Epidemiology and Genetics

The incidence of HD is approximately 1 in 5000 live births. In approximately 85% of cases, aganglionosis is limited to the rectum and distal sigmoid colon; it involves a significantly longer portion of the remainder of the colon, potentially including the distal ileum in 15% of patients (total colonic aganglionosis). Aganglionosis can rarely involve the entire large and small intestine (total intestinal aganglionosis). Overall, HD occurs more frequently in boys, with a ratio of nearly 4:1, but in patients with total colonic aganglionosis, the male-to-female ratio is approximately 2:1. Most cases of HD are sporadic but approximately 20% are familial, and 30% of patients have genetic abnormalities or additional developmental defects that make up a clinical syndrome. The incidence of familial involvement is increased in patients with total colonic involvement, nearly one-third of whom will have a positive family history.

Although the etiology of HD is not known, there are clues to suggest that there is a significant genetic basis. Heredity patterns are not straightforward and are non-Mendelian with variable penetrance. Mutations in a number of key genes, including RET , GDNF , GFRα1 , NRTN , EDNRB , ET3 , ZFHX1B , PHOX2b , SOX10 , and SHH , have been associated with HD with the RET proto-oncogene considered the major disease-causing gene. These genes play a key role in the migration, proliferation, differentiation, survival, and/or apoptosis of normal neural crest cells. The genetic complexity of HD, however, is exemplified by the fact that mutations in these genes account for only approximately 30% to 50% of the known cases of HD. This variation appears to account to some degree for the variability in associated anomalies. Other anomalies are found in nearly one-third of patients with HD: trisomy 21 affects 2% to 15% of patients with HD. Congenital heart disease occurs in approximately 5% of patients without trisomy 21 and nearly one-half of those with trisomy 21 who also have HD. HD also occurs in association with other disorders of neural crest development such as Waardenburg-Shah syndrome, con­genital central hypoventilation syndrome, also known as Ondine’s curse, and associated with a mutation of the PHOX2B gene, multiple endocrine neoplasia (MEN) 2, neurofibromatosis, and neuroblastoma. Rarely, HD forms part of specific genetic syndromes such as Smith-Lemli-Opitz.

Pathophysiology

Aganglionosis results in a lack of receptive relaxation in the affected segment of bowel, creating a pseudo-obstruction. When this occurs in the rectum and distal colon as it does most commonly in HD, the result is a functional obstruction clinically manifested as constipation. Normal peristalsis depends on adjacent portions of the intestine contracting and relaxing in sequence. An intestine that cannot relax does not allow propagation of the peristaltic wave, and it does not serve as an effective reservoir, perhaps explaining the fact that the rectal vault is usually empty in patients with HD. Instead, the normal bowel becomes dilated proximal to the aganglionic segment, as it might in the presence of a true mechanical obstruction. Thus, the typical HD bowel pattern includes normal-appearing distal colon, dilated proximal colon (megacolon), and a tapered or funnel-shaped transition zone in between.

The enteric nervous system is derived from a multipotent progenitor cell population that originates in the neural crest. These cells migrate and differentiate into ganglion cells, which are located within the myenteric plexuses (Auerbach and Meissner) of the intestinal wall during early embryonic development ( Figure 54-1 ). The foregut is populated first; the cells then proceed distally along the entire length of the bowel, arriving at the level of the distal colon and rectum last. HD results from the incomplete caudal migration of neural crest cells along the intestinal tract, such that the proximal bowel is normally ganglionated but some portion of the distal portion remains aganglionated. Where this migration stops is variable; consequently, patients differ with respect to the length of rectum and colon that is involved.

Ganglion cells within the myenteric plexus of the rectum (hematoxylin and eosin.)

As an integral component of the enteric nervous system, ganglion cells inhibit local smooth muscle activity via a mechanism that is mediated by nitric oxide, which allows normal receptive relaxation of the bowel. In addition, the absence of reflexive inhibitory activity at the level of the anal sphincter results in loss of the rectosphincteric reflex, an important component of defecation in which the anal sphincter relaxes in response to stimulation of the rectum by the arrival of a stool bolus. This forms the basis for anal manometric studies that are frequently used to confirm the diagnosis.

Hirschsprung’s disease–associated enterocolitis (HAEC) is an acute and sometimes recurrent diarrheal illness that occurs only in children with HD. It occurs less frequently after the age of 2 years, but can affect even those who have undergone definitive surgical repair. The etiology is not known, and understanding of the pathophysiology remains incomplete. Bacterial overgrowth due to stasis probably plays a role in the pathogenesis; however, infants with other forms of mechanical or functional obstruction almost never develop true enterocolitis. There are clearly other factors that specifically place children with HD at risk for this potentially lethal illness. Possibilities include a specific immunodeficiency or mucosal barrier defect that is associated with the absence of ganglion cells.

