Moore Sam W, Fieggen Karen, Honey Engela, Zaahl Monique
Division of Paediatric Surgery, University of Stellenbosch, Tygerberg, Western Cape Tygerberg.
Division of Clinical Genetics, University of Cape Town, Western Cape Red Cross Children's.
J Pediatr Surg. 2016 Feb;51(2):268-71. doi: 10.1016/j.jpedsurg.2015.10.070. Epub 2015 Nov 5.
Mowat Wilson syndrome (MWS) is an uncommon association of Hirschsprung's disease (HSCR). Phenotypic features may develop with time, causing initial difficulties in diagnosis. MWS results from haploinsufficiency of the Zinc finger E-box-binding homeobox 2 (ZEB2) gene, and molecular diagnosis of ZEB2 mutation is required to confirm the diagnosis. We report the first confirmed cases of MWS in three children with the typical facial features, mental retardation, absent corpus callosum, epilepsy, and HSCR and novel Zeb2 variations on DNA analysis.
Clinical features were monitored. DNA extracted from peripheral blood was subjected to bidirectional sequencing analysis following PCR DNA amplification. ZEB2 gene results were compared to the ZEB2 reference sequence (ENS00000169554) for variation. Bioinformatic investigation of novel gene variants was via the "Blastx" program function available via the National Center for Biotechnology Information (http://www.bioinfo.org/NPInter/blast/blast_link.cgi).
Clinical follow-up showed that the phenotypic features were not all present at birth but developed with time in 2 surviving patients. Several Zeb2 variations were detected in the promoter region of the ZEB2 gene of which 2 were novel (-56A/T 1174 11A/12A). In addition, a novel heterozygous single nucleotide insertion in exon 2 of ZEB2 in one patient results in a frameshift causing deletion of the first 8 amino acids of the ZEB2 protein and an alteration of amino acids 9 (G9A), 11 (R11G), and 12 (C12A). In the third patient, a novel single nucleotide deletion exon 8 (1784delC Het) results in a frameshift at amino acid 595 of translated protein. This shortens protein from 1214 to 594 amino acids and affects the functionality of the critical ZEB2 protein.
MWS is an important link to recognise clinically. It underlines the functionality of the Zeb2 gene in certain syndromic Hirschsprung's disease. These variations probably contribute to the clinical features of the Mowat Wilson phenotype in Hirschsprung's disease but should be confirmed in further research.
莫瓦特·威尔逊综合征（MWS）是一种罕见的与先天性巨结肠症（HSCR）相关的疾病。其表型特征可能随时间发展，导致最初诊断困难。MWS由锌指E盒结合同源框2（ZEB2）基因单倍剂量不足引起，确诊需要对ZEB2突变进行分子诊断。我们报告了首例经确诊的3例患有典型面部特征、智力发育迟缓、胼胝体缺失、癫痫和HSCR的儿童MWS病例，并在DNA分析中发现了新的Zeb2变异。
监测临床特征。从外周血中提取的DNA在PCR DNA扩增后进行双向测序分析。将ZEB2基因结果与ZEB2参考序列（ENS00000169554）进行变异比较。通过美国国立生物技术信息中心（http://www.bioinfo.org/NPInter/blast/blast_link.cgi）提供的“Blastx”程序功能对新基因变异进行生物信息学研究。
临床随访显示，2例存活患者出生时并非所有表型特征都存在，而是随时间发展出现的。在ZEB2基因的启动子区域检测到多个Zeb2变异，其中2个是新的变异（-56A/T 1174 11A/12A）。此外，1例患者的ZEB2外显子2中出现一个新的杂合单核苷酸插入，导致移码，使ZEB2蛋白的前8个氨基酸缺失，并改变了第9（G9A）、11（R11G）和12（C12A）位氨基酸。在第3例患者中，外显子8出现一个新的单核苷酸缺失（1784delC Het），导致翻译蛋白的第595位氨基酸移码。这使蛋白质从1214个氨基酸缩短至594个氨基酸，并影响关键ZEB2蛋白的功能。
MWS是临床上需要识别的重要关联疾病。它强调了Zeb2基因在某些综合征性先天性巨结肠症中的功能。这些变异可能导致先天性巨结肠症中莫瓦特·威尔逊表型的临床特征，但有待进一步研究证实。
