#142623 HIRSCHSPRUNG DISEASE
HIRSCHSPRUNG DISEASE 1; HSCR1
MEGACOLON, AGANGLIONIC; MGC
Gene Map Locus: 19p13.3,
Note: pressing the
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text most closely matches the text of the preceding
OMIM paragraph, using the Entrez MEDLINE
A number sign (#) is used with this entry
because of the evidence that the phenotype can
result from mutation in any one of several
different genes operating either alone or in
combination. These mutations include dominant
mutations in the RET gene (164761)
and a recessive mutation in the endothelin receptor
type B gene (131244)
on 13q22; see also Hirschsprung disease-2
The genes for endothelin-3 (131242),
glial cell line-derived neurotrophic factor
and endothelin-converting enzyme-1 (ECE1; 600423)
have also been implicated in HSCR. Hofstra
et al. (1997) pointed out that mutations of
these genes give dominant, recessive, or polygenic
patterns of inheritance. Hirschsprung disease, with
major and modifying sequence variants in a variety
of genes, may serve as a model for other complex
disorders for which the search for defective genes
The disorder described by Hirschsprung
(1888) and known as Hirschsprung disease or
aganglionic megacolon is a congenital disorder
characterized by absence of enteric ganglia along a
variable length of the intestine. For a long time
this disorder was considered to be multifactorial
in its inheritance with the possible operation of a
major autosomal recessive gene. Indeed, this
disorder appeared in the autosomal recessive
catalog (without an asterisk) through many
editions. As an increasing number of surviving
patients reached child-bearing age, families
consistent with autosomal dominant inheritance were
reported by Carter et al.
(1981), Lipson and
Harvey (1987), and Lipson
et al. (1990). Linkage studies, detailed later,
supported the autosomal dominant inheritance of
Boggs and Kidd (1958)
described sibs with absence of the innervation of
the entire intestinal tract below the ligament of
Treitz. Bodian and Carter
(1963) suggested that cases of Hirschsprung
disease with extensive involvement of the gut, such
as those reported by Boggs
and Kidd (1958), are more likely to be
familial. For the series of Hirschsprung disease as
a whole, they could not demonstrate simple
mendelian inheritance. They concluded that
Hirschsprung disease is probably multifactorial
(polygenic) in its causation. Multifactorial traits
have a 'sliding' risk. Not only does the recurrence
risk increase as the number of affected sibs
increases, but it also is greater when involvement
is more severe. Thus it is not unexpected that
cases with more extensive involvement are more
likely to be familial. Passarge
(1967) arrived at a similar conclusion of
multifactorial inheritance. Empiric risk figures
were as follows: 7.2% for the sibs of an affected
female, 2.6% for the sibs of an affected male. In
at least 4 instances, parent-child involvement is
1970). In all 4 cases, the parent was the
Aganglionic megacolon is clearly a heterogeneous
category. It is a frequent finding in cases of
trisomy 21 (Down syndrome). See the review by
Passarge (1993) who gave
a listing of disorders in which congenital
intestinal aganglionosis is a feature. Six of 63
probands in the Passarge
(1967) study were cases of Down syndrome.
Garver et al. (1985)
confirmed the relatively high frequency of
Hirschsprung disease in Down syndrome (5.9%). Of
134 cases, 103 had short-segment disease and 31 had
the long-segment type of aganglionosis. For the 2
types, the sex ratio was 5.4 and 1.4, respectively.
Other syndromes in which Hirschsprung disease
occurs include cartilage-hair hypoplasia (250250),
the Smith-Lemli-Opitz syndrome, type II (268670),
and primary central hypoventilation syndrome
(Ondine-Hirschsprung disease; 209880).
Skinner and Irvine
(1973) described 4 unrelated patients with
Hirschsprung disease and profound congenital
deafness. There were no stigmata of Waardenburg
syndrome, which is sometimes accompanied by
megacolon (see 193500).
