© Borgis - New Medicine 1/2003, s. 5-7
Intestinal neuronal dysplasia
Department of Paediatric Diabetology and Birth Defects, Medical University of Warsaw
Head of the Department: Lech Korniszewski, MD, PhD
Report of a case of a 5-month-old infant affected with intestinal neuronal dysplasia, together with a review of recent literature.
Intestinal neuronal dysplasia (IND) is a clinical condition resembling Hirschsprung´s disease (HSCR). It was first described by Meier-Ruge in 1971 (14). It is a complex alteration of the enteric nervous system that may involve the rectum, colon or the whole intestine. The characteristic histological features of IND include hyperplasia of the submucosal and myenteric plexuses, giant ganglia, ectopic ganglion cells and increased acetylcholinesterase (AChE) activity in the lamina propria and around submucosal blood vessels (19). IND may exist as an isolated condition, or in association with Hirschsprung´s disease reported in 10% to 49% of cases (18). The frequency of IND ranges from 1/4000 to 1/60 000 live births (12).
J.K. is the first and only child of young, healthy unconsanguineous parents. She was born at term after an uneventful pregnancy, passing her first stool within 48hrs of birth. She was admitted to hospital at 5 months because of a history of chronic constipation (she passed a hard stool with difficulty, every 4-5 days), loss of appetite, vomiting, and failure to thrive. She weighed 6700 g (10th percentile). There was a history of constipation since birth but in the first weeks of life she passed her stools without effort, her appetite was good and she gained weight. From the 3rd month the symp-toms started to aggravate. Clinical examination revealed significant abdominal distension with palpable faeces-filled loops of bowel. There was presence of stool in the ampulla on rectal examination. Because of the suspicion of Hirschsprung´s disease, we performed a barium enema which showed gross faecal loading of the sigmoid colon and the rectum and distended colon. There was marked retention of barium on a 24 hr. delayed film. No transition zone was noted. Rectal manometry revealed a normal response. Finally, a full-thickness excision biopsy was performed, taken at 3cm above the dentate line. This revealed hyperganglionosis in the submucous layer with giant ganglia and ectopic ganglia in the muscular layer. Neither increased AChE activity nor large numbers of hypertrophied nerve bundles were noted. A diagnosis of intestinal neuronal dysplasia was proposed. She was started on saline enemas with liquid paraffin, prokinetics (cisaprid) and lactulose, with good effect. Her appetite returned to normal, she started to gain weight, passing her stools without effort every one or two days. She remains under our follow-up care in the outpatient clinic.
The collective expression ”malformations of the enteric nervous system” covers very different forms of developmental disturbances of intrinsic intestinal innervation. Whereas the clinical course of Hirschs-prung´s disease is well known and references are found for its genetic cause, commonly available information on intestinal neuronal dysplasia (IND) is very sparse. IND is a disease of the enteric nervous system, which clinically resembles Hirschsprung´s disease. It may involve the rectum, colon, or the whole intestine. Ten years after its first description in 1971 by Meier-Ruge (14), it was divided into two clinically and histologically distinct subtypes (5). Type A that occurs in less than 5% of cases is characterized by congenital aplasia or hypoplasia of the sympathetic innervation, and presents acutely in the neonatal period with intestinal obstruction, diarrhoea, and bloody stools. Type B in its clinical picture resembles Hirschsprung´s disease, charac-terised by malformation of the parasympathetic submucous and myenteric plexuses. IND type A is extremely rare. The incidences of type B reported range from 1:4000 to 1:60 000 live births. In general the incidence of isolated IND ranges from 0.3% to 40% of all suction rectal biopsies in different centres (17). This difficulty in exact estimation of the frequency of IND results from the considerable confusion regarding the essential diagnostic criteria. Diagnostic difficulties centre on the wide variations in the literature in respect of diagnostic criteria, biopsy procedure, staining techni-ques and patient´s age. There is also a high interobserver variation with regard to the different morphological features and final diagnosis of IND. The high frequency of histological ”abnormalities” that are age-dependent (physiological presence of hyperganglionosis in neonates under 4weeks) may represent a normal variant of postnatal development rather than a pathological process (4, 11).
The diffuse form of IND type B (16% patients) usually presents with chronic pseudoobstruction. In the remaining patients with rectocolonic dysplasia initial symptoms are constipation with pseudo-HSCR presentation. Symptoms usually start in infancy. Neonatal onset of symptoms with ileus, meconium plug syndrome or neonatal constipation occurs in those with a coincidence of IND and aganglio-nosis (21). There is no significant difference in sex distribution. In 30% of cases there may be IND-associated anomalies that include anorectal malformation, intestinal malrotation, megacystis, congenital short small bowel, hypertrophic pyloric stenosis, necrotizing enterocolitis, intestinal atresia, diffuse intestinal angiomatosis or microvillus agenesis (13). There is also a report of two siblings with IND, mental retardation, dysmorphic features, hearing loss and short stature (13). Additional anomalies are more often observed in cases with diffuse IND (80%). Martuciello et al. observed three families with multiple IND cases and hypothesized a recessive mode of inheritance (in two of their families parents were consanguineous) but in all their cases IND was associated with other gastrointestinal associated anomalies (13). Other authors have also recorded associated gastro-intestinal anomalies (1, 20). They also concluded that familial recurrence of associated IND-Malrotation-Short Bowel Syndrome suggests the possible presence of an autosomal recessive mode of inheritance. The role of genetic factors in etiology in that disorder is also suggested by two reports of IND in monozygotic twins (10,16).
