Seminars in Pediatric Surgery (2008) 17, 266-275

Hirschsprung disease
Ramanath N. Haricharan, MBBS, MPH, Keith E. Georgeson, MD
From the Division of Pediatric Surgery, Department of General Surgery, University of Alabama at Birmingham, Birmingham, Alabama. KEYWORDS
Hirschsprung disease; Enterocolitis; Endorectal pull-through; Postoperative complications; Risk factors; Ganglionated bowel Hirschsprung disease is a relatively common condition managed by pediatric surgeons. Signicant advances have been made in understanding its etiologies in the last decade, especially with the explosion of molecular genetic techniques and early diagnosis. The surgical management has progressed from a two- or three-stage procedure to a primary operation. More recently, denitive surgery for Hirschsprung disease through minimally invasive techniques has gained popularity. In neonates, the advancement of treatment strategies for Hirschsprung disease continues with reduced patient morbidity and improved outcomes. 2008 Elsevier Inc. All rights reserved.

Hirschsprung disease (HSCR) was rst described by Harald Hirschsprung in older children in 1886. The pathogenesis remained elusive for several decades, until the late 1940s, when the distal aganglionosis was noted.1,2 In subsequent years, it was realized that the inability of the colon to empty secondary to functional obstruction was a major contributing factor for disease progression. Swenson and Bill, Duhamel, and Soave developed various operations, usually involving two or three stages, for surgical management of HSCR.2,3 Single-stage pull-through was described by So and coworkers in 19804,5 and, since then, has been increasingly practiced. Single-stage pull-through, both with and without laparoscopic assistance, has enabled surgeons to perform denitive surgical correction at an earlier age than previously possible. Although surgical management of HSCR has improved considerably in recent years, the understanding of the underlying pathophysiology is incomplete. Increased awareness of HSCR, improved neonatal nursing care, and the use of suction rectal biopsy have all
Address reprint requests and correspondence: Keith E. Georgeson, MD, Division of Pediatric Surgery, 1600 7th Avenue South, ACC300, Birmingham, AL 35233. This research was supported by departmental funds only. E-mail: keith.georgeson@ccc.uab.edu.

contributed to earlier diagnosis and management of neonates with HSCR.6 This chapter is intended to highlight important aspects of HSCR, with particular focus on neonates.

Etiology
Cellular and molecular abnormalities during the development of enteric nervous system (ENS) and migration of neural crest cells into the developing intestine represent the primary etiology in HSCR.7-9 Neural crest-derived neuroblasts rst appear in the developing esophagus by 5 weeks gestation in the human fetus. These cells migrate in a craniocaudal fashion into the rest of the developing gut from 5 to 12 weeks of gestation.7,10 The HSCR phenotype is variable due to a wide range of possible abnormalities during the development of ENS and the different times at which the arrest in the migration of neural crest-derived cells can occur.9-11 Early arrest of migration in the developing fetus leads to a long segment of aganglionosis. Other factors, such as altered extracellular matrix components, abnormalities in neurotrophic factors, and neural cell adhesion molecules, have also been suggested to contribute to the development of HSCR.10,12,13

1055-8586/$ -see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.sempedsurg.2008.07.005

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Table 1

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Frequency of different types of HSCR Typical level of aganglionosis Sigmoid Splenic exure or transverse colon Terminal ileum Frequency (%) 74-80 12-22 4-13

Classication
The proximal extent of aganglionosis from the internal anal sphincter is helpful in classifying a majority of the patients into those with rectosigmoid HSCR, long-segment HSCR, and total colonic aganglionosis. Total intestinal aganglionosis and ultrashort-segment HSCR are also described. Table 1 shows the relative frequency of common forms of HSCR.14,26-28 The most severe, but rarest, form of HSCR manifests as total intestinal aganglionosis with absent ganglion cells from duodenum to the rectum.

