Successful long-term growth hormone therapy in a girl with haploinsufficiency of the insulin-like growth factor-I receptor due to a terminal 15q26.2->qter deletion detected by multiplex ligation probe amplification.
BACKGROUND
Microscopically visible heterozygous terminal 15q deletions encompassing the IGF1R gene are rare and usually associated with intrauterine growth retardation and short stature. The incidence of submicroscopic deletions is unknown, as is the effect of GH therapy in this condition.


OBJECTIVE
The objective of the study was to describe the use of a novel genetic technique [multiplex ligation probe amplification (MLPA)] to detect haploinsufficiency of the IGF1R gene in a patient suspected of an IGF1R gene defect and evaluate the effect of long-term GH therapy.


METHODS
A 15-yr-old adolescent, born small for gestational age, showed persistent postnatal growth retardation, microcephaly, and elevated IGF-I levels. She had been treated with GH since the age of 5 yr.


METHODS
MLPA and array comparative genomic hybridization (aCGH) were performed to examine gene copy number changes. Dermal fibroblast cultures were used for functional analysis.


RESULTS
With MLPA, a deletion of one copy of the IGF1R gene was detected, defined by aCGH as a loss of 15q26.2->qter. IGF1R mRNA expression was decreased in fibroblasts. IGF-I binding and type 1 IGF receptor protein expression as well as activation of type 1 IGF receptor autophosphorylation and protein kinase B/Akt by IGF-I tended to be lower, but this did not reach statistical significance. GH treatment resulted in a good growth response and a normal adult height.


CONCLUSIONS
MLPA and aCGH are useful tools to detect submicroscopic deletions of the IGF1R gene in patients born small for gestational age with persistent growth failure. The phenotype resembles that of a heterozygous inactivating IGF1R mutation. Long-term GH therapy causes growth acceleration in childhood and a normal adult height.
Walenkamp
Marie J E
MJ
Department of Pediatrics J6-S, Leiden University Medical Center, Leiden, The Netherlands. m.j.e.walenkamp@lumc.nl
de Muinck Keizer-Schrama
Sabine M P F
SM
de Mos
Marianne
M
Kalf
Margot E
ME
van Duyvenvoorde
Hermine A
HA
Boot
Annemieke M
AM
Kant
Sarina G
SG
White
Stefan J
SJ
Losekoot
Monique
M
Den Dunnen
Johan T
JT
Karperien
Marcel
M
Wit
Jan M
JM
D000293:Adolescent; D002872:Chromosome Deletion; D002884:Chromosomes, Human, Pair 15; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D006130:Growth Disorders / Q000188:drug therapy* / Q000235:genetics; D020249:Hormone Replacement Therapy; D019382:Human Growth Hormone / Q000627:therapeutic use*; D006801:Humans; D019656:Loss of Heterozygosity; D015336:Molecular Probe Techniques; D021141:Nucleic Acid Amplification Techniques / Q000379:methods; D017526:Receptor, IGF Type 1 / Q000235:genetics*; D013997:Time Factors; D016896:Treatment Outcome
D019382:Human Growth Hormone; D017526:Receptor, IGF Type 1