Is the RET proto-oncogene involved in the pathogenesis of intestinal neuronal dysplasia type B?

Fernández, Raquel M.; Sánchez-Mejías, Avencia; Ruiz-Ferrer, Maria Macarena; López-Alonso, Manuel; Antiñolo, Guillermo; Borrego, Salud

doi:10.3892/mmr_00000094

Cited by 4 publications

(3 citation statements)

References 17 publications

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“…In addition, reports on familial occurrence of IND-B and its association with other intestinal and extraintestinal diseases reinforce the theory that IND-B has a primary, genetically determined origin[ 34 , 47 - 49 ]. Among these associations, HD, incomplete intestinal rotation, and multiple endocrine neoplasia type 2 (NEM 2) are the most important[ 23 , 28 ].…”

Section: Uncertainties and Recent Advancesmentioning

confidence: 80%

Challenges in the diagnosis of intestinal neuronal dysplasia type B: A look beyond the number of ganglion cells

Terra¹,

Gonçalves²,

Lourenção³

et al. 2021

WJG

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Intestinal neuronal dysplasia type B (IND-B) is a controversial condition among gastrointestinal neuromuscular disorders. Constipation is its most common clinical manifestation in patients. Despite intense scientific research, there are still knowledge gaps regarding the diagnostic criteria for IND-B in the histopathological analysis of rectal biopsies. The guidelines published in the past three decades have directed diagnostic criteria for quantifying the number of ganglion cells in the nervous plexus of the enteric nervous system. However, it is very complex to distinguish numerically what is pathological from what is normal, mainly because of the difficulty in determining a reliable control group composed of healthy children without intestinal symptoms. Thus, a series of immunohistochemical markers have been proposed to assist in the histopathological analysis of the enteric nervous system. Several of these markers facilitate the identification of other structures of the enteric nervous system, in addition to ganglion cells. These structures may be related to the etiopathogenesis of IND-B and represent new possibilities for the histopathological diagnosis of this disease, providing a view beyond the number of ganglion cells. This review critically discusses the aspects related to the disease definitions and diagnostic criteria of this organic cause of constipation.

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Section: Uncertainties and Recent Advancesmentioning

confidence: 80%

Challenges in the diagnosis of intestinal neuronal dysplasia type B: A look beyond the number of ganglion cells

Terra¹,

Gonçalves²,

Lourenção³

et al. 2021

WJG

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show abstract

“…Obtaining rectal biopsies from healthy, asymptomatic children, to be used as controls, is a great challenge, due to the potential complications of an invasive procedure, which is also not ethically accepted. In other studies 14,32–34 , rectal tissue samples used as controls were obtained from patients with intestinal congenital malformations, such as anorectal anomalies or other intestinal dysganglionosis, which cannot be considered healthy controls. Limitations related to the lack of healthy controls in IND-B studies are widely discussed in the literature 4,14,30 .…”

Section: Discussionmentioning

confidence: 99%

“…Although mutations in genes related to the etiology of HD, such as RET, glial cell line-derived neutrophic factor (GDNF) have not been identified in IND-B, some studies attempted to link these two conditions in the same molecular pathways 32,33,57–60 . To date, only a few combinations of polymorphisms in the RET proto-oncogene was described in IND-B patients 34 .…”

Section: Discussionmentioning

confidence: 99%

Identification of potential molecular pathogenesis mechanisms modulated by microRNAs in patients with Intestinal Neuronal Dysplasia type B

Angelini

Silva

Felix

et al. 2019

Sci Rep

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This study proposed to determine global microRNA (miRNA) expression and miRNA-regulated pathways in Intestinal Neuronal Dysplasia type B (IND-B). Fifty patients (0–15 years old) with IND-B were included in the study. Peripheral blood samples were collected from all 50 patients and from 10 healthy asymptomatic children (controls). Rectal biopsies were collected from 29/50 patients; biopsy tissues were needle microdissected to isolate the different intestinal layers, for molecular analysis. Global miRNA expression was determined using TaqMan arrays. Correlation analysis between miRNA expression in plasma and biopsy samples as well as among tissues derived from the distinct intestinal layers was performed. Computational approaches were used for miRNA target prediction/identification of miRNA-regulated genes and enriched pathways biologically relevant to IND-B pathogenesis. miRNAs were statistically significantly deregulated (FC ≥ 2 and p ≤ 0.05) in submucosal and muscular layers: over-expressed (miR-146a and miR-146b) and under-expressed (miR-99a, miR-100, miR-130a, miR-133b, miR-145, miR-365, miR-374-5p, miR-451). Notably, let-7a-5p was highly over-expressed in patient plasma compared to healthy controls (FC = 17.4). In addition, miR-451 was significantly under-expressed in both plasma and all biopsy tissues from the same patients. Enriched pathways (p < 0.01) were axon guidance, nerve growth factor signalling, NCAM signalling for neurite out-growth, neuronal system and apoptosis. miRNA expression is deregulated in the submucosa and muscular layers of the rectum and detected in plasma from patients with IND-B. Biologically enriched pathways regulated by the identified miRNAs may play a role in IND-B disease pathogenesis, due to the activity related to the neurons of the enteric nervous system.

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Advances in understanding functional variations in the Hirschsprung disease spectrum (variant Hirschsprung disease)

Moore

2016

Pediatr Surg Int

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Hirschsprung disease (HSCR) is a fairly well understood congenital, genetically based functional obstruction due to the congenital absence of ganglion cells in the distal bowel. However, although over 90% of Hirschsprung cases conform to the normally accepted histological diagnostic criteria, it has become increasingly clear that in addition to HSCR, there is a group of functional disturbances relating to a number of other congenital neurodysplastic conditions causing some degree of gastrointestinal tract malfunction. Although these represent a variety of possibly separate conditions of the enteric nervous system, this spectrum it would appear to be also influenced by similar developmental processes. The term "variant Hirschsprung" is commonly used to describe these conditions, but ganglion cells are mostly present if abnormal in number and distribution. These conditions are a problem group being amongst the most difficult to diagnose and treat with possible practical and legal consequences. The problem appears to be possibly one of definition which has proven difficult in the relative paucity of normal values, especially when correlated to age and gestation. It is the purpose of this paper to review the current position on these conditions and to explore possible shared common pathogenetic and genetic mechanisms. This article explores those conditions where a similar pathogenetic mechanisms to HSCR can be demonstrated (e.g. hypoganglionosis) as well as other neural features, which appear to represent separate conditions possibly linked to certain syndromes.

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Is the RET proto-oncogene involved in the pathogenesis of intestinal neuronal dysplasia type B?

Cited by 4 publications

References 17 publications

Challenges in the diagnosis of intestinal neuronal dysplasia type B: A look beyond the number of ganglion cells

Challenges in the diagnosis of intestinal neuronal dysplasia type B: A look beyond the number of ganglion cells

Identification of potential molecular pathogenesis mechanisms modulated by microRNAs in patients with Intestinal Neuronal Dysplasia type B

Advances in understanding functional variations in the Hirschsprung disease spectrum (variant Hirschsprung disease)

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