[Syndromic Hirschsprung′s disease and its mode of inheritance].

Hirschsprung′s disease (HSCR) is one of the major causes of chronic incomplete intestinal obstruction in children. HSCR is considered a type of neurocristopathy caused by no colonization of ganglion cells on some parts of the bowel wall due to abnormal termination of the migration of vagal neural cells during embryonic development. This disease can be classified into different types according to the length of the affected intestinal canal. Most HSCR patients present with single deformity, but some HSCR patients are affected by other deformities, which constitutes syndromic HSCR, such as congenital central hypoventilation syndrome, Fryns syndrome, and cartilage-hair hypoplasia syndrome. Most syndromes have abnormal genetic material. An adequate knowledge of syndromic HSCR is of vital importance for accurate diagnosis and prognostic evaluation. This article reviews the clinical manifestations, genetic basis, and genetic modes of different types of syndromic HSCR.

Abundance and significance of neuroligin-1 and glutamate in Hirschsprung's disease.

AIM: To investigate the abundance and potential diagnostic significance of neuroligin-1 and glutamate (Glu) in Hirschsprung's disease (HSCR). METHODS: Ninety children with HSCR and 50 children without HSCR matched for similar nutritional status, age and basal metabolic index were studied. The expression and localization of neuroligin-1 and Glu were assessed using double-labeling immunofluorescence staining of longitudinal muscles with adherent myenteric plexus from the surgically excised colon of children with HSCR. Western blot analysis, quantitative real-time PCR (qRT-PCR) and immunohistochemistry were performed to evaluate the abundance of neuroligin-1 and Glu in different HSCR-affected segments (ganglionic, transitional, and aganglionic segments). Enzyme-linked immunosorbent assay (ELISA) was used to detect and compare serum Glu levels in the long-segment HSCR, short-segment HSCR and non-HSCR samples. RESULTS: Neuroligin-1 and Glu were co-expressed highest to lowest in the ganglionic, transitional and aganglionic segments based on Western blot (neuroligin-1: 0.177 ± 0.008 vs 0.101 ± 0.006, 0.177 ± 0.008 vs 0.035 ± 0.005, and 0.101 ± 0.006 vs 0.035 ± 0.005, P < 0.005; Glu: 0.198 ± 0.006 vs 0.115 ± 0.008, 0.198 ± 0.006 vs 0.040 ± 0.003, and 0.115 ± 0.008 vs 0.040 ± 0.003, P < 0.005) and qRT-PCR (neuroligin-1: 9.58 × 10(-5) ± 9.94 × 10(-6) vs 2.49 × 10(-5) ± 1.38 × 10(-6), 9.58 × 10(-5) ± 9.94 × 10(-6) vs 7.17 × 10(-6 ±) 1.12 × 10(-6), and 2.49 × 10(-5) ± 1.38 × 10(-6) vs 7.17 × 10(-6) ± 1.12 × 10(-6), P < 0.005). Serum Glu level was the highest to lowest in the non-HSCR, short-type HSCR and long-type HSCR samples based on ELISA (in nmol/µL, 0.93 ± 0.31 vs 0.57 ± 0.25, 0.93 ± 0.31 vs 0.23 ± 0.16, and 0.57 ± 0.25 vs 0.23 ± 0.16, P < 0.005). CONCLUSION: Neuroligin-1 and Glu may represent new markers of ganglion cells, whose expression may correlate with the pathogenesis, diagnosis, differential diagnosis or classification of HSCR.

Total colonic aganglionosis and Hirschsprung's disease: a review.

