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Hirschsprung Disease Overview

Synonyms: Aganglionic Megacolon, HSCR
, MD, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development
National Institutes of Health
Bethesda, Maryland

Initial Posting: ; Last Revision: November 10, 2011.

Summary

Disease characteristics. Hirschsprung disease (HSCR), or congenital intestinal aganglionosis, is a birth defect characterized by complete absence of neuronal ganglion cells from a portion of the intestinal tract. The aganglionic segment includes the distal rectum and a variable length of contiguous proximal intestine. In 80% of individuals, aganglionosis is restricted to the rectosigmoid colon (short-segment disease); in 15%-20%, aganglionosis extends proximal to the sigmoid colon (long-segment disease); in about 5%, aganglionosis affects the entire large intestine (total colonic aganglionosis). Rarely, the aganglionosis extends into the small bowel or even more proximally to encompass the entire bowel (total intestinal aganglionosis). HSCR is considered a neurocristopathy, a disorder of cells and tissues derived from the neural crest, and may occur as an isolated finding or as part of a multisystem disorder. Affected infants frequently present in the first two months of life with symptoms of impaired intestinal motility such as failure to pass meconium within the first 48 hours of life, constipation, emesis, abdominal pain or distention, and occasionally diarrhea. However, because the initial diagnosis of HSCR may be delayed until late childhood or adulthood, HSCR should be considered in anyone with lifelong severe constipation. Individuals with HSCR are at risk for enterocolitis and/or potentially lethal intestinal perforation.

Diagnosis/testing. The diagnosis of HSCR requires histopathologic demonstration of absence of enteric ganglion cells in the distal rectum. Suction biopsies of rectal mucosa and submucosa are the preferred diagnostic test in most centers because they can be performed safely without general anesthesia. Syndromes associated with HSCR are diagnosed by clinical findings, cytogenetic analysis, or in some cases, by specific molecular or biochemical tests. Isolated HSCR is a multigene disorder that has been associated with mutations in at least six different genes.

Genetic counseling. Recurrence risk depends on the underlying cause.

Management. Treatment of manifestations: Resection of the aganglionic segment and anastomosis of proximal bowel to the anus ("pull-through") is the standard treatment for HSCR. Individuals with extensive intestinal aganglionosis who develop irreversible intestinal failure may be candidates for intestinal transplantation.

Definition

Clinical Manifestations

Hirschsprung disease (HSCR), or congenital intestinal aganglionosis, is a birth defect characterized by complete absence of neuronal ganglion cells from a portion of the intestinal tract. The aganglionic segment includes the distal rectum and a variable length of contiguous proximal intestine.

  • In 80% of individuals, aganglionosis is restricted to the rectosigmoid colon ("short-segment disease").
  • In approximately 15%-20%, the aganglionosis extends proximal to the sigmoid colon (long-segment disease).
  • In approximately 5% of individuals, aganglionosis affects the entire large intestine (total colonic aganglionosis).
  • Rarely, the aganglionosis extends into the small bowel or even more proximally to encompass the entire bowel (total intestinal aganglionosis) [Badner et al 1990].

Affected infants frequently present in the first two months of life with symptoms of impaired intestinal motility such as failure to pass meconium within the first 48 hours of life (50%-90% of newborns with HSCR), constipation, emesis, abdominal pain or distention, and occasionally diarrhea. However, initial diagnosis of HSCR later in childhood or in adulthood occurs frequently enough that HSCR should be considered if an individual reports lifelong severe constipation.

Individuals with HSCR are at risk for enterocolitis and/or potentially lethal intestinal perforation.

The incidence of short-segment disease (80% of HSCR) is four times greater in males than in females; equal numbers of males and females present with long-segment HSCR [Badner et al 1990].

Establishing the Diagnosis

The diagnosis of HSCR requires histopathologic demonstration of absence of enteric ganglion cells in the distal rectum. Suction biopsies of rectal mucosa and submucosa are the preferred diagnostic test in most centers because they can be performed safely without general anesthesia. Absence of ganglion cells in the submucosa of 50-75 sections examined from a biopsy establishes the diagnosis. Accessory findings include hypertrophic submucosal nerves and/or an abnormal acetylcholinesterase enzyme staining pattern [Kapur 1999].

The diagnosis may be supported by anorectal manometry, abdominal radiographs that show a dilated proximal colon with empty rectum, or barium enema studies that demonstrate delayed emptying time and a funnel-like transition zone between proximal dilated and distal constricted bowel [Amiel & Lyonnet 2001, De Lorijn et al 2005].

Although radiographic studies may be helpful in delineating the proximal extent of aganglionosis, intraoperative intestinal rectal biopsy is used to establish the precise boundary during surgical resection.