Megacolon has also been reported in familial
Hultgren (1982) reported
the same in the horse. The lethal white foal
syndrome is a congenital abnormality of overo
spotted horses which appears to be a model for
human aganglionic megacolon. Affected foals are all
white or nearly all white and succumb to intestinal
obstruction in the first few days of life. (The
designation 'overo' comes from the Spanish for
'egg-colored' or 'speckled.') McCabe
et al. (1990) described 2 affected foals and
discussed 2 possible mechanisms of inheritance. In
mice, aganglionic megacolon is associated with
piebald trait and is inherited apparently as an
autosomal recessive (Bielschowsky
and Schofield, 1962). We know of a human case
of heterochromia iridis and megacolon (R.C.,
in which congenital deafness is also present.
Liang et al. (1983)
reported a Mexican family in which 2 brothers and a
sister of second-cousin parents had Hirschsprung
disease and bicolored irides. (They used the term
'bicolor' rather than the more usual
'heterochromia' to emphasize that 2 distinct colors
were present in the same iris.)
Lipson and Harvey
(1987) described nonsyndromic, biopsy-proven
Hirschsprung disease involving both short and long
segments of the large bowel in members of 3
successive generations, with a total of 4
definitely affected members and 2 probably affected
members. The authors suggested that because of
improved diagnosis and treatment over the last few
decades, other such families may be described.
Lipson et al. (1990)
provided further information on the family: the
affected mother of the propositus (a member of the
third generation) had another child with
Hirschsprung disease affecting the entire large
bowel, who was fathered by a different man. A
history of long-segment Hirschsprung disease in a
half cousin who had normal parents and grandparents
suggested multifactorial inheritance with females,
when affected, having a higher likelihood of
transmitting the condition to their children.
Lipson et al. (1990)
pointed to a male predominance of 3:1 to 5:1 in
Hirschsprung disease. Badner
et al. (1990) performed complex segregation
analysis of data on 487 probands and their
families. An increased sex ratio (3.9 males:1
female) and an elevated risk to sibs (4%), as
compared with the population incidence (0.02%),
were observed, with the sex ratio decreasing and
the recurrence risk to sibs increasing as the
aganglionosis became more extensive. For cases with
aganglionosis beyond the sigmoid colon, the mode of
inheritance was compatible with a dominant gene
with incomplete penetrance, while for cases with
aganglionosis extending no farther than the sigmoid
colon, the inheritance pattern was equally likely
to be either multifactorial or due to a recessive
gene with very low penetrance. Auricchio
et al. (1996) raised the intriguing hypothesis
that CIIPX (300048)
may represent an additional, X-linked
susceptibility locus in Hirschsprung disease.
Lipson (1988) raised
the question of hyperthermia in early gestation as
a factor in Hirschsprung disease. Larsson
et al. (1989) could not confirm a correlation
between hyperthermia during pregnancy and
Hirschsprung disease in the offspring.
Taking advantage of a proximal deletion of
chromosome 10q, del10(q11.21q21.2), in a patient
with total colonic aganglionosis (Martucciello
et al., 1992) and making use of a high-density
genetic map of microsatellite DNA markers,
Lyonnet et al. (1993)
performed genetic linkage analysis in 15
nonsyndromic long-segment and short-segment
Hirschsprung disease families. Multipoint linkage
analysis indicated that the most likely location
for the HSCR locus is between D10S208 and D10S196,
suggesting that a dominant gene for this disorder
maps to 10q11.2, a region to which other neural
crest defects have been mapped. Fewtrell
et al. (1994) also found total colonic
aganglionosis in association with a 10q deletion:
Total colonic aganglionosis was described in
association with congenital failure of autonomic
control of ventilation (Ondine's curse) by
O'Dell et al. (1987).
Hirschsprung disease has been observed in
association with MEN2A (171400;
see Verdy et al., 1982)
and MEN2B (162300;
see Mahaffey et al.,
1990). It should be noted that the
piebald-lethal mutation in the mouse (locus S), a
model of aganglionic megacolon, has been assigned
to mouse chromosome 14, whose proximal long arm is
homologous to human 10q11-q21. By the molecular
characterization of the previously reported
familial microdeletion and of 3 additional
cytogenetically visible de novo deletions, isolated
in somatic cell hybrids, Luo
et al. (1993) identified a smallest region of
overlap of 250 kb. This contained the RET gene.
