1 Hirschsprung’s Disease in Africa in the 21 st Century 1. Definition and background Hirschsprung's disease (HD) is a form of functional intestinal obstruction caused by absence of ganglion cells in the myenteric and submucosal plexuses of the intestine, which results in absent peristalsis in the affected bowel. It is also referred to as congenital megacolon or congenital colonic aganglionosis, and occurs in 1 in 5,000- 7,200 newborns. (1-3)In Africa only 20-40% present as neonates, compared to more than 90% in developed countries. (4-8)The male: female ratio is 4:1, but this becomes equal in long segment disease and familial cases. Congenital megacolon was first described by Ruysch in 1691, and then more widely reported by Danish Paediatrician Harald Hirschsprung in 1886. The pathophysiology of aganglionosis was not determined until the middle of the 20th century following which Swenson recommended rectosigmoidectomy as the optimal treatment in 1948. (9-10) Initially this operation was performed without colostomy, but the debilitated and malnourished state in which many children presented caused most surgeons to adopt a multi-staged approach. Recent advances and refinements in surgical technique have resulted in a shift towards one-stage and minimal access procedures for the treatment of this disease. (1-2) In Africa, ignorance and poverty on the part of the parents, late presentation with attendant complications, limited access to trained paediatric surgeons and limitation of facilities for prompt diagnosis characterize management of this disease. Hence, multiple stages of management still predominate in sub Saharan Africa, (7)(8) (11) 2. Embryology and aetiology Neural crest cells originate in the vagal neural crest and then migrate craniocaudally into the embryonic intestine reaching the rectum at the 12 th week. Auerbach’s myenteric plexus layer is formed first and Meissner’s submucosal plexus develops later, with cells maturing after arriving at their destination. (2) Abnormalities in the microenvironment result in the neural crest cells failing to reach the distal bowel. There are differences in extracellular matrix proteins (fibronectin, laminin), abnormal cell-cell interactions (absent neural cell adhesion molecule) and absence of neurotrophic factors in aganglionic bowel when compared with normal bowel. (12-13) Other investigators suggest that neural crest cells originate in both vagal and sacral sites and migrate toward the middle of the intestine, raising the possibility that the neural crest cells get to their destination, but then fail to survive, proliferate, or differentiate. (14) Additionally, the observation that the smooth muscle cells of aganglionic colon are electrically inactive points to a myogenic component in the development of HD. (15) Abnormalities in the pacemaker Interstitial Cells of Cajal, have also been postulated as an important contributing factor. (16) 3. Genetic Abnormalities Sporadic occurrence accounts for 80% to 90% of cases of HD. Variable expressivity and incomplete sex- dependent penetrance are observed, suggestive of a more complex pattern of inheritance and the involvement of several genes. A positive family history occurs in approximately 10% of children, especially those with longer segment disease. Children with Down syndrome and other genetic abnormalities also have a higher incidence of HD. HD has been associated with the RET proto-oncogene the endothelin family of genes, SOX-10 gene and SIP1.
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Hirschsprung’s Disease in Africa in the 21st Century
1. Definition and background
Hirschsprung's disease (HD) is a form of functional intestinal obstruction caused by absence of ganglion cells in
the myenteric and submucosal plexuses of the intestine, which results in absent peristalsis in the affected bowel.
It is also referred to as congenital megacolon or congenital colonic aganglionosis, and occurs in 1 in 5,000-
7,200 newborns. (1-3)In Africa only 20-40% present as neonates, compared to more than 90% in developed
countries. (4-8)The male: female ratio is 4:1, but this becomes equal in long segment disease and familial cases.
Congenital megacolon was first described by Ruysch in 1691, and then more widely reported by Danish
Paediatrician Harald Hirschsprung in 1886. The pathophysiology of aganglionosis was not determined until the
middle of the 20th century following which Swenson recommended rectosigmoidectomy as the optimal
treatment in 1948. (9-10) Initially this operation was performed without colostomy, but the debilitated and
malnourished state in which many children presented caused most surgeons to adopt a multi-staged approach.
