半增生和半增生通过引起骨骼不对称而导致腿部长度差异(LLD)。Beckwith-Wiedemann综合征(BWS)和Silver-Russell综合征(SRS)是由相同染色体位点的相反表观遗传改变引起的相反的影响生长的疾病,11p15,诱导半增生和半增生,分别。因为它们的躯体镶嵌,BWS和SRS显示了广泛的临床表型。我们评估了潜在的表观遗传改变和潜在的表观基因型-表型相关性,专注于LLD,在一组患有孤立性半增生/半发育不全的个体中。
我们前瞻性收集了30例接受LLD手术的孤立性半增生/半增生患者的配对血液组织样本。使用患者样品对染色体11p15上的差异甲基化区域1和2(DMR1和DMR2)进行甲基化特异性多重连接依赖性探针扩增测定(MS-MLPA)和亚硫酸氢盐焦磷酸测序。通过单核苷酸多态性(SNP)微阵列和CDKN1CSanger测序分析了在MS-MLPA或亚硫酸氢盐焦磷酸测序中未显示异常的患者样品。我们引入了一个名为甲基化差异的度量,定义为DMR1和DMR2之间DNA甲基化水平的差异。甲基化差异与骨骼成熟度预测的LLD之间的相关性,使用乘数法计算,进行了评估。预测的LLD对身高进行了标准化。10例患者(33%)在MS-MLPA和亚硫酸氢盐焦磷酸测序中表现出表观遗传改变。其中,6例和4例患者有与BWS和SRS相关的表观遗传学改变,分别。在这10例患者中,有4例患者的半增生/半增生的临床诊断与表观遗传学改变不符。没有患者在SNP阵列或其CDKN1C序列中显示异常。在所有患者中,使用脂肪组织(r=0.53;p=0.002)和皮肤组织(r=0.50;p=0.005),标准化预测的LLD与甲基化差异中度相关。
孤立的半增生和半增生可以作为BWS和SRS的频谱发生。尽管孤立性半增生和孤立性半增生之间的准确区分在肿瘤监测计划中很重要,如果没有表观遗传测试,通常很难在临床上区分这两种疾病。表观遗传测试可能在LLD的预测中发挥作用,这将有助于治疗计划。
Hemihyperplasia and hemihypoplasia result in leg length discrepancy (LLD) by causing skeletal asymmetry. Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS) are opposite growth-affecting disorders caused by opposite epigenetic alterations at the same chromosomal locus, 11p15, to induce
hemihyperplasia and hemihypoplasia, respectively. Because of their somatic mosaicism, BWS and SRS show a wide spectrum of clinical phenotypes. We evaluated the underlying epigenetic alterations and potential epigenotype-phenotype correlations, focusing on LLD, in a group of individuals with isolated hemihyperplasia/hemihypoplasia.
We prospectively collected paired blood-tissue samples from 30 patients with isolated
hemihyperplasia/hemihypoplasia who underwent surgery for LLD. Methylation-specific multiplex-ligation-dependent probe amplification assay (MS-MLPA) and bisulfite pyrosequencing for differentially methylated regions 1 and 2 (DMR1 and DMR2) on chromosome 11p15 were performed using the patient samples. Samples from patients showing no abnormalities in MS-MLPA or bisulfite pyrosequencing were analyzed by single nucleotide polymorphism (SNP) microarray and CDKN1C Sanger sequencing. We introduced a metric named as the methylation difference, defined as the difference in DNA methylation levels between DMR1 and DMR2. The correlation between the methylation difference and the predicted LLD at skeletal maturity, calculated using a multiplier method, was evaluated. Predicted LLD was standardized for stature. Ten patients (33%) showed epigenetic alterations in MS-MLPA and bisulfite pyrosequencing. Of these, six and four patients had epigenetic alterations related to BWS and SRS, respectively. The clinical diagnosis of hemihyperplasia/hemihypoplasia was not compatible with the epigenetic alterations in four of these ten patients. No patients showed abnormalities in SNP array or their CDKN1C sequences. The standardized predicted LLD was moderately correlated with the methylation difference using fat tissue (r = 0.53; p = 0.002) and skin tissue (r = 0.50; p = 0.005) in all patients.
Isolated
hemihyperplasia and hemihypoplasia can occur as a spectrum of BWS and SRS. Although the accurate differentiation between isolated
hemihyperplasia and isolated hemihypoplasia is important in tumor surveillance planning, it is often difficult to clinically differentiate these two diseases without epigenetic tests. Epigenetic tests may play a role in the prediction of LLD, which would aid in treatment planning.