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This version published online on October 28, 2009
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2008-1502
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Submitted on July 14, 2008
Accepted on September 15, 2009

Two Short Children Born Small for Gestational Age with Insulin-Like Growth Factor 1 Receptor Haploinsufficiency Illustrate the Heterogeneity of Its Phenotype

Wietske A. Ester*, Hermine A. van Duyvenvoorde, Caroline C. de Wit, Alexander J. Broekman, Claudia A. L. Ruivenkamp, Lutgarde C. P. Govaerts, Jan M. Wit, Anita C. S. Hokken-Koelega, and Monique Losekoot

Department of Pediatrics, Subdivision of Endocrinology, Erasmus Medical Center Sophia Children's Hospital (W.A.E., A.C.S.H.-K.), Department of Clinical Genetics, Erasmus Medical Center (L.C.P.G.), 3015 GE Rotterdam, The Netherlands; and Department of Pediatrics (H.A.v.D., C.C.d.W., J.M.W.), Department of Endocrinology and Metabolic Diseases (H.A.v.D.), and Centre for Human and Clinical Genetics (H.A.v.D., A.J.B., C.A.L.R., M.L.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands

* To whom correspondence should be addressed. E-mail: w.ester{at}erasmusmc.nl.

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/m2 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.






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