Hirschsprung Disease

Background

This is a rare congenital condition affecting the lower gastrointestinal tract. It results in obstruction because the intestines lose its normal nervous tissue resulting in megacolon or a dilated section of colon. The symptoms differ depending upon the age of presentation. In a newborn period, there is failure to pass a meconium stool within 24-48 hours after birth, reluctance to eat, vomiting, and abdominal distension. During infancy the child has difficulty gaining weight , constipation, abdominal distension, episodes of diarrhea and vomiting. In older children, symptoms become chronic and include constipation, passage of ribbon-like, foul-smelling stools, abdominal distension and visible peristalsis. Usually there is evidence of poor nutrition and anemia.

OUTLINE

Epidemiology

Disease Associations

Pathogenesis

Laboratory/Radiologic/Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Differential Diagnosis

Prognosis and Treatment

Commonly Used Terms

Internet Links

EPIDEMIOLOGY CHARACTERIZATION

SEX (M:F)
Males favored

DISEASE ASSOCIATIONS CHARACTERIZATION

DOWN SYNDROME

MEN SYNDROMES

RET mutation profile and variable clinical manifestations in a family with multiple endocrine neoplasia type 2A and Hirschsprung's disease.

Pasini B, Rossi R, Ambrosio MR, Zatelli MC, Gullo M, Gobbo M, Collini P, Aiello A, Pansini G, Trasforini G, degli Uberti EC.

Department of Biomedical Sciences and Advanced Therapies, Section of Endocrinology, University of Ferrara, Via Savonarola 9, I-44100 Ferrara, Italy.
Surgery 2002 Apr;131(4):373-81 Abstract quote
BACKGROUND: RET proto-oncogene germ line mutations are associated with the inherited multiple endocrine neoplasia type 2 syndromes (MEN 2), as well as with familial and sporadic Hirschsprung's disease (HSCR). In this study, we report a family in which the MEN 2A and the HSCR phenotypes are associated with a single point mutation in exon 10 of the RET proto-oncogene. Furthermore, we have investigated polymorphic sequence variants of the RET proto-oncogene.

METHODS: Family members were tested for RET proto-oncogene mutations in exons 10, 11, 13, 14, 15, and 16 by double-gradient denaturing-gradient gel electrophoresis, nucleotide sequence analysis, and restriction endonuclease digestion of polymerase chain reaction products. The status of exon 2 and 13 polymorphic sites was investigated by EagI and TaqI digestion in 12 selected patients.

RESULTS: A heterozygous C618R mutation of RET exon 10 was identified in 12 family members. Five out of 7 children with mildly elevated pentagastrin-stimulated calcitonin levels who carried the mutation underwent prophylactic thyroidectomy before the age of 12. C-cell hyperplasia (CCH) was found in 4 children and a microscopic medullary thyroid carcinoma (MTC) in an 8-year-old female. Neither CCH nor MTC was found in the only family member affected with HSCR, an 8-year-old male. This patient inherited the mutated RET allele from his mother, who had MTC but not HSCR, together with a rare allelic variant at codon 45 of RET exon 2.

CONCLUSIONS: This report of a newly-described kindred with the infrequent clinical association between MEN 2A and HSCR confirms the risk of the latter phenotype among carriers of RET exon 10 cysteine codon mutations. Nevertheless, the influence of other genetic or environmental factors cannot be excluded.

MOWAT-WILSON SYNDROME

"Mowat-Wilson" syndrome with and without Hirschsprung disease is a distinct, recognizable multiple congenital anomalies-mental retardation syndrome caused by mutations in the zinc finger homeo box 1B gene.

Zweier C, Albrecht B, Mitulla B, Behrens R, Beese M, Gillessen-Kaesbach G, Rott HD, Rauch A.

Institute of Human Genetics, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
Am J Med Genet 2002 Mar 15;108(3):177-81 Abstract quote
Recently mutations in the gene ZFHX1B (SIP1) were shown in patients with "syndromic Hirschsprung disease" with mental retardation (MR) and multiple congenital anomalies (MCA), but it was unclear if Hirschsprung disease is an obligate symptom of these mutations and if the distinct facial phenotype delineated by Mowat et al. [1998: J Med Genet 35: 617-623] is specific for ZFHX1B mutations.

In order to address these open questions we analyzed the ZFHX1B gene in five patients, three of whom had "syndromic Hirschsprung disease" two with and one without the facial phenotype described by Mowat et al. [1998], and two of whom had the distinct facial gestalt without Hirschsprung disease. Analyses of microsatellite markers and newly identified SNPs, and/or FISH with BACs from the ZFHX1B region excluded large deletions in all five patients. Direct sequencing demonstrated truncating ZFHX1B mutations in all four patients with the characteristic facial phenotype, but not in the patient with syndromic Hirschsprung disease without the distinct facial appearance.

We demonstrate that there is a specific clinical entity with a recognizable facial gestalt, mental retardation and variable MCAs which we propose be called the "Mowat-Wilson syndrome."

PATHOGENESIS CHARACTERIZATION

CARBON MONOXIDE PRODUCING NEURONS

Distribution of carbon monoxide-producing neurons in human colon and in Hirschsprung's disease patients.

Chen Y, Lui VC, Sham MH, Tam PK.

Division of Paediatric Surgery, Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, and Department of Biochemistry, University of Hong Kong, Hong Kong SAR, China.

Hum Pathol 2002 Oct;33(10):1030-6 Abstract quote
Hirschsprung's disease (HSCR) is characterized by the absence of ganglion cells and impaired relaxation of the gut. Nitric oxide (NO) and, more recently, carbon monoxide (CO) have been identified as inhibitory neurotransmitters causing relaxation.

A deficiency in NO has been reported in aganglionic gut; we hypothesized that CO could also be involved in impaired gut motility in HSCR. The aim of the study was to determine the distribution of CO-and NO-producing enzymes in the normal and aganglionic gut.

We performed laser capture microdissection, reverse transcription-polymerase chain reaction, and immunohistochemistry on colon biopsies of normal controls (n = 9) and patients with HSCR (n = 10). The mRNA expression of heme oxygenase-2 (HO-2), immunoreactivities of HO-2 and NO synthase, was determined and compared. Results show a high level of expression of HO-2 mRNA localized in the myenteric plexus. Expression of HO-2 mRNA was also detected in the mucosa, submucosa, and muscular layer. Down-regulation of HO-2 mRNA expression was detected in the aganglionic colon. Immunoreactivities of HO-2 and NO synthase were localized mainly to the ganglion plexus and to nerve fibers within the muscle in the control colons and normoganglionic colons. HO-2-containing neurons were more abundant than NO synthase-containing neurons in the myenteric plexus. Nearly all of the NO synthase-containing neurons also contained HO-2. HO-2 and NO synthase were selectively absent in the myenteric and submucosal regions and in the muscle of the aganglionic colon.

Our findings suggest involvement of both CO and NO in the pathophysiology of HSCR.

CHROMOSOMAL ABNORMALITIES

Segregation at three loci explains familial and population risk in Hirschsprung disease.

Gabriel SB, Salomon R, Pelet A, Angrist M, Amiel J, Fornage M, Attie-Bitach T, Olson JM, Hofstra R, Buys C, Steffann J, Munnich A, Lyonnet S, Chakravarti A.

Department of Genetics and Center for Human Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
Nat Genet 2002 May;31(1):89-93 Abstract quote
Hirschsprung disease (HSCR), the most common hereditary cause of intestinal obstruction, shows considerable variation and complex inheritance. Coding sequence mutations in RET, GDNF, EDNRB, EDN3 and SOX10 lead to long-segment (L-HSCR) and syndromic HSCR but fail to explain the transmission of the much more common short-segment form (S-HSCR).