Clinical Presentation

HD typically presents in infancy but can present at any age, including occasionally in adults. The hallmark of the disease is constipation, but there are several recognizable patterns of initial presentation. The first is the healthy-appearing newborn infant who fails to pass meconium in the first 48 hours of life, which should always raise the suspicion of HD. The second is the newborn infant who develops abdominal distension and feeding intolerance within the first day or two of life, often accompanied by bilious emesis. Although the differential diagnosis also includes malrotation with volvulus, intestinal atresia, meconium ileus, and meconium plug/small left colon syndrome, HD is also in the differential diagnosis. Some infants with HD initially stool normally, especially if they are breast-fed, and then develop severe constipation either when weaned to formula or table food: any child with constipation who requires rectal stimulation, suppositories, or enemas to evacuate should be evaluated for HD, especially if the history of constipation begins before attempts at potty training. Finally, the rare child with HD will present with an acute diarrheal illness, HAEC, rather than constipation. The clinical picture resembles a severe gastroenteritis, including vomiting, diarrhea, and abdominal distension and pain. Sometimes there is a history of constipation, but this is not always the case. These children can become extremely ill very quickly, with the rapid onset of severe dehydration, lethargy, and overwhelming sepsis. A low index of suspicion and aggressive management is necessary to avoid a lethal outcome.

Of interest, there appears to be no correlation between the length of the aganglionic segment and the severity of the clinical presentation: some infants with total colonic aganglionosis have mild constipation, whereas others with short-segment disease can have severe obstipation. Although it is important to consider the diagnosis of HD in any child with constipation, children with mild symptoms that respond well to dietary changes or gentle laxatives are unlikely to have the disease. Similarly, older children with encopresis and soiling are much more likely to have functional constipation than HD.

Differential Diagnosis

Constipation is an extremely common complaint. Most cases can be classified as idiopathic or functional and are usually treated successfully with dietary changes, modification of toilet training technique, or mild stool softeners. Severe constipation is defined somewhat subjectively, but a more extensive evaluation should be considered for children who routinely go more than 2 days without a bowel movement, have a great deal of difficulty passing their stool, or cannot spontaneously defecate without extraneous influence in the form of suppositories, enemas, or digital disimpaction.

The differential diagnosis of severe constipation depends on the age of the patient ( Table 54-1 ). In newborns, failure to pass meconium in the first 48 hours of life, especially if associated with feeding intolerance, bilious emesis, or abdominal distension, requires consideration of other congenital intestinal anomalies that fall into the category of neonatal bowel obstruction: meconium plug, meconium ileus, or intestinal atresia. One should also consider imperforate anus, incarcerated hernia, volvulus, and intestinal duplication cyst. Meconium plug syndrome is a mechanical distal colonic obstruction that results from inspissated meconium and thick mucus. In the majority of cases, the cause is unknown and there are no long-term sequelae. However, meconium plug syndrome can be the harbinger of a more serious condition, specifically cystic fibrosis or HD, and may be associated with small left colon syndrome, which commonly occurs in infants of mothers with diabetes. A water-soluble contrast enema is therapeutic, allowing passage of the meconium plug and complete relief of the obstruction. Meconium ileus is also caused by inspissated meconium, but the site of obstruction is the ileum. It is nearly always associated with cystic fibrosis. Water-soluble contrast enema is the initial treatment of choice, as it confirms the diagnosis, revealing a small, unused colon (microcolon) and ileal pellets of hard meconium, and is sometimes successful in relieving the obstruction. Intestinal atresia most commonly occurs in the ileum or jejunum, although rare cases of colonic atresia have been reported. Contrast enema is sometimes necessary to confirm the diagnosis, but surgical repair is always required. A careful physical examination should exclude the diagnosis of imperforate anus, although in some patients a perianal fistula may be present and can be mistaken for an anal opening. Finally, children with partial sacral agenesis can have severe constipation, presumably due to poor development of associated muscles or nerves in the pelvis.

Children with HD who are breast-fed will occasionally do well initially, presumably because of the loose consistency of the stool. Constipation might then develop when they transition to formula or solid food.

Toddlers who develop constipation are usually diagnosed with functional constipation or withholding behavior due to the pressures of toilet training. Although children with HD classically have a history of constipation from birth, the diagnosis should be considered in any child with severe constipation, even if it develops beyond the newborn period. Children with functional constipation sometimes require mechanical assistance (suppositories, enemas) to have a bowel movement and will often demonstrate frequent soiling of their underpants or frank incontinence (encopresis). On physical examination, their rectal vault is usually filled with a large amount of hard stool. Children with HD, on the other hand, very rarely develop fecal incontinence, and on examination, the rectum is essentially normal and nearly always empty. Nevertheless, some older children or adolescents with what otherwise appears to be more typical severe constipation should undergo a workup to exclude the diagnosis of HD.

