Intestinal neuronal dysplasia type B (IND-B) is a controversial entity that affects the submucosal nerve plexus of the distal intestine. The lack of definition of the causal relationship between histological findings and clinical symptoms has been identified as the primary point to be elucidated in the scientific investigation related to IND-B, which is essential for it to be considered a disease.

To investigate the relationship between histopathological findings and symptoms in a series of patients with IND-B.

Twenty-seven patients with histopathological diagnosis of IND-B, according to the Frankfurt Consensus (1990), who underwent surgical treatment through colorectal resections were included. Data from medical records regarding the clinical picture of the patients at the time of diagnosis, including the intestinal symptom index (ISI) and a detailed histopathological analysis of the rectal specimens, were retrieved. Exploratory factor analysis was performed, applying the principal components method for clusters with Varimax rotation.

Two factors were determined: the first, determined by histopathological and clinical variables, and the second, composed of the main symptoms presented in patients with IND-B, including ISI. Factorial rotation showed the association between the two factors and, through a graph, demonstrated the proximity between ISI values and histopathological alterations.

There was evidence of an association between the clinical features presented by patients with IND-B and the histopathological findings of the rectal samples. These results support the understanding of IND-B as a disease.

Intestinal neuronal dysplasia type B (IND-B) is a controversial entity among the gastrointestinal neuromuscular disorders. It may occur alone or associated with other neuropathies, such as Hirschsprung's disease (HD). Chronic constipation is the most common clinical manifestation of patients. IND-B primarily affects young children and mimics HD, but has its own histopathologic features characterized mainly by hyperplasia of the submucosal nerve plexus. Thus, IND-B should be included in the differential diagnoses of organic causes of constipation. In recent years, an increasing number of cases of IND-B in adults have also been described, some presenting severe constipation since childhood and others with the onset of symptoms at adulthood. Despite the intense scientific research in the last decades, there are still knowledge gaps regarding definition, pathogenesis, diagnostic criteria and therapeutic possibilities for IND-B. However, in medical practice, we continue to encounter patients with severe constipation or intestinal obstruction who undergo to diagnostic investigation for HD and their rectal biopsies present hyperganglionosis in the submucosal nerve plexus and other features, consistent with the diagnosis of IND-B. This review critically discusses aspects related to the disease definitions, pathophysiology and genetics, epidemiology distribution, clinical presentation, diagnostic criteria and therapeutic possibilities of this still little-known organic cause of intestinal chronic constipation.

Intestinal neuronal dysplasia type B (IND) denotes an increased proportion of hyperplastic submucosal ganglia, as resolved histochemically in 15-μm-thick frozen sections. IND has been reported proximal to the aganglionic segment in patients with Hirschsprung disease (HSCR) and is putatively associated with a higher rate of postsurgical dysmotility. We developed and validated histological criteria to diagnose IND-like submucosal ganglion cell hyperplasia (IND-SH) in paraffin sections and used the approach to study the incidence and clinical and/or genetic associations of IND-SH at the proximal margins of HSCR pull-through resection specimens. Full-circumference paraffin sections from the proximal margins of 64 HSCR colonic pull-through specimens and 24 autopsy controls were immunostained for neuron-specific Hu antigen, and nucleated ganglion cells in each submucosal ganglion were counted. In controls, an age-related decline in the relative abundance of "giant" ganglia (≥7 nucleated Hu-positive [Hu+] ganglion cells) was observed. A conservative diagnostic threshold for IND-SH (control mean ± 3× standard deviation) was derived from 15 controls less than 25 weeks of age. No control exceeded this threshold, whereas in the same age range, IND-SH was observed at the proximal margins in 15% (7 of 46) of HSCR resections, up to 15 cm proximal to the aganglionic segment. No significant correlation was observed between IND-SH and length of or distance from the aganglionic segment, sex, trisomy 21, RET or SEMA3C/D polymorphisms, or clinical outcome, but analysis of more patients, with better long-term follow-up will be required to clarify the significance of this histological phenotype.

Varied intestinal neuromuscular pathologies are responsible for Hirschsprung disease and other forms of chronic pseudo-obstruction that are encountered in pediatrics. Pathologically distinct subtypes discussed in this review include aganglionosis, hypoganglionosis, neuronal intranuclear inclusion disease, ganglionitis, degenerative neuropathy, diffuse ganglioneuromatosis, neuronal dysplasia, malformations of the muscularis propria, degenerative leiomyopathy, leiomyositis, and mitochondriopathies. Emphasis is given to the histopathologic features that distinguish these conditions and their differential diagnoses.