We conducted a genome scan in families with S-HSCR and identified susceptibility loci at 3p21, 10q11 and 19q12 that seem to be necessary and sufficient to explain recurrence risk and population incidence. The gene at 10q11 is probably RET, supporting its crucial role in all forms of HSCR; however, coding sequence mutations are present in only 40% of linked families, suggesting the importance of noncoding variation.

Here we show oligogenic inheritance of S-HSCR, the 3p21 and 19q12 loci as RET-dependent modifiers, and a parent-of-origin effect at RET. This study demonstrates by a complete genetic dissection why the inheritance pattern of S-HSCR is nonmendelian.

L1CAM

Hydrocephalus and intestinal aganglionosis: Is L1CAM a modifier gene in Hirschsprung disease?

Parisi MA, Kapur RP, Neilson I, Hofstra RM, Holloway LW, Michaelis RC, Leppig KA.

Division of Genetics and Development, Department of Pediatrics, University of Washington and Children's Hospital and Regional Medical Center, Seattle, Washington.
Am J Med Genet 2002 Feb 15;108(1):51-6 Abstract quote
Congenital hydrocephalus associated with aqueductal stenosis and/or agenesis of the corpus callosum has been described in newborn males with mutations in L1CAM, a gene that encodes a neural cell adhesion molecule. These males usually have severe mental retardation and may have spastic paraplegia and adducted thumbs. In contrast, Hirschsprung disease, or absence of ganglion cells in the distal gut, has rarely been described in such individuals.

We report a male infant who had severe hydrocephalus identified in the prenatal period with evidence of aqueductal stenosis and adducted thumbs at birth. He developed chronic constipation, and rectal biopsy confirmed the diagnosis of Hirschsprung disease. Molecular testing of the L1CAM gene revealed a G2254A mutation, resulting in a V752M amino acid substitution. A common polymorphism in RET, but no mutation, was identified. Our patient represents the third example of coincident hydrocephalus and Hirschsprung disease in an individual with an identified L1CAM mutation.

We hypothesize that L1CAM-mediated cell adhesion may be important for the ability of ganglion cell precursors to populate the gut, and that L1CAM may modify the effects of a Hirschsprung disease-associated gene to cause intestinal aganglionosis.

NEUROTRANSMITTERS

Widespread changes in neurotransmitter expression and number of enteric neurons and interstitial cells of Cajal in lethal spotted mice: an explanation for persisting dysmotility after operation for Hirschsprung's disease?
Sandgren K, Larsson LT, Ekblad E.

Department of Pediatrics, Lund University Hospital, Sweden.
Dig Dis Sci 2002 May;47(5):1049-64 Abstract quote
Gastrointestinal motor dysfunction persists in a large number of children subjected to surgical treatment for Hirschsprung's disease, indicating abnormalities in the remaining intestine.

The aim of the study was to detect possible alterations in frequency and topographic distribution of enteric neurons and interstitial cells of Cajal in an experimental model (the lethal spotted mouse displaying a short rectal aganglionosis) for Hirschsprung's disease. Specimens from the intestinal tract from homozygous (aganglionic) and heterozygous (healthy littermates) were examined using histochemistry, in situ hybridization, and immunohistochemistry.

In ileum and colon, ie, regions proximal to the aganglionosis, changes in the expression of neuropeptides and neuronal nitric oxide synthase and in the number of enteric neurons and interstitial cells of Cajal could be detected in homozygous versus heterozygous mice.

The described changes are suggested to contribute to the dysmotility remaining after surgical resection of the aganglionic segment in Hirschsprung's disease.

SMOOTH MUSCLE ABNORMALITIES

Altered cytoskeleton in smooth muscle of aganglionic bowel.

Nemeth L, Rolle U, Puri P.

Children's Research Centre, Our Lady's Hospital for Sick Children, Dublin, Ireland (Drs Nemeth, Rolle, and Puri); and the Department of Paediatric Surgery, University of Szeged, Szeged, Hungary (Dr Nemeth).

Arch Pathol Lab Med 2002 Jun;126(6):692-6 Abstract quote
Context.-Intestinal motility is under the control of smooth muscle cells, enteric plexus, and hormonal factors. In Hirschsprung disease (HD), the aganglionic colon remains spastic or tonically enhanced and unable to relax. The smooth muscle cell's cytoskeleton consists of proteins or structures whose primary function is to link or connect protein filaments to each other or to the anchoring sites. Dystrophin is a subsarcolemmal protein with a double adhesion property, one between the membrane elements and the contractile filaments of the cytoskeleton and the other between the cytoskeletal proteins and the extracellular matrix. Desmin and vinculin are functionally related proteins that are present in the membrane-associated dense bodies in the sarcolemma of the smooth muscle cells.

Objective.-To examine the distribution of the cytoskeletal proteins in the smooth muscle of the aganglionic bowel. Design.-Bowel specimens from ganglionic and aganglionic sections of the colon were collected at the time of pull-through surgery from 8 patients with HD. Colon specimens collected from 4 patients at the time of bladder augmentation acted as controls. Anti-dystrophin, anti-desmin, and anti-vinculin antibodies were used for fluorescein immunostaining using confocal laser scanning microscopy.

Results.-Moderate to strong dystrophin immunoreactivity was observed at the periphery of smooth muscle fibers in normal bowel and ganglionic bowel from patients with HD, whereas dystrophin immunoreactivity was either absent or weak in the smooth muscle of aganglionic colon. Moderate to strong cytoplasmic immunostaining for vinculin and desmin was seen in the smooth muscle of normal bowel and ganglionic bowel from patients with HD, whereas vinculin and desmin staining in the aganglionic colon was absent or weak.

Conclusion.-This study demonstrates that the cytoskeletal proteins are abundant in the smooth muscle of normal bowel, but are absent or markedly reduced in the aganglionic bowel of HD. As cytoskeletal proteins are required for the coordinated contraction of muscle cells, their absence may be responsible for the motility dysfunction in the aganglionic segment.

LABORATORY/RADIOLOGIC/
OTHER TESTS
CHARACTERIZATION

RADIOLOGIC

Adult Hirschprung disease: radiographic findings.

Mindelzun RE, Hicks SM.
Radiology 1986 Sep;160(3):623-5 Abstract quote
Hirschprung disease is usually diagnosed in infancy. Occasionally patients reach adulthood without diagnosis or treatment.

Four cases of adult Hirschprung disease are described. The principal radiographic findings are a markedly dilated, feces-filled colon above the zone of transition; a narrowed rectum; a cone- or funnel-shaped zone of transition; and a mosaic colonic pattern caused by collapsed redundant mucosa after colonic cleansing.

In an adult, identification on a barium enema examination of an abrupt, smooth transition zone in the rectum with proximal colonic dilatation, in conjunction with an appropriate clinical history, should suggest the diagnosis of adult Hirschprung disease.

LABORATORY MARKERS

ELECTROMYOGRAPHY

Electromyography of the rectum and colon in Hirschsprung's disease.

Marin AM, Rivarola A, Garcia H.
J Pediatr Surg 1976 Aug;11(4):547-552 Abstract quote
The electromyographic activity of the large bowel was studied in patients suffering from aganglionic megacolon and in comparable normal infants and children, using of an intraluminal electrode.

Graphs obtained in control children showed a basic electrical rhythm of 4-6 waves/min with bursts of high frequency spikes, 3-4/sec, superimposed on the top of the slow waves. The recordings in Hirschprung's disease showed an irregular basic electrical rhythm with waves of variable duration and no high frequency potentials, as long as the electrode was positioned in the aganglionic zone.

