Molecular IGF-1 and IGF-1 receptor defects: from genetics to clinical management.

Molecular defects of the insulin-like growth factor 1 gene (IGF1) are rare in the human. Only three homozygous and two families with heterozygous mutations of the IGF1 gene have been described, resulting in a variable degree of intrauterine and postnatal growth retardation, microcephaly, developmental delay and deafness. Detailed genetic analysis and functional experiments have shown that IGF-1 plays a key role in pre- and postnatal growth and development in human. Eleven patients with heterozygous and 2 patients with compound heterozygous mutations in the type 1 IGF1 receptor gene (IGF1R) have been reported. Intrauterine and postnatal growth retardation, microcephaly and IGF-1 levels above the mean of age references are consistent findings in these patients, although IGF-1 levels can be low initially because of feeding problems. The first reported patients showed the most severe phenotype, but with the identification of additional patients the phenotype appears to be more variable. The functional effect of the defects has been studied by in vitro experiments. From these studies, receptor haploinsufficiency, decreased IGF1R biosynthesis, interference with ligand binding and transmembrane signaling, and disruption of the intrinsic tyrosine kinase activity have been suggested as possible mechanisms with a variable pathogenetic spectrum. Data on GH treatment in these children are limited, showing a poor to modest growth response.