Clinical features and growth harmone response in 25 children with duplications in the SHOX region

Objective: SHOX plays an important role in growth plate development and function. The clinical implications of duplications of the SHOX region remain uncertain. We evaluated phenotypic characteristics, genotype–phenotype correlations and the response to treatment with recombinant human growth hormone (rhGH) in children with duplications of the SHOX region. Methods: Twenty-five children (15 boys and 10 girls) with a likely pathogenic duplication and >1 year of rhGH treatment were identified in the Dutch National Registry of GH treatment in children. Results: We identified 23 different duplications of the SHOX region in 25 children. Median (IQR) height was −2.5 SDS (−3.0 to −2.1). The majority (76%) had features of SHOX haploinsufficiency, most frequently an increased sitting-height-to-height (SH/H) ratio. No height differences were found between duplication types. In 19 prepubertal children, median age at start of rhGH was 6.9 years (5.8 to 9.6), and median height gain after 1 year was 0.8 SDS (0.7 to 1.1). Adult height (AH) was reached in 7 children, with a median of −1.1 SDS (−2.1 to −0.3). For pubertal children, median age at start of rhGH was 12.0 years (11.0 to 13.6), and median height gain after 1 year was 0.4 SDS (0.1 to 0.8). AH was reached in 3 children, with a median of −2.9 SDS (−3.6 to −2.7). Conclusion: The majority of children had features associated with SHOX haploinsufficiency, with an increased SH/H ratio most frequently described. Furthermore, rhGH treatment leads to a significant growth response in prepubertal children with a duplication of the SHOX region.