Hirschsprung's disease
Definition
Hirschsprung's disease (HD or HSCR) is a birth defect in which nerves are missing from parts of the intestine. The most prominent symptom is constipation. Other symptoms may include vomiting, abdominal pain, diarrhea and slow growth. Symptoms usually become apparent in the first two months of life. Complications may include enterocolitis, megacolon, bowel obstruction and intestinal perforation.
The disorder may occur by itself or in association with other genetic disorders such as Down syndrome or Waardenburg syndrome. About half of isolated cases are linked to a specific genetic mutation, and about 20% occur within families. Some of these occur in an autosomal dominant manner. The cause of the remaining cases is unclear. If otherwise normal parents have one child with the condition, the next child has a 4% risk of being affected. The condition is divided into two main types, short-segment and long-segment, depending on how much of the bowel is affected. Rarely, the small bowel may be affected, as well. Diagnosis is based on symptoms and confirmed by biopsy.
Treatment is generally by surgery to remove the affected section of bowel. The surgical procedure most often carried out is known as a "pull through". Occasionally, an intestinal transplantation may be recommended. Hirschsprung's disease occurs in about one in 5,000 of newborns. Males are more often affected than females. The condition is believed to have first been described in 1691 by Dutch anatomist Frederik Ruysch and is named after Danish physician Harald Hirschsprung following his description in 1888.
History
The first report of Hirschsprung's disease dates to 1691, when it was described by Dutch anatomist Frederik Ruysch. However, the disease is named after Harald Hirschsprung, 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 cells, are absent, causing chronic constipation. The lack of ganglion cells is in the myenteric plexus (Auerbach's 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 first publication on an important genetic discovery of the disease was from Martucciello Giuseppe et al. in 1992. The authors described a case of a patient with total colonic aganglionosis associated with a 46, XX, del 10 (q11.21 q21.2) karyotype. The major gene of Hirschsprung disease was identified in this chromosomal 10 region, it was the RET proto-oncogene.
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. For a long time, Hirschsprung’s was considered a multifactorial disorder, where a combination of nature and nurture was 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.
Epidemiology
According to a 1984 study conducted in Maryland, Hirschsprung's disease appears in 18.6 per 100,000 live births. In Japan, it occurs at a similar rate of about one in 5,000 births (20 per 100,000). It is more common in male than female (4.32:1) and in white rather than nonwhite. Nine percent of the Hirschsprung cases were also diagnosed as having Down syndrome. Most cases are diagnosed before the patient is 10 years of age.
Statistics and Incidences
Cases of aganglionic megacolon is seen in approximately 1 per 5000 live births.
• Prevalence may vary by region and has been shown to be as high as 1 per 3000 live births in the Federated States of Micronesia.
• The overall mortality of Hirschsprung enterocolitis is 25-30%, which accounts for almost all of the mortality from Hirschsprung disease.
• Hirschsprung disease is approximately 4 times more common in males than females.
• Nearly all children with Hirschsprung disease are diagnosed during the first 2 years of life.
• Approximately one-half of children affected with this disease are diagnosed before they are aged 1 year; a small number of children with Hirschsprung disease are not recognized until much later in childhood or adulthood.
Signs and symptoms
Typically, Hirschsprung disease is diagnosed shortly after birth, although it may develop well into adulthood, because of the presence of megacolon, or because the baby fails to pass the first stool (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, excessive gas, and bloody diarrhea.
Some cases are diagnosed later, into childhood, but usually before age 10. The child may experience fecal retention, constipation, or abdominal distention.
Clinical Manifestations
Examination of infants affected with Hirschsprung disease reveals:
• Abdominal distention. Infants with aganglionic megacolon show tympanitic abdominal distention and symptoms of intestinal obstruction.
• Chronic constipation. Older infants and children with Hirschsprung disease usually present with chronic constipation.
• Palpable intestinal loops. Upon abdominal examination, these children may demonstrate marked abdominal distention with palpable dilated loops of colon.
• Absence/delayed passage of meconium. During the newborn period, infants affected with Hirschsprung disease may present with failure of passage of meconium.
• Vomiting. Repeated vomiting is present due to intestinal obstruction.
