ESPE Abstracts

Short stature is a frequent reason for referral to pediatric endocrinologists and this phenotype has been associated with a large number of gene variations during the last decades, highlighting its complex and heterogeneous etiology. We evaluated the detection rate of the analysis of a selected gene panel in a cohort of patients with short stature defined as height below -2 standard deviations (SD). Overall, 134 patients were included in the study: 73 with GH deficiency (GHD), isolated or associated with other pituitary hormone deficiencies (CPHD), and 61 without GH deficiency (NGHD). A pathological brain MRI was found in 78.9% of patients with CPHD compared to those with isolated GHD (22.9%) (P<0.0001). Most patients with GHD had a severe GH deficiency (peak after stimulation < 5 ng/ml). In 14 NGHD patients, SHOX deletions or duplications were identified by MLPA analysis. A multigene panel including 77 genes known to be associated with short stature were analysed by Next Generation Sequencing (NGS) in SHOX-negative NGHD patients and in all GHD patients. Variants identified in probands were searched in their parents for a better interpretation. Results were statistically evaluated using the Mann-Whitney test or Kruskal Wallis one-way ANOVA test (continuous variables) and the chi-square test or Fisher's exact test (categorical variables); P-values <0.05 were considered statistically significant. Overall, one or more potentially relevant variants (positive test) were detected in 65.8% of patients studied by NGS. Among GHD patients, 48 (65.8%) tested positive, including 20 cases carrying variants classified as pathogenic (P) or likely pathogenic (LP) according to the American College of Medical Genetics criteria. The detection rate was higher in patients with isolated GHD (73.6%) than those with CPHD (45%) (P=0.02) confirming the frequent multifactorial origin of CPHD. Among SHOX-negative NGHD patients, 31 (66%) tested positive at the NGS analysis, including 9 cases carrying P/LP variants. Pathogenic variants were inherited from a parent with a similar phenotype in 66.7% of cases (P=0.001), revealing the genetic etiology of the familiar short stature. Our data showed a good detection rate of a custom multi-gene panel sequencing test in a cohort of patients with short stature who underwent deep auxological phenotyping. A genetic cause of the short stature was identified in approximately 27% of our GHD patients and 19% of SHOX-negative NGHD patients.