Familial and genetic aspects of neuronal intestinal dysplasia and Hirschsprung's disease

A familial occurrence of Hirschsprung's disease and neuronal intestinal dysplasia (NID) is reported. Familial occurrence of NID in a parent and long-segment Hirschsprung's disease in two children in a family as well as a further report of NID in monozygotic twins is described. The linkage of these neurodevelopmental conditions is explored and a common etiologic mechanism for the two conditions is postulated. Correspondence to: S. W. Moore     

Neuronal intestinal dysplasia

Findings in 23 children with neuronal intestinal dysplasia (NID) are presented. Twelve children had Hirschsprung's disease that masked the existence of proximal NID. In all cases the diagnosis was established by histological-histochemical examination. Amelioration of symptoms by conservative treatment alone was achieved in 4 children; in 13 cases colostomy was necessary. In 6 patients colon resection was performed: 2 suffered from both colitis and obstruction; the other 4 were treated for obstruction, multiple perforations, persistant adynamia of the left colon, and fistulation. In 9 patients the colostomy was closed. Four of 6 children who did not have sonographic confirmation of motility had complications due to colon dysmotility after closure of their normally functioning colostomy. Therapeutic measures are based exclusively on clinical and functional parameters. The clinical picture dictates the emergency measures (colostomy, colon resection, and colectomy). Normal colostomy function is not a sufficient criterion of normal colon motility. Functional sonography of the colon is included in the planning of further therapy. Indications, timing, and extent of colon resection can be reliably determined using the sonographic method. Offprint requests to: G. Pistor     

Neuronal intestinal dysplasia

Neuronal intestinal dysplasia (NID) is an inhibitory malformation of the submucous and myenteric plexuses. The diagnosis is made by examination of mucosal biopsies after histotopochemical reactions for acetylcholinesterase and lactate or succinate dehydrogenase. The rare NID type A is a disorder of the sympathetic nerves and usually leads to obstructive symptoms, diarrhea containing blood and mucus, and occasionally bowel perforation. Colostomy and resection of the affected bowel segment are unavoidable. Type B involves hyperplasia of the submucous plexus. The biopsy technique and criteria for evaluation have been standardized by prominent pathologists; the histochemical characteristics have been analzed morphometrically. Despite virtually uniform clinical symptoms, varying degrees of histochemical involvement may occur. Since maturation of the propulsive activity is possible in all forms, as a general rule a trial of conservative therapy should be made for at least 6 months. Persistent fecal retention with absence of internal sphincter relaxation can be treated successfully in 90% of cases by posterior sphincteromyotomy. Patients with massive rectal dilatation and absent propulsion require resection of the rectum and descending colon, as rectosigmoidectomy is associated with a high incidence of recurrence. The treatment of aganglionosis in combination with NID necessitates a differentiated work-up and set of indications.     

Unusual cases of neuronal intestinal dysplasia

Six children with isolated neuronal intestinal dysplasia (NID) and unusual complications are presented. Three had meconium peritonitis, one of them in association with a solid pyloric atresia, one midgut volvulus, one rectal stenosis, and one jejunojejunal intussusception. These cases show that patients with isolated NID may present with a heterologous pattern of symptoms very different from those generally reported, indicating that NID may not be a distinct clinical entity. The symptomatology of NID seems to be directly correlated with the degree of functional defect of gut motility. NID should be suspected in any case of functional small-bowel obstruction. Offprint requests to: P. Sacher     

Mast-cells distribution and colonic mucin composition in Hirschsprung's disease and intestinal neuronal dysplasia

 Intestinal neuronal dysplasia (IND) is a malformation of the enteric plexus that clinically resembles Hirschsprung's disease (HD). In HD, the aganglionic bowel is characterized by the presence of hypertrophic nerve trunks and increased numbers of adrenergic and cholinergic nerve fibers, whereas IND type B (IND-B) is characterized by dysplasia of parasympathetic nerves, hyperganglionosis, and gaint ganglia. The aims of this study were to investigate the relationship between the distribution of mast cells (MC) and abnormal neuronal innervation and the impact of abnormal neuronal innervation on colonic epithelial differentiation in relation to the typical innervation abnormalities seen in HD and IND. Full-thickness rectal-biopsy or resected surgical specimens from 15 patients (7 HD, 4 IND, 4 control) were examined by conventional hematoxylin-eosin, periodic acid-Schiff Alcian blue (PAS-AB), toluidine blue staining. The aganglionic and IND-B segments had larger numbers of MC in all layers than the ganglionic and control segments. There was a close relationship between the hypertrophic nerve fibers and the distribution of the MC. In contrast to the aganglionic segments, the mucin composition of the IND-B segments was normal. This finding suggests that innervation anomalies do not reflect epithelial differentiation to the same extent. Accepted: 10 March 2000     

