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NCBI Bookshelf. This publication is provided for historical reference only and the information may be out of date. 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. 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. 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 i. 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.
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. Absence of ganglion cells in the submucosa of sections examined from a biopsy establishes the diagnosis.
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.
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:. The incidence varies among different ethnic groups [ Torfs ]:. Conversely, approximately 0.
Some chromosome aberrations include deletions that encompass HSCR-associated genes:. Identification of individuals with HSCR and such deletions aided in discovery of several of these genes, and reinforces the haploinsufficiency model of HSCR pathogenesis in individuals with a deletion of one of the genes.
View in own window. 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. 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.
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. 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. 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.
FD occurs with relatively high frequency within the Ashkenazi Jewish population , live births. 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 ].
One report noted that three of 11 individuals with Fryns syndrome who had survived the neonatal period had HSCR [ Dentici et al ]. Although a specific genetic etiology has not been identified for Fryns syndrome, inheritance is generally presumed to be autosomal recessive.
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 6 months to 6 years [ Kapur , Kapur ].
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 ]. L1 syndrome. No pathogenic variant was identified in RET in the one individual examined [ Parisi et al ]; it is unknown whether mutation of other HSCR-associated genes is 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. Mowat-Wilson syndrome Hirschsprung disease - intellectual disability syndrome. Clinical features include microcephaly, intellectual disability, seizures, and distinctive facial features including ocular hypertelorism, broad eyebrows, saddle nose, small rotated ears with upturned lobes, and pointed chin [ Lurie et al , Mowat et al ].
Mowat-Wilson syndrome is associated with deletions or heterozygous pathogenic variants in ZEB2 zinc finger homeobox 1B localized to 2q22 see Table 1 [ Amiel et al , Cacheux et al , Wakamatsu et al ]. Gastrointestinal involvement includes findings described as intestinal neuronal dysplasia with myenteric plexus hypertrophy [ Saul et al ] as well as HSCR [ Clausen et al ]. 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 ], thus reinforcing the role of multiple gene interactions in the development of HSCR.
Although only one affected individual has been reported with HSCR [ Peippo et al ], severe constipation is a common finding.
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.
SLOS is caused by pathogenic variants in DHCR7 , the gene encoding the enzyme that catalyzes the final step in cholesterol biosynthesis. Waardenburg syndrome type 4 WS4, Waardenburg-Shah syndrome. Clinical features include HSCR, sensorineural deafness, and pigmentary anomalies e. Since melanocytes and the inner hair cells critical for cochlear function are both derived from neural crest cells, WS4 is considered a generalized neurocristopathy. However, this correlation is not always straightforward [ Edery et al , Hofstra et al , Syrris et al ].
In contrast, all the pathogenic SOX10 alleles reported in individuals with WS4 to date have been de novo or inherited in an autosomal dominant manner [ Pingault et al , Southard-Smith et al ]. Some individuals with WS4 and SOX10 pathogenic variants 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 , Pingault et al , Inoue et al ].
Of note, 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 ]. Chromosome locus from OMIM. In FMTC, affected individuals do not have pheochromocytoma or hyperparathyroidism. Click here pdf for more information on genes associated with isolated HSCR.
Click here pdf for further details. Homozygous pathogenic variants have been associated with total colonic aganglionosis in some cases. A variant in this gene is insufficient by itself to cause disease in most cases Click here pdf for further details.
The syndromic form is usually associated with homozygous pathogenic variants in this gene. Most pathogenic variants are associated with nonsyndromic forms of HSCR; however, because a few individuals are reported to have other anomalies this form of HSCR may also be syndromic. Copy number variants mostly deletions in this gene have also been implicated in HSCR.
Most reported deletions have been intragenic rather than large copy number variants [ Tang et al b ]. 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. Incidence figures are derived from Badner et al  , Ryan et al  , and Sarioglu et al  and exclude cases of Down syndrome.
Identification of the cause of Hirschsprung disease HSCR aids in establishing prognosis and mode of inheritance for 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. In probands with nonsyndromic HSCR without a clear etiology, HSCR is considered to be a polygenic disorder with reduced penetrance , variable expressivity , and a predominance in males.
Based on Badner et al . Other family members of a proband. 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for nonsyndromic autosomal dominant HSCR are possible.
Requests for prenatal testing for conditions such as nonsyndromic HSCR are not common since a fetus identified as having a potential pathogenic variant may never develop manifestations 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.
While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here. 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. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.
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Hirschsprung disease is a congenital anomaly of innervation of the lower intestine, usually limited to the colon, resulting in partial or total functional obstruction. Symptoms are obstipation and distention. Diagnosis is by barium enema and rectal biopsy. Anal manometry can help in the evaluation and reveals lack of relaxation of the internal anal sphincter. Treatment is surgical. Also see Overview of Congenital Gastrointestinal Anomalies. Hirschsprung disease is caused by congenital absence of the Meissner and Auerbach autonomic plexus aganglionosis in the intestinal wall.
NCBI Bookshelf. This publication is provided for historical reference only and the information may be out of date. 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. Rarely, the aganglionosis extends into the small bowel or even more proximally to encompass the entire bowel total intestinal aganglionosis.