ESPE Abstracts

Background: Short stature homeobox-containing gene (SHOX) is located within the pseudoautosomal region 1 (PAR1) of the sex chromosomes. SHOX mutations and PAR1 deletions encompassing SHOX or its upstream/downstream enhancers have been identified in ~60% of Léri-Weill dyschondrosteosis (LWD) and ~5–15% of idiopathic short stature (ISS) patients. Recently SHOX duplications have been described in LWD/ISS individuals.

Case presentation: The boy was born full-term, BW 3200 g, BL 47 cm. At the first endocrine investigation for short stature at 11 years, his height was 128.5 cm (−2.9 SD), P2, testes 5/5 ml, bone age slightly advanced up to 12.6 years (TW3-RUS). His father and paternal mother have short stature (final height −3.2 SD; −4.6 SD respectively). Neither proband nor family members have Madelung deformity, other skeletal deformities or mesomelic disproportion of the extremities. The basic laboratory work up was normal: chronic inflammation, thyroid disease, celiac disease was excluded, IGF1 was normal (241 μg/l; −0.57 SD).

Method: We performed FISH; MLPA and array-CGH in proband and his father.

Results: Both of them carry two duplications within the PAR1 region. First large duplication of 267 kbp reaches the Y subtelomere; the second duplication consisting of 58 kbp is located upstream from SHOX gene in the region of gene transcription regulatory elements. Following these findings, we started GH administration in dose 50 μg/kg per day at age 11.5 years. The growth velocity accelerated up to 10 cm/year.

Conclusion: In conclusion, we have identified the first PAR1 duplication encompassing the upstream SHOX transcription regulatory elements in a family with ISS. The loss of these elements may result in SHOX haploinsufficiency because of decreased SHOX transcription.