Context: 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 well as the effect of growth hormone (GH) therapy in this condition.

Objective: 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.

Patient: A 15 yr old adolescent, born small for gestational age (SGA) 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 IGF1R protein expression, as well as activation of IGF1R autophosphorylation and PKB/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 SGA 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.