Types of HSCR Rectosigmoid Long-segment Total colonic aganglionosis

Genetic factors
The increased risk of HSCR in siblings of individuals with HSCR, the unbalanced sex ratio, and the association of HSCR with other malformation syndromes and chromosomal anomalies provide evidence of underlying genetic factors of HSCR.14-16 Genetic studies have identied mutations in 10 different genes contributing to the development of HSCR.16 The more common among these include mutations in RET gene (7-35% of sporadic cases), EDNRB gene (7%), and END3 gene ( 5%).11,15,16 More than 20 different mutations have been described in the RET protooncogene, and some polymorphisms in this gene are associated with particular phenotypes of HSCR (ie, rectosigmoid or long-segment disease).17,18 Although HSCR occurs as an isolated phenotype, it is associated with congenital abnormalities and associated syndromes (such as trisomy 21, cardiac septal defects, congenital central hypoventilation syndrome, multiple endocrine neoplasia type 2, neurobromatosis, and Waardenburg syndrome) in 5-32% of children with HSCR.14-16,19,20 Trisomy 21 (Down syndrome) associated with HSCR is reported in approximately 7% of children with HSCR.15,16 Among organ systems, gastrointestinal abnormalities are the most common, followed by central nervous system and genitourinary abnormalities.15 HSCR has a complex inheritance with penetrance varying on the gender of the affected individual. Studies have shown that the recurrence risk of HSCR in the sibling of the proband is 4%, which translates to a relative risk of 200.16,21

Epidemiology and clinical features

The incidence of HSCR is estimated to be approximately 1 in 5000 live births.19,28 The California Birth Defects Monitoring Program survey from 1983 to 1997 found HSCR in 2.8 children in 10,000 live births in Asians, 2.1 in 10,000 live births in AfricanAmericans, 1.5 in 10,000 live births in Whites, and 1 in 10,000 live births in Hispanics.29 HSCR appears to have a complex inheritance with sex-dependent penetrance. The male-to-female ratio in rectosigmoid disease is 4:1, but it is 1:1-2:1 in longer segment disease.20 With increased awareness and improved diagnostic methods, the age at diagnosis of HSCR has decreased considerably in the recent years to where the condition is mostly diagnosed in the newborn period.29 Singh and coworkers6 showed that the diagnosis of HSCR was conrmed in the neonatal period in 91% of children from 1997 to 2000. Delayed passage of meconium, distended abdomen, bilious vomiting, and feeding intolerance are the common symptoms. Typically, a neonate with HSCR is a full-term baby30,31 presenting with delay in passage of meconium. Almost all normal full-term infants pass meconium in the rst 24-48 hours of life.32 However, 60-90% of children with HSCR fail to pass meconium in that time period.6,30,33 Table 2 highlights the differential diagnosis to be considered in a

Table 2 Differential diagnosis of delayed passing of meconium Small intestine Intestinal atresia Malrotation, volvulus Meconium ileus due to cystic brosis Large intestine Meconium plug syndrome Anorectal malformation Hirschsprung disease Hypoplastic left colon syndrome Other causes Narcotics Electrolyte abnormalities Hypothyroidism Sepsis Very low birth weight infant

Pathophysiology
In HSCR, the underlying pathophysiological feature is functional obstruction caused by a narrowed colon that hinders the propagation of peristaltic waves due to the absence of parasympathetic intrinsic ganglion cells.22 Despite extensive research, the reason for tonic contraction of aganglionic bowel is not completely clear. Aganglionosis, cholinergic hyperinnervation, defective distribution of nerves with nitric oxide synthetase (NOS), and abnormalities of the interstitial cells of Cajal have all been implicated in the pathogenesis of HSCR,23-25 but a complete understanding of the causative factors for the abnormalities seen in HSCR is elusive.

268 neonate with delayed passage of meconium. HSCR should also be suspected in any child with difculty passing stool in the newborn period. In several cases, digital rectal examination may reveal a tight anus and may also lead to passage of meconium relieving an acute intestinal obstruction. Distended abdomen is seen in 63-91% of neonates with HSCR, and bilious vomiting in 19-37% of children.34-36 Approximately 5%35 to 44%37 of children may present with Hirschsprung-associated enterocolitis (HAEC). Development of explosive foul-smelling diarrhea, fever, and abdominal distension indicates HAEC, which, when unrecognized, may further worsen to a potentially fatal toxic megacolon. Prompt recognition of HAEC and treatment with uid resuscitation, rectal irrigation, and antibiotics is important to decrease the risk of mortality. HAEC has been suggested to be more frequent in children in whom the diagnosis of HSCR is delayed,6,38 highlighting the importance of early diagnosis.

