Background

Hirschsprung disease is a developmental disorder characterized by absence of ganglia in the distal

colon, resulting in a functional obstruction.[1] See the image below.

Hirschsprung disease. Contrast enema demonstrating transition zone in the rectosigmoid

region.

Although this condition was described by Ruysch in 1691 and popularized by Hirschsprung in 1886,
the pathophysiology was not clearly determined until the middle of the 20th century, when Whitehouse
and Kernohan reported aganglionosis of the distal intestine as the cause of obstruction in a patient
series.[2]
In 1949, Swenson described the first consistent definitive procedure for Hirschsprung disease,
rectosigmoidectomy with coloanal anastomosis. Since then, other operations have been described,
including the Duhamel and Soave techniques. More recently, earlier diagnosis and advances in
surgical technique have resulted in decreased morbidity and mortality for patients with Hirschsprung
disease.
Most cases of Hirschsprung disease are diagnosed in the newborn period. Hirschsprung disease
should be considered in any newborn that fails to pass meconium within 24-48 hours of birth.
Although contrast enema is useful in establishing the diagnosis, full-thickness rectal biopsy remains
the criterion standard. Once the diagnosis is confirmed, the definitive treatment is to remove
aganglionic bowel and to restore continuity of the healthy bowel with the distal rectum, with or without
an initial intestinal diversion.
Also see Pediatric Hirschsprung Disease and Hirschsprung Disease Imaging.

Pathophysiology
Three nerve plexuses innervate the intestine: the submucosal (Meissner) plexus, the myenteric
(Auerbach) plexus, and the smaller mucosal plexus. All of these plexuses are finely integrated and
involved in all aspects of bowel function, including absorption, secretion, motility, and blood-flow
regulation.
Normal motility is primarily under the control of intrinsic neurons. In the absence of extrinsic signals,
bowel function remains adequate, owing to the complex reflexive architecture of the enteric nervous
system (ENS). For this reason, the ENS is often referred to as the second brain. Intestinal smooth
muscle contraction and relaxation are under the control of enteric ganglia. Most enteric nervous
activation causes muscle relaxation, mediated by nitric oxide and other enteric neurotransmitters.
Extrinsic neural afferents to the ENS contain cholinergic and adrenergic fibers. The cholinergic fibers
generally cause contraction, while the adrenergic fibers mainly cause inhibition.
In patients with Hirschsprung disease, both myenteric and submucosal plexuses are absent. The
anus is invariably affected, and aganglionosis continues proximally for a variable distance. In the
absence of ENS reflexes, control of the intestinal smooth muscle is overwhelmingly extrinsic. The
activity of both the cholinergic system and the adrenergic system is 2-3 times that of normal intestine.
The adrenergic (excitatory) system is thought to predominate over the cholinergic (inhibitory) system,
leading to an increase in smooth muscle tone. With the loss of the intrinsic enteric relaxing impulses,
the increased muscle tone is unopposed. This phenomenon leads to an imbalance of smooth muscle
contractility, uncoordinated peristalsis, and a functional obstruction.

Enteric ganglion cells are derived from the neural crest during embryonic development. In normal
development, neuroblasts are found in the esophagus by the fifth week of gestation, and they migrate
to the small intestine by the seventh week and to the colon by the twelfth week. [3] One possible
etiology of Hirschsprung disease is the arrest of aboral neuroblast migration. Alternatively, while
normal cell migration may occur, neuroblasts may be subject to apoptosis, failure of proliferation, or
improper differentiation within the affected distal intestinal segment. Fibronectin, laminin, neural cell
adhesion molecule (NCAM), and neurotrophic factors present in the intestinal stroma are necessary
for normal enteric ganglion development, while their absence or dysfunction may also have a role in
the etiology of Hirschsprung disease.[4, 5, 6]
Recently, investigators have identified several genes whose improper expression results in a
Hirschsprung disease phenotype. The RET protooncogene has been implicated in several studies of
Hirschsprung pathogenesis.
In 2011, So and colleagues discovered that rare variants of RET were associated with more severe
phenotypes among Chinese Hirschsprung patients.[7] Leon and colleagues in 2012 determined that
sporadic RET coding sequence mutations in Hirschsprung patients resulted in protein truncations that
would deter cell membrane translocation and anchoring. [8]
In 2013, Qin and colleagues performed microarray analyses of aganglionic colon and normal tissue.
They discovered 622 genes with anomalous expression in the aganglionic tissue, and
myenteric HAND2 expression was significantly attenuated.[9]
In a comparison of gene expression among normal and aganglionic colon, Chen and colleagues
determined that overexpression of DVL1 and DVL3 genes was associated with the Hirschsprung
phenotype.[10]
In a 2013 review, Butler Tjaden and colleagues report that mutations in the genes,RET, GDNF,
GFR1, NRTN, EDNRB, ET3, ZFHX1B, PHOX2b, SOX10, and SHHare present in approximately
50% of Hirschsprung disease patients.[11]
These studies indicate the complexity of Hirschsprung pathogenesis, while ongoing studies of genetic
and environmental factors will continue to elucidate this problematic disease in the future.
While enteric ganglion cells are the primary pathogenic entity in Hirschsprung disease, some studies
suggest other cell types may also be implicated. When extrinsically stimulated, smooth muscle cells in
aganglionic colon are electrically inactive.[12] Furthermore, interstitial cells of Cajal, pacemaker cells
connecting enteric nerves and intestinal smooth muscle, have also been postulated as an important
contributing factor.[13, 14, 15] These findings suggests that Hirschsprung pathophysiology is not limited to
cells normally present within enteric ganglia, alone.