Differential Diagnosis

The following disorders should be readily distinguished from HSCR on the basis of other clinical signs, specific tests for those disorders, and a suction biopsy that does not show evidence of aganglionosis.

In newborns with evidence of intestinal obstruction, other possible causes include the following:

  • Gastrointestinal malformations such as atresia, malrotation, or duplication
  • Meconium ileus secondary to cystic fibrosis (see CFTR-related disorders)
  • Conditions that cause ganglioneuromatosis, such as MEN 2B [Smith et al 1999]
  • Conditions associated with abnormalities of the enteric nervous system or musculature, termed chronic intestinal pseudoobstruction (including intestinal neuronal dysplasia [IND]) [Kapur 2001]

Acquired forms of severe constipation/obstruction may be caused by maternal factors such as infection, alcohol ingestion, or congenital hypothyroidism [Amiel & Lyonnet 2001].

Prevalence

The incidence of HSCR is approximately one in 5000 live births [Badner et al 1990, Parisi & Kapur 2000]. The incidence varies among different ethnic groups [Torfs 1998]:

  • Persons of northern European origin: 1.5 in 10,000 live births
  • African Americans: 2.1 in 10,000
  • Asians: 2.8 in 10,000

Within the Mennonite population of Pennsylvania, a founder mutation in EDNRB accounts for a significant proportion of children with HSCR [Puffenberger et al 1994].

Causes

Chromosomal Causes

A chromosomal abnormality is present in approximately 12% of individuals with HSCR (Table 1) [Amiel & Lyonnet 2001].

The most common chromosomal abnormality associated with HSCR is Down syndrome (trisomy 21), which occurs in 2%-10% of all individuals with HSCR [Moore & Johnson 1998]. Although individuals with Down syndrome are at a hundred-fold higher risk for HSCR than the general population [Moore & Johnson 1998], none of the established "HSCR genes" reside on chromosome 21; thus the association between trisomy 21 and HSCR remains unexplained.

Other chromosomal aberrations include deletions that encompass HSCR-associated genes:

Identification of individuals with HSCR and such deletions aided in discovery of these genes, and reinforces the haploinsufficiency model of HSCR pathogenesis in individuals with a deletion of one of these genes.

Other chromosomal anomalies have been described in individuals with HSCR, but the relevant gene(s) of interest have not been identified.

Table 1. Chromosomal Abnormalities Associated with HSCR

Chromosomal AbnormalityFeaturesChromosomal Locus (Gene Symbol)% of Individuals with HSCR
Down SyndromeID, short stature, CHD, craniofacialTrisomy 210.6%-3%
Deletion 10qID, hypotoniadel 10q11.2 (RET) Unknown
Deletion 13qID, growth failure, craniofacial featuresdel 13q22 (EDNRB) Unknown
Deletion 2q22ID, microcephaly, craniofacial features, seizuresdel 2q22 (ZFHX1B) Unknown

CHD = congenital heart disease; ID = intellectual disability

Single-Gene Causes

Monogenic disorders are those caused by mutation of a single gene and inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Both syndromic and nonsyndromic causes of HSCR are recognized.

Syndromic HSCR

Syndromes associated with HSCR are listed in alphabetical order; the prevalence of HSCR in each syndrome varies widely and is estimated in Table 2.

Bardet-Biedl syndrome (BBS) includes the features of progressive pigmentary retinopathy, obesity, postaxial polydactyly, hypogenitalism, and renal abnormalities, with variable but generally mild intellectual disability. HSCR has been reported in approximately 2% of individuals with BBS [Beales et al 1999]. In approximately 10% of affected individuals, BBS overlaps with HSCR and McKusick-Kaufman syndrome (MKKS), which includes hydrometrocolpos and heart disease [Davenport et al 1989]. A total of 14 genes have been identified for BBS, including MKKS, mutations in which cause McKusick-Kaufman syndrome [Stone et al 2000]. Specific genotype-phenotype correlations with HSCR have not been established. Inheritance is autosomal recessive.

Cartilage-hair hypoplasia. This skeletal dysplasia, prevalent among the Old Order Amish and Finnish populations, is characterized by short-limbed dwarfism, sparse hair, hypoplastic anemia, and a variety of immune defects. HSCR occurs in roughly 7%-9%, and is more likely to be associated with severe manifestations of the disorder [Makitie & Kaitila 1993, Makitie et al 2001]. The gene in which mutation is causative is the endoribonuclease RNase MRP (RMRP), important in processing of nuclear ribosomal RNA and in mitochondrial DNA synthesis [Ridanpaa et al 2001]. Inheritance is autosomal recessive.

