A spectrum of congenital disorders affecting the sub- mucous plexus of the gut is summarized as intestinal neuronal dysplasia (IND). Other congenital malforma-.
Pediatr Surg Int (1998) 13: 474±479
Ó Springer-Verlag 1998
MAIN TOPIC
S. Berger á P. Ziebell á M. Kessler á S. Hofmann-von Kap-herr
Congenital malformations and perinatal morbidity associated with intestinal neuronal dysplasia
Abstract A close relation between dierent 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. Key words Intestinal neuronal dysplasia á Intestinal dysganglionosis á Aganglionosis á Hirschsprung's disease á Congenital malformations á Intestinal atresia S. Berger (&) á P. Ziebell á M. Keûler á S. Hofmann-v. Kap-herr Department of Pediatric Surgery, Johannes-Gutenberg-University, Langenbeckstrasse, D-55131 Mainz, Germany
Introduction A spectrum of congenital disorders aecting the submucous plexus of the gut is summarized as intestinal neuronal dysplasia (IND). Other congenital malformations appearing in combination with IND were described by several authors. These malformations aect the gastrointestinal (GI) tract as well as other organ systems. First, a close relation between IND and Hirschsprung's disease (HD) was found and termed HANID (Hirschsprung-associated IND) by Hanimann et al. [7]. A coincidence of IND with Down's syndrome [2, 31] has also been described. Except for these two associations, no speci®c pattern of intestinal or extraintestinal malformations has been detected with IND. Upon review of the literature, however, several midline occlusion defects such as spina bi®da [2], gastroschisis [13], and diaphragmatic hernia [26] have been found in patients with IND. Intestinal congenital malformations such as esophageal atresia (EA) [23], hypertrophic pyloric stenosis (HPS) [26], ileal atresia [23, 26], colonic atresia [2], or anal atresia (AA) [23, 29], were also mentioned in association with IND. When these occasional reports are collected, stenoses and atresias appear throughout the entire GI tract. Another important aspect of IND is its association with abdominal complications during the perinatal period, especially in preterm infants [2, 26]. Necrotizing enterocolitis (NEC) [8, 22, 26, 29], bowel perforations independent of NEC [20, 22], and meconium peritonitis [22, 23] are mentioned in context with IND. Such an early onset of symptoms of IND may mark a severe course of the disease. Analysis of perinatal morbidity from IND seems important to obtain further information about the clinical relevance of the pathologist's diagnosis of dysganglionosis. As present data about combined malformations involving IND are limited and the pathogenesis of IND is not yet fully understood, an analysis of associated malformations and morbidity might shed light on how and why intestinal dysganglionosis develops.
475
aganglionosis (Zuelzer-Wilson) was found in 2 children (4.3%).
Materials and methods The data of 109 consecutive patients with histologically con®rmed IND were reviewed in regard to additional congenital malformations and perinatal morbidity. These patients were treated at the Department of Pediatric Surgery in Mainz from 1977 to 1996. All histologic investigations were performed at the Institute for Pediatric Pathology in Mainz (director: Prof. H. MuÈntefering). Analyses included histochemistry for acetylcholinesterase and neuron-speci®c enolase. Histologic classi®cation of tissue specimens was made according to the results of the 1990 consensus conference of the Study Group for Gastroenterologic Pathology [1] in those 89 patients investigated after 1990. Selected specimens were sent to Prof. W. A. Meier-Ruge, Basel, for con®rmation of the histologic diagnosis. If a diagnosis of IND was made from tissue specimens other than rectal full-thickness biopsies (e.g., at a colostomy site), a rectal biopsy was performed afterwards to evaluate for accompanying HD. If a diagnosis of IND was made from bowel specimens of preterm babies, histology was con®rmed afterwards, usually before closure of the enterostomy, when the children were aged 3 months or more. In cases with HD the oral extent of the aganglionosis was documented as precisely as possible. Extension of IND was investigated by open biopsy only when a laparotomy was inevitable. IND-related morbidity during the neonatal period, such as preterm birth or perinatal bowel perforation and NEC, was analyzed. The family history was evaluated as to intestinal innervation disorders in siblings, especially twins.