Epidemiology
Frequency
United States
Hirschsprung disease affects approximately 1 case per 5400-7200 newborns annually.
International
While the exact worldwide incidence is unknown, international studies have reported rates ranging
from approximately 1 case per 1500-7000 newborns. [16, 17]

Mortality/Morbidity
Hirschsprung disease is confined to the rectosigmoid region in about 75% of cases. Approximately
60% of infants with Hirschsprung disease have an associated condition, ranging from subtle to
severe. Ophthalmologic problems affect 43% of infants, 20% have congenital anomalies of the
genitourinary tract, 5% have congenital heart disease, 5% have hearing impairment, and 2% have
central nervous system anomalies.[18, 19]
Hirschsprung disease is associated with chromosomal abnormalities or syndromes in approximately
9% of cases.[19] It may be associated with the following syndromes:

Down syndrome: Trisomy 21 is characterized by physical growth delays, characteristic facial

features, and varying ranges of intellectual disability.
Neurocristopathy syndromes: Neurocristopathies represent a broad range of disorders
characterized by aberrant neural crest development.
Waardenburg-Shah syndrome: Patients have a sensorineural hearing deficit and
hypopigmentation of the iris and hair.
Yemenite deaf-blind syndrome: Affected patients have a mutation in the SRY-related HMGbox gene. The syndrome is characterized by a severe hearing deficit, nystagmus, patchy
pigmentation abnormalities, and defects of the iris and cornea.
Piebaldism: Patients have patches of hypopigmentation due to a congenital disorder of
melanocytes. Underlying pathology in the neural crest development is also common to Hirschsprung
disease.
Multiple endocrine neoplasia type II (MEN2): Mutations in the RETprotooncogene are
associated with medullary thyroid cancer in MEN2 and with Hirschsprung disease.
Congenital central hypoventilation syndrome (CCHS): CCHS is characterized by absent
autonomic control of ventilation. PHOX2B transcription factor mutations may be associated in both
CCHS and Hirschsprung disease.
Untreated aganglionic megacolon in infancy may result in a mortality rate as high as 80%. Operative
mortality rates for any of the interventional procedures are very low. Even in cases of treated
Hirschsprung disease, the mortality rate may approach 30% as a result of severe enterocolitis.
Possible complications of surgery include anastomotic leak (5%), anastomotic stricture (5-10%),
intestinal obstruction (5%), pelvic abscess (5%), and wound infection (10%). Long-term complications
mostly affect patients with long-segment disease. They include chronic obstructive symptoms,
incontinence, chronic constipation, enterocolitis, and late mortality. Although many patients encounter
one or more of these problems postoperatively, long-term follow-up studies have shown that greater
than 90% of children experience significant improvement. [20]Patients with a syndromic association and
those with long-segment disease have poorer outcomes. [21, 22, 23]

Race
Hirschsprung disease affects all races; however, it is roughly 3 times more common among AsianAmericans.[24]

Sex
Hirschsprung disease occurs more often in males than in females, with a male-to-female ratio of
approximately 4:1; however, the ratio in long-segment disease decreases to 2:1.

