Systematic or targeted molecular screening of SHOX gene variations in children with idiopathic short stature?

Context: Diagnosing SHOX gene variations is important because growth hormone treatment is an approved option for affected children. Subtle clinical and radiological abnormalities were reported in SHOX deficiency associated with idiopathic short stature (ISS). Whether systematic or phenotype-based molecular screening should be performed remains debated. Objective: To determine whether simple radiological features on left-hand radiography could serve as indicators for molecular analysis of the SHOX gene, and to compare these with published clinical/radiological scores. Methods: This retrospective study included 266 patients diagnosed with ISS who underwent SHOX gene analysis without any predefined selection criteria at the Pediatric Endocrinology Unit of Angers University Hospital from 2016 to 2023, aiming to determine the rate of SHOX gene variations. We also included 33 ISS patients diagnosed with a SHOX gene variation between 2005 and 2015 to refine sensitivity analyses. Results: Systematic screening using MLPA identified SHOX gene variations in 9.8% of ISS children and sequencing in MLPA-negative subjects detected an additional 6%. Variations occurred in the coding regions in one-third and in the enhancer regions in two-thirds. A cutoff of 147° for the convexity of the distal radial metaphysis showed sensitivity/specificity of 89%/50%. A cutoff of 128° for pyramidalization of the carpal row yielded sensitivity/specificity of 86%/49%. Combining both criteria yielded 91% sensitivity and 70% specificity. Previous scores proposed by Rappold and Binder had sensitivity/specificity of 36%/51% and 81%/10%, respectively. Conclusion: Systematic molecular screening by MLPA and sequencing is recommended to detect all SHOX gene variants in children with ISS.