Recent advances and refinements in surgical technique have resulted in a shift towards one-stage and minimal
access procedures for the treatment of this disease. (1-2) In Africa, ignorance and poverty on the part of the
parents, late presentation with attendant complications, limited access to trained paediatric surgeons and
limitation of facilities for prompt diagnosis characterize management of this disease. Hence, multiple stages of
management still predominate in sub Saharan Africa, (7)(8) (11)
2. Embryology and aetiology
Neural crest cells originate in the vagal neural crest and then migrate craniocaudally into the embryonic
intestine reaching the rectum at the 12th
week. Auerbach’s myenteric plexus layer is formed first and Meissner’s
submucosal plexus develops later, with cells maturing after arriving at their destination. (2)
Abnormalities in the microenvironment result in the neural crest cells failing to reach the distal bowel. There
are differences in extracellular matrix proteins (fibronectin, laminin), abnormal cell-cell interactions (absent
neural cell adhesion molecule) and absence of neurotrophic factors in aganglionic bowel when compared with
normal bowel. (12-13)
Other investigators suggest that neural crest cells originate in both vagal and sacral sites and migrate toward the
middle of the intestine, raising the possibility that the neural crest cells get to their destination, but then fail to
survive, proliferate, or differentiate. (14) Additionally, the observation that the smooth muscle cells of
aganglionic colon are electrically inactive points to a myogenic component in the development of HD. (15)
Abnormalities in the pacemaker Interstitial Cells of Cajal, have also been postulated as an important
contributing factor. (16)
3. Genetic Abnormalities
Sporadic occurrence accounts for 80% to 90% of cases of HD. Variable expressivity and incomplete sex-
dependent penetrance are observed, suggestive of a more complex pattern of inheritance and the involvement of
several genes.
A positive family history occurs in approximately 10% of children, especially those with longer segment
disease. Children with Down syndrome and other genetic abnormalities also have a higher incidence of HD.
HD has been associated with the RET proto-oncogene the endothelin family of genes, SOX-10 gene and SIP1.
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It is unclear exactly how these genetic abnormalities result in the phenotype of HD. Development of the disease
is a multi-genic phenomenon that can occur at any number of stages during the normal process of neural crest
cell migration, differentiation, and survival.
Animal models demonstrate that some mutations may produce early maturation or differentiation of neural crest
cells, and mutations in the RET proto-oncogene likely act by depriving the migrating neural crest cells of an
adequately supportive microenvironment. (17)
The genetic mutations associated with HD can best be understood by examining how they relate to the family of
neurocristopathies, many of which have similar genetic patterns (Table 1).
TABLE 1
Syndromes and Genetic Abnormalities Associated with Hirschsprung's Disease.
Syndrome Identified Genetic Basis
Down syndrome Trisomy 21
Neurocristopathy syndromes
Waardenberg-Shah syndrome
Yemenite deaf-blind-hypopigmentation
Piebaldism
Other hypopigmentation syndromes
Endothelin and SOX-10
Goldberg-Shprintzen syndrome Possibly SIP1
Multiple Endocrine Neoplasia 2 RET
Central hypoventilation syndrome (Ondine's curse) Unknown
4. Pathology
Normal intestinal motility is primarily under the control of intrinsic neurons that control both contraction and
relaxation of smooth muscle, with relaxation predominating. Extrinsic control is mainly through the cholinergic
and adrenergic fibers (2) In HD, ganglion cells are absent, leading to a marked increase in smooth muscle tone
and an imbalance of smooth muscle contractility, uncoordinated peristalsis, and a functional obstruction.
The gross appearance of a bowel segment affected by HD is an aganglionic distal spastic and narrow segment
with a proximal hypertrophic and dilated bowel separated by a 5-10cm transition zone.
Histologically, the absence of ganglion cells in the distal intestine is the hallmark of the disease. Ganglion cells
are absent in both the submucosal (Meissner's) plexus and the myenteric (Auerbach's) plexus. There is usually a
marked hypertrophy of nerve fibers that extend into the submucosa that may be seen on routine hematoxylin-
eosin stained slides but are more easily seen using an acetylcholinesterase stain (Figure 1 and 2) Cases with
long segment or total colon HD may not have nerve hypertrophy on rectal biopsy.
