Mussa Alessandro, Russo Silvia, De Crescenzo Agostina, Freschi Andrea, Calzari Luciano, Maitz Silvia, Macchiaiolo Marina, Molinatto Cristina, Baldassarre Giuseppina, Mariani Milena, Tarani Luigi, Bedeschi Maria Francesca, Milani Donatella, Melis Daniela, Bartuli Andrea, Cubellis Maria Vittoria, Selicorni Angelo, Cirillo Silengo Margherita, Larizza Lidia, Riccio Andrea, Ferrero Giovanni Battista
Department of Pediatric and Public Health Sciences, University of Torino, Torino, Italy.
Laboratory of Cytogenetics and Molecular Genetics, Istituto Auxologico Italiano, Milan, Italy.
Eur J Hum Genet. 2016 Feb;24(2):183-90. doi: 10.1038/ejhg.2015.88. Epub 2015 Apr 22.
Beckwith-Wiedemann syndrome (BWS) is characterized by cancer predisposition, overgrowth and highly variable association of macroglossia, abdominal wall defects, nephrourological anomalies, nevus flammeus, ear malformations, hypoglycemia, hemihyperplasia, and organomegaly. BWS molecular defects, causing alteration of expression or activity of the genes regulated by two imprinting centres (IC) in the 11p15 chromosomal region, are also heterogeneous. In this paper we define (epi)genotype-phenotype correlations in molecularly confirmed BWS patients. The characteristics of 318 BWS patients with proven molecular defect were compared among the main four molecular subclasses: IC2 loss of methylation (IC2-LoM, n=190), IC1 gain of methylation (IC1-GoM, n=31), chromosome 11p15 paternal uniparental disomy (UPD, n=87), and cyclin-dependent kinase inhibitor 1C gene (CDKN1C) variants (n=10). A characteristic growth pattern was found in each group; neonatal macrosomia was almost constant in IC1-GoM, postnatal overgrowth in IC2-LoM, and hemihyperplasia more common in UPD (P<0.001). Exomphalos was more common in IC2/CDKN1C patients (P<0.001). Renal defects were typical of UPD/IC1 patients, uretheral malformations of IC1-GoM cases (P<0.001). Ear anomalies and nevus flammeus were associated with IC2/CDKN1C genotype (P<0.001). Macroglossia was less common among UPD patients (P<0.001). Wilms' tumor was associated with IC1-GoM or UPD and never observed in IC2-LoM patients (P<0.001). Hepatoblastoma occurred only in UPD cases. Cancer risk was lower in IC2/CDKN1C, intermediate in UPD, and very high in IC1 cases (P=0.009). In conclusion, (epi)genotype-phenotype correlations define four different phenotypic BWS profiles with some degree of clinical overlap. These observations impact clinical care allowing to move toward (epi) genotype-based follow-up and cancer screening.
贝克威思-维德曼综合征（BWS）的特征包括癌症易感性、生长过度，以及巨舌症、腹壁缺损、泌尿系统异常、葡萄酒色斑、耳部畸形、低血糖、半身肥大和器官肿大等高度可变的关联症状。BWS的分子缺陷也具有异质性，这些缺陷会导致11p15染色体区域中两个印记中心（IC）调控的基因的表达或活性发生改变。在本文中，我们定义了分子确诊的BWS患者的（表观）基因型-表型相关性。比较了318例经证实存在分子缺陷的BWS患者在四个主要分子亚类中的特征：IC2甲基化缺失（IC2-LoM，n = 190）、IC1甲基化增加（IC1-GoM，n = 31）、11号染色体p15区域父源单亲二倍体（UPD，n = 87）以及细胞周期蛋白依赖性激酶抑制剂1C基因（CDKN1C）变异（n = 10）。在每组中都发现了一种特征性的生长模式；IC1-GoM组中新生儿巨大儿几乎恒定，IC2-LoM组中产后生长过度，UPD组中半身肥大更为常见（P<0.001）。脐膨出在IC2/CDKN1C患者中更为常见（P<0.001）。肾脏缺陷是UPD/IC1患者的典型特征，IC1-GoM病例中输尿管畸形较为常见（P<0.001）。耳部异常和葡萄酒色斑与IC2/CDKN1C基因型相关（P<0.001）。巨舌症在UPD患者中较少见（P<0.001）。肾母细胞瘤与IC1-GoM或UPD相关，在IC2-LoM患者中从未观察到（P<0.001）。肝母细胞瘤仅发生在UPD病例中。IC2/CDKN1C组的癌症风险较低，UPD组为中等，IC1组非常高（P = 0.009）。总之，（表观）基因型-表型相关性定义了四种不同表型的BWS概况，且存在一定程度的临床重叠。这些观察结果对临床护理产生影响，有助于朝着基于（表观）基因型的随访和癌症筛查方向发展。