Age
Hirschsprung disease is uncommon in premature infants.
The age at which Hirschsprung disease is diagnosed has progressively decreased over the past
century. In the early 1900s, the median age at diagnosis was 2-3 years; from the 1950s to 1970s, the
median age was 2-6 months. Currently, approximately 90% of patients with Hirschsprung disease are
diagnosed in the newborn period.[25]

Workup

Laboratory Studies
Chemistry panel: For most patients, electrolyte and renal panel findings are within reference ranges.
Children presenting with diarrhea may have findings consistent with dehydration. Test results may aid
in directing fluid and electrolyte management.
Complete blood count (CBC): This test is obtained to ensure that the preoperative hematocrit and
platelet count are suitable for surgery. In most cases, values are within reference ranges.

Coagulation studies: These studies are obtained to ensure that clotting disorders are corrected before
surgery. Coagulation parameters are expected to be within reference ranges.

Imaging Studies
Plain abdominal radiographs may show distended bowel loops with a paucity of air in the rectum.
With regard to barium enema, avoid washing out the distal colon with enemas before obtaining the
contrast enema because this may distort a low transition zone. The catheter is placed just inside the
anus without inflation of the balloon to avoid distortion of a low transition zone and perforation.
Radiographs are taken immediately after hand injection of contrast and 24 hours later. The classic
finding of Hirschsprung disease is a narrowed distal colon with proximal dilation; however, findings are
difficult to interpret in neonates (< 1 mo) and do not demonstrate this transition zone approximately
25% of the time.[30] Retention of rectal contrast for longer than 24 hours after the barium enema has
been performed also suggests a diagnosis of Hirschsprung disease.

Other Tests
Anorectal manometry detects the relaxation reflex of the internal sphincter after distension of the
rectal lumen. This normal inhibitory reflex is presumed absent in patients with Hirschsprung disease.
[31]
Swenson initially used this test. In the 1960s, it was refined but has fallen out of favor because of its
many limitations. Sedation is usually necessary. Although some authors find this test useful, falsepositive results have been reported in up to 62% and false-negative results have been reported in up
to 24% of cases. Because of these limitations, anorectal manometry is not commonly performed in the
United States.
Echocardiography and chromosomal analyses may be warranted to evaluate for associated
congenital conditions.[#WorkupProcedures]

Procedures
Full-thickness rectal biopsy
The definitive diagnosis of Hirschsprung disease is confirmed by a full-thickness rectal biopsy
demonstrating absence of ganglion cells. The specimen must be obtained at least 1.5 cm above the
dentate line because aganglionosis may normally be present below this level. Disadvantages of fullthickness rectal biopsy include the frequent necessity of general anesthesia and risks of bleeding and
scarring.

Suction rectal biopsy

Recently, simple suction rectal biopsy has been used to obtain tissue for histologic examination.
Rectal mucosa and submucosa are sucked into the suction device, and a self-contained cylindrical
blade excises the tissue. The distinct advantage of the suction biopsy is that it can be easily
performed at the bedside. The diagnostic yield of the full-thickness rectal biopsy is significantly better
than that of the suction biopsy.

Histologic Findings

Acetylcholinesterase staining reveals hypertrophied nerve trunks throughout the lamina propria and
muscularis propria layers of the bowel wall. Recent studies suggest that immunohistochemical (IHC)
staining for calretinin might be more accurate than acetylcholinesterase staining in diagnosing
congenital aganglionosis among suction biopsy specimens.[32, 33]
Guinard-Samuel and colleagues evaluated the diagnostic value of calretinin immunochemistry for
Hirschsprung disease in 131 pediatric rectal biopsies. Of 131 biopsies, 130 were accurately
diagnosed based on calretinin staining. When an additional 12 cases were considered doubtful based
on the standard evaluation method, they were accurately diagnosed with calretinin IHC. The
investigators found calretinin superior to acetylcholinesterase to complete histology.[33] Yang and
colleagues in 2013 correctly identified the presence or absence of ganglion cells via IHC staining for
calretinin and microtubule associated protein-2 (MAP-2) in 52 samples of normal and aganglionic
bowel. Calretinin IHC correctly identified ganglia in 11 samples originally reported as false positives
from surgical pathology reports.[34]

Differential Diagnoses

Constipation
Hypothyroidism
Ileus
Intestinal Motility Disorders
Intestinal Pseudo-obstruction: Surgical Perspective
Irritable Bowel Syndrome
Megacolon, Acute
Megacolon, Chronic
Megacolon, Toxic

