Hirschsprung's disease
Encyclopedia
Hirschsprung's disease (HSCR), or congenital aganglionic megacolon is a serious medical problem where the enteric
nervous system is missing from the end of the bowel. The enteric nervous system
is a complex network of neurons
(i.e., ganglion cells) and glia that controls most aspects of intestinal function. When the ENS is absent, the region of the bowel that is aganglionic
fails to relax causing a blockage in the bowel. People with Hirschsprung disease always have aganglionosis (lack of neurons) at the end of the bowel, but the length of bowel that is aganglionic varies. Severe symptoms may occur with even short segments of aganglionosis and symptom severity does not correlate well with the extent of aganglionic bowel.
, the Danish
physician
who first described two infants who died of this disorder in 1888,.
Hirschsprung’s disease is a congenital disorder of the colon
in which certain nerve cells, known as ganglion cell
s, are absent, causing chronic
constipation
. The lack of ganglion cells is in the myenteric plexus, which is responsible for moving food in the intestine
. A barium enema
is the mainstay of diagnosis of Hirschsprung’s, though a rectal biopsy
showing the lack of ganglion cells is the only certain method of diagnosis
.
The usual treatment is "pull-through" surgery
where the portion of the colon
that does have nerve cells is pulled through and sewn over the part that lacks nerve cells (National Digestive Diseases Information Clearinghouse). For a long time, Hirschsprung’s was considered a multi-factorial disorder, where a combination of nature and nurture were considered to be the cause. However, in August 1993, two articles by independent groups in Nature Genetics said that Hirschsprung’s disease could be mapped to a stretch of chromosome 10
.
This research also suggested that a single gene was responsible for the disorder. However, the researchers were unable to isolate it.
and loci have been shown or suggested to be associated with Hirschsprung's disease:
Hirschsprung's disease can also present as part of a syndrome
in Waardenburg-Shah syndrome, Mowat-Wilson syndrome
, Goldberg-Shpritzen megacolon syndrome, and congenital central hypoventilation syndrome.
In 2002, scientists thought they found the solution. According to this new research, Hirschsprung's is caused by the interaction between two proteins encoded
by two variant genes. The RET proto-oncogene
on chromosome 10 was identified as one of the gene
s involved. The protein with which RET has to interact in order for Hirschsprung’s disease to develop is termed EDNRB
and is encoded by the gene
EDNRB located on chromosome 13
.
RET codes for proteins that assist cells of the neural crest (which later become ganglion cells) in their movement through the digestive tract during the development of the embryo. EDNRB codes for proteins that connect these nerve cells to the digestive tract. This means that the absence of certain nerve fibers in the colon could be directly related to these two genes mutating so the wrong proteins are produced. Research published in June 2004 suggests that there are several genes associated with Hirschsprung’s disease. Also, new research suggests that mutations in genomic sequences involved in regulating EDNRB have a bigger impact on Hirschsprung’s disease than previously thought.
RET can mutate in many ways and is associated with Down's syndrome. Since Down Syndrome
is comorbid in two percent of Hirschsprung’s cases, there is a likelihood that RET is involved heavily in both Hirschprung's disease and Down Syndrome. RET is also associated with thyroid cancer
and neuroblastoma
. Both of these disorders have also been observed in Hirschsprung’s patients with greater frequency than in the general population. One function that RET controls is the travel of the neural crest cells through the intestine
s in the developing fetus
. The earlier the mutation
of RET occurs in Hirschsprung’s disease, the more severe the disorder becomes.
Hirschsprung's disease, hypoganglionosis, gut dysmotility, gut transit disorders and intussusception
have been recorded with the dominantly inherited neurovisceral porphyrias (acute intermittent porphyria
, hereditary coproporphyria
, variegate porphyria
). Children may require enzyme
or DNA testing for these disorders as they may not produce or excrete porphyrins prepuberty.
Diagnostic techniques involve anorectal manometry
, barium enema
, and rectal biopsy
.
Radiologic findings may also assist with diagnosis.