Total colonic aganglionosis is a relatively uncommon form of Hirschsprung's disease (HSCR). It occurs in approximately 2-13 % of HSCR cases and involves the entire colon which is aganglionic but may extend proximally into varying lengths of small bowel. As a result, it should be separated into Total colonic aganglionosis (TCA) [defined as aganglionosis extending from the anus to at least the ileocaecal valve but no more than 50 cm small bowel proximal to the ileocaecal valve] and total colonic and small bowel aganglionosis (TCSA) which may involve very long segments of small bowel aganglionosis. Clinically, TCA appears to represent a different spectrum of disease in terms of presentation and difficulties which may be experienced in diagnosis suggesting a different pathophysiology from the more common forms of HSCR. It is therefore not yet clear whether TCA merely represents a long form of HSCR or a different expression of the disease. A number of differences exist between TCA and other forms of HSCR which require explanation if its ubiquitous clinical features are to be understood. In addition to the usual explanations for the aganglionosis of HSCR, there is some evidence suggesting that in place of being purely congenital, it may represent certain different pathophysiologic mechanisms, some of which may continue to be active after birth. This study reviews what is known about the clinical, radiological and histopathologic differences between TCA and the more frequently encountered recto-sigmoid (or short-segment; S-HSCR) and correlates them with what is currently known about the genetic and molecular biologic background to find possible pathogenetic mechanisms.

Classification and diagnostic criteria of variants of Hirschsprung's disease.

"Variants of Hirschsprung's disease" are conditions that clinically resemble Hirschsprung's disease (HD), despite the presence of ganglion cells in rectal suction biopsies. The diagnosis and management of these patients can be challenging. Specific histological, immunohistochemical and electron microscopic investigations are required to characterize this heterogeneous group of functional bowel disorders. Variants of HD include intestinal neuronal dysplasia, intestinal ganglioneuromatosis, isolated hypoganglionosis, immature ganglia, absence of the argyrophil plexus, internal anal sphincter achalasia and congenital smooth muscle cell disorders such as megacystis microcolon intestinal hypoperistalsis syndrome. This review article systematically classifies variants of HD based on current diagnostic criteria with an additional focus on pathogenesis, epidemiology, clinical presentation, management and outcome.

RET mutational spectrum in Hirschsprung disease: evaluation of 601 Chinese patients.

Rare (RVs) and common variants of the RET gene contribute to Hirschsprung disease (HSCR; congenital aganglionosis). While RET common variants are strongly associated with the commonest manifestation of the disease (males; short-segment aganglionosis; sporadic), rare coding sequence (CDS) variants are more frequently found in the lesser common and more severe forms of the disease (females; long/total colonic aganglionosis; familial).Here we present the screening for RVs in the RET CDS and intron/exon boundaries of 601 Chinese HSCR patients, the largest number of patients ever reported. We identified 61 different heterozygous RVs (50 novel) distributed among 100 patients (16.64%). Those include 14 silent, 29 missense, 5 nonsense, 4 frame-shifts, and one in-frame amino-acid deletion in the CDS, two splice-site deletions, 4 nucleotide substitutions and a 22-bp deletion in the intron/exon boundaries and 1 single-nucleotide substitution in the 5' untranslated region. Exonic variants were mainly clustered in RET the extracellular domain. RET RVs were more frequent among patients with the most severe phenotype (24% vs. 15% in short-HSCR). Phasing RVs with the RET HSCR-associated haplotype suggests that RVs do not underlie the undisputable association of RET common variants with HSCR. None of the variants were found in 250 Chinese controls.

[Hirschsprung's disease in adults].

Up-to-date information about Hirschsprung's disease in children and adults is presented including definition of this pathology, data on its prevalence, and debatable questions of terminology. Etiology and pathogenesis of Hirschsprung"s disease, the role of hereditary factors in its development and clinico-anatomic classification are considered. Clinical variants of Hirschsprung's disease in children and adults are discussed along with its complications and combinations with other congenital malformations. Diagnostic and informative value of clinical and instrumental tools is assessed. Modern methods of conservative and surgical treatment are described.

Novel classification and pathogenetic analysis of hypoganglionosis and adult-onset Hirschsprung's disease.

