HIRSCHSPRUNG'S DISEASE

or congenital aganglionic megacolon, involves an enlargement of the colon, caused by bowel obstruction resulting
from an aganglionic section of bowel (the normal enteric nerves are absent) that starts at the anus and progresses
upwards. The length of bowel that is affected varies but seldom stretches for more than a foot or so.

History and Description

This disease is named after Harald Hirschsprung, the Danish physician who first described the disease in 1886,
describing two infants who had died with swollen bellies. "The autopsies showed identical pictures with a pronounced
dilatation and hypertrophy of the colon as the dominant features" (Madsen 17:2).

Hirschsprung’s disease is a congenital disorder of the colon in which certain nerve cells, known as ganglion cells, are
absent, causing chronic constipation [1]. A barium enema is the mainstay of diagnosis of Hirschsprung’s, though a rectal
biopsy showing the lack of ganglion cells is the only certain method of diagnosis.

The usual treatment is "pull-through" surgery where the portion of the colon that does have nerve cells is pulled through
and sewn over the part that lacks nerve cells (National Digestive Diseases Information Clearinghouse). For a long time,
Hirschsprung’s was considered a multi-factorial disorder, where a combination of nature and nurture were considered to
be the cause (Madsen 19). However, in August of 1993, two articles by independent groups in Nature Genetics said that
Hirschsprung’s disease could be mapped to a stretch of chromosome 10 [2][3]. This research also suggested that a single
gene was responsible for the disorder. However, the researchers were unable to isolate the single gene that they thought
caused Hirschsprung’s.

Genetic basis

In 2002, scientists thought they found the solution. According to this new research, Hirschsprung's is caused by the
interaction between two proteins encoded by two variant genes. The RET proto-oncogene on chromosome 10 was
identified as one of the genes involved, and it was determined that dominant mutations may occur within this gene
leading to a loss of function for the protein it encodes (Passarge 11). The protein with which RET has to interact in order
for Hirschsprung’s disease to develop is termed EDNRB, and is encoded by the gene EDNRB located on chromosome
13. Six other genes were discovered to be associated with Hirschsprung’s. According to the study, these genes are GDNF
on chromosome 5, EDN3 on chromosome 20, SOX10 on chromosome 22, ECE1 on chromosome 1, NRTN on
chromosome 19, and SIP1 on chromosome 2. The authors conclude that the mode of inheritance for Hirschsprung’s is
oligogenic (Passarge 11). This means that two mutated genes interact to cause a disorder. Variations in RET and EDNRB
have to coexist in order for a child to get Hirschsprung’s. However, although six other genes were shown to have an
effect on Hirschsprung’s, the researchers were unable to determine how they interact with RET and EDNRB. Thus, the
specifics of the origins of the disease are still not entirely clear. More recently, syndromic cases of Hischprung's disease
(that is, Hirschsprung's associated with the symptoms of other defects of the autonomic nervous system) were shown to
be caused by mutations in the homeobox gene PHOX2B.

RET codes for proteins that assist cells of the neural crest (which later become ganglion cells) in their movement through
the digestive tract during the development of the embryo (Sawin). EDNRB codes for proteins that connect these nerve
cells to the digestive tract. This means that the absence of certain nerve fibers in the colon could be directly related to
these two genes mutating so the wrong proteins are produced. Research published in June 2004 suggests that there are
ten genes associated with Hirschsprung’s disease (Puri and Shinkai). Also, new research suggests that mutations in
genomic sequences involved in regulating EDNRB have a bigger impact on Hirschsprung’s disease than previously
thought.

Dr. Bob Sawin of Seattle’s Children's Hospital notes that it is generally accepted in the scientific community that the
gene RET is the most important gene when looking for the genetic cause of Hirschsprung’s disease. RET can mutate in
many ways, and is associated with Down's syndrome. Since Down Syndrome is comorbid in two percent of
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Hirschsprung’s cases, there is a likelihood that RET is involved heavily in both Hirschprung's disease and Down
Syndrome. RET is also associated with thyroid cancer and neuroblastoma (Sawin). Both of these disorders have also
been observed in Hirschsprung’s patients with greater frequency than in the general population. One function that RET
controls is the travel of the neural crest cells through the intestines in the developing fetus. When RET mutations cause
Hirschsprung’s disease, “the cells start traveling through the colon, only to be stopped once the mutation occurs”
(Sawin). The earlier the mutation of RET occurs in Hirschsprung’s disease, the more severe the disorder becomes
(Sawin).