As soon as the electrode was introduced further up into the normally innervated colon the graph became identical to that seen in the normal bowel. Intraluminal electromyography of the rectum and colon seems to be a suitable procedure to diagnose aganglionosis of the rectum and the extent of the lesion.

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

GENERAL

VARIANTS

ADULT

Adult Hirschsprung's disease: results of surgical treatment at Mayo Clinic.

McCready RA, Beart RW Jr.
Dis Colon Rectum 1980 Sep;23(6):401-7 Abstract quote
Fifty adult patients with Hirschsprung's disease were operated on at the Mayo Clinic between 1950 and 1978. Six different operations were used. Of the three patients treated by the Soave endorectal pull-through procedure, two suffered anastomotic leaks and required diverting colostomies; all three had excellent long-term results, however. All four patients who underwent the Duhamel procedure had excellent results, with only one minor complication. Of the 17 patients undergoing the Swenson procedure, 6 had major postoperative complications, including 2 with impotence; 3 (17.6 per cent) patients who underwent rectal myectomy, there was one minor complication, although 5 (38.5 per cent) had unsatisfactory results. Six patients had anterior resection, one of whom died of generalized peritonitis from an anastomotic leak, and one patient suffered recurrent megacolon that required resection of an additional segment of colon. Four of the five survivors had excellent results.

Of the seven patients who underwent left hemicolectomy or total abdominal colectomy, two had serious postoperative complications, and two required resection of an additional segment of colon because of recurrent symptoms. All seven patients eventually had excellent results.

FAMILIAL

Familial Hirschsprung's disease: 20 cases in 12 kindreds.

Engum SA, Petrites M, Rescorla FJ, Grosfeld JL, Morrison AM, Engles D.

Department of Surgery, Indiana University School of Medicine, Indianapolis.
J Pediatr Surg 1993 Oct;28(10):1286-90 Abstract quote
This report describes 20 infants and children with a family history of Hirschsprung's disease in 12 kindreds.

A total of 260 patients were treated for Hirschsprung's disease (1972 to 1991), yielding a familial incidence of 8%. There were no families with consanguineous marriage. Sixteen patients were male and four were female. The mean age at diagnosis was 18 days. Clinical presentation included delayed passage of meconium in 15, abdominal distention in 11, vomiting in 9, feeding abnormalities in 3, and complete bowel obstruction in 1. Associated congenital anomalies occurred in 25% of the patients. The extent of aganglionosis was rectal in 4, sigmoid in 4, left colon in 2, transverse or right colon in 2, and total colonic in 8. Enterocolitis occurred in 7 patients (35%); 2 at diagnosis, 2 after an ostomy, and 3 after a pull-through procedure. There were no deaths associated with enterocolitis. All patients had a proximal diverting colostomy or ileostomy, and 19 of 20 underwent a definitive pull-through procedure. Three patients were lost to follow-up and one patient died of complications of multiple congenital anomalies unassociated with Hirschsprung's disease.

Of the remaining 16 patients, all of whom have undergone a pull-through procedure, 11 are fully continent, 2 have nighttime soiling, 2 are too young to evaluate bowel function, and 1 still has an ostomy.

SEGMENTAL

Hirschsprung's disease with skip area (segmental aganglionosis).

Martin LW, Buchino JJ, LeCoultre C, Ballard ET, Neblett WW.
J Pediatr Surg 1979 Dec;14(6):686-7 Abstract quote
Hirschsprung's disease is characterized by a single aganglionic segment of colon extending distally to the anal margin. Well documented reports of segmental aganglionosis have been rare.

We report a case of segmental aganglionosis in which there were two distinct aganglionic segments resected. The entire transverse colon between the two aganglionic segments was normally ganglionated, preserved, and utilized and functions in a normal fashion.

TOTAL COLONIC AGANGLIONOSIS

Entire colon aganglionosis, and extensive aganglionosis: analysis of 94 cases in Japan.

Suzuki H, Chiba T, Kasai M.
Jpn J Surg 1978 Jun;8(2):119-22 Abstract quote
Incidence, sex distribution, length of the involved bowel, associated malformations, treatment and operative results were analysed in 94 cases of entire colon aganglionosis, 87 of which were collected from 42 institutions in Japan and seven treated in our department. In this series, 62 were entire colon aganglionosis and 32 were extensive aganglionosis.

Incidence of entire colon aganglionosis was four per cent of all aganglionosis seen, and that of extensive aganglionosis was two per cent. Male: female ratio was 2:1 in cases with entire colon aganglionosis and 1.3:1 in extensive aganglionosis. Associated malformation was rare in both of entire colon, or extensive aganglionosis. Of the 94 cases, 41 cases survived neonatal period, and cure was obtained in 23 of entire colon aganglionosis and three of extensive aganglionosis.

Total colonic aganglionosis. Analysis of 16 cases.

Careskey JM, Weber TR, Grosfeld JL.
Am J Surg 1982 Jan;143(1):160-8 Abstract quote
Sixteen of 116 infants (14 percent) with Hirschsprung's disease had total colonic aganglionosis. Treatment was delayed in 6 of 16 patients because the condition was not recognized.

Diagnosis was eventually achieved by rectal biopsy and the extent of aganglionosis was documented after multiple intestinal biopsies. All patients were initially managed by diverting enterostomy. Ileoanal pull-through operation was performed in nine patients at 12 to 24 months of age with no operative mortality. The overall mortality rate was 25 percent, including the deaths of two infants with diagnostic delay. Survivors had normal growth and satisfactory bowel function, Hirschsprung's disease should be suspected and rectal biopsy performed in infants with persistent or intermittent abdominal distention and constipation. Instances of total colonic aganglionosis can be documented by appropriate biopsies at the time of laparotomy.

The modified Duhamel operation is an acceptable procedure for this condition. A ganglionic antimesenteric patch enteroplasty may prove a useful adjunct in infants with extensive aganglionosis involving the proximal small bowel.

Total colonic aganglionosis (with or without ileal involvement): a review of 27 cases.

N-Fekete C, Ricour C, Martelli H, Jacob SL, Pellerin D.
J Pediatr Surg 1986 Mar;21(3):251-4 Abstract quote
From 1960 to 1984, 27 cases of total colonic aganglionosis were treated at the Sick Children's Hospital in Paris; in 19 cases there was ileal involvement, 16 of them extending more than 15 cm above the ileocecal valve.

Five had a family history of Hirschsprung's disease. Nine infants died without having had definitive surgery, because of delayed diagnosis, or intractable malabsorption in extensive ileal aganglionosis. Two cases were diagnosed only at the ages of 6 and 13 years. Eleven children had Martin's modification of the Duhamel operation, the oldest of these being now 13 years old; and one girl aged 13 underwent a Swenson operation with ileoanal anastomosis, and one child has had a Kimura procedure. Four infants still have a diverting ileostomy. One out of the 14 operated children died 3 years after operation with fulminating enterocolitis. Late surgical nutritional results are analyzed with regard to the length of the side-to-side ileocolorectal anastomosis, and to the size of the ileorectal anastomosis, on which adequate pouch emptying depends.

The essential problem in total colonic aganglionosis is not the surgical management of the condition, but rather its prompt diagnosis and the handling of the neonatal intestinal obstruction.

HISTOLOGICAL TYPES CHARACTERIZATION

GENERAL

VARIANTS

SUBMUCOSAL HYPOGANGLIONOSIS

Submucosal hypoganglionosis causing chronic idiopathic intestinal pseudo-obstruction.

Von Boyen GB, Von der Ohe M, Krammer HJ, Singer MV.

Department of Medicine II (Gastroenterology), University Hospital of Heidelberg at Mannheim, Germany.
Indian J Gastroenterol 2002 Jan-Feb;21(1):29-30 Abstract quote
A 39-year-old woman presented with recurrent symptoms suggestive of intestinal obstruction.

