Total colonic aganglionosis and imperforate anus in a severely affected infant with Pallister-Hall syndrome.

Pallister-Hall syndrome is a complex malformation syndrome characterized by a wide range of anomalies including hypothalamic hamartoma, polydactyly, bifid epiglottis, and genitourinary abnormalities. It is usually caused by truncating frameshift/nonsense and splicing mutations in the middle third of GLI3. The clinical course ranges from mild to lethal in the neonatal period. We present the first patient with Pallister-Hall syndrome reported with total colonic aganglionosis, a rare form of Hirschsprung disease with poor long-term outcome. The patient also had an imperforate anus, which is the third individual with Pallister-Hall syndrome reported with both Hirschsprung disease and an imperforate anus. Molecular testing via amniocentesis showed an apparently de novo novel nonsense mutation c.2641 C>T (p.Gln881*). His overall medical course was difficult and was complicated by respiratory failure and pan-hypopituitarism. Invasive care was ultimately withdrawn, and the patient expired at three months of age. This patient's phenotype was complex with unusual gastrointestinal features ultimately leading to a unfavorable prognosis and outcome, highlighting the range of clinical severity in patients with Pallister-Hall syndrome.

Chronic constipation and abdominal distension in a patient with adult Hirschprung's disease and bilateral ovarian teratomas.

Hirschprung's disease is a congenital disorder characterized by aganglionic bowel, usually diagnosed in infancy. Here, we present a unique case of Hirschprung's disease diagnosed in a 29-year-old female with acute on chronic constipation. As part of her work up, a computerized tomography of her abdomen and pelvis revealed large, bilateral dermoid cysts. A diagnostic and therapeutic colonoscopy allowed manual disimpaction and decompression of her bowel, as well as biopsy attainment. Histopathology revealed absence of ganglionic cells on haematoxylin and eosin stain and calretinin immunostaining. This case underscores the diagnostic challenges of Adult Hirschprung's disease and how this impacts patient quality of life, as well as the work up and management of concurrent causes abdominopelvic conditions.

Clinical significance and biological effect of ZFAS1 in Hirschsprung's disease and preliminary exploration of its underlying mechanisms using integrated bioinformatics analysis.

BACKGROUND: The pathogenesis of Hirschprung's disease (HSCR) remains largely unknown. The lncRNA ZNFX1 antisense RNA 1 (ZFAS1) has been found to have vital regulatory roles in a number of diseases. However, the association between ZFAS1 and HSCR has not been reported. AIMS: The present study was aimed at investigating the expression pattern and biological function and underlying mechanisms of ZFAS1 in HSCR. METHODS: The expression of ZFAS1 was detected in surgical excision samples of 30 children diagnosed with HSCR and 30 control cases. Functional experiments were conducted after over-expression or knockdown of ZFAS1 in human neuronal cell line SH-SY-5Y. Multiple bioinformatics databases and tools were used to explore the potential regulatory mechanisms of ZFAS1 in HSCR. RESULTS: Compared with the control group, the HSCR group has a significantly higher level of ZFAS1(P = 0.0012). The area under the curve (AUC) of the receiver operating characteristic (ROC) curve was 0.7133 (P = 0.0045), which indicated good biomarker potency of ZFAS1 in HSCR. Functionally, over-expression of ZFAS1 significantly inhibited cell proliferation, whereas knockdown of ZFAS1 promoted cell proliferation and colony formation of SH-SY-5Y cells. Using multiple databases, a competing endogenous RNA (ceRNA) network, containing ZFAS1,13 candidate miRNAs, and 110 potential gene targets, was established. Further enrichment analysis suggested that ZFAS1 may regulate a number of genes and signaling pathways that were crucial for neuron development. CONCLUSIONS: Our findings revealed that ZFAS1 may participate in the pathogenesis of HSCR through regulating neuron functions. Bioinformatics analysis highlighted an important perspective for the following mechanical researches.

Novel variants in EDNRB gene in Waardenburg syndrome type II and SOX10 gene in PCWH syndrome.

