Hirschsprung's Disease Hirschsprung's disease occurs in 1 out of every 5000 live births and is characterized pathologically by absent ganglion cells in the myenteric (Auerbach's) and submucosal (Meissner's) plexus. This neurogenic abnormality is associated with muscular spasm of the distal colon and internal anal sphincter resulting in a functional obstruction. Hence, the abnormal bowel is the contracted, distal segment, whereas the normal bowel is the proximal, dilated portion. The area between the dilated and contracted segments is referred to as the transition zone. In this area, ganglion cells begin to appear, but in reduced numbers. The aganglionosis always involves the distal rectum and extends proximally for variable distances. The rectosigmoid is affected in roughly 75% of cases, splenic flexure or transverse colon in 17%, and the entire colon with variable extension into the small bowel in 8%. The risk for Hirschsprung's disease is greater if there is a positive family history and in patients with Down syndrome.Clinical Presentation Most infants with Hirschsprung's disease have symptoms within the first 24 hours of life with progressive abdominal distention and bilious emesis. Failure to pass meconium in the first 24 hours is a highly significant and cardinal feature of this condition. In some infants, diarrhea may develop as a result of enterocolitis. The diagnosis of Hirschsprung's disease may also be overlooked for prolonged periods. In these cases, older children may present with a history of poor feeding, chronic abdominal distention, and a history of significant constipation. Because constipation is a common problem among normal children, referral for surgical biopsy to exclude Hirschsprung's disease occurs relatively frequently. Enterocolitis is the most common cause of death in patients with uncorrected Hirschsprung's disease and may manifest as diarrhea alternating with periods of obstipation, abdominal distention, fever, hematochezia, and peritonitis.Diagnosis The initial diagnostic step in a newborn with radiographic evidence of a distal bowel obstruction is a barium enema. Before this study, rectal examination and enemas are avoided so that they do not interfere with the identification of a transition zone. In a normal barium enema study, the rectum is wider than the sigmoid colon. In patients with Hirschsprung's disease, spasm of the distal rectum usually results in a smaller caliber when compared with the more proximal sigmoid colon. Identification of a transition zone may be quite helpful ( Fig. 71-13 ); however, determination of the location of the transition zone is considered to be relatively inaccurate. Failure to completely evacuate the instilled contrast material after 24 hours would also be consistent with Hirschsprung's disease and may provide additional diagnostic yield. An important goal of this study is to exclude other causes of constipation in the newborn, such as meconium plug, small left colon syndrome, and atresia.

Figure 71-13 Hirschsprung's disease. A barium enema demonstrating the zone of transition (arrows) from the dilated proximal normal colon to the reduced caliber of the distal aganglionic colonAnorectal manometry may also suggest the diagnosis of Hirschsprung's disease. The classic finding is failure of the internal sphincter to relax when the rectum is distended with a balloon. The advantage of this method is that it can be done in an outpatient setting, without the need for general anesthesia. This is more often useful in an older patient and is seldom used in neonates.A rectal biopsy is the gold standard for the diagnosis of Hirschsprung's disease. In the newborn period, this is done at the bedside with minimal morbidity using a special suction rectal biopsy instrument. It is important to obtain the sample at least 2 cm above the dentate line to avoid sampling the normal transition from ganglionated bowel to the paucity or absence of ganglia in the region of the internal sphincter. In older children, because the rectal mucosa is thicker, a full-thickness biopsy is obtained under general anesthesia. Absent ganglia, hypertrophied nerve trunks, and robust immunostaining for acetylcholinesterase are the pathologic criteria to make the diagnosis.Surgical Management Multiple surgical options exist for the management of Hirschsprung's disease. Traditionally, a leveling procedure is done, followed by proximal diversion. This consists of a formal laparotomy, which is usually performed through a small incision in the left lower quadrant of the abdomen. The location of the transition zone is then identified and confirmed by multiple seromuscular biopsies. A diverting colostomy is then performed in the region of normal ganglionated bowel. A definitive procedure is then performed later.The definitive management of Hirschsprung's disease involves variations among three main procedures. In the Swenson procedure, the aganglionic bowel is removed down to the level of the internal sphincters and a coloanal anastomosis is performed on the perineum. In the Duhamel procedure, the aganglionic rectal stump is left in place, and the ganglionated, normal colon is pulled behind this stump. A GIA stapler is then inserted through the anus with one arm within the normal, ganglionated bowel posteriorly and the other in the aganglionic rectum anteriorly. Firing of the stapler therefore results in formation of a neorectum that empties normally because of the posterior patch of ganglionated bowel. Finally, the Soave technique involves an endorectal mucosal dissection within the aganglionic distal rectum. The normally ganglionated colon is then pulled through the remnant muscular cuff and a coloanal anastomosis performed. More recently, these procedures have been performed in the newborn period as a primary procedure and without an initial ostomy. Further, the same procedure has been described in infants completely through a transanal approach with or without laparoscopic guidance.[27] The overall survival of patients with Hirschsprung's disease is excellent; however, long-term stooling problems are not infrequent. Constipation is the most frequent postoperative problem followed by soiling, incontinence, and enterocolitis.SABISTON

