OBJECTIVE: To explore the genetic basis for a girl with distinctive facial features, epilepsy, intellectual disability, chronic constipation and hypopigmentation of neck and upper extremities. METHODS: Whole exome sequencing was carried out for the proband. Candidate variant was verified by Sanger sequencing. RESULTS: The proband was found to harbor a heterozygous nonsense c.586G>T (p.Glu196*) variant of the ZEB2 gene, which was unreported previously. The variant was not detected in either parent. CONCLUSION The ZEB2 gene c.586G>T (p.Glu196*) variant probably underlay the Mowat-Wilson syndrome in this patient. Hypopigmentation in the neck and upper extremities may be related to Mowat-Wilson syndrome. Prenatal diagnosis was recommended for subsequent pregnancies.
Facies ; Female ; Hirschsprung Disease ; Humans ; Hypopigmentation ; Intellectual Disability/genetics* ; Microcephaly ; Pregnancy ; Zinc Finger E-box Binding Homeobox 2/genetics*

OBJECTIVE: To explore the genetic basis of three children with unexplained mental retardation/developmental delay. METHODS: Peripheral venous blood samples were collected for routine G-banding karyotyping analysis and chromosomal microarray analysis (CMA). Whole exome sequencing (WES) was also carried out for patient 3. RESULTS: The karyotypes of the 3 children were normal. The result of CMA analysis of patient 1 was arr[GRCh37]: 2q22/3(145 128 071-145 159 029)×1, with a 31 kb deletion, which was predicted to be a pathogenic copy number variation. The deletion has involved exons 8 to 10 of the ZEB2 gene. Patient 2 was arr[hg19]:2q22.3 (145 071 457-146 881 759)×1, with a 1.81 Mb deletion involving the ZEB2 and GTDC1 genes. Patient 3 was arr[GRCh37]: 9p23p23(11 698 261-12 106 261)×1, with a 408 kb deletion containing no disease-associated gene. WES has identified a c.2102C>A (p.Ser701*) variant in exon 8 of the ZEB2 gene, which was included in ClinVar database and rated as pathogenic, and verified by Sanger sequencing as a de novo variant. CONCLUSION For the substantial clinical and genetic heterogeneity of Mowat-Wilson-syndrome, CMA and WES are helpful to identify the etiology of children with developmental delay/mental retardation of unknown causes, particularly those with peculiar facial features and multiple congenital malformations.
Child ; DNA Copy Number Variations ; Facies ; Glycosyltransferases/genetics* ; Hirschsprung Disease ; Humans ; Intellectual Disability/genetics* ; Microcephaly/genetics*

OBJECTIVE: To identify pathogenic variants in two patients with suspected for Mowat-Wilson syndrome (MWS). METHODS: Genomic DNA was extracted from peripheral blood samples of the patients and his family members, and gene variants were analysis by Trio-whole exome sequences and copy number variation sequencing. RESULTS: Patient 1 was found to carried a de novo heterozygous c.2769C>A (p.Y923*) nonsense variant of ZEB2 gene. The variant was not found in his healthy parents and sister. Patient 2 carried a de novo heterozygous frameshift variant of the ZEB2 gene, namely c.315delC (p.A105Afs*3), which has not been previously reported. Both variants were predicted to be pathogenic and can lead to premature occurrence of stop codons. CONCLUSION The heterozygous c.2769C>A (p.Y923*) and c.315delC (p.A105Afs*3) variants of the ZEB2 gene probably underlay the pathogenesis in the two patients. Gene testing has facilitated confirmation of the diagnosis and genetic counselling.
DNA Copy Number Variations ; Facies ; Hirschsprung Disease ; Humans ; Intellectual Disability/genetics* ; Microcephaly/genetics* ; Zinc Finger E-box Binding Homeobox 2/genetics*

Adult megacolon is a rare disease with heterogeneneous etiology. The treatment schemes of megacolon caused by different causes are also different, but surgery is the final and the most effective method. Due to the lack of early understanding of the disease, many patients have not been clearly diagnosed as adult megacolon and have not been properly treated. This article classifies adult megacolon according to the etiology and summarizes its surgical options. For adult Hirschsprung's disease, modified Duhamel, the Jinling procedure, low anterior resection, or pull-through low anterior resection can be used. For patients with idiopathic megacolon, one-stage subtotal colorectal resection can be selected with adequate preoperative preparations. Some patients admitted to the hospital with emergency intestinal obstruction can be treated with conservative treatment or decompression under colonoscopy followed by selective surgery. For patients with aganglionosis, the procedure is subtotal colorectal resection, the same as that of idiopathic megacolon. The procedure is to remove both the dilated proximal intestine and the stenotic distal intestine, then an ileorectal anastomosis or ascending colon rectal anastomosis is performed. For toxic megacolon, colostomy can be done for mild cases, and for severe infections, subtotal colorectal resection is required. Latrogenic megacolon is mostly caused by segmental stenosis or lack of peristalsis, resulting in chronic dilatation of the proximal end and the formation of megacolon. It is necessary to choose a reasonable surgical procedure according to the specific conditions of the patient. The first choice for the treatment of acute colonic pseudo-obstruction syndrome is decompression under colonoscopy. For those with the secondary changes in the intestine, ostomy is still the most effective surgical procedure, but should be performed with caution.
Anastomosis, Surgical ; Colostomy ; Hirschsprung Disease/surgery* ; Humans ; Megacolon/surgery* ; Rectum/surgery*

