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In a cohort of 41 children with intrauterine growth retardation (IUGR) and sustained postnatal growth retardation, the investigators detected 1 female subject (birth weight —3.5 SDS; adult height —4.5 SDS; exaggerated spontaneous and stimulated growth hormone [GH] secretion; normal to elevated IGF-1 concentrations; adult height apparently unresponsive to therapy with GH) who was a compound heterozygote for loss-of-function missense mutations in the gene encoding the receptor for insulin-like growth factor I (IGF1R). Both parents were heterozygous for different mutations in exon 2 of IGF1R (mother, Lys115Asp; father, Arg108Gln). The birth weights and adult heights of both parents were modestly impaired (mother’s birth weight —2.0 SDS, adult height —0.6 SDS; father’s birth weight —2.0 SDS, adult height —2.8 SDS). The mutations in exon 2 impaired IGF-1 binding and decreased sensitivity to this growth factor, hence limiting intracellular signal transduction.
A heterozygous nonsense mutation (exon 2: Arg59Stop) resulting in a truncated product was identified In 1 (male) of 9 children studied with short stature (height SDS —3.8 SDS at chronologic age 14 months) and elevated serum concentrations of IGF-1 who also had IUGR (birth weight —3.0 SDS, birth length —4.6 SDS). A similar mutation was present in the mother (birth weight —2.4 SDS; adult height —2.6 SDS) and brother. The mutation led to decreased numbers of IGF1R expressed on the plasma membrane of the patient’s cultured fibroblasts and presumably to decreased sensitivity to ligand. The authors conclude that inactivating mutations of IGF1R are present in a small number of children with both IUGR and postnatal growth retardation, particularly in those with an elevated serum concentration of IGF-1.
Abuzzahab MJ, Schneider A, Goddard A, et al. IGF-1 receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med. 2003;349:2211-2222.
First Editor’s Comment: This report documents another abnormality leading to GH non-responsive growth retardation—this in the gene encoding the IGF-1 receptor. There are now documented loss-of-function mutations in the genes encoding the receptor for GH-releasing hormone, GH, the GH receptor, an essential protein (STAT5) in the signal transduction system for GH, IGF-1, and the IGF-1 receptor; abnormalities in the GHRHR and IGF1R signal transduction systems likely exist as well. An interesting perspective by Rosenfeld 1 discussing factors that control growth accompanies this article.
Allen W. Root, MD
Second Editor’s Comment: Abuzzahab and colleagues described 2 patients with IUGR and sustained post-natal growth failure due to IGF1R gene mutations. In a related paper published the same month, Okubo et al 2 described a girl with IUGR and sustained postnatal growth failure through 10 years of age, despite GH therapy due to a de novo terminal deletion of chromosome 15q26.1, which led to a single gene copy of IGF1R. In vitro studies with cultured fibroblasts from skin biopsy revealed: decreased cell proliferation in response to IGF-1, a reduced IGF-1-stimulated IGF1R tyrosine phosphorylation, and decreased [ 125I]IGF-1 binding sites per cell but normal IGF-1 binding affinity. The girl also had facial and musculoskeletal dysmorphisms, a single café-au-lait spot, cardiac anomalies (atrial septal defect and ventricular septal defect), and developmental delays with learning difficulties. Her chromosomal deletion was cytogenetically visible; thus, the girl’s phenotype may be due, in part, to contiguous gene deletions beyond the IGF1R.
As an elegant counterpoint, Okubo and colleagues also described a boy with 3 copies of the IGF1R gene due to chromosomal translocation who had dysmorphic features and was large from birth on. 2 Thus, alterations in the IGF1R gene—either mutations or abnormal gene copy numbers—may significantly affect growth, both prenatally and postnatally.
Adda Grimberg, MD
References - (linked to  )
- Rosenfeld RG. N Engl J Med. 2003;349:2184-2186.
- Okubo Y, et al. J Clin Endocrinol Metab. 2003;88:5981-5988.
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Current GGH - Vol. 24 No. 1
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