Clinical and genetic spectrum of SHOX deficiency: phenotypic heterogeneity and the "Jumping SHOX" phenomenon.

Short stature homeobox gene (SHOX) deficiency disorders, caused by deletions or duplications involving the SHOX gene or its enhancer regions, as well as pathogenic variants, exhibit a broad phenotypic spectrum ranging from Langer mesomelic dysplasia (LMD) to Léri-Weill dyschondrosteosis (LWD) and idiopathic short stature (ISS). In this study, we aimed to highlight the phenotypic and genetic heterogeneity of SHOX deficiency disorders, with particular emphasis on the rare "jumping SHOX" phenomenon. Genetic diagnosis was performed using karyotyping, fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and chromosomal microarray analysis. A total of 41 patients from 23 unrelated families were included, comprising 25 children and 16 adults. The mean age was 11.7 years in children and 40.1 years in adults. LWD was diagnosed in 24 patients, ISS in 12, and LMD in two. The current median height SDS was - 6.3 in patients with LMD, - 2.4 in those with LWD, and - 2.1 in those with ISS. Additionally, three other patients with a SHOX deletion were identified: two had mosaic Turner syndrome (one with severe short stature), and one had 45,X/46,XY mosaicism. The "jumping SHOX" phenomenon was observed in four families. Growth hormone therapy was administered to 15 patients, and the mean height SDS improved from - 2.5 before treatment to - 2.0 after therapy. Dual diagnoses were identified in six patients: four related patients had a 9q34.3 duplication (EHMT1), one had DiGeorge syndrome with craniosynostosis, and one with cortical dysplasia and thin corpus callosum had a 16q22.2 duplication.

conclusionOur findings expand both the clinical and genetic spectrum of SHOX deficiency disorders and highlight the phenotypic heterogeneity of the condition. The presence of the "jumping SHOX" phenomenon should be considered during genetic counseling. In addition, the possibility of dual diagnoses should be kept in mind in patients presenting with atypical clinical features. WHAT IS KNOWN: • SHOX deficiency disorders, caused by deletions, duplications, or pathogenic variants involving the SHOX gene or its enhancer regions, exhibit a broad phenotypic spectrum ranging from Langer mesomelic dysplasia to Léri-Weill dyschondrosteosis and idiopathic short stature. WHAT IS NEW: • In the present study, we describe the clinical and genetic characteristics of 41 patients with SHOX deficiency disorders. Notably, the "jumping SHOX" phenomenon was observed in four families, and dual diagnoses were identified in six patients. These findings underscore the marked genetic and phenotypic heterogeneity of SHOX deficiency.