Orvar Swenson, who discovered the cause of Hirschsprung’s, first performed it in 1948. The pull-through procedure repairs the colon by connecting the functioning portion of the bowel to the anus. The pull-through procedure is the typical method for treating Hirschsprung’s in younger patients. Swenson devised the original procedure, and the pull-through surgery has been modified many times.
The Swenson, Soave, Duhamel, and Boley procedures all vary slightly from each other:
Of those 15% of children who do not obtain full control, other treatments are available. If constipation is the problem then usually laxatives or a high fiber diet will overcome the problem. If lack of control is the problem then a stoma
may be necessary. The Malone ACE is also an answer. This is where a tube goes through the abdominal wall to the appendix or, if available, to the colon. Then once a day the bowel is flushed. Children as young as 6 do fine with administering this on their own. Details of ostomical sugery and its results can be found in the book Unwanted Baggage by P. and E. Prosser.
If the affected portion of the lower intestine is restricted to the lower portion of the rectum, other surgical procedures, such as the posterior rectal myectomy, can be performed.
Enteric nervous system
The enteric nervous system is a subdivision of the autonomic nervous system that directly controls the gastrointestinal system in vertebrates.It is derived from neural crest.-Function:...
nervous system is missing from the end of the bowel. The enteric nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
is a complex network of neurons
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
(i.e., ganglion cells) and glia that controls most aspects of intestinal function. When the ENS is absent, the region of the bowel that is aganglionic
Ganglion
In anatomy, a ganglion is a biological tissue mass, most commonly a mass of nerve cell bodies. Cells found in a ganglion are called ganglion cells, though this term is also sometimes used to refer specifically to retinal ganglion cells....
fails to relax causing a blockage in the bowel. People with Hirschsprung disease always have aganglionosis (lack of neurons) at the end of the bowel, but the length of bowel that is aganglionic varies. Severe symptoms may occur with even short segments of aganglionosis and symptom severity does not correlate well with the extent of aganglionic bowel.
History and description
The first report of Hirschsprung disease dates back to 1691, however, the disease is named after Harald HirschsprungHarald Hirschsprung
Harald Hirschsprung was a Danish physician who first described Hirschsprung's disease in 1886.-Life and medical career:Harald Hirschsprung was a native of Copenhagen....
, the Danish
Denmark
Denmark is a Scandinavian country in Northern Europe. The countries of Denmark and Greenland, as well as the Faroe Islands, constitute the Kingdom of Denmark . It is the southernmost of the Nordic countries, southwest of Sweden and south of Norway, and bordered to the south by Germany. Denmark...
physician
Physician
A physician is a health care provider who practices the profession of medicine, which is concerned with promoting, maintaining or restoring human health through the study, diagnosis, and treatment of disease, injury and other physical and mental impairments...
who first described two infants who died of this disorder in 1888,.
Hirschsprung’s disease is a congenital disorder of the colon
Colón
Colón is a Spanish and Portuguese surname, comparable to the Italian and Portuguese Colombo . It may refer to:People:* Cristóbal Colón, the Spanish language name for the explorer Christopher Columbus...
in which certain nerve cells, known as ganglion cell
Ganglion cell
A retinal ganglion cell is a type of neuron located near the inner surface of the retina of the eye. It receives visual information from photoreceptors via two intermediate neuron types: bipolar cells and amacrine cells...
s, are absent, causing chronic
Chronic
Chronic may refer to:* Chronic , a disease that is long-lasting and reoccurring.* Chronic toxicity, a substance with toxic effects after continuous or repeated exposure* The Chronic, a 1992 album by Dr. Dre...
constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
. The lack of ganglion cells is in the myenteric plexus, which is responsible for moving food in the intestine
Intestine
In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...
