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


METHODS
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.
Binder
G
G
Pediatric Endocrinology Section, University-Children's Hospital, 72076 Tübingen, Germany. gerhard.binder@med.uni-tuebingen.de
Seidel
A-K
AK
Weber
K
K
Haase
M
M
Wollmann
H A
HA
Ranke
M B
MB
Eggermann
T
T
D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D044127:Epigenesis, Genetic; D005787:Gene Frequency; D005838:Genotype; D006130:Growth Disorders / Q000097:blood* / Q000453:epidemiology* / Q000235:genetics*; D006801:Humans; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D007335:Insulin-Like Growth Factor II / Q000032:analysis* / Q000235:genetics*; D009154:Mutation; D013577:Syndrome
D007335:Insulin-Like Growth Factor II