BACKGROUND AND AIMS: Researchers have not clearly described the clinical and pathogenetic features of hypoganglionosis and adult-onset Hirschsprung's disease, which cause pseudo-obstruction or intractable constipation. We conducted this study to explore these features of hypoganglionosis and adult-onset Hirschsprung's disease in Korean patients. METHODS: We enrolled 24 patients pathologically confirmed as having hypoganglionosis and 11 as having adult-onset Hirschsprung's disease. We recruited 26 subjects who had undergone operation for nonobstructive colon cancer and 45 healthy volunteers as controls. We described their clinical features, investigated ganglion cells and interstitial cells of Cajal (ICC), and analyzed RET, EDNRB, EDN3, and SOX10 genes. RESULTS: We classified hypoganglionosis patients into two groups: type I (focal type, n = 13), with focally narrowed transition zone (TZ); and type II (diffuse type, n = 11), without transition zone. Hypoganglionosis patients had significantly fewer ganglion cells than the controls, and those cells were scarcer in the transition zone than in the proximal dilated area (P < 0.05). The ICC numbers in both diseases were significantly lower than in controls; however, they were similar between transition zone and the proximal dilated area in hypoganglionosis. In adult-onset Hirschsprung's disease, two significant intronic RET polymorphic variants, IVS14-24G>A and IVS19+47T>C, were significantly associated with adult-onset Hirschsprung's disease (P = 0.0122 and 0.0295, respectively), but not with hypoganglionosis. CONCLUSIONS: Hypoganglionosis and adult-onset Hirschsprung's disease have different pathophysiologic characteristics, although their clinical presentations are similar. We suggest that there are two subgroups of hypoganglionosis: those with or without a focally narrowed transition zone with a profoundly diminished number of ganglion cells.

[Enzyme histochemistry of classical and ultrashort Hirschsprung's disease]. / Enzymhistochemie des klassischen und des ultrakurzen Morbus Hirschsprung.

Hirschsprung's disease is the most important type of gastrointestinal dysmotility in neonatal pathology. Aberrant craniocaudal migration of neural crest stem cells results in an intestinal aganglionic segment of variable length. In 'classical' Hirschsprung's disease (60-75% of cases), the aganglionic segment spans the rectum and sigma. Ultrashort Hirschsprung's disease (5-10%) is restricted to the most distal 3-4 cm or immediate rectoanal transition only. In the normal enteric nervous system, myenteric ganglia modulate the parasympathetic innervation of the sacral roots S2-S4. The absence of myenteric ganglia in Hirschsprung's disease results in massively increased parasympathetic activity with abundant acetylcholine release and pseudo-obstruction in the aganglionic segment. This can be demonstrated in an enzyme histochemical reaction for acetylcholinesterase on frozen sections, which is sufficient to diagnose the classical disease in rectal mucosal biopsies. In ultrashort Hirschsprung's disease, increased acetylcholinesterase activity is demonstrable only in nerve fibres of the muscularis mucosae and submucosa, but not the lamina propria mucosae. Submucosal and myenteric ganglia are physiologically scarce in the most distal rectum; absence of ganglia in a biopsy of the rectoanal transition must not be (wrongly) interpreted as ultrashort Hirschsprung's disease. Therefore, a diagnosis of ultrashort Hirschsprung's disease can be made exclusively using an enzyme histochemical reaction for acetylcholinesterase.

[X-ray diagnosis of different forms of Hirschsprung's disease in children].

The purpose of this study was to examine and compare X-ray signs and roentgenometric parameters in different forms of childhood Hirschsprung's disease for their more accurate diagnosis. A hundred and thirty-eight children with different forms of Hirschsprung's disease were followed up. Among them, the children with a supershort segment of the disease amounted to 55%. All the children underwent a comprehensive examination including barium irrigography according to the procedure described by M.D. Levin, followed by an estimation of roentgenometric parameters. The long forms of Hirschsprung's disease had characteristic X-ray symptoms and their appropriate roentgenometric parameters. The supershort segment of the disease had not a complete complex of characteristic X-ray symptoms and its roentgenometric parameters were in direct opposition to the similar parameters in the long form of this disease.

Disseminated mixed intestinal dysmotility (DMID): a new intestinal ganglion cell disorder?

