IGF1 – Growth delay due to insulin-like growth factor type 1 deficiency

Insulin-like growth factor 1 (IGF1) is a key mediator of prenatal and postnatal growth, acting downstream of growth hormone to promote cellular proliferation and differentiation. Biallelic defects in IGF1 cause a rare syndrome of intrauterine and postnatal growth failure, microcephaly, sensorineural hearing loss, and metabolic disturbances. This summary outlines the genetic and functional evidence linking IGF1 to growth delay due to insulin-like growth factor type 1 deficiency, supporting diagnostic evaluation and therapeutic intervention.

Clinical Validity Assessment

Overall, the IGF1–growth delay association is classified as Moderate. Two unrelated patients with homozygous IGF1 lesions—one with a partial gene deletion and another with a missense variant—demonstrate the phenotype. There is supportive segregation in one consanguineous pedigree, and functional studies show concordant loss of receptor binding and response to recombinant IGF1 therapy.

Genetic Evidence

Inheritance is Autosomal recessive. Two unrelated probands have biallelic IGF1 defects: a 17.2-year-old with a partial IGF1 deletion leading to undetectable serum IGF1 and severe growth retardation (PMID:10549306), and a 55-year-old male homozygous for c.274G>A (p.Val92Met) presenting with intrauterine growth retardation, microcephaly, and deafness (PMID:15769976). No additional affected relatives were reported, though heterozygous carriers displayed mild growth reduction.

Variant Spectrum

Reported pathogenic alleles include large deletions and the missense variant c.274G>A (p.Val92Met). The latter causes a 90-fold decrease in IGF1 receptor affinity and poor downstream signaling, correlating with clinical severity.

Functional Evidence

IGF1 haploinsufficiency is the primary mechanism. In vitro assays of p.Val92Met IGF1 demonstrate drastically reduced IGF1R activation and downstream ERK/Akt signaling. In the deletion case, recombinant human IGF1 therapy normalized serum IGF1, improved linear growth, and restored GH–IGF axis homeostasis, confirming functional rescue of the deficiency.

Integration and Clinical Utility

These genetic and functional data coherently support that biallelic IGF1 defects cause a consistent clinical syndrome amenable to diagnosis by sequencing and copy-number analysis. Recombinant IGF1 therapy produces measurable catch-up growth, underscoring therapeutic benefit. Additional rare variants and larger cohorts may further refine penetrance and treatment guidelines.

Key take-home: Biallelic IGF1 loss-of-function leads to a recognizable growth failure syndrome with proven responsiveness to recombinant IGF1 replacement.

References

• Growth hormone & IGF research • 1999 • Insulin-like growth factor-I deficiency caused by a partial deletion of the IGF-I gene: effects of rhIGF-I therapy. PMID:10549306
• The Journal of clinical endocrinology and metabolism • 2005 • Homozygous and heterozygous expression of a novel insulin-like growth factor-I mutation. PMID:15769976

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