Seminars in Pediatric Surgery, Vol 17, No 4, November 2008 abnormal rectosigmoid index (RSI).42,48 A recent systematic review by de Lorijn and coworkers45 estimated that the sensitivity and specicity of CE is 70% and 83%, respectively. Roseneld and coworkers48 have reported lower sensitivity of TZ for the diagnosis of HSCR in the neonatal period compared with later in life (65% versus 75%). Diamond and coworkers36 found that age 30 days increased the risk of a false-positive CE result by three times, and Garcia and coworkers49 reported poor negative and positive predictive values of RSI in neonates. Also, in children with a radiological transitional zone (RTZ), the pathologic extent of aganglionosis was concurrent to the level of RTZ approximately 63-90% of the time.50-52 In these studies, age 30 days and presence of a long-segment disease increased the chances of discordance between RTZ and the level of aganglionosis. Conclusions from all of the above-mentioned studies suggest that CE in the neonatal age has to be cautiously interpreted. In HSCR, ARM is done to establish the presence of high baseline resting pressures and absence of rectoanal inhibitory reex (RAIR). The technique of ARM is described in detail elsewhere,53 and only the principle behind the procedure is discussed briey here. In normal children, distending the rectum with a balloon lled with air or water results in a transient increase in rectal pressure with a simultaneous reduction in the anal sphincter pressure. However, this RAIR is absent in children with HSCR. The use of ARM to assess RAIR is widely accepted in older children to diagnose HSCR, but ARM in neonates has been controversial, with some studies supporting39,54 and some questioning55,56 the diagnostic accuracy of the procedure. Holschneider and coworkers55 reported that normal rectosphincteric reex is present only after 14 days of age, and hence, RAIR could be diagnostic after that. However, Tamate and coworkers54 demonstrated the presence of rectosphincteric reex in all 60 normal neonates in their study and absence of the reex in neonates with HSCR. They concluded that failure to detect the rectosphincteric reex in the very young could be due to technical difculties only. Kawahara and coworkers57 have successfully used a micromanometry technique with a sleeve sensor to diagnose HSCR among neonates. This technique appears to have improved the accuracy of ARM. Rectal biopsy demonstrating the absence of ganglion cells and presence of acetyl cholinesterase (AChE)-positive hypertrophic nerve bers is conrmatory of HSCR. With the advent of RSB, the conrmatory test can be done in the outpatient setting, instead of a FTB that requires an operation under general anesthesia.58 In RSB, prophylactic antibiotics are given, and biopsies of the rectum are taken using a suction biopsy tube starting at least 2.5 cm above the anal verge. Collection of sufcient mucosa with attached submucosa must be ensured. A rectal examination is performed after completion to exclude active bleeding. The child should be observed for at least 1 hour before discharge.

Diagnosis
HSCR should be suspected in a neonate with the aforementioned clinical presentation. Tests available for diagnosing HSCR include contrast enema (CE), anorectal manometry (ARM), full-thickness rectal biopsy (FTB), and rectal suction biopsy (RSB). The initial test for diagnosing HSCR differs among various medical centers based on availability of the test and the availability of expertise. The range of sensitivity and specicity for CE, ARM, and RSB compared with the gold standard FTB reported in studies that included neonates39-47 is shown in Table 3. Initial plain radiograph (supine, lateral decubitus, or prone lateral view) in a baby with HSCR may show marked gaseous distension of colon with undilated rectum with a transition zone in-between. In a few centers, CE may usually be the rst test performed to investigate a child with suspected HSCR presenting with signs of large bowel obstruction.45 The features of CE suggestive of HSCR include presence of a transition zone (TZ), irregular colonic contractions, irregular mucosa suggesting enterocolitis, or an

Table 3 Range of sensitivity and specicity of tests used to diagnose Hirschsprung disease (data from only studies that included neonates 39-47) Test Contrast enema (CE) Anorectal manometry (ARM) Rectal suction biopsy (RSBAChE)* Rectal suction biopsy (RSBH&E) Sensitivity (%) 65-80 75-100 91-100 97-100 Specicity (%) 66-100 85-97 97-100 99-100

*RSBAChE indicates studies using acetyl cholinesterase staining for RSB. RSBH&E indicates studies using hematoxylin and eosin for staining for RSB.

