MIM Entry: 142623
#142623 HIRSCHSPRUNG DISEASE, SUSCEPTIBILITY TO, 1; HSCR1
;;HIRSCHSPRUNG DISEASE; HSCR;;
MEGACOLON, AGANGLIONIC; MGC
A number sign (#) is used with this entry because susceptibility to the
development of Hirschsprung disease-1 (HSCR1) is caused by mutation in
RET gene (164761) on chromosome 10q11.
The disorder described by Hirschsprung (1888) and known as Hirschsprung
disease or aganglionic megacolon is characterized by congenital absence
of intrinsic ganglion cells in the myenteric (Auerbach) and submucosal
(Meissner) plexuses of the gastrointestinal tract. Patients are
diagnosed with the short-segment form (S-HSCR, approximately 80% of
cases) when the aganglionic segment does not extend beyond the upper
sigmoid, and with the long-segment form (L-HSCR) when aganglionosis
extends proximal to the sigmoid (Amiel et al., 2008). Total colonic
aganglionosis and total intestinal HSCR also occur.
- Genetic Heterogeneity of Hirschsprung Disease
Several additional loci for isolated Hirschsprung disease have been
mapped. HSCR2 (600155) is associated with variation in the EDNRB gene
(131244) on 13q22; HSCR3 (613711) is associated with variation in the
GDNF gene (600837) on 5p13.1-p12; HSCR4 (613712) is associated with
variation in the EDN3 gene (131242) on 20q13; HSCR5 (600156) maps to
9q31; HSCR6 (606874) maps to 3p21; HSCR7 (606875) maps to 19q12; HSCR8
(608462) maps to 16q23; and HSCR9 (611644) maps to 4q31-q32.
HSCR also occurs as a feature of several syndromes including the
Waardenburg-Shah syndrome (277580), Mowat-Wilson syndrome (235730),
Goldberg-Shpritzen megacolon syndrome (609460), and congenital central
hypoventilation syndrome (CCHS; 209880).
Whereas mendelian modes of inheritance have been described for syndromic
HSCR, isolated HSCR stands as a model for genetic disorders with complex
patterns of inheritance. Isolated HSCR appears to be of complex
nonmendelian inheritance with low sex-dependent penetrance and variable
expression according to the length of the aganglionic segment,
suggestive of the involvement of one or more genes with low penetrance.
The development of surgical procedures decreased mortality and
morbidity, which allowed the emergence of familial cases (Amiel et al.,
2008). HSCR occurs as an isolated trait in 70% of patients, is
associated with chromosomal anomaly in 12% of cases, and occurs with
additional congenital anomalies in 18% of cases.
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
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,
fathered by a different man, with Hirschsprung disease affecting the
entire large bowel. 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.
Staiano et al. (1999) evaluated the autonomic nervous system in patients
with Hirschsprung disease. Pupillary and cardiovascular testing of
sympathetic adrenergic and cholinergic function and cardiovagal
cholinergic function was undertaken in 17 children (mean age, 8.6 years)
with Hirschsprung disease and 19 age- and sex-matched control children
(mean age, 9.9 years). Autonomic dysfunction was found in 7 of 17
patients with Hirschsprung disease. Evidence of sympathetic denervation
was found in 3 of the 7 patients; 2 showed a parasympathetic
dysfunction, and the remaining 2 had dysfunction of both sympathetic and
parasympathetic tests. A RET mutation was found in one of the patients.
- Hirschsprung Disease as a Feature of Other Disorders
Aganglionic megacolon is clearly a heterogeneous category. It is a
frequent finding in cases of trisomy 21 (Down syndrome; 190685). 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. Quinn et al. (1994) cited a 10 to
15% incidence of HSCR in trisomy 21. Sakai et al. (1999) described a
1-year-old male patient with short-segment sporadic HSCR associated with
Down syndrome. The patient carried mutations in both the RET gene
(164761) and the EDNRB gene (131244).
