IGF1, IGF1R and SHOX mutation analysis in short children born small for gestational age and short children with normal birth size (idiopathic short stature).

Background/aims: Because the criteria for genetic screening of short children are unknown, we performed genetic analysis of 199 short children born small for gestational age (SGA) or with normal birth size (idiopathic short stature, ISS).

Methods: After selection with a modified scoring system for SHOX and a novel score for IGF1 and IGF1R defects, direct sequencing and multiplex ligation-dependent probe amplification (MLPA) was performed for SHOX and IGF1R in selected patients, and confirmed by SNP array analysis.

Results: In 6 children, gene variants were identified in SHOX, its adjacent pseudoautosomal region (PAR) and IGF1R: a SHOX mutation, terminal 15q deletion, a SHOX and IGF1R defect, a deletion of the Xp22.3 PAR region, and two patients with duplications in the Xp22.3 PAR region. In a seventh patient, steroid sulfatase deficiency was detected because a probe for STS was used as control; this syndrome has not been associated with short stature before.

Conclusion: A selection process using clinical scores for SHOX, IGF1 and IGF1R defects followed by genetic testing with MLPA and direct sequencing led to the detection of a SHOX or IGF1R genetic variant in 6% of short children.