Intestinal neuronal dysplasia is a rare cause of bowel obstruction in neonates and infants, the diagnosis of which poses a formidable challenge to both clinicians and pathologists alike. The importance of this entity lies not only in the fact that it mimics Hirschsprung's disease, but also in that untreated cases, particularly of type A, may prove fatal. The authors describe one such case of intestinal neuronal dysplasia of type A, which was diagnosed at autopsy.

The infant or child with intestinal pseudo-obstruction poses many challenges for geneticists and other specialists. Although a well-defined anatomic diagnosis (e.g., Hirschsprung disease) can be established for a subset of patients, the pathological correlates for many patients are non-existent or controversial. Intestinal neuronal dysplasia (IND) is frequently considered in the differential diagnosis, despite the fact that existence and significance of the abnormal histopathological features that characterize IND are hotly debated. This review highlights some of the concerns regarding this diagnosis including problems with the diagnostic criteria, the manner in which these criteria are applied in contemporary pathology practices, and the likelihood that many of the pathological findings are secondary consequences of impaired motility with no other clear clinical significance. Possible genetic and developmental bases for IND are also discussed.

Chronic intestinal pseudo-obstruction (CIP) in paediatric patients is due to heterogeneous aetiologies that include primary disorders of the enteric nervous system. These conditions are poorly delineated by contemporary diagnostic approaches, in part because the complex nature of the enteric nervous system may shelter significant physiological defects behind subtle or quantitative anatomical changes. Until recently, relatively few experimental animal models existed for paediatric CIP. However, the availability of rodent models, particularly novel mutants created in the last few years by genetic manipulations, has brought unprecedented opportunities to investigate molecular, cellular, physiological, and histological details of enteric neuropathology. Information gleaned from studies of these animals is likely to change diagnostic and therapeutic approaches to paediatric CIP and related conditions.

Hirschsprung disease (HSCR) is a frequent congenital disorder with an incidence of 1 in 5000 live births, characterised by the absence of parasympathetic intramural ganglion cells in the hindgut resulting in intestinal obstruction in neonates and severe constipation in infants and adults. Intestinal neuronal dysplasia (IND) shares clinical features with HSCR but the submucosal parasympathetic plexus is affected. IND has been proposed as one of the most frequent causes of chronic constipation and is often associated with HSCR.

We examined 29 patients diagnosed with sporadic HSCR, 20 patients with IND, and 12 patients with mixed HSCR/IND for mutations in the coding regions of the RET, GDNF, EDNRB, and EDN3 genes. The entire coding regions were analysed by single strand conformational polymorphism and DNA sequencing.

Only three RET mutations were detected in patients with HSCR. In patients with IND or a mixed HSCR/IND phenotype, no mutations in these genes were observed. While HSCR and HSCR/IND showed over representation of a specific RET polymorphism in exon 2, IND exhibited a significantly lower frequency comparable with that of controls.

The mutation frequency found in our sporadic HSCR patients (10%) and the allelic distribution of RET polymorphisms are comparable with earlier published data. A significantly different allelic distribution in an established HSCR associated polymorphism argues against common genetic pathways for HSCR and IND.

Omphalomesenteric duct remnants (ODR) including Meckel diverticula often present with symptoms of bowel obstruction. Their histologic features are varied and include heterotopic gastrointestinal mucosa and/or pancreatic tissue within the wall. Abnormalities of the submucosal plexus of Meissner, however, have not been documented in the literature. Thus, we have examined a number of ODR for evidence of ganglion abnormalities. Fifty-three cases of ODR were retrieved from our archives, along with 25 nonduodenal small bowel control specimens obtained from autopsies of patients without clinical or pathologic evidence of enteropathy. Histologic criteria for the diagnosis of abnormal hypercellular/heterotopic ganglia (HHG) in ODR were defined as a single submucosal ganglion/plexus containing > 10 neurons, or > 5 submucosal ganglions per high-power (x 40) field, or heterotopic ganglion cells within the muscularis mucosa or the lamina propria. HHG, histologically indistinguishable from intestinal neuronal dysplasia type B, were found in more than half of the ODR (ODR: 51.9%, n = 50 vs. control: 4%, n = 25, P = 3.6 x 10(-6), particularly those excised for obstructive complications (ODR with acute abdomen: 65.7%, n = 35, vs. ODR without acute abdomen: 33.3%, n = 15, P = 0.035). HHG were present in equal numbers of inflamed and noninflamed ODR (inflamed: 53.6%, n = 28, vs. noninflamed: 59.1%, n = 22, P = 0.70). A similar incidence was found in ODR with heterotopia and without (with heterotopia: 61.1%, n = 18, vs. without: 53.1%, n = 32, P = 0.59). ODR frequently contained HHG histomorphologically similar to those found in intestinal neuronal dysplasia, type B (IND-B). The overrepresentation of HHG in symptomatic ODR patients suggests an association with bowel obstruction. The data did not demonstrate a relationship with either inflammation or heterotopia.