临床诊断为先天性巨结肠症的肠神经元发育不良症

目的：对临床诊断为先天性巨结肠症（HD）而术后病理诊断确定为肠神经元发育不良症（IND）病例进行回顾性分析。方法：1995年1月－1999年12月140例临床诊断HD并经过根治手术患儿，其中12例（8．6％）术后病理诊断为IND，女1例，男11例，平均年龄29．28个月。结果：所有IDN患儿切除肠管病检均可发现粘膜下神经丛神经节细胞增多和巨大神经节，术前测压检查有4例，肛管直肠抑制反射（RAIR）阳性，占33．33％（4／12），直肠粘膜AchE组织化学检查有5例阴性，占41．675（5／12），而128例HD患儿则分别为15例占11．72％（15／128）和17例占13．28％（17／128），两组病例的测压和组化检查结果有明显差异，所有患儿均行手术治疗。结论：IND病例的术前检查表现为测压RAIR反射阳性率和组化检测阴性率明显高于典型HD病例；目前所沿用的测压－组化－钡灌肠诊断模式尚不能解决IND的术前诊断问题，临床及术中表现极类似地HD的病例，经典的根治术也可获得良好的治疗效果。     

Suction rectal biopsy in the diagnosis of Hirschsprung's disease and chronic constipation

Suction rectal biopsy has gained increased acceptance as the means of definitively diagnosing Hirschsprung's disease as well as excluding this diagnosis when evaluating the child with chronic constipation. During the 11-year period from 1 July 1974 through 30 June 1985 at the University of Michigan, Mott Children's Hospital, 309 suction rectal biopsy specimens were evaluated. Of these, 293 were done for the evaluation of chronic constipation and/or Hirschsprung's disease. The remaining 16 were performed as a part of the work-up in patients with neuromuscular, glycogen storage, inflammatory bowel, or other diseases. Forty-two (14%) of the 293 patients were diagnosed as having Hirschsprung's disease at an average age of 14.4 months. This diagnosis was ruled out in the remaining 251 patients, whose age at biopsy averaged 2.7 years. There was one false-negative reading representing an incidence of 0.3%, with no false-positives. There were no complications. The suction rectal biopsy is a bedside or clinic procedure that reliably provides pathologic material adequate for the accurate diagnosis or exclusion of Hirschsprung's disease and offers a number of advantages over manometric, radiographic, histochemical, and open, full-thickness biopsy techniques.     

A new instrument for suction rectal biopsy in the diagnosis of Hirschsprung's disease

A new instrument for suction rectal biopsy in infants suspected of having Hirschsprung's disease is described that can be completely dismantled, physically cleaned, lubricated, and heat-sterilised. These attributes are new and are absolutely critical today. The instrument has been used in 60 patients (ca. 180 biopsies) from 1988 to 1994. A successful biopsy was usually achieved and no major complications occurred. Recently, a second biopsy capsule with a larger port has been added, thus enhancing the versatility of the instrument. The original instrument has never been sharpened or repaired and is still in use. A direct descendant of this prototype instrument is now commercially available.     

NADPH-diaphorase histochemical staining of suction rectal biopsies in the diagnosis of Hirschsprung's disease and allied disorders

The purpose of this study was to investigate the specificity and sensitivity of NADPH-diaphorase (NADPH-D) staining in suction rectal biopsies (SRB) to determine whether it can be used as a diagnostic test for Hirschsprung's disease (HD) and related disorders. We studied SRB material in 80 patients suspected of having such disorders taken at 3, 5, and 7 cm above the pectinate line. Eight-micron sections were stained with hematoxylin and eosin, acetylcholinesterase histochemistry, and NADPH-D histochemistry. Normal biopsy specimens demonstrated strong NADPH-D reactivity in the submucosal ganglia and a large number of NADPH-D-positive fibers in the muscularis mucosae (MM). In contrast, there were no NADPH-D-positive fibers in the MM in patients with HD and hypertrophic nerve trunks stained weakly. Patients with hypoganglionosis (HYPG) demonstrated only a few NADPH-D-positive fibers in the MM and scant submucosal ganglia. Our results show that it is possible to diagnose HD and HYPG in mucosal rectal biopsies containing MM only and stained by NADPH-D histochemistry. As there is no background staining in NADPH-D histochemistry, it is easy to detect NADPH-D-positive fibers. NADPH-D histochemical staining may be an important additional technique for diagnosing HD and related disorders.     