Other syndromes in which Hirschsprung disease occurs include
cartilage-hair hypoplasia (250250), Smith-Lemli-Opitz syndrome (270400),
and primary central hypoventilation syndrome (Ondine-Hirschsprung
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
McKusick (1966) observed a child with heterochromia iridis and megacolon
who also had congenital deafness. 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.) They suggested that the
inheritance was autosomal recessive. This may have been been the
Waardenburg-Shah syndrome, which is a recessive disorder (277580).
Kim et al. (1994) reported a 15-year-old dysmorphic boy who was found to
have Hirschsprung disease shortly after birth. He had pharyngeal
webbing, short stature, microcephaly, ptosis, and dysmorphic features
characterized by a flat occiput, receding forehead, low anterior
hairline, bushy eyebrows, long eyelashes, anteverted ears, high nasal
bridge, long nose, small mandible, and severe malocclusion.
Developmental delay, speech abnormalities, ataxia, spasticity, and
scoliosis developed later. A muscle biopsy performed when he was 15
years old demonstrated numerous minicores as well as a preponderance of
type 1 fibers and fiber type disproportion. Chromosomes were normal. The
patient's brother had mild developmental delay. Multicore myopathy (see
602771) in association with mental retardation and short stature has
been reported with hypogonadism (253320), but the association with
Hirschsprung disease was novel. A paternal cousin of the proband had
Hirschsprung disease but no other abnormalities.
Total colonic aganglionosis was described in association with congenital
failure of autonomic control of ventilation (Ondine's curse; 209880) 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).
Because they could not demonstrate simple mendelian inheritance in their
series of Hirschsprung disease as a whole, Bodian and Carter (1963)
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 known (Ehrenpreis, 1970). In all 4 cases, the affected
parent was the mother.
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
Hofstra et al. (1997) pointed out that mutations of the RET, GDNF
(600837), EDNRB (131244), and EDN3 (131242) genes appear to give
dominant, recessive, or polygenic patterns of inheritance. They
concluded that 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 has begun.
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.
Carrasquillo et al. (2002) used a genomewide association study and a
mouse model to identify interaction between the RET and EDNRB pathways
in the pathogenesis of Hirschsprung disease.
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 a
likely location for a HSCR locus 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
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 region contained
the RET (164761) gene. Adult HSCR patients with deletions of the RET
gene were negative by the pentagastrin test, which detects preclinical
forms of MEN2A (171400) or MEN2B (162300). 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 for
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 recombination between the disease locus and the
RET locus. Thus, the 2 anatomical forms of familial Hirschsprung
disease, which have been separated on the basis 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 mutation
(164761.0018) 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.
Chakravarti (1996) 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 had not been observed. Chakravarti (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.
Borrego et al. (1999) studied polymorphic sequence variation in RET in
64 prospectively ascertained individuals with HSCR from the Andalusia
region of Spain. For 2 polymorphic variants the rare allele was
overrepresented in HSCR cases as compared to controls, while the rare
allele for 2 other variants was underrepresented in HSCR cases. Borrego
et al. (1999) concluded that RET polymorphisms predispose to HSCR in a
complex low-penetrance manner and may modify phenotypic expression.
Sakai et al. (1999) described a 1-year-old male patient with
short-segment sporadic HSCR associated with Down syndrome. Two mutations
were found: a de novo T-to-A heterozygous transition at the splicing
donor site of intron 10 of the RET gene (164761), and a G-to-A
substitution in exon 1 in the noncoding region of the EDNRB gene
(131244), inherited from the mother. They stated that no patient had
been described to that time with point mutations in different loci known
to lead to HSCR.
