ABSTRACT

The SHOX (short stature homeobox containing gene) haploinsufficiency can result in phenotypes ranging from idiopathic short stature to Leri-Weill dyschondrosteosis (LWD). It has been reported to have been detected in 5-17% of children diagnosed with idiopathic short stature, and in 60-90% of children with LWD. SHOX duplications, although typically associated with tall stature, can result in short stature and/or extremity anomalies in rare cases when partial or complete duplications involving the SHOX region occur. In this case report, two patients with extremity anomalies who were found to have SHOX region duplications with two different clinical features are presented. The first case was an eleven-month-old male, referred to the pediatric endocrinology clinic due to short stature, and skeletal deformities. On physical examination, the patient’s weight was 8.6 kilograms (-1.19 standard deviation score; SDS), and his height was 68 cm (-2.57 SDS). The systemic examination was unremarkable, but examination of the extremities revealed the absence of the right thumb and left forearm bones. Radiographic images of the bones revealed possible rudimentary bone tissue of the radius and ulna in the left upper extremity. DNA extracted from the patient’s peripheral blood was subjected to multiplex ligation-dependent probe amplification (MLPA) analysis, which revealed a duplication extending from the upstream regulatory regions of the SHOX gene on Xp22.3/Yp11.32 to the downstream CNE8 (conserved noncoding elements) region, including all of the gene's coding regions and upstream regulatory areas. The second case involved a fourteen-month-old male, who was referred after SHOX duplication was detected in a microarray analysis performed due to epilepsy. On physical examination, his weight was 10.3 kg (-0.3 SDS), and his height was 79 cm (-0.11 SDS). Systemic examination was normal, but Madelung deformities were observed in the extremity examination. DNA obtained from the patient’s peripheral blood was analyzed using MLPA for deletions and duplications of the SHOX gene and the associated regulatory regions on Xp22.3/Yp11.32. This analysis revealed a heterozygous duplication which extended from the entire SHOX gene and upstream CNE regions to the CNE7/8 regions downstream. SHOX duplications can result in short, normal, or tall stature depending on the size, location, and transcriptional characteristics (such as containing non-coding elements) of the duplicated region. This case report emphasizes that, in the presence of idiopathic short stature and/or extremity anomalies, SHOX duplications should be considered in addition to the other common genetic causes.