NORD gratefully acknowledges Philip K. Frykman, MD, PhD, MBA, FACS, FAAP, Associate Professor of Surgery and Biomedical Sciences; Associate Director, Pediatric Surgery Division of Pediatric Surgery; Principal Investigator, Pediatric Surgery Laboratory, Cedars-Sinai Medical Center, for assistance in the preparation of this report.
Symptoms in the newborn period include failure to pass the meconium within a short time after birth. Meconium is the dark sticky substance that is normally present in the intestine at birth and is passed as an infant’s first bowel movement after birth. Failure to pass a first stool for 24-48 hours is suggestive of HSCR.
Infants with HSCR will very often have abdominal swelling (distention), abdominal pain, and vomiting. Affected infants have constipation and often exhibit poor weight gain, and slow growth.
HSCR can sometimes lead to a condition called enterocolitis, which is inflammation of the small intestines and colon. This is often referred to as Hirschsprung-associated enterocolitis. Hirschsprung-associated enterocolitis is the most frequent complication of HSCR occurring in 30-40% of individuals with HSCR and can be mild to severe in nature. Hirschsprung-associated enterocolitis often presents with fever, explosive diarrhea, abdominal swelling, lethargy, and vomiting. Some individuals with either severe or untreated Hirschsprung-associated enterocolitis may develop sepsis, which is a widespread bacterial infection of the bloodstream and is potentially life-threatening. Severe or untreated enterocolitis can also lead to toxic megacolon, another life-threatening complication. It cannot be overemphasized that an individual with HSCR who develops these symptoms should urgently seek medical attention.
Approximately 90% of initial HSCR diagnoses in the United States are made within the first year of life. Most of the remaining 10% are made in early childhood, with less than 1% being made in teenage years or adulthood. Not surprisingly, these individuals often report a lifelong history of constipation.
Hirschsprung disease that occurs as an isolated problem has been associated with mutations in several different genes. Approximately 50% of affected individuals have one of these gene abnormalities. This gene changes cause people to be susceptible or predisposed to developing the disorder. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental factors (multifactorial inheritance).
Inheritance of these gene changes can be dominant or recessive depending on the gene involved, but it is probably necessary for multiple abnormal genes to be present for the disorder to occur. The abnormal genes involved in HSCR can have different effects in members of the same family. If parents have an affected child, their chance of having another child with the disorder is increased. A parent who has HSCR also has an increased chance of having a child with the disorder.
The genes associated with HSCR are in two major groups called RET genes and EDNRB genes. When the disorder involves a short segment of the colon, the major gene involved is the RET gene located on chromosome 10q11.2.
When HSCR occurs along with other abnormalities, the cause is frequently a chromosome abnormality or genetic syndrome. People with Down syndrome are at a greater risk of developing HSCR than people in the general population. Genetic syndromes that can be associated with HSCR include Mowat-Wilson syndrome, Waardenburg syndrome, Bardet-Biedel syndrome, Cartilage-Hair hypoplasia, congenital central hypoventilation syndrome, Fryns syndrome, multiple endocrine neoplasia type 2, Smith-Lemli-Optiz syndrome, L1 syndrome, and Pitt-Hopkins syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
Signs and symptoms of HSCR occur because of the failure of specific nerve cells called ganglions to develop in a part of the large intestine of an infant. HSCR is sometimes called a neurocristopathy, meaning that the disorder results from abnormalities in cells and tissues that arise from the neural crest. The neural crest is a temporary group of cells found in the developing embryo. The neural crest gives to various types of cells in the body. In HSCR, ganglions do not develop properly from the neural crest. Since ganglions are missing from the intestine, stool cannot be pushed through the intestine and out of the body via peristalsis.
The length of the intestines that is affected in HSCR can vary. In approximately 80% of affected infants, it is the large intestine, commonly referred to as the colon and rectum, that are affected. The rectum is the last portion of the large intestine and connects the anus to the sigmoid colon. Infants with an absence of ganglion cells in the rectum and sigmoid colon are said to have “short-segment” Hirschsprung disease. While approximately 12% of infants will have ganglion cells missing from most of the large intestine and are referred to as “long-segment” Hirschsprung disease, and approximately 7% will have ganglion cells missing in the entire colon and possibly part of the small intestine, these are called “total colonic” Hirschsprung disease. In rare instances, ganglionic nerve cells are missing from the entire length of the large and small intestine. This is referred to as total intestinal aganglionosis.
Hirschsprung disease affects males 3 to 4 times more often than females, although long-segment HSCR has a gender ratio of 1:1. The disorder occurs in approximately one in 5,000 live births. It is usually apparent shortly after birth, but may present in older children and adults. Hirschsprung disease should be considered in people with a history of severe constipation.
A diagnosis of HSCR can be suspected based on a physical examination, a complete patient and family history, identification of characteristic symptoms and a variety of specialized tests. Most people (85-90%) are diagnosed in early infancy. The first symptom is usually failure to pass the first bowel movement (meconium). The preferred diagnostic test for HSCR is a suction biopsy of the rectum. A biopsy involves surgically cutting out a small sample of affected tissue and studying it under a microscope. Absence of ganglion cells confirms the diagnosis.
Additional tests that can be used include an abdominal x-ray, which can reveal the presence of an intestinal blockage, an anorectal manometry, which involves using balloons and pressure sensors to assess the health and function of the rectum, and a contrast or barium enema, which involves using a contrast agent in the rectum. A contrast agent is a substance that is used to enhance how a structure or part of the body appears on an x-ray. After using a contrast enema in the rectum, x-rays are taken to assess the health and function of the large intestines.
When other abnormalities are present in addition to HSCR, it is possible that the HSCR is due to a chromosomal abnormality or genetic syndrome. Individuals with multiple anomalies should be evaluated by a clinical geneticist in order to attempt to establish an underlying diagnosis.
In almost all cases, treatment of HSCR requires surgery to remove the part of the colon and/or rectum that lacks the normal nerve development, and to join the two healthy ends together. There are three standard surgical procedures designed to correct this disorder. The choice of procedure is a function of the training and experience of the surgeon. Each procedure removes the affected part and attaches the healthy part of the bowel to the rectum completing what is known as a “pull-through” procedure. Currently most procedures are performed in a single stage.
If the child is born prematurely, has low-birth weight, or if he/she is critically ill the surgeon may counsel the parents that a safer approach is a multi-stage strategy. The first stage is to create a temporary colostomy in which the healthy end intestine, upstream of the affected intestine, is brought to the surface of the abdomen creating stoma. Through this opening or ‘stoma’, the contents of the bowel are eliminated into a special bag and removed. After a time, the second stage “pull through” operation is carried out at which time the stoma may be closed. Most children with HSCR do not need a colostomy or an ileostomy.
According to the medical literature, most children enjoy a good to excellent quality of life following successful surgery. Some children may require bowel management after surgery. In rare instances, some children may require revisional or repeat “pull-through” surgery.
Genetic counseling may be of benefit for affected individuals and their families.
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