Adult HSCR patients with deletions of the RET gene
were negative by the pentagastrin test (which
detects preclinical forms of MEN2A or MEN2B).
Because of the striking phenotypic diversity
displayed by alleles at the same locus, such as
spinal bulbar muscular atrophy and testicular
feminization, due to different mutations in the
androgen receptor gene (313700),
Luo et al. (1993)
considered it plausible that the RET gene is the
site of the mutation causing Hirschsprung disease.
In 5 HSCR families, Angrist
et al. (1993) identified linkage to the
pericentromeric region of chromosome 10. A maximum
2-point lod score of 3.37 at theta = 0.045 was
observed between HSCR and D10S176, under an
incompletely penetrant dominant model. Multipoint,
affecteds-only and nonparametric analyses supported
this finding and localized the gene to a region of
approximately 7 cM, in close proximity to the locus
Edery et al. (1994)
presented strong evidence that both the
short-segment (accounting for 80% of cases of
Hirschsprung disease) and long-segment (accounting
for 20% of cases) forms of aganglionic megacolon
are fundamentally the same disorder due to
mutations in the RET gene. Genetic linkage analysis
using microsatellite DNA markers of 10q in 11
long-segment families and 8 short-segment families
showed tight linkage with no recombinant events
between the disease locus and the RET locus. Thus,
the 2 anatomical forms of familial Hirschsprung
disease, which have been separated on the bais of
clinical criteria, have no fundamental reason to be
separated but must be regarded as the variable
clinical expression of mutations at the RET locus.
Such point mutations had specifically been
identified in 6 HSCR families linked to 10q11.2.
These mutations resulted in either amino acid
substitutions or protein termination. Long-segment
and short-segment HSCR occurred in the same family
and lack of penetrance was observed. The
arg180-to-ter nonsense mutation (164761.0021)
was observed in 2 patients with long-segment HSCR
and in their unaffected mother in family 3. The
pro64-to-leu mutation (164761.0019)
was observed in a proband with short-segment HSCR
and in 2 persons with severe constipation in family
15. The arg330-to-gln mutation (164761.0022)
was found in 1 patient with short-segment HSCR, 1
patient with long-segment HSCR, and in 3 unaffected
subjects in family 2. Finally, the ser32-to-leu
was found in a patient with long-segment HSCR, in 2
patients with short-segment HSCR, in a subject with
severe constipation, and in an unaffected subject
in family 5.
estimated that RET mutations account for
approximately 50% of HSCR cases and EDNRB mutations
account for approximately 5%. Short-segment HSCR
occurs in about 25% of RET-caused cases and in more
than 95% of EDNRB-related cases. Whereas
homozygosity for mutations of the EDNRB gene causes
deafness and pigmentary anomalies in addition to
HSCR (e.g., 131244.0002),
the homozygous phenotype for RET has not been
(1996) provided a figure showing the
distribution of RET mutations causing HSCR; they
numbered about 48 and were widely distributed
through the gene.
Iwashita et al.
(1996) introduced 5 HSCR mutations into the
extracellular domain of human RET cDNA. These
mutations were introduced with or without a MEN2A
mutation (cys634arg; 164761.0011).
The investigators demonstrated that with the 5 HSCR
extracellular domain RET mutations cell surface
expression of the protein was low. Iwashita
et al. (1996) concluded that sufficient levels
of RET expression on the cell surface are required
for migration of ganglia toward the distal portion
of the colon or for full differentiation.
Another possible cause of, or contributing
factor to, megacolon in humans was suggested by the
results of 'knockout' experiments in mice by
Hatano et al. (1997)
involving a Hox11 gene: Ncx/Hox11L.1. This gene was
inactivated in embryonic stem cells by homologous
recombination. The homozygous mutant mice were
viable and had no morphologic abnormalities at
birth, but developed megacolon with enteric ganglia
by age 3 to 5 weeks. Histochemical analysis of the
ganglia revealed that the enteric neurons
'hyperinnervated' in the narrow segment of
megacolon. Some of these neuronal cells degenerated
and neuronal cell death occurred in later stages.