We experienced two cases with disseminated HP and IND occurring with normal bowel in between (disseminated mixed intestinal dysmotility--DMID) and postulate whether it could be classified as a new intestinal motility disorder. Our cases, both boys, died at 3 and 7 months, respectively. Both had irregular stool passage, and abdominal distention with bilious vomiting since birth. On barium enema, both had rigid distal ileum and colon with narrow lumens, with dilated and atonic proximal ileum and jejunum. An ileostomy was created on days 3 and 2 of life, respectively, however, they did not function and jejunostomies were created, which also did not function well. Both boys died after repeated episodes of severe enterocolitis. In each case, three 10 cm specimens were obtained randomly from the jejunum and ileum, and two 5 cm specimens were obtained randomly from each of the ascending colon, transverse colon, descending colon, and rectum and treated with hematoxylin and eosin (H & E) staining, acetylcholine esterase (AchE) histochemistry, and protein gene product 9.5 (PGP9.5) and neural cell adhesion molecule (NCAM) immunohistochemistry for histopathologic assessment. All specimens showed a mixture of disseminated IND and HP, with normal intestine in between. There was abnormal expression of NCAM activity in the intestinal smooth muscle layers in small and large intestine. This is the first report about disseminated IND and HP occurring with normal bowel in between (DMID) and we suggest it should be classified as a new intestinal motility disorder. The present findings demonstrate that patients with DMID have a complicated abnormality of NMJ that may directly influence bowel motility and prognosis according to the severity of the abnormality.

The genetics of Hirschsprung disease.

Understanding the genetics of Hirschsprung disease will naturally expand our understanding of other neurocristopathies, the enteric nervous system, and autonomic system biology. As other disorders of gastrointestinal motility are investigated, genetics may resolve certain clinical questions. For example, isolated hypoganglionosis without aganglionosis has been reported as a primary cause of intestinal pseudo-obstruction. Is such hypoganglionosis merely a forme-fruste of Hirschsprung disease, or a result from an entirely different pathogenetic mechanism? Can irritable bowel syndrome or severe constipation be related to specific mutations, polymorphisms, or haplotypes? How might an understanding of derangements of the ENS be translated to understanding derangements of the CNS? Clearly, we should anticipate improved prognostication, counseling, and hopefully, therapies with future genetic insights.

Radiological findings in total colon aganglionosis and allied disorders.

OBJECTIVE: The aim of this study was to review the radiological findings of three cases of total colon aganglionosis (TCA), hypoganglionosis, and immature ganglionosis, and to compare the differences in diagnosis and follow-up of these three disease entities. MATERIALS AND METHODS: Three neonates with neonatal onset of abdominal distension with vomiting were investigated, and the cases were diagnosed as TCA, hypoganglionosis, and immature ganglionosis, respectively. Radiological examination of each neonate was performed during the neonatal period and at follow-up. RESULTS: A plain abdominal radiograph showed massive abdominal bowel gas and multiple air-fluid levels in all cases. Barium enema findings including no transition zone, normal rectosigmoid index, reflux of barium into a dilated ileum, and retention of barium on delayed film were observed in all three cases. In aganglionosis and hypoganglionosis, a normal-sized colon, irregular contraction, shortening of the colon, and lack of redundancy were observed. In immature ganglionosis, microcolon was present but there was no shortening of the colon or loss of redundancy. Barium studies following ileostomy during childhood revealed no efficient peristalsis after the neonatal period in patients with aganglionosis and hypoganglionosis. Conversely, the patient with immature ganglionosis showed maturity of colonic function on barium studies after infancy. CONCLUSION: The clinical and radiological findings of TCA and allied disorders are similar in neonates. Sequential contrast intestinal studies could reveal peristalsis of the colon wall, suggesting maturity of the ganglion cells.

Intestinal neuronal dysplasia.