Congenital central hypoventilation syndrome (CCHS). Classic CCHS is characterized by adequate ventilation while the affected individual is awake and by hypoventilation with normal respiratory rates and shallow breathing during sleep; more severely affected individuals hypoventilate when both awake and asleep. Both of these phenotypes present in the newborn period. Children with CCHS often have physiologic and anatomic manifestations of a generalized autonomic nervous system dysfunction, tumors of neural crest origin including neuroblastoma, ganglioneuroma, and ganglioneuroblastoma-altered development of neural crest-derived structures (i.e., Hirschsprung disease). Approximately 20% of individuals with CCHS have HSCR [Trang et al 2005], a combination known as Haddad syndrome.

De novo heterozygous mutations in PHOX2B have been found in 90% of individuals with CCHS [Amiel et al 2003, Matera et al 2004]. A subset of individuals with CCHS have a heterozygous mutation in RET, EDN3, GDNF, or BDNF (Table 3) [Bolk et al 1996, Amiel et al 1998, Sakai et al 1998, Weese-Mayer et al 2002]. In one study, RET was shown to act as a modifier gene for the development of HSCR in persons with CCHS [de Pontual et al 2006].

Familial dysautonomia (FD, Riley-Day syndrome) affects the development and survival of sensory, sympathetic, and parasympathetic neurons. It is a debilitating disease present from birth. Progressive neuronal degeneration continues throughout life. Affected individuals have gastrointestinal dysfunction, vomiting episodes, recurrent pneumonia, altered sensitivity to pain and temperature, and cardiovascular instability. About 40% of affected individuals have autonomic crises. FD occurs with relatively high frequency within the Ashkenazi Jewish population (1:3700 live births). FD has been associated with HSCR in some individuals [Azizi et al 1984].

Inheritance is autosomal recessive. The involved gene, IKBKAP, a molecule with an immune modulatory role [Anderson et al 2001, Slaugenhaupt et al 2001], maps to 9q31, the location for a presumed genetic modifier locus identified in several families with HSCR [Bolk et al 2000].

Fryns syndrome is characterized by hypoplasia of the distal digits, coarse facial features, variable diaphragmatic hernia, and a variety of other anomalies of the cardiac, gastrointestinal, genitourinary, and central nervous systems [Slavotinek 2004]. At least six persons have had HSCR in addition to features of Fryns syndrome, suggesting that Fryns syndrome may represent a neurocristopathy, like HSCR [Alkuraya et al 2005]. Although a specific genetic etiology has not been identified for Fryns syndrome, inheritance is generally presumed to be autosomal recessive.

Goldberg-Shprintzen syndrome shares many of the clinical features of Mowat-Wilson syndrome including microcepthaly, intellectual disability, facial dysmorphism, and HSCR, but affected individuals may also have cleft palate and colocoma, and the condition is presumed to be inherited in an autosomal recessive manner on the basis of several affected sibling pairs [Goldberg & Shprintzen 1981, Hurst et al 1988, Brooks et al 1999]. Two families with features of microcephaly, intellectual disability, generalized polymicrogyria, and variable HSCR were identified as having homozygous mutations in KIAA1279, thereby suggesting that this is the gene in which mutations occur to cause Goldberg-Shprintzen syndrome [Brooks et al 2005].

Note: Goldberg-Shprintzen syndrome is distinct from the Shprintzen-Goldberg syndrome.

Intestinal neuronal dysplasia, type B (IND) is associated with severe symptoms of bowel obstruction and may be clinically indistinguishable from HSCR, although age of onset tends to be later (six months to six years) [Kapur 1999, Kapur 2001]. In contrast to HSCR, the pathologic findings include hyperplasia of enteric ganglia (vs absent ganglion cells in HSCR) and other features such as "giant ganglia" that many pathologists find controversial [Kapur 2003]. IND can be found in isolation or proximal to aganglionic bowel in approximately 20% of individuals with HSCR. Attempts to identify mutations in known HSCR-associated genes have been unsuccessful in at least one series of individuals with IND or mixed IND/HSCR [Gath et al 2001].

L1 syndrome. Seven individuals with HSCR and X-linked aqueductal stenosis with documented mutations in L1CAM have been reported [Okamoto et al 1997, Vits et al 1998, Parisi et al 2002, Okamoto et al 2004, Basel-Vanagaite et al 2006]. No mutation was identified in RET in the one individual examined [Parisi et al 2002], although it is unknown whether mutations in other HSCR-associated genes may be implicated in the development of this condition. The association of hydrocephalus and HSCR suggests that the neuronal cell adhesion molecule, L1CAM, may be important for ganglion cell population of the gut. In addition, reduced L1CAM expression has been described in the extrinsic innervation of aganglionic gut from individuals with HSCR [Ikawa et al 1997]. Although HSCR is documented as having a male predominance, L1CAM is the only X-linked gene identified in association with HSCR; however, in one series of males with HSCR, no pathogenic L1CAM mutations were identified [Hofstra et al 2002].