Waardenburg syndrome (WS) is a clinically and genetically heterogeneous group of inherited disorders manifesting with sensorineural hearing loss and pigmentary anomalies. Here we present two Caucasian families with novel variants in EDNRB and SOX10 representing both sides of phenotype spectrum in WS. The c.521G>A variant in EDNRB identified in Family 1 leads to disruption of the cysteine disulfide bridge between extracellular segments of endothelin receptor type B and causes relatively mild phenotype of WS type II with low penetrance. The novel nonsense variant c.900C>A in SOX10 detected in Family 2 leads to PCWH syndrome and was found to be lethal.

Autologous Transplantation of Skin-Derived Precursor Cells in a Porcine Model.

BACKGROUND: Hirschprung's disease is characterized by aganglionic bowel and often requires surgical resection. Cell-based therapies have been investigated as potential alternatives to restore functioning neurons. Skin-derived precursor cells (SKPs) differentiate into neural and glial cells in vitro and generate ganglion-like structures in rodents. In this report, we aimed to translate this approach into a large animal model of aganglionosis using autologous transplantation of SKPs. METHODS: Juvenile pigs underwent skin procurement from the shoulder and simultaneous chemical denervation of an isolated colonic segment. Skin cells were cultured in neuroglial-selective medium and labeled with fluorescent dye for later identification. The cultured SKPs were then injected into the aganglionic segments of colon, and the specimens were retrieved within seven days after transplantation. SKPs in vitro and in vivo were assessed with histologic samples for various immunofluorescent markers of multipotency and differentiation. SKPs from the time of harvest were compared to those at the time of injection using PCR. RESULTS: Prior to transplantation, 72% of SKPs stained positive for nestin and S100b, markers of neural and glial precursor cells of neural crest origin, respectively. Markers of differentiated neurons and gliocytes, TUJ1 and GFAP, were detected in 47% of cultured SKPs. After transplantation, SKPs were identified in both myenteric and submucosal plexuses of the treated colon. Nestin co-expression was detected in the SKPs within the aganglionic colon in vivo. Injected SKPs appeared to migrate and express early neuroglial differentiation markers. CONCLUSIONS: Autologous SKPs implanted into aganglionic bowel demonstrated immunophenotypes of neuroglial progenitors. Our results suggest that autologous SKPs may be potentially useful for cell-based therapy for patients with enteric nervous system disorders. TYPE OF STUDY: Basic science.

Acquired segmental colonic hypoganglionosis in an adult Caucasian male: A case report.

BACKGROUND: Hypoganglionosis is a rare condition that most often presents with abnormal gastrointestinal transit and usually arises in early childhood or adolescence. Two types have been described (Type I and Type II). The adult-onset form (acquired hypoganglionosis) is extremely uncommon and is thought to arise due to cellular remodelling as a result of chronic inflammation. It differs from Hirschprung's disease in that there is a reduction in ganglion cells in the colonic neural plexuses as opposed to being completely absent. CASE SUMMARY: A 31 year-old male presented to hospital with recurrent abdominal pain and vomiting over thirteen months. Abdominal computed tomography scans demonstrated thickening and stranding affecting the transverse, descending and sigmoid colon. Endoscopic appearances were non-specific but confirmed a mixed picture of mucosal inflammation and necrosis in various stages of healing. Numerous investigations were performed to elucidate an underlying aetiology but neither an infective nor ischaemic cause could be proven. Biopsy features were not typical of inflammatory bowel disease. Due to persistence of his symptoms and failure of medical management, a segmental colectomy was performed. Histological examination of the specimen revealed an unexpected finding of segmental hypoganglionosis. Complete surgical excision of the diseased segment of colon was curative and since his operation the patient has had no recurrence of symptoms requiring hospitalisation. CONCLUSION: Our case serves to raise awareness of acquired hypoganglionosis as a rare condition that can result from chronic colitis.

SOX10 mutation causes Waardenburg syndrome associated with distinctive phenotypic features in an Iranian family: A clue for phenotype-directed genetic analysis.