She was put on total parenteral nutrition (TPN) and consequently developed sepsis and endocarditis. TPN was stopped and a venting enterostomy was performed. Biopsies of mucosa and submucosa were taken at surgery; immunohistochemistry for neuronal proteins, protein gene product 9.5 (PGP 9.5) and the glial S-100-protein was done.

Many enlarged nerve fiber strands were found in the submucosa. Few small ganglia containing a small number of nerve cells could be observed, suggesting hypoganglionosis.

his patient with chronic idiopathic intestinal pseudoobstruction of neurogenic type had a defect in the submucous plexus, whereas visceral neuropathies are usually characterized by defects of the myenteric plexus with normal submucous plexus.

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES

HYPOGANGLIONOSIS

Abnormalities of C-Kit-positive cellular network in isolated hypoganglionosis.

Rolle U, Yoneda A, Solari V, Nemeth L, Puri P.

Dublin, Ireland and Szeged, Hungary.
J Pediatr Surg 2002 May;37(5):709-14 Abstract quote
BACKGROUND/PURPOSE: C-Kit-positive interstitial cells of Cajal (ICCs) have a key role in the normal motility function and development of the bowel. They are pacemaker cells, which facilitate active propagation of electrical events and neurotransmission in the bowel wall. ICCs are present in the bowel as myenteric ICCs (ICC(my)S) and muscular ICCs (ICC(mus)S). The aim of this study was to examine the distribution of c-Kit-positive ICCs and their relationship to the autonomic intrinsic innervation in bowel specimens from patients with isolated hypoganglionosis.

METHODS: Full-thickness large bowel specimens were obtained from 6 patients with hypoganglionosis and from 4 patients during bladder augmentation (controls). Frozen sections and whole-mount preparations were stained using c-Kit immunohistochemistry, nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase, and acetylcholinesterase (AChE) histochemistry and evaluated using normal brightfield and confocal laser scanning microscopy.

RESULTS: NADPH-diaphorase and AChE histochemistry findings showed characteristic histologic features of hypoganglionosis, eg, sparse and small myenteric ganglia and low or absent AChE activity in the lamina propria. Myenteric plexus in the normal bowel was surrounded by a dense network of c-Kit-positive ICC(my)S, whereas in hypoganglionosis sparse isolated ICC(my)S were found. C-Kit-positive ICC(mus)S were reduced markedly in the longitudinal and circular muscle layer and at the innermost part of the circular muscle in hypoganglionosis.

CONCLUSION: Deficient expression of c-Kit-positive myenteric and muscular ICCs in the hypoganglionic colon may contribute to the motility dysfunction in the affected bowel.

PROGNOSIS AND TREATMENT CHARACTERIZATION

PROGNOSTIC FACTORS

GENERAL

Hirschprung's disease: long-term follow-up of 65 cases.

Cram RW.
Can J Surg 1982 Jul;25(4):435-7 Abstract quote
The author reviews 65 cases of Hirschsprung's disease seen and treated in Saskatoon between 1951 and 1981.

The annual incidence of this disease is 1/4000 live births. Overall mortality was 25% and related to two factors: (a) delay in diagnosis and surgical treatment with a high incidence of enterocolitis in the earlier years of the series; (b) a mortality of 83% in patients with small bowel aganglionosis. Thirty-five resections were done for colonic aganglionosis; there was one death that occurred 20 years ago, indicating that surgery is safe in this disease, but delay in treatment is not. Of six patients with small bowel aganglionosis, only three had resection and only one of these survived. The two patients who died had very high small bowel aganglionosis, probably incompatible with survival. The Rehbein type of procedure proved useful in high colonic aganglionosis where, by necessity, anastomosis was done at up to 7 cm above the white line of the pelvis, with excellent end results.

There was a 35% incidence of Hirschsprung's disease in females; 37% had high aganglionosis (above the sigmoid). Low (white line) anastomosis was done in three patients available for 12-year follow-up. All have some degree of incontinence.

Twenty-five years' experience with Hirschsprung's disease.

Foster P, Cowan G, Wrenn EL Jr.

Department of General Surgery, Rush-Presbyterian-St Luke's Medical Center, Chicago, IL 60612.
J Pediatr Surg 1990 May;25(5):531-4 Abstract quote
Sixty-three patients with biopsy-proven Hirschsprung's disease were diagnosed at LeBonheur Children's Medical Center, Memphis, TN between 1955 and 1980. Fifty-eight of these patients had pull-through procedures performed by three similarly trained pediatric surgeons.

The follow-up was 100 percent, averaging 8 years from initial diagnosis. Demographics, surgical procedures performed, and complications are reviewed. Significant findings are (1) anastomotic strictures occurred most frequently when the level of aganglionosis was at the sigmoid colon; (2) postoperative encopresis was most likely when the endorectal pull-through procedures were performed before the age of 10 months; and (3) with selective use of colostomies or enterostomies performed prior to the pull-through procedure, the incidence of enterocolitis was low, with 0% mortality. On the basis of these findings, we recommend that, when the most proximal level of aganglionosis is the sigmoid colon, it is important to critically inspect the angulation of mesenteric blood vessels and viability of the splenic flexure pull-through colon segment to prevent ischemia and therefore anastomotic strictures. The endorectal pull-through procedure should be delayed until after 10 months of age. Infants with Hirschsprung's disease should have a colostomy or enterostomy prior to a pull-through procedure.

Patients diagnosed at 10 months of age or more, who have not had earlier bouts of enterocolitis, are not low percentile weight, and are without signs of severe obstruction, are candidates for pull-through without a prior fecal diversion procedure.

Hirschsprung's disease. Evaluation of mortality and long-term function in 260 cases.

Rescorla FJ, Morrison AM, Engles D, West KW, Grosfeld JL.

Department of Surgery, Indiana University School of Medicine, Indianapolis.
Arch Surg 1992 Aug;127(8):934-41; discussion 941-2 Abstract quote
This report describes 260 patients treated for Hirschsprung's disease. There were 213 boys (82%) and 47 girls (18%).

Age at diagnosis was younger than 30 days in 106 patients (41%), 1 month to 1 year in 90 patients (35%), and older than 1 year in 64 patients (25%). Diagnosis was achieved with barium enema and rectal biopsy. Aganglionosis involved the rectum or rectosigmoid in 174 patients (67%), the left colon in 38 patients (15%), and the proximal colon in 23 patients (9%); 25 patients (9%) had total colonic aganglionosis. Enterocolitis occurred in 47 cases (18%). Following an initial colostomy or ileostomy, a definitive pull-through procedure was performed in 247 patients (95%) (modified Duhamel in 185, Soave in 25, Swenson procedure in 15, and anomyectomy/sphincterotomy in 22); the overall survival rate was 93.8% (244 of 260 patients). An increased mortality was associated with Down syndrome, total colonic aganglionosis, and enterocolitis. Long-term follow-up (mean, 6 years 10 months) was available in 103 patients who underwent a Duhamel procedure. Sixty-seven (65%) had normal bowel function, 28 (27%) occasionally used enemas or stool softeners, and eight (8%) had severe constipation or soiling. Bowel habits improved with time and were considered normal in 58% of patients at less than 5 years of follow-up and in 88% of patients at more than 15 years of follow-up.

The Duhamel operation is a very effective definitive procedure for Hirschsprung's disease. Long-term follow-up is an important component of patient care.

Gastrointestinal function after surgical correction of Hirschsprung's disease: long-term follow-up in 135 patients.

Marty TL, Seo T, Matlak ME, Sullivan JJ, Black RE, Johnson DG.

University of Utah, Primary Children's Medical Center, Salt Lake City 84113-1100, USA.