Medical Care
The general goals of medical care are 3-fold: (1) to treat the manifestations and complications of
untreated Hirschsprung disease, (2) to institute temporizing measures until definitive reconstructive
surgery, and (3) to manage postoperative bowel function.
The goals of medical care are to maintain normal fluid and electrolyte balance, to minimize bowel
distension and prevent perforation, and to manage complications. Intravenous fluid resuscitation and
maintenance, nasogastric decompression, and administration of intravenous antibiotics (as indicated)
remain the cornerstones of initial medical management.
Colonic lavage, consisting of mechanical irrigation with a large-bore rectal tube and large volumes of
irrigant, may be required.
Intravenous administration of balanced salt solutions may help prevent electrolyte imbalances.
Postoperatively, routine colonic irrigation and prophylactic antibiotic therapy may decrease the risk of
developing enterocolitis.[35, 36] For patients who do develop enterocolitis, nasogastric decompression,
intravenous fluids, antibiotics, and colonic lavage may be necessary. Sodium cromoglycate, a mast
cell stabilizer, has also been reported to benefit these patients. [37]
Botulinum toxin injections within the contracted internal sphincter mechanism have been reported to
induce more normal patterns of bowel movements in postoperative patients with enterocolitis. [38]
Also see Pediatric Hirschsprung Disease and Hirschsprung Disease Imaging.

Surgical Care

Surgical management of Hirschsprung disease begins with the initial diagnosis, which often requires a
full-thickness rectal biopsy. Traditionally, a diverting colostomy was created at the time of diagnosis,
and definitive repair was delayed until the child grew to a weight of 10 kilograms.
This standard of treatment was developed in the 1950s after Swenson reported relatively high leak
and stricture rates with a single-stage operation. Advancements in anesthesia administration and
hemodynamic monitoring have led many surgeons to advocate a single-stage pull-through procedure
without initial diversion. Contraindications to a single-stage procedure include severely dilated
proximal bowel, severe enterocolitis, perforation, malnutrition, and inability to accurately determine the
zone of transition between healthy and aganglionic bowel, intraoperatively.
For neonates undergoing creation of a diverting colostomy, the transition zone is identified and the
colostomy is placed proximal to this area. The presence of ganglion cells at the colostomy site must
be unequivocally confirmed by histological evaluation of a frozen-section biopsy. Either a loop- or endcolostomy is created at the surgeons discretion.
A number of definitive procedures demonstrate excellent results when performed by experienced
surgeons. The most commonly performed repairs are the Swenson, Duhamel, and Soave procedures.
In any elective operation for Hirschsprung disease, a robust preoperative colon cleanse must be
performed.[39]Intraoperatively, histological examination of a frozen-section biopsy must confirm the
presence of ganglion cells at the proximal margin of bowel intended for anastomosis. A meta-analysis
performed by Friedmacher and Puri in 2011 reported that residual aganglionosis and transition-zone
tissue account for persistent bowel symptoms in one third of patients undergoing a second, corrective
pull-through procedure.[40]
Also see Pediatric Hirschsprung Disease and Hirschsprung Disease Imaging.

Swenson procedure
The Swenson procedure was the original pull-through procedure used to treat Hirschsprung disease.
The aganglionic segment is resected down to the sigmoid colon and rectum, and an oblique
anastomosis is performed between the normal colon and the low rectum.

Duhamel procedure
The Duhamel procedure was first described in 1956 as a modification to the Swenson procedure. A
retrorectal approach is used, and a significant segment of aganglionic rectum is retained.
The aganglionic bowel is resected down to the rectum, and the rectum is oversewn. The proximal
bowel is then brought through the retrorectal space (between rectum and sacrum), and an end-to-side
anastomosis is performed on the remaining rectum.

Soave (endorectal) procedure

The Soave procedure was introduced in the 1960s. The mucosa and submucosa of the rectum are
resected, and the ganglionic bowel is pulled through the aganglionic muscular cuff of the rectum.
The original operation did not include a formal anastomosis, relying on scar tissue formation between
the pull-through segment and the surrounding aganglionic bowel. The procedure has since been
modified by Boley to include a primary anastomosis at the anus.

Anorectal myomectomy
For patients with extremely short-segment Hirschsprung disease, anorectal myomectomy is an
alternative surgical option.
The surgeon removes a 1-cm-wide strip of extramucosal rectal wall, beginning immediately proximal
to the dentate line and extending to the normal ganglionic rectum. The mucosa and submucosa are
preserved and closed.

Procedures for long-segment Hirschsprung disease

Patients with total colonic involvement require modified procedures to exclude the aganglionic colon
while preserving maximal absorptive epithelium. The goal of these procedures is to bypass
dysfunctional bowel while maximizing the chance of postoperative nutritional function and growth.