Hatano et al. (1997)
proposed that Ncx/Hox11L.1 is required for
maintenance of proper functions of the enteric
nervous system. They pointed out that neuronal
intestinal dysplasia is a human congenital disorder
that is characterized by megacolon with a normal
number of ganglia or hyperplasia of enteric neurons
(McMahon et al., 1981;
Munakata et al., 1985).
- Passarge (1993)
stated that Harald Hirschsprung (1830-1916) was
a Danish physician in Copenhagen and that his
family lent its name to the Hirschsprung Art
Gallery of Copenhagen.
- Lane (1966) ;
Lowry (1975) ;
Passarge (1972) ;
Puffenberger et al.
- 1. Angrist, M.;
Kauffman, E.; Slaugenhaupt, S. A.; Matise, T.
C.; Puffenberger, E. G.; Washington, S. S.;
Lipson, A.; Cass, D. T.; Reyna, T.; Weeks, D.
E.; Sieber, W.; Chakravarti, A. :
- A gene for Hirschsprung disease
(megacolon) in the pericentromeric region of
human chromosome 10. Nature
Genet. 4: 351-356, 1993.
PubMed ID : 8401581
- 2. Auricchio, A.;
Brancolini, V.; Casari, G.; Milla, P. J.; Smith,
V. V.; Devoto, M.; Ballabio, A. :
- The locus for a novel syndromic form
of neuronal intestinal pseudoobstruction maps to
Xq28. Am. J. Hum. Genet. 58:
PubMed ID : 8644737
- 3. Badner, J. A.;
Sieber, W. K.; Garver, K. L.; Chakravarti, A.
- A genetic study of Hirschsprung
disease. Am. J. Hum. Genet.
46: 568-580, 1990.
PubMed ID : 2309705
- 4. Bielschowsky, M.;
Schofield, G. C. :
- Studies on megacolon in piebald
mice. Aust. J. Exp. Biol. Med.
Sci. 40: 395-403, 1962.
- 5. Bodian, M.;
Carter, C. O. :
- A family study of Hirschsprung's
disease. Ann. Hum. Genet. 26:
- 6. Boggs, J. D.;
Kidd, J. M. :
- Congenital abnormalities of
intestinal innervation: absence of innervation
of jejunum, ileum and colon in
siblings. Pediatrics 21:
- 7. Carter, C. O.;
Evans, K.; Hickman, V. :
- Children of those treated surgically
for Hirschsprung's disease. J. Med.
Genet. 18: 87-90, 1981.
PubMed ID : 7241539
- 8. Chakravarti, A.
- Endothelin receptor-mediated
signaling in Hirschsprung disease.
Hum. Molec. Genet. 5: 303-307,
PubMed ID : 8852653
- 9. Edery, P.; Pelet,
A.; Mulligan, L. M.; Abel, L.; Attie, T.; Dow,
E.; Bonneau, D.; David, A.; Flintoff, W.; Jan,
D.; Journel, H.; Lacombe, D.; Le Merrer, M.;
Meijers, C.; Parent, P.; Philip, N.; Plauchu,
H.; Sarda, P.; Verloes, A.; Nihoul-Fekete, C.;
Williamson, R.; Ponder, B. A. J.; Munnich, A.;
Lyonnet, S. :
- Long segment and short segment
familial Hirschsprung's disease: variable
clinical expression at the RET locus.
J. Med. Genet. 31: 602-606, 1994.
PubMed ID : 7815416
- 10. Ehrenpreis, T.
- Hirschsprung's Disease.
Chicago: Year Book Med. Publ. (pub.) 1970.
- 11. Fewtrell, M.
S.; Tam, P. K. H.; Thomson, A. H.; Fitchett, M.;
Currie, J.; Huson, S. M.; Mulligan, L. M. :
- Hirschsprung's disease associated
with a deletion of chromosome 10 (q11.2q21.2): a
further link with the
neurocristopathies?. J. Med.
Genet. 31: 325-327, 1994.
