SHOX gene deficiency causes Langer mesomelic dysplasia with severe disproportionate short stature and limb hypoplasiaSHOX Gene Deficiency Linked to Specific Skeletal Growth Disorders

Langer mesomelic dysplasia is an exceptionally rare skeletal dysplasia caused by complete or functionally complete deficiency of the SHOX (short stature homeobox) gene located within the pseudoautosomal region 1 (PAR1) of the sex chromosomes. Clinically, the disorder is characterized by severe disproportionate short stature and marked mesomelic shortening of the limbs, particularly involving hypoplasia or aplasia of the ulna and fibula, while cognitive development and life expectancy are generally preserved. This narrative review summarizes current knowledge regarding the molecular genetics, developmental biology, clinical manifestations, radiographic findings, prenatal diagnosis, and differential diagnosis of Langer mesomelic dysplasia. The SHOX protein functions as a homeodomain-containing transcription factor essential for chondrocyte proliferation, differentiation, and growth plate organization. Pathogenic mechanisms include biallelic SHOX deletions, enhancer-region defects, missense variants affecting the homeodomain and nuclear localization signal, as well as splice-site variants leading to severe reduction of functional protein dosage. The article also discusses the broad phenotypic spectrum of SHOX deficiency, genotype-phenotype variability, and the relationship between Langer mesomelic dysplasia and related disorders such as Léri-Weill dyschondrosteosis and Turner syndrome. Understanding the molecular basis of this condition is essential for accurate diagnosis, genetic counseling, and prenatal assessment in affected families.