Database: OMIM
Entry: 142623
LinkDB: 142623
MIM Entry: 142623
  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
  mendelian inheritance.
  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
  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
  piebaldness (172800).
  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
  deletion: del(10)(q11.2q21.2).
  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).
See Also:
  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:
  1-14, 2008.
  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:
  1381-1386, 1995.
  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:
  568-580, 1990.
  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:
  771-774, 1999.
  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.
  Pp. 6231-6255.
  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:
  8949-8954, 2005.
  30. Kim, J. J.; Armstrong, D. D.; Fishman, M. A.: Multicore myopathy,
  microcephaly, aganglionosis, and short stature. J. Child Neurol. 9:
  275-277, 1994.
  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:
  117-124, 1988.
  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:
  231-235, 1985.
  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):
  63-67, 1972.
  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:
  11-12, 2002.
  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:
  1257-1266, 1994.
  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:
  542-547, 1998.
  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:
  960-965, 1999.
  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.
Clinical Synopsis:
     Autosomal dominant
     Failure to pass meconium in first 48 hours of life;
     Abdominal distention;
     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
Creation Date: 
  John F. Jackson: 6/15/1995
Edit Dates: 
  joanna: 01/05/2001
  kayiaros: 3/16/2000
  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
Creation Date: 
  Victor A. McKusick: 9/10/1993
Edit Dates: 
  carol: 01/25/2011
  terry: 12/16/2009
  ckniffin: 9/18/2009
  wwang: 4/16/2009
  wwang: 11/11/2008
  terry: 11/6/2008
  alopez: 12/6/2007
  wwang: 12/5/2007
  alopez: 12/5/2007
  terry: 9/20/2006
  alopez: 9/19/2005
  terry: 9/16/2005
  terry: 7/11/2005
  carol: 2/3/2005
  tkritzer: 9/29/2004
  carol: 5/13/2004
  carol: 2/11/2004
  alopez: 8/26/2003
  terry: 8/26/2003
  mgross: 11/7/2002
  alopez: 9/25/2002
  tkritzer: 9/23/2002
  alopez: 6/6/2002
  alopez: 4/24/2002
  terry: 4/22/2002
  cwells: 8/16/2001
  cwells: 8/8/2001
  terry: 8/7/2001
  alopez: 2/18/2000
  alopez: 1/19/2000
  carol: 7/23/1999
  terry: 7/19/1999
  jlewis: 6/17/1999
  terry: 6/11/1999
  carol: 5/18/1999
  terry: 4/30/1999
  carol: 4/2/1999
  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: 4/17/1996
  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
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