Partial primary deficiency of insulin-like growth factor (IGF)-I activity associated with IGF1 mutation demonstrates its critical role in growth and brain development.
BACKGROUND
IGF-I is essential for fetal and postnatal development. Only three IGF1 defects leading to dramatic loss of binding to its type 1 receptor, IGF-1R, have been reported.


METHODS
We describe a very lean boy who has intrauterine growth restriction and progressive postnatal growth failure associated with normal hearing, microcephaly, and mild intellectual impairment. He had markedly reduced concentrations of IGF-I, with IGFBP-3 and ALS serum levels in the upper normal range or above. IGF-I serum concentrations differed according to the immunoassay used. A higher than average GH dose was required for catch-up growth. Given the mismatch between IGF-I and IGFBP-3 levels, we sequenced his IGF1 gene.


RESULTS
We identified a homozygous missense IGF1 mutation. This causes the replacement of a highly conserved amino acid (arginine 36) by a glutamine (R36Q) in the C domain of the predicted peptide. We showed that the abnormal IGF-I peptide has reduced mitogenic activity and partial loss of binding to its receptor IGF-1R. The patient's IGF-I level was undetectable in a highly specific monoclonal assay but elevated in a polyclonal assay.


CONCLUSIONS
This first report of mild deficiency of IGF-I activity demonstrates that the integrity of IGF-I signaling is important for normal growth and brain development. Molecular defects leading to partial loss of IGF-I activity may not be uncommon in patients born small for gestational age. The characterization of this complex phenotype and identification of such molecular defects have therapeutic implications, particularly now that, in addition to GH, recombinant IGF-I is available for clinical use.
Assistance Publique-Hôpitaux de Paris, Hôpital Armand-Trousseau, Explorations Fonctionnelles Endocriniennes, 75012 Paris, France. irene.netchine@trs.aphp.fr
Irène
I
Netchine
Salah
S
Azzi
Muriel
M
Houang
Danielle
D
Seurin
Laurence
L
Perin
Jean-Marc
JM
Ricort
Claudine
C
Daubas
Christine
C
Legay
Jan
J
Mester
Robert
R
Herich
François
F
Godeau
Yves
Y
Le Bouc
D001120:Arginine; D001921:Brain / Q000254:growth & development* / Q000378:metabolism; D049109:Cell Proliferation; D002648:Child; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000032:analysis; D005260:Female; D005973:Glutamine; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010766:Phosphorylation
D018076:DNA, Complementary; D018972:Insulin-Like Growth Factor Binding Protein 3; D005973:Glutamine; D007334:Insulin-Like Growth Factor I; D001120:Arginine