Hirschsprung's disease and genetics
Hirschsprung's disease is a rare congenital disorder that affects approximately one in 5,000 newborns in the U.S. It results in bowel obstruction due to the absence of nerve cells (ganglia) in a segment of the colon, preventing normal bowel movements. The condition is more prevalent in males and may coexist with other congenital defects. Genetic factors play a significant role in Hirschsprung's disease, with mutations in various genes contributing to its development. The RET gene, responsible for about half of the cases, is crucial for cell growth and differentiation. Other genes associated with the disease include EDN3, ECE1, and EDNRB, which are involved in vascular signaling. Symptoms typically manifest in infancy, but may not be diagnosed until later in life, and can range from failure to pass meconium to severe constipation and abdominal distention. The primary treatment is surgical, with a high success rate in eliminating symptoms, particularly when intervention occurs early. While there are no known prevention measures, understanding the genetic underpinnings offers valuable insights into the condition.
Hirschsprung's disease and genetics
ALSO KNOWN AS: Hirschsprung disease; congenital megacolon; colonic aganglionosis
DEFINITION Hirschsprung’s disease is a rare congenital disorder, affecting about one in five thousand American newborns, that results in an obstruction of the bowel. This prevents normal bowel movements. It usually occurs as an isolated finding but can also be part of a syndrome.
Risk Factors
Individuals with family members who have Hirschsprung’s disease are at risk for the disorder. The disease is more common in males by a four-to-one ratio, and may be associated with other congenital defects. According to 2023 estimates from the US National Institutes of Health, the condition occurred in 1 in 5,000 live births.
Etiology and Genetics
Isolated Hirschsprung’s disease, in which the disease is not associated with other syndromes, has been proposed as a model for genetic disorders with a complex pattern of inheritance. Mutations in a dozen or more different genes may contribute to the or increase the predisposition to develop the disease, so it is not surprising that no single predictable pattern of inheritance can be found. Most of these mutations also exhibit low sex-dependent penetrance, meaning that not all individuals with the mutant gene or genes will develop the disease, and among those who do, there are four times as many affected males as females.
The gene most often involved in cases of Hirschsprung’s disease (about 50 percent of cases) is the RET gene, found on the long arm of chromosome 10 at position 10q11. This gene encodes the RET receptor protein, a tyrosine found on the surface of cells that is involved in signaling pathways for cell growth and differentiation. Three of the other genes reported to be involved in some cases specify proteins that determine the proper functioning of endothelins, which are small peptides produced by endothelial cells that maintain vascular homeostasis by constricting blood vessels and raising blood pressure. The EDN3 gene (at position 20q13.2-q13.3) specifies the endothelin-3 precursor peptide; the ECE1 gene (at position 1p36.1) specifies an endothelin converting enzyme, which cleaves the precursor peptide to its biologically active form; and the EDNRB gene (at position 13q22) specifies an endothelin receptor protein. Other genes associated with occasional cases of Hirschsprung’s disease include GDNF, found on the short arm of chromosome 5 at position 5p13.1-p12, and HSCRS2, found on the short arm of chromosome 3 at position 3p21.
Symptoms
Hirschsprung’s disease is usually diagnosed in infancy but can also be diagnosed later. Symptoms can differ with age. Symptoms in newborns include a failure to pass meconium within the first forty-eight hours of life; meconium is a dark sticky substance that is the first bowel movement. Other symptoms for newborns are vomiting after eating and abdominal distention. Symptoms in young children include severe constipation, diarrhea, anemia, and growth delay. Symptoms in teenagers include severe constipation for most of their lives and anemia.
Screening and Diagnosis
Most cases of Hirschsprung’s disease are diagnosed in infancy, although some may not be diagnosed until adolescence or early adulthood. Tests for diagnosis may include a barium enema—an injection of fluid into the rectum that makes the colon show up on an X-ray, so the doctor can see abnormal areas in the colon. Other tests include a biopsy, in which a sample of bowel tissue is removed to check for ganglia (or the absence of ganglia); and an anorectal manometry, in which the pressures of the internal and external sphincter are measured with a rectal balloon.
Treatment and Therapy
The primary treatment for Hirschsprung’s disease is surgery to remove the affected portion of the colon. There are three potential phases to the surgery, but all three phases may not be needed. The doctor will discuss the best methods for a parent or child’s condition.
The first phase is colostomy. This involves surgically creating an opening into the colon, which is brought to the abdominal surface. Stool contents are excreted through this opening and into a bag. In the second phase, a pull-through operation, the affected area of the colon is removed, and the healthy colon is then brought down to the rectum and joined to the rectal wall. In the third phase, the colostomy opening is closed and bowel function gradually returns to normal.
Symptoms are eliminated in 90 percent of children after surgical treatment. A better outcome is associated with early treatment and shorter bowel segment involvement. Complications may include perforation of the intestine, enterocolitis, and short gut syndrome.
Prevention and Outcomes
There are no guidelines for the prevention of Hirschsprung’s disease.
Bibliography
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