Mowat-Wilson syndrome (Hirschsprung disease - intellectual disability syndrome). Clinical features include microcephaly, intellectual disability, seizures, and distinctive facial features (ocular hypertelorism, broad eyebrows, saddle nose, small rotated ears with upturned lobes, and pointed chin) [Lurie et al 1994, Mowat et al 1998]. HSCR has been reported in 41%-71% of affected individuals depending on the series [Mowat et al 2003, Zweier et al 2003, Cerruti Mainardi et al 2004, Zweier et al 2005]. Many individuals also demonstrate short stature, ocular anomalies, agenesis of the corpus callosum, congenital heart defects, and/or genitourinary abnormalities. Mowat-Wilson syndrome is associated with deletions or heterozygous mutations in ZFHX1B (zinc finger homeobox 1B) localized to 2q22 (see Table 1) [Amiel et al 2001, Cacheux et al 2001, Wakamatsu et al 2001].

Multiple endocrine neoplasia type 2 (MEN 2)

  • MEN 2A is an autosomal dominant disorder characterized by neoplastic transformation of C cells in the thyroid (medullary thyroid carcinoma, MTC), parathyroid hyperplasia, and adrenal medullary tumors (pheochromocytoma). In familial MTC (FMTC), development of medullary thyroid cancer in at least four family members is observed, without the other manifestations of MEN 2A. In the majority of individuals and families with MEN 2A or FMTC, the disease is caused by a single base-pair substitution in one of five codons of RET, which results in an amino acid substitution for a cysteine residue that confers constitutive activity by dimerization of the receptor [Eng et al 1996, Eng & Mulligan 1997, Sijmons et al 1998]. In some families with RET mutations in the cysteine codons 609, 611, 618, or 620, MEN 2A or FMTC is associated with HSCR [Sijmons et al 1998, Eng 1999, Hansford & Mulligan 2000], although in one series, this association was found in only 1% of individuals [Yip et al 2003].

    While most individuals with MEN 2A do not have aganglionosis, and vice versa, in some series an estimated 2.5%-5% of individuals with HSCR have a MEN 2A-associated RET mutation. As HSCR may be the initial finding in such individuals, molecular genetic testing could lead to recognition of RET mutations associated with MEN 2A and a cancer predisposition, with significant impact on care of the affected individual and family members [Amiel & Lyonnet 2001, Pakarinen et al 2005].
  • MEN 2B manifests as diffuse ganglioneuromas of the alimentary canal, marfanoid skeletal abnormalities, MTC, and pheochromocytoma. A heterozygous mutation in RET (p.Met918Thr) that alters its substrate specificity has been identified in more than 90% of individuals with MEN 2B. Individuals with MEN 2B may present in the newborn period with intestinal obstruction that clinically resembles HSCR but is caused by diffuse ganglioneuromatosis [Smith et al 1999]. Aside from one report of coincident HSCR in an individual with MEN 2B and the p.Met918Thr mutation [Romeo et al 1998], the majority of these individuals do not have HSCR.

Neurofibromatosis 1 (NF1) is an autosomal dominant condition characterized by café-au-lait spots, skin-fold freckling, and neurofibromas, among other neuroectodermal features. Gastrointestinal involvement includes findings described as intestinal neuronal dysplasia with myenteric plexus hypertrophy [Saul et al 1982] as well as HSCR [Clausen et al 1989]. In one family, cosegregation of the NF1 and megacolon phenotypes was associated with inheritance of both an abnormal NF1 allele from one parent and an abnormal GDNF allele from the other parent [Bahuau et al 2001], thus reinforcing the role of multiple gene interactions in the development of HSCR.

Smith-Lemli-Opitz syndrome (SLOS) is characterized by microcephaly, congenital heart disease, growth and developmental delays, distinctive facial features, undermasculinization with hypospadias in males, and characteristically, syndactyly of toes two or three. HSCR has been described in several individuals with this disorder, generally with more severe manifestations [Curry et al 1987, Cass 1990], although mild phenotypes of SLOS may be associated with HSCR [Mueller et al 2003]. SLOS is caused by mutations in DHCR7, the gene encoding the enzyme that catalyzes the final step in cholesterol biosynthesis. Inheritance is autosomal recessive.

Waardenburg syndrome type 4 (WS4, Waardenburg-Shah syndrome). Clinical features include HSCR, sensorineural deafness, and pigmentary anomalies (e.g., heterochromic irides, piebaldism). Since melanocytes and the inner hair cells critical for cochlear function are both derived from neural crest cells, WS4 is considered a generalized neurocristopathy.