PubMed ID : 7915329
- 12. Garver, K. L.;
Law, J. C.; Garver, B. :
- Hirschsprung disease: a genetic
study. Clin. Genet. 28:
PubMed ID : 2934185
- 13. Hatano, M.;
Aoki, T.; Dezawa, M.; Yusa, S.; Iitsuka, Y.;
Koseki, H.; Taniguchi, M.; Tokuhisa, T. :
- A novel pathogenesis of megacolon in
Ncx/Hox11L.1 deficient mice. J.
Clin. Invest. 100: 795-801, 1997.
PubMed ID : 9259577
- 14. Hirschsprung,
- Stuhltragheit Neugeborener in Folge
von Dilatation und Hypertrophie des
Colons. Jahrb. Kinderheilk.
27: 1-7, 1888.
- 15. Hofstra, R. M.
W.; Osinga, J.; Buys, C. H. C. M. :
- Mutations in Hirschsprung disease:
when does a mutation contribute to the
phenotype? Europ. J. Hum.
Genet. 5: 180-185, 1997.
- 16. Hultgren, B. D.
- Ileocolonic aganglionosis in white
progeny of overo spotted horses. J.
Am. Vet. Med. Assoc. 180: 289-292,
PubMed ID : 7056678
- 17. Iwashita, T.;
Murakami, H.; Asai, N.; Takahashi, M. :
- Mechanism of Ret dysfunction by
Hirschsprung mutations affecting its
extracellular domain. Hum. Molec.
Genet. 5: 1577-1580, 1996.
PubMed ID : 8894691
- 18. Lane, P. W.
- Association of megacolon with two
recessive spotting genes in the mouse.
J. Hered. 57: 29-31, 1966.
PubMed ID : 5917257
- 19. Larsson, L. T.;
Okmian, L.; Kristoffersson, U. :
- No correlation between hyperthermia
during pregnancy and Hirschsprung disease in the
offspring. (Letter) Am. J. Med.
Genet. 32: 260-261, 1989.
PubMed ID : 2929665
- 20. Liang, J. C.;
Juarez, C. P.; Goldberg, M. F. :
- Bilateral bicolored irides with
Hirschsprung's disease: a neural crest
syndrome. Arch. Ophthal. 101:
PubMed ID : 6849656
- 21. Lipson, A.
- Hirschsprung disease in the
offspring of mothers exposed to hyperthermia
during pregnancy. Am. J. Med.
Genet. 29: 117-124, 1988.
PubMed ID : 3344764
- 22. Lipson, A. H.;
Harvey, J. :
- Three-generation transmission of
Hirschsprung's disease. Clin.
Genet. 32: 175-178, 1987.
PubMed ID : 3621664
- 23. Lipson, A. H.;
Harvey, J.; Oley, C. A. :
- Three-generation transmission of
Hirschsprung's disease. (Letter)
Clin. Genet. 37: 235, 1990.
PubMed ID : 2323095
- 24. Lowry, R. B.
- Hirschsprung's disease and
congenital deafness. (Letter) J.
Med. Genet. 12: 114-115, 1975.
PubMed ID : 1121019
- 25. Luo, Y.;
Ceccherini, I.; Pasini, B.; Matera, I.;
Bicocchi, M. P.; Barone, V.; Bocciardi, R.;
Kaariainen, H.; Weber, D.; Devoto, M.; Romeo, G.
- Close linkage with the RET
protooncogene and boundaries of deletion
mutations in autosomal dominant Hirschsprung
disease. Hum. Molec. Genet. 2:
PubMed ID : 7904208
- 26. Lyonnet, S.;
Bolino, A.; Pelet, A.; Abel, L.; Nihoul-Fekete,
C.; Briard, M. L.; Mok-Siu, V.; Kaariainen, H.;
Martucciello, G.; Lerone, M.; Puliti, A.; Luo,
Y.; Weissenbach, J.; Devoto, M.; Munnich, A.;
Romeo, G. :
- A gene for Hirschsprung disease maps
to the proximal long arm of chromosome
10. Nature Genet. 4: 346-350,
PubMed ID : 8401580
- 27. Mahaffey, S.
M.; Martin, L. W.; McAdams, A. J.; Ryckman, F.
C.; Torres, M. :
- Multiple endocrine neoplasia type
IIB with symptoms suggesting Hirschsprung's
disease: a case report. J. Pediat.