The early diagnosis of Hirschsprung's disease

The majority of cases of aganglionosis present and can be diagnosed in the neonatal period. Enterocolitis is a common and fatal complication so that early diagnosis is important. The plain films and enema features of 47 cases diagnosed in the neonatal period were examined. Except when a bowel wash out had been given, all these cases showed obstructive fluid levels in the plain films and the common type of short segment aganglionosis gave an egg on end appearance of low small bowel obstruction in the inverted lateral view. The classical enema features take time to develop and the narrowed aganglio wic area is not always obvious but can be shown by a careful technique of slow filling with delayed films. A high degree of accuracy was obtained except in the cases of preliminary lavage, enterocolitis and meconium plug. To make an early correct diagnosis, it is important to have close correlation between clinicians, radiologists, and pathologists.     

What are the diagnostic criteria for intestinal neuronal dysplasia?

The incidence of isolated intestinal neuronal dysplasia (IND) has varied from 0.3% to 62% of all suction rectal biopsies in different centres. The uncertainty regarding the incidence has resulted from the considerable confusion regarding the essential diagnostic criteria. In an attempt to clarify the diagnostic criteria for IND, we examined biopsy material from the following three groups using acetylcholinesterase (AChE) histochemistry: (1) full-thickness normal colon from 23 controls; (2) suction rectal biopsies from 9 patients who had isolated IND; and (3) full-thickness biopsies from 10 patients with Hirschsprung's disease (HD) who demonstrated IND in the proximal margin of the resected segment. Our data show that hyperganglionosis is the most consistent finding in both IND associated with HD and isolated IND. Other histochemical criteria of IND were dependent upon whether the biopsy was full-thickness or a suction rectal biopsy. Where full-thickness biopsies were available, giant ganglia and ectopic ganglion cells were seen in all cases. Increases in AChE-positive nerve fibres in the mucosa was a frequent finding in patients with IND diagnosed by suction rectal biopsies. We recommend that patients suspected to have IND on suction rectal biopsy should have a full-thickness biopsy for detailed examination of the submucous and myenteric plexuses.     

Congenital malformations and perinatal morbidity associated with intestinal neuronal dysplasia

A close relation between different forms of dysganglionosis such as intestinal neuronal dysplasia (IND) type B and aganglionosis has been established. No systematic analysis of other malformations and diseases accompanying IND has been made as yet. Congenital malformations and perinatal morbidity were analyzed in 109 patients with IND seen at the Department of Pediatric Surgery in Mainz from 1977 to 1996. IND was associated with Hirschsprung's disease in 47 cases; 22 children with IND had other abdominal malformations, including anal atresia, rectal stenosis, sigmoidal stenosis, ileal atresia, pyloric stenosis, and esophageal atresia. A cystic bowel duplication, a choledochal cyst, and a persisting urachus were also found. Extra-abdominal malformations such as Down's syndrome, congenital diaphragmatic hernia, aortic stenosis, and malformations of vertebral bodies were seen. Twin siblings of children with IND were either healthy (n=3) or died in utero (n=1). Seventeen children with IND developed severe intra-abdominal complications during the perinatal period such as necrotizing enterocolitis (NEC), meconium ileus, or bowel perforations. NEC was frequently associated with preterm birth. Bowel perforations were seen in mature and preterm newborns with IND. Taken together, IND is found in a variety of obstructive bowel diseases. This may support the hypothesis that IND is a secondary phenomenon or that congenital atresias and stenoses of the digestive tract have a pathogenesis similar to that of intestinal innervation disturbances. IND may also be a part of complex malformation patterns since it occurs with a number of extraintestinal and non-obstructive intestinal malformations.     

