Search Results (11)

Obstruction differential diagnosis involves tumors, “acute abdomen”, and chronic pseudo-obstruction (CIPO). Pediatric CIPO cases have different backgrounds than adults’ and impairs development. The cases are rare; diagnosis and treatment are still not well established. Diagnosis is complex; clinical, radiological, molecular, and manometric pathologic data are essential. The performance of broad radiological investigations and manometry is cumbersome in a small intestine. Herein, we present cases of a 14-year-old girl and 11-year-old boy with visceral myopathies (VMs). Presented cases show unique hardship in the analysis of standing and contrast bedside X-ray images—the colon distension alone speaks to Hirschsprung, and the clinicians could not confirm suspected short-segment disease for a long time. VMs are usually diagnosed up to 12 months of life and accompanied by other organ dysfunctions, which are herein absent. The key features here were also the involvement of the small intestine, lack of distant colon contraction, and for the long-lasting case in the boy, loss of haustration. The initial diagnosis relied on clinical data (vomiting, malabsorption, >6-month obstruction, and uncharacteristic biochemical tests), radiology (lack of tumor, enlargement of diameter, and fluid in small and large intestines), and manometry (presence of propagation wave and of anal inhibitory reflex in recto–anal manometry). Examination of intestinal muscle biopsies involved hematoxylin-eosin, trichrome-Masson staining, and immunohistochemistry. The characteristics were fibrosis, small vacuoles, muscle layer thinning, and decreased expression of smooth muscle actin and desmin. The localization of biopsies was chosen after X-ray examination, due to interruption and with various degree changes. The final diagnosis was put forward after the analysis of all accessible data. The diagnosis of VM underlines the importance of interdisciplinary co-work. An earlier intestine muscle biopsy and well-designed molecular panel might fasten the process of diagnosis. Deeper exploration of phenotype–genotype correlation of various VM presentations in the future is crucial for personalized treatment. Full article

Prokineticins (PKs) are low molecular weight proteins that exert their effects by binding to two seven-transmembrane G-protein-coupled receptors (prokineticin receptors, PKRs). The prokineticin system is an important player in the development of various diseases. Several polymorphisms that are associated with infertility, neuroendocrine disorders, Hirschsprung’s syndrome (HSCR), idiopathic central precocious puberty (CPP) and congenital disorders such as Kallmann syndrome (KS) have been described for both the PKs and PKR genes. The aim of this study is to summarize and describe the impact of PK/PKR polymorphisms on the pathogenesis and outcome of the above diseases, highlighting the PK system as a therapeutic target and diagnostic biomarker in pathological conditions. Full article

Hirschsprung’s disease (HSCR, incidence 1/5000 live births) is caused by the failure of neural crest-derived precursors to migrate, survive, proliferate, or differentiate during the embryonic development of the Enteric Nervous System (ENS), which could be disrupted by many factors, including inflammatory processes. The NF-κB family controls several biological processes, including inflammation, neurogenesis, and cell migration. With the aim of studying the potential role of NF-κB in HSCR, we have analyzed the expression of the NF-κB main subunits and other NF-κB-related genes by RT-qPCR in HSCR tissue samples (sub-divided into ganglionic and aganglionic segments). We found decreased gene expression of the NF-κB main subunit RELA but also of NFKBIA, TNFA, TFGBR2, and ERBB3 in the pathologic distal aganglionic segments compared to the proximal ganglionic segments. Moreover, we could also confirm the lower protein expression of RelA/p65 in the aganglionic distal segments by immunofluorescence staining. Further, we show that the expression of RelA/p65 protein in the proximal segments concurs with lymphocyte infiltration in the bowel tissue, indicating a pro-inflammatory activation of p65 in the proximal ganglionic HSCR tissue in the patients analyzed. All in all, our findings suggest that the modulation of NF-κB signaling in the neuro-enteric system does obviously contribute to the pathological effects of HSCR. Full article

