Introduction: Short stature homeobox-containing gene (SHOX) haploinsufficiency is associated with short stature, Madelung deformity and mesomelia. Current clinical screening tools are based on patients with intragenic variants or deletions. However, recent discoveries showed that deletions of the enhancer elements are quite common. The majority of these patients show less body disproportion and respond better to recombinant human growth hormone treatment. We redefined clinical criteria for genetic analysis to facilitate detection of the full spectrum of SHOX haploinsufficiency. Methods: We analyzed 51 children with SHOX variants or deletions and 25 children with a deletion in its enhancer region. Data were compared to 277 children referred for suspicion of growth failure without endocrine or genetic pathology. Results: Only half of the patients with an enhancer region deletion fulfilled any of the current screening criteria. We propose new clinical criteria based on sitting height to height ratio >1 SDS or arm span ≥3 cm below height, with a sensitivity of 99%. When these criteria are combined with obligatory short stature, the sensitivity to detect SHOX haploinsufficiency is 68.1%, the specificity 80.6%, and the number needed to screen 21 patients. Conclusion: Novel clinical criteria for screening for SHOX haploinsufficiency allow the detection of patients within the full genetic spectrum, that is, intragenic variants and enhancer region deletions.

Clinical features, Gene enhancer mutation, Genetic screening, Short stature homeobox-containing gene deficiency,
Hormone Research in Paediatrics
Department of Pediatrics

Joustra, S.D, Kamp, G.A, Stalman, S.E. (Susanne E.), Donze, S.H, Losekoot, M, Kant, S.G, … Wit, J.M. (2020). Novel Clinical Criteria Allow Detection of Short Stature Homeobox-Containing Gene Haploinsufficiency Caused by Either Gene or Enhancer Region Defects. Hormone Research in Paediatrics. doi:10.1159/000507215