No evidence for RET mutations as a cause of WS4 exists, although mutations in EDN3, EDNRB, and SOX10 [SRY (sex-determining region Y)-box 10] have been reported in affected individuals. In general, WS4 results from homozygosity for EDN3 or EDNRB mutant alleles, whereas heterozygotes exhibit isolated HSCR without the other features, although this correlation is not always straightforward [Edery et al 1996, Hofstra et al 1996, Syrris et al 1999]. In contrast, all the mutant SOX10 alleles reported in individuals with WS4 to date have been de novo or inherited in an autosomal dominant manner [Pingault et al 1998, Southard-Smith et al 1999]. SOX10 encodes a transcription factor that is expressed by hindbrain neural crest cells from the stage at which they leave the neural tube and throughout the colonization process [Bondurand et al 1998]. Defects in SOX10 have been reported in only a small number of individuals with HSCR, and in none with isolated HSCR [Sham et al 2001]. Some individuals with WS4 and SOX10 mutations in the terminal exon exhibit the additional neurologic symptoms of peripheral neuropathy with central nervous system myelination abnormalities and developmental delays, termed PCWH (peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and HSCR) [Inoue et al 2000, Pingault et al 2000, Inoue et al 2004].

Table 2. Monogenic Syndromic Forms of HSCR

SyndromeFeaturesMode of InheritanceChromosomal Locus 1 / Gene Symbol% with HSCR
Bardet-Biedl syndrome Retinal dystrophy, obesity, ID, polydactyly, hypogenitalism, renal abnormalitiesARAt least 14 loci / genes2%-10% 2
Cartilage-hair hypoplasiaShort-limbed dwarfism, sparse hair, immune defectsAR9p21-p12/RMRP 7%-9%
CCHS Hypoxia, reduced ventilatory drive, neuroblastomaVariable4p13 / PHOX2B
10q11.21 / RET
5p13.2 / GDNF
20q13.32 / EDN3
11p14.1 / BDNF
20%
Familial dysautonomia (Riley-Day syndrome)Sensory and autonomic dysfunction (including abnormal sweat, tear, and saliva production)AR9q31.3 / IKBKAP Unknown
Fryns syndromeDistal digital hypoplasia, diaphragmatic hernia, CHD, craniofacial, IDARUnknownUnknown
Goldberg-Shprintzen syndromeCraniofacial, microcephaly, ID, PMGAR10q22.1 / KIAA1279
Others?
Common
Intestinal neuronal dysplasiaAbnormal intestinal innervation with giant gangliaUnknownUnknown≤20% 2
L1 syndrome ID, hydrocephalus, ACC, adducted thumbsXLRXq28 / L1CAM Rare
MEN 2A/FMTCMTC, pheo, hyperpara-
thyroidism 3
AD10q11.21 / RET ≤1%
MEN 2B MTC, pheo, mucosal and intestinal neuromas, skeletal abnormalities, corneal changesAD10q11.21 / RET Rare
Mowat-Wilson syndromeID, microcephaly, craniofacial, CHD, ACC, epilepsy, short statureAD2q22.3 / ZFHX1B41%-71%
Neurofibromatosis 1 Café-au-lait macules, neurofibromas, Lisch nodulesAD17q11.2 / NF1,
5p13.2 / GDNF?
Unknown
Smith-Lemli-Opitz syndrome ID, hypospadias, 2/3 syndactyly, CHD, craniofacialAR11q13.4 / DHCR7 Unknown
Waardenburg syndrome type 4 (Waardenburg-Shah syndrome)Pigmentary abnormalities, deafnessAR (usually)13q22.3 / EDNRB
20q13.32 / EDN3
Common
AD22q13.1 / SOX10 Almost 100%

ID = intellectual disability; CHD = congenital heart disease; PMG = polymicrogyria; AD = autosomal dominant; AR = autosomal recessive; XLR = X-linked recessive; pheo = pheochromocytoma; MTC = medullary thyroid carcinoma; DHCR7 = 7-dehydrocholesterol reductase; ACC = agenesis of the corpus callosum; ZFHX1B = zinc finger homeobox protein 1b; RMRP = RNAse mitochondrial RNA processing; BDNF = brain-derived neurotrophic factor; L1CAM = neural cell adhesion molecule L1; NF1 = neurofibromin; CCHS = congenital central hypoventilation syndrome; MEN = multiple endocrine neoplasia

1. Chromosomal locus from OMIM

2. Limited data are available.

3. In FMTC, affected individuals do not have pheochromocytoma or hyperparathyroidism.

Nonsyndromic HSCR

Nonsyndromic HSCR (in which HSCR occurs without other anomalies) has been associated with mutations in at least six genes [Wartiovaara et al 1998, Kapur 1999, Parisi & Kapur 2000] (Table 3).