Results Associated HD Aganglionosis was detected in 47 of 109 children with IND (43%). Extension of the aganglionosis was limited to the rectum in 33 cases (70%) and the sigmoid was included in 8 (17%). In 4 (8.5%) the aganglionosis reached the left colonic ¯exure, and total colonic Table 1 Intestinal neuronal dysplasia (IND) and associated congenital malformations
Case no.
Associated intestinal malformations Atresias and stenoses of the GI tract were found in 15 children with IND (14%). In 13 of these, HD was excluded. AA was present in 1 child with IND and HD and 8 children with isolated IND (total frequency: 8.3%). One case of ileal atresia was associated with HD and IND. EA was seen in 2 children with multiple malformations. HPS and congenital sigmoid or rectal stenosis were seen in 1 child each with isolated IND. These data are summarized in Table 1. Localizations of the dierent intestinal malformations are depicted in Fig. 1, showing cumulation in the ileocecal and anorectal regions. Complex malformations and other associated malformations Complex malformation syndromes were seen in 4 children with IND. Larrey's diaphragmatic hernia was found in a child with EA, IND, and psychomotor retardation. One child presented with aortic stenosis, malformations of the T1±3 vertebral bodies, and IND. Malrotation was present in a child with Down's syndrome, AA, and IND. One child showed a combination of IND, AA, EA, and a dysplastic right kidney. A Meckel's diverticulum was found in a child with IND and NEC. One preterm infant with IND developed a choledochal cyst. In a child with HD and IND a syndactyly of ®ngers II and III was seen (Table 1).
IND
M.H.
Down
Atresia/Stenosis
Other
1
B
)
)
Esophageal atresia
2 3 4 5 6 7 8 9 10 11
B B B B B B B B B B
) ) + ) ) ) ) ) ) )
) ) ) ) ) ) ) ) ) )
Esophageal atresia Pyloric stenosis Ileal atresia Sigmoid stenosis Rectal stenosis Anal atresia Anal atresia Anal atresia Anal atresia Anal atresia
12 13 14 15 16 17 18 19 20 21 22
B B B B B B B B B B B
) + ) + + + + ) ) + )
) ) + + + + + ) ) ) )
Anal atresia Anal atresia Anal atresia ) ) ) ) ) ) ) )
Larrey's hernia, psychomotor retardation Anal atresia ) ) ) ) ) ) ) ) Aortic stenosis, T1±3, malformations, cervical rib ) ) ) ) ) ) Urachus Urachus Urachus Syndactyly
476 Table 2 Intestinal neuronal dysplasia (IND), preterm birth, and perinatal morbidity (HD Hirschsprung's disease, NEC necrotizing enterocolitis)
Fig. 1 Localizations of intestinal malformations. stenosis; perforation
atresia;
Associated Down's syndrome Five children presented with Down's syndrome, which was con®rmed by chromosomal analysis; 3 of these additionally had HD while 1 had a high form of AA without ®stula. In the 5th child, IND without aganglionosis was combined with Down's syndrome. Associated malformations of the urogenital tract A persisting urachus was found (and corrected) in 3 children as an intraoperative diagnosis during laparotomy. Nephrectomy became necessary in 1 child with a dysplastic right kidney. Associated preterm birth A total of 18 children with IND were born preterm at 26 to 37 weeks of gestation. In 15 of these, congenital malformations or severe intra-abdominal complications were present. Eleven children (9 with IND and 2 with HD + IND) required neonatal intensive care for preterm birth; 8 of these developed NEC (Table 2). Early clinical manifestations of IND Eighteen children showed early symptoms of IND during the perinatal period. IND was diagnosed in a consistent number of newborns with NEC (n 10) and pre-or postnatal bowel perforations (n 7). Bowel perforations were seen in 3/10 children with NEC. Meconium peritonitis was seen in 1 newborn as a sign of prenatal bowel disruption. Necrotized bowel areas and sites of perforation are shown in Fig. 1 and data are summarized in
Case no.