Hirschsprung's DiseasePathogenesisIn his classic textbook entitled Pediatric Surgery, Dr. Orvar Swenson, who is eponymously associated with one of the classic surgical treatments for Hirschsprung's disease, described this condition as follows: "Congenital megacolon is caused by a malformation in the pelvic parasympathetic system which results in the absence of ganglion cells in Auerbach's plexus of a segment of distal colon. Not only is there an absence of ganglion cells, but the nerve fibers are large and excessive in number, indicating that the anomaly may be more extensive than the absence of ganglion cells." This description of Hirschsprung's disease is as accurate today as it was >50 years ago and summarizes the essential pathologic features of this disease: absence of ganglion cells in Auerbach's plexus and hypertrophy of associated nerve trunks. The cause of Hirschsprung's disease remains incompletely understood, although current thinking is that the disease results from a defect in the migration of neural crest cells, which are the embryonic precursors of the intestinal ganglion cell. Under normal conditions, the neural crest cells migrate into the intestine from cephalad to caudad. The process is completed by the twelfth week of gestation, but the migration from midtransverse colon to anus takes 4 weeks. During this latter period, the fetus is most vulnerable to defects in migration of neural crest cells. This may explain why most cases of aganglionosis involve the rectum and rectosigmoid. The length of the aganglionic segment of bowel is therefore determined by the most distal region that the migrating neural crest cells reach. In rare instances, total colonic aganglionosis may occur.Recent studies have shed light on the molecular basis for Hirschsprung's disease. Patients with Hirschsprung's disease have an increased frequency of mutations in several genes, including GDNF, its receptor Ret, and its coreceptor Gfra-1. Moreover, mutations in these genes also lead to aganglionic megacolon in mice, which provides the opportunity to study the function of the encoded proteins. Initial investigations indicate that GDNF promotes the survival, proliferation, and migration of mixed populations of neural crest cells in culture. Other studies have revealed that GDNF is expressed in the gut in advance of migrating neural crest cells and is chemoattractive for neural crest cells in culture. These findings raise the possibility that mutations in the GDNF or Ret genes could lead to impaired neural crest migration in utero and the development of Hirschsprung's disease.Clinical PresentationThe incidence of sporadic Hirschsprung's disease is 1 in 5000 live births. There are reports of increased frequency of Hirschsprung's disease in multiple generations of the same family, especially in families with long-segment Hirschsprung's disease. Occasionally, such families have mutations in the genes described earlier, including the Ret gene. Because normal peristalsis cannot occur in the aganglionic colon, children with Hirschsprung's disease present with a functional distal intestinal obstruction. In the newborn period, the most common symptoms are abdominal distention, failure to pass meconium, and bilious emesis. Any infant who does not pass meconium by 48 hours from birth must be investigated for the presence of Hirschsprung's disease. Occasionally, infants present with a dramatic complication of Hirschsprung's disease called enterocolitis. This pattern of presentation is characterized by abdominal distention and tenderness, and is associated with manifestations of systemic toxicity that include fever, failure to thrive, and lethargy. Infants are often dehydrated and demonstrate leukocytosis or an increase in circulating band forms on hematologic evaluation. On rectal examination, forceful expulsion of foul-smelling liquid feces is typically observed and represents the accumulation of stool under pressure in an obstructed distal colon. Treatment includes rehydration, systemic antibiotics, nasogastric decompression, and rectal irrigations while the diagnosis of Hirschsprung's disease is being confirmed. In children who do not respond to nonoperative management, a decompressive stoma is required. The surgeon must ensure that this stoma is placed in ganglion-containing bowel, and this must be confirmed by frozen-section analysis of bowel tissue performed at the time of stoma creation.In approximately 20% of cases, the diagnosis of Hirschsprung's disease is made beyond the newborn period. These children have severe constipation, which has usually been treated with laxatives and enemas. Abdominal distention and failure to thrive may also be present at diagnosis.DiagnosisThe definitive diagnosis of Hirschsprung's disease is made by rectal biopsy. Samples of mucosa and submucosa are obtained at 1 cm, 2 cm, and 3 cm from the dentate line. In the neonatal period this biopsy can be performed at the bedside without anesthesia, because samples are taken in bowel that does not have somatic innervation and thus the procedure is not painful to the child. In older children, the procedure should be performed as an open rectal biopsy using IV sedation. The histopathologic features of Hirschsprung's disease are the absence of ganglion cells in the myenteric plexuses, increased acetylcholinesterase staining, and the presence of hypertrophied nerve bundles.A barium enema examination should be performed in children in whom the diagnosis of Hirschsprung's disease is suspected. This test may demonstrate the location of the transition zone between the dilated ganglionic colon and the distal constricted aganglionic rectal segment. The authors' practice is to order this test before instituting rectal irrigations if possible, so that the difference in size between the proximal and distal bowel is preserved. Although a barium enema study can only suggest the diagnosis of Hirschsprung's disease, and not reliably establish it, the test is very useful in excluding other causes of distal intestinal obstruction. These include small left colon syndrome (as occurs in infants of diabetic mothers), colonic atresia, meconium plug syndrome, and the unused colon observed in infants after the administration of magnesium or tocolytic agents. In cases of total colonic aganglionosis, the barium enema study may reveal a markedly shortened colon. Some surgeons have found the use of rectal manometry helpful, particularly in older children, although the results are relatively inaccurate.TreatmentA diagnosis of Hirschsprung's disease requires surgery in all cases. The classic surgical approach consisted of a multiple-stage procedure. This included a colostomy in the newborn period, followed by a definitive pull-through operation after the child weighed >10 kg. There are three viable options for the definitive pull-through procedure that are currently used. Although individual surgeons may advocate one procedure over another, studies have demonstrated that the outcome after each type of operation is similar. For each of the operations that is performed, the principles of treatment include confirming the location in the bowel where the transition zone between ganglionic and aganglionic bowel exists, resecting the aganglionic segment of bowel, and performing an anastomosis of ganglionated bowel to either the anus or a cuff of rectal mucosa (Fig. 39-23).