• Malnourishement. Poor nutrition results from the early satiety, abdominal discomfort, and distention associated with chronic constipation.
Assessment and Diagnostic Findings
The diagnosis of aganglionic megacolon is made through the following data:
• Laboratory studies. CBC count, order this test if enterocolitis is suspected; elevation of WBC count or a bandemia should raise concern for enterocolitis.
• Plain abdominal radiography. Perform this test with any signs or symptoms of abdominal obstruction.
• Unprepared single-contrast barium enema. If perforation and enterocolitis are not suspected, an unprepared single-contrast barium enema may help establish the diagnosis by identifying a transition zone between a narrowed aganglionic segment and a dilated and normally innervated segment; the study may also reveal a nondistensible rectum, which is a classic sign of Hirschsprung disease.
• Rectal biopsy. Diagnosis is confirmed through rectal biopsy.
• Rectal manometry. In older children who present with chronic constipation and an atypical history for either Hirschsprung disease or functional constipation, anorectal manometry can be helpful in making or excluding the diagnosis.
Causes
The disorder may occur by itself or in association with other genetic disorders such as Down syndrome. About half of isolated cases are linked to a specific genetic mutation and about 20% occur within families. Some of these occur in an autosomal dominant manner. The cause of the remaining cases is unclear. If otherwise normal parents have one child with the condition, the next child has a 4% risk of being affected.
Genetics
Several genes and specific regions on chromosomes (loci) have been shown or suggested to be associated with Hirschsprung's disease:
The RET proto-oncogene accounts for the highest proportion of both familial and sporadic cases, with a wide range of mutations scattered along its entire coding region. A proto-oncogene can cause cancer if it is mutated or overexpressed.
• Genetic causes. The disease is generally sporadic, although incidence of familial disease has been increasing; multiple loci appear to be involved, including chromosomes 13q22, 21q22, and 10q; mutations in the Ret proto-oncogene have been associated with multiple endocrine neoplasias (MEN) 2A or MEN 2B and familial Hirschsprung disease; other genes associated with Hirschsprung disease include the glial cell-derived neurotrophic factor gene, the endothelin-B receptor gene, and the endothelin-3 gene.
Associated syndromes
• Associated conditions. Hirschsprung disease is strongly associated with Down syndrome; 5-15% of patients with Hirschsprung disease also have trisomy 21; other associations include Waardenburg syndrome, congenital deafness, malrotation, gastric diverticulum, and intestinal atresia.
Hirschsprung's disease can also present as part of multisystem disorders, such as:
• Bardet–Biedl syndrome
• Cartilage–hair hypoplasia
• Congenital central hypoventilation syndrome
• MEN2
• Mowat–Wilson syndrome
• Smith–Lemli–Opitz syndrome
• Trisomy 21 (Down syndrome)
• Some forms of Waardenburg syndrom
Hirschsprung's disease (HD or HSCR) is a birth defect in which nerves are missing from parts of the intestine. The most prominent symptom is constipation. Other symptoms may include vomiting, abdominal pain, diarrhea and slow growth. Symptoms usually become apparent in the first two months of life. Complications may include enterocolitis, megacolon, bowel obstruction and intestinal perforation.
The disorder may occur by itself or in association with other genetic disorders such as Down syndrome or Waardenburg syndrome. About half of isolated cases are linked to a specific genetic mutation, and about 20% occur within families. Some of these occur in an autosomal dominant manner. The cause of the remaining cases is unclear. If otherwise normal parents have one child with the condition, the next child has a 4% risk of being affected. The condition is divided into two main types, short-segment and long-segment, depending on how much of the bowel is affected. Rarely, the small bowel may be affected, as well. Diagnosis is based on symptoms and confirmed by biopsy.
Treatment is generally by surgery to remove the affected section of bowel. The surgical procedure most often carried out is known as a "pull through". Occasionally, an intestinal transplantation may be recommended. Hirschsprung's disease occurs in about one in 5,000 of newborns. Males are more often affected than females. The condition is believed to have first been described in 1691 by Dutch anatomist Frederik Ruysch and is named after Danish physician Harald Hirschsprung following his description in 1888.