Constipation in young children can also be due to dietary causes such as milk-protein allergy, neurologic causes such as an unrecognized tethered cord, or true mechanical causes such as a rectal duplication cyst. Children with pelvic tumors such as neuroblastoma or sacrococcygeal teratoma can also sometimes present with the chief complaint of constipation. Finally, a child with one of the much less common types of intestinal pseudo-obstruction can present with severe constipation at an older age. Intestinal neuronal dysplasia is similar to HD in that it is caused by dysfunction of intestinal ganglion cells but is much less completely understood and difficult to treat. It can also occur in association with HD. Syndromes associated with chronic intestinal pseudo-obstruction, an example of which is hollow visceral myopathy, can initially present much like HD. Finally, although rarely seen in the United States, acquired enteric ganglionopathy (Chagas’ disease) can cause severe constipation; however, most patients also have significant esophageal dysmotility.

Diagnosis

The diagnosis of HD cannot be confirmed with certainty on the basis of history and physical examination alone. On physical examination, the child is typically well nourished and asymptomatic, although older infants and children with the disease can be malnourished. The abdomen is sometimes distended and tympanitic to percussion, but can be unremarkable. There is often stool palpable in the lower abdomen and left lower quadrant. Although some experienced pediatricians and surgeons believe that digital rectal examination in patients with HD is notable for a characteristic hypertonicity, this is clearly very subjective and not sufficient to make the diagnosis. Likewise, an explosive bowel movement upon removal of the examining finger has been taught for many years to be a classic sign of HD. However, because the sensitivity and specificity of this sign appear to be poor, it cannot be used to confirm or exclude the diagnosis with any degree of certainty. Although history and physical examination findings might suggest the diagnosis of HD, further testing is always necessary to confirm or exclude the diagnosis.

There exist three main diagnostic modalities to evaluate HD: contrast enema, anorectal manometry, and rectal biopsy. In reality, patients often require more than one modality in the diagnostic process and definitive diagnosis requires intestinal biopsy of sufficient depth and appropriate site demonstrating the absence of ganglion cells. A systematic review of the literature highlights that the different modalities vary in their specificity and sensitivity and the least invasive test, contrast enema, has the lowest sensitivity and specificity ( Table 54-2 ). Therefore, the limitations and benefits of each diagnostic modality must be considered when assessing a patient for HD.

Contrast Enema

A contrast enema is usually the first diagnostic test recommended. In newborns with a clinical picture of obstruction, it is useful as a diagnostic tool to evaluate for HD as well as to rule out other conditions such as meconium ileus, intestinal atresia, and meconium plug. In addition, for conditions such as meconium plug or meconium ileus, it can also be therapeutic. Because children with HD can have a great deal of difficulty clearing inspissated barium, it is usually preferable to use a water-soluble contrast agent. In normal individuals, the rectum is always larger in diameter than the sigmoid colon. The diagnosis of HD is suspected if the anterior-posterior diameter of the mid-rectum is less than that of the descending colon ( Figure 54-2 ). The diagnosis is further supported by the combination of dilated proximal bowel and narrow or normal-appearing distal colon, separated by a tapered or funnel-shaped “transition zone.” A distinct transition may not be apparent in children with total colonic aganglionosis or ultra-short–segment HD. A normal or equivocal contrast enema, especially in the newborn period, does not rule out HD, especially when clinical suspicion remains high. Furthermore, even when the contrast enema reveals what is considered to be a classic picture of HD, further confirmation is required before surgical intervention is undertaken. In each of these situations, rectal biopsy to look for ganglion cells is considered a more definitive test.

Contrast enema in two newborn patients with Hirschsprung’s disease. Note the transition zone as the more dilated proximal colon tapers down to a narrower distal colon at the rectosigmoid junction.

Rectal Biopsy

As mentioned earlier, before definitive surgical intervention is planned a rectal biopsy is performed, confirming the diagnosis of HD by demonstrating the lack of ganglion cells. Rectal biopsy can be performed in one of several ways. In children younger than 4 to 6 months of age, suction rectal biopsy is the procedure of choice: It is painless and can be performed safely at the bedside or in the office. It is also rapid and accurate, although it requires an experienced pathologist to review the histopathology. It is important to note that the very distal portion of the rectum normally lacks ganglion cells, so the biopsy must be taken at least 2 to 3 cm above the dentate line. The biopsy is performed by inserting a suction rectal biopsy device into the rectum, applying suction with a large syringe to draw the intestinal mucosa into a side hole at the end of the device, and then advancing a blade on the biopsy device to excise a small piece of tissue. An adequate sample contains submucosa, which is visible as whitish tissue that has a firm consistency, distinguishable from the mucosa, which is red or pink and much more delicate. The technique is generally safe; however, bacteremia and bleeding may occur. Bowel perforation can occur if the device is advanced above the level of the peritoneal reflection, especially in very small infants, but this is extremely uncommon. The specimen is assessed for the presence of ganglion cells. When ganglion cells are not seen, the diagnostic accuracy of the study is increased by finding hypertrophied nerve trunks and by staining for acetylcholinesterase, the level of which is markedly increased in patients with Hirschsprung’s disease ( Figure 54-3 ).