Table 3. Genes Associated with Nonsyndromic HSCR

Gene SymbolProtein NameChromosomal Locus 1InheritanceFrequencyType of HSCRSyndromic? 2
RET
OMIM 164761
Proto-oncogene tyrosine-protein kinase receptor ret10q11.2AD17%-38%Short segmentYes
70%-80%Long segment 3
50%Familial
3%-10% 4 Simplex
GDNF 5
OMIM 600837
Glial cell line-derived neutrotrophic factor5p13.2AD<1% 6 VariableYes
NRTN 5
OMIM 602018
Neurturin19p13.3AD<1% 6 VariableUnknown
EDNRB
OMIM 131244
Endothelin B receptor13q22.3AD/AR3%-7%VariableYes 7
EDN3
OMIM 131242
Endothelin-320q13.32AD/AR5%VariableYes 7
ECE1
OMIM 600423
Endothelin-converting enzyme 2 1p36.12AD 6 <1% 6 VariableUnknown

1. Chromosomal locus from OMIM

2. Mutations in the gene have also been reported with syndromic forms of HSCR (see Table 2).

3. Homozygous mutations have been associated with total colonic aganglionosis in some cases.

4. RET mutations are reported to be higher (10%-35%) in simplex HSCR (HSCR in a single family member) in some referral series (see Genes for RET and its ligands).

5. A mutation in this gene is insufficient by itself to cause disease in most cases (see Genes for RET and its ligands).

6. Limited data are available.

7. The syndromic form is usually associated with homozygous mutations in this gene.

The genes associated with isolated HSCR fall into two major groups:

Genes for RET and its ligands. The tyrosine kinase receptor, RET (proto-oncogene tyrosine-protein kinase receptor; rearranged during transfection), is expressed by enteric neural precursors shortly after they leave the neural plate and throughout their colonization of the entire gut. GDNF (glial cell line-derived neurotrophic factor) and NRTN (or NTN; neurturin) are two of the ligands for RET expressed by adjacent mesenchymal cells. Although coreceptors for RET and its ligands exist, testing for mutations in the specific coreceptor associated with GDNF (GFR alpha-1) has not revealed any causative mutations in humans [Myers et al 1999].

Mutations in RET appear to be dominant loss-of-function mutations with incomplete penetrance and variable expressivity.

RET mutations alone are estimated to account for 7%-41% of all individuals with HSCR and 70%-80% of those with long-segment disease [Angrist et al 1995, Seri et al 1997, Sancandi et al 2000]. Homozygous RET mutations have been associated with total colonic aganglionosis in some individuals [Inoue et al 2000, Shimotake et al 2001].

RET is implicated in up to 50% of all familial HSCR [Attie et al 1995, Hofstra et al 2000]. The involvement of RET has been estimated to occur in 10%-35% of simplex cases of HSCR (i.e., HSCR in a single family member) in several referral series, which may be biased toward more severe or familial cases [Angrist et al 1995, Attie et al 1995, Eng & Mulligan 1997]; in the few population-based series reported, the incidence is 3%-10% [Svensson et al 1999, Borrego et al 2000, Sancandi et al 2000].

The penetrance of RET mutations is approximately 50%-70% [Bolk et al 2000]. Several candidate loci that may be responsible for the incomplete penetrance and variable expressivity observed in individuals with RET mutations have already been identified [Bolk et al 2000, Gabriel et al 2002].

Common polymorphisms in RET that do not cause amino acid changes appear to be over-represented within a population of individuals with HSCR [Borrego et al 1999, Fitze et al 1999, Borrego et al 2000], adding further complexity to the task of determining if a sequence variant is a disease-causing mutation. In addition, specific RET haplotypes, including polymorphisms in promoter elements and 5' introns, may also modify the risk of developing HSCR based on differences in RET protein expression, even in the absence of a pathogenic RET mutation [Fitze et al 2003a, Fitze et al 2003b, Sancandi et al 2003, Burzynski et al 2005, Lantieri et al 2006]. Specific RET promoter single nucleotide polymorphisms that decrease transcription may predispose to the development of HSCR in some populations [Garcia-Barcelo et al 2005], and one enhancer variant with differential effects in males and females may explain the increased occurrence in males, at least in part [Emison et al 2005].

Mutations in GDNF and NRTN have been identified in only a small minority of individuals with HSCR, and in almost all of those individuals, a mutation was also identified in RET or another HSCR gene, suggesting that mutation in one of the ligands is not sufficient by itself to cause disease [Angrist et al 1996, Hofstra et al 1996, Ivanchuk et al 1996, Salomon et al 1996, Doray et al 1998, Eketjall & Ibanez 2002].

