The growth response to GH treatment is greater in patients with SHOX enhancer deletions compared to SHOX defects

Objective: Short stature caused by point mutations or deletions of the short stature homeobox (SHOX) gene (SHOX haploinsufficiency (SHI)) is a registered indication for GH treatment. Patients with a SHOX enhancer deletion (SED) have a similar phenotype, but their response to GH is unknown. It is uncertain if duplications of SHOX or its enhancer (SDUP) cause short stature. This study aimed to describe the clinical characteristics and growth response to GH treatment in patients with aberrations of SHOX and its enhancers. Design: In this retrospective multi-center study (2002-March 2014) clinical information was available from 130 patients (72 SHI, 44 SED, and 14 SDUP) of whom 52 patients were treated with GH. We evaluated height, sitting height (SH), arm span, dysmorphic features and indicators of the growth response to GH (delta height SDS, height velocity, and index of responsiveness). Results: Patients with SEDs showed similar HtSDS to patients with SHI (-2.3 and -2.6, respectively, P=0.2), but they were less disproportionate (SH/height ratio SDS 2.0 vs 3.1 (P<0.01) and extremities/trunk ratio 2.57 vs 2.43 (P=0.03)). The 1st year growth response to GH treatment was significantly greater in prepubertal patients with SEDs than SHI. None of the patients with an SDUP was disproportionate and SDUP cosegregated poorly with short stature; their growth response to GH treatment (n=3) was similar to the other groups. Conclusions: Patients with SEDs are equally short, but less disproportionate than patients with SHI, and show a greater response to GH.