Two short children born small for gestational age with insulin-like growth factor 1 receptor haploinsufficiency illustrate the heterogeneity of its phenotype.
BACKGROUND
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.
Department of Pediatrics, Subdivision of Endocrinology, Erasmus Medical Center Sophia Children's Hospital, 3015 GE Rotterdam, The Netherlands. w.ester@erasmusmc.nl
Wietske A
WA
Ester
Hermine A
HA
van Duyvenvoorde
Caroline C
CC
de Wit
Alexander J
AJ
Broekman
Claudia A L
CA
Ruivenkamp
Lutgarde C P
LC
Govaerts
Jan M
JM
Wit
Anita C S
AC
Hokken-Koelega
Monique
M
Losekoot
D000328:Adult; D001827:Body Height / Q000235:genetics*; D002675:Child, Preschool; D002872:Chromosome Deletion; D002884:Chromosomes, Human, Pair 15; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D018740:Genetic Heterogeneity; D006128:Growth / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age / Q000254:growth & development*; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D017526:Receptor, IGF Type 1 / Q000172:deficiency* / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000166:cytology
D004247:DNA; D017526:Receptor, IGF Type 1