Sijmons et al. (1998) investigated the possibility that some patients
with Hirschsprung disease and germline mutations in the RET gene may be
exposed to an increased risk of tumor formation. Among 60 patients with
Hirschsprung disease, the authors found 3 with MEN2A-type RET mutations,
2 with cys620 to arg (164761.0009) and 1 with cys609 to tyr
(164761.0029). Two of these patients were children in whom no evidence
of MEN2A-related pathology was found. One of these children had
inherited her mutation from her mother, who presented with medullary
thyroid carcinoma and pheochromocytoma at the age of 28. This child
underwent prophylactic thyroidectomy. The adult patient was a
34-year-old woman who had undergone surgery for short-segment
Hirschsprung disease at the age of 8 weeks and in whom pentagastrin
stimulation had produced grossly abnormal calcitonin levels, raising the
possibility of thyroid C-cell pathology. The authors concluded that
these cases, together with a small number of others reported in the
literature, suggest that screening for RET mutations in patients with
familial or sporadic Hirschsprung disease is not recommended outside a
complete clinical research setting. They added that if a MEN2A-type RET
mutation is found in such a patient, screening for MEN2 tumors should be
Borrego et al. (2000) reported that isolated cases of Hirschsprung
disease are more likely to have genotypes containing the allelic variant
ala45 to ala (A45A; 164761.0038) than do controls or unaffected parents.
Bolk Gabriel et al. (2002) stated that RET (164761) appears to be the
major gene involved in HSCR because (i) only 1 affected family unlinked
to RET had been reported (Bolk et al., 2000); (ii) coding sequence
mutations occur in RET in 50% of familial and 15 to 35% of sporadic
cases (Attie et al., 1995); (iii) even when the major mutation is in
EDNRB (131244), RET variants make some contribution to susceptibility
(Puffenberger et al., 1994); and (iv) homozygous RET-null mice have full
sex-independent penetrance of aganglionosis (Schuchardt et al., 1994).
RET mutations may not be sufficient to lead to aganglionosis, as the
penetrance of mutant alleles is 65% in males and 45% in females.
As indicated, mutations in RET (164761), GDNF (600837), EDNRB, EDN3
(131242), and SOX10 (602229) lead to long-segment Hirschsprung disease
(L-HSCR) and syndromic HSCR but fail to explain the transmission of the
much more common short-segment form (S-HSCR). Bolk Gabriel et al. (2002)
conducted a genome scan in families with S-HSCR and identified
susceptibility loci at 3p21 (HSCR6; 606874), 10q11, and 19q12 (HSCR7;
606875) that seemed to be necessary and sufficient to explain recurrence
risk and population incidence. The gene at 10q11 was thought to be RET,
supporting its crucial role in all forms of HSCR; however, coding
sequence mutations in RET were present in only 40% of families linked to
10q11, suggesting the importance of noncoding variation. Bolk Gabriel et
al. (2002) showed oligogenic inheritance of S-HSCR with 3p21 and 19q12
loci functioning as RET-dependent modifiers. They also demonstrated a
parent-of-origin effect at the RET locus. Of the 49 families they
studied, 27 shared 1 allele identical by descent (IBD) at the RET locus;
although the shared allele was expected to be equally transmitted by
either parent, they observed, instead, 21 maternal and 6 paternal
transmissions. This effect was not gender-specific but a true
parent-of-origin effect, as, within the 27 nuclear families with 1
allele IBD, there were 29 affected males and 25 affected females. No
similar parent-of-origin effect was observed at the 3p21 and 19q12 loci.
Carrasquillo et al. (2002) noted that although 8 genes with mutations
that could be associated with Hirschsprung disease had been identified,
mutations at individual loci are neither necessary nor sufficient to
cause clinical disease. They conducted a genomewide association study in
43 Mennonite family trios (parents and affected child) using 2,083
microsatellites and SNPs and a new multipoint linkage disequilibrium
method that searched for association arising from common ancestry. They
identified susceptibility loci at 10q11, 13q22, and 16q23 (HSCR8;
608462); they showed that the gene at 13q22 is EDNRB and the gene at
10q11 is RET. Statistically significant joint transmission of RET and
EDNRB alleles in affected individuals and noncomplementation of
aganglionosis in mouse intercrosses between Ret-null and the Ednrb
hypomorphic piebald allele were suggestive of epistasis between EDNRB
and RET. Thus, genetic interaction between mutations in RET and EDNRB is
an underlying mechanism for this complex disorder.
