Objective Short stature is the most common reason for referral to pediatric endocrinology. Diagnosis primarily relies on history, physical exam and auxological assessment. Although growth hormone (GH) stimulation tests (GHST) are controversial, they remain relevant for determining eligibility for GH therapy. Individuals with idiopathic short stature (ISS) exhibit normal GHST results and lack features of skeletal dysplasia or syndromic conditions. Despite the strong genetic contribution to adult height (70-90%), genetic testing is not included in routinely evaluation of children with short stature. Design To assess the added diagnostic value of exome sequencing (ES) in children with short stature evaluated by GHST with variable outcomes. Methods Sixty children with short stature were evaluated by ES and stratified into three groups based on GHST peak concentrations: group a, ≤7 ng/ml; group b, 7-10 ng/ml and group c, ≥10 ng/ml (n=20 per group). Identified variants were analyzed and genotype-phenotype associations explored. Results Disease-causing variants were identified in 8/60 children (13.3%), most commonly in the GH peak 7-10 ng/ml group (n=4), followed by ≥10 ng/ml (n=3) and ≤7 ng/ml (n=1) groups. Most pathogenic variants were in genes related to growth plate development; a subset was associated with syndromic conditions. Fourteen candidate variants of uncertain significance potentially linked to short stature were detected in 13 children (21.6%). Conclusions The limited correlation between GHST results and genetic findings highlights the diagnostic value of ES. Integrating genetic testing into the evaluation of short stature can enhance etiological understanding and support personalized management, particularly in ISS cases and decisions regarding GH therapy.