Neonatal one-stage repair of Hirschsprung's disease

In this series of 13 patients a one-stage repair, suitable for use in the 1st postnatal week, was developed. The endorectal technique was utilised for the pelvic dissection and an end-to-end anastomosis was then constructed. Modification of adult instruments assisted dissecting in the neonatal pelvis as well as allowing for a precise colo-anal anastomosis. There were no associated deaths and the complication rate was low. Although the technique is a variation of established methods, there are features that should stimulate theoretical discussion and further consideration of neonatal treatment of Hirschsprung's disease.     

Clinical impact of intestinal neuronal malformations: a prospective study in 141 patients

A prospective study of 141 consecutive patients with intestinal neuronal malformations is presented. The single malformation of the autonomic nervous system that always required surgical intervention was aganglionosis. Giant ganglia, reduced parasympathetic tone, immature ganglia, and hypogenetic or heterotopic nerve cells were seen in all forms of malformations. However, the incidence in specific malformations was variable. Multiple giant ganglia were identified in all patients with intestinal neuronal dysplasia (IND) type B, but also in various other malformations. Heterotopic nerve cells in the myenteric plexus were seen in the proximal segment of 15 of 74 patients (20.3%) with aganglionosis and 5 of 9 patients (55.6%) with hypoganglionosis. A significant impact on symptoms was found for IND type B: 34 (45.9%) of 74 children with aganglionosis had associated IND type B, and these children more frequently developed ileus (P < 0.001) and more often needed a second resection (P < 0.05) compared to those with isolated aganglionosis. This indicates an additive effect of both malformations, and therefore, in these patients an extended resection should be carried out.Twelve of 67 patients (17.9%) without aganglionosis needed resection for untreatable constipation. This included 7 of 9 children with hypoganglionosis, both patients with heterotopia of the myenteric plexus, 1 of 20 with isolated IND type B, and 2 of 12 with reduced parasympathetic tone. None of the patients with immaturity, heterotopia of the submucous plexus, or mild dysganglionosis required surgery. Six children (8.9%) without aganglionosis underwent sphincteromyotomy and 2 with IND type B had a temporary colostomy. At follow-up (mean 2.4 ± 1.4 years), the outcome in patients with resected aganglionosis was better than in patients who had resections for other malformations; 49 (69%) of 71 patients with aganglionosis were asymptomatic compared to 4 (33.3%) of 12 with other malformations (P < 0.05). It is concluded that some intestinal malformations have a relevant clinical impact. However, the severity of symptoms in the individual patient may not be explained by specific histochemical findings from a limited number of mucosal biopsies. The pathognomonic histochemical criteria of isolated IND typeB — immaturity, reduced parasympathetic tone, heterotopia of the submucous plexus, and mild dysganglionosis —rarely require surgical therapy and should be treated conservatively.     

Diagnosis of Hirschsprung's disease: a prospective, comparative accuracy study of common tests

OBJECTIVE: To compare the diagnostic accuracy of contrast enema (CE), anorectal manometry (ARM), and rectal suction biopsy (RSB) for the detection of Hirschsprung's disease (HD). STUDY DESIGN: Following a prospective protocol, infants suspected of HD underwent all 3 index tests. Children with positive results on 2 or more index tests or who continued to have severe bowel problems underwent a full thickness biopsy as reference standard. Clinical follow-up was the reference standard in all other children. RESULTS: Between 2000 and 2003, 111 consecutive patients (67 boys; median age, 5.3 months) in whom HD was suspected were enrolled. HD was found in 28 patients. RSB had the highest sensitivity (93%) and specificity (100%) rates, but values were not significantly different from CE (sensitivity, 76%; specificity, 97%) or from ARM (sensitivity, 83%; specificity, 93%). Inconclusive test results occurred in 8 infants with CE, in 15 infants with ARM because of agitation, and in 2 infants with RSB. CONCLUSION: RSB is the most accurate test for diagnosing HD, and it has the lowest rate of inconclusive test results.     

The association of malrotation and Hirschsprung's disease

Malrotation and Hirschsprung's disease are common gastrointestinal abnormalities in neonates and infants. Four patients with the association of malrotation and Hirschsprung's disease are reported. A delay in diagnosis may be complicated by midgut volvulus or enterocolitis. The diagnostic and therapeutic implications of this important association are discussed.     

