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      Waardenburg Syndrome Type IV De Novo SOX10 Variant Causing Chronic Intestinal Pseudo-Obstruction

      case-report

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          Abstract

          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.

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          Most cited references11

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          Deletions at the SOX10 gene locus cause Waardenburg syndrome types 2 and 4.

          Waardenburg syndrome (WS) is an auditory-pigmentary disorder that exhibits varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair and skin. Depending on additional symptoms, WS is classified into four subtypes, WS1-WS4. Absence of additional features characterizes WS2. The association of facial dysmorphic features defines WS1 and WS3, whereas the association with Hirschsprung disease (aganglionic megacolon) characterizes WS4, also called "Waardenburg-Hirschsprung disease." Mutations within the genes MITF and SNAI2 have been identified in WS2, whereas mutations of EDN3, EDNRB, and SOX10 have been observed in patients with WS4. However, not all cases are explained at the molecular level, which raises the possibility that other genes are involved or that some mutations within the known genes are not detected by commonly used genotyping methods. We used a combination of semiquantitative fluorescent multiplex polymerase chain reaction and fluorescent in situ hybridization to search for SOX10 heterozygous deletions. We describe the first characterization of SOX10 deletions in patients presenting with WS4. We also found SOX10 deletions in WS2 cases, making SOX10 a new gene of WS2. Interestingly, neurological phenotypes reminiscent of that observed in WS4 (PCWH syndrome [peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, WS, and Hirschsprung disease]) were observed in some WS2-affected patients with SOX10 deletions. This study further characterizes the molecular complexity and the close relationship that links the different subtypes of WS.
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            A new syndrome combining developmental anomalies of the eyelids, eyebrows and nose root with pigmentary defects of the iris and head hair and with congenital deafness.

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              Segregation of a missense variant in enteric smooth muscle actin γ-2 with autosomal dominant familial visceral myopathy.

              Familial visceral myopathy (FVM) is a rare inherited form of myopathic pseudo-obstruction; little is known about the genetic factors that cause this disorder. FVM is characterized by impaired functions of enteric smooth muscle cells, resulting in abnormal intestinal motility, severe abdominal pain, malnutrition, and even death. We searched for genetic factors that might cause this disorder. We performed whole-exome sequence analysis of blood samples from 2 individuals in a family that had 7 members diagnosed with FVM. Sanger sequencing was used to analyze additional family members and 280 individuals without this disorder (controls). Intestinal tissue samples from 4 patients and 2 controls were analyzed by immunohistochemistry. Functional studies, including immunofluorescence, cell contractility, and actomyosin structure analyses, were performed using CRL-1976 and U2OS sarcoma cell lines. Whole-exome sequence analysis of DNA from 2 siblings identified 83 gene variants that were shared between the siblings and considered as possible disease-causing changes. A heterozygous variant, R148S in enteric smooth muscle actin γ-2 (ACTG2), segregated with disease phenotype. Intestinal smooth muscle (muscularis propria) from individuals with FVM had reduced levels of cytoplasmic ACTG2 and abnormal accumulation of the protein into intracellular inclusions compared with controls. Sarcoma cells that expressed exogenous ACTG2(R148S) incorporated reduced amounts of this protein into actin filaments compared with cells expressing ACTG2(wt) (P < .001). ACTG2(R148S) also interfered with actin cytoskeleton organization and the contractile activities of the cells, indicating a dominant-negative effect. These findings, along with the site of the variation in the protein, indicate that ACTG2 R148S interferes with actin filament assembly. We identified the R148S variant in ACTG2 as a cause of FVM in one family. The altered ACTG2 protein appears to aggregate, rather than form actin filaments, in intestinal smooth muscle tissue. This defect could impair contraction of the visceral smooth muscle cells and reduce bowel motility. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Pediatr Gastroenterol Hepatol Nutr
                Pediatr Gastroenterol Hepatol Nutr
                PGHN
                Pediatric Gastroenterology, Hepatology & Nutrition
                The Korean Society of Pediatric Gastroenterology, Hepatology and Nutrition
                2234-8646
                2234-8840
                September 2019
                11 September 2019
                : 22
                : 5
                : 487-492
                Affiliations
                [1 ]Division of Pediatric Surgery, Department of Surgery, University of Miami Miller School of Medicine , Miami, FL, United States.
                [2 ]Division of Clinical and Translational Genetics, Department of Human Genetics, University of Miami Miller School of Medicine , Miami, FL, United States.
                Author notes
                Correspondence to Anthony R. Hogan. Division of Pediatric Surgery, Department of Surgery, University of Miami Miller School of Medicine, 1120 NW 14th Street, 450F, Miami, FL 33136, United States. ahogan@ 123456med.miami.edu
                Author information
                https://orcid.org/0000-0002-8472-2638
                https://orcid.org/0000-0002-6211-0673
                https://orcid.org/0000-0003-0230-5046
                https://orcid.org/0000-0003-2296-6263
                https://orcid.org/0000-0003-1352-0307
                https://orcid.org/0000-0002-0523-272X
                Article
                10.5223/pghn.2019.22.5.487
                6751108
                93a5349d-eb54-4bf5-9912-62456241a3ef
                Copyright © 2019 by The Korean Society of Pediatric Gastroenterology, Hepatology and Nutrition

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 27 July 2018
                : 27 October 2018
                : 06 November 2018
                Categories
                Case Report

                waardenburg syndrome,sox10, intestinal pseudo obstruction,hirschsprung disease,meconium ileus,volvulus of midgut

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