ESPE Abstracts

Introduction: Short stature is frequently caused by SHOX variants causing functional deficiency. SHOX resides in the pseudoautosomal region (PAR1) of the sex chromosomes and SHOX/enhancer alterations result in a broad phenotypic range: from Langer mesomelic dysplasia, Léri-Weill dyschondrosteosis to idiopathic short stature (ISS). Growth hormone (GH) therapy is indicated for those individuals with short stature due to SHOXdeficiency. A frequent limitation in molecular studies is the identification of genetic variants of unknown significance (VUS), limiting the access to GH therapy. Our purpose was to compare the clinical characteristics of patients with short stature with pathogenic SHOX variants vs those with VUS.

Methods: Retrospective observational study analyzing the results of SHOX positive genetic studies in patients of our Genetic Unit, Cadiz from 2015-2021. Molecular studies (MLPA, HRM, sequencing) were performed at the Institute of Medical & Molecular Genetics (INGEMM, Madrid). Patients were divided in two groups according to the genetic results: Pathogenic variants vs. VUS. Those with chromosopathies were excluded from the study.

Results: We found 13 patients with SHOX/enhancer alterations (5 deletions, 2 missense variants, and 6 duplications). All duplications were classified as VUS, while the remaining variants were classified as pathogenic. Clinical characteristics are summarized in table 1. Both groups had similar height z-scores. The only difference between groups was sitting height z-scores, which was significantly lower in the VUS group.

Conclusions: In our small series, patients with short stature and SHOX duplications (VUS) have a significantly lower sitting height SDS than those with pathogenic variants. No other phenotypic characteristic helped to differentiate between groups. This finding emphasizes the need to analyse larger cohorts, perform functional studies of their genetic variants and/or to continue to search for a different cause to their short stature.