Most procedures include a side-to-side anastomosis of healthy small bowel to a short segment of the
aganglionic/absorptive colon. Either a short right colonic patch or the small bowel is anastomosed to
the rectal wall, similar to a Duhamel procedure. Importantly, a short patch (< 10 cm) is maintained.
Long-segment anastomoses, such as the Martin procedure, are no longer advocated.

Laparoscopic approach
A laparoscopic approach to the surgical treatment of Hirschsprung disease was first described in 1999
by Georgeson.[41] The transition zone is first identified laparoscopically, after which the rectum is
mobilized below the peritoneal reflection. A transanal mucosal dissection is performed, and the rectum
and aganglionic bowel is prolapsed through the anus. The healthy proximal bowel is anastomosed to
the rectal cuff. Functional outcomes of this laparoscopic approach appear to be equivalent to open
techniques based on short-term results.[41, 42, 43]

Transanal pull-through procedures

Transanal pull-through procedures have been described in which no intra-abdominal dissection is
performed.[21, 44] The entire procedure is performed transanally in a manner similar to perineal
rectosigmoidectomy.
The mucosa and is incised circumferentially above the dentate line, and a submucosal dissection is
directed proximally. The muscularis is incised circumferentially, and the remainder of the dissection is
carried external to the rectal wall until the transition zone is identified. Upon confirmation of ganglion
cells on frozen section, the aganglionic bowel is resected and an anastomosis is performed.
Outcomes of the transanal pull-through procedure have been similar to open single-stage
approaches, and analgesia requirements and hospital stays are decreased. [21, 45, 46] Recent studies also
report lower rates of postoperative incontinence and shorter operating times among transanal pullthrough procedures.[47, 48]

Novel strategies
Several other creative approaches have been described, including a modification of the transanal
approach with transabdominal open or laparoscopic assistance, single-incision laparoscopic
endorectal pull-through (SILEP), and natural orifice transluminal endoscopic surgery (NOTES). [49, 50, 51, 52]
Regenerative strategies are under investigation to restore function in aganglionic intestine. Stem cell
transplantation to regenerate the enteric nervous system is a subject of many recent experimental
series.[53] Stem cells derived from the neural crest persist into adulthood, and several are capable of
proliferation and differentiation within the intestine. Hotta and colleagues recently reported successful
generation of functional enteric neurons from precursor cells transplanted into recipient colon.
[54]
Though auspicious, these discoveries warrant further study to translate cell-based therapies into
clinical practice.

Consultations

Pediatric surgeons
Pediatric gastroenterologists
Geneticists (if a heritable or chromosomal anomaly is suspected)

Diet
The patient should have nothing by mouth for 6-8 hours prior to operation.
Tube feeding or formula/breast milk may resume with return of bowel function.
Diets of consisting of fresh fruits, vegetables, and high-fiber articles may improve postoperative bowel
function.

Activity
Limit physical activity for about 6 weeks to allow incisions to heal properly (applies more to older
children).

Medication Summary
The goals of pharmacotherapy are to eradicate infection, to reduce morbidity, and to prevent
complications.

Antibiotics
Class Summary
Empiric antimicrobial therapy must be comprehensive and cover all likely pathogens in the context of
this clinical setting. Antibiotic selection should be guided by blood culture sensitivity whenever
feasible.
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Ampicillin (Marcillin, Omnipen, Principen)

Bactericidal activity against susceptible organisms. Alternative to amoxicillin when unable to take
medication orally.
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Gentamicin (Garamycin, Jenamicin)

Aminoglycoside antibiotic for gram-negative coverage. Used in combination with both an agent
against gram-positive organisms and one that covers anaerobes. Not the DOC. Consider if penicillins
or other less-toxic drugs are contraindicated, when clinically indicated, and in mixed infections caused
by susceptible staphylococci and gram-negative organisms.
Dosing regimens are numerous; adjust dose based on CrCl and changes in volume of distribution.
May be administered IV/IM.
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Metronidazole (Flagyl)

Imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. Used in
combination with other antimicrobial agents (except for Clostridium difficile enterocolitis).

Toxins
Class Summary
Induce more normal patterns of bowel movements in postoperative patients with enterocolitis.
View full drug information

OnabotulinumtoxinA (BOTOX)

Binds to receptor sites on motor nerve terminals and inhibits release of acetylcholine, which in turn
inhibits transmission of impulses in neuromuscular tissue.