IGF1R – Growth delay due to insulin-like growth factor I resistance

Haploinsufficiency of the insulin-like growth factor 1 receptor (IGF1R) impairs IGF-I signaling, leading to primary IGF-I resistance, intrauterine growth retardation, postnatal growth failure and short stature (PMID:22423513). Short stature (HP:0004322) and elevated circulating IGF-I levels are characteristic findings.

Genetic evidence supports an autosomal dominant mode of inheritance for IGF1R-mediated IGF-I resistance. Six individuals from three unrelated pedigrees harbored heterozygous IGF1R variants and segregated with short stature and IGF-I resistance (PMID:16569742; PMID:17264177; PMID:20962017). Affected first-degree relatives (n=6) confirm dominant transmission.

Variant spectrum includes both loss-of-function truncating alleles and missense changes clustered in the extracellular and kinase domains. Reported variants include c.265C>T (p.Arg89Ter), c.1532G>A (p.Arg511Gln) and c.420del (p.Ala110fsTer20), each associated with growth impairment and biochemical evidence of IGF-I resistance.

Functional studies demonstrate consistent receptor haploinsufficiency: Arg89Ter fibroblasts express reduced IGF1R protein with diminished IGF-I-stimulated receptor autophosphorylation and downstream Akt activation (PMID:16569742). Likewise, R481Q and c.420del mutations result in attenuated IGF1R tyrosine phosphorylation, ERK/Akt signaling and cell proliferation in vitro (PMID:17264177; PMID:20962017).

Integration of genetic segregation and functional concordance yields a ClinGen classification of Strong for the IGF1R–IGF-I resistance association. Additional evidence from animal models and broader variant screening exceeds scoring caps but further supports haploinsufficiency as the pathogenic mechanism.

Key Take-home: IGF1R sequencing should be incorporated into diagnostic workflows for unexplained prenatal and postnatal growth failure, as molecular confirmation guides prognosis, genetic counseling and potential GH therapy response.

References

• Pediatric endocrinology reviews • 2011 • Diagnosis and management of disorders of IGF-I synthesis and action PMID:22423513
• The Journal of clinical endocrinology and metabolism • 2006 • Clinical and functional characteristics of the human Arg59Ter insulin-like growth factor i receptor (IGF1R) mutation: implications for a gene dosage effect of the human IGF1R PMID:16569742
• The Journal of clinical endocrinology and metabolism • 2007 • A familial insulin-like growth factor-I receptor mutant leads to short stature: clinical and biochemical characterization PMID:17264177
• The Journal of clinical endocrinology and metabolism • 2011 • Clinical and functional characteristics of a novel heterozygous mutation of the IGF1R gene and IGF1R haploinsufficiency due to terminal 15q26.2->qter deletion in patients with intrauterine growth retardation and postnatal catch-up growth failure PMID:20962017

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