. A barium enema
Barium enema
A lower gastrointestinal series, also called a barium enema, is a medical procedure used to examine and diagnose problems with the human colon . X-ray pictures are taken while barium sulfate fills the colon via the rectum.-Procedure:...
is the mainstay of diagnosis of Hirschsprung’s, though a rectal biopsy
Biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
showing the lack of ganglion cells is the only certain method of diagnosis
Diagnosis
Diagnosis is the identification of the nature and cause of anything. Diagnosis is used in many different disciplines with variations in the use of logics, analytics, and experience to determine the cause and effect relationships...
.
The usual treatment is "pull-through" surgery
Surgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...
where the portion of the colon
Colón
Colón is a Spanish and Portuguese surname, comparable to the Italian and Portuguese Colombo . It may refer to:People:* Cristóbal Colón, the Spanish language name for the explorer Christopher Columbus...
that does have nerve cells is pulled through and sewn over the part that lacks nerve cells (National Digestive Diseases Information Clearinghouse). For a long time, Hirschsprung’s was considered a multi-factorial disorder, where a combination of nature and nurture were considered to be the cause. However, in August 1993, two articles by independent groups in Nature Genetics said that Hirschsprung’s disease could be mapped to a stretch of chromosome 10
Chromosome 10 (human)
125px|rightChromosome 10 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 10 spans about 135 million base pairs and represents between 4 and 4.5 percent of the total DNA in cells.Identifying genes on each chromosome is an active area...
.
This research also suggested that a single gene was responsible for the disorder. However, the researchers were unable to isolate it.
Epidemiology
According to a 1984 study, Hirshsprung's disease appears on 18.6 per 100,000 live births. It is more common in male rather than female (4.32:1) and in white rather than non-white 9% of the Hirschsprung cases were also diagnosed as having Down's Syndrome.Genetic basis
Several genesGênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
and loci have been shown or suggested to be associated with Hirschsprung's disease:
| Type | OMIM | Gene | Locus |
|---|---|---|---|
| HSCR1 | RET RET proto-oncogene The RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor family of extracellular signalling molecules.... |
10q11.2 | |
| HSCR2 | EDNRB | 13q22 | |
| HSCR3 | GDNF | 5p13.1-p12 | |
| HSCR4 | EDN3 | 20q13.2-q13.3 | |
| HSCR5 | ? | 21q22 | |
| HSCR6 | ? | 3p21 | |
| HSCR7 | ? | 19q12 | |
| HSCR8 | ? | 16q23 | |
| HSCR9 | ? | 4q31-32 | |
| - | SOX10 SOX10 Transcription factor SOX-10 is a protein that in humans is encoded by the SOX10 gene.... |
22q13 | |
| - | ECE1 Endothelin converting enzyme 1 Endothelin converting enzyme 1, also known as ECE1, is a enzyme which in humans is encoded by the ECE1 gene.- Function :Endothelin-converting enzyme-1 is involved in the proteolytic processing of endothelin-1 , -2 , and -3 to biologically active peptides.-Further reading:... |
1p36.1 | |
| - | NRTN Neurturin Neurturin is a ligand used to bind to GFRA2 receptors. It is related to Glial cell line-derived neurotrophic factor.... |
19p13.3 | |
| - | SIP1 Survival of motor neuron protein-interacting protein 1 Survival of motor neuron protein-interacting protein 1 is a protein that in humans is encoded by the SIP1 gene.-Interactions:Survival of motor neuron protein-interacting protein 1 has been shown to interact with DDX20 and SMN1.-Further reading:... |
14q13-q21 |
Hirschsprung's disease can also present as part of a syndrome
Syndrome
In medicine and psychology, a syndrome is the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one or more features alerts the physician to the possible presence of the others...
in Waardenburg-Shah syndrome, Mowat-Wilson syndrome
Mowat-Wilson Syndrome
Mowat Wilson syndrome is a rare genetic disorder that was clinically delineated by Dr. D. R. Mowat and Dr. M. J. Wilson in 1998.-Presentation:...
, Goldberg-Shpritzen megacolon syndrome, and congenital central hypoventilation syndrome.