Three operations for surgical correction of Hirschsprung's disease. A. The Duhamel procedure leaves the rectum in place and brings ganglionic bowel into the retrorectal space. B. Swenson's procedure is a resection with end-to-end anastomosis performed by exteriorizing bowel ends through the anus. C. In the Soave operation endorectal dissection is performed and mucosa is removed from the aganglionic distal segment. The ganglionic bowel is then brought down to the anus within the seromuscular tunnel.

It is now well established that a primary pull-through procedure can be performed safely, even in the newborn period. This approach follows the same treatment principles as a staged procedure and saves the patient from an additional operation. Many surgeons perform the intra-abdominal dissection using the laparoscope. This approach is especially useful in the newborn period, because it provides excellent visualization of the pelvis. In children with significant colonic distention, it is important to allow for a period of decompression using a rectal tube if a single-staged pull-through is to be performed. In older children with a very distended, hypertrophied colon, it may be prudent to perform a colostomy to allow the bowel to decompress, before performing a pull-through procedure. However, one should emphasize that there is no upper age limit for performing a primary pull-through.Of the three pull-through procedures performed for Hirschsprung's disease, the first is the original Swenson's procedure. In this operation, the aganglionic rectum is dissected in the pelvis and removed down to the anus. The ganglionic colon is then anastomosed to the anus via a perineal approach. In the Duhamel procedure, dissection outside the rectum is confined to the retrorectal space, and the ganglionic colon is anastomosed posteriorly just above the anus. The anterior wall of the ganglionic colon and the posterior wall of the aganglionic rectum are anastomosed using a stapler. Although both of these procedures are extremely effective, they are limited by the possibility of damage to the parasympathetic nerves that are adjacent to the rectum. To circumvent this potential problem, the Soave procedure calls for dissection entirely within the rectum. The rectal mucosa is stripped from the muscular sleeve, and the ganglionic colon is brought through this sleeve and anastomosed to the anus. This operation may be performed completely from below. In all cases, it is critical that the level at which ganglionated bowel exists be determined. Most surgeons believe that the anastomosis should be performed at least 5 cm from the point at which ganglion cells are found. This avoids performing a pull-through in the transition zone, which is associated with a high incidence of complications due to inadequate emptying of the pull-through segment. Up to one third of patients who undergo a transition zone pull-through will require a reoperation.The main complications of all procedures include postoperative enterocolitis, constipation, and anastomotic stricture. As mentioned earlier, long-term results for the three procedures are comparable and are generally excellent in experienced hands. These three procedures also can be adapted for total colonic aganglionosis in which the ileum is used for the pull-through segment.

