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. 2016 Apr;7(1):19-25.
doi: 10.1159/000444430. Epub 2016 Mar 12.

Short Stature in Isodicentric Y Chromosome and Three Copies of the SHOX Gene: Clinical Report and Review of Literature

Angelo Valetto  1 , Veronica Bertini  1 , Angela Michelucci  1 , Benedetta Toschi  1 , Eleonora Dati  2 , Giampietro I Baroncelli  3 , Silvano Bertelloni  3
Affiliations

Short Stature in Isodicentric Y Chromosome and Three Copies of the SHOX Gene: Clinical Report and Review of Literature

Angelo Valetto et al. Mol Syndromol. 2016 Apr.

Abstract

Short stature homeobox gene (SHOX) mutations and pseudoautosomal region 1 (PAR1) deletions encompassing SHOX are known causes of Léri-Weill dyschondrosteosis and isolated short stature, while 3 copies of SHOX in cases with triple sex chromosome constitution are responsible for tall stature. Duplications involving SHOX have been rarely reported, and they were found in individuals with short, normal and tall stature. An adopted boy with short stature, isodicentric Y chromosome and 3 copies of SHOX is described. Normal growth hormone (GH) secretion and insulin-like growth factor 1 (IGF1) increase during an IGF1 generation test were found, ruling out impaired GH-IGF1 axis. No other organic or psychiatric causes of impaired growth were found. GH treatment improved linear growth, as reported in children with SHOX haploinsufficiency. This new report and the review of literature support that SHOX duplication may cause short stature, especially in those children with duplications of the 5'SHOX regulatory elements. Chromosome analysis and detailed molecular characterization of the duplicated region should be warranted in individuals with SHOX duplications in order to investigate the presence of occult chromosome imbalance. Additional reports and follow-up till adult height are needed to give conclusions on long-term efficacy and safety of GH treatment in short children with SHOX duplication.

Keywords: GH-IGF1 axis; SHOX; SHOX duplications; Short stature; Y chromosome rearrangement.

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Figures

Fig. 1
Fig. 1
Chromosome constitution of the boy with triple SHOX. a Q-banded karyotype showing the idic(Y). b Scheme of the structure of a normal Y chromosome and an idic(Y) chromosome.
Fig. 2
Fig. 2
Possible mechanisms of idic(Y) formation. A double-strand break occurs in the Y chromosome, and the broken ends are joined to stabilize the chromosome. This results in an idic(Y) and an acentric fragment (a). A misalignment, due to palindromic sequences in Y(p), occurs between sister chromatids followed by NAHR. Again this results in an idic(Yp) and an acentric fragment which has the length of Yp (b).
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