IGF-II serum levels are normal in children with Silver-Russell syndrome who frequently carry epimutations at the IGF2 locus

J Clin Endocrinol Metab. 2006 Nov;91(11):4709-12. doi: 10.1210/jc.2006-1127. Epub 2006 Aug 29.

Abstract

Context: Epigenetic mutations of 11p15 encompassing IGF2 are present in short children with Silver-Russell syndrome (SRS) with high frequency (31-50%). It has been speculated that these mutations characterized by demethylation of ICR1 cause diminished IGF2 expression.

Objective: We aimed to determine the prevalence of pathologically low IGF-II serum levels in children with SRS.

Subjects: SRS was defined by birth weight or length below the 3rd percentile, lack of postnatal catch-up growth, and the presence of two of the following characteristics: typical face, relative macrocephaly, and skeletal asymmetry. Serum samples of 30 patients were available. Mean age was 5.4 +/- 2.1 yr.

Methods: The serum levels of IGF-I, IGF-II, IGF binding protein (IGFBP)-2, and IGFBP-3 were measured by RIA and compared with age-related reference values and with serum concentrations measured in age- and gender-matched controls born small for gestational age (SGA), but lacking major dysmorphic features. Analysis of genomic DNA was possible in a subgroup of children with SRS: the methylation status of the ICR1 locus on 11p15 and the parental origin of chromosome 7 were analyzed in 9 and 23 children, respectively.

Results: Demethylation of ICR1 was found in 44% and uniparental disomy in 17% of the tested children with SRS. The median IGF-II serum level in SRS was 441 microg/liter (range, 238-875). This was significantly higher than in the SGA controls: 387 microg/liter (range, 265-596) (P < 0.03), but below the median value of the age-related reference, which was 532 microg/liter. The four children with SRS and ICR1 demethylation had high-normal and normal IGF-II serum levels that were higher than the levels of their SGA controls. IGF-I, IGFBP-2, and IGFBP-3 serum levels were not different between the SRS children and their SGA controls.

Conclusions: Our data render it unlikely that demethylation of ICR1 on 11p15 does cause diminished IGF-II serum levels in children with SRS. This observation does not exclude deficient IGF-II action before birth.

Publication types

  • Comparative Study

MeSH terms

  • Case-Control Studies
  • Child
  • Child, Preschool
  • Cross-Sectional Studies
  • Epigenesis, Genetic
  • Gene Frequency
  • Genotype
  • Growth Disorders / blood*
  • Growth Disorders / epidemiology*
  • Growth Disorders / genetics*
  • Humans
  • Infant, Low Birth Weight
  • Infant, Newborn
  • Infant, Small for Gestational Age
  • Insulin-Like Growth Factor II / analysis*
  • Insulin-Like Growth Factor II / genetics*
  • Mutation
  • Syndrome

Substances

  • Insulin-Like Growth Factor II