SCHWARTZ

Hirschsprung's Disease Hirschsprung's disease is due to a congenital absence of ganglion cells in both the submucosal (Meissner's) and myenteric (Auerbach's) plexuses. This absence of ganglia extends continuously for a variable distance proximal to the internal anal sphincter. It may extend up to the splenic flexure or even more proximally, involving the entire colon, as well as portions of the small intestine (long-segment Hirschsprung's disease); it may be restricted to the rectum and sigmoid (short-segment Hirschsprung's disease); or it may involve only a few centimeters proximal to the dentate line (ultra-short-segment Hirschsprung's disease). With an incidence of 1 in 5000 live births, approximately 700 new cases of Hirschsprung's disease occur each year in the United States. Familial occurrence has been reported in about 7% of cases, particularly in those with long aganglionic segments. Hirschsprung's disease is seen most commonly in full-term infants but, on occasion, does occur in premature births. In the short-segment type, a 4:1 male preponderance is observed, and in the long-segment type, the ratio is reduced to about 2:1. Short-segment Hirschsprung's disease accounts for nearly 90% of cases in childhood, and long-segment Hirschsprung's disease accounts for the remainder. It is rare that ultra-short-segment Hirschsprung's disease manifests in the pediatric population, but it does explain certain cases of chronic constipation that come to attention in adulthood.[59] Twelve percent of children with Hirschsprung's disease have chromosomal abnormalities, 2% to 8% of which are trisomy 21 (Down syndrome); other associated congenital birth defects and syndromes are noted in Table 93-5 .[60] Table 93-5Congenital Anomalies and Syndromes Associated with Hirschsprung's Disease

Congenital Anomalies Genitourinary (5.6%)

Cardiac (4.5%)

Central nervous system (3.9%)

Gastrointestinal (3.9%)

Syndromes Shah-Waardenburg (regional hyperpigmentation, white forelock, bicolored irides, sensorineural deafness)

Movat-Wilson (characteristic facies, microcephaly, mental retardation)

Smith-Lemli-Opitz (anteverted nostrils, ptosis of eyelids, syndactyly of second and third toes, hypospadias and cryptorchidism in males)

Congenital central hypoventilation

Syndromes with limb abnormalities (metaphyseal dysplasia, McKusick-typemild bowing of legs, irregular metaphyses, fine sparse hair)

MEN II (medullary thyroid cancer, pheochromocytoma, parathyroid hyperplasia)

Piebaldism (hypopigmentation of skin and hair)

MEN, multiple endocrine neoplasia.

Data from Skinner M: Hirschsprung disease. Curr Probl Surg 32:393, 1996; and Ryan ET, Ecker JL, Christakis NA, et al: Hirschsprung disease: Associated anomalies and demography. J Pediatr Surg 27:76, 1992.

Pathogenesis Two pathogenetic mechanisms have been proposed for Hirschsprung's disease: (1) failure of migration and (2) alteration of the colonic microenvironment. Genetic, vascular, and infectious factors are invoked to explain these alterations.Failure of Migration. The genetics of Hirschsprung's disease have now been characterized.[28] Inheritance of the disease can be either autosomal dominant, autosomal recessive, or polygenic. Three genetic characteristics have been identified: the penetration of mutations generally is low, a gender difference in the penetrance and expression of mutations has been observed, and the penetrance of the gene mutation depends on the extent of aganglionosis in affected family members. It appears that the mutation, while increasing the child's odds of having Hirschsprung's disease, is not predictive of the specific abnormality. Alterations of several genes have been implicated: RET proto-oncogene, c-kit, endothelin, SOX10, and ErbB2 ( Table 93-6 ).[61] Mutation of the RET proto-oncogene, a gene that codes for a receptor tyrosine kinase protein, has been noted in familial Hirschsprung's disease and in sporadic cases. A reduced c-kit level in the colon of patients with Hirschsprung's disease has been observed.[62] Identified gene mutations currently account for only approximately half of all cases of Hirschsprung's disease, but it is recommended that RET exon 10 mutation analysis be done in all children with Hirschsprung's disease[28]; germline RET mutations also can cause multiple endocrine neoplasia type IIA (MEN II), and although the test results will be negative in the vast majority of cases, the significance of identifying MENIIA mutation carrier status for that individual and family may appear to justify such testing.

Table 93-6 -- Genetic Bases of Hirschsprung's Disease GeneAssociated Syndromes[*]Pathogenesis

RETMEN IIAAbnormal development of enteric nervous system

c-kitPiebaldism

Waardenburg type 4 (Shah-Waardenburg)

SOX10Shah-WaardenburgReduced survival of neural cells

ZFHXIBMovat-Wilson

ErbB2Impaired maintenance of enteric nervous system[61]

Data from Gariepy E: Developmental disorders of the enteric nervous system: Genetic and molecular bases. J Pediatr Gastroenterol Nutr 39:5, 2004; and Skinner M: Hirschsprung disease. Curr Probl Surg 32:393, 1996. *See Table 93-5 for details of the named syndromes.

