Two short children born small for gestational age with insulin-like growth factor 1 receptor haploinsufficiency illustrate the heterogeneity of its phenotype

J Clin Endocrinol Metab. 2009 Dec;94(12):4717-27. doi: 10.1210/jc.2008-1502. Epub 2009 Oct 28.


Context: Small for gestational age (SGA)-born children comprise a heterogeneous group in which only few genetic causes have been identified.

Objective: To determine copy number variations in 18 growth-related genes in 100 SGA children with persistent short stature.

Methods: Copy number variations in 18 growth-related genes (SHOX, GH1, GHR, IGF1, IGF1R, IGF2, IGFBP1-6, NSD1, GRB10, STAT5B, ALS, SOCS2, and SOCS3) were determined by an "in house" multiplex ligation-dependent probe amplification kit. The deletions were further characterized by single-nucleotide polymorphism array analysis.

Results: Two heterozygous de novo insulin-like growth factor 1 receptor (IGF1R) deletions were found: a deletion of the complete IGF1R gene (15q26.3, exons 1-21), including distally flanking sequences, and a deletion comprising exons 3-21, extending further into the telomeric region. In one case, serum IGF-I was low (-2.78 sd score), probably because of a coexisting growth hormone (GH) deficiency. Both children increased their height during GH treatment (1 mg/m(2) per day). Functional studies in skin fibroblast cultures demonstrated similar levels of IGF1R autophosphorylation and a reduced activation of protein kinase B/Akt upon a challenge with IGF-I in comparison with controls.

Conclusions: IGF1R haploinsufficiency was present in 2 of 100 short SGA children. GH therapy resulted in moderate catch-up growth in our patients. A review of the literature shows that small birth size, short stature, small head size, relatively high IGF-I levels, developmental delay, and micrognathia are the main predictors for an IGF1R deletion.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Body Height / genetics*
  • Child, Preschool
  • Chromosome Deletion
  • Chromosomes, Human, Pair 15
  • Cohort Studies
  • DNA / genetics
  • Female
  • Fibroblasts / metabolism
  • Genetic Heterogeneity*
  • Growth / genetics
  • Haplotypes
  • Humans
  • Infant
  • Infant, Newborn
  • Infant, Small for Gestational Age / growth & development*
  • Male
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Pregnancy
  • Receptor, IGF Type 1 / deficiency*
  • Receptor, IGF Type 1 / genetics*
  • Signal Transduction / physiology
  • Skin / cytology


  • DNA
  • Receptor, IGF Type 1