Intestinal neuronal dysplasia (IND) is a disorder of the enteric nervous system that was first described by Meier-Ruge in 1971. IND may be associated with Hirschsprung's disease or may occur as an isolated disorder. The incidence of isolated IND varies from 0.3% to 40% of suction rectal biopsies. The uncertainty regarding the incidence of IND has resulted from considerable confusion concerning essential diagnostic criteria. The diagnostic difficulties reflect the wide variability in the literature in terms of diagnostic criteria, biopsy procedures, staining techniques, and patient age. The recent application of histochemical and immunohistochemical techniques indicates that IND is a distinct histopathologic entity. The majority of patients with IND can be treated conservatively with laxatives and enemas. If bowel symptoms persist after at least 6 months of conservative treatment, internal sphincter myectomy should be considered.

Functional innervation of the aganglionic segment in Hirschsprung's disease--a comparison of the short- and long-segment type.

The authors examined the neuro-effector transmission in the aganglionic segment from 13 patients with Hirschsprung's disease, 10 patients had short-segment type and three patients had long-segment type. Circular muscle strips were prepared and the responses to transmural electrical field stimulation were examined using the isometric tension recording technique. In the ganglionic preparations from the short- and long-segment cases, the stimulation evoked a biphasic response consisting of a relaxation and an atropine-sensitive contraction. The relaxation was partly inhibited by N-omega-nitro-L-arginine (NNLA, a nitric oxide [NO] synthase inhibitor), and the effect of NNLA was abolished completely in the presence of L-arginine, which suggested the presence of NO-mediated inhibitory innervation. In the aganglionic preparations from the short-segment-type cases, stimulation evoked only an atropine-sensitive contraction, while in the aganglionic preparations from the long-segment-type cases, a weak inhibitory response persisted after the contractile response was abolished by atropine. This NO-mediated inhibitory response was frequently detected as the examined region approached the ganglionic segment. These results suggest that the aganglionic segment in the long-segment-type cases might therefore receive NO-mediated inhibitory input from the proximal ganglionic segment.

Hirschsprung's disease as a neurochristopathy.

Recent molecular-genetic and histochemical studies of intestinal aganglionosis have confirmed the initial classification established by Bolande, who considered Hirschsprung's disease (HD) a neurocristopathy. This paper is a critical review of the results of molecular-genetic studies carried out from 1992 to date. In particular, the author focuses on the possible clinical impact of the identification of RET as a causative gene for HD.

Hirschsprung's disease and allied disorders--a review.

Despite scepticism in the English speaking literature today there is international agreement on the existence of neuronal intestinal dysplasia and other intestinal malformations which may well be differentiated from classical aganglionosis. In large series of patients with neuronal intestinal malformations it was found that only one fourth suffers from Hirschsprung's disease. Therefore this article presents the state of our recent knowledge of classical aganglionosis and allied disorders which include hypoganglionosis, neuronal intestinal dysplasia type A and B, immaturity of ganglion cells and not classifiable dysganglionosis. We want to emphasize the morphological differentiation of these neuronal intestinal malformations. However, the relationship between morphological findings, clinical symptoms and bowel motility remain to be clarified by further studies.

The neuropathological diagnosis of neuronal intestinal dysplasia (NID B).

Between 1986 and 1991 773 infants were investigated by biopsy. 209 children suffered from a neuronal dysplasia of the submucous plexus (NID B). 64 of these 209 cases had concomitant Hirschsprung's disease with NID. The combination of Hirschsprung's disease with NID was established at biopsy not earlier than at 12 +/- 6 months of age. The classical form of an isolated aganglionosis had a median age at diagnosis of 4 +/- 2 months. The preconditions for a reliable diagnosis of NID are mucosal biopsies with submucosa taken 1, 3 and 9 cm above the pectinate line, the preparation of 15 microns thick serial sections, a acetylcholinesterase- and lactate-reaction and a systematic examination of all serial sections. Giant ganglia, which are 2-3 times as large as normal ganglia and having more than 7 LDH-positive nerve cells (10 +/- 3 nerve cells in the mean), are the most relevant parameters in the diagnosis of NID. They can be observed in infants as well as in adults. The NID proximal to aganglionosis is in principle not different from an isolated form of NID. Increase of acetylcholinesterase-activity in muscularis mucosae and lamina propria mucosae and a "hyperplasia" of the submucous plexus in early infancy disappears with advancing age and are very seldom observed at 2 years of age or in adulthood. NID B is the mildest form of a developmental abnormality of the autonomic nervous system, which shows in most cases a spontaneous normalization of gut motility.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuronal intestinal dysplasia: clinical experience in Italian patients.