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269 Advances in neonatal nursing, anesthesia, and critical care over the last decade have enabled the pediatric surgeon to perform a one-stage repair for HSCR. With a majority of patients diagnosed in the neonatal period, several centers have employed single-stage repair with encouraging results since the initial report by So and coworkers.3,5,35 The major contraindications for the primary pull-through include associated life-threatening anomalies, severe enterocolitis, severe dilation of the proximal bowel, and deteriorating general health. At our institution, a laparoscopic-assisted transanal endorectal pull-through (LATEP) is preferred in neonates presenting with left-sided HSCR without any contraindications for a primary repair. Laparoscopic biopsies provide a minimally invasive approach to conrm the extent of aganglionosis before the division of colonic mesentery or rectal ablation. This is particularly advantageous in a neonate with aganglionosis extending proximal to the splenic exure or total colonic aganglionosis that is not previously suspected. Allowing for a delay in denitive operation until histopathological results from a permanent section are available prevents unnecessary resection of long segments of colon due to errors in rapid frozen section analysis. Furthermore, while avoiding the morbidity of laparotomy, laparoscopy helps to perform a tension-free mesocolic pedicle and to ensure that there is no twisting of the pull-through segment while anastomosing. In neonates with near-total or total colonic aganglionosis, a primary diversion is preferred, followed by a laparoscopic-assisted Duhamel procedure and ostomy reversal. The Duhamel procedure may offer the advantage of creating a larger rectal reservoir in patients with near-total or total colonic HSCR. The operative techniques used at our institution are discussed in detail elsewhere.68,69 Briey, the steps in LATEP are as follows. Port placement is as shown in Figure 1. Seromuscular biopsies are obtained laparoscopically at var-

Along with hematoxylin and eosin (H&E) staining of RSB specimen, the use of AChE staining has made the morphological diagnosis easier and more reliable.59 Several other enzyme-staining techniques have been used to diagnose HSCR, such as lactate dehydrogenase, succinic dehydrogenase, and NADPH-diaphorase enzyme histochemistry.60 The reported advantages of these techniques include rapid visualization and assessment of submucous and myenteric plexi. In a study evaluating the AChE-staining method to diagnose HSCR in neonates, Nakao and coworkers47 reported a sensitivity of 91%, specicity of 100%, and false-negative rate of 8%. The authors suspected that decreased proliferation of AChE-positive bers in the neonatal period contributed to the false-negative cases. Despite this limitation, RSB is more sensitive and specic than both CE and ARM (Table 3), even without using other newer enzyme histochemistry methods. In children presenting with enterocolitis, a histological grading of HAEC ranging from grade I (normal mucosa) to grade V (severe necrosis with perforation) on the rectal biopsy specimen has been proposed by Teitelbaum and coworkers.61 Elhalaby and coworkers62 suggested that detection of histological changes of grade II enterocolitis predicted a higher risk of subsequent development of clinical HAEC. However, our results represent ndings that do not corroborate their conclusion.63

Management
After conrmation of the diagnosis, plans for operative management are developed. If the neonate presents with HAEC, aggressive resuscitation, rectal irrigation, and antibiotics are initially used to manage the enterocolitis. Traditionally, a two- or three-stage operative repair is done. The rst stage is a diverting ostomy after doing leveling colonic biopsies to determine extent of aganglionosis. The second stage, performed later, usually at 3 months to 1 year of age, involves resection of aganglionated bowel and coloanal anastomosis. The preexisting stoma is either closed at this operation or during a third-stage procedure. A number of different operations have been described for the management of HSCR. The most commonly used procedures include rectosigmoidectomy described by Swenson and Bill, the retrorectaltransanal approach described by Duhamel, and the endorectal procedure described by Soave. These procedures have also been performed using laparoscopic techniques.64-66 Yamataka and coworkers67 performed a novel approach of laparoscopyassisted transanal pull-through at the time of RSB in a carefully selected population. These authors described a case series of children with a strong suspicion of HSCR on CE who underwent an intraoperative conrmatory RSB and a primary pull-through in the same setting. Rapid AChEstaining technique was used for the RSB and to identify ganglionated bowel.