BACKGROUND: Waardenburg syndrome (WS) is a neurocristopathy characterized by hearing impairment and pigmentary disturbances in hair, eyes, and skin. WS is clinically heterogeneous and can be subdivided into four major types (WS1-WS4) where WS4 or Shah-Waardenburg is diagnosed when WS2 is accompanied by Hirschsprung disease (HD). Mutations of SOX10, EDN3/EDNRB have been identified in association with WS4. This study was aimed to determine the pathogenic variant in an Iranian pedigree affected with WS4. METHOD: A two-generation pedigree with three affected members and considerable phenotypic heterogeneity was recruited. The proband was a 15-year-old boy, with severe to profound sensorineural hearing impairment, heterochromia iridis, hypoplastic blue eyes and Hirschprung disease. The other two also presented characteristics of WS2 and complained of chronic constipation with normal anorectal reflex. Sequencing of all exons and exon-intron boundaries of SOX10, EDN3/EDNRB revealed a heterozygous variant c.422T > C in exon 3 of SOX10 confirmed by a series of evidence to be pathogenic. It resulted in p.L141P at the protein level. Leucin 141 is located in Nuclear Export signal, HMG box of the protein. CONCLUSION: This study is the first report of a WS4 family in the Iranian population. The mutation is associated with distinctive phenotypic profile (association of anosmia and chronic constipation with SOX10 mutations) and could further improve diagnosis and counseling of WS in the Iranian population and can contribute to phenotype-directed genetic analysis.

Pediatric intestinal obstruction in Malawi: characteristics and outcomes.

BACKGROUND: Intestinal obstruction (IO) is a common pediatric surgical emergency in sub-Saharan Africa with high morbidity and mortality, but little is known about its etiopathogenesis in Malawi. METHODS: Retrospective analysis of patients seen from February 2012 to June 2014 at Kamuzu Central Hospital in Lilongwe, Malawi (n = 3,407). Pediatric patients with IO were analyzed (n = 130). RESULTS: Overall, 57% of patients were male with a mean age of 3.5 ± 4.1 years. A total of 52% of patients underwent operative intervention. The overall mortality rate was 3%. Leading causes of IO were Hirschprung's 29%, anorectal malformation 18%, and intussusception 4%. Neonates and patients with congenital causes of IO underwent surgery less frequently than infants and/or children and patients with acquired causes, respectively. These groups also demonstrated increased number of days from admission to surgery. CONCLUSIONS: Increasing pediatric-specific surgical education and/or training and expanding access to resources may improve mortality after IO in poor medical communities within sub-Saharan Africa.

Calretinin immunohistochemistry for the diagnosis of Hirschprung disease in rectal biopsies.

In this study we aimed to evaluate the usability of calretinin staining in the diagnosis and exclusion of HD in 36 rectal biopsies. Through immunohistochemical examination, in of a total of 21 pediatric patients in whom ganglion cells were detected in first rectal biopsies and in re-biopsies, ganglion cells were seen through nuclear and cytoplasmic staining. In the lamina propria and superficial submucosa, staining of nerve fibers was detected in a granular pattern in varying intensities. Out of a total of 5 biopsies (including one re-biopsy) of non-HD patients, where ganglion cells could not be seen, the nerve fibers were all stained. On the other hand, in 10 HD patients, diagnosed by a colon pull through operation, calretinin staining was not detected in any area of the rectal biopsies except for the mast cells. We conclude that calretinin immunostaining for the diagnosis of HD is an easy and reliable method for use in daily practice.

Adenocarcinoma of an Ileostomy in a Case of Hirschprung's Disease with Retroviral Disease.

The number of ileostomies created for benign diseases such as familial adenomatous polyposis and ulcerative colitis is increasing. Long-term ileostomies are prone to develop various complications over time. Ileostomy site carcinoma is a well-established complication in ulcerative colitis and familial adenomatous polyposis that have undergone total colectomy. However, no case of ileostomy site carcinoma has been described in a patient with Hirschprung's disease. We present the first case of adenocarcinoma at an ileostomy site in a patient with Hirschprung's disease with retroviral disease.

Hirschsprung's disease diagnosis: Comparison of immunohistochemical, hematoxilin and eosin staining.