The authors present a review of 431 children biopsied and studied with the following histochemical and immunohistochemical techniques: 1) acetylcholinesterase activity; 2) alphanaphthylesterase activity; 3) S-100 protein immunohistochemical technique; 4) glyoxylic acid method. Two hundred forty-eight patients of our series presented different forms of dysganglionosis, 12 of them (4.8%) presenting neuronal intestinal dysplasia type B. In 7 cases, NID type B was diffuse, whereas in 5 recto-colonic NID type B was confined to the splenic flexure. Male:female ratio was 9:3. Familial recurrence was present in 2 of the 12 cases of our series, affected by severe neuronal intestinal dysplasia extended to the small intestine, associated with intestinal malrotation and short bowel syndrome. Four of the 7 cases of diffuse NID type B and 2 of the 5 cases of rectocolonic NID type B were surgically treated. Three patients with diffuse NID died from sepsis within the 2nd year of life. This study confirms that NID type B is a form of dysganglionosis which can be diagnosed in a Mediterranean country if histochemical techniques are applied in the study of a large series of constipated and pseudo-Hirschsprung patients. From a pathogenetic point of view, the authors compared the histochemical findings of biopsies from their series of NID patients with those of recto-colonic biopsies from patients with MEN II B syndrome. The similarity of GI symptoms in MEN II B and NID pediatric patients suggests that the two disorders could be the result of mutations affecting the same domain of the RET proto-oncogene.

A histological grading system for the evaluation of co-existing NID with Hirschsprung's disease.

The significance of dysplastic features in the surgical pullthrough segment of bowel in patients with Hirschsprung's disease (HD) has not yet been clarified. The aim of this study was to evaluate prospectively the ganglionated proximal bowel in 26 patients with HD (January 1988 through January 1991). The significance of dysplastic features and their influence on post operative outcome were evaluated by means of a newly devised histological scoring system based on the morphological features. Functional outcome was assessed clinically at follow-up interview. Comparison was with control specimens from 22 patients undergoing unrelated bowel surgery and a further 5 patients with neuronal intestinal dysplasia (NID). Results indicated a wide spectrum of histologically identified dysplastic features in patients with NID, the ganglionated bowel of HD and controls. Although individual abnormal features were noted in the control group, significant degrees of dysplasia were absent. The overall degree of dysplasia was less striking than that observed in NID and in the 5 patients in whom NID co-existed with HD. Dysplasia of the ENS in residual bowel could be correlated with postoperative dysfunction in 4 out of 5 patients (80%) with HD and features of co-existing NID. In addition, milder symptoms were noted in 50% of patients having a borderline score (5-6/12). This study emphasizes the relationship between clinical obstructive symptoms and a high degree of dysplasia within the ENS. A histological grading system is of value in evaluating the spectrum of abnormal findings and prospectively identifying those with functional significance in patients with NID co-existing with HD.

Experience with neuronal intestinal dysplasia (NID) in adults.

In paediatrics neuronal intestinal dysplasia (NID) has frequently been described, but in adults the clinical picture was not recognised. NID has been diagnosed in adults as well as children with impaired colonic motility since enzymehistochemical methods became available. Patients with primary chronic constipation (n = 41) and with diverticulosis of the sigmoid colon (n = 23) showed neuronal colonic dysplasia, whereas healthy controls (n = 15) had a normal innervation of the intestinal wall (p < 0.001). The results of this clinical study make a worthwile contribution to the understanding of the aetiology and pathogenesis of primary chronic constipation and diverticulosis of the colon in adults. Conservative treatment is usually unavailing and surgical intervention is needed. Hence, where strictly indicated, resection of the pathologically disturbed colon segment is often the only successful therapeutic procedure.