Figure 1 Position of ports for laparoscopic-assisted endorectal pull-through in neonates.

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Seminars in Pediatric Surgery, Vol 17, No 4, November 2008

Figure 2 Location of the intended transanal circumferential incision (dotted line).

ious levels and sent for frozen section analysis. After the level of normal bowel is identied, the mesocolon close to the aganglionic bowel is divided by using hook electrocautery or ultrasonic scalpel. Transanal circumferential incision is made 5 mm above the dentate line (Figure 2), and endorectal dissection is continued in the submucosal plane of the rectum until the muscular cuff of the rectal wall intussuscepts freely and the level of the peritoneal cavity is reached. The division of the muscular rectal wall is continued circumferentially, freeing the intraabdominal colon from the muscle sleeve. The muscular cuff is divided posteriorly all the way down to the level of the intended anastomosis (Figure 3). The aganglionic colon is pulled through the divided muscular sleeve out onto the anus (Figure 4) and subsequently resected. Anastomosis of the ganglionated colon and the anus is performed (Figure 5). Laparoscopic

Figure 4 Mobilized colon pulled through the anus to a level proximal to the transition zone before the resection.

inspection is done to ensure that the neorectum is not twisted as it goes into the pelvis and to close any potential hernia space.

Figure 3 Rectal cuff split posteriorly to the level of intended anastomosis.

Figure 5 sutures.

Anastomosis completed with interrupted absorbable

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271 the risk of these complications include tension or ischemia at the anastomosis, poor nutritional status, steroid usage, and residual aganglionosis. Suspected leaks are evaluated by using water-soluble contrast enemas. Management strategies include surgical exploration, diverting colostomy, and revision of anastomosis. Bowel obstruction due to adhesions is seen both in the early and late postoperative period. It occurs in approximately 7.5-10% of children, and, in the majority of the patients, it is responsive to bowel decompression without the necessity of operative repair.75,76 The factors increasing the risk of adhesions include prior operation and anastomotic leak. Some authors have suggested that the laparoscopic approach may decrease the incidence of adhesive bowel obstruction.75 Perineal excoriation is common after denitive repair or stomal takedown. The severity of the excoriation may be limited by using barrier creams beginning on postoperative day 1. The condition usually improves with the resolution of diarrhea, typically within 2-3 months postoperatively. Stomal complications include prolapse, stenosis, retraction, parastomal hernia, and peristomal skin breakdown. However, the incidence and management of these conditions are no different from the same in the non-HSCR neonate. With the present trend toward primary repair in neonates,3 the incidence of stomal complications may further decrease. Wound infection is noted in nearly 4% and wound dehiscence in 1% of children.35 Meticulous technique, adequate hemostasis, good nutrition, and avoidance of ischemia and tension may help in preventing the wound complications. HAEC has been a major cause of increased morbidity and mortality after the denitive pull-through procedure. Despite the advances in management of children with HSCR, the pathogenesis of HAEC remains incompletely understood. It is suggested that obstructive mechanisms result in intestinal stasis with proliferation of luminal pathogens, mucosal invasion by pathogens, and subsequent local and systemic inammatory response. The incidence of postoperative HAEC reported in literature varies from 5% to 42% depending on the denition and method of diagnosing HAEC.35,62,63,77,78 In a recent retrospective study, it was shown that the initial admission for HAEC in this series was unusual beyond 2 years after pull-through.63 Risk factors suggested for HAEC include younger age at diagnosis, anastomotic stricture, and malnutrition.35,63 Other researchers have suggested that a shorter rectal muscular cuff length may also decrease the incidence of enterocolitis79 by decreasing the constriction. All of these ndings further strengthen the hypothesis that intestinal stasis and immature mucosal immunity due to younger age may contribute in the development of enterocolitis. Earlier diagnosis may be a surrogate marker of increased severity of the disease and hence a higher risk of enterocolitis. It is widely believed that longer segments of ganglionated bowel resection may be required to decrease risk of HAEC. A study designed to determine the optimal length of resection of ganglionated