This paper reviews the distribution of interstitial cells of Cajal (ICC) in the human gastrointestinal (GI) tract, based on ultrastructural and immunohistochemical evidence. The distribution and morphology of ICC at each level of the normal GI tracts is addressed from the perspective of their functional significance. Alterations of ICC reported in achalasia of cardia, infantile hypertrophic pyloric stenosis, chronic intestinal pseudoobstruction, Hirschsprung's disease, inflammatory bowel diseases, slow transit constipation, and some other disorders of GI motility as well as in gastrointestinal stromal tumors are reviewed, with emphasis on the place of ICC in the pathophysiology of disease.

This paper reviews the distribution of interstitial cells of Cajal (ICC) in the human gastrointestinal (GI) tract, based on ultrastructural and immunohistochemical evidence. The distribution and morphology of ICC at each level of the normal GI tracts is addressed from the perspective of their functional significance. Alterations of ICC reported in achalasia of cardia, infantile hypertrophic pyloric stenosis, chronic intestinal pseudoobstruction, Hirschsprung's disease, inflammatory bowel diseases, slow transit constipation, and some other disorders of GI motility as well as in gastrointestinal stromal tumors are reviewed, with emphasis on the place of ICC in the pathophysiology of disease.

Diagnostic pathologists remain uncomfortable with the diagnosis of Hirschsprung disease (HD) via rectal (mucosal/submucosal) biopsy and with performance and interpretation of the associated acetylcholinesterase (AChE) assay. This report details the different diagnostic approaches taken by four major pediatric institutions-Children's Hospital, Columbus, OH; Children's Hospital Medical Center, Cincinnati, OH; Children's Hospital, Pittsburgh, PA; Children's Hospital, Los Angeles, CA-in confirming or excluding the presence of HD. The Columbus approach emphasizes serial morphologic examination of rectal biopsies, while Cincinnati emphasizes the primary diagnostic utility of the AChE stain. Pittsburgh and Los Angeles emphasize a detailed gross and microscopic analysis of rectal biopsies to detect both conventional HD and its more rare subtypes. The diagnostic approaches of these four institutions can be used on a complementary basis to the advantage of the general diagnostic pathologist, especially in HD cases with subtle clinical presentations. The need for careful and continual communication between the clinician and pathologist in diagnosing or excluding the presence of HD is imperative.

Hirschsprung disease has become a paradigm for multigene disorders because the same basic phenotype is associated with mutations in at least seven distinct genes. As such, the condition poses distinct challenges for clinicians, patients, diagnostic pathologists, and basic scientists, who must cope with the implications of this genetic complexity to comprehend the pathogenesis of the disorder and effectively manage patients. This review focuses on the anatomic pathology, genetics, and pathogenesis of Hirschsprung disease and related conditions. The nature and functions of "Hirschsprung disease genes" are examined in detail and emphasis is placed on the importance of animal models to this field. Where possible, potential uses and limitations of new data concerning molecular genetics and pathogenesis are discussed as they relate to contemporary medical practices.

Intestinal neuronal dysplasia of the submucous plexus (IND B) is an indicator of a developmental abnormality of vegetative gut innervation. It is the mildest form of an inborn error of intestinal innervation. The diagnosis of IND B does not result in a functional conclusion or clinical recommendation but is often accompanied by oligoneuronal hypoganglionosis of the myenteric plexus or an aganglionosis of the rectum. The aim of this study was to demonstrate by morphometric means a way in which the diagnosis of IND B could be made much more reliable. In 20 control subjects, 40 IND B cases and 10 hypoganglionoses with IND B, it was shown that a specific nerve cell staining (e.g. Lactic dehydrogenase, Succinic dehydrogenase, Diaphorase reaction or an immunohistochemical nerve cell staining) was necessary for diagnosis. Cross sections of giant ganglions and cross sections with large nerve cell numbers (> 7 nerve cell profiles) were the most reliable diagnostic criteria. The morphometric examinations were performed with an optic electronic image analysis system. Biopsy serial sections of the rectum-mucosa that contained submucosa demonstrated that 30-40% of the sections contained no submucous ganglion. Sixty to 70% of the sections showed ganglia of the submucous plexus. In 100 biopsy sections in subjects with IND B, 20 +/- 5% contained giant ganglions cross sections. In the patients with hypoganglionosis of the submucous plexus, 55 +/- 4% sections had no ganglion and 18 +/- 3% had giant ganglion cross sections. The data demonstrate that for a reliable diagnosis of IND B, at least 30 sections are necessary, stained with a dehydrogenase reaction that contain a minimum of 4 giant ganglion cross sections. These data demonstrate that IND B is not a qualitative diagnosis as Hirschsprung's disease but rather a quantitative diagnosis.