J Pediatr Surg 1995 May;30(5):655-8 Abstract quote.
This study is a retrospective review of all children treated for Hirschsprung's disease over the past 22 years at a single pediatric institution.

During this time 177 patients had definitive surgical reconstruction. Five children died of causes unrelated to Hirschsprung's disease, and five children died from enterocolitis after an uneventful postoperative course. Clinical follow-up information was obtained from 135 (78%). Demographic data includes the following: sex ratio 74% male, 26% female; current mean age 9.9 years; mean length of follow-up 7.9 years (range, 3 months to 21.5 years). Mean age at surgical reconstruction was 1.6 years. Definitive surgical procedures included endorectal pull-through (Soave), 21%; modified Duhamel, 67%; extended side-to-side ileocolic anastomosis, 8%; rectal myomectomy, 4%. Transition zone was within rectum or rectosigmoid region in 86%. Overall, 32% (43/135) report difficulty with fecal soiling, and 12.6% (17/135) identify this as a severe problem. These numbers include patients with trisomy 21 and total colonic aganglionosis. Severe fecal soiling was reported in 7.1% (2/28) after an endorectal pull-through, and in 12.1% (11/91) after the modified Duhamel. The difference in incidence of soiling after these two procedures is not statistically significant. However, 40% (4/10) of the patients after the long side-to-side anastomosis for total colonic aganglionosis report severe problems with fecal soiling (P = .03).

Surgical reconstruction for Hirschsprung's disease provides near-normal gastrointestinal function for the majority of children, but long-term follow-up shows significant residual problems with soiling in 12.6% of the patients. This is consistent with reported experience worldwide.

Altered distribution of interstitial cells of cajal in hirschsprung disease.

Rolle U, Piotrowska AP, Nemeth L, Puri P.

Children's Research Centre, Our Lady's Hospital for Sick Children, Dublin, Ireland (Drs Rolle and Piotrowska, and Mr Puri); Department of Paediatric Surgery, University of Szeged, Szeged, Hungary (Dr Nemeth).
Arch Pathol Lab Med 2002 Aug;126(8):928-33 Abstract quote
Context.-Constipation or recurrent intestinal dysmotility problems are common after definitive surgical treatment in Hirschsprung disease (HD). c-Kit-positive interstitial cells of Cajal (ICCs) play a key role in the motility function and development of the gastrointestinal tract. Interstitial cells of Cajal that carry the tyrosine kinase receptor (c-Kit) develop as either myenteric ICCs or muscular ICCs under the influence of the kit ligand, which can be provided by neuronal and nonneuronal cells, for example, smooth muscle cells.

Objective.-To investigate the distribution of myenteric and muscular ICCs in different parts of the colon in HD. Methods.-Resected bowel specimens from 8 patients with rectosigmoid HD were investigated using combined staining with c-Kit enzyme and fluorescence immunohistochemistry and acetylcholinesterase and nicotinamide adenine dinucleotide phosphate (NADPH) histochemistry in whole-mount preparations and conventional frozen sections.

Results.-In the normal bowel, ICCs formed a dense network surrounding the myenteric plexus and at the innermost part of the circular muscle. Myenteric ICCs were absent or sparse in the aganglionic bowel and sparse in the transitional zone. The expression of myenteric ICCs in the ganglionic bowel in HD was reduced compared to that in the normal bowel, and they formed only sparse networks. Muscular ICCs were found in the aganglionic bowel, transitional zone, and normoganglionic bowel of HD in a reduced density compared to the normal bowel.

Conclusion.-This study demonstrates altered distribution of ICCs in the entire resected bowel of HD patients. This finding suggests that persistent dysmotility problems after pull-through operation in HD may be due to altered distribution and impaired function of ICCs.

TREATMENT

GENERAL

Diagnosis and treatment of Hirschsprung's disease in Japan. An analysis of 1628 patients.

Ikeda K, Goto S.
Ann Surg 1984 Apr;199(4):400-5 Abstract quote
A nationwide survey on Hirschsprung's disease was conducted to clarify the recent trends of diagnosis and treatment of Hirschsprung's disease seen in Japan from 1978 to 1982. A total number of 1628 cases were collected from 135 medical institutions. Estimated incidence of Hirschsprung's disease was 1/4697. In diagnosis, anorectal manometry was carried out in 64.7% of the patients and histochemistry in 28.7%. Barium enema with manometry was most frequently used in combination of the methods. A total of 48.7% of the patients were diagnosed in the first month of life. The overall rate of creation of colostomy was 61.3% in aganglionosis extended to the sigmoid colon. Retrorectal transanal pull-through was used most frequently at 57.4%, including Z-shaped anastomosis at 30.4%, then endorectal pull-through at 27.6% as the definitive operation. Considerably high incidence (12.1%-33.7%) of postoperative enterocolitis was noted after major operative procedures, but the mortality rate was low (1.8%-2.4%) except total colonic with or without small bowel aganglionosis. The large number of patients studied in the present survey reveals that there still is much room for improvement in the diagnosis and treatment of Hirschsprung's disease, especially in total colonic with or without small bowel aganglionosis.

Eighteen years' experience with neonatal Hirschsprung's disease treated by endorectal pull-through without colostomy.

So HB, Becker JM, Schwartz DL, Kutin ND.

Long Island Jewish Medical Center, Schneider Children's Hospital, New Hyde Park, NY, USA.
J Pediatr Surg 1998 May;33(5):673-5 Abstract quote
METHODS: In the past 18 years, the authors have treated 84 patients with Hirschsprung's disease. Of these, 43 patients were under 1 month of age and underwent endorectal pull-through without colostomy. Some have undergone follow-up for as long as 18 years.

RESULTS: Thirty-four of these 43 (79%) newborn patients were available for follow-up. Twenty-two were totally continent. The remaining 12 have normal sphincter tone. Of the 41 patients above 1 month of age, 34 (83%) were available for follow-up. Some have undergone follow-up for as long as 18 years.

CONCLUSION: Twenty-two of this latter group (79%) have normal bowel control.

SWENSON PROCEDURE

Long-term outcome and quality of life after the Swenson procedure for Hirschsprung's disease.

Bai Y, Chen H, Hao J, Huang Y, Wang W.

Department of Pediatric Surgery, The Second Clinical College, China Medical University, Shenyang, China.
J Pediatr Surg 2002 Apr;37(4):639-42 Abstract quote
BACKGROUND/PURPOSE: The aim of this study was to investigate long-term outcome and quality of life after the Swenson operation for rectosigmoid Hirschsprung's Disease (HD).

METHODS: Forty-five patients who underwent the Swenson procedure for HD underwent follow-up for 8 to 16 years. Long-term outcome and quality of life were assessed by interviews and questionnaires including scoring systems. Forty-four healthy children with similar age, sex, and education level distributions used as controls.

RESULTS: In 45 patients, 23 (51.1%) had bowel dysfunction. Seventeen patients (37.8%) suffered from fecal soiling. According to the clinical bowel function scoring system, the patients' scores (7.6 +/- 2.1) were significantly lower than those of the controls (11.4 +/- 0.6; P <.05). Because of poor fecal continence, 25 patients (55.7%) had to restrict their foods. School absence occurred in 6 (13.3%) patients. Seven patients (15.6%) had problems in peer relationships. According to the Quality-of-Life Scoring Criteria, 86.7% patients had good or fair quality of life. The patients' scores (7.7 +/- 2.9) were significantly lower than those of the controls (11.6 +/- 0.7; P <.05). And the scores of patients who had fecal soiling and incontinence (6.3 +/- 2.7) were significantly lower than those of patients without fecal soiling and incontinence (8.4 +/- 2.6; P <.05).