The resected segment of the bowel is sent for pathological review. At our institution, it is regular practice to obtain a longitudinal jelly-roll section of the entire resected specimen, cut, mount it on a slide, and stain using H&E and AChE for analysis.70,71 This enables us to obtain specic measurements of the aganglionated bowel and ganglionated bowel resected.

Surgical course and hospital stay

Intraoperative complications, including tension at the anastomosis and ischemia of the pull-through segment, occur in approximately 6% of children.35 Oral diet is started usually 2 days after the procedure and advanced to full-feeds as tolerated. Total length of stay after a primary pull-through procedure is typically between 3 and 7 days (mean stay at our institution is 3.7 days).3,69 Postoperative care at our institution routinely involves a clinic visit 2-3 weeks after the initial hospitalization. During these visits, interval history is obtained and physical examination is performed, including a digital rectal examination when possible. The children are followed up every 3-4 weeks until they are 3 months of age and less frequently thereafter for several years. Routine postoperative home dilatations are not usually employed.

Postoperative outcomes
Large studies evaluating complications exclusively in children who underwent neonatal denitive pull-through procedures are scarce. The complications data are mostly extrapolations from studies evaluating denitive repair in infants and older children with HSCR. The complications after pull-through can be classied as early (weeks to months) and late (months to years). The postoperative complications are listed in Table 4, and a few common complications are discussed below. There is signicant overlap between early and late complications. Some early complications, including bowel obstruction, prolonged ileus, and pelvic and wound infection, may not be unique to Hirschsprung disease. Anastomotic leak has been reported in 1-10% and cuff abscess in approximately 5% of children operated for HSCR.31,72-75 Factors that have been suggested to increase

Table 4 Early

Post-operative complications Late Bowel obstruction Constipation Enterocolitis Incontinence Stricture

Anastomotic leak and cuff abscess Bowel obstruction Perineal excoriation Stomal complications Wound infection Wound dehiscence

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Table 5

Seminars in Pediatric Surgery, Vol 17, No 4, November 2008

Results of HAEC admissions by length of ganglionated bowel resected63 Overall 5 cm ganglionated bowel resected 18 6 (33%) 0.6 7.7 5 cm ganglionated bowel resected 18 7 (39%) 0.9 3.8 P value 0.99 0.52 0.4

No. of patients No. of children with HAEC (%) No. of admissions, mean Days hospitalized, mean

36 13 (36%) 0.7 5.7

bowel margin assessed the inuence of length of resection ( 5 cm versus 5 cm) on hospital admissions due to HAEC in the rst 2 years after endorectal pull-through.63 Subgroup analyses did not show signicant differences in the number of HAEC admissions (Table 5). The authors concluded that longer length of ganglionated bowel resection may not necessarily aid in decreasing the number of admissions for Hirschsprung enterocolitis. Stricture formation after denitive pull-through procedure is another important complication. The reported incidence of stricture varies widely from 0% to 35%, depending on the denition.80,81 The risk factors for these strictures include anastomotic ischemia or dehiscence and circular anastomosis.80 No particular type of pull-through has been associated with a signicant risk of stricture. However, as discussed previously, stricture has been consistently associated with a higher risk of postoperative enterocolitis. Most strictures can be managed conservatively by adhering to a strict dilation regimen, and only a few persistent strictures require a more aggressive operative correction. Techniques employing oblique anastomosis at the anus may also decrease stricture formation. Stooling frequency is usually high (5 to 10 times per day) during the immediate postoperative period. This generally improves with time and, by 6 months to 1 year after surgery, declines to 1 to 4 times per day.81 Constipation develops after a few weeks to months after pull-through and depends on the type of operation, with a higher incidence in operations with retained aganglionic bowel (eg, Duhamel or Rehbein procedure). Constipation is reported in approximately 8% of children,75,80 but the incidence may be underestimated as more than 20% of children are maintained on stool-softeners after operation.72,82,83 A recently published study83 reported that nearly 37% children had difculty in evacuating stool after operation for HSCR. The functional form of constipation may be managed with conservative measures, such as laxatives or enemas, or may require a multidisciplinary biopyschosocial approach.84 However, in children with persistent constipation as a result of sphincter achalasia, stricture formation, incomplete resection of the aganglionic colon, or dysganglionic bowel may require extensive evaluation with repeat biopsy, CE, and/or ARM. Management strategy depends on the results of the investigations and includes aggressive dilatations, botox, myectomy, or revision pull-through.81,85 Fecal continence is determined usually in children greater than 4 years of age. Large series published in the previous decades on outcomes after pull-through often did not carefully