EDNRB and related genes. Components of another cell signaling pathway that probably interacts with the RET pathway during enteric neural crest-colonization have been implicated in HSCR [Carrasquillo et al 2002]; these include the endothelin receptor type B (EDNRB) and its ligand, endothelin-3 (EDN3). Synthesis of the mature active form of endothelin-3 requires post-translational modification by endothelin-converting enzyme 1 (encoded by ECE1). EDNRB and EDN3 mutations probably account for approximately 10% of individuals with HSCR [Amiel et al 1996, Kusafuka et al 1996, Svensson et al 1999]. Within the Mennonite community, however, a significant proportion of affected individuals have a missense mutation in EDNRB, representing a founder mutation, and some of these individuals have manifestations of Waardenburg syndrome type 4 (WS4) [Puffenberger et al 1994]. In general, individuals with a heterozygous mutation in EDNRB or EDN3 present with HSCR or occasionally features of WS4, while those with homozygous mutations in either gene are more likely to have more severe manifestations of WS4 [Verheij et al 2002]. A mutation in ECE1 has been reported in only one individual, who also had craniofacial anomalies and a heart defect [Hofstra et al 1999].

Unknown Cause

Approximately 18% of individuals with HSCR have at least one other congenital anomaly [Amiel & Lyonnet 2001]. The association of HSCR with other birth defects is often part of a recognized syndrome resulting from abnormalities in other neural crest derivatives (see Table 2). Often, a specific syndrome cannot be identified (Table 4).

Some of the most frequent anomalies include congenital heart defects (up to 5% of individuals with HSCR, excluding those with Down syndrome), gastrointestinal malformations (including Meckel diverticulum, malrotation, and imperforate anus, with an incidence of up to 4% of individuals with HSCR), central nervous system abnormalities (a broad spectrum of disorders, in up to 4%), and genitourinary abnormalities (including cryptorchidism, hypospadias, and renal malformations, in up to 7%). Craniofacial abnormalities and spina bifida have also been seen in association with HSCR [Badner et al 1990, Ryan et al 1992, Sarioglu et al 1997, Parisi & Kapur 2000, Amiel & Lyonnet 2001].

Table 4. HSCR with Congenital Anomalies of Unknown Cause

AnomalyFeaturesMode of InheritanceGenetic Locus/Gene% in HSCR 1
Central nervous systemID, Dandy-Walker malformation, microcephalyUnknownUnknown3.6%-3.9%
Congenital heart diseaseASD, VSD, PDA, tetralogy of FallotUnknownUnknown2.3%-4.8%
GastrointestinalMalrotation, imperforate anus, Meckel diverticulum, sacral-rectal fistulaUnknownUnknown3.3%-3.9%
GenitourinaryCryptorchidism, inguinal hernia, hypospadias, kidney malformations, urethral fistulaUnknownUnknown5.6%-7.3%

ID = intellectual disability; ASD = atrial septal defect; VSD= ventricular septal defect; PDA = patent ductus arteriosus

1. Incidence figures are derived from Badner et al [1990], Ryan et al [1992], and Sarioglu et al [1997] and exclude cases of Down syndrome. For these associations, the final column represents the % of individuals with HSCR who also have at least one congenital anomaly within this category.

Evaluation Strategy

Identification of the cause of HSCR aids in establishing prognosis and mode of inheritance for genetic counseling.

To help establish the cause of HSCR, the work-up for an individual with HSCR includes the following:

  • Physical examination to identify findings that could establish the diagnosis of monogenic syndromic HSCR
  • A detailed family history with emphasis on infants with signs of intestinal obstruction and its complications and adults with chronic constipation
  • If monogenic causes seem unlikely and if multiple anomalies, growth failure, and/or developmental delay are present, a chromosome analysis of blood that examines at least 20 metaphases at the 550 band level or greater should be performed.

    Note: Chromosome analysis of the parents is recommended only if the proband has an abnormal karyotype (other than trisomy 21).
  • If monogenic nonsyndromic HSCR is confirmed or likely, molecular genetic testing of RET should be considered. HSCR-associated mutations have been described in each of the 20 RET exons and no single specific defect is particularly common. In addition, because of incomplete penetrance of mutant alleles, it is difficult to predict the phenotypic effect of a given sequence change. In some circumstances (e.g., a family with highly penetrant, long-segment HSCR) RET molecular genetic testing may be helpful in providing genetic counseling. Some groups recommend testing for the MEN2-associated mutations in RET in all individuals with HSCR. If a RET mutation is not identified, molecular genetic testing of EDN3 and/or EDNRB may be considered.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

If a proband has an inherited or de novo chromosome abnormality, a specific syndrome associated with HSCR (see Table 2), or a disease-causing mutation in RET, EDN3, or EDNRB (see Evaluation Strategy), counseling for that condition is indicated. In probands with nonsyndromic HSCR without a clear etiology, HSCR is considered to be a polygenic disorder with incomplete penetrance, variable expressivity, and a 4:1 predominance in males.

