Hirschsprung's disease

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Hirschsprung's disease
ICD-10 Q43.1
ICD-9 !1.3
OMIM 14"#"3
DiseasesDB !$%1
MedlinePlus %%114%
eMedicine med&1%1#
Hirschsprung's disease, or congenital aganglionic megacolon, involves an enlargement
of the colon, caused 'y 'o(el o'struction resulting from an aganglionic section of 'o(el
)the normal enteric nerves are a'sent* that starts at the anus and progresses up(ards. +he
length of 'o(el that is affected varies 'ut seldom stretches for more than a foot or so.
Contents
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1 .istory and /escription
" 0enetic 'asis
3 1urgical treatment
4 1ee also
! 23ternal links
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History and Description
+his disease is named for .arald .irschsprung, the /anish physician (ho first descri'ed
the disease in 144#, descri'ing t(o infants (ho had died (ith s(ollen 'ellies. 5+he
autopsies sho(ed identical pictures (ith a pronounced dilatation and hypertrophy of the
colon as the dominant features5 )6adsen 1*.
.irschsprung7s disease is a congenital disorder of the colon in (hich certain nerve cells,
kno(n as ganglion cells, are a'sent, causing chronic constipation )Worman and 0aniats
44*. +he lack of ganglion cells, proven 'y 8rvar 1(enson to 'e the cause of the disease,
disa'les the muscular peristalsis needed to move stool through the colon, thus creating a
'lockage. 8ne in five thousand children suffer from .irschsprung7s. Four times as many
males get this disease than females. .irschsprung7s develops in the fetus during the early
stages of pregnancy. +ypical symptoms for infants include not having their first 'o(el
movement )meconium* (ithin 44 hours of 'irth, and repeated vomiting. 1ome infants
may have a s(ollen a'domen. +(o thirds of the cases of .irschsprung7s are diagnosed
(ithin three months of the 'irth. 8ccasionally symptoms do not appear until early
adulthood. 9 'arium enema is the mainstay of diagnosis of .irschsprung7s, though a
rectal 'iopsy sho(ing the lack of ganglion cells is the only certain method of diagnosis.
+he usual treatment is 5pull:through5 surgery (here the portion of the colon that does
have nerve cells is pulled through and se(n over the part that lacks nerve cells );ational
/igestive /iseases <nformation =learinghouse*. For a long time, .irschsprung7s (as
considered a multi:factorial disorder, (here a com'ination of nature and nurture (ere
considered to 'e the cause )6adsen 1$*. .o(ever, in 9ugust of 1$$3, t(o articles 'y
independent groups in Nature Genetics said that .irschsprung7s disease could 'e mapped
to a stretch of chromosome 1% )9ngrist 3!1*. +his research also suggested that a single
gene (as responsi'le for the disorder. .o(ever, the researchers (ere una'le to isolate
the single gene that they thought caused .irschsprung7s.
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enetic !asis
<n "%%", scientists thought they found the solution. 9ccording to this ne( research, the
interaction of t(o variant genes caused .irschsprung7s. >2+ (as isolated as the gene on
chromosome 1%, and it (as determined that it could have dominant mutations that cause
loss of function )?assarge 11*. 9n important gene that >2+ has to interact (ith in order
for .irschsprung7s to develop is 2/;>@, (hich is on chromosome 13. 1i3 other genes
(ere discovered to 'e associated (ith .irschsprung7s. 9ccording to the study, these
genes are 0/;F on chromosome !, 2/;3 on chromosome "%, 18A1% on chromosome
"", 2=21 on chromosome 1, ;+; on chromosome 1$, and 1<?1 on chromosome ".
+hese scientists concluded that the mode of inheritance for .irschsprung7s is oligogenic
inheritance )?assarge 11*. +his means that t(o mutated genes interact to cause a disorder.
Bariations in >2+ and 2/;>@ have to coe3ist in order for a child to get .irschsprung7s.
.o(ever, although si3 other genes (ere sho(n to have an effect on .irschsprung7s, the
researchers (ere una'le to determine ho( they interacted (ith >2+ and 2/;>@. +hus,
the specifics of the origins of the disease are still not completely kno(n.
>2+ codes for proteins that help the neural crest cells )(hich 'ecome ganglion cells*
move through the digestive tract during the development of the em'ryo )1a(in*. 2/;>@
codes for proteins to actually connect these nerve cells to the digestive tract. +his means
that the a'sence of certain nerve fi'ers in the colon could 'e directly related to these t(o
genes mutating so the (rong proteins are produced. >esearch pu'lished in June of "%%4
suggests that there are actually ten genes associated (ith .irschsprung7s disease )?uri
and 1hinkai*. 9lso, ne( research suggests that mutations in genomic seCuences involved
in regulating 2/;>@ have a 'igger impact on .irschsprung7s disease than previously
thought.