Passarge (2002) reviewed the genes implicated in Hirschsprung disease.
Burzynski et al. (2004) typed 13 markers within and flanking the RET
gene in 117 Dutch patients with sporadic HSCR, 64 of whom had been
screened for RET mutations and found negative, and their parents. There
was a strong association between 6 markers in the 5-prime region of RET
and HSCR, with significant transmission distortion of those markers.
Homozygotes for this 6-marker haplotype had a highly increased risk of
developing HSCR (OR greater than 20). Burzynski et al. (2004) concluded
that RET may play a crucial role in HSCR even when no RET mutations are
found, and that disease-associated variants are likely to be located
between the promoter region and exon 2 of the RET gene.
Emison et al. (2005) used family-based association studies to identify a
disease interval, and integrated this with comparative and functional
genomic analysis to prioritize conserved and functional elements within
which mutations in RET can be sought. Emison et al. (2005) showed that a
common noncoding RET variant within a conserved enhancer-like sequence
in intron 1 (164761.0050) is significantly associated with HSCR
susceptibility and makes a 20-fold greater contribution to risk than
rare alleles do. This mutation reduces in vitro enhancer activity
markedly, has low penetrance, and has different genetic effects in males
and females, and explains several features of the complex inheritance
pattern of HSCR. Thus, Emison et al. (2005) concluded that common
low-penetrance variants identified by association studies can underlie
both common and rare diseases. Emison et al. (2005) concluded that RET
mutations, coding and/or noncoding, are probably a necessary feature in
all cases of HSCR. However, RET mutations are not sufficient for HSCR
because disease incidence also requires mutations at additional loci.
Amiel et al. (2008) reviewed the genetics of Hirschspring disease and
associated syndromes and stated that isolated HSCR appears to be a
nonmendelian malformation with low, sex-dependent penetrance and
variable expression that can serve as a model for genetic disorders with
complex patterns of inheritance.
Kashuk et al. (2005) reported the alignment of the human RET protein
sequence with the orthologous sequences of 12 nonhuman vertebrates,
their comparative analysis, the evolutionary topology of the RET
protein, and predicted tolerance for all published missense mutations.
Using gene expression profiling, Iwashita et al. (2003) determined that
genes associated with Hirschsprung disease were highly upregulated in
rat gut neural crest stem cells relative to whole-fetus RNA. Among the
genes with highest expression were GDNF (600837), SOX10 (602229), GFRA1
(601496), and EDNRB (131244). The highest expression was seen in RET,
which was found to be necessary for neural crest stem cell migration in
the gut. GDNF promoted the migration of neural crest stem cells in
culture but did not affect their survival or proliferation. The
observations made by Iwashita et al. (2003) were confirmed by
quantitative RT-PCR, flow cytometry, and functional analysis.
The Danish pediatrician Harald Hirschsprung (1888) first described 2
unrelated boys who died from chronic severe constipation with abdominal
distention resulting in congenital megacolon. The absence of intramural
ganglion cells of the myenteric and submucosal plexuses (the Auerbach
and Meissner plexuses, respectively) downstream of the dilated part of
the colon was recognized as the cause of the disorder in the 1940s
(Whitehouse and Kernohan, 1948).
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.
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
of Mendelian Inheritance in Man and OMIM (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).
Hultgren (1982) described ileocolonic aganglionosis 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). The disorder in both the horse and
the mouse is caused by mutation in Ednrb (131244).
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).
Chakravarti and Lyonnet (2001); Lane (1966); Lowry (1975); Passarge
1. Amiel, J.; Sproat-Emison, E.; Garcia-Barceo, M.; Lantieri, F.;
Burzynski, G.; Borrego, S.; Pelet, A.; Arnold, S.; Miao, X.; Griseri,
P.; Brooks, A. S.; Antinolo, G.; and 12 others: Hirschsprung disease:
associated syndromes and genetics: a review. J. Med. Genet. 45:
2. 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.
