Familial short stature and intrauterine growth retardation associated with a novel mutation in the IGF-I receptor (IGF1R) gene.

Context: IGF-I is essential for normal human growth and mediates its effects through the IGF1R. IGF1R mutations have been associated with varying degrees of intrauterine and postnatal growth retardation.

Objective: To identify IGF1R gene mutations in a short-statured family with intrauterine growth retardation and microcephaly.

Methods: Direct DNA sequencing was used to identify IGF1R mutations. Multiplex ligation-dependent probe amplification analyses were performed for deletions and duplications of all IGF1R exons. Functional studies were conducted to assess mutation pathogenicity.

Results: A novel heterozygous IGF1R missense mutation in exon 7 (c.A1549T, p.Y487F) was identified in a short-statured girl with severe prenatal growth retardation and microcephaly. The same mutation was also identified in her mother, who presented prenatal and postnatal growth failure, and her short-statured maternal grandmother, both of whom exhibited microcephaly. The index case showed a partial response to rhGH. Functional studies performed in dermal fibroblasts from the index case and her mother showed normal IGF-I binding; however, IGF-I activation of intracellular signalling measured as AKT and extracellular signal-regulated kinase phosphorylation was markedly reduced, with patients' values being lower than those of her mother. IGF-I stimulation of DNA synthesis was significantly reduced compared with controls.

Conclusion: 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. The functional studies are in line with the inactivation of one copy of the IGF1R gene with variable expression within the same family.