BACKGROUND: The diagnosis of Hirschsprung's disease (HD) is based on the absence of ganglion cells. In hemotoxilin and eosin (H and E) as well as acetylcholine esterase staining there are limitations in the diagnosis of immature ganglion cells in neonates. METHODS: In this prospective study, 54 biopsies taken from suspected HD patients (five mucosal specimens and 49 full thickness specimens) were studied. In the laboratory, after preparing sections of paraffin embedded tissues, H and E staining slides were compared with immunohistochemical (IHC) staining including: S100, NSE, CD117, CD56, Cathepsin D, Vimentin, BCL2, GFAP, Synaptophysin and chromogranin. RESULTS: The study revealed 30 negative (absence of ganglion cells) cases (55.5%), 17 positive cases (31.04%) and seven suspected cases (12.9%) of ganglion cells on the H and E staining. On IHC staining with CD56 and Cathepsin D, all of the 17 positive cases detected through H and E, were confirmed for having ganglion cells and out of 30 cases reported negative on H and E staining, 28(93.3%) were reported negative and two (6.7%) positive by IHC staining. Of the seven suspected cases H and E staining), IHC staining detectedganglion cells only in five slides; two remained negative. CONCLUSIONS: IHC staining using CD56 and Cathepsin D improved the accuracy of diagnosis in HD when used in addition to H and E staining technique, especially for negative or suspicious slides.

Papel de la colonoscopia virtual en la evaluación de la enfermedad no polipoidea en pediatría / Virtual colonoscopy in pediatrics. Its role in the evaluation of non-polypoid lesions

Virtual colonoscopy is a new non-invasive method useful in the evaluation of elevated lesions. Due to the fact that the method has only been used for that purpose in the adult and pediatric population, the aim of this paper is to determine its utility in pediatric pathologies other than elevated lesions. Twenty patients with abdominal pain, chronic constipation and defecation problems were evaluated. The studies were performed with a 4-row CT scanner, using 1 mm slice thickness collimation. The acquisition time was 7-12 seconds. Neither sedation nor anesthesia was necessary. CT colonography can generate images similar to those from barium enema studies, without the use of barium contrast, avoiding related complications. The CT exam also provides information about the rest of the abdominal organs. All studies were performed without complications. Patients with Hirschprung disease, colorectal malformations, post-surgical complications and psichogenic megacolon were detected.

La colonoscopia virtual es una modalidad diagnóstica no invasiva para la valoración de enfermedad colorrectal sobre elevada. Dada su escasa aplicación en la población pediátrica, el objetivo de este trabajo es determinar su utilidad en otras patologías pediátricas. Se evaluaron 20 pacientes con síntomas como dolor abdominal, constipación crónica y dificultad en la defecación. Los estudios se realizaron con un tomógrafo de 4 filas de detectores, con cortes de 1 mm de espesor. La adquisición de las imágenes se realizó en decúbito supino, sin necesidad de apnea ni de anestesia. El tiempo de adquisición fue de aproximadamente 7 a 12 segundos. La colonoscopia virtual permite obtener imágenes similares a las de un colon por enema sin utilizar ningún tipo de contraste, por lo que evita posibles complicaciones. A ello se agrega la extrema rapidez del estudio, sin necesidad de movilizar al paciente. Además, brinda información adicional sobre el resto de los órganos abdominales, lo que determina un estudio más completo del paciente. No se observaron complicaciones. Se detectaron diversas patologías pediátricas como enfermedad de Hirschprung, megacolon psicógeno, malformaciones anorrectales y complicaciones posquirúrgicas

Preliminary results of the treatment of Hirschprung's disease by survey through posterior sagittal approach

The aim of the study is to describe the technique of operation for Hirschprung's disease by a Soave modified procedure through the posterior sagittal approach, to propose the indications and to evaluate the early result. From January 2000 to April 2000, 26 children suffering from Hirschprung's disease were operated by this technique. There was no mortality during and after operation. The anastomosis leakage occurred in one patient. The posterior sagittal approach is a convenient and safe one in survey for Hirschprung's disease with the ganglionic segment involves in the rectum and sigmoid.

Hirschsprung disease or congenital nonglandular digestive abnormality

Hirschsprung disease or congenital nonglandular digestive abnormality

Clinical Features and Diagnosis of Hirschsprung's Disease

Diagnosing Hirschprungs disease (HD) is a clinical challenge to pediatric surgeons. The cardinal symptoms are failure of passage of meconium within first 24 hours of life, abdominal distension, and vomiting. The severity of these symptoms and the degree of consitpation vary considerably between patients. HD is suspected on the basis of history and clinical findings and the diagnosis is established by radiological examination, anorectal manometry, and histochemical analysis of biopsy specimens. In this review, the advantages and pitfalls of each diagnostic modality are discussed. And a diagnostic approach utilizing these diagnostic modalities in children with suspicious HD is presented.