History
The first report of Hirschsprung's disease dates to 1691, when it was described by Dutch anatomist Frederik Ruysch. However, the disease is named after Harald Hirschsprung, 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 cells, are absent, causing chronic constipation. The lack of ganglion cells is in the myenteric plexus (Auerbach's 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 first publication on an important genetic discovery of the disease was from Martucciello Giuseppe et al. in 1992. The authors described a case of a patient with total colonic aganglionosis associated with a 46, XX, del 10 (q11.21 q21.2) karyotype. The major gene of Hirschsprung disease was identified in this chromosomal 10 region, it was the RET proto-oncogene.
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. For a long time, Hirschsprung’s was considered a multifactorial disorder, where a combination of nature and nurture was 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.
Epidemiology
According to a 1984 study conducted in Maryland, Hirschsprung's disease appears in 18.6 per 100,000 live births. In Japan, it occurs at a similar rate of about one in 5,000 births (20 per 100,000). It is more common in male than female (4.32:1) and in white rather than nonwhite. Nine percent of the Hirschsprung cases were also diagnosed as having Down syndrome. Most cases are diagnosed before the patient is 10 years of age.
Statistics and Incidences
Cases of aganglionic megacolon is seen in approximately 1 per 5000 live births.
• Prevalence may vary by region and has been shown to be as high as 1 per 3000 live births in the Federated States of Micronesia.
• The overall mortality of Hirschsprung enterocolitis is 25-30%, which accounts for almost all of the mortality from Hirschsprung disease.
• Hirschsprung disease is approximately 4 times more common in males than females.
• Nearly all children with Hirschsprung disease are diagnosed during the first 2 years of life.
• Approximately one-half of children affected with this disease are diagnosed before they are aged 1 year; a small number of children with Hirschsprung disease are not recognized until much later in childhood or adulthood.
Signs and symptoms
Typically, Hirschsprung disease is diagnosed shortly after birth, although it may develop well into adulthood, because of the presence of megacolon, or because the baby fails to pass the first stool (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, excessive gas, and bloody diarrhea.
Some cases are diagnosed later, into childhood, but usually before age 10. The child may experience fecal retention, constipation, or abdominal distention.
Clinical Manifestations
Examination of infants affected with Hirschsprung disease reveals:
• Abdominal distention. Infants with aganglionic megacolon show tympanitic abdominal distention and symptoms of intestinal obstruction.
• Chronic constipation. Older infants and children with Hirschsprung disease usually present with chronic constipation.
• Palpable intestinal loops. Upon abdominal examination, these children may demonstrate marked abdominal distention with palpable dilated loops of colon.
• Absence/delayed passage of meconium. During the newborn period, infants affected with Hirschsprung disease may present with failure of passage of meconium.
• Vomiting. Repeated vomiting is present due to intestinal obstruction.
• Malnourishement. Poor nutrition results from the early satiety, abdominal discomfort, and distention associated with chronic constipation.
Assessment and Diagnostic Findings
The diagnosis of aganglionic megacolon is made through the following data:
• Laboratory studies. CBC count, order this test if enterocolitis is suspected; elevation of WBC count or a bandemia should raise concern for enterocolitis.
• Plain abdominal radiography. Perform this test with any signs or symptoms of abdominal obstruction.
• Unprepared single-contrast barium enema. If perforation and enterocolitis are not suspected, an unprepared single-contrast barium enema may help establish the diagnosis by identifying a transition zone between a narrowed aganglionic segment and a dilated and normally innervated segment; the study may also reveal a nondistensible rectum, which is a classic sign of Hirschsprung disease.
• Rectal biopsy. Diagnosis is confirmed through rectal biopsy.
• Rectal manometry. In older children who present with chronic constipation and an atypical history for either Hirschsprung disease or functional constipation, anorectal manometry can be helpful in making or excluding the diagnosis.
Causes
The disorder may occur by itself or in association with other genetic disorders such as Down syndrome. About half of isolated cases are linked to a specific genetic mutation and about 20% occur within families. Some of these occur in an autosomal dominant manner. The cause of the remaining cases is unclear. If otherwise normal parents have one child with the condition, the next child has a 4% risk of being affected.
