Genetics of SHOX Deficiency


Isolated heterozygous SHOX defects are the most frequent monogenic cause of short stature, being associated with several phenotypes ranging from idiopathic short stature (ISS) without any specific features to Léri–Weill dyschondrosteosis. SHOX deficiency is also accountable for some clinical findings detected in Turner syndrome. SHOX gene is highly expressed in osteogenic cells and encodes a transcription factor, which is essential for bone development and growth. Molecular analysis of SHOX is essential as it can identify the aetiology of short stature, enables early diagnosis in other family members, allows genetic counselling and also supports the use of rhGH therapy in affected children. Even 14 years after the discovery of SHOX, and countless published studies, little is known about the real function of this gene and the mechanisms underlying SHOX‐related disorders. Further investigations will be essential for better understanding the exact role of this gene in the biological growth process.

Key Concepts:

  • Isolated SHOX gene defects are the most frequent monogenic cause of short stature.

  • SHOX gene encodes a transcriptional activator, which is a member of the paired‐like homeodomain proteins.

  • SHOX is predominantly expressed in osteogenic cells and is essential for bone development and growth.

  • The loss of one active allele leads to growth deficit, resulting in a wide spectrum of short stature phenotypes, including Léri–Weill dyschondrosteosis (LWD) and idiopathic short stature (ISS) with no specific skeletal features.

  • The molecular analysis of SHOX gene elucidates the aetiology of short stature, enables genetic counselling and supports the use of recombinant growth hormone treatment.

  • Heterozygous SHOX mutations are identified in approximately 50–90% of patients with LWD.

  • Approximately 2–15% of patients with ISS have SHOX defects.

  • Deletions are responsible for approximately 80% of SHOX haploinsufficiency.

  • Longitudinal follow‐up studies of children with SHOX defects suggest a relatively well‐preserved prepubertal growth followed by compromised pubertal growth due to premature growth plate fusion.

  • Recombinant human growth hormone therapy improves growth velocity and final height in prepubertal patients with isolated SHOX haploinsufficiency.

Keywords: disproportionate short stature; growth; idiopathic short stature; Leri–Weill dyschondrosteosis; SHOX; skeletal dysplasia

Figure 1.

Chromosomal localisation (a) and (b) and genomic structure (c) of SHOX gene. CNE: conserved noncoding elements. In (c) the blue boxes symbolise 5′ or 3′ untranslated regions, whereas the yellow boxes symbolise SHOX gene coding regions.

Figure 2.

Patients with SHOX haploinsufficiency. Height SDS and the presence of Madelung deformity are indicated. (a) and (d) illustrate two pair of siblings with heterozygous SHOX defects (CA, chronological age; y, year; SDS, standard deviation score). Patients and/or patients’ relatives consented to use these images.

Figure 3.

Representative wrist X‐rays illustrating different aspects of skeletal involvement of SHOX haploinsufficiency. (a) Patient without Madelung deformity and (b) patient with Madelung deformity. In (b) it is observed a bowing of the radius (A), triangularisation of the distal radial epiphysis (B), pyramidalisation of the distal carpal row (C) and radial lucency (D).

Figure 4.

Sitting height/total height ratio for chronological age and sex (SH/H SDS) chart for female (a) and male (b). Individual results observed in our patients with SHOX haploinsufficiency are shown as solid circles and clearly demonstrate the presence of body disproportion in these patients. Growth charts were constructed using Growth analyser 3.5 (Ed. Dutch Growth Foundation, PO Box 23068, 3001 KB, Rotterdam, The Netherlands) based on Gerver WJM and Bruin R 2001 Paediatric morphometrics. A reference manual. 2nd ed. Maastricht, The Netherlands: Universitaire Pers Maastricht.



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Further Reading

Alanay Y and Lachman RS (2011) A review of the principles of radiological assessment of skeletal dysplasias. Journal of Clinical Research in Pediatric Endocrinology 3(4): 163–178.

Banerjee‐Basu S and Baxevanis AD (2001) Molecular evolution of the homeodomain family of transcription factors. Nucleic Acids Research 29(15): 3258–3269.

Binder G (2011) Short stature due to SHOX deficiency: genotype, phenotype, and therapy. Hormone Research in Paediatrics 75(2): 81–89.

Zebala LP, Manske PR and Goldfarb CA (2007) Madelung's deformity: a spectrum of presentation. Journal of Hand Surgery (American) 32(9): 1393–1401.

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Funari, Mariana FA, Nishi, Mirian Y, Scalco, Renata C, and Jorge, Alexander AL(Jul 2012) Genetics of SHOX Deficiency. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023852]