CONCLUSIONS: Although most patients had good or fair quality of life after surgical correction for HD, the long-term outcome and quality of life are not as good as surgeons expected. The bowel function and quality of life of the patients were poorer than those of healthy children. Fecal soiling is very common and affects patients' quality of life. Long-term regular follow-up is indispensable. Close attention should be paid to minimizing bowel dysfunction for patients with HD postoperatively to improve their quality of life.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.

Commonly Used Terms

Colon

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Last Updated 11/7/2002

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PATHOGENESIS	CHARACTERIZATION
CARBON MONOXIDE PRODUCING NEURONS
Distribution of carbon monoxide-producing neurons in human colon and in Hirschsprung's disease patients. Chen Y, Lui VC, Sham MH, Tam PK. Division of Paediatric Surgery, Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, and Department of Biochemistry, University of Hong Kong, Hong Kong SAR, China.	Hum Pathol 2002 Oct;33(10):1030-6 Abstract quote Hirschsprung's disease (HSCR) is characterized by the absence of ganglion cells and impaired relaxation of the gut. Nitric oxide (NO) and, more recently, carbon monoxide (CO) have been identified as inhibitory neurotransmitters causing relaxation. A deficiency in NO has been reported in aganglionic gut; we hypothesized that CO could also be involved in impaired gut motility in HSCR. The aim of the study was to determine the distribution of CO-and NO-producing enzymes in the normal and aganglionic gut. We performed laser capture microdissection, reverse transcription-polymerase chain reaction, and immunohistochemistry on colon biopsies of normal controls (n = 9) and patients with HSCR (n = 10). The mRNA expression of heme oxygenase-2 (HO-2), immunoreactivities of HO-2 and NO synthase, was determined and compared. Results show a high level of expression of HO-2 mRNA localized in the myenteric plexus. Expression of HO-2 mRNA was also detected in the mucosa, submucosa, and muscular layer. Down-regulation of HO-2 mRNA expression was detected in the aganglionic colon. Immunoreactivities of HO-2 and NO synthase were localized mainly to the ganglion plexus and to nerve fibers within the muscle in the control colons and normoganglionic colons. HO-2-containing neurons were more abundant than NO synthase-containing neurons in the myenteric plexus. Nearly all of the NO synthase-containing neurons also contained HO-2. HO-2 and NO synthase were selectively absent in the myenteric and submucosal regions and in the muscle of the aganglionic colon. Our findings suggest involvement of both CO and NO in the pathophysiology of HSCR.
CHROMOSOMAL ABNORMALITIES
Segregation at three loci explains familial and population risk in Hirschsprung disease. Gabriel SB, Salomon R, Pelet A, Angrist M, Amiel J, Fornage M, Attie-Bitach T, Olson JM, Hofstra R, Buys C, Steffann J, Munnich A, Lyonnet S, Chakravarti A. Department of Genetics and Center for Human Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.	Nat Genet 2002 May;31(1):89-93 Abstract quote Hirschsprung disease (HSCR), the most common hereditary cause of intestinal obstruction, shows considerable variation and complex inheritance. Coding sequence mutations in RET, GDNF, EDNRB, EDN3 and SOX10 lead to long-segment (L-HSCR) and syndromic HSCR but fail to explain the transmission of the much more common short-segment form (S-HSCR). We conducted a genome scan in families with S-HSCR and identified susceptibility loci at 3p21, 10q11 and 19q12 that seem to be necessary and sufficient to explain recurrence risk and population incidence. The gene at 10q11 is probably RET, supporting its crucial role in all forms of HSCR; however, coding sequence mutations are present in only 40% of linked families, suggesting the importance of noncoding variation. Here we show oligogenic inheritance of S-HSCR, the 3p21 and 19q12 loci as RET-dependent modifiers, and a parent-of-origin effect at RET. This study demonstrates by a complete genetic dissection why the inheritance pattern of S-HSCR is nonmendelian.
L1CAM
Hydrocephalus and intestinal aganglionosis: Is L1CAM a modifier gene in Hirschsprung disease? Parisi MA, Kapur RP, Neilson I, Hofstra RM, Holloway LW, Michaelis RC, Leppig KA. Division of Genetics and Development, Department of Pediatrics, University of Washington and Children's Hospital and Regional Medical Center, Seattle, Washington.	Am J Med Genet 2002 Feb 15;108(1):51-6 Abstract quote Congenital hydrocephalus associated with aqueductal stenosis and/or agenesis of the corpus callosum has been described in newborn males with mutations in L1CAM, a gene that encodes a neural cell adhesion molecule. These males usually have severe mental retardation and may have spastic paraplegia and adducted thumbs. In contrast, Hirschsprung disease, or absence of ganglion cells in the distal gut, has rarely been described in such individuals. We report a male infant who had severe hydrocephalus identified in the prenatal period with evidence of aqueductal stenosis and adducted thumbs at birth. He developed chronic constipation, and rectal biopsy confirmed the diagnosis of Hirschsprung disease. Molecular testing of the L1CAM gene revealed a G2254A mutation, resulting in a V752M amino acid substitution. A common polymorphism in RET, but no mutation, was identified. Our patient represents the third example of coincident hydrocephalus and Hirschsprung disease in an individual with an identified L1CAM mutation. We hypothesize that L1CAM-mediated cell adhesion may be important for the ability of ganglion cell precursors to populate the gut, and that L1CAM may modify the effects of a Hirschsprung disease-associated gene to cause intestinal aganglionosis.
NEUROTRANSMITTERS
Widespread changes in neurotransmitter expression and number of enteric neurons and interstitial cells of Cajal in lethal spotted mice: an explanation for persisting dysmotility after operation for Hirschsprung's disease? Sandgren K, Larsson LT, Ekblad E. Department of Pediatrics, Lund University Hospital, Sweden.	Dig Dis Sci 2002 May;47(5):1049-64 Abstract quote Gastrointestinal motor dysfunction persists in a large number of children subjected to surgical treatment for Hirschsprung's disease, indicating abnormalities in the remaining intestine. The aim of the study was to detect possible alterations in frequency and topographic distribution of enteric neurons and interstitial cells of Cajal in an experimental model (the lethal spotted mouse displaying a short rectal aganglionosis) for Hirschsprung's disease. Specimens from the intestinal tract from homozygous (aganglionic) and heterozygous (healthy littermates) were examined using histochemistry, in situ hybridization, and immunohistochemistry. In ileum and colon, ie, regions proximal to the aganglionosis, changes in the expression of neuropeptides and neuronal nitric oxide synthase and in the number of enteric neurons and interstitial cells of Cajal could be detected in homozygous versus heterozygous mice. The described changes are suggested to contribute to the dysmotility remaining after surgical resection of the aganglionic segment in Hirschsprung's disease.
SMOOTH MUSCLE ABNORMALITIES
Altered cytoskeleton in smooth muscle of aganglionic bowel. Nemeth L, Rolle U, Puri P. Children's Research Centre, Our Lady's Hospital for Sick Children, Dublin, Ireland (Drs Nemeth, Rolle, and Puri); and the Department of Paediatric Surgery, University of Szeged, Szeged, Hungary (Dr Nemeth).	Arch Pathol Lab Med 2002 Jun;126(6):692-6 Abstract quote Context.-Intestinal motility is under the control of smooth muscle cells, enteric plexus, and hormonal factors. In Hirschsprung disease (HD), the aganglionic colon remains spastic or tonically enhanced and unable to relax. The smooth muscle cell's cytoskeleton consists of proteins or structures whose primary function is to link or connect protein filaments to each other or to the anchoring sites. Dystrophin is a subsarcolemmal protein with a double adhesion property, one between the membrane elements and the contractile filaments of the cytoskeleton and the other between the cytoskeletal proteins and the extracellular matrix. Desmin and vinculin are functionally related proteins that are present in the membrane-associated dense bodies in the sarcolemma of the smooth muscle cells. Objective.-To examine the distribution of the cytoskeletal proteins in the smooth muscle of the aganglionic bowel. Design.-Bowel specimens from ganglionic and aganglionic sections of the colon were collected at the time of pull-through surgery from 8 patients with HD. Colon specimens collected from 4 patients at the time of bladder augmentation acted as controls. Anti-dystrophin, anti-desmin, and anti-vinculin antibodies were used for fluorescein immunostaining using confocal laser scanning microscopy. Results.-Moderate to strong dystrophin immunoreactivity was observed at the periphery of smooth muscle fibers in normal bowel and ganglionic bowel from patients with HD, whereas dystrophin immunoreactivity was either absent or weak in the smooth muscle of aganglionic colon. Moderate to strong cytoplasmic immunostaining for vinculin and desmin was seen in the smooth muscle of normal bowel and ganglionic bowel from patients with HD, whereas vinculin and desmin staining in the aganglionic colon was absent or weak. Conclusion.-This study demonstrates that the cytoskeletal proteins are abundant in the smooth muscle of normal bowel, but are absent or markedly reduced in the aganglionic bowel of HD. As cytoskeletal proteins are required for the coordinated contraction of muscle cells, their absence may be responsible for the motility dysfunction in the aganglionic segment.