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Figure 1: Normal ganglion cells in myenteric plexus
Figure 2: Staining with acetylcholinesterase shows abnormal pattern of hypertrophic nerves in HD (source
BHC)
Aganglionosis is always present in the rectum and progresses proximally and continuously for a varying
distance. Exceptions have been documented (skip lesions (18)), though these cases are so rare that the finding
of ganglion cells proximal to an aganglionic segment indicates that the biopsy was taken within the transition
zone. The transition zone has a 5-10cm progressive decrease of ganglion cells until the aganglionosis level is
reached. The transition zone may not be symmetric circumferentially, which has implications in deciding how
much bowel to remove.
5. Classification
Hirschsprung’s disease is classified based on the length of involved bowel and location of transition zone.
Length of bowel involved Proportion of HD cases
Rectosigmoid 70-80%
Long segment (above sigmoid) 10- 25%
Total colonic 3- 15%
Total intestinal 0.4- 4%
Ultrashort segment <1%
6. Clinical presentations
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There are three ways that HD characteristically presents: neonatal bowel obstruction, chronic constipation, and
enterocolitis. Most patients in the African series presented with intestinal obstruction while about 30%
presented with constipation, 11% with enterocolitis, and 2% with intestinal perforation. (5-7) (11)
In developed countries, the age at which HD is diagnosed has progressively decreased over the past century so
that 90% of patients with HD are now diagnosed in the newborn period. In Africa less than 50% of HD cases
present as neonates, and those usually present with complete intestinal obstruction or cecal perforation and
suffer high morbidity and mortality. (7) (8) (11) (19) (20) Presentation in adulthood has also been reported.
(21), (22)
6.1. Neonatal bowel obstruction
There is a history of delayed passage of meconium in about 80% of newborns with HD. A study of normal
African newborns found that 75% passed meconium within 24 hours of birth, 92% within 48 hours and 98%
within 72 hours. (23) A delay of more than 48 hours in passage of meconium should raise concern about HD.
6.2. Chronic constipation
Many children in the African settings with delayed passage of meconium or infrequent passage of stool are
managed with traditional enemas. (Figure 3 (24))
Children with HD may present later with chronic constipation, failure to thrive, gross abdominal distention and
dependence on enemas without significant encopresis. (Figures 4 and 5) The impacted sigmoid megacolon
may also undergo volvulus (Fig 6).
Figure 4
Figure 3: Congolese wooden traditional
enema cup (source BHC)
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Figures 4 and 5: Gross abdominal distension and failure to thrive in children with chronic constipation and
intestinal obstruction due to Hirschsprung’s disease (Courtesy Prof. E. A. Ameh, ABUTH, Zaria).
Figure 6a. Dilated rectosigmoid segment loaded with faeces above the transition zone, leading to a sigmoid
volvulus (arrow shows point of volvulus).
Figure 6b: Hugely dilated sigmoid above transition zone has become gangrenous. Note the viable pink bowel
adjacent to gangrenous sigmoid. (source, author LOA)
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6.3. Enterocolitis
Hirschsprung’s Enterocolitis (HEC) is characterized by fever, abdominal distention, and explosive or foul-
smelling diarrhea, and may lead to life threatening septic shock. Approximately 10% of children with HD have
diarrhea as part of the presentation, and the diagnosis may therefore be missed. (8) Suspicion of HD should be
raised if a history of failure to pass meconium and intermittent obstructive episodes is elicited.
6.4. Associated Anomalies and Syndromes
The incidence of associated congenital anomalies is approximately 20% involving the neurological,
cardiovascular, urological, or gastrointestinal system. (25) In addition, HD may be part of a large number of
recognized syndromes, some of which have an identifiable chromosomal or genetic basis (Table 1). HD should
therefore be suspected in any child with constipation or neonatal intestinal obstruction who is known to have
one of these syndromes. In addition, a diagnosis of HD should alert the clinician to the increased possibility of
these associated anomalies.
7. Diagnosis
The differential diagnosis of HD in infancy includes other causes of neonatal intestinal obstruction. (Table 2)
HD may be suspected in older children presenting with functional constipation who do not respond to usual
treatments.