Microenvironment Changes. A basic defect in the microenvironment necessary for the migration, development, and survival of ganglion cells has been postulated. Levels of various substances such as laminin, NADPH-diaphorase, and neural cell adhesion molecules,[63] as well as other polypeptides, have been shown to be reduced in the aganglionic segment,[59] and some investigators postulate that an alteration in the extracellular matrix with decreased concentrations of laminin and collagen IV constitutes a barrier to neutrophin 3, thereby perhaps impairing the neuroblastic migration and colonization. [64] [65] Neutrophin 3 promotes survival of sympathetic and sensory neurons in vitro and supports growth and survival of differing subsets of neurons. Nitric oxide synthase is reduced in the aganglionic segment in Hirschsprung's disease, explaining the failure of relaxation of the affected colonic segment.[66] Isolated case reports have linked the destruction of ganglion cells in segmental Hirschsprung's disease to cytomegalovirus infection[67] and muscular hyperplasia of pericolonic vessels.[68] Clinical Features Most children with Hirschsprung's disease should be diagnosed in the newborn nursery. Any full-term infant who does not pass meconium within the first 48 hours of life should be suspected of having the disorder. Frequently, such infants will have abdominal distention and feeding difficulties. They also may have bilious emesis from partial bowel obstruction. Dilation of the empty rectum by the first examiner usually results in the explosive expulsion of retained fecal material and decompression of the proximal normal bowel.[69] Hirschsprung's diseaseassociated enterocolitis occurs more frequently in the first 3 months of life, in patients with delayed diagnosis, in trisomy 21, and with long-segment involvement; females and patients with a positive familial history also are more frquently affected. Enterocolitis develops secondary to ischemia from colonic distention proximal to the aganglionic segment, with secondary infection from bacteria of the colonic content, but isolated cases also have been reported of Hirschsprung's diseaseassociated enterocolitis in the aganglionic segment. No specific bacteria have been isolated.[70] Mortality rates of up to 30% have been reported for enterocolitis, which remains the major cause of death in Hirschsprung's disease. Colonic perforation, most frequently involving the cecum and rarely the appendix, may occur even in utero.Most commonly, infants younger than 6 months of age with Hirschsprung's disease will continue to have variable but significant constipation, punctuated by recurrent obstructive crises or impaction, often with failure to thrive. The abdomen may be distended with fecal masses, and peristaltic waves may be visible. Anemia and hypoalbuminemia are common. Blood-flecked diarrhea should suggest the presence of enterocolitis, and immediate evaluation should be undertaken. As the child with Hirschsprung's disease grows older, these problems continue, and fecal soiling occasionally may occur.[69] An infant with Hirschsprung's disease who is breast-fed may have fewer difficulties with defecation because the high concentration of lactose in breast milk produces watery stools that are passed more easily. Once breast milk is discontinued, symptoms of Hirschsprung's disease may increase.Diagnosis The child with symptomatic Hirschsprung's disease usually demonstrates signs and symptoms of bowel obstruction. The diagnosis may be made by one or a combination of the following tests: barium enema, rectal biopsy, and anal manometry. Flexible sigmoidoscopy plays a complementary role in diagnosis.A barium enema performed on the unprepared colon will show the distal narrowed hypertonic segment of bowel (usually seen best in a lateral projection). The transition zone between the narrowed distal and dilated proximal intestine will be seen in the most common form of Hirschsprung's diseasethe rectosigmoid form ( Fig. 93-22A )but may not be seen with long- or ultra-short-segment intestinal involvement. In ultra-short-segment Hirschsprung's disease, a radiologic picture indistinguishable from that in functional constipation with dilated bowel extending to the anus usually is seen. The transition zone may not be evident in rectosigmoid Hirschsprung's disease if the patient has undergone cleansing enemas or colonic irrigation before the study. Although it has been suggested that the transition zone also may not be evident in the first 6 weeks of life, it almost always is noted in the neonate with partial bowel obstruction.[69]

Figure 93-22 Hirschsprung's disease. A, Film from a barium enema examination showing the transition zone between the narrowed distal aganglionic segment (na) and the proximal dilated ganglionic segment (dg). B, Anal manometry. Left tracing illustrates normal function. In the right tracing note the lack of relaxation of the internal sphincter in Hirschsprung's disease upon rectal distention. C, Photomicrograph of a rectal suction biopsy specimen showing the absence of ganglion cells and thickened nerve trunks (nt) characteristic of Hirschsprung's disease. Hematoxylin-eosin stain, 125. D, Acetylcholinesterasepositive fibers stained brown (arrows) in the muscularis mucosae and lamina propria. 250 (From Markowitz J: Gastrointestinal motility. In Silverberg M, Daum F [eds]: Textbook of Pediatric Gastroenterology, 2nd ed. Chicago, Year Book Medical Publishers, 1988.)