In 2002, scientists thought they found the solution. According to this new research, Hirschsprung's is caused by the interaction between two proteins encoded
Genetic code
The genetic code is the set of rules by which information encoded in genetic material is translated into proteins by living cells....
by two variant genes. The RET proto-oncogene
RET proto-oncogene
The RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor family of extracellular signalling molecules....
on chromosome 10 was identified as one of the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s involved. The protein with which RET has to interact in order for Hirschsprung’s disease to develop is termed EDNRB
Endothelin receptor type B
Endothelin receptor type B, also known as ETB is a protein that in humans is encoded by the EDNRB gene.- Function :Endothelin receptor type B is a G protein-coupled receptor which activates a phosphatidylinositol-calcium second messenger system. Its ligand, endothelin, consists of a family of three...
and is encoded by the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
EDNRB located on chromosome 13
Chromosome 13 (human)
Chromosome 13 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 13 spans about 114 million base pairs and represents between 3.5 and 4 % of the total DNA in cells....
.
RET codes for proteins that assist cells of the neural crest (which later become ganglion cells) in their movement through the digestive tract during the development of the embryo. EDNRB codes for proteins that connect these nerve cells to the digestive tract. This means that the absence of certain nerve fibers in the colon could be directly related to these two genes mutating so the wrong proteins are produced. Research published in June 2004 suggests that there are several genes associated with Hirschsprung’s disease. Also, new research suggests that mutations in genomic sequences involved in regulating EDNRB have a bigger impact on Hirschsprung’s disease than previously thought.
RET can mutate in many ways and is associated with Down's syndrome. Since Down Syndrome
Down syndrome
Down syndrome, or Down's syndrome, trisomy 21, is a chromosomal condition caused by the presence of all or part of an extra 21st chromosome. It is named after John Langdon Down, the British physician who described the syndrome in 1866. The condition was clinically described earlier in the 19th...
is comorbid in two percent of Hirschsprung’s cases, there is a likelihood that RET is involved heavily in both Hirschprung's disease and Down Syndrome. RET is also associated with thyroid cancer
Thyroid cancer
Thyroid neoplasm is a neoplasm or tumor of the thyroid. It can be a benign tumor such as thyroid adenoma, or it can be a malignant neoplasm , such as papillary, follicular, medullary or anaplastic thyroid cancer. Most patients are 25 to 65 years of age when first diagnosed; women are more affected...
and neuroblastoma
Neuroblastoma
Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 cases per year in the US , and 100 cases per year in the UK . Close to 50 percent of neuroblastoma cases occur in children younger than two years old...
. Both of these disorders have also been observed in Hirschsprung’s patients with greater frequency than in the general population. One function that RET controls is the travel of the neural crest cells through the intestine
Intestine
In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...
s in the developing fetus
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
. The earlier the mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
of RET occurs in Hirschsprung’s disease, the more severe the disorder becomes.
Hirschsprung's disease, hypoganglionosis, gut dysmotility, gut transit disorders and intussusception
Intussusception
Intussusception may refer to:* Intussusception * Intussusception...
have been recorded with the dominantly inherited neurovisceral porphyrias (acute intermittent porphyria
Acute intermittent porphyria
Acute intermittent porphyria is a rare autosomal dominant metabolic disorder affecting the production of heme, the oxygen-binding prosthetic group of hemoglobin. It is characterized by a deficiency of the enzyme porphobilinogen deaminase. Acute intermittent porphyria is the second most common...
, hereditary coproporphyria
Hereditary coproporphyria
Hereditary coproporphyria is a type of acute porphyria that is associated with a deficiency of the enzyme coproporphyrinogen III oxidase....
, variegate porphyria
Variegate porphyria
Variegate porphyria is an autosomal dominant porphyria that can have acute symptoms along with symptoms that affect the skin...
). Children may require enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
or DNA testing for these disorders as they may not produce or excrete porphyrins prepuberty.
