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 ... 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-Shprintzen 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 ... 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).
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 ... 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.
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 ... 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. 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.