3. Attie, T.; Pelet, A.; Edery, P.; Eng, C.; Mulligan, L. M.; Amiel,
J.; Boutrand, L.; Beldjord, C.; Nihoul-Fekete, C.; Munnich, A.; Ponder,
B. A. J.; Lyonnet, S.: Diversity of RET proto-oncogene mutations
in familial and sporadic Hirschsprung disease. Hum. Molec. Genet. 4:
4. 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: 743-748, 1996.
5. Badner, J. A.; Sieber, W. K.; Garver, K. L.; Chakravarti, A.:
A genetic study of Hirschsprung disease. Am. J. Hum. Genet. 46:
6. Bielschowsky, M.; Schofield, G. C.: Studies on megacolon in piebald
mice. Aust. J. Exp. Biol. Med. Sci. 40: 395-403, 1962.
7. Bodian, M.; Carter, C. O.: A family study of Hirschsprung's disease. Ann.
Hum. Genet. 26: 261-277, 1963.
8. Boggs, J. D.; Kidd, J. M.: Congenital abnormalities of intestinal
innervation: absence of innervation of jejunum, ileum and colon in
siblings. Pediatrics 21: 261-266, 1958.
9. Bolk, S.; Pelet, A.; Hofstra, R. M. W.; Angrist, M.; Salomon, R.;
Croaker, D.; Buys, C. H. C. M.; Lyonnet, S.; Chakravarti, A.: A human
model for multigenic inheritance: phenotypic expression in Hirschsprung
disease requires both the RET gene and a new 9q31 locus. Proc. Nat.
Acad. Sci. 97: 268-273, 2000.
10. Bolk Gabriel, S.; Salomon, R.; Pelet, A.; Angrist, M.; Amiel,
J.; Fornage, M.; Attie-Bitach, T.; Olson, J. M.; Hofstra, R.; Buys,
C.; Steffann, J.; Munnich, A.; Lyonnet, S.; Chakravarti, A.: Segregation
at three loci explains familial and population risk in Hirschsprung
disease. Nature Genet. 31: 89-93, 2002.
11. Borrego, S.; Ruiz, A.; Saez, M. E.; Gimm, O.; Gao, X.; Lopez-Alonso,
M.; Hernandez, A.; Wright, F. A.; Antinolo, G.; Eng, C.: RET genotypes
comprising specific haplotypes of polymorphic variants predispose
to isolated Hirschsprung disease. J. Med. Genet. 37: 572-578, 2000.
12. Borrego, S.; Saez, M. E.; Ruiz, A.; Gimm, O.; Lopez-Alonso, M.;
Antinolo, G.; Eng, C.: Specific polymorphisms in the RET proto-oncogene
are over-represented in patients with Hirschsprung disease and may
represent loci modifying phenotypic expression. J. Med. Genet. 36:
13. Burzynski, G. M.; Nolte, I. M.; Osinga, J.; Ceccherini, I.; Twigt,
B.; Maas, S.; Brooks, A.; Verheij, J.; Menacho, I. P.; Buys, C. H.
C. M.; Hofstra R. M. W.: Localizing a putative mutation as the major
contributor to the development of sporadic Hirschsprung disease to
the RET genomic sequence between the promoter region and exon 2. Europ.
J. Hum. Genet. 12: 604-612, 2004.
14. Carrasquillo, M. M.; McCallion, A. S.; Puffenberger, E. G.; Kashuk,
C. S.; Nouri, N.; Chakravarti, A.: Genome-wide association study
and mouse model identify interaction between RET and EDNRB pathways
in Hirschsprung disease. Nature Genet. 32: 237-244, 2002.
15. Carter, C. O.; Evans, K.; Hickman, V.: Children of those treated
surgically for Hirschsprung's disease. J. Med. Genet. 18: 87-90,
16. Chakravarti, A.: Endothelin receptor-mediated signaling in Hirschsprung
disease. Hum. Molec. Genet. 5: 303-307, 1996.