Adult ; Anastomosis, Surgical ; Constipation/surgery* ; Humans ; Megacolon/surgery* ; Proctocolectomy, Restorative

OBJECTIVE: To summarize the clinical phenotype and genotype of a Chinese child affected with Mowat-Wilson syndrome (MWS). METHODS: Clinical data of the patient were collected. The patient was analyzed by whole-exome sequencing (WES) as well as Sanger sequencing. RESULTS: The patient was a male infant with recurrent fever and slow growth. He also had characteristic facies, recurrent spasm, and growth retardation. WES revealed that he has carried a heterozygous nonsense c.2609C>G (p.Ser870X) variant of the ZEB2 gene (30% mosaicism). Based on the American College of Medical Genetics and Genomics standards and guidelines, the variant was predicted to be pathogenic (PVS1+PS1+PS2+PM2). CONCLUSION The c.2609C>G variant of the ZEB2 gene probably underlay the MWS in this child. The mosaicism of the variant may explain his mild symptoms.
Child ; Facies ; Hirschsprung Disease/genetics* ; Humans ; Infant ; Intellectual Disability/genetics* ; Male ; Microcephaly/genetics* ; Mutation

OBJECTIVE: To explore the genetic basis of a proband with distinctive facial features, global developmental delay, seizures and hypoplasia of corpus callosum through next generation sequencing (NGS). METHODS: Genomic DNA was extracted from peripheral blood samples of the proband and his family members. Whole exome and flanking sequences were screened by NGS. Suspected variants were verified by Sanger sequencing. RESULTS: The proband was found to carry a heterozygous c.2824G>T (p.G942X) variant of the ZEB2 gene, which was verified by Sanger sequencing to be a de novo variant. CONCLUSION The heterozygous c.2824G>T (p.G942X) variant of the ZEB2 gene probably underlies the Mowat-Wilson syndrome in the proband.
Facies ; Genetic Variation ; Heterozygote ; Hirschsprung Disease ; genetics ; Humans ; Intellectual Disability ; genetics ; Microcephaly ; genetics ; Whole Exome Sequencing ; Zinc Finger E-box Binding Homeobox 2 ; genetics

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.
Facies ; Female ; Hirschsprung Disease ; Homeodomain Proteins ; Humans ; Intellectual Disability ; Microcephaly ; Repressor Proteins

Waardenburg syndrome (WS) type IV is characterized by pigmentary abnormalities, deafness and Hirschsprung's disease. This syndrome can be triggered by dysregulation of the SOX10 gene, which belongs to the SOX (SRY-related high-mobility group-box) family of genes. We discuss the first known case of a SOX10 frameshift mutation variant defined as c.895delC causing WS type IV without Hirschsprung's disease. This female patient of unrelated Kuwaiti parents, who tested negative for cystic fibrosis and Hirschsprung's disease, was born with meconium ileus and malrotation and had multiple surgical complications likely due to chronic intestinal pseudo-obstruction. These complications included small intestinal necrosis requiring resection, development of a spontaneous fistula between the duodenum and jejunum after being left in discontinuity, and short gut syndrome. This case and previously reported cases demonstrate that SOX10 gene sequencing is a consideration in WS patients without aganglionosis but with intestinal dysfunction.
Cystic Fibrosis ; Deafness ; Duodenum ; Female ; Fistula ; Frameshift Mutation ; Hirschsprung Disease ; Humans ; Ileus ; Intestinal Pseudo-Obstruction ; Jejunum ; Meconium ; Necrosis ; Parents ; Waardenburg Syndrome

OBJECTIVE: To study the expression levels of glial cell line-derived neurotrophic factor family receptor α-1 (GFRα1) and enhancer of zeste homolog 2 (EZH2) in the intestinal tissue of children with Hirschsprung's disease (HSCR), as well as the role of EZH2 in the regulation of GFRα1 gene expression and the pathogenesis of HSCR. METHODS: The samples of colon tissue with spasm from 24 children with HSCR after radical treatment of HSCR were selected as the experimental group, and the samples of necrotized colon tissue from 18 children with neonatal necrotizing enterocolitis after surgical resection were selected as the control group. Real-time PCR and Western blot were used to measure the expression levels of GFRα1 and EZH2 in colon tissue in both groups. Human neuroblastoma SH-SY5Y cells were divided into an EZH2 over-expression group and a negative control group. The cells in the EZH2 over-expression group were transfected with pCMV6-EZH2 plasmid, and those in the negative control group were transfected with pCMV6 plasmid. The expression levels of EZH2 and GFRα1 were measured after transfection. RESULTS: Compared with the control group, the experimental group had significant reductions in the mRNA and protein expression levels of GFRα1 and EZH2 in colon tissue (P<0.05), and the protein expression of EZH2 was positively correlated with that of GFRα1 (r=0.606, P=0.002). Compared with the negative control group, the EZH2 over-expression group had significant increases in the expression levels of EZH2 and GFRα1 after SH-SY5Y cells were transfected with EZH2 over-expression plasmid (P<0.05). CONCLUSIONS Low expression of EZH2 in the colon tissue of children with HSCR may be one of the causes of inadequate expression of GFRα1 and onset of HSCR.
Child ; Colon ; Enhancer of Zeste Homolog 2 Protein ; genetics ; Glial Cell Line-Derived Neurotrophic Factor Receptors ; genetics ; Hirschsprung Disease ; genetics ; Humans ; Infant, Newborn ; RNA, Messenger