assess rates of incontinence or likely underestimated them due to the retrospective nature of these studies.81,86 In recent years, lack of fecal continence after pull-through has been reported between 1% and 39%,35,83,87 and in reality, it may be expected to be closer to the higher rather than the lower end of the reported range. Ludman and coworkers86 have shown that surgeons assessment likely underestimates fecal incontinence compared with patients experience of incontinence. Several authors have noted poor continence after pullthrough.83,88 In their landmark study, Catto-Smith and coworkers83 assessed continence after operation for HSCR in a cohort of 84 children with a mean age of 12 years. They noted that fecal urgency was common (58%), with many unable to hold back stool (29%) or discriminate stool consistency (32%), and loose (liquid or pasty) stool was more common in children with long-segment disease. Nearly 20% of the children were using continence aids or kept extra underwear available beyond the toilet-training years. Food intolerance was common after operation for HSCR, and 44% of the children had modied their diet to prevent loose stools or constipation. ARM results showed higher baseline sphincter pressures and marked blunting of the sensation to rectal distension in all children, with more severe blunting in the group with signicant soiling. The authors, however, noted that some aspects of continence (urgency, soiling) and stool consistency improved with age. Enuresis has been reported in 5-26% of children80,83 and has been attributed to iatrogenic pelvic nerve injuries or a neuropathy. The techniques employing laparoscopic-assisted or transanal approach have been designed and modied to decrease iatrogenic pelvic nerve injuries. Late mortality has been reported in 0.7-5.0%72,89 of children undergoing operation for HSCR. Although the exact cause of death in many series is not mentioned, a large percentage of deaths have been closely associated with severe enterocolitis. With improvements in the recognition and treatment, mortality due to HAEC could be minimized. Stooling issues, including constipation and incontinence, and enuresis may have the most impact on the postoperative quality of life (QOL) of the child and the parents.83 A trend of improvement in these stooling issues as the child gets older has been noted by several authors.31,76,82,83,88,90 Presence of long-segment disease has been associated with a worse QOL.83 In a recent prospective follow-up study, Hartman and coworkers90 evaluated global and disease-specic QOL of children who had undergone operative management of HSCR. The authors found that fecal incontinence, constipation, and the emotional response to the disease (such as

