Hirschsprung Disease, Susceptibility To, 1

A number sign (#) is used with this entry because of evidence that susceptibility to Hirschsprung disease-1 (HSCR1) is associated with variation in the 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; 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-Shprintzen 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. 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 (summary by Amiel et al., 2008).

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 disease.

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.

Torroglosa et al. (2014) compared the expression patterns of genes involved in human stem cell pluripotency between enteric precursors from controls and patients with Hirschsprung disease. The authors further evaluated the role of DNMT3B (602900) in the context of Hirschsprung disease by immunocytochemistry, global DNA methylation assays, and mutational screening. Seven differentially expressed genes were identified, and 3 missense mutations were found in DNMT3B that could potentially be pathogenic. These mutations were present in conjunction with RET mutations in patients with long-segment Hirschsprung disease. Torroglosa et al. (2014) found that Hirschsprung disease neural precursors derived from neurosphere-like bodies (NLBs) had reduced levels of DNMT3B mRNA and protein compared to control cells. Additionally, methylation levels in Hirschsprung disease NLBs were lower than those of control NLBs.

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 MEN2.

Susceptibility to Hirschsprung Disease

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 offered.

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.

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). 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. 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 Hirschsprung 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.

Tilghman et al. (2019) genotyped and exome sequenced samples from 190 patients with Hirschsprung disease to quantify the genetic burden in patients with this condition. The presence of 5 or more variants in 4 noncoding elements defined a widespread risk of Hirschsprung disease (48.4% of patients and 17.1% of controls; odds ratio (OR) = 4.54, 95% confidence interval (CI) 3.19 to 6.46). Rare coding variants in 24 genes that play roles in enteric neural crest cell fate, 7 of which were novel, were also common (34.7% of patients and 5.0% of controls) and conferred a much greater risk than noncoding variants (OR = 10.02, 95% CI 6.45 to 15.58). Large copy number variants, which were present in fewer patients (11.4%, as compared with 0.2% of controls), conferred the highest risk (OR = 63.07, 95% CI 36.75 to 108.25). At least 1 identifiable genetic risk factor was found in 72.1% of the patients, and at least 48.4% of patients had a structural or regulatory deficiency in the RET gene. For individual patients, the estimated risk of Hirschsprung disease ranged from 5.33 cases per 100,000 live births (approximately 1 per 18,800) to 8.38 per 1,000 live births (approximately 1 per 120). Tilghman et al. (2019) concluded that among the patients in their study, Hirschsprung disease arose from common noncoding variants, rare coding variants, and copy number variants affecting genes involved in enteric neural crest cell fate that exacerbate the widespread genetic susceptibility associated with RET. For individual patients, the genotype-specific odds ratios varied by a factor of approximately 67, which provided a basis for risk stratification and genetic counseling.

Protection Against Hirschsprung Disease

Griseri et al. (2000) analyzed a 2508C-T SNP in exon 14 of the RET gene, finding that the T variant was less frequent in patients with HSCR than in the normal population. They demonstrated that the anomalous allelic distribution was due to nonrandom segregation of the T and C alleles in Italian families with HSCR. Griseri et al. (2002) undertook a study to determine whether the observed segregation distortion was due to an increased risk of developing HSCR conferred by the C allele or to a protective effect of the T allele. The typing of several different markers across the RET gene demonstrated that a whole conserved haplotype displayed anomalous distribution and nonrandom segregation in families with HSCR. They provided genetic evidence concerning a protective role of this low-penetrant haplotype in the pathogenesis of HSCR and demonstrated a possible functional effect linked to RET mRNA expression, namely a decrease in the total amount of RET, with enrichment of the RET51 isoform. Griseri et al. (2007) identified a 128496T-C polymorphism (rs3026785; 164761.0052) in the 3-prime untranslated region of the RET gene that was responsible for the protective effect of the haplotype identified by Griseri et al. (2000, 2002). The SNP slows down the physiologic decay of RET mRNA.

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.

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 (MacMahon 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.

The Danish pediatrician Harald Hirschsprung (1888) first described 2 unrelated boys who died from chronic severe constipation with abdominal distention resulting from 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).

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).