17. Chakravarti, A.; Lyonnet, S.: Hirschsprung disease.In: Scriver,
C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic
and Molecular Bases of Inherited Disease. Vol. IV. New York: 2001.
18. 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.
19. Ehrenpreis, T.: Hirschsprung's Disease. Chicago: Year Book
Med. Publ. (pub.) 1970.
20. Emison, E. S.; McCallion, A. S.; Kashuk, C. S.; Bush, R. T.; Grice,
E.; Lin, S.; Portnoy, M. E.; Cutler, D. J.; Green, E. D.; Chakravarti,
A.: A common sex-dependent mutation in a RET enhancer underlies Hirschsprung
disease risk. Nature 434: 857-863, 2005.
21. 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.
22. Garver, K. L.; Law, J. C.; Garver, B.: Hirschsprung disease:
a genetic study. Clin. Genet. 28: 503-508, 1985.
23. 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.
24. Hirschsprung, H.: Stuhltragheit Neugeborener in Folge von Dilatation
und Hypertrophie des Colons. Jahrb. Kinderheilk. 27: 1-7, 1888.
25. 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.
26. Hultgren, B. D.: Ileocolonic aganglionosis in white progeny of
overo spotted horses. J. Am. Vet. Med. Assoc. 180: 289-292, 1982.
27. Iwashita, T.; Kruger, G. M.; Pardal, R.; Kiel, M. J.; Morrison,
S. J.: Hirschsprung disease is linked to defects in neural crest
stem cell function. Science 301: 972-976, 2003.
28. 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.
29. Kashuk, C. S.; Stone, E. A.; Grice, E. A.; Portnoy, M. E.; Green,
E. D.; Sidow, A.; Chakravarti, A.; McCallion, A. S.: Phenotype-genotype
correlation in Hirschsprung disease is illuminated by comparative
analysis of the RET protein sequence. Proc. Nat. Acad. Sci. 102:
30. Kim, J. J.; Armstrong, D. D.; Fishman, M. A.: Multicore myopathy,
microcephaly, aganglionosis, and short stature. J. Child Neurol. 9:
31. Lane, P. W.: Association of megacolon with two recessive spotting
genes in the mouse. J. Hered. 57: 29-31, 1966.
32. 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.
33. Liang, J. C.; Juarez, C. P.; Goldberg, M. F.: Bilateral bicolored
irides with Hirschsprung's disease: a neural crest syndrome. Arch.
Ophthal. 101: 69-73, 1983.
34. Lipson, A.: Hirschsprung disease in the offspring of mothers
exposed to hyperthermia during pregnancy. Am. J. Med. Genet. 29:
35. Lipson, A. H.; Harvey, J.: Three-generation transmission of Hirschsprung's
disease. Clin. Genet. 32: 175-178, 1987.
36. Lipson, A. H.; Harvey, J.; Oley, C. A.: Three-generation transmission
of Hirschsprung's disease. (Letter) Clin. Genet. 37: 235, 1990.
37. Lowry, R. B.: Hirschsprung's disease and congenital deafness.
(Letter) J. Med. Genet. 12: 114-115, 1975.
38. 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: 1803-1808, 1993.
39. 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, 1993.
40. 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,
41. 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.
42. 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.
43. McKusick, V. A.: Personal Communication. Baltimore, Md. 1966.
44. 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.
45. Munakata, K.; Morita, K.; Okabe, I.; Sueoka, H.: Clinical and
histologic studies of neuronal intestinal dysplasia. J. Pediat. Surg. 20:
46. 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: 1019-1020,
47. Passarge, E.: Genetic heterogeneity and recurrence risk of congenital
intestinal aganglionosis. Birth Defects Orig. Art. Ser. VIII(2):
48. Passarge, E.: Wither polygenic inheritance: mapping Hirschsprung
disease. Nature Genet. 4: 325-326, 1993.