Background: Constipation and outlet obstruction may persist after successful pull-through in Hirschsprung Disease (HD). The radiographic assessment of the faecal load is widely used but exposes the child to radiation. This study aims to evaluate whether the transrectal diameter (TRD) assessed with ultrasound correlates with symptoms of faecal load and whether the TRD normalises when symptoms disappear. Method: Children with HD after pullthrough and functional constipation presenting to our colorectal clinic between 4/23 and 4/24 were assessed for symptoms of constipation, smearing and outlet obstruction, as well as healthy controls. Ultrasound measurement of the TRD was conducted. Bowel management was initiated according to our institutional pathway using Peristeen© irrigation after an orthograde disimpaction regime. Results: A total of 193 children underwent TRD assessment. Of 60 children with HD, 26 (43.3%) presented with obstructive symptoms, and 34 (56.7%) were asymptomatic. In asymptomatic patients with HD, the mean TRD of 2.26 cm (SD 0.61) was significantly (p < 0.001) lower than in HD with symptoms, with a mean TRD of 3.35 cm (SD 1.03). Individuals without colorectal pathology had a mean TRD of 2.04 cm (SD 0.37), and children with functional constipation and symptoms showed a mean TRD of 4.36 cm (SD 1.32). The mean TRD after symptom resolution was 2.37 cm. Conclusions: Children with HD without obstructive symptoms have a TRD < 3 cm, as do controls. The transrectal diameter allows the clinician to sonographically assess the faecal load in children with HD at the bedside without radiation. The TRD is useful for monitoring a bowel management program in children with HD. Full article

Introduction: Hirschsprung disease (HD) manifests as a developmental anomaly affecting the enteric nervous system, where there is an absence of ganglion cells in the lower part of the intestine. This deficiency leads to functional blockages within the intestines. HD is usually confirmed or ruled out through rectal biopsy. The identification of any ganglion cells through hematoxylin and eosin (H&E) staining rules out HD. If ganglion cells are absent, further staining with acetylcholine-esterase (AChE) histochemistry or calretinin immunohistochemistry (IHC) forms part of the standard procedure for determining a diagnosis of HD. In 2017, our Institute of Pathology at University Hospital of Heidelberg changed our HD diagnostic procedure from AChE histochemistry to calretinin IHC. In this paper, we report the impact of the diagnostic procedure change on surgical HD therapy procedures and on the clinical outcome of HD patients. Methods: We conducted a retrospective review of the diagnostic procedures, clinical data, and postoperative progress of 29 patients who underwent surgical treatment for HD in the Department of Pediatric Surgery, University of Heidelberg, between 2012 and 2021. The patient sample was divided into two groups, each covering a treatment period of 5 years. In 2012–2016, HD diagnosis was performed exclusively using AChE histochemistry (AChE group, n = 17). In 2017–2021, HD diagnosis was performed exclusively using calretinin IHC (CR group, n = 12). Results: There were no significant differences between the groups in sex distribution, weeks of gestation, birth weight, length of the aganglionic segment, or associated congenital anomalies. Almost half of the children in the AChE group, twice as many as in the CR group, required an enterostomy before transanal endorectal pull-through procedure (TERPT). In the AChE group, 4 patients (23.5%) required repeat bowel sampling to confirm the diagnosis. Compared to the AChE group, more children in the CR group suffered from constipation post TERPT. Discussion: Elevated AChE expression is linked to hypertrophied extrinsic cholinergic nerve fibers in the aganglionic segment in the majority of patients with HD. The manifestation of increased AChE expression develops over time. Therefore, in neonatal patients with HD, especially those in the first 3 weeks of life, an increase in AChE reaction is not detected. Calretinin IHC reliably identifies the presence or absence of ganglion cells and offers multiple benefits over AChE histochemistry. These include the ability to perform the test on paraffin-embedded tissue sections, a straightforward staining pattern, a clear binary interpretation (negative or positive), cost-effectiveness, and utility regardless of patient age. Conclusions: The ability of calretinin IHC to diagnose HD early and time-independently prevented repeated intestinal biopsies in our patient population and allowed us to perform a one-stage TERPT in the first months of life, reducing the number of enterostomies and restoring colonic continuity early. Patients undergoing transanal pull-through under the age of 3 months require a close follow-up to detect cases with bowel movement problems. Full article