Risk to Family Members — Nonsyndromic HSCR

Parents of a proband

Sibs of a proband

  • Nonsyndromic autosomal dominant HSCR
  • Nonsyndromic HSCR of unknown etiology: empiric risks
    • The overall risk to sibs of a proband is 4% (vs 0.02%, the incidence of HSCR in the general population) [Badner et al 1990].
    • The risk is higher to sibs of probands with long-segment disease and depends on the sex of the proband and sib (Table 5).
    • The risk to sibs of probands with short-segment disease is lower and more consistent with the risks associated with a recessive or multifactorial pattern of inheritance (Table 5).

Table 5. Recurrence Risk for HSCR in Sibs Based on Length of Involved Segment

ProbandSibRisk to Sib for HSCR When the Proband Has:
Long-segment HSCRShort-segment HSCR
MaleMale17%5%
Female13%1%
FemaleMale33%5%
Female9%3%

Offspring of a proband

  • Nonsyndromic autosomal dominant HSCR
    • Each child of an individual with nonsyndromic autosomal dominant HSCR has a 50% chance of inheriting the mutation.
    • Because of incomplete penetrance, the offspring who inherits a mutant allele may not develop symptoms of HSCR, and for those who do develop HSCR, the degree of severity cannot be predicted.
  • Nonsyndromic HSCR of unknown etiology: empiric risks
    • Offspring of a proband with nonsyndromic HSCR of unknown etiology are at increased risk of having HSCR; however, precise estimates are not available.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation(s) have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). Such testing may be available through laboratories that offer either testing for the gene of interest or custom testing. Because of incomplete penetrance and variable expressivity, it is not possible to predict if the fetus will develop clinical HSCR.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions such as nonsyndromic HSCR are not common since a fetus identified as having a potential disease-causing mutation may never develop symptoms of HSCR. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified in an affected family member.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • International Foundation for Functional Gastrointestinal Disorders (IFFGD)
    PO Box 170864
    Milwaukee WI 53217-8076
    Phone: 888-964-2001 (toll-free); 414-964-1799
    Fax: 414-964-7176
    Email: iffgd@iffgd.org
  • International Foundation for Functional Gastrointestinal Disorders (IFFGD) - Pediatric
    PO Box 170864
    Milwaukee WI 53217-8076
    Phone: 888-964-2001 (toll-free); 414-964-1799
    Fax: 414-964-7176
    Email: iffgd@iffgd.org
  • Pull-thru Network (PTN)
    2312 Savoy Street
    Hoover AL 35226-1528
    Phone: 205-978-2930
    Email: PTNmail@charter.net

Management

Treatment of Manifestations

Resection of the aganglionic segment and anastomosis of proximal bowel to the anus ("pull-through") is the standard treatment for HSCR and can be performed as a single procedure or in stages. A variety of surgical anastomoses have been developed with the general goal of eliminating obstruction while preserving continence.

An effort is generally made to resect a variable length of gut just proximal to the aganglionic zone since this transitional area may have altered pathologic properties (e.g., hypoganglionosis) and physiologic properties that are not conducive to normal intestinal motility [Coran & Teitelbaum 2000]. However, persistent intestinal dysmotility (usually constipation but sometimes diarrhea) after a pull-through procedure occurs frequently and may reflect an underlying abnormality of ganglionic gut that is not understood [Engum & Grosfeld 2004]. Hirschsprung-associated enterocolitis can be a post-surgical complication with significant morbidity [Engum & Grosfeld 2004].

Individuals with extensive intestinal aganglionosis who develop irreversible intestinal failure may be candidates for intestinal transplantation [Bond & Reyes 2004].

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

References

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Suggested Reading

  1. Chakravarti A, McCallion AS, Lyonnet S. Hirschsprung disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 251. Available online. Accessed 12-18-12.

Chapter Notes

Author History

Raj Paul Kapur, MD, PhD; University of Washington (2002-2004)
Melissa Parisi, MD, PhD (2002-present)

Revision History

  • 10 November 2011 (cd) Revision: sequence analysis and prenatal testing available for mutations in EDN3 and EDNRB
  • 26 December 2006 (me) Comprehensive update posted to live Web site
  • 28 July 2004 (me) Comprehensive update posted to live Web site
  • 12 July 2002 (me) Overview posted to live Web site
  • 23 February 2002 (mp) Original submission

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