49. 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, 1967.
50. Passarge, E.: Dissecting Hirschsprung disease. Nature Genet. 31:
51. Puffenberger, E. G.; Hosoda, K.; Washington, S. S.; Nakao, K.;
deWit, D.; Yanagisawa, M.; Chakravarti, A.: A missense mutation of
the endothelin-B receptor gene in multigenic Hirschsprung's disease. Cell 79:
52. Quinn, F. M. J.; Surana, R.; Puri, P.: The influence of trisomy
21 on outcome in children with Hirschsprung's disease. J. Pediat.
Surg. 29: 781-783, 1994.
53. Sakai, T.; Wakizaka, A.; Nirasawa, Y.; Ito, Y.: Point nucleotidic
changes in both the RET proto-oncogene and the endothelin-B receptor
gene in a Hirschsprung disease patient associated with Down syndrome. Tohoku
J. Exp. Med. 187: 43-47, 1999.
54. Schuchardt, A.; D'Agati, V.; Larsson-Blomberg, L.; Costantini,
F.; Pachnis, V.: Defects in the kidney and enteric nervous system
of mice lacking the tyrosine kinase receptor Ret. Nature 367: 380-383,
55. Sijmons, R. H.; Hofstra, R. M. W.; Wijburg, F. A.; Links, T. P.;
Zwierstra, R. P.; Vermey, A.; Aronson, D. C.; Tan-Sindhunata, G.;
Brouwers-Smalbraak, G. J.; Maas, S. M.; Buys, C. H. C. M.: Oncological
implications of RET gene mutations in Hirschsprung's disease. Gut 43:
56. Skinner, R.; Irvine, D.: Hirschsprung disease and congenital
deafness. J. Med. Genet. 10: 337-339, 1973.
57. Staiano, A.; Santoro, L.; De Marco, R.; Miele, E.; Fiorillo, F.;
Auricchio, A.; Carpentieri, M. L.; Celli, J.; Auricchio, S.: Autonomic
dysfunction in children with Hirschsprung's disease. Dig. Dis. Sci. 44:
58. 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.
59. Whitehouse, F.; Kernohan, J.: Myenteric plexuses in congenital
megacolon: study of 11 cases. Arch. Int. Med. 82: 75-111, 1948.
Failure to pass meconium in first 48 hours of life;
Barium enema shows transition zone between aganglionic contracted
segment and dilated proximal bowel
Absent enteric ganglia beginning at the rectum and extends proximally
by varying degrees;
Acetylcholinesterase staining reveals nerve trunk hypertrophy
Male predominance of 3:1 to 5:1;
Familial (10%) and isolated cases
Caused by mutations in the RET protooncogene (RET, 164761.0014);
Caused by mutations in the endothelin receptor type B gene (EDNRB,
Caused by mutations in the endothelin 3 gene (EDN3, 131242.0004);
Caused by mutations in the glial cell line-derived neurotrophic factor
gene (GDNF, 600837.0001);
Caused by mutations in the endothelin converting enzyme-1 gene (ECE1,
Ada Hamosh - reviewed: 01/05/2001
Kelly A. Przylepa - revised: 3/16/2000
John F. Jackson: 6/15/1995
Marla J. F. O'Neill - updated: 11/6/2008
Anne M. Stumpf - reorganized: 12/5/2007
Victor A. McKusick - updated: 9/20/2006
Ada Hamosh - updated: 9/16/2005
Marla J. F. O'Neill - updated: 7/11/2005
Ada Hamosh - updated: 8/26/2003
Victor A. McKusick - updated: 9/23/2002
Victor A. McKusick - updated: 4/22/2002
Michael J. Wright - updated: 8/7/2001
Paul Brennan - updated: 2/18/2000
Michael J. Wright - updated: 1/19/2000
Victor A. McKusick - updated: 7/19/1999
Victor A. McKusick - updated: 6/11/1999
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