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15. Moore SW. Congenital anomalies and genetic associations in Hirschsprungs disease. In: Holschneider AM, Puri P, eds. Hirschsprungs Disease and Allied Disorders (ed 3). New York, NY: Springer, 2008: 115-31. 16. Amiel J, Sproat-Emison E, Garcia-Barcelo M, et al. Hirschsprung disease, associated syndromes and genetics: a review. J Med Genet 2008;45:1-14. 17. Kim JH, Yoon KO, Kim JK, et al. Novel mutations of RET gene in Korean patients with sporadic Hirschsprungs disease. J Pediatr Surg 2006;41:1250-4. 18. Fitze G, Cramer J, Ziegler A, et al. Association between c135G/A genotype and RET proto-oncogene germline mutations and phenotype of Hirschsprungs disease. Lancet 2002;359:1200-5. 19. Spouge D, Baird PA. Hirschsprung disease in a large birth cohort. Teratology 1985;32:171-7. 20. Ryan ET, Ecker JL, Christakis NA, et al. Hirschsprungs disease: associated abnormalities and demography. J Pediatr Surg 1992;27: 76-81. 21. Badner JA, Sieber WK, Garver KL, et al. A genetic study of Hirschsprung disease. Am J Hum Genet 1990;46:568-80. 22. Swenson O. Hirschsprungs disease: a review. Pediatrics 2002;109: 914-8. 23. Vizi ES, Zseli J, Kontor E, et al. Characteristics of cholinergic neuroeffector transmission of ganglionic and aganglionic colon in Hirschsprungs disease. Gut 1990;31:1046-50. 24. Kusafuka T, Puri P. Altered mRNA expression of the neuronal nitric oxide synthase gene in Hirschsprungs disease. J Pediatr Surg 1997; 32:1054-8. 25. Vanderwinden JM, Rumessen JJ, Liu H, et al. Interstitial cells of Cajal in human colon and in Hirschsprungs disease. Gastroenterology 1996; 111:901-10. 26. Kleinhaus S, Boley SJ, Sheran M, et al. Hirschsprungs disease: a survey of the members of the Surgical Section of the American Academy of Pediatrics. J Pediatr Surg 1979;14:588-97. 27. Sherman JO, Snyder ME, Weitzman JJ, et al. A 40-year multinational retrospective study of 880 Swenson procedures. J Pediatr Surg 1989; 24:833-8. 28. Suita S, Taguchi T, Ieiri S, et al. Hirschsprungs disease in Japan: analysis of 3852 patients based on a nationwide survey in 30 years. J Pediatr Surg 2005;40:197-201, discussion 201-2. 29. Puri P, Montedonico S. Hirschsprungs Disease: clinical features. In: Holschneider AM, Puri P, eds. Hirschsprungs Disease and Allied Disorders (ed 3). New York, NY: Springer, 2008:107-13. 30. Klein MD, Coran AG, Wesley JR, et al. Hirschsprungs disease in the newborn. J Pediatr Surg 1984;19:370-4. 31. Polley TZ Jr, Coran AG, Wesley JR. A ten-year experience with ninety-two cases of Hirschsprungs disease. Including sixty-seven consecutive endorectal pull-through procedures. Ann Surg 1985;202: 349-55. 32. Clark DA. Times of rst void and rst stool in 500 newborns. Pediatrics 1977;60:457-9. 33. Dasgupta R, Langer JC. Hirschsprung disease. Curr Probl Surg 2004; 41:942-88. 34. Hackam DJ, Reblock KK, Redlinger RE, et al. Diagnosis and outcome of Hirschsprungs disease: does age really matter? Pediatr Surg Int 2004;20:319-22. 35. Teitelbaum DH, Cilley RE, Sherman NJ, et al. A decade of experience with the primary pull-through for hirschsprung disease in the newborn period: a multicenter analysis of outcomes. Ann Surg 2000;232: 372-80. 36. Diamond IR, Casadiego G, Traubici J, et al. The contrast enema for Hirschsprung disease: predictors of a false-positive result. J Pediatr Surg 2007;42:792-5. 37. Bill AH, Chapman ND. The enterocolitis of Hirschsprungs disease: its natural history and treatment. Am J Surg 1962;103:70-4. 38. Teitelbaum DH, Qualman SJ, Caniano DA. Hirschsprungs disease. Identication of risk factors for enterocolitis. Ann Surg 1988;207: 240-4.

feelings of shame) diminished with growing age. Diseasespecic improvement was thought to be due to several reasons, including development of more muscle control and the aid of tools (such as diapers, enemas, and dietary manipulations). They also suggested that children learn to cope with their disease over the years by developing stronger psychosocial competency skills. Notwithstanding the improvement with time, the goal of the surgeon is to minimize these complications by providing meticulous operative, postoperative, and long-term follow-up care.

Conclusions
Improvements in diagnosis of HSCR and critical care of newborns have enabled surgeons to perform denitive repair at earlier ages than possible in the previous years. Neonatal primary pull-through procedures have become increasingly popular with reports of good outcomes. Despite satisfactory outcomes in the majority of the children, a close and long-term follow-up is recommended for early detection and management of complications.

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