LABORATORY/RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
Adult Hirschprung disease: radiographic findings. Mindelzun RE, Hicks SM.	Radiology 1986 Sep;160(3):623-5 Abstract quote Hirschprung disease is usually diagnosed in infancy. Occasionally patients reach adulthood without diagnosis or treatment. Four cases of adult Hirschprung disease are described. The principal radiographic findings are a markedly dilated, feces-filled colon above the zone of transition; a narrowed rectum; a cone- or funnel-shaped zone of transition; and a mosaic colonic pattern caused by collapsed redundant mucosa after colonic cleansing. In an adult, identification on a barium enema examination of an abrupt, smooth transition zone in the rectum with proximal colonic dilatation, in conjunction with an appropriate clinical history, should suggest the diagnosis of adult Hirschprung disease.
LABORATORY MARKERS
ELECTROMYOGRAPHY
Electromyography of the rectum and colon in Hirschsprung's disease. Marin AM, Rivarola A, Garcia H.	J Pediatr Surg 1976 Aug;11(4):547-552 Abstract quote The electromyographic activity of the large bowel was studied in patients suffering from aganglionic megacolon and in comparable normal infants and children, using of an intraluminal electrode. Graphs obtained in control children showed a basic electrical rhythm of 4-6 waves/min with bursts of high frequency spikes, 3-4/sec, superimposed on the top of the slow waves. The recordings in Hirschprung's disease showed an irregular basic electrical rhythm with waves of variable duration and no high frequency potentials, as long as the electrode was positioned in the aganglionic zone. As soon as the electrode was introduced further up into the normally innervated colon the graph became identical to that seen in the normal bowel. Intraluminal electromyography of the rectum and colon seems to be a suitable procedure to diagnose aganglionosis of the rectum and the extent of the lesion.

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
VARIANTS
ADULT
Adult Hirschsprung's disease: results of surgical treatment at Mayo Clinic. McCready RA, Beart RW Jr.	Dis Colon Rectum 1980 Sep;23(6):401-7 Abstract quote Fifty adult patients with Hirschsprung's disease were operated on at the Mayo Clinic between 1950 and 1978. Six different operations were used. Of the three patients treated by the Soave endorectal pull-through procedure, two suffered anastomotic leaks and required diverting colostomies; all three had excellent long-term results, however. All four patients who underwent the Duhamel procedure had excellent results, with only one minor complication. Of the 17 patients undergoing the Swenson procedure, 6 had major postoperative complications, including 2 with impotence; 3 (17.6 per cent) patients who underwent rectal myectomy, there was one minor complication, although 5 (38.5 per cent) had unsatisfactory results. Six patients had anterior resection, one of whom died of generalized peritonitis from an anastomotic leak, and one patient suffered recurrent megacolon that required resection of an additional segment of colon. Four of the five survivors had excellent results. Of the seven patients who underwent left hemicolectomy or total abdominal colectomy, two had serious postoperative complications, and two required resection of an additional segment of colon because of recurrent symptoms. All seven patients eventually had excellent results.
FAMILIAL
Familial Hirschsprung's disease: 20 cases in 12 kindreds. Engum SA, Petrites M, Rescorla FJ, Grosfeld JL, Morrison AM, Engles D. Department of Surgery, Indiana University School of Medicine, Indianapolis.	J Pediatr Surg 1993 Oct;28(10):1286-90 Abstract quote This report describes 20 infants and children with a family history of Hirschsprung's disease in 12 kindreds. A total of 260 patients were treated for Hirschsprung's disease (1972 to 1991), yielding a familial incidence of 8%. There were no families with consanguineous marriage. Sixteen patients were male and four were female. The mean age at diagnosis was 18 days. Clinical presentation included delayed passage of meconium in 15, abdominal distention in 11, vomiting in 9, feeding abnormalities in 3, and complete bowel obstruction in 1. Associated congenital anomalies occurred in 25% of the patients. The extent of aganglionosis was rectal in 4, sigmoid in 4, left colon in 2, transverse or right colon in 2, and total colonic in 8. Enterocolitis occurred in 7 patients (35%); 2 at diagnosis, 2 after an ostomy, and 3 after a pull-through procedure. There were no deaths associated with enterocolitis. All patients had a proximal diverting colostomy or ileostomy, and 19 of 20 underwent a definitive pull-through procedure. Three patients were lost to follow-up and one patient died of complications of multiple congenital anomalies unassociated with Hirschsprung's disease. Of the remaining 16 patients, all of whom have undergone a pull-through procedure, 11 are fully continent, 2 have nighttime soiling, 2 are too young to evaluate bowel function, and 1 still has an ostomy.
SEGMENTAL
Hirschsprung's disease with skip area (segmental aganglionosis). Martin LW, Buchino JJ, LeCoultre C, Ballard ET, Neblett WW.	J Pediatr Surg 1979 Dec;14(6):686-7 Abstract quote Hirschsprung's disease is characterized by a single aganglionic segment of colon extending distally to the anal margin. Well documented reports of segmental aganglionosis have been rare. We report a case of segmental aganglionosis in which there were two distinct aganglionic segments resected. The entire transverse colon between the two aganglionic segments was normally ganglionated, preserved, and utilized and functions in a normal fashion.
TOTAL COLONIC AGANGLIONOSIS
Entire colon aganglionosis, and extensive aganglionosis: analysis of 94 cases in Japan. Suzuki H, Chiba T, Kasai M.	Jpn J Surg 1978 Jun;8(2):119-22 Abstract quote Incidence, sex distribution, length of the involved bowel, associated malformations, treatment and operative results were analysed in 94 cases of entire colon aganglionosis, 87 of which were collected from 42 institutions in Japan and seven treated in our department. In this series, 62 were entire colon aganglionosis and 32 were extensive aganglionosis. Incidence of entire colon aganglionosis was four per cent of all aganglionosis seen, and that of extensive aganglionosis was two per cent. Male: female ratio was 2:1 in cases with entire colon aganglionosis and 1.3:1 in extensive aganglionosis. Associated malformation was rare in both of entire colon, or extensive aganglionosis. Of the 94 cases, 41 cases survived neonatal period, and cure was obtained in 23 of entire colon aganglionosis and three of extensive aganglionosis.
Total colonic aganglionosis. Analysis of 16 cases. Careskey JM, Weber TR, Grosfeld JL.	Am J Surg 1982 Jan;143(1):160-8 Abstract quote Sixteen of 116 infants (14 percent) with Hirschsprung's disease had total colonic aganglionosis. Treatment was delayed in 6 of 16 patients because the condition was not recognized. Diagnosis was eventually achieved by rectal biopsy and the extent of aganglionosis was documented after multiple intestinal biopsies. All patients were initially managed by diverting enterostomy. Ileoanal pull-through operation was performed in nine patients at 12 to 24 months of age with no operative mortality. The overall mortality rate was 25 percent, including the deaths of two infants with diagnostic delay. Survivors had normal growth and satisfactory bowel function, Hirschsprung's disease should be suspected and rectal biopsy performed in infants with persistent or intermittent abdominal distention and constipation. Instances of total colonic aganglionosis can be documented by appropriate biopsies at the time of laparotomy. The modified Duhamel operation is an acceptable procedure for this condition. A ganglionic antimesenteric patch enteroplasty may prove a useful adjunct in infants with extensive aganglionosis involving the proximal small bowel.
Total colonic aganglionosis (with or without ileal involvement): a review of 27 cases. N-Fekete C, Ricour C, Martelli H, Jacob SL, Pellerin D.	J Pediatr Surg 1986 Mar;21(3):251-4 Abstract quote From 1960 to 1984, 27 cases of total colonic aganglionosis were treated at the Sick Children's Hospital in Paris; in 19 cases there was ileal involvement, 16 of them extending more than 15 cm above the ileocecal valve. Five had a family history of Hirschsprung's disease. Nine infants died without having had definitive surgery, because of delayed diagnosis, or intractable malabsorption in extensive ileal aganglionosis. Two cases were diagnosed only at the ages of 6 and 13 years. Eleven children had Martin's modification of the Duhamel operation, the oldest of these being now 13 years old; and one girl aged 13 underwent a Swenson operation with ileoanal anastomosis, and one child has had a Kimura procedure. Four infants still have a diverting ileostomy. One out of the 14 operated children died 3 years after operation with fulminating enterocolitis. Late surgical nutritional results are analyzed with regard to the length of the side-to-side ileocolorectal anastomosis, and to the size of the ileorectal anastomosis, on which adequate pouch emptying depends. The essential problem in total colonic aganglionosis is not the surgical management of the condition, but rather its prompt diagnosis and the handling of the neonatal intestinal obstruction.

