IGF1R gene mutations have been associated with varying degrees of intrauterine and postnatal growth retardation, and microcephaly.

To identify and characterize IGF1R gene variations in a cohort of 28 Argentinean children suspected of having IGF‐1 insensitivity, who were selected on the basis of the association of pre/postnatal growth failure and microcephaly.

The coding sequence and flanking intronic regions of IGF1R gene were amplified and directly sequenced. Functional characterization was performed by two in vitro assays: 1) [Methyl‐³H] thymidine incorporation into DNA in fibroblast cell primary cultures from patients and controls treated with IGF‐1 for 16‐24 h. 2) PI3K/Akt pathway was evaluated with phospho‐Akt (Ser473) STAR ELISA Kit (Millipore) in fibroblast cultures from patients and controls stimulated with IGF‐1 for 10 min. Prepubertal clinical and GH‐IGF‐1 axis evaluation was followed up.

We identified three novel heterozygous missense mutations in three unrelated patients, de novo p.Arg1256Ser, de novo p.Asn359Tyr and p.Tyr865Cys. In control cells, proliferation assay showed that IGF‐1 significantly induced DNA synthesis at 20 h and Akt phosphorylation assay that it significantly stimulated phosphorylation after 10 min (P < 0·05 by anova and Bonferroni Tests). However, no significant increase was observed in any of the three patient fibroblasts in both functional studies. GH therapy growth response in two patients was inconsistent.

These variations led to failure of the IGF1R function causing pre‐ and postnatal growth retardation and microcephaly. Microcephaly should be considered in the evaluation of SGA patients, because it seems to favour the frequency of detection of IGF1R mutations.