In an attempt to determine when to screen for SHOX gene deletion in subjects with short stature, Müsebeck and colleagues determined the frequency of SHOX deletions in 50 children with short stature.  All children studied had a height < -2 SDS and 3 of the subjects also had the Madelung deformity (shortening and bowing of the radius with dorsal subluxation of the distal ulna and partial foreleg anomalies).  Thirty-five of the 50 subjects had idiopathic short stature (ISS) accompanied by the absence of skeletal, endocrine, or organic symptoms and had no family history of short stature.  Twelve subjects had upper limb abnormalities such as cubitus valgus. Two subjects had Léri-Weill dyschondrosteosis, and 3 had a congenital heart defect.  Blood was analyzed by FISH process (Fluorescence In Situ Hybridization) for the SHOX deletion.

Microdeletions of the SHOX gene were not detected in any of the 35 patients with ISS.  Of the 12 patients with additional upper limb abnormalities 5 (41.7%) displayed SHOX signals on only one sex chromosome.  Of the 7 with short stature who displayed SHOX signals on 2 sex chromosomes, 3 had Madelung deformity and brachymetacarpia was present in the other 4.  Point mutations of course are not picked up in the FISH technique.  Molecular genetic methods will possibly detect point mutations in patients such as the 7 referred to above.  Three patients with congenital heart defects did not carry SHOX deletions.

The authors state that their findings provide important guidelines for selecting patients for SHOX analysis.  They state that children with ISS are unlikely to carry such a mutation of the SHOX gene.  Indeed, other studies have shown the SHOX mutation in about 1% of all patients with ISS.  The combination of short stature and skeletal abnormalities of the forearm, however, makes the SHOX mutation much more probable.  The authors caution that a father carrying a SHOX mutation on the X chromosome could transmit these mutations to his son because of crossing over between the pseudoautosomal regions of the X and Y chromosomes during paternal meiosis.

Editor’s Comment: SHOX gene deletion determinations have become increasingly popular in endocrine/genetic clinics evaluating children with short stature.  Although, the number of subjects studied by Müsebeck et al is relatively small (n=50), their data are convincing. Apparently, SHOX gene determinations have little place in the evaluation of the child with ISS and should be reserved for those children who have deformities of the upper extremities even when those are very mild.  Hopefully, data can be pooled in the future from numerous centers so that definitive guidelines for evaluation of SHOX gene determinations are more clearly defined.

William L. Clarke, MD

Print version (pdf) |Printer-Friendly