Flexible sigmoidoscopy reveals a normal but empty rectum. The dilated proximal bowel, if within reach of the scope, is traversed easily, except for abundant feces in the lumen; occasionally stercoral ulcers may be seen.Anal manometry is the most reliable method by which the gastroenterologist can make the diagnosis of ultra-short-segment Hirschsprung's disease. A normal physiologic response to distention of the rectum is relaxation of the smooth muscle internal sphincter pressure. In Hirschsprung's disease, not only does rectal distention fail to induce internal sphincter relaxation, but a paradoxical rise in external sphincter pressure often is seen (see Fig. 93-22B ). Sufficient volumes of air must be used to stimulate rectal distention for a reliable study. A false-positive result most commonly is caused by a capacious rectum in constipation or with megacolon, in which case balloon distention may not stimulate the reflex. Up to 20% of normal children have a falsely absent reflex, especially if they are premature or of low birth weight. Nonetheless, a positive response, such as internal sphincter relaxation, is strong evidence against Hirschsprung's disease.A suction biopsy of the rectal mucosa is the most reliable method of diagnosis, except in patients with ultra-short-segment Hirschsprung's disease. The biopsy capsule should be placed at least 2 cm above the mucocutaneous junction in infants and 3 cm above the junction in older children to avoid the physiologic hypoganglionic zone. To be certain of the absence of ganglion cells in the submucosal plexus, an experienced pathologist may need to review many serial sections. Hyperplastic sympathetic nerve fibers and proliferating Schwann cells are associated findings (see Fig. 93-22C ), but can be absent in total aganglionosis.Controversy exists regarding the type of stains necessary to make a diagnosis of Hirschsprung's disease. Because acetylcholinesterase is increased in the muscularis mucosae and lamina propria in the aganglionic segment (see Fig. 93-22D ), staining for this enzyme has been used for many years.[71] This technique requires fresh, nonformalin-fixed tissue and technical expertise; at best, this stain is confirmatory. False-positive and false-negative reports have been documented in total colonic aganglionosis.[72] A variety of histochemical staining methods have been proposed for the identification of ganglion cells,[73] but all are expensive, time-consuming, and unnecessary.In all instances, biopsy of the muscularis propria of the bowel is indicated at the time of surgery to assess for the presence of ganglion cells in the myenteric plexus and to delineate the proximal extension of aganglionosis. A full-thickness biopsy of the anorectal wall performed by a surgeon is diagnostic of ultra-short-segment Hirschsprung's disease, in contrast with the suction biopsy, which is not as reliable.In the neonate, considerations in the differential diagnosis in Hirschsprung's disease include other causes of intestinal obstruction, such as meconium ileus, ileal atresia, meconium plug syndrome, and the microcolon seen in infants of diabetic mothers.[69] When symptoms and signs of enterocolitis are present, diagnostic possibilities in the neonate also include primary necrotizing enterocolitis, Hirschsprung's diseaseassociated enterocolitis, milk protein-induced colitis (see Chapter 19 ), and sepsis with possible disseminated intravascular coagulation.[69] In the older child, Hirschsprung's disease must be differentiated from functional constipation (stool withholding, fecal retention). In the latter condition, history indicates that the child did pass meconium in the newborn nursery and that the clinical problems did not arise until the child usually was 18 months of age or older. Fecal impaction almost always is present in fecal retention, and fecal soiling is characteristic. Children with anterior displacement of the anus may be more prone to fecal retention.[69] Idiopathic pseudo-obstruction and intestinal neuronal dysplasia generally can be distinguished from Hirschsprung's disease by rectal biopsy.Management Definitive treatment of Hirschsprung's disease is surgical. All full-term babies with meconium plug in the newborn nursery should be evaluated for this disorder before discharge because approximately 15% of children with Hirschsprung's disease have a history of meconium plug. Discharge of any newborn with undiagnosed Hirschsprung's disease with consequent delay in operative intervention may result in a greater frequency of enterocolitis, with resultant morbidity and even mortality.The specific method of surgery is operator dependent. In general, long-term results are good, but 10% to 20% of children have residual problems, usually with fecal soiling. Long-term prognosis varies and may depend on the length of the aganglionic segment. Even in the most common form of Hirschsprung's disease (short-segment), it is usual to see older children continue to have defecatory issues with fecal retention and encopresis. The exact reasons for these continuing problems remain unclear, but the mechanism may involve an intrinsic abnormality in what is described as normal colon or in the pacemaker system of the colon.SLEISENGER AND FORDTRAN GASTRO AND INTESTINAL DISEASE