The procedure of choice in diagnosis of IND is a rectal biopsy. This is contrary to Hirschsprung´s disease where a biopsy of only mucosal tissue is sufficient to make the diagnosis, but in cases of IND it is essential to include parts of the submucous layer. Even in excision biopsies the submucosa may sometimes be missed, and biopsies may be rendered useless by mechanical traumatisation (22). Despite all these comments, a correctly practised rectal suction biopsy still remains the procedure of choice in the diagnosis of IND. Recently a novel method for colonic mapping of dysganglionosis was proposed by Carvalho et al. (3). Instead of additional laparotomy they performed a laparoscopic-assisted mapping. With the use of a laparoscope inserted in the supraumbilical area different fragments of colon are pulled through the abdominal wall and full-thickness biopsies are taken.
IND can be characterised by different histochemical findings. Mucosal and submucosal biopsies show two or more of the following aspects (2):
–Submucosal plexus hyperplasia (obligatory criterion).
–AChE-positive fibres around submucosal vessels (obligatory criterion).
–Weak staining of the finest nerve fibres in the lamina propria.
–Heterotopic ganglia in the muscularis mucosae or in the lamina propria.
–”Button-like” ganglia in the submucosa.
In full-thickness intestinal biopsies, the following aspects are also found:
–giant ganglia in the myenteric plexus,
–increased AchE-positive fibres in the muscular coat, especially in the circular layer,
–heterotopic ganglia in the muscular layer rather than in the interstitium between the two coats.
In neonatal cases it may be necessary to use other neuronal markers such as neural cell adhesion molecule, nerve growth factor receptor and NADPH-diaphorase to confirm the diagnosis of IND (9).
Anorectal manometry is not very useful for the definite diagnosis of IND because the rectoanal reflex may be absent, present, or may be abnormal (12).
IND type B is initially treated conservatively with prokinetics (cisapride) and enemas, surgery being adopted only in non-responders at more than 3 years of life. In cases of diffuse IND surgery should be avoided since radical treatment cannot be obtained, although sometimes it is necessary due to severe obstruction. It has been proved that the enteric nervous system continues to develop in the postnatal period. Wester et al. discovered that the density of ganglia in the submucous plexus decreased during the first 3 to 4 years of life (24). These results imply that an adequate period of conservative treatment is essential in these patients before consideration of surgery. According to Gillick, who followed-up 33 patients with IND, 64% of patients have a good response to conservative treatment and either require no or only intermittent laxatives. The median age of these good responders is 1 year. Twelve patients underwent internal sphincter myectomy after failed conservative treatment and 7 of those have a good response to myectomy and normal bowel habits with normal continence. Only 3 patients required resection of a redundant and dilated sigmoid colon (7). Similar results of the efficacy of conservative treatment in the majority of patients with IND were recorded by Ure etal. (23). Martuciello in his observation of 12 patients with IND recorded three deaths from sepsis in the 2nd year of life in patients with the diffuse form (12).
The pathogenesis of IND still remains unclear. It seems to be related to premature expression of laminin A during embryogenesis, resulting in premature nerve cell differentiation in the myenteric and submucosal plexus, which in turn blocks neuroblast colonization of the rectum. IND type B, hypoganglionosis, and aganglio-nosis which are often combined may therefore be considered to be different manifestations of the same developmental abnormality (15). Martucciello et al. concluded that the frequent association of IND with aganglionosis and multiple endocrine neoplasia type II (MEN II) may be due to different mutations of the RET proto-oncogen (12). Recently, analysis of some genes known to be involved in the pathogenesis of HSCR was performed in patients with IND. No mutations of RET, GDNF, EDN3 and EDNRB genes were observed in IND patients and the frequency of specific RET poly-morphism was significantly lower in comparison to HSCR patients. The authors conclude that although HSCR and IND share some clinical features and are frequently associated they probably have different genetic pathways (6). The precursors of enteric neurones and glia migrate into the primitive intestine as a heterogeneous population of pluripotent cells. The subsequent development of these cells is determined by the action of growth factors. The cells become sorted into lineages that give rise to progressively smaller subsets of neurones. One of the elements of different signalling cascades essential to normal enteric nervous system (ENS) development is the Ncx/Hox11L.1 gene. Recently a mouse model has provided strong clinical and histological evidence that isolated IND exists as a separate disease entity. Two different knockout mice models with homozygous deletion of the Ncx/Hox11L.1 homeobox gene were viable but developed megacolon by an age of 3 to 5 weeks. Hyperganglionosis was evident on histological examination of their enteric nervous system and was similar to that observed in human IND (8).
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