor head control in infancy due to relatively large head compared with neck/trunk. Motor impairment due to poor muscle mass/function.
  • About half have learning difficulties, particularly problems with arithmetic and language.
• Skeletal abnormalities:
  • Late closure of the anterior fontanelle.
  • Limb asymmetry and hemihypertrophy.
  • Clinodactyly (incurving) of little finger.
  • Camptodactyly (fixed flexion) of fingers.
  • Syndactyly (fusion) of toes.
  • Sprengel's neck deformity - unilateral shortening and webbing to trunk.
  • X-ray abnormalities include:
    • Delayed bone age.
    • 'Ivory' epiphyses of distal phalanges.
    • Small middle phalanx of little finger - present in 4 out of 5 cases.
    • Pseudoepiphyses at the base of second metacarpal.
• Miscellaneous features:
  • Increased sweating affecting the head and upper trunk.
  • Urogenital anomalies - hyopspadias, posterior urethral valves.
  • Cardiac abnormalities.
  • Tendency to tumours such as Wilms' tumour, hepatocellular carcinoma, testicular seminoma and craniopharyngioma.

Differential diagnosis

• Causes of intrauterine growth restriction and failure to thrive.
• Fetal alcohol syndrome and Fanconi's syndrome also present similarly.

Investigations

• Karyotyping of a child and both parents to look for known underlying genetic abnormalities.
• Radiographs of the hand may detect typical skeletal abnormalities.

Management

• Growth can be improved by optimising nutrition:
  • Enteral feeding may be needed.
  • Growth hormone has been used in patients with a deficiency, although many have normal growth hormone (GH) levels.
• Early use of physiotherapy.
• Educational support.

Prognosis

Good, on the whole, with a reasonably full life expectancy.

However, there have been no long-term follow-up studies of sufficient numbers of sufferers to define life expectancy, morbidity and mortality definitively.