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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/m 2 ).    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.

IGF2/H19 hypomethylation in a patient with very low birthweight, preocious pubarche and insulin resistance