Short stature and the SHOX gene

The SHOX gene (short stature homeobox-containing gene) located in the pseudoautosomal region of the X and Y chromosomes is an important cause of short stature in a diversity of clinical conditions ⁽¹⁾.

SHOX haploinsufficiency causes a wide spectrum of short stature phenotypes, including patients with Turner syndrome, Leri-Weill dyschondrosteosis (which includes Madelung deformity of the wrists) and short stature without any specific features. Homozygous loss of SHOX results in the more severe Langer mesomelic dysplasia (LMD). Two active copies of SHOX are required for its normal function in both males and females ⁽¹⁾.

The most frequent clinical finding reported in patients with SHOX mutations is the presence of height disproportion (short limbs compared with the trunk), even in individuals without short stature or the Madelung deformity. Although not every child with disproportional short stature will present with SHOX mutation, it is recommended that children with ISS and/or a family history of Leri-Weill dyschondrosteosis undergo molecular analysis of the SHOX gene ⁽¹⁾.

SHOX defects represent a relatively frequent cause of short stature, particularly in children with evidence of shortening and/or bowing of the forearms and lower legs. Presence of any combination of the following physical findings:

• reduced arm span/height ratio
• increased sitting height/height ratio
• above average BMI
• Madelung deformity
• cubitus valgus
• short or bowed forearm
• dislocation of the ulna at the elbow
• or the appearance of muscular hypertrophy.

should prompt the clinician to obtain a molecular analysis of the SHOX gene ⁽²⁾.

Mater Pathology is now able to test for SHOX microdeletions using FISH (fluorescent in situ hybridization).

FISH is a cytogenetic technique which can be used to detect and localize the presence or absence of specific DNA sequences on chromosomes. It uses fluorescent probes which bind only to those parts of the chromosome with which they show a high degree of similarity. Fluorescent microscopy can then be used to visualise the fluorescent probe bound to the chromosome.

The probe for the SHOX gene is a locus-specific probe. These probes are made so that they will hybridise to regions that are commonly deleted or amplified and analysis is as simple as counting fluorescent dots.

The specimen requirements for this test are the same as for routine cytogenetic analysis—peripheral blood collected in lithium heparin (no gel). For enquiries please phone MaryLou Doody, Cytogenetics Division, Mater Pathology, on +61 7 3163 8212.

References:
(1) Alexander ALJ et al. (2007) SHOX mutations in idiopathic short stature and Leri-Weill dyschondrosteosis: frequency and phenotypic variability. Clinical Endocrinology, 66, 130-135.
(2) Rappold G et al. (2006) Genotypes and phenotypes in children with short stature: clinical indicators of SHOX haploinsufficiency. Journal of Medical Genetics, Dec 20 [Epub ahead of print].