324.3 Congenital Aganglionic Megacolon (Hirschsprung Disease) Kristin Fiorino,Chris A. LiacourasHirschsprung disease, or congenital aganglionic megacolon, is a developmental disorder (neurocristopathy) of the enteric nervous system, characterized by the absence of ganglion cells in the submucosal and myenteric plexus. It is the most common cause of lower intestinal obstruction in neonates, with an overall incidence of 1 in 5,000 live births. The male:female ratio for Hirschprung disease is 4:1 for short-segment disease and closer to 1:1 as the length of the involved segment increase. Prematurity is uncommon.There is an increased familial incidence in long-segment disease. Hirschsprung disease may be associated with other congenital defects, including Down, Goldberg-Shprintzen, Smith-Lemli-Opitz, Shah-Waardenburg, cartilage-hair hypoplasia, and congenital hypoventilation (Ondine's curse) syndromes and urogenital or cardiovascular abnormalities. Hirschsprung disease has been seen in association with microcephaly, mental retardation, abnormal facies, autism, cleft palate, hydrocephalus, and micrognathia.Pathology Hirschsprung disease is the result of an absence of ganglion cells in the bowel wall, extending proximally and continuously from the anus for a variable distance. The absence of neural innervation is a consequence of an arrest of neuroblast migration from the proximal to distal bowel. Without the myenteric and submucosal plexus, there is inadequate relaxation of the bowel wall and bowel wall hypertonicity, which can lead to intestinal obstruction.Hirschsprung disease is usually sporadic, although dominant and recessive patterns of inheritance have been demonstrated in family groups. Genetic defects have been identified in multiple genes that encode proteins of the RET signaling pathway (RET, GDNF, and NTN) and involved in the endothelin (EDN) type B receptor pathway (EDNRB, EDN3, and EVE-1). Syndromic forms of Hirschsprung disease have been associated with the L1CAM, SOX10, and ZFHX1B (formerly SIP1) genes.The aganglionic segment is limited to the rectosigmoid in 80% of patients. Approximately 10% to 15% of patients have long-segment disease, defined as disease proximal to the sigmoid colon. Total bowel aganglionosis is rare and accounts for approximately 5% of cases. Observed histologically is an absence of Meissner and Auerbach plexus and hypertrophied nerve bundles with high concentrations of acetylcholinesterase between the muscular layers and in the submucosa.Clinical Manifestations Hirschsprung disease is usually diagnosed in the neonatal period secondary to a distended abdomen, failure to pass meconium, and/or bilious emesis or aspirates with feeding intolerance. In 99% of healthy full-term infants, meconium is passed within 48 hr of birth. Hirschsprung disease should be suspected in any full-term infant (the disease is unusual in preterm infants) with delayed passage of stool. Some neonates pass meconium normally but subsequently present with a history of chronic constipation. Failure to thrive with hypoproteinemia from protein-losing enteropathy is a less common presentation because Hirschsprung disease is usually recognized early in the course of the illness. Breast-fed infants might not suffer disease as severe as formula-fed infants.Failure to pass stool leads to dilatation of the proximal bowel and abdominal distention. As the bowel dilates, intraluminal pressure increases, resulting in decreased blood flow and deterioration of the mucosal barrier. Stasis allows proliferation of bacteria, which can lead to enterocolitis (Clostridium difficile, Staphylococcus aureus, anaerobes, coliforms) with associated diarrhea, abdominal tenderness, sepsis and signs of bowel obstruction. Early recognition of Hirschsprung disease before the onset of enterocolitis is essential in reducing morbidity and mortality.Hirschsprung disease in older patients must be distinguished from other causes of abdominal distention and chronic constipation (Table 324-3 and Fig. 324-1). The history often reveals constipation starting in infancy that has responded poorly to medical management. Fecal incontinence, fecal urgency, and stool-withholding behaviors are usually not present. The abdomen is tympanitic and distended, with a large fecal mass palpable in the left lower abdomen. Rectal examination demonstrates a normally placed anus that easily allows entry of the finger but feels snug. The rectum is usually empty of feces, and when the finger is removed, there may be an explosive discharge of foul-smelling feces and gas. The stools, when passed, can consist of small pellets, be ribbon-like, or have a fluid consistency, unlike the large stools seen in patients with functional constipation. Intermittent attacks of intestinal obstruction from retained feces may be associated with pain and fever. Urinary retention with enlarged balder or hydronephrosis can occur secondary to urinary compression.

Table 324-3 -- DISTINGUISHING FEATURES OF HIRSCHSPRUNG DISEASE AND FUNCTIONAL CONSTIPATIONVARIABLEFUNCTIONALHIRSCHSPRUNG DISEASE

HISTORY

Onset of constipationAfter 2 yr of ageAt birth

EncopresisCommonVery rare

Failure to thriveUncommonPossible

EnterocolitisNonePossible

Forced bowel trainingUsualNone

EXAMINATION

Abdominal distentionUncommonCommon

Poor weight gainRareCommon

RectumFilled with stoolEmpty

Rectal ExaminationStool in rectumExplosive passage of stool

MalnutritionNonePossible

INVESTIGATIONS

Anorectal manometryRelaxation of internal anal sphincterFailure of internal anal sphincter relaxation

Rectal biopsyNormalNo ganglion cells, increased acetylcholinesterase staining

Barium enemaMassive amounts of stool, no transition zoneTransition zone, delayed evacuation (>24 hr)

Figure 324-1 Barium enema in a 14 yr old boy with severe constipation. The enormous dilatation of the rectum and distal colon is typical of acquired functional megacolon.

