Jacob C. Langer

Incidence and Spectrum of Disease

HD occurs in approximately 1 : 5,000 live births. Approximately 80% of children have a ‘transition zone’ in the rectum or rectosigmoid colon. Another 10% have more proximal colonic involvement, and about 5–10% have total colonic aganglionosis with variable involvement of the distal small intestine. Rarely, babies are afflicted with near-total intestinal aganglionosis.

A number of syndromes are associated with HD including trisomy 21, congenital central hypoventilation syndrome, Goldberg–Shprintzen syndrome, Smith–Lemli–Opitz syndrome, neurofibromatosis, and neuroblastoma (Box 34-1).

Etiology and Genetic Basis of Disease

Ganglion cells are derived from the neural crest. By 13 weeks post-conception, the neural crest cells have migrated from proximal to distal through the gastrointestinal tract, after which they differentiate into mature ganglion cells.⁹ There are two main theories why this process is disturbed in children with HD. The first possibility is that the neural crest cells never reach the distal intestine due to early maturation or differentiation into ganglion cells. Data supporting this theory come from animal models showing spontaneous aganglionosis^10,11 and from studies of normal neural crest cell migration performed in chick embryos and human fetuses.^12,13 The second possibility is that the neural crest cells reach their destination, but fail to survive or differentiate into ganglion cells due to an inhospitable microenvironment.^14,15 It is likely that HD is actually a heterogeneous group of diseases with multiple genetic causes and etiologies.

A genetic basis for HD has long been suspected because of the presence of a family history in many cases and the known association with trisomy 21 and other genetically based conditions. Over the past two decades, an increasing number of researchers have made significant progress in identifying and elucidating the complex array of genetic mutations and mechanisms responsible for this disease.16–18 The first and most common gene to be identified is the RET proto-oncogene, which encodes a tyrosine kinase receptor. Many mutations of this gene and related genes, such as neurturin and glial cell line-derived neurotrophic factor (GDNF), have been described. It remains unclear how these mutations result in aganglionosis, but there is evidence that early neuronal cell death may be a prominent mechanism.^19,20 RET abnormalities are most commonly found in patients with familial and long-segment involvement. Mutations in the endothelin family of genes, particularly endothelin-3 and the endothelin-B receptor, are also commonly associated with HD. Many of these children have other neurocristopathies such as dysfunction of melanocytes, congenital deafness, central hypoventilation, and neuroblastoma. From animal models, there is evidence that mutations in the endothelin and SOX-10 genes may produce early maturation or differentiation of neural crest cells, which decreases the number of available progenitor cells and prevents the neural crest cells from migrating any further.^21,22 Other genes associated with HD include S1P1 (now known as ZFHX1B), Phox2B, and the Hedgehog/Notch complex.²³

Clinical Presentation and Diagnosis

Prenatal diagnosis of HD is rare, and is usually due to total colonic disease resulting in ultrasound (US) findings of fetal intestinal obstruction.²⁴ Most affected patients present during the neonatal period with abdominal distension, bilious vomiting, and feeding intolerance. Delayed passage of meconium beyond the first 24 hours is present in approximately 90%. Occasionally, cecal or appendiceal perforation may be the initial event.²⁵ Plain radiographs characteristically show dilated bowel loops throughout the abdomen. The next step is a water-soluble contrast enema. The pathognomonic finding of HD is a transition zone between the normal and aganglionic bowel (Fig. 34-1), although approximately 10% of neonates with HD may not have a demonstrable radiological transition zone.²⁶ Occasionally, false positive studies occur.²⁷ It is also important to obtain a plain radiograph 24 hours later. Retention of the contrast is very suggestive for HD (Fig. 34-2). It is also important to use a water-soluble material as the enema potentially may be a definitive treatment for other conditions in the differential diagnosis, such as meconium ileus and meconium plug syndrome. Once the diagnosis of HD is suspected, the diagnosis must be confirmed by rectal biopsy, which in the neonate can be done at the bedside without sedation and using a suction technique.