Table: 2 Differential diagnoses for Hirschsprung’s disease according to age of presentation
Neonates Older children
Distal intestinal obstruction:
– Ileal atresia
– Meconium ileus
– Meconium plug syndrome
Small left colon syndrome
Prematurity
Sepsis and electrolyte imbalance
Cretinism and myxedema
Intestinal neuronal dysplasia
Functional constipation
Fecal impaction
Abdominal tumor
Abdominal Tuberculosis and lymphoma
Metabolic abnormalities
Pseudo-obstruction
The appropriate diagnostic approach varies, depending on the age of the patient and the presenting clinical
picture. After a careful history eliciting delayed passage of meconium, chronic constipation and or repeated
diarrhea and adequate physical examination including a digital rectal examination which gives a tight rectum
with absent fecal content, the diagnostic steps should include radiographic studies, and rectal biopsy.
7.1. Plain radiographs usually show dilated bowel loops with characteristic flank fullness (Figure 7a). The
colon may show stippled shadows which are evidence of large amounts of fecal stasis proximal to the
obstruction. Pneumoperitoneum may be evident in those who have developed intestinal perforation. In
newborns, a prone lateral x-ray (Figure 7b) can demonstrate that the rectum is narrower than the proximal
bowel in HD.
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Figure 7a
Prone Lateral view
Figures 7a and 7b: Grossly dilated large bowel loop on anteroposterior view. The prone lateral x-ray shows a
more dilated sigmoid compared with the rectum (arrow): a rectosigmoid index of less than 1 is abnormal and
suggests HD. (source BHC)
7.2. Contrast enema
In older children with HD, a water soluble contrast enema will demonstrate a funnel shaped transition zone
between the normal and aganglionic bowel. These features are better elicited on the lateral or oblique films
since superimposed loops of sigmoid colon make the interpretation difficult on the anteroposterior film.
(Figures 8a and 8b) The transition zone may be absent in 25% of neonates and in older children with a very
short aganglionic segment. (26) A rectosigmoid index (the ratio of rectal diameter/sigmoid diameter) less than
1.0 and retention of barium on a 24-hour post evacuation film are other findings supporting the diagnosis of
HD.
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The findings in total colonic HD may include a normal barium enema, a short colon of normal caliber, a
microcolon, or a transition zone in the ileum. There may also be an easy, extensive reflux far back into small
bowel, a pseudo-transition zone in the colon, and intraluminal small bowel calcification.
Figure 8a
Figure 8a and 8b: Contrast enema demonstrating the funnel shaped transition zone (arrow) (source LOA)
Figure 9: CT scan of abdomen in a child presenting with an abdominal ‘tumor’ (source BHC)
Transition
zone
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Although a computerised tomographic scan is not generally indicated in the diagnosis of HD, this 20 month old
infant with an abdominal ‘tumor’ has faecal loading in the grossly dilated rectosigmoid segment and was found
to have HD. (Fig 9)
7.3. Anorectal Manometry may show absence of the rectoanal inhibitory reflex. It is not widely available in
Africa and not used frequently in Canada because it is unreliable and not diagnostic.
7.4. Rectal Biopsy
The gold standard for definitive diagnosis of HD is rectal biopsy, looking for the absence of ganglion cells and
the finding of hypertrophied nerve trunks. The biopsy is taken 2-3 cm above the dentate line on the posterior
wall of the rectum. Going too distally may result in a false-positive diagnosis of HD because ganglion cells are
normally absent in the anal canal.
The most common technique used in Africa is full thickness rectal wall biopsy, which requires close
collaboration with a good pathologist. Disadvantages of full thickness biopsy include the potential for bleeding
and scarring and the need for general anesthesia. Evaluation of biopsy specimens may be enhanced by staining
of the tissue for acetylcholinesterase and immunohistochemistry with calretinin. (27) Histochemistry is also
useful in differentiating between HD and intestinal neuronal dysplasia.
A suction rectal biopsy can be used to obtain tissue for histologic examination. Rectal mucosa and submucosa
are sucked into the suction device, and a self-contained cylindrical knife cuts off the tissue (Figure 10). The
distinct advantage of the suction biopsy is that it can be easily performed at the bedside without general
anaesthesia and can be repeated several times. In experienced centres, the accuracy is 99.7%. Interpretation of
the specimen is technically more demanding for pathologists, and some will require a full thickness biopsy to
confirm the diagnosis of HD. This device is expensive and not readily available in Africa.