Surg. 25: 101-103, 1990.
PubMed ID : 1967641
- 28. Martucciello,
G.; Bicocchi, M. P.; Dodero, P.; Lerone, M.;
Cirillo, M. S.; Puliti, A.; Gimelli, G.; Romeo,
G.; Jasonni, V. :
- Total colonic aganglionosis with
interstitial deletion of the long arm of
chromosome 10. Pediat. Surg.
Int. 7: 308-310, 1992.
- 29. McCabe, L.;
Griffin, L. D.; Kinzer, A.; Chandler, M.;
Beckwith, J. B.; McCabe, E. R. B. :
- Overo lethal white foal syndrome:
equine model of aganglionic megacolon
(Hirschsprung disease). Am. J. Med.
Genet. 36: 336-340, 1990.
PubMed ID : 2363434
- 30. McMahon, R. A.;
Moore, C. C. M.; Cussen, L. J. :
- Hirschsprung-like syndromes in
patients with normal ganglion cells on suction
rectal biopsy. J. Pediat.
Surg. 16: 835-839, 1981.
PubMed ID : 7338763
- 31. Munakata, K.;
Morita, K.; Okabe, I.; Sueoka, H. :
- Clinical and histologic studies of
neuronal intestinal dysplasia. J.
Pediat. Surg. 20: 231-235, 1985.
PubMed ID : 3891955
- 32. O'Dell, K.;
Staren, E.; Bassuk, A. :
- Total colonic aganglionosis
(Zuelzer-Wilson syndrome) and congenital failure
of automatic control of ventilation (Ondine's
curse). J. Pediat. Surg. 22:
PubMed ID : 3430302
- 33. Passarge, E.
- Wither polygenic inheritance:
mapping Hirschsprung disease.
Nature Genet. 4: 325-326, 1993.
PubMed ID : 8401573
- 34. Passarge, E.
- The genetics of Hirschsprung's
disease: evidence for heterogeneous etiology and
a study of sixty-three families.
New Eng. J. Med. 276: 138-143,
PubMed ID : 4224912
- 35. Passarge, E.
- Genetic heterogeneity and recurrence
risk of congenital intestinal
aganglionosis. Birth Defects Orig.
Art. Ser. VIII(2): 63-67, 1972.
- 36. Puffenberger,
E. G.; Kauffman, E. R.; Bolk, S.; Matise, T. C.;
Washington, S. S.; Angrist, M.; Weissenbach, J.;
Garver, K. L.; Mascari, M.; Ladda, R.;
Slaugenhaupt, S. A.; Chakravarti, A. :
- Identity-by-descent and association
mapping of a recessive gene for Hirschsprung
disease on human chromosome 13q22.
Hum. Molec. Genet. 3: 1217-1225,
PubMed ID : 7987295
- 37. Skinner, R.;
Irvine, D. :
- Hirschsprung disease and congenital
deafness. J. Med. Genet. 10:
PubMed ID : 4774830
- 38. Verdy, M.;
Weber, A. M.; Roy, C. C.; Morin, C. L.; Cadotte,
M.; Brochu, P. :
- Hirschsprung's disease in a family
with multiple endocrine neoplasia type
2. J. Pediat. Gastroent. Nutr.
1: 603-607, 1982.
PubMed ID : 6136579
Clinical Synopsis Entry
Victor A. McKusick - updated : 3/2/1999
Victor A. McKusick - updated : 10/30/1997
Victor A. McKusick - updated : 10/29/1997
Moyra Smith - updated : 10/23/1996
Mark H. Paalman - updated : 4/25/1996
Victor A. McKusick : 9/10/1993
terry : 3/2/1999
dkim : 7/21/1998
dholmes : 11/18/1997
terry : 11/4/1997
terry : 10/30/1997
terry : 10/29/1997
mark : 10/8/1997
mark : 10/23/1996
mark : 4/25/1996
mark : 4/25/1996
mark : 4/17/1996
terry : 4/10/1996
mark : 6/6/1995
terry : 10/19/1994
mimadm : 9/24/1994
carol : 9/2/1994
jason : 6/23/1994
pfoster : 4/20/1994