Hirschsprung′s disease (HSCR) is one of the major causes of chronic incomplete intestinal obstruction in children. HSCR is considered a type of neurocristopathy caused by no colonization of ganglion cells on some parts of the bowel wall due to abnormal termination of the migration of vagal neural cells during embryonic development. This disease can be classified into different types according to the length of the affected intestinal canal. Most HSCR patients present with single deformity, but some HSCR patients are affected by other deformities, which constitutes syndromic HSCR, such as congenital central hypoventilation syndrome, Fryns syndrome, and cartilage-hair hypoplasia syndrome. Most syndromes have abnormal genetic material. An adequate knowledge of syndromic HSCR is of vital importance for accurate diagnosis and prognostic evaluation. This article reviews the clinical manifestations, genetic basis, and genetic modes of different types of syndromic HSCR.
Hirschsprung Disease ; classification ; complications ; genetics ; Humans ; Syndrome

In order to investigate the relationship between the expression of heme oxygenase-2 (HO-2) mRNA and the pathogenesis of Hirschsprung's disease (HD), total ribonucleic acid (RNA) was extracted in the aganglionic and ganglionic segments of colon respectively from 15 cases of HD. The single-stranded cDNA of HO-2 was synthesized and further amplified by reverse transcription-polymerase chain reaction (RT-PCR). The expression of HO-2 mRNA was normal in ganglionic segments, but absent in aganglionic segments. It is concluded that the absence of HO-2 mRNA expression may be an important mechanism responsible for HD.
Colon/enzymology ; Heme Oxygenase (Decyclizing)/biosynthesis ; Heme Oxygenase (Decyclizing)/*genetics ; Hirschsprung Disease/*enzymology ; Hirschsprung Disease/etiology ; Hirschsprung Disease/genetics ; RNA, Messenger/biosynthesis ; RNA, Messenger/genetics

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 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*

Hirschsprung's disease is one of the most common causes of intestinal obstruction in neonates and infants. The underlying pathology of this disease is the absence of the ganglion cells in both the myenteric (Auerbach's) plexus and the submucosal (Meissner's) plexus. Since Hirschsprung's report in 1886, there have been thousands of papers on Hirschsprung's disease but the cause of the absence of the ganglion cells has not been identified. Hirschsprung's disease can be successfully treated with the Swenson, the Duhamel, and the Soave operations even though the pathogenesis is unknown. With the recent progress of molecular biology and genetics, a more detailed approach to the pathogenesis of Hirschsprung's disease can be undertaken. In addition, there have been recent developments in the surgical approach. In this review, recent advances in surgery for Hirschsprung's disease are presented.
Ganglion Cysts ; Genetics ; Hirschsprung Disease* ; Humans ; Infant ; Infant, Newborn ; Intestinal Obstruction ; Molecular Biology ; Pathology

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 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

OBJECTIVETo explore the UL139 gene polymorphism of human cytomegalovirus (HCMV), and the relationship between polymorphisms of HCMV UL139 ORF and Hirschsprung's disease (HD).

METHODSForty-three specimens of the aganglionic intestinal segment and 6 urine samples of HD infants were amplified by nested polymerase chain reaction (PCR) method. The amplicons were sequenced in both strands directly. The control group consisted of 10 asymptomatic HCMV infected infants, and their urine specimens were also analyzed using the same method.

RESULTSHCMV UL139 genes of 28 clinical strains from HD 1 patients were successfully amplified and sequenced. UL139 was hypervariable and was clustered into 3 major groups and 5 genotypes. The predominant genotype of HCMV in HD infants was UL139 Group 3 (48 percent). Comparison of strains distribution between the two groups did not reach statistical significance using chi square test (chi square=7.378, P=0.194). The results of correlation analysis between UL139 and UL144 genes showed a p value 0.05 by Kendall test. Clinically, strains from the rectosigmoid segment, total colon aganglionosis, and long-segment were distributed sporadically in UL139 genotypes.

CONCLUSIONUL139 gene displayed polymorphisms. No linkage was found between UL139 genotype and clinical phenotype of HD. There was no correlation between HCMV UL144 and UL139.

Cytomegalovirus ; genetics ; Female ; Genotype ; Hirschsprung Disease ; etiology ; virology ; Humans ; Male ; Membrane Glycoproteins ; genetics ; Open Reading Frames ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Viral Proteins ; chemistry ; genetics

OBJECTIVETo investigate the relationship of WNT8b and SHH genes mutation and Hirschsprung disease(HSCR) in Chinese children.

METHODSPreoperative whole blood preparations in 72 children with sporadic HSCR from northeast China were collected(study group). Seventy-two healthy children were used as controls(matched for sex and age). Genomic DNA was obtained from peripheral blood. Exon 1 of WNT8b gene and the exon 1 of SHH gene were analyzed for gene mutation. The mutation products were automatically sequenced. The levels of WNT8b and SHH mRNA were detected by quantitative real-time PCR(qRT-PCR) in blood samples.

RESULTSOn sequencing, 13 out of 72 children with HSCR had WNT8b gene mutation in the coding area, including heterozygosity deletion in 8 cases (11.1%) and base replacement in 5(6.9%). Eleven children with HSCR had SHH gene mutation in the coding area including heterozygosity deletion in 7 cases(9.7%) and base replacement in 4(5.6%). No mutations in WNT8b and SHH genes were found in the control group. The WNT8b and SHH mRNA levels were different between the study group and the control group(30.01±1.13 vs. 17.33±0.62, and 28.25±1.27 vs. 18.94±0.31, P<0.05).

CONCLUSIONSWNT8b and SHH mutations and abnormal expressions are present in the peripheral blood of children with sporadic HSCR. These two genes may be related to the development of sporadic HSCR in children in the northeastern China.

Adolescent ; Base Sequence ; Case-Control Studies ; Child ; Child, Preschool ; Exons ; Female ; Hedgehog Proteins ; genetics ; Heterozygote ; Hirschsprung Disease ; genetics ; Humans ; Male ; Mutation ; Wnt Proteins ; genetics

OBJECTIVETo explore the relationship between exon 3 mutation in the methyl CpG-binding protein 2 (MeCP2-E3) gene and Hirschsprung disease (HSCR) and anorectal malformations (ARMs).

METHODSPCR and DNA sequencing were used to detect the mutation of MeCP2-E3 in 120 healthy controls, 120 HSCR, and 50 ARMs.

RESULTSOn sequencing, 45(37.5%) children with HSCR had basic replacement in MeCP2-E3, 12(10.0%) of them were homozygous mutation. Fourteen(28.0%) children with ARMs had basic replacement in MeCP2-E3, 4(8%) of them were homozygous mutation. There were no mutation in the control group.

CONCLUSIONSMutation of MeCP2-E3 is present in the peripheral blood of children with HSCR or ARMs, which may contribute to the development of Hirschsprung disease or anorectal malformations.

Anorectal Malformations ; Anus, Imperforate ; genetics ; Case-Control Studies ; Child, Preschool ; Exons ; Female ; Hirschsprung Disease ; genetics ; Humans ; Male ; Methyl-CpG-Binding Protein 2 ; genetics ; Mutation ; Phenotype