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 colon

Anorectal 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 Disease
Pathogenesis
In 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 Presentation
The 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.
Diagnosis
The 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.
Treatment
A 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 93-5
Congenital 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
Gene

Associated Syndromes[*]

Pathogenesis

RET

MEN IIA

Abnormal development of enteric nervous

system

c-kit

Piebaldism
Waardenburg type 4 (ShahWaardenburg)

SOX10

Shah-Waardenburg

Reduced survival of neural cells

ZFHXIB Movat-Wilson
ErbB2

Impaired 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, Acetylcholinesterase
positive 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. 9322B ). 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 proteininduced 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. Liacouras
Hirschsprung 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, SmithLemli-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 CONSTIPATION
VARIABLE

FUNCTIONAL

HIRSCHSPRUNG DISEASE

HISTORY
Onset of
constipation

After 2 yr of age

At birth

Encopresis

Common

Very rare

VARIABLE

FUNCTIONAL

HIRSCHSPRUNG DISEASE

Failure to thrive

Uncommon

Possible

Enterocolitis

None

Possible

Forced bowel
training

Usual

None

Uncommon

Common

EXAMINATION
Abdominal
distention

Poor weight gain Rare

Common

Rectum

Filled with stool

Empty

Rectal
Examination

Stool in rectum

Explosive passage of stool

Malnutrition

None

Possible

INVESTIGATIONS
Anorectal
manometry

Relaxation of internal anal

sphincter

Failure of internal anal sphincter

relaxation

Rectal biopsy

Normal

No ganglion cells, increased

acetylcholinesterase staining

Barium enema

Massive amounts of stool, no

transition zone

Transition 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