Genetics
Several genes and specific regions on chromosomes (loci) have been shown or suggested to be associated with Hirschsprung's disease:
The RET proto-oncogene accounts for the highest proportion of both familial and sporadic cases, with a wide range of mutations scattered along its entire coding region. A proto-oncogene can cause cancer if it is mutated or overexpressed.
• Genetic causes. The disease is generally sporadic, although incidence of familial disease has been increasing; multiple loci appear to be involved, including chromosomes 13q22, 21q22, and 10q; mutations in the Ret proto-oncogene have been associated with multiple endocrine neoplasias (MEN) 2A or MEN 2B and familial Hirschsprung disease; other genes associated with Hirschsprung disease include the glial cell-derived neurotrophic factor gene, the endothelin-B receptor gene, and the endothelin-3 gene.
Associated syndromes
• Associated conditions. Hirschsprung disease is strongly associated with Down syndrome; 5-15% of patients with Hirschsprung disease also have trisomy 21; other associations include Waardenburg syndrome, congenital deafness, malrotation, gastric diverticulum, and intestinal atresia.
Hirschsprung's disease can also present as part of multisystem disorders, such as:
• Bardet–Biedl syndrome
• Cartilage–hair hypoplasia
• Congenital central hypoventilation syndrome
• MEN2
• Mowat–Wilson syndrome
• Smith–Lemli–Opitz syndrome
• Trisomy 21 (Down syndrome)
• Some forms of Waardenburg syndrom
Diagnosis
Definitive diagnosis is made by suction biopsy of the distally narrowed segment. A histologic examination of the tissue would show a lack of ganglionic nerve cells. Diagnostic techniques involve anorectal manometry, barium enema, and rectal biopsy. The suction rectal biopsy is considered the current international gold standard in the diagnosis of Hirschsprung's disease.
Radiologic findings may also assist with diagnosis. Cineanography (fluoroscopy of contrast medium passing anorectal region) assists in determining the level of the affected intestines.
Hirschsprung disease". Genetics Home Reference. August 2012. Retrieved 14 December 2017.
Hirschsprung's disease". Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. 2017. Retrieved 14 December 2017.
Hirschsprung Disease". NORD (National Organization for Rare Disorders). 2017. Retrieved 14 December 2017.
Holschneider, Alexander Matthias; Puri, Prem (2007). Hirschsprung's Disease and Allied Disorders. Springer Science & Business Media. p. 1. ISBN 9783540339359.
Hirschsprung disease". Genetics Home Reference. August 2012. Retrieved 14 December 2017.
Hirschsprung's disease". Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. 2017. Retrieved 14 December 2017.
Hirschsprung Disease". NORD (National Organization for Rare Disorders). 2017. Retrieved 14 December 2017.
Holschneider, Alexander Matthias; Puri, Prem (2007). Hirschsprung's Disease and Allied Disorders. Springer Science & Business Media. p. 1. ISBN 9783540339359.
Radiologic findings may also assist with diagnosis. Cineanography (fluoroscopy of contrast medium passing anorectal region) assists in determining the level of the affected intestines.
Hirschsprung disease". Genetics Home Reference. August 2012. Retrieved 14 December 2017.
Hirschsprung's disease". Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. 2017. Retrieved 14 December 2017.
Hirschsprung Disease". NORD (National Organization for Rare Disorders). 2017. Retrieved 14 December 2017.
Holschneider, Alexander Matthias; Puri, Prem (2007). Hirschsprung's Disease and Allied Disorders. Springer Science & Business Media. p. 1. ISBN 9783540339359.
Hirschsprung disease". Genetics Home Reference. August 2012. Retrieved 14 December 2017.
Hirschsprung's disease". Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. 2017. Retrieved 14 December 2017.
Hirschsprung Disease". NORD (National Organization for Rare Disorders). 2017. Retrieved 14 December 2017.
Holschneider, Alexander Matthias; Puri, Prem (2007). Hirschsprung's Disease and Allied Disorders. Springer Science & Business Media. p. 1. ISBN 9783540339359.