Genetic disorders affecting the functioning of the brain lead not only to the development of numerous hereditary diseases but also to the development of neurodegenerative and cognitive disorders. The result of this may be the disability of part of the able-bodied population. Almost all pathological states of the brain are characterized by serious defects in the intracellular and intercellular signaling of neurons and glial cells. At the same time, the mechanisms of disruption of these signaling cascades are not well understood due to the large number of molecules, including transcription factors that, when mutated, cause brain malformations. The transcription factor Satb1 is one of the least studied factors in the cerebral cortex, and the effects of its deletion in the postnatal brain are practically not studied. Hyperexcitability of neurons is observed in many genetic diseases of the nervous system (Hirschsprung’s disease, Martin–Bell syndrome, Huntington’s disease, Alzheimer’s, etc.), as well as in ischemic brain phenomena and convulsive and epileptic conditions of the brain. In turn, all these disorders of brain physiology are associated with defects in intracellular and intercellular signaling and are often the result of genetic disorders. Using Satb1 mutant mice and calcium neuroimaging, we show that Satb1 deletion in projection neurons of the neocortex causes downregulation of protein kinases PKC, CaMKII, and AKT/PKB, while a partial deletion does not cause a dramatic disruption of kinome and Ca²⁺ signaling. As a result, Satb1-null neurons are characterized by increased spontaneous Ca²⁺ activity and hyperexcitability when modeling epileptiform activity. As a result of the deletion of Satb1, preconditioning mechanisms are disrupted in neurons during episodes of hypoxia. This occurs against the background of increased sensitivity of neurons to a decrease in the partial pressure of oxygen, which may indicate the vulnerability of neuronal networks and be accompanied by impaired expression of the Satb1 transcription factor. Here, we show that Satb1 deletion impaired the expression of a number of key kinases and neuronal hyperexcitation in models of epileptiform activity and hypoxia. Full article

Background: The heterogeneity of rectal biopsy techniques has encouraged us to search for a surgical and pathological standardisation of this diagnostic technique to exclude Hirschsprung’s disease. The different amounts of information on the anatomopathology report prompted us to compile a template for the anatomopathology report for diagnostic rectal biopsies for surgical colleagues and pathologists working on Hirschsprung’s disease. Methods: We gathered the anonymous biopsy information and its pathology information from five hospitals for all patients in which rectal biopsies were taken to diagnose Hirschsprung’s disease over two years (2020–2021). Results: Of the 82 biopsies, 20 suction (24.4%), 31 punch (37.8%) and 31 open biopsies (37.8%) were taken. Of all biopsies, 69 were conclusive (84.2%), 13 were not (15.8%). In the suction biopsy group, 60% were conclusive and 40% were not; for punch biopsy, the values were 87% and 13%, respectively and for open biopsy, 97% and 3%. Inconclusive results were due to insufficient submucosa in 6/8 suction biopsies, 4/4 punch biopsies and 0/1 open biopsies. An insufficient amount of submucosa was the reason for an inconclusive result in 6/20 cases (30%) after suction biopsy, 4/31 (12.9%) cases after punch biopsy and 0 cases (0%) after open biopsy. We had one case with major postoperative bleeding post suction biopsy; there were no further adverse effects after biopsy. Conclusions: Diagnostic rectal biopsies in children are safe. Non-surgical biopsies are more likely to give inconclusive results due to smaller amounts of submucosa present in the specimen. Open biopsies are especially useful when previous non-surgical biopsies are inconclusive. An experienced pathologist is a key factor for the result. The anatomopathology report should specify the different layers present in the specimen, the presence of ganglion cells and hypertrophic nerve fibres, their description and a conclusion. Full article

