SHOX is a transcription factor located in the pseudoautosomal region of the X and Y chrX|Y that plays a fundamental role in growth and skeletal development. The protein preferentially binds DNA sequences with the consensus 5'-TAATNNNATTA-3' and directly activates NPPB transcription in osteogenic cells, likely functioning as a homodimer 1. SHOX is most strongly expressed in bone marrow fibroblasts, implicating it in bone growth and development 2. Because SHOX escapes X-inactivation, it exerts dosage effects across sex chromosome X|Y. Heterozygous SHOX mutations represent one of the most common monogenic causes of short stature, occurring in approximately 1 in 1,000 newborns 3. These mutations are identified in 50–90% of patients with Leri-Weill dyschondrosteosis, 2–15% of children with idiopathic short stature, and contribute to the short stature and skeletal abnormalities in Turner syndrome 4. Homozygous mutations cause the more severe Langer mesomelic dysplasia 3. Clinically, SHOX haploinsufficiency is an FDA-approved indication for recombinant human growth hormone (rhGH) therapy 5, 6. Growth hormone treatment is considered an accepted therapeutic approach for short stature associated with isolated SHOX deficiency 4. Recent evidence suggests that SHOX whole gene duplications containing variable amounts of flanking regulatory elements may also impair normal SHOX expression and warrant clinical consideration 7.