IND
HD
Preterm, week
NEC
Perforation
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
B B B B B B B B B B B B B B B B B B B A B
) ) ) ) + ) ) ) ) ) ) ) ) ) ) ) ) ) ) + +
32 32 33 34 ) 26 26 29 33 36 ) ) 31 29 29 28 26 37 34 34 )
) ) ) ) ) ) ) ) ) ) ) + + + + + + + + + +
) ) ) ) Duodenum Ileum Ileum Ileum Appendix Asc. colon Sigma Desc. colon Ileum Ileum ) ) ) ) ) ) )
Table 2. The ileocecal area and distal third of the colon were mainly involved in this pathology. Associated mental retardation Two children showed marked retardation in psychomotor development independent of premature birth or known perinatal hypoxia. Twins of children with IND Four of the 109 children had twins. One twin died in utero due to severe malformations that were not documented speci®cally. One was monozygotic and two were dizygotic; all of the surviving twins were healthy without clinical signs of HD or IND. A rectal biopsy was not performed in any of the siblings of patients with IND.
Discussion In the current analysis, additional malformations and perinatal diseases were found at a surprisingly high frequency in children with IND. Since patient cohorts in the literature are usually limited to 10±40 patients with IND, analysis of the Mainz cohort, which includes 109 patients, is more appropriate to estimate the frequency and clinical importance of such associations. Additional malformations were seen in 22/109 patients with IND, or 20.2%, when aganglionosis itself is not considered as an additional malformation. Focusing on the 62 cases with IND without associated HD, the incidence of congenital malformations is even higher, at 15/62 (24.2%).
477
The general incidence of additional malformations in HD (without IND) was reported to be about 11% [11, 28]. The incidence of associated malformations is therefore at least twice as high in IND compared to HD. A summary of previously described malformations in children with IND is given in Tables 3 (GI malformations) and 4 (extraintestinal malformations). Most of these malformations were also seen in the patients of the present series, as indicated. IND and HD The coincidence of IND and HD is reported in two ways throughout the literature: as IND accompanied by HD or vice versa. The respective ratios are listed in Table 5. IND was found in an average of 26.3% (153/582, sum of all studies) of patients with HD. Conversely, HD was reported to be present in an average of 38.2% (187/489, sum of all studies) of patients with IND. In the current series aganglionosis was detected in 43% of patients with IND. The slightly higher incidence of combined IND and HD in this study re¯ects the routine search for IND in all cases of HD prior to closure of the enterostomy. The ratio of HD-associated IND in the present material is therefore comparable to previous ®ndings of the authors named in Table 5.
tum and migration of ganglia down the developing gut both occur during the same embryological period [27]. The association of AA and HD has been described by dierent authors. Kiesewetter et al. [12] reviewed the literature in 1965 and found that 3.4% of patients with AA had an aganglionic bowel segment. The diagnosis of aganglionosis in AA, however, depends on the site of the biopsy. Aganglionosis is common in the ®stula or rectal pouch [9], but not in the colon above the AA [21]. Rintala et al. [21] described 1 case of true aganglionosis among 208 patients with AA (0.5%). Ikeda and Goto [11] reported 5 cases of AA in 1828 patients (0.3%) with HD. Among the current 47 patients with IND and HD, 1 had AA. The present study includes 8 other patients without HD with IND and AA, and therefore, the frequency of AA in IND was 8.2%. This is signi®cantly higher than the frequency in HD, probably due to the fact that all surgically removed bowel specimens were routinely sent un®xated for histology, allowing histochemical investigation and thereby detection of IND Table 4 Extraintestinal malformations in children with IND as described in literature and found in present study Malformation