Patients presenting later in childhood have chronic severe constipation. As constipation is common in children, it can be difficult to differentiate HD from more common causes. Clinical features pointing to the diagnosis include delayed passage of meconium at birth, failure to thrive, abdominal distention, and dependence on enemas without significant encopresis.²⁸ Although a contrast enema usually demonstrates a transition zone in older children, a false negative study may be due to massive rectal distension in combination with a very short aganglionic segment. Reversal of the usual rectosigmoid ratio and retention of contrast on a 24-hour postevacuation film also support the diagnosis. Anorectal manometry is another useful screening technique, in which the presence of a recto-anal inhibitory reflex (reflex relaxation of the internal anal sphincter in response to balloon distension of the rectum) essentially rules out HD (Fig. 34-3). In older children, the suction rectal biopsy may be less reliable because of a higher risk of sampling error. Full-thickness biopsies, usually under general anesthesia, may be necessary in these patients.

Approximately 10% of neonates with HD present with fever, abdominal distention, and diarrhea due to Hirschsprung-associated enterocolitis (HAEC), which can be life-threatening. Since HD characteristically causes constipation rather than diarrhea, this presentation may be confusing and the diagnosis may not be considered. A careful history, including a history of delayed passage of meconium and intermittent stooling, should lead to an investigation for HD.

The gold standard for the diagnosis is the absence of ganglion cells in the submucosal and myenteric plexuses on histological examination (Fig. 34-4A). Most patients will also have evidence of hypertrophied nerve trunks (Fig. 34-4B), although this finding is not always present, particularly in children with total colonic disease or a very short aganglionic segment. As there is normally a paucity of ganglion cells in the area 0.5–1.0 cm above the dentate line, the rectal biopsy should be taken at least 1.0–1.5 cm above it. However, a biopsy too proximal may miss a short aganglionic segment. In addition to hematoxylin and eosin, many pathologists also stain for acetylcholinesterase, which has a characteristic pattern in the submucosa and mucosa in children with HD (Fig. 34-5). Recently, it has been shown that immunochemical staining for calretinin is almost always absent in patients with HD (Fig. 34-6).²⁹

Preoperative Preparation

Once the diagnosis of HD is made, the child should be appropriately resuscitated with intravenous fluids and treated with broad-spectrum antibiotics, nasogastric drainage, and rectal decompression using rectal stimulation and/or irrigation. Patients with associated abnormalities such as cardiac disease or congenital central hypoventilation syndrome must be thoroughly evaluated prior to operative correction.

Once the infant or child has been resuscitated and stabilized, the operation can be done semi-electively. While waiting, many infants can be discharged home on breast milk or an elemental formula, in combination with rectal stimulations or irrigations. In the older child with an extremely dilated colon, pull-through should be delayed until the diameter of the colon has decreased sufficiently to perform a safe procedure. Weeks or months of irrigations may occasionally be needed. Some of these children may need an initial colostomy to adequately decompress the dilated colon.

Some physicians have advocated nonoperative long-term management of short segment HD using enemas and laxatives. Others have suggested that simple myectomy may be adequate.³⁰ However, these approaches do not provide a good quality of life for most infants and children with HD, and most pediatric surgeons recommend a pull-through procedure even for short segment disease.

Surgical Management

The goals of surgical management for HD are to remove the aganglionic bowel and reconstruct the intestinal tract by bringing the normally innervated bowel down to the anus while preserving normal sphincter function. The most commonly performed operations are the Swenson, Duhamel and Soave procedures, although a number of other operations, such as the Rebhein and State procedures, have been described and are still performed in some centers.³¹ As there are very few prospective studies comparing operations, the best operation for an individual patient is the one that the surgeon has been trained to do and does frequently.

Although Swenson’s operation was initially developed as a one-stage procedure, the relatively high incidence of stricture, leak, and other adverse outcomes led to the adoption of a routine preliminary colostomy, with definitive pull-through performed three to 12 months later.³² In the 1980s, a number of surgeons reported series of single-stage pull-through operations even in small infants.^33,34 Over the following ten to 15 years, many reports suggested that a one-stage approach was safe, avoided the morbidity of stomas in infants, and was more cost effective.^35–37 However, a stoma may still be needed for infants and children with severe enterocolitis, perforation, malnutrition, or massively dilated proximal bowel, and in situations when it is not possible to reliably identify the transition zone on frozen section.