Abstract
Short stature homeobox-containing gene (SHOX) haploinsufficiency is an important genetic cause of short stature associated with well recognised dysmorphic signs. SHOX is located in pseudoautosomal region 1 (PAR 1) of both sex chromosomes (Xp22.3, Yp11.3).
Because genes in PAR 1 do not undergo X inactivation, heathy individuals express two copies of the SHOX gene. As a regulatory gene, SHOX encodes a homeodomain transcription factor expressed during early fetal life in developing skeletal tissue.
SHOX deficiency (as a result of deletion or point mutation) is present in 2.4% of individuals with short stature (< -2.0 SDS). SHOX-deficient patients have variable degrees of growth impairment with or without a spectrum of skeletal abnormalities such as Madelung deformity, shortening of the middle segments of the upper and lower limbs (mesomelia) and bowing of the forearms consistent with dyschondrosteosis, short metatarsals and metacarpals (in particular short metacarpal IV or metatarsal IV), and high arched palate.
SHOX deficiency includes a continuum of clinical conditions spanning from severe Langer syndrome (homozygous SHOX mutations) to a less severe phenotype in Leri-Weill syndrome (LWS) and isolated idiopathic short stature (ISS) without dysmorphic features. Because they lack all or part of their second X chromosome, individuals with Turner syndrome also have only a single copy of the SHOX gene.
The gene was identified in 1997 and Turner syndrome served as a model for growth hormone treatment. Growth hormone significantly improves growth velocity and adult height.
The growth hormone treatment outcomes in prepubertal patients with SHOX deficiency are comparable to those seen in girls with Turner syndrome. SHOX deficiency (confirmed by DNA analysis) has been considered as one of the indications for growth hormone therapy in the Czech Republic since 2008.