Cases
Author(s)
Present series
Down's syndrome
2 1 2 2 1 1 1 1
Briner 1986 [2] Scho®eld 1991 [26] Kunde 1991 [13] Scho®eld 1991 [26] Scho®eld 1991 [26] Scho®eld 1991 [26] Scho®eld 1991 [26] Briner 1986 [2]
5
Gastroschisis
IND and AA A signi®cant association of innervation de®cits and AA seems possible since development of the urorectal sepTable 3 Intestinal malformations in children with IND as described in literature and found in present study
Diaphragmatic hernia Cystic ®brosis Arthrogryposis Spina bi®da
± 1 ± ± ±
Malformation
Cases
Author(s)
Present series
Esophageal atresia Pyloric stenosis
1 1 1 1 1 1 1 1 1 1 2 1 1 1 1 1 2
SchaÈrli 1992 [23] Scho®eld 1991 [25] Martuciello 1994 [14] Briner 1986 [2] Sacher 1992 [22] Sacher 1992 [22] Bussmann 1990 [3] Schmidt 1990 [24] Scho®eld 1991 [26] SchaÈrli 1992 [23] Holschneider 1994 [10] Briner 1986 [2] Heiming 1990 [8] Heiming 1990 [8] Sacher 1992 [22] Szavay 1993 [29] SchaÈrli 1992 [23] (IND in rectal biopsies) Holschneider 1994 [9] (IND in ®stula/pouch) Szavay 1993 [29] Martuciello 1994 [14] Briner 1986 [2] Briner 1986 [2] Briner 1986 [2] Sacher 1992 [22]
2 1
Ileal stenosis Ileal atresia
Colonic atresia Rectal stenosis Anterior anus VATER syndrome Anal atresia
5 Malrotation Cystic bowel duplication Meckel's diverticulum Volvulus
2 2 1 1 1 1
± 1
± 1 ± 1 9
1 ± 1 1 (partial)
478
Cases
Author
Cases
Author
isolated IND, while 4 had HD-associated IND. The frequency of Down's syndrome in isolated IND is therefore estimated to be lower than in isolated HD (3%±4% [6, 11]) or HD-associated IND.
24/96 11/45 64/187
Fadda 1987 [5] Heiming 1990 [8] Meier-Ruge 1991 [15] SchaÈrli 1992 [23] Hanimann 1991 [7] Ure 1994 [31] Moore 1993 [18]
12/16 12/23 6/10
Briner 1986 [2] Pistor 1987 [20] Schmidt 1990 [24]
IND and perinatal morbidity
3/12 8/54 35/56 64/209
Bussmann 1990 [2] SchaÈrli 1992 [23] Ure 1994 [31] Meier-Ruge 1992 [16] This study
Table 5 Incidence of intestinal neuronal dysplasia (IND) in patients with Hirschsprung's disease (HD) (left column) and incidence of HD, in patients with IND (right column)
3/22 11/47 35/159 5/26
47/109
[17]. In children with AA, the diagnosis of IND was made either from a bowel segment removed during placement of the colostomy or after correction of the atresia by rectal full-thickness biopsies. The diagnosis of IND was never made from a resected ®stula or pouch as described by Holschneider et al. [10]. IND and other intestinal stenoses and atresias As depicted in Fig. 1, stenoses and atresias were found throughout the GI tract. It is therefore assumed that the underlying pathomechanism for generation of an atresia/stenosis is similar to that of innervation de®cits. The two major theories of how innervation de®cits develop are: (1) disturbances of the craniocaudal migration of ganglion cells [19]; and [2] ischemic episodes [4], which may interfere with either migration and dierentiation of the cells or lead to degeneration of formerly normal ganglia [30]. Ischemia has also been shown to induce bowel atresia. Damage to the bowel wall that is signi®cant enough to cause an atresia or stenosis will probably interfere with the more fragile innervation system as well. Innervation de®cits may therefore be expected in the vicinity of atretic bowel segments. IND and Down's syndrome Five of 109 children with IND had trisomy 21, a frequency of 4.6%. In fact, only one of the 5 children had Table 6 Perinatal morbidity in children with IND as described in literature and found in present series (NEC necrotizing enterocolitis)
Condition NEC
Bowel perforation Meconium peritonitis Meconium ileus Intussusception Preterm birth (