/r. @o' 1a(in of 1eattle7s =hildrenDs .ospital notes that it is generally accepted in the
scientific community that the gene >2+ is the most important gene (hen looking for the
genetic cause of .irschsprung7s disease. >2+ can mutate in many (ays, and is associated
(ith /o(n syndrome. 1ince /o(n 1yndrome occurs in t(o percent of .irschsprung7s
cases, there is a likelihood that >2+ is involved heavily in 'oth .irschprungDs disease and
/o(n 1yndrome. >2+ is also associated (ith thyroid cancer and neuro'lastoma )1a(in*.
@oth of these disorders have also 'een o'served in .irschsprung7s patients (ith greater
freCuency than in the general population. 8ne function that >2+ controls is the travel of
the neural crest cells through the intestines in the developing fetus. When >2+ mutations
cause .irschsprung7s disease, Ethe cells start traveling through the colon, only to 'e
stopped once the mutation occursF )1a(in*. +he earlier the mutation of >2+ occurs in
.irschsprung7s disease, the more severe the disorder 'ecomes )1a(in*.
While researchers remain uncertain of the e3act genetic cause of .irschsprung7s disease,
/r. 1a(in notes that in familial cases, )in (hich families have multiple affected patients*
.irschsprung7s disease e3hi'its autosomal dominant transmission, (ith the gene >2+
'eing dominant. .o(ever, in sporadic cases, 1a(in notes that there has 'een no
inheritance pattern identified. While scientists remain convinced that .irschsprung7s
disease is genetic, the e3act cause remains a mystery.
+reating .irschsprung7s is much easier than determining the genetic causes of this
disorder. +he only (ay to treat .irschsprung7s disease is through surgery );ational
/igestive /iseases <nformation =learinghouse*. <f .irschsprung7s goes untreated, the
patient can develop enterocolitis, the inflammation of the small intestine and the colon
)1a(in*. +his (as the cause of death of the t(o 'oys that .arald .irschsprung o'served.
1urgery is no( used to remove the non:functioning portion of the 'o(el in order to
restore 'o(el function )1a(in*.
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"urgical treatment
+here used to 'e t(o steps typically used to achieve this goal. +he first stage used to 'e a
colostomy. When a colostomy is performed, the large intestine is cut and an opening is
made through the a'domen. +his allo(s 'o(el contents to 'e discharged into a 'ag.
Gater, (hen the child7s (eight, age, and condition is right, a pull:through procedure is
performed. 8rvar 1(enson, the same man (ho discovered the cause of .irschsprung7s,
first performed it in 1$44 )1(enson 43$*. +he pull:through procedure repairs the colon
'y connecting the functioning portion of the 'o(el to the anus. +he pull through
procedure is the typical method for treating .irschsprung7s in younger patients. 1(enson
devised the original procedure, 'ut the pull:through surgery has 'een modified many
times. 1a(in, an e3pert in pull:through surgery, notes that, 59lthough there are a'out five
different pull:through procedures, they are all more or less eCually effective in treating
the disorder.5 +he 1(enson, 1oave, /uhamel, and @oley procedures all vary slightly
from each other (ith eCuivalent results )1a(in*. +he 1(enson procedure leaves a small
portion of the diseased 'o(el. +he 1oave procedure leaves the outer (all of the colon
unaltered. +he @oley procedure is Hust a small modification of the 1oave procedure.
6ean(hile, the /uhamel procedure uses a surgical stapler to connect the good and 'ad
'o(el. +he front of the 'o(el (ill end up (ith no cells, 'ut the 'ack (ill 'e healthy
)1a(in*. 1a(in notes that E?ull:through procedures used to reCuire a colostomy, 'ut (ith
increased a(areness among doctors and parents a'out the symptoms of .irschsprung7s
and (ith early diagnosis, doctors can keep the colon clean and perform the pull:through
procedure (ithout a colostomyF. <n general, E4! percent of patients that have the pull:
through surgery live normal lives after(ards. +he other 1! percent have to take a la3ative
for the rest of their livesF. <n rare cases, if the mother has .irschsprung7s and passes it on
to her child, the child is said to have Etotal .irschsprung7sF, (here there are no ganglion
cells at all in the colon )1a(in*. <n this case, the 6artin pull:through operation is
conducted. +he 6artin operation is the most invasive of the operations, for it reCuires a
colostomy no matter ho( early you diagnose total .irschsprung7s. 2ven rarer, notes /r.
1a(in, 5there are times (here the disease 'egins in the small intestine, making treatment
even harder5. 9 colostomy is conducted along (ith the 6artin operation (hen a child has
total .irschsprung7s or small intestine .irschsprung7s. 8n very rare occasions, pull:
through surgery is not the preferred method (hen it comes to treating .irschsprung7s
disease.
<f the affected portion of the lo(er intestine is restricted to the lo(er portion of the
rectum, other surgical procedures, such as the posterior rectal myectomy, can 'e
performed.
When suspicion of .irschsprungDs is high, and 'arium enema has 'een inconclusive,
rectal 'iopsy can 'e used to definitively diagnose the disease.
,edit-
"ee also
<ntestinal ;euronal /ysplasia