■SHOX基因中的分子缺陷,包括缺失,重复或致病点突变是导致以身材矮小为临床表现的众所周知的病理的原因:Léri-Weill软骨发育不良,兰格膜异常增生,特纳综合征或特发性身材矮小。已经描述了SHOX基因侧翼(完整SHOX基因的上游或下游,涉及保守的非编码顺式调节DNA元件-CNE)的重复,但其临床参与仍然难以理解。
■我们描述了两种身材矮小且GH-IGF1状态正常的情况。在这两种情况下都鉴定出涉及SHOX基因下游区域的杂合重复的多重连接依赖性探针扩增(MLPA)和阵列比较基因组杂交(arrayCGH),在CNEs(CNE8、CNE9和CNE4、CNE5、CNE6、ECR1、CNE8、CNE9及周边地区,分别)。其中一例显示了母系遗传的重复。尽管每个案件都有几个特殊性,我们认为SHOX基因这些非编码区的重复可以解释身材矮小的表型。
■据我们所知,这是罗马尼亚报道的首例ISS病例,其下游SHOX增强子CNEs区域大量重复。这些遗传改变的表型后果谱和假定的临床表达的确切机制仍需要评估和描述。
UNASSIGNED: Molecular defects in the SHOX gene including deletions, duplications or pathogenic point mutations are responsible for well-known pathologies involving short stature as a clinical manifestation: Léri-Weill dyschondrosteosis, Langer mesomelic dysplasia, Turner syndrome or idiopathic short stature. Duplications flanking the SHOX gene (upstream or downstream of the intact SHOX gene involving conserved non-coding cis-regulatory DNA elements - CNEs) have been described but their clinical involvement is still difficult to understand.
UNASSIGNED: We describe two cases with short stature and normal GH-IGF1 status. Multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (arrayCGH) identified in both cases heterozygous duplications involving downstream regions of SHOX gene, within CNEs (CNE8, CNE9 and CNE4, CNE5, CNE6, ECR1, CNE8, CNE9 and surrounding areas, respectively). One of the cases showed a maternally inherited duplication. Although every case has several particularities, we consider that duplications in these non-coding regions of SHOX gene may explain the short stature phenotype.
UNASSIGNED: To our knowledge, these are the first Romanian-reported cases of ISS with a large duplication of downstream SHOX enhancers CNEs region. The spectrum of phenotypic consequences and the exact mechanism of the presumed clinical expression of these genetic alterations still needs to be evaluated and described.