ClinVar

In a Lebanese brother and sister with intrauterine growth retardation, short stature, microcephaly, dysmorphic facial features, mild developmental delay, and elevated IGF1 levels (IGF1RES; 270450), Fang et al. (2012) identified compound heterozygosity for missense mutations in the IGF1R gene: a c.361G-A transition in exon 2, resulting in a glu121-to-lys (E121K) substitution, and a c.700G-A transition in exon 3, resulting in a glu234-to-lys (E234K; 147370.0007) substitution. Their unaffected consanguineous parents were each heterozygous for 1 of the mutations. Analysis of patient fibroblasts showed an 80% reduction in processed alpha and beta subunits compared to controls; in contrast, IGF1R precursor and alpha and beta subunits in the fibroblasts of their mother, who was heterozygous for E121K, were indistinguishable from controls. In transfected HEK293 cells, ERK activation was significantly reduced with the E121K mutant compared to wildtype, and ERK activation was comparable to vector with the E234K mutant. Consistent with these findings, patient fibroblasts responded poorly to IGF1 stimulation, showing an 85% reduction in AKT activation compared to control fibroblasts. The brother developed insulin-requiring diabetes mellitus in adolescence (see 222100), whereas the sister died at age 5 years from Burkitt lymphoma (see 113970).