Genetics of SHOX Deficiency

Abstract

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.