Rectal biopsy from a patient with Hirschsprung’s disease. Ganglion cells were not identified. Hypertrophied nerves are clearly visible, which confirms the diagnosis of Hirschsprung’s disease (hematoxylin and eosin.)

Suction rectal biopsy is felt to be accurate and, in most centers, is the standard approach to the diagnosis of HD. However, in children older than about 6 months of age and in those in whom suction rectal biopsy has been performed but is inconclusive, open rectal biopsy may be necessary. This is performed in the operating room under general anesthesia. A full-thickness biopsy is usually performed and, because it provides the opportunity to examine both myenteric and submucosal plexuses for the presence of ganglion cells, it is considered the diagnostic gold standard. It is also generally very safe and produces minimal if any postoperative discomfort.

Treatment

Most children with HD are candidates for definitive surgery, which involves removal of the aganglionic segment of colon and rectum, and the creation of a neorectum using proximal normally ganglionated bowel. Three operations have been developed since operative repair became feasible in the 1950s and 1960s ( Figure 54-4 ). The selection of the operation to perform is based principally on the training and preference of the surgeon and sometimes on the clinical characteristics of the patient. The operations have been studied extensively, and each has produced similar excellent results. In the past, all children with HD initially underwent a diverting colostomy at the time of diagnosis and prior to definitive surgery. The colostomy was performed at the distal most level of normal ganglionation and is referred to as a “leveling” colostomy. Definitive surgery was usually felt to be safe after 3 to 6 months, depending on the child’s growth and the presence of comorbidities. This was considered mandatory in order to allow the dilated proximal bowel to return to normal caliber, and for the child to be large enough for the operation to be performed safely. Today, the diagnosis of HD is being made earlier prior to the development of massive dilation of the intestine. Thus, in the absence of significantly dilated bowel or long-segment disease and with refined surgical techniques, leveling colostomies are often unnecessary and definitive surgical correction via one of the three operations described later can be performed in the newborn period.

The three most commonly performed operations for Hirschsprung’s disease. (A) Swenson’s operation: The aganglionic rectum is removed and the normally ganglionated proximal bowel is pulled through and anastomosed at the dentate line. (B) Duhamel-Martin operation: The aganglionic rectum is preserved, the normally ganglionated proximal bowel is brought down behind the native rectum, and the wall between the two is obliterated with a stapling device to create a single common lumen. (C) Soave operation: The mucosa and submucosa of the distal rectum is removed, preserving the outer muscle layer, and the proximal ganglionated bowel is delivered through the muscle cuff and sutured just above the dentate line.

Hirschsprung’s Disease–Associated Enterocolitis

Hirschsprung’s disease–associated enterocolitis (HAEC) is a severe infectious colitis that is peculiar to children with HD. It has been documented to occur both before and after surgery in 25% to 45% of children with HD. It is the leading cause of morbidity and responsible for half of the deaths associated with HD. Although, HAEC may occur in any patient with HD, risk factors for its development include a family history of HD, trisomy 21, long-segment disease, and previous episodes of HAEC. Children who present with signs and symptoms suggestive of enterocolitis must be treated urgently and with extreme vigilance ( Table 54-3 ). The classic picture includes abdominal distension and diarrhea that is often described as “explosive.” Patients often also have fever, lethargy, and/or vomiting. The stool sometimes contains obvious blood or mucus, and parents frequently describe it as intensely malodorous. Infants with HAEC especially can progress rapidly to dehydration, obtundation, and shock. On physical examination, the child might have an explosive bowel movement immediately after digital rectal examination. The important thing to remember is that the initial clinical clues to the diagnosis can be subtle and nonspecific. Therefore, any child with HD who presents with a clinical picture that suggests gastroenteritis or a viral syndrome should be aggressively evaluated for the possibility of enterocolitis. Although diagnostic tests such as plain abdominal radiographs, contrast enemas, and colonoscopies are available, their contribution to the diagnosis of HAEC is minimal and they should be used with extreme caution as they are relatively contraindicated secondary to the increased risk of intestinal perforation.

TABLE 54-3

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related posts:

Eating Disorders in Children and Adolescents Developmental Anatomy and Physiology of the Esophagus Maldigestion and Malabsorption Appendicitis Stomas of the Small and Large Intestine Total Pancreatectomy with Islet Autotransplantation and Pancreatic Allotransplantation

Stay updated, free articles. Join our Telegram channel

Join