ESPE Abstracts

Objectives: Deficiency of the short stature homeobox-containing (SHOX) gene is a potential etiology of short stature in children. The phenotypic spectrum of SHOX deficiency disorders, caused by haploinsufficiency of the SHOX-gene and inherited in a pseudo-autosomal dominant manner, is highly variable, even within the same family, ranging from nonspecific short stature to Leri-Weill dyschondrosteosis (LWD). Short stature, mesomelia and Madelung deformity define the classic clinical triad in LWD. SHOX deficiency can be caused either by single nucleotide variants or deletions encompassing the SHOX coding region and/or the enhancer region regulating SHOX expression. We describe two brothers (21-month and 4-year old) with short stature and disproportion. Both children had an unremarkable past medical history. Family history was notable for several individuals with short stature. The parents presented both with short stature, but the father was proportioned, while the mother showed stigmas indicating LWD. Physical exam revealed short stature with disproportion and height standard deviation score (SDS) of −3.4 SDS for the older- and −3.2 SDS for the younger child. In both children laboratory was noncontributory for common causes of short stature and growth hormone stimulation test showed normal response. Due to family history, we performed SHOX gene analysis with a surprising result.

Methods: Multiplex Ligation-dependent Probe Amplification (MLPA) of the PAR region on Xp22.32 and Yp11.32 containing the coding region and 5’ and 3’ flanking sequences of the SHOX gene was performed using the MRC-Holland kit P018-G1 according to the manufacturer’s instructions.

Results: SHOX gene analysis revealed a known heterozygous ~47, 5 kb deletion in the 3’-flanking region (probes L25091-L24249) in the mother and the older child, whereas a novel duplication in the SHOX 5’-flanking sequence (probes L24430-L20651) was found in the father and the younger child. This duplication has not been described previously, but likely influences the regulation of SHOX protein expression.

Conclusions: Short stature can be caused by different SHOX gene mutations and there is no established correlation between the severity of phenotype and the underlying pathogenic variant. The penetrance of SHOX deficiency is high, and it’s clinical expression highly variable, even in the same family. Phenotypic characteristics become more pronounced with age and are more severe in females. All the more it was a surprise to find two different SHOX gene variants in two short siblings.