IGF2/H19 hypomethylation in a patient with very low birthweight, preocious pubarche and insulin resistance.
BACKGROUND
Insulin like growth factor 2 (IGF2) is an imprinted gene, which has an important role in fetal growth as established in mice models. IGF2 is downregulated through hypomethylation of a differentially methylated region (DMR) in Silver Russell syndrome (SRS), characterised by growth restriction. We have previously reported that severe pre- and post-natal growth restriction associated with insulin resistance and precocious pubarche in a woman without body asymmetry or other SRS features resulted from a balanced translocation affecting the regulation of her IGF2 gene expression. We hypothesised that severe pre- and post-natal growth restriction associated with insulin resistance and precocious pubarche in the absence of SRS are also caused by downregulation of IGF2 through hypomethylation, gene mutation or structural chromosomal abnormalities.


METHODS
We performed routine karyotyping, IGF2 gene sequencing and investigated DNA methylation of the IGF2 differentially methylated region (DMR)0 and H19 DMR using pyrosequencing, in four women selected for very low birth weight (<-3 SDS for gestational age), precocious pubarche, short adult stature (<-2 SDS), and insulin resistance (defined as HOMA-IS < 80%); and compared their methylation results to those of 95 control subjects.


RESULTS
We identified a 20 year old woman with severe hypomethylation at both DMRs. She was the smallest at birth (birthweight SDS,-3.9), and had the shortest adult height (143 cm). The patient was diagnosed with polycystic ovarian syndrome at the age of 15 years, and had impaired fasting glucose in the presence of a low BMI (19.2 kg/m2).


CONCLUSIONS
Our case of growth restriction, premature pubarche and insulin resistance in the absence of body asymmetry or other features of SRS adds to the expanding phenotype of IGF2/H19 methylation abnormalities. Further studies are needed to confirm whether growth restriction in association with premature pubarche and insulin resistance is a specific manifestation of reduced IGF2 expression.
Faculty of Medical and Health Sciences, University of Auckland, Auckland, Private Bag 92019, New Zealand. R.Murphy@auckland.ac.nz
Rinki
R
Murphy
Lourdes
L
Ibáñez
Andrew
A
Hattersley
Jörg
J
Tost
D000015:Abnormalities, Multiple; D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002869:Chromosome Aberrations; D019175:DNA Methylation; D004392:Dwarfism / Q000235:genetics; D005260:Female; D018392:Genomic Imprinting; D006801:Humans; D007231:Infant, Newborn; D019102:Infant, Very Low Birth Weight; D007333:Insulin Resistance / Q000235:genetics*; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D010641:Phenotype; D011379:Prognosis; D011629:Puberty, Precocious / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics*; D056730:Silver-Russell Syndrome / Q000235:genetics; D055815:Young Adult
C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding; D007335:Insulin-Like Growth Factor II