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. Most children develop signs and symptoms shortly after birth. However, others may be diagnosed later in infancy or early childhood. About half of all children with Hirschsprung's disease are diagnosed in the first year 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.
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. Some other signs and symptoms in newborns include a swollen belly, vomiting (green or brown vomit), and flatulence. In older children, some other signs and symptoms include chronic constipation, flatulence, swollen belly, fatigue, and failure to thrive. Other symptoms include symptoms of bowel perforation such as vomiting, constipation, poor feeding, lethargy, and diarrhea. Symptoms of bowel obstruction would include vomiting of bile and abdominal distension. Those who do not pass stools after 36 to 48 hours after birth should raise suspicion of Hirschsprung disease. Such suspicion can also be risen if there is only passage of stools after suppository, rectal exam, or enema. Children who do not respond to constipation treatment for six months should also raise suspicion of such disease. Enterocolitis, an acute complication of Hirschsprung disease, is characterized by sudden onset of fever, abdominal distension, vomiting, passage of bloody stools or release of explosive gas or stools after rectal examination. Some cases are diagnosed later, into childhood, but usually before age 10. The child may experience fecal retention, constipation, or abdominal distention.
Associated syndromes Hirschsprung's disease can also present as part of multi system 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 syndrome
Cause 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.
RET proto-oncogene RET is a gene that codes for proteins that assist cells of the neural crest in their movement through the digestive tract during the development of the embryo. Those neural crest cells eventually form bundles of nerve cells called ganglions. EDNRB codes for proteins that connect these nerve cells to the digestive tract. Thus, mutations in these two genes could directly lead to the absence of certain nerve fibers in the colon. Research suggests that several genes are 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 syndrome. Since Down syndrome is comorbid in 2% of Hirschsprung's cases, a likelihood exists that RET is involved heavily in both Hirschsprung's disease and Down syndrome. RET is also associated with medullary thyroid cancer and neuroblastoma, which is a type of cancer common in children. Both of these disorders are more common in Hirschsprung's patients than in the general population. One function that RET controls is the travel of the neural crest cells through the intestines in the developing fetus. The earlier the RET mutation occurs in Hirschsprung's disease, the more severe the disorder becomes.
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