SHOX Haploinsufficiency as a Cause of Syndromic and Nonsyndromic Short Stature

Abstract

SHOX in the short arm pseudoautosomal region (PAR1) of sex chromosomes is one of the major growth genes in humans. SHOX haploinsufficiency results in idiopathic short stature and Léri-Weill dyschondrosteosis and is associated with the short stature of patients with Turner syndrome. The SHOX protein likely controls chondrocyte apoptosis by regulating multiple target genes including BNP,Fgfr3, Agc1, and Ctgf. SHOX haploinsufficiency frequently results from deletions and duplications in PAR1 involving SHOX exons and/or the cis-acting enhancers, while exonic point mutations account for a small percentage of cases. The clinical severity of SHOX haploinsufficiency reflects hormonal conditions rather than mutation types. Growth hormone treatment seems to be beneficial for cases with SHOX haploinsufficiency, although the long-term outcomes of this therapy require confirmation. Future challenges in SHOX research include elucidating its precise function in the developing limbs, identifying additional cis-acting enhancers, and determining optimal therapeutic strategies for patients.

Keywords: Bone; Léri-Weill syndrome; Mutation; Pseudoautosomal region; Short stature; Skeletal deformity; Turner syndrome.

Fig. 1

Genomic structure of SHOX and its putative enhancer regions. SHOX (red box) is located in PAR1 of sex chromosomes. Previous studies identified 7 highly evolutionarily conserved noncoding DNA elements (CNEs) with cis-regulatory activity (blue boxes). These elements were designated as CNE-5, −3, −2, 4, 5, and 9 [Chen et al., 2009; Durand et al., 2010]; evolutionarily conserved region (ECR) 1 [Benito-Sanz et al., 2012b]; and evolutionarily conserved sequence (ECS) 4 [Fukami et al., 2006]. The horizontal line indicates the physical distance from the Xp/Yp telomere (hg 19, build 37).

Fig. 2

A, B Structural comparison among SHOXa, SHOX2a, and SHOXb. All of these proteins contain a homeodomain, while an OAR domain is present only in SHOXa and SHOX2a.

Fig. 3

Madelung deformity of LWD. Bowing and shortening of the radius, prominence of the ulnar head, palmar and ulnar deviation of the carpal bones, and dorsal subluxation of the ulnar head are shown.