While researchers remain uncertain of the exact genetic cause of Hirschsprung’s disease, Dr. Sawin notes that in familial
cases, (in which families have multiple affected patients) Hirschsprung’s disease exhibits autosomal dominant
transmission, with the gene RET being dominant. However, in sporadic cases, Sawin notes that there has been no
inheritance pattern identified.

Treating Hirschsprung’s is much easier than determining the genetic causes of this disorder. The only way to treat
Hirschsprung’s disease is through surgery (National Digestive Diseases Information Clearinghouse). If Hirschsprung’s
goes untreated, the patient can develop enterocolitis, the inflammation of the small intestine and the colon (Sawin). This
was the cause of death of the two boys that Harald Hirschsprung observed. Surgery is now used to remove the non-
functioning portion of the bowel in order to restore bowel function (Sawin).

Hirschsprung's disease, hypoganglionosis, gut dysmotility, gut transit disorders and intussusception have been recorded
with the dominantly inherited neurovisceral porphyrias (acute intermittent porphyria, hereditary coproporphyria,
variegate porphyria). Children may require enzyme or DNA testing for these disorders as they may not produce or
excrete porphyrins prepuberty.

Clinical features

With an incidence of 1/5000 births, the most cited feature is absence of ganglion cells: notably in males, 75% have none
in the recto-sigmoid, and 8% with none in the entire colon. The enlarged section of the bowel is found proximally, while
the narrowed, aganglionic section is found distally; the absence of ganglion cells results in a persistent over-stimulation
of nerves within the affected region, resulting in contraction. 1). delayed passage of meconium.... 2).abdominal
distension 3).constipation

Diagnosis

Suspect Hirschsprung's in a baby who has not passed meconium within 48 hours of delivery. (Recall that 90% of babies
pass their first meconium within 24 hours, and 99% within 48 hours.) Definitive diagnosis is made by suction biopsy of
the distally narrowed segment.

Treatment

Treatment of Hirschsprung's disease consists of surgical removal (resection) of the abnormal section of the colon,
followed by reanastomosis. There used to be two steps typically used to achieve this goal.

• The first stage used to be a colostomy. When a colostomy is performed, the large intestine is cut and an opening
is made through the abdomen. This allows bowel contents to be discharged into a bag.
• Later, when the child’s weight, age, and condition is right, a pull-through procedure is performed.

Orvar Swenson, the same man who discovered the cause of Hirschsprung’s, first performed it in 1948 (Swenson 839).
The pull-through procedure repairs the colon by connecting the functioning portion of the bowel to the anus. The pull
through procedure is the typical method for treating Hirschsprung’s in younger patients. Swenson devised the original
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procedure, but the pull-through surgery has been modified many times. Sawin, an expert in pull-through surgery, notes
that, "Although there are about five different pull-through procedures, they are all more or less equally effective in
treating the disorder."

The Swenson, Soave, Duhamel, and Boley procedures all vary slightly from each other with equivalent results (Sawin).

• The Swenson procedure leaves a small portion of the diseased bowel.

• The Soave procedure leaves the outer wall of the colon unaltered.
• The Boley procedure is just a small modification of the Soave procedure.
• The Duhamel procedure uses a surgical stapler to connect the good and bad bowel. The front of the bowel will
end up with no cells, but the back will be healthy (Sawin).

Sawin notes that “Pull-through procedures used to require a colostomy, but with increased awareness among doctors and
parents about the symptoms of Hirschsprung’s and with early diagnosis, doctors can keep the colon clean and perform
the pull-through procedure without a colostomy”. In general, “85 percent of patients that have the pull-through surgery
live normal lives afterwards. The other 15 percent have to take a laxative for the rest of their lives”.

In rare cases, if the mother has Hirschsprung’s and passes it on to her child, the child is said to have “total
Hirschsprung’s”, where there are no ganglion cells at all in the colon (Sawin). In this case, the Martin pull-through
operation is conducted. The Martin operation is the most invasive of the operations, for it requires a colostomy no matter
how early you diagnose total Hirschsprung’s.

Even rarer, notes Dr. Sawin, "there are times where the disease begins in the small intestine, making treatment even
harder". When a child has total Hirschsprung's or small intestine Hirschsprung's, an ileostomy or jejunostomy is
conducted along with the Martin operation, and the child is then treated for short bowel syndrome. On very rare
occasions, pull-through surgery is not the preferred method when it comes to treating Hirschsprung’s disease.

If the affected portion of the lower intestine is restricted to the lower portion of the rectum, other surgical procedures,
such as the posterior rectal myectomy, can be performed.