摘要 Mowat-Wilson综合征（MWS）是一种由E盒结合锌指蛋白2（ZEB2）基因突变导致的罕见常染色体显性遗传病，临床表现多样，主要表现为智力障碍/全面发育迟缓、面容特殊，并伴有多种先天畸形。该文报道3例经ZEB2基因分析确诊为MWS患儿的临床特点和基因突变结果。3例均有先天性巨结肠及面容异常，其中病例1于4月龄死于重型心衰和肺炎，因年龄小，家长未能发现其全面发育迟缓，另2例均有重度全面发育迟缓。3例患儿均为ZEB2基因新生杂合无义突变携带者，其中c.756C > A （p.Y252X）为未见报道的新发突变，该类突变可产生截短蛋白，具有明确致病性。MWS临床和遗传异质性大，若患儿面容与MWS高度符合，且存在智力障碍/全面发育迟缓，合并多种先天畸形，临床医生应警惕MWS，基因检测有助于确立诊断。
Abstract：Mowat-Wilson syndrome (MWS) is a rare autosomal dominant genetic disease caused by zinc finger E-box-binding homeobox 2 (ZEB2) gene mutation and has various clinical manifestations including intellectual disability/global developmental delay, unusual facies and multiple congenital malformations. This article reports the clinical features and gene mutations of three children diagnosed with MWS by ZEB2 gene analysis. All three children had Hirschsprung disease and unusual facies. One child died of severe heart failure and pneumonia at the age of 4 months. Global developmental delay was not discovered by her parents due to her young age. The other two children had severe global developmental delay. All three children carried a de novo heterozygous nonsense mutation in the ZEB2 gene, among which c.756C > A (p.Y252X) had not been reported before. Such mutations produced truncated proteins and were highly pathogenic. MWS is presented with strong clinical and genetic heterogeneity. Clinicians should consider the possibility of MWS when a child has unusual facies of MWS, intellectual disability/global developmental delay and multiple congenital malformations. Gene detection helps to make a confirmed diagnosis.
Mowat DR, Croaker GD, Cass DT, et al. Hirschsprung disease, microcephaly, mental retardation, and characteristic facial features:delineation of a new syndrome and identification of a locus at chromosome 2q22-q23[J]. J Med Genet, 1998, 35(8):617-623.
[2]
Ghoumid J, Drevillon L, Alavi-Naini SM, et al. ZEB2 zinc-finger missense mutations lead to hypomorphic alleles and a mild Mowat-Wilson syndrome[J]. Hum Mol Genet, 2013, 22(13):2652-2661.
[3]
Ivanovski I, Djuric O, Caraffi SG, et al. Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care[J]. Genet Med, 2018, 20(9):965-975.
[4]
Cacheux V, Dastot-Le Moal F, Kääriäinen H, et al. Loss-of-function mutations in SIP1 Smad interacting protein 1 result in a syndromic Hirschsprung disease[J]. Hum Mol Genet, 2001, 10(14):1503-1510.
[5]
Wakamatsu N, Yamada Y, Yamada K, et al. Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease[J]. Nat Genet, 2001, 27(4):369-370.
[6]
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5):405-424.
[7]
Ishihara N, Yamada K, Yamada Y, et al. Clinical and molecular analysis of Mowat-Wilson syndrome associated with ZFHX1B mutations and deletions at 2q22-q24.1[J]. J Med Genet, 2004, 41(5):387-393.
[8]
Zweier C, Thiel CT, Dufke A, et al. Clinical and mutational spectrum of Mowat-Wilson syndrome[J]. Eur J Med Genet, 2005, 48(2):97-111.
[9]
Garavelli L, Zollino M, Mainardi PC, et al. Mowat-Wilson syndrome:facial phenotype changing with age:study of 19 Italian patients and review of the literature[J]. Am J Med Genet A, 2009, 149A(3):417-426.
[10]
Garavelli L, Ivanovski I, Caraffi SG, et al. Neuroimaging findings in Mowat-Wilson syndrome:a study of 54 patients[J]. Genet Med, 2017, 19(6):691-700.
[11]
Hegarty SV, Sullivan AM, O'Keeffe GW. Zeb2:a multifunctional regulator of nervous system development[J]. Prog Neurobiol, 2015, 132:81-95.
[12]
Bar Yaacov R, Eshel R, Farhi E, et al. Functional characterization of the ZEB2 regulatory landscape[J]. Hum Mol Genet, 2019, 28(9):1487-1497.
[13]
He L, Yu K, Lu F, et al. Transcriptional regulator ZEB2 is essential for bergmann glia development[J]. J Neurosci, 2018, 38(6):1575-1587.
Jiang Q, Zhang T, Wang S, et al. Mowat-Wilson syndrome:clinical and molecular report of the first case in mainland China[J]. Int J Clin Exp Pathol, 2016, 9(2):1195-1203.
[16]
Heinritz W, Zweier C, Froster UG, et al. A missense mutation in the ZFHX1B gene associated with an atypical Mowat-Wilson syndrome phenotype[J]. Am J Med Genet A, 2006, 140(11):1223-1227.
[17]
Yuan H, Zhang L, Chen M, et al. A de novo triplication on 2q22.3 including the entire ZEB2 gene associated with global developmental delay, multiple congenital anomalies and behavioral abnormalities[J]. Mol cytogenet, 2015, 8:99.
[18]
Baxter AL, Vivian JL, Hagelstrom RT, et al. A novel partial duplication of ZEB2 and review of ZEB2 involvement in Mowat-Wilson syndrome[J]. Mol syndromol, 2017, 8(4):211-218.
[19]
Wilson M, Mowat D, Dastot-Le Moal F, et al. Further delineation of the phenotype associated with heterozygous mutations in ZFHX1B[J]. Am J Med Genet A, 2003, 119A(3):257-265.
[20]
Spaggiari E, Baumann C, Alison M, et al. Mowat-Wilson syndrome in a fetus with antenatal diagnosis of short corpus callosum:advocacy for standard autopsy[J]. Eur J Med Genet, 2013, 56(6):297-300.