Long-term follow-up of bowel function, behaviors and psychological situations of the children underwent operations for Hirschsprung's disease

目的 对心形吻合术治疗先天性巨结肠(HD)的远期疗效进行大样本随访研究,希望能对HD患儿术后远期排便功能及行为心理状态做出一个较为中肯的评定.方法 对2001年1月至2011年1月接受心形吻合术,自愿参与并配合随访的218例HD患儿采用电话、信件及来院复诊等多种方式进行随访.按随访时间将这些患儿分为术后1年组23例、术后1～5年组144例及术后5～10年组51例.内容包括患儿术后有无污粪、大便失禁、便秘复发、结肠炎、顽固性尿潴留等主观指标和钡剂灌肠及直肠肛门测压等客观指标;同时对患儿术后行为心理状态使用儿童行为量表(CBCL)进行评定.结果 术后1年组无便秘复发病例,但Keding评分2.5±0.5低于其他2组3.2±0.7和3.3±0.6,污粪比例39.1％(9/23)高于其他2组9.0％(13/144)和9.8％(5/51),3组均无大便失禁及顽固性尿潴留出现.术后1年组患儿肛管静息压(31.6±13.2)mmHg、高压带长度(13.2±6.5)mm、主动收缩压(4.6±1.9)mmHg均低于其他2组(47.6±4.2)mmHg和(51.3±8.6)mmHg、(24.3±4.6)mm和(26.7±6.9)mm、(6.7±3.8)mmHg和(7.4±4.3)mmHg.钡剂灌肠显示术后1年组患儿肛管长度(16.9±6.8)mm明显短于其他2组(23.9±4.8)mm和(26.1±7.1)mm,钡剂残留及钡剂外溢多于其他2组;有8例患儿在术后1年内结肠形态僵直,未形成典型直肠肛管角.患儿行为心理问题主要表现为躯体诉述、社交退缩、多动、违纪等.结论 心形吻合术是一种成熟可靠的手术方式,术后严重并发症少.但大样本长期随访发现,HD患儿在心形吻合术后各时段内仍有发生各种并发症的可能性,因此有必要建立长期随访制度,以便及时发现问题并积极处理,这将有利于改善患儿术后的排便功能及行为心理状况.     

The treatment and postoperative complications of Hirschsprung's disease

One hundred and ten patients with Hirschsprung's disease diagnosed and treated from 1981 to 1990 at the Royal Children's Hospital, Melbourne, were studied retrospectively. Eighty (72.7%) were treated by the Boley modification of the Soave procedure, 13 by the original Soave procedure, 13 had a Duhamel operation, and 4 had other procedures. Postoperative mortality was 2.7% (3 patients, 2 of whom died of early complications). Early postoperative complications occurred in 29 patients (26%); the most common was bowel obstruction, which included anastomotic obstruction (16 cases). Eight of these patients required anal dilatation to resolve obstruction. Enterocolitis occurred in 5 patients. There were no significant differences in incidence of early complications related to surgical procedure. Late postoperative complications occurred in 43 (39%) cases. Enterocolitis developed in 31 patients, with 19 requiring anal dilatation; 17 had bowel obstructions at various levels. The incidence of bowel obstruction was significantly higher in post-Boley patients (P <0.05). Length of follow-up was up to 10 years (average: 3.9 years). At the final follow-up (average age: 5.4 years) nearly 20% of patients were constipated, and 20% had some degree of incontinence or soiling. One half of the patients had normal bowel habits.     

An epidemiological study of Hirschsprung's disease and additional anomalies

Russell MB, Russell CA, Niebuhr E. An epidemiological study of Hirschsprung's disease and additional anomalies. Acta Pædiatr 1994;83:68–71. Stockholm. ISSN 0803–5253.
The incidence of Hirschsprung's disease was studied in approximately 1.5 million consecutive live births in Denmark by hospital records. A diagnosis of Hirschsprung's disease required a histologic verified absence of ganglion cells in either biopsy or surgical colonic specimens. The incidence of Hirschsprung's disease was found to be 0.140 per 1000 live births (1:7,165) with a male: female ratio of 4.1:1 in short segment, and 2.4:1 in long segment Hirschsprung's disease (p = 0.36). Maternal age and birth order were unimportant factors. The association of Hirschsprung's disease and Down's syndrome was seen in 9 of the 207 patients and may represent a real association, whereas the association with congenital heart defects seen in 2% (not including patients with Down's syndrome) is more doubtful. A mortality of 16% among the patients with Hirschsprung's disease emphasizes the extreme importance of early diagnosis.