SHOX

The SHOX gene, short for short stature homeobox-containing gene, is located in the pseudoautosomal region PAR1 of the X and Y chromosomes. It encodes a transcription factor of the homeobox family that is expressed in developing limb buds and growth plates, where it influences chondrocyte proliferation and maturation.

SHOX plays a critical role in longitudinal skeletal growth, particularly of the arms and legs. Variants that reduce SHOX expression or disrupt its regulatory elements lead to haploinsufficiency and impaired growth. Because the gene resides in a region shared by X and Y, SHOX-related disorders can arise from haploinsufficiency on either chromosome and show variable phenotypic expressivity.

Clinical disorders associated with SHOX deficiency include Leri-Weill dyschondrosteosis (LWD), characterized by mild-to-moderate short stature with mesomelic shortening of the limbs and Madelung deformity of the distal radius. Langer mesomelic dysplasia (LMD) is a more severe condition, usually due to biallelic SHOX mutations or deletions. SHOX haploinsufficiency also contributes to short stature in Turner syndrome and other karyotypes with partial SHOX loss. Radiographs may reveal mesomelic diminution and Madelung deformity in LWD.

Diagnosis relies on genetic testing to detect SHOX sequence variants and copy-number changes in regulatory regions, alongside clinical and radiographic assessment. Management often includes growth hormone therapy to improve height, with additional orthopedic interventions for skeletal deformities as needed. Inheritance is typically described as pseudoautosomal dominant with variable penetrance and expressivity, with cases arising from either parent or de novo mutations.