Clinical features
With an incidence of 1/5000 births, the most cited feature is absence of ganglion cells: notably in males, 75% have none in the recto-sigmoid and 8% with none in the entire colon. The enlarged section of the bowel is found proximally, while the narrowed, aganglionic section is found distally. The absence of ganglion cells results in a persistent over-stimulation of nerves in the affected region, resulting in contraction.- Delayed passage of meconiumMeconiumMeconium is the earliest stools of an infant. Unlike later feces, meconium is composed of materials ingested during the time the infant spends in the uterus: intestinal epithelial cells, lanugo, mucus, amniotic fluid, bile, and water. Meconium is almost sterile, unlike later feces, is viscous and...
- Abdominal distensionAbdominal distensionAbdominal distension is a sensation of elevated abdominal pressure and volume. It is estimated that close to 25% of the US population has some degree of abdominal distension on a regular basis. Some describe it as belching, others claim they feel nausea and yet others say they pass excessive gas...
- ConstipationConstipationConstipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
Diagnosis
Hirschsprung's disease is suspected in a baby who has not passed meconium within 48 hours of delivery. Normally, 90% of babies pass their first meconium within 24 hours, and 99% within 48 hours. Other symptoms include, green or brown vomit, explosive stools after a doctor inserts a finger into the rectum, swelling of the abdomen, lots of gas and bloody diarrhea. Definitive diagnosis is made by suction biopsy of the distally narrowed segment.Diagnostic techniques involve anorectal manometry
Anorectal manometry
Anorectal manometry is a technique used to measure contractility in the anus and rectum.It may be used to assist in the diagnosis of Hirschprung disease....
, barium enema
Barium enema
A lower gastrointestinal series, also called a barium enema, is a medical procedure used to examine and diagnose problems with the human colon . X-ray pictures are taken while barium sulfate fills the colon via the rectum.-Procedure:...
, and rectal biopsy
Biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
.
Radiologic findings may also assist with diagnosis.
Treatment
Treatment of Hirschsprung's disease consists of surgical removal (resection) of the abnormal section of the colon, followed by reanastomosis. There used to be two steps typically used to achieve this goal.- The first stage used to be a colostomyColostomyA colostomy is a surgical procedure in which a stoma is formed by drawing the healthy end of the large intestine or colon through an incision in the anterior abdominal wall and suturing it into place. This opening, in conjunction with the attached stoma appliance, provides an alternative channel...
. When a colostomy is performed, the large intestine is cut and an opening is made through the abdomen. This allows bowel contents to be discharged into a bag. - Later, when the child’s weight, age, and condition is right, a pull-through procedure is performed.
Orvar Swenson, who discovered the cause of Hirschsprung’s, first performed it in 1948. The pull-through procedure repairs the colon by connecting the functioning portion of the bowel to the anus. The pull-through procedure is the typical method for treating Hirschsprung’s in younger patients. Swenson devised the original procedure, and the pull-through surgery has been modified many times.
The Swenson, Soave, Duhamel, and Boley procedures all vary slightly from each other:
- The Swenson procedure leaves a small portion of the diseased bowel.
- The Soave procedure leaves the outer wall of the colon unaltered. The Boley procedure is a small modification of the Soave procedure. The term "Soave-Boley" procedure is sometimes used.
- The Duhamel procedure uses a surgical stapler to connect the good and bad bowel.
Of those 15% of children who do not obtain full control, other treatments are available. If constipation is the problem then usually laxatives or a high fiber diet will overcome the problem. If lack of control is the problem then a stoma
Stoma (medicine)
A stoma is an opening , either natural or surgically created, which connects a portion of the body cavity to the outside environment...
may be necessary. The Malone ACE is also an answer. This is where a tube goes through the abdominal wall to the appendix or, if available, to the colon. Then once a day the bowel is flushed. Children as young as 6 do fine with administering this on their own. Details of ostomical sugery and its results can be found in the book Unwanted Baggage by P. and E. Prosser.
If the affected portion of the lower intestine is restricted to the lower portion of the rectum, other surgical procedures, such as the posterior rectal myectomy, can be performed.