In neonates, Hirschsprung disease must be differentiated from meconium plug syndrome, meconium ileus, and intestinal atresia. In older patients, the Currarino triad must be considered, which includes anorectal malformations (ectopic anus, anal stenosis, imperforate anus), sacral bone anomalies (hypoplasia, poor segmentation), and presacral anomaly (anterior meningoceles, teratoma, cyst).Diagnosis Rectal suction biopsy is the gold standard for diagnosing Hirschsprung disease. The biopsy material should contain an adequate amount of submucosa to evaluate for the presence of ganglion cells. To avoid obtaining biopsies in the normal area of hypoganglionosis, which ranges from 3 to 17 mm in length, the suction rectal biopsy should be obtained no closer than 2 cm above the dentate line. The biopsy specimen should be stained for acetylcholinesterase to facilitate interpretation. Patients with aganglionosis demonstrate a large number of hypertrophied nerve bundles that stain positively for acetylcholinesterase with an absence of ganglion cells.Anorectal manometry measures the pressure of the internal anal sphincter while a balloon is distended in the rectum. In normal patients, rectal distention initiates relaxation of the internal anal sphincter in response to rectal distention with a balloon. In patients with Hirschsprung disease, the internal anal sphincter fails to relax in response to rectal distention. Although the sensitivity and specificity can vary widely, in experienced hands, the test can be quite sensitive. The test, however, can be technically difficult to perform in young infants. A normal response in the course of manometric evaluation precludes a diagnosis of Hirschsprung disease; an equivocal or paradoxical response requires a repeat motility or rectal biopsy.An unprepared contrast enema is most likely to aid in the diagnosis in children older than 1 mo because the proximal ganglionic segment might not be significantly dilated in the first few weeks of life. Classic findings are based on the presence of an abrupt narrow transition zone between the normal dilated proximal colon and a smaller-caliber obstructed distal aganglionic segment. In the absence of this finding, it is imperative to compare the diameter of the rectum to that of the sigmoid colon, because a rectal diameter that is the same as or smaller than the sigmoid colon suggests Hirschsprung disease. Radiologic evaluation should be performed without preparation to prevent transient dilatation of the aganglionic segment. As many as 10% of newborns with Hirschsprung disease have a normal contrast study. Twenty-four hour delayed films are helpful in showing retained contrast (Fig. 324-2). If significant barium is still present in the colon, it increases the suspicion of Hirschsprung disease even if a transition zone is not identified. Barium enema examination is useful in determining the extent of aganglionosis before surgery and in evaluating other diseases that manifest as lower bowel obstruction in a neonate. Full-thickness rectal biopsies can be performed at the time of surgery to confirm the diagnosis and level of involvement.

Figure 324-2 Lateral view of a barium enema in a 3 yr old girl with Hirschsprung disease. The aganglionic distal segment is narrow, with distended normal ganglionic bowel above it.

Treatment Once the diagnosis is established, the definitive treatment is operative intervention. Previously, a temporary ostomy was placed and definitive surgery was delayed until the child was older. Currently, many infants undergo a primary pull-through procedure except if there is associated enterocolitis or other complications, when a decompressing ostomy is usually required.There are 3 basic surgical options. The first successful surgical procedure, described by Swenson, was to excise the aganglionic segment and anastomose the normal proximal bowel to the rectum 1-2 cm above the dentate line. The operation is technically difficult and led to the development of 2 other procedures. Duhamel described a procedure to create a neorectum, bringing down normally innervated bowel behind the aganglionic rectum. The neorectum created in this procedure has an anterior aganglionic half with normal sensation and a posterior ganglionic half with normal propulsion. The endorectal pull-through procedure described by Soave involves stripping the mucosa from the aganglionic rectum and bringing normally innervated colon through the residual muscular cuff, thus bypassing the abnormal bowel from within. Advances in techniques have led to successful laparoscopic single-stage endorectal pull-through procedures, which are the treatment of choice.In ultrashort-segment Hirschsprung disease or internal sphincter achalasia, the aganglionic segment is limited to the internal sphincter. The clinical symptoms are similar to those of children with functional constipation. Ganglion cells are present on rectal suction biopsy, but the anorectal manometry is abnormal, with failure of relaxation of the internal anal sphincter in response to rectal distention. Current treatment, although still controversial, includes anal botulism injection to relax the anal sphincter and anorectal myectomy if indicated.Long-segment Hirschsprung disease involving the entire colon and, at times, part of the small bowel presents a difficult problem. Anorectal manometry and rectal suction biopsy demonstrate findings of Hirschsprung disease, but radiologic studies are difficult to interpret because a colonic transition zone cannot be identified. The extent of aganglionosis can be determined accurately by biopsy at the time of laparotomy. When the entire colon is aganglionic, often together with a length of terminal ileum, ileal-anal anastomosis is the treatment of choice, preserving part of the aganglionic colon to facilitate water absorption, which helps the stools to become firm.The prognosis of surgically treated Hirschsprung disease is generally satisfactory; the great majority of patients achieve fecal continence. Long-term postoperative problems include constipation, recurrent enterocolitis, stricture, prolapse, perianal abscesses, and fecal soiling. Some children require myectomy or a redo pull-through procedure.NELSON PEDIATRIC