Zollino Marcella, Murdolo Marina, Marangi Giuseppe, Pecile Vanna, Galasso Cinzia, Mazzanti Laura, Neri Giovanni
Department of Medical Genetics, Università Cattolica Sacro Cuore, Roma, Italy.
Am J Med Genet C Semin Med Genet. 2008 Nov 15;148C(4):257-69. doi: 10.1002/ajmg.c.30190.
Based on genotype-phenotype correlation analysis of 80 Wolf-Hirschhorn syndrome (WHS) patients, as well as on review of relevant literature, we add further insights to the following aspects of WHS: (1) clinical delineation and phenotypic categories; (2) characterization of the basic genomic defect, mechanisms of origin and familiarity; (3) identification of prognostic factors for mental retardation; (4) chromosome mapping of the distinctive clinical signs, in an effort to identify pathogenic genes. Clinically, we consider that minimal diagnostic criteria for WHS, defining a "core" phenotype, are typical facial appearance, mental retardation, growth delay and seizures (or EEG anomalies). Three different categories of the WHS phenotype were defined, generally correlating with the extent of the 4p deletion. The first one comprises a small deletion not exceeding 3.5 Mb, that is usually associated with a mild phenotype, lacking major malformations. This category is likely under-diagnosed. The second and by far the more frequent category is identified by large deletions, averaging between 5 and 18 Mb, and causes the widely recognizable WHS phenotype. The third clinical category results from a very large deletion exceeding 22-25 Mb causing a severe phenotype, that can hardly be defined as typical WHS. Genetically, de novo chromosome abnormalities in WHS include pure deletions but also complex rearrangements, mainly unbalanced translocations. With the exception of t(4p;8p), WHS-associated chromosome abnormalities are neither mediated by segmental duplications, nor associated with a parental inversion polymorphism on 4p16.3. Factors involved in prediction of prognosis include the extent of the deletion, the occurrence of complex chromosome anomalies, and the severity of seizures. We found that the core phenotype maps within the terminal 1.9 Mb region of chromosome 4p. Therefore, WHSCR-2 should be considered the critical region for this condition. We also confirmed that the pathogenesis of WHS is multigenic. Specific and independent chromosome regions were characterized for growth delay and seizures, as well as for the additional clinical signs that characterize this condition. With the exception of parental balanced translocations, familial recurrence is uncommon.
基于对80例Wolf-Hirschhorn综合征（WHS）患者的基因型-表型相关性分析以及相关文献回顾，我们对WHS的以下方面有了进一步认识：（1）临床描述与表型分类；（2）基本基因组缺陷的特征、起源机制及家族性情况；（3）智力发育迟缓预后因素的识别；（4）独特临床体征的染色体定位，以努力鉴定致病基因。临床上，我们认为定义“核心”表型的WHS最小诊断标准为典型面容、智力发育迟缓、生长发育延迟和癫痫发作（或脑电图异常）。定义了WHS表型的三种不同类别，通常与4p缺失的范围相关。第一类包括不超过3.5 Mb的小缺失，通常与轻度表型相关，无主要畸形。这类可能诊断不足。第二类也是迄今为止更常见的类别，其特征为大缺失，平均在5至18 Mb之间，导致广泛认可的WHS表型。第三类临床情况是由超过22 - 25 Mb的非常大的缺失导致的严重表型，几乎不能定义为典型的WHS。在遗传学上，WHS中的新发染色体异常包括单纯缺失，也包括复杂重排，主要是非平衡易位。除了t(4p;8p)，与WHS相关的染色体异常既不由节段性重复介导，也与4p16.3上的亲本倒位多态性无关。预测预后的因素包括缺失范围、复杂染色体异常的发生情况以及癫痫发作的严重程度。我们发现核心表型定位于染色体4p末端1.9 Mb区域内。因此，应将WHSCR-2视为该病症的关键区域。我们还证实WHS的发病机制是多基因的。生长发育延迟和癫痫发作以及该病症的其他临床体征具有特定且独立的染色体区域特征。除了亲本平衡易位外，家族性复发并不常见。