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Differential Diagnosis
Prognosis and Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
SEX (M:F)	Males favored

DISEASE ASSOCIATIONS	CHARACTERIZATION
DOWN SYNDROME
MEN SYNDROMES
RET mutation profile and variable clinical manifestations in a family with multiple endocrine neoplasia type 2A and Hirschsprung's disease. Pasini B, Rossi R, Ambrosio MR, Zatelli MC, Gullo M, Gobbo M, Collini P, Aiello A, Pansini G, Trasforini G, degli Uberti EC. Department of Biomedical Sciences and Advanced Therapies, Section of Endocrinology, University of Ferrara, Via Savonarola 9, I-44100 Ferrara, Italy.	Surgery 2002 Apr;131(4):373-81 Abstract quote BACKGROUND: RET proto-oncogene germ line mutations are associated with the inherited multiple endocrine neoplasia type 2 syndromes (MEN 2), as well as with familial and sporadic Hirschsprung's disease (HSCR). In this study, we report a family in which the MEN 2A and the HSCR phenotypes are associated with a single point mutation in exon 10 of the RET proto-oncogene. Furthermore, we have investigated polymorphic sequence variants of the RET proto-oncogene. METHODS: Family members were tested for RET proto-oncogene mutations in exons 10, 11, 13, 14, 15, and 16 by double-gradient denaturing-gradient gel electrophoresis, nucleotide sequence analysis, and restriction endonuclease digestion of polymerase chain reaction products. The status of exon 2 and 13 polymorphic sites was investigated by EagI and TaqI digestion in 12 selected patients. RESULTS: A heterozygous C618R mutation of RET exon 10 was identified in 12 family members. Five out of 7 children with mildly elevated pentagastrin-stimulated calcitonin levels who carried the mutation underwent prophylactic thyroidectomy before the age of 12. C-cell hyperplasia (CCH) was found in 4 children and a microscopic medullary thyroid carcinoma (MTC) in an 8-year-old female. Neither CCH nor MTC was found in the only family member affected with HSCR, an 8-year-old male. This patient inherited the mutated RET allele from his mother, who had MTC but not HSCR, together with a rare allelic variant at codon 45 of RET exon 2. CONCLUSIONS: This report of a newly-described kindred with the infrequent clinical association between MEN 2A and HSCR confirms the risk of the latter phenotype among carriers of RET exon 10 cysteine codon mutations. Nevertheless, the influence of other genetic or environmental factors cannot be excluded.
MOWAT-WILSON SYNDROME
"Mowat-Wilson" syndrome with and without Hirschsprung disease is a distinct, recognizable multiple congenital anomalies-mental retardation syndrome caused by mutations in the zinc finger homeo box 1B gene. Zweier C, Albrecht B, Mitulla B, Behrens R, Beese M, Gillessen-Kaesbach G, Rott HD, Rauch A. Institute of Human Genetics, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.	Am J Med Genet 2002 Mar 15;108(3):177-81 Abstract quote Recently mutations in the gene ZFHX1B (SIP1) were shown in patients with "syndromic Hirschsprung disease" with mental retardation (MR) and multiple congenital anomalies (MCA), but it was unclear if Hirschsprung disease is an obligate symptom of these mutations and if the distinct facial phenotype delineated by Mowat et al. [1998: J Med Genet 35: 617-623] is specific for ZFHX1B mutations. In order to address these open questions we analyzed the ZFHX1B gene in five patients, three of whom had "syndromic Hirschsprung disease" two with and one without the facial phenotype described by Mowat et al. [1998], and two of whom had the distinct facial gestalt without Hirschsprung disease. Analyses of microsatellite markers and newly identified SNPs, and/or FISH with BACs from the ZFHX1B region excluded large deletions in all five patients. Direct sequencing demonstrated truncating ZFHX1B mutations in all four patients with the characteristic facial phenotype, but not in the patient with syndromic Hirschsprung disease without the distinct facial appearance. We demonstrate that there is a specific clinical entity with a recognizable facial gestalt, mental retardation and variable MCAs which we propose be called the "Mowat-Wilson syndrome."

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
VARIANTS
SUBMUCOSAL HYPOGANGLIONOSIS
Submucosal hypoganglionosis causing chronic idiopathic intestinal pseudo-obstruction. Von Boyen GB, Von der Ohe M, Krammer HJ, Singer MV. Department of Medicine II (Gastroenterology), University Hospital of Heidelberg at Mannheim, Germany.	Indian J Gastroenterol 2002 Jan-Feb;21(1):29-30 Abstract quote A 39-year-old woman presented with recurrent symptoms suggestive of intestinal obstruction. She was put on total parenteral nutrition (TPN) and consequently developed sepsis and endocarditis. TPN was stopped and a venting enterostomy was performed. Biopsies of mucosa and submucosa were taken at surgery; immunohistochemistry for neuronal proteins, protein gene product 9.5 (PGP 9.5) and the glial S-100-protein was done. Many enlarged nerve fiber strands were found in the submucosa. Few small ganglia containing a small number of nerve cells could be observed, suggesting hypoganglionosis. his patient with chronic idiopathic intestinal pseudoobstruction of neurogenic type had a defect in the submucous plexus, whereas visceral neuropathies are usually characterized by defects of the myenteric plexus with normal submucous plexus.