J Med Genet 47:760-768 doi:10.1136/jmg.2010.079111
  • Original article

Epigenotype–phenotype correlations in Silver–Russell syndrome

Open Access
  1. J M Cobben13
  1. 1North West Thames Regional Genetic Service (Kennedy-Galton Centre), North West London Hospitals NHS Trust, Harrow, UK
  2. 2Institute of Child Health, University College London, London, UK
  3. 3Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands
  4. 4Centre for Rare Diseases and Personalised Medicine and School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, and West Midlands Genetics Service, Birmingham Women's Hospital, Birmingham, UK
  5. 5Department of Medical and Molecular Genetics, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, and West Midlands Genetics Service, Birmingham Women's Hospital, Birmingham, UK
  6. 6Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK
  7. 7Division of Human Genetics, University of Southampton, School of Medicine, Southampton, UK
  8. 8Department of Clinical Genetics, Northampton General Hospital, Northampton, UK
  9. 9Division of Pediatrics, Oslo University Hospital, Rikshospitalet, Oslo, Norway
  10. 10Department of Medical Genetics, University Medical Center, Utrecht, The Netherlands
  11. 11DNA Laboratory, Medical Genetics Unit, St Georges Hospital, London, UK
  12. 12Wessex Clinical Genetics Service, Southampton University Hospitals Trust, Southampton, UK
  13. 13Department of Pediatric Genetics, Emma Kinderziekenhuis AMC, Amsterdam, The Netherlands
  1. Correspondence to Dr E L Wakeling, North West Thames Regional Genetic Service (Kennedy-Galton Centre), Level 8V, North West London Hospitals NHS Trust, Watford Rd, Harrow, Middlesex HA1 3UJ, UK; e.wakeling{at}
  • Received 17 March 2010
  • Revised 10 May 2010
  • Accepted 13 May 2010
  • Published Online First 3 August 2010


Background Silver–Russell syndrome (SRS) is characterised by intrauterine growth restriction, poor postnatal growth, relative macrocephaly, triangular face and asymmetry. Maternal uniparental disomy (mUPD) of chromosome 7 and hypomethylation of the imprinting control region (ICR) 1 on chromosome 11p15 are found in 5–10% and up to 60% of patients with SRS, respectively. As many features are non-specific, diagnosis of SRS remains difficult. Studies of patients in whom the molecular diagnosis is confirmed therefore provide valuable clinical information on the condition.

Methods A detailed, prospective study of 64 patients with mUPD7 (n=20) or ICR1 hypomethylation (n=44) was undertaken.

Results and conclusions The considerable overlap in clinical phenotype makes it difficult to distinguish these two molecular subgroups reliably. ICR1 hypomethylation was more likely to be scored as ‘classical’ SRS. Asymmetry, fifth finger clinodactyly and congenital anomalies were more commonly seen with ICR1 hypomethylation, whereas learning difficulties and referral for speech therapy were more likely with mUPD7. Myoclonus-dystonia has been reported previously in one mUPD7 patient. The authors report mild movement disorders in three further cases. No correlation was found between clinical severity and level of ICR1 hypomethylation. Use of assisted reproductive technology in association with ICR1 hypomethylation seems increased compared with the general population. ICR1 hypomethylation was also observed in affected siblings, although recurrence risk remains low in the majority of cases. Overall, a wide range of severity was observed, particularly with ICR1 hypomethylation. A low threshold for investigation of patients with features suggestive, but not typical, of SRS is therefore recommended.


  • Funding Child Growth Foundation, 2 Mayfield Avenue, Chiswick, London W4 1PW.

  • Competing interests None.

  • Patient consent Informed consent was obtained from all patients/parents for publication of photographs.

  • Ethics approval This study was conducted with the approval of the Trent Research Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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