Background: Transanal irrigation (TAI) is employed for children with fecal incontinence, but it can present several problems which require a study of their outcomes among different pathologies and without a tailored work up. The aim of our study was to evaluate the effectiveness of an advanced protocol in order to tailor TAI, prevent complications, and evaluate outcomes. Methods: We included 70 patients (14 anorectal malformation, 12 Hirschsprung’s disease, 24 neurological impairment, 20 functional incontinence) submitted to a comprehensive protocol with Peristeen^®: fecal score, volumetric enema, rectal ultrasound, anorectal 3D manometry, and diary for testing and parameter adjustment. Results: Among the patients, 62.9% needed adaptations to the parameters, mainly volume of irrigated water and number of puffs of balloon. These adaptations were positively correlated with pre-treatment manometric and enema data. In each group, the improvement of score was statistically significant in all cases (p 0.000); the main factor influencing the efficacy was the rate of sphincter anomalies. The ARM group had slower improvement than other groups, whereas functional patients had the best response. Conclusions: Our results showed that TAI should not be standardized for all patients, because each one has different peculiarities; evaluation of patients before TAI with rectal ultrasound, enema, and manometry allowed us to tailor the treatment, highlighting different outcomes among various pathologies, thus improving the efficacy. Full article

The nucleoli are membrane-less nuclear substructures that govern ribosome biogenesis and participate in multiple other cellular processes such as cell cycle progression, stress sensing, and DNA damage response. The proper functioning of these organelles is ensured by specific proteins that maintain nucleolar structure and mediate key nucleolar activities. Among all nucleolar proteins, treacle encoded by TCOF1 gene emerges as one of the most crucial regulators of cellular processes. TCOF1 was initially discovered as a gene involved in the Treacher Collins syndrome, a rare genetic disorder characterized by severe craniofacial deformations. Later studies revealed that treacle regulates ribosome biogenesis, mitosis, proliferation, DNA damage response, and apoptosis. Importantly, several reports indicate that treacle is also involved in cancer development, progression, and response to therapies, and may contribute to other pathologies such as Hirschsprung disease. In this manuscript, we comprehensively review the structure, function, and the regulation of TCOF1/treacle in physiological and pathological processes. Full article

Hirschsprung disease (HSCR) is a neurocristopathy defined by intestinal aganglionosis due to alterations during the development of the Enteric Nervous System (ENS). A wide spectrum of molecules involved in different signaling pathways and mechanisms have been described in HSCR onset. Among them, epigenetic mechanisms are gaining increasing relevance. In an effort to better understand the epigenetic basis of HSCR, we have performed an analysis for the identification of long non-coding RNAs (lncRNAs) by qRT-PCR in enteric precursor cells (EPCs) from controls and HSCR patients. We aimed to test the presence of a set lncRNAs among 84 lncRNAs in human EPCs, which were previously related with crucial cellular processes for ENS development, as well as to identify the possible differences between HSCR patients and controls. As a result, we have determined a set of lncRNAs with positive expression in human EPCs that were screened for mutations using the exome data from our cohort of HSCR patients to identify possible variants related to this pathology. Interestingly, we identified three lncRNAs with different levels of their transcripts (SOCS2-AS, MEG3 and NEAT1) between HSCR patients and controls. We propose such lncRNAs as possible regulatory elements implicated in the onset of HSCR as well as potential biomarkers of this pathology. Full article

Waardenburg syndrome (WS) has the characteristic clinical features caused by the embryologic abnormality of neural crest cells. WS patients sometimes suffer from functional intestinal obstruction. When it is Hirschsprung disease (HD), the WS is diagnosed as type 4 WS. We report a case of WS which did not have myenteric ganglion cells in the sigmoid colon and rectum. Whether to diagnosis this case as type 1 or 4 WS is controversial. Moreover, this is the third report which has peristalsis failure caused by abnormal myenteric plexus. In all three cases, the eosinophils had aggregated in the myenteric layer of the transition zone. During embryonic life, enteric ganglion cells migrate to the myenteric layer from the proximal to the distal side sequentially and, subsequently, to the submucosal layer through the circular muscle. Therefore, we hypothesize that myenteric ganglion cells that had already migrated were eliminated by an eosinophil-mediated mechanism in these three cases. We believe this report may be helpful to elucidate the pathogenesis of some types of HD. Full article