The insulin-like growth factor1 receptor (IGF1R) is important in growth and development, and inactivating <i>IGF1R</i> mutations cause short stature and relatively high levels of serum IGF-I.
While short stature is considered a phenotypic hallmark of IGF1R haploinsufficiency, the present report suggests that in frame exon deletions of IGF1R present predominantly with cognitive and neuropsychiatric phenotypes.
Our results show a novel missense mutation in the IGF1R gene (c.A1549T, p.Y487F) associated with prenatal and postnatal growth failure and microcephaly in the context of familial short stature.
In addition, heterozygous mutations or gene deletions in the growth hormone-insulin-like growth factor (GH-IGF) axis such as the GH, GH-releasing hormone receptor, GH receptor, STAT5b, IGF-I, IGF-I receptor and the acid labile subunit have also been observed in children with growth failure and short stature.
IGF1R (insulin-like growth factor 1 receptor) haploinsufficiency is a rare event causing difficulties in defining clear genotype-phenotype correlations, although short stature is its well established hallmark.
Microscopically visible heterozygous terminal 15q deletions encompassing the IGF1R gene are rare and usually associated with intrauterine growth retardation and short stature.
Using rodent models of caloric restriction and genetic mouse models, e.g. the Ames and Snell dwarf mice, fat-specific insulin receptor knockout mice (FIRKO) and mice that are heterozygous for the IGF-I receptor (Igf1r+/-), investigators have shown that a reduction in plasma levels of insulin and/or IGF-I or reductions in insulin/IGF-I signalling appear to be correlated with increased longevity and retarded ageing.
Three patients who had suffered severe growth failure in early childhood were hemizygous at the IGF1R locus, while one patient with borderline short stature had two copies of the IGF1R gene.