S M Pricea, R Stanhopeb, C Garrettc, M A Preeceb, R C Trembathd
a Child Health
Directorate, Northampton General Hospital NHS Trust, Cliftonville,
Northampton NN1 5BD, UK, b Biochemistry, Endocrinology, and Metabolism
Unit, Institute of Child Health, University College London, 30 Guilford
Street, London WC1N 1EH, UK, c The Kennedy-Galton Centre, North West Thames
Regional Genetic Service, Level 8V, Northwick Park Hospital, Watford
Road, Harrow HA1 3UJ, UK, d Department
of Clinical Genetics, Leicester Royal Infirmary, Leicester LE1 5WW, UK
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Abstract |
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The Silver-Russell syndrome (SRS) is characterised by severe
intrauterine growth retardation, with a preserved head circumference, leading to a lean body habitus and short stature. Facial dysmorphism and asymmetry are considered typical features of the syndrome, although
the range of phenotypic variance is unknown. Fifty seven subjects
varying in age from 0.84 to 35.01 years, in whom the diagnosis of SRS
had been considered definite or likely, were re-evaluated in a combined
clinical and molecular study by a single observer (SMP).
In 50 patients the clinical findings complied with a very
broad definition of SRS. Notable additional findings included
generalised camptodactyly seen in 11 (22%), many with distal
arthrogryposis. Thirteen of the 25 males required genital surgery for
conditions including hypospadias and inguinal hernia.
Fourteen (36.8%) subjects above school age have received a
statement of special educational needs.
Molecular genetic analysis was performed in 42 subjects and
has identified maternal uniparental disomy of chromosome 7 in four. The
phenotype was generally milder with birth weights for one patient above
and three below 
2 SD from the mean. Two children had classical
facial dysmorphic features, and two had a milder facial phenotype. Of
relevance to the possible molecular mechanism underlying this
condition, none of the four disomic patients had significant asymmetry.
Keywords:
Silver-Russell syndrome;
uniparental disomy of
chromosome 7
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Introduction |
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The original report of Silver et al1 in 1953 of two low birth weight children with asymmetry and growth retardation was promptly followed by the description by Russell2 of five children with similar features, two with asymmetry. In 1964, Silver3 reported 16 further cases and reviewed the findings of six other published cases. Silver discussed the wide variation in expression of this emerging syndrome and emphasised the distinction of SRS from other causes of poor pre- and postnatal growth. However, neither he nor other authors were able to offer diagnostic criteria for SRS. Of the total of 29 cases, eight were reported to be significantly and one mildly delayed, with no comment on developmental progress made for 10 cases.
Since 1970, the combined term Silver-Russell syndrome (SRS) has been used to describe subjects of low birth weight and reduced postnatal growth, often in combination with asymmetry, café au lait patches, and fifth finger clinodactyly. The classical facial features, as described by Russell, comprise a high forehead tapering to a small jaw. The nasal bridge is prominent, the philtrum well demarcated, and the corners of the mouth downturned (fig 1). Tanner and Ham4 reported the use of growth hormone in this condition. The potential for increasing eventual height using early growth hormone treatment is still being assessed.5-7 Postnatal growth in untreated subjects is well characterised.8 9 Bone age is often delayed in early childhood but catches up by puberty, and growth studies in 386 cases found a mean adult height of 151.2 cm (SD 7.8) in males and 139.9 cm (SD 9.0) in females.10
SRS is a well recognised syndrome,11 but diagnostic criteria have remained inconsistent and the range of phenotypic variance unclear. This, at least in part, is likely to reflect the heterogeneous aetiology of the syndrome. A more severe end of the spectrum was described by Donnai et al12 in 1989, while many milder patients are likely to remain undiagnosed. Most cases are sporadic,13 although Duncan et al14 described two families with apparent dominant transmission of an SRS phenotype, including asymmetry, over three generations. Additional instances of autosomal recessive and X linked inheritance have also been proposed. Verification of familial examples of SRS has proven difficult, particularly since the facial features of the syndrome tend to lessen with age. Various chromosomal abnormalities have been reported in patients with features suggestive but not characteristic of SRS and include deletions of distal 15q or ring chromosome 15, 18p-, trisomy 18 mosaicism, and diploid/triploid mosaicism. Two subjects with a translocation involving 17q25 have more consistent features of SRS, and a paternally inherited deletion of the CSH1 gene at 17q22-24 has been noted in one subject.15 Genetic changes recorded in SRS have recently been reviewed by Wakeling et al.16
In 1990, Hall17 discussed the possibility of uniparental disomy in SRS following the observation that uniparental disomy of certain chromosomes caused intrauterine growth retardation in mice.17 Uniparental disomy of chromosome 7 was suggested by three cases with unexpectedly severe short stature in association with diseases at this chromosome location. Two had cystic fibrosis caused by homozygosity of a maternal cystic fibrosis mutation, and a third child was homozygous for a maternal COL1A2 mutation. In addition, postnatal growth failure with an SRS phenotype, but without IUGR, was described by Eggerding et al18 in a child with maternal isodisomy for 7q and paternal isodisomy of 7p. Kotzot et al19 reported uniparental disomy of chromosome 7 in three of 25 cases diagnosed with SRS and a further case described as primordial growth retardation. We have ascertained a cohort of subjects diagnosed with SRS to characterise the condition further and